Fatigue in HCV Infection: A Review (1989 - 2011)

Fatigue in HCV Infection: A Review (1989 - 2011) Doug Mellors Linda McInnes

Genesis of Fatigue Review It is unusual to preface a review with an explanation of its genesis as this should be evident in its stated aims, nevertheless, a number of people who helped in creating this review have asked me to do so, and I thought, I should gratefully respond to their request.

The review began with a question “Why are the symptoms of hepatitis C such a mystery?” put to me by Kerry Paterson, (Executive Officer) of the South Australian Hepatitis C Council. We had been discussing symptoms and I had stated, with considerable consternation, that almost twenty years after the discovery of the hepatitis C virus there were still many health professionals who either denied the existence of subjective symptoms in HCV patients, or showed little interest in treating them. My answer to Kerry’s question was that no one had done a comprehensive review of studies which, had examined the symptoms of hepatitis C; there wasn’t even a clear consensus on what these symptoms were until the first careful survey was published in 2006 – in a word, very few people would have known what research had been done. This answer was followed by a second question from Kerry “Will you do it?”

To which I answered, “Yes, if you can help me to get the journal articles I will need”. I hadn’t done any real research (my professional background was in psychology) for more than twelve years, my statistics, never brilliant, were very rusty, and my computer of archaic vintage – I realized I couldn’t possibly do this on my own, a brief visit to Adelaide University to do some preliminary searches to see what literature was out there, only confirmed my conclusion.

I first met Linda at the Council towards the end of 2000. I was very impressed that with only her son to help her, she had created the AHCS – Australian Hepatitis C Support website and forums. When I described the task ahead of me to Linda she showed a great deal of interest, – after a few further meetings with her, I asked her if she would help me with the review and was delighted when she accepted. A few months later Cecilia Lim, (Co-ordinator, Information and Resources) also from the Council, told us that her negotiations with the Department of Health, to allow us access to the journals we needed, had been successful.

When we had completed the first comprehensive searches (on five symptoms) we realized that there was much more material than we had expected, and too much for us to take on. We decided we would take one symptom at a time, we chose fatigue for three reasons: firstly, it is the symptom most commonly reported by people infected with the hepatitis C virus; secondly, fatigue has been studied more than any other symptom; and finally most studies that investigated fatigue also looked at other symptoms and this review also includes those results.

Writing began in early 2007, and went through many drafts; about 18 months ago we had the review completed, from 1989 – 2008, but we decided on a last revision and editing. After about 9 months of revision we decided it was taking too long, we needed to get something out there, so we stopped and concentrated on getting the first half of the review finished. It has taken four and a half years to produce the first half of the review – which is an incredibly long time, an academic would have easily polished off an eighty article review within a few months, however, we have fewer resources and neither Linda’s health or my own has been good throughout this period so the work has progressed at a snail’s pace.

Earlier in the writing of the review it had begun to dawn on us that what we really wanted to create was an archive – because if something is archived and is easily accessible it is no longer likely to be a ‘mystery’. We also wanted something that was not static so the commentaries could be changed or added to – providing a safeguard against any mistakes or misinterpretations that we may have made.

Although mentioned in the “Introduction” it is probably worth stating here that Part 1 of the review is a very long document, more than 30,000 words (half the length of an average novel!). It takes 50 pages to describe and comment on 43 studies. It may be less taxing to first read the section “Results, Discussion, Summary and Conclusion” at the end of the document which only takes up a little more than 9 pages and is a brief summary of every study in the review. For those people who knew about this work, we apologise for its delay – we hope we can finish off the remainder by the end of this year. We also hope the reader will receive at least some small benefit from reading it.

Doug Mellors

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Fatigue in HCV Infection: A Review (1989 – 2011) Part 1 (1989 – 2000)

Abstract An important but neglected symptom of HCV is fatigue. Fatigue is thought to impact on well-being and mood in patients with HCV, but this remains to be fully established. To better understand the role of fatigue in HCV we undertook a review of the literature published from 1989- 2011. We examined the prevalence and severity of fatigue and its relationship to disease severity. Fatigue was the most frequently reported symptom with estimates ranging from 39% to 97% and evident in even mild HCV. We found little evidence for a relationship between fatigue severity and liver disease, however, it was correlated with depression, anxiety and disordered sleep. After controlling for the latter, fatigue remained an independent factor suggesting that it is intrinsic to HCV. Fatigue is partly reversed following treatment with interferon but is not normalised and the response rate is generally low. Future studies should include more comprehensive and psychometrically validated instruments to better permit an exploration of the components of fatigue most effected by HCV, e.g. mental, physical, behavioural fatigue, and need to explore alternate pharmacological and non-pharmacological treatments of fatigue that may be of benefit. st

Doug Mellors & Linda McInnes, June 1 , Adelaide, South Australia, 2011

Introduction In May 1988, researchers at Chiron laboratories in California discovered the virus that caused Non-A Non-B hepatitis, they renamed it the hepatitis C virus (HCV). The first antibody tests became available in 1990; this was followed in 1995 by the PCR (polymerase chain reaction) test that detects both the presence of the virus and the amount of viral load. Genotyping of the virus also became possible at this time. The HCV virus has 6 variants or genotypes i.e. 1a, 1b, 2, 3, 4, 5 and 6. The most common genotype in developed countries is genotype 1, which has the poorest response to anti-viral treatment.

Being a blood borne virus HCV has a number of possible routes of transmission. In developed countries transmission is predominantly due to intravenous drug use (IDU), for example in the USA, Norway and Australia the proportion of current HCV infections due to IDU have been reported as 68%, 67% and 80% respectively (Shepard et al., 2005). HCV infection through transfusion, or contaminated blood products has now almost ceased since the advent of systematic screening of all blood supplies in developed countries. Other reported important sources of HCV infection in developed countries are organ transplant from infected donors and occasional lapses in infection control. Less effective sources of transmission include: mother-to-child (vertical) transmission, occupational (e.g. needle stick), and tattooing equipment. In poorer countries, much less is known about how HCV is transmitted due to a lack of research. What little evidence there is suggests that the main sources of transmission are unsterilized medical equipment including re-usable glass syringes and inadequate screening of blood donors or blood supplies (Shepard et al., 2005). Evidence for the sexual transmission of HCV suggests that, if it happens at all, it is rare (Cavalheiro, 2007). Despite a high world prevalence rate, estimated at 170 million by the WHO, and more than 20 years research, our understanding of the natural history of HCV infection remains imperfect. Initially the course of the virus was thought to be benign and mainly asymptomatic (Seef et al., 1992). By 1995, this view was seriously challenged by studies that showed much higher rates of fibrosis, cirrhosis and liver cancer (Tong et al., 1995, 1996). However, within a few years a number of studies, particularly those based on a single source of infection, showed extremely low prevalence rates for fibrosis and cirrhosis (Kenny-Walsh, 1999; Weise et al., 2005). The prevailing view is that progression to severe liver damage may be due to other factors unrelated to the virus (Weissenborn et al., 2009). The existence, cause and clinical importance of subjective symptoms in HCV infected patients, such as fatigue and depression, have been even more vigorously disputed (Wessely & Parriante, 2002; Jones, 2004). This is despite a number of authors who have criticized the research community for ignoring the subjective symptoms of HCV (Desmet et al., 1994; Hassoun et al., 2002; Weissenborn et al., 2006). The symptoms associated with HCV include: fatigue, depression, anxiety,

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cognitive deficits (brain fog), nausea, pruritus (itching), arthritic-like muscle and joint pain, sleep disorders and upper right quadrant pain. Of these symptoms, fatigue is the most commonly reported.

Although some groups have argued that patients with HCV may be no more fatigued than those in the general population (Hoofnagle, 1997; Wessely & Parriante. 2002) most studies report a high prevalence rate with estimates varying in clinical samples from a low of 24% (Barrett, 2001) to a high of 97% (Goh et al., 1999) with a median of approximately 50% (Wiessenborn et al, 2009). Consequently, fatigue has been the most studied symptom.

Fatigue is usually defined as either ‘peripheral’ i.e. affecting the muscles, or ‘central’ i.e. affecting the central nervous system (brain and spine), (Jones, 2004) – the consensus view is that fatigue in HCV infection is centrally mediated. The first study to systematically investigate fatigue was commenced in 1992 by Poynard et al. but not published until 2002. Poynard’s group undertook a prospective case study and used a self-devised fatigue scale. However, the first studies to use a standardised fatigue scale with known reliability and validity were first published in 1996 (Mahl et al.; Nelles., et al.). Since then researchers have generally employed standardised fatigue scales allowing for a much better understanding of the relationship between HCV and fatigue.

The aim of the present review was to collate and synthesize the research into HCV and fatigue and thereby try and establish what has been discovered since the virus was identified more than twenty years ago.

Over the last 20 years, four hypotheses have been posited for the cause of fatigue in HCV infected patients. First, it has been suggested that fatigue may be due to concomitant illness (Wessely & Parriante, 2002); second is that it may be related to severity of liver damage (the view of the majority of studies in this review); third, that fatigue may be caused by psychological factors thought to be triggered by e.g. the impact of an IDU lifestyle (Wessely & Parriante, 2002), or the impact of being given a diagnosis (Rodger et al., 1999; Cordoba et al., 2003); and finally that fatigue may be caused by the virus interacting with immune (Goh et al., 1999; Gershon et al. , 2000) or hormonal systems (Ahboucha et al. , 2008) or directly within the brain effecting changes in neurotransmission – the “Trojan Horse” theory (Forton et al. , 2002; Weissenborn et al., 2006).

In preparing this review we conducted a number of searches using the search words ‘HCV + fatigue’, ‘HCV + quality of life’ in Google scholar, Medline, Psychlit, and Social Sciences Index databases and also searched the reference sections of relevant journal articles. We included any article, which mentioned fatigue and assessed it as a prevalence rate, on a simple scale, or on a standardized fatigue test, or quality of life questionnaire. We also included reviews and theoretical papers. However, we excluded non-English language journals and studies with less than 10 people (there were only 2). We also excluded studies that included patients with more than one serious illness unless the study included an HCV only infected group. In addition we excluded interferon trials that assessed only interferon related fatigue or in one case ribavirin induced fatigue. At present, we have examined 85 journal articles.

The review includes a summary table of research studies set out chronologically in separate sections containing all published fatigue studies for that year. With the exception of reviews or theoretical papers, all studies are presented in the same format i.e. (1) Name of first author, name of study, name of journal and date of publication etc. (2) Methods: description of what the study was about, who was involved, who was excluded, how they were assessed, the name of the assessment measures and the statistical procedures used to analyze the data. (3) Aim: this is often the same as the hypothesis of the study, sometimes neither the hypothesis nor the aim of a study is reported, but can usually be inferred. (4) Results: general and specific results from the data. (5) Commentary: the present authors’ interpretation and evaluation of the results: the commentary also helps to put the study into an historical and clinical context, the latter by providing cross-referencing.

This review is very long, it is meant to be an archive, a document that may be useful as a reference, especially for those infected with hepatitis C virus who may take some comfort in knowing that it exists even though they may have no desire or perhaps little energy to examine it in detail – we do not expect people to read it from start to finish. We strongly recommend reading the summary at the end of the review before reading anything else, or alternatively reading the final summing up and conclusions, which only take up a few paragraphs. In preparing this review, we wanted to create an online permanent archive that could be refined, added to, and re- analyzed by people who have HCV or an interest in it.

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List of all articles in this review 1989-2000.

The first 11 years:

1989 Davis - First study to record pre-treatment symptoms in interferon trial 1991 Dale - Chronic Fatigue Syndrome study (Only one patient with HCV) 1993 Merican - Natural History study 1994 Desmet - Review of natural history of liver diseases 1994 Davis - QOL study of 1989 Interferon trial 1995 Shakil - Natural history study 1995 Tong - Natural history study of Transfusion patients 1996 Tong - Natural history study of Intravenous Drug Users (IDU’s) 1996(A) Taruschio - Small study of psychiatric symptoms *1996(A) Mahl - Fatigue study: Compared fatigue (FAI) with psychopathology *1996(A) Nelles - Fatigue study: Compared fatigue (FSS) with psychopathology 1996(A) Crowe - Natural history study of Irish Anti-D women 1996 Carithers - QOL study of Interferon candidates using modified SF-36 1997 Hoofnagle - Symptom study 1997 Hunt - Small QOL study of Interferon candidates using SF-36 1997 Anonymous - Online consensus statement on HCV 1997 Lee - Natural history study 1998(A) Desmorat - QOL SF-36 study 1998 Sladden - Symptom survey 1998 Bayliss – Validation study of modified SF-35 QOL measure 1998 Foster – Small QOL study using SF-36 with HCV and HBV patients 1998(A) Wollschlaeger – QOL study of PCR+ and PCR- women.

1998 Karatsune – CFS study which included HCV group 1998(A) Younossi - Small study of rheumatologic symptoms and SF-36 QOL 1999 Bonkovsky - Interferon trial outcomes study using modified SF-36 QOL 1999 Neary - Interferon trial outcomes study using modified SF-36 QOL 1999 Dale - Interferon trial outcomes study using modified SF-36 QOL 1999 Rodger – Small study of QOL SF-36 in patients aware and unaware of diagnosis

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*1999 (A) Lau – Small study comparing fatigue (FIS) with REE, BMI and exercise tolerance *1999(A) Goh - Study of fatigue (FIS) and autoimmune disease in Irish Anti-D women *1999(A) Sherman – Validation study using a large sample of fatigue measures 1999 Foster – Review of QOL studies in HCV infection 1999 Kenny-Walsh – Natural history study of Irish Anti-D women *1999 Jones – Fatigue treatment study using ondansetron in a single patient *1999 Barkhuisen – Prevalence study of fatigue and rheumatologic symptoms *2000 Dwight - Study of additive effect of depression/psychopathology on fatigue (MAF) 2000 Piche - Study of Resting Energy Expenditure, but no assessment of fatigue 2000 Forman - Letter to Rodger et al., (1999) 2000 Rodger - Reply to letter by Forman et al *2000 Gershon - Study comparing cytokine levels with fatigue (FAQ) *2000 Kleinman - Validation of the Fatigue Severity Scale (FSS) with SF-36 2000 Cotler - Study showing additive effect of interferon on pre-treatment symptoms *2000 Wolf - Treatment of fatigue with Ritalin * = fatigue in title (N=11) FAI = fatigue assessment inventory MAF = multifunctional assessment of fatigue FSS = fatigue severity scale FAQ = fatigue assessment questionnaire SF-36 – medical outcomes study short form-36 quality of life questionnaire (A) = Abstract only REE= Resting energy expenditure BMI = body mass index.

List of studies by focus - prevalence studies, SF-36 QOL studies and studies with “Fatigue” in title: Fatigue and Other Symptoms – Prevalence rates only 1989 Davis - First study to record pre-treatment symptoms in interferon trial 1991 Dale - Chronic Fatigue Syndrome study (Only one patient with HCV) 1993 Merican - Natural History study 1994 Davis - QOL study of 1989 Interferon trial 1995 Shakil - Natural history study 1995 Tong - Natural history study of Transfusion patients 1996 Tong - Natural history study of Intravenous Drug Users (IDU’s) 1996(A) Crowe - Natural history study of Irish Anti-D women 1997 Hoofnagle - Symptom study 1997 Lee - Natural history study 1998 Sladden - Symptom survey 1999 Kenny-Walsh - Natural history study of Irish Anti-D women

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SF-36 QOL Studies 1996 Carithers - QOL study of Interferon candidates using modified SF-36 *1997 Hunt - Small QOL study of Interferon candidates using SF-36 *1998(A) Desmorat – QOL SF-36 study *1998 Bayliss - Validation study of modified SF-35 QOL measure 1998 Foster - Small QOL study using SF-36 with HCV and HBV patients 1998(A) Younossi - Small study of rheumatologic symptoms and SF-36 QOL *1999 Bonkovsky - Interferon trial outcomes study using modified SF-36 QOL 1999 Neary - Interferon trial outcomes study using modified SF-36 QOL *1999 Ware - Interferon trial outcomes study using modified SF-36 QOL 1999 Rodger - Small study of QOL SF-36 in patients aware and unaware of diagnosis

Fatigue Main Focus - (all these studies had the word “fatigue in their title): 1996(A) Mahl - Fatigue study: Compared fatigue with psychopathology 1996(A) Nelles - Fatigue study: Compared fatigue with psychopathology 1999 Lau - Small study comparing fatigue with REE, BMI and exercise tolerance 1999(A) Goh - Study of fatigue and autoimmune disease in Irish Anti-D women 1999 Jones – Fatigue treatment study using ondansetron in a single patient 1999 Barkhuisen - Prevalence study of fatigue and rheumatologic symptoms 1999(A) Sherman - Validation study using a large sample of fatigue measures 2000 Dwight - Study of fatigue and psychiatric symptoms.

2000 Gershon - Study of fatigue and cytokine levels 2000 Kleinman - Validation of the Fatigue Severity Scale (FSS) with SF-36 2000 Wolf - Treatment of fatigue with Ritalin

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Review (Chronological by year)

1989 (1 study) Author: (1) Davis, et al 1989: Treatment of Chronic Hepatitis C with Recombinant Interferon Alfa The New England Journal of Medicine, November, Vol. 321, No. 22, pp. 1501-1506, Interferon Trial. U.S.A. Methods: 160 people with chronic HCV, approx. half of whom were shown to have cirrhosis, were randomly assigned to: 1. No treatment i.e. wait-list controls n=51, (M=63%; Mean age=50yrs).

2. One million units per dose for 24 weeks, n =57 (M=51%; Mean age=51yrs).

3. Three million units per dose for 24 weeks n=58 (M=52%; Mean age=54yrs).

All 3 groups were asked about 12 symptoms although it is not clear at what point in the 24 wk period this was done. However the published data reflect estimates collected from a single assessment. Data on symptoms were recorded to assess the side effects of interferon treatment. A QoL measure, the symptoms impact profile (SIP) was also administered – but the results were not published until 1994.

Aim of Study: To assess the efficacy of interferon using 2 different dosing regimens i.e. 1 million versus 3 million units per dose.

Results: There was very little difference in the symptom profiles of the 3 groups except for symptoms known to be associated with interferon treatment i.e. fever, myalgia, headache and diarrhoea. Fatigue was the most reported symptom. The number (%) reporting fatigue (yes) was: non-treatment group n=39/51 (76%); 1 million units group n=44/57 (77%); 2 million units group n=45/58 (78%).

Commentary: This was the first well-controlled HCV Interferon trial. Although symptoms were assessed and recorded, there are few details of how that was done and the very high prevalence rate for fatigue receives no comment. Desmet (2004) criticised this study for missing the “opportunity” to collect data on symptoms and QoL. However, a few months’ later, too soon to be a response to Desmet’s article, Davis et al (2004) published a QoL study which had been implemented at the same time as this study and with the same patients. The QoL study was probably not published because it found no significant overall difference in QoL between those who were treated with Interferon and those who were not. The author blamed the poor sensitivity of the QoL measure for the insignificant results. A further limitation of this study is that in 1989 there were no HCV antibody or PCR tests to confirm HCV status. As such, it is unclear how many of the patients had a definitive diagnosis.

1991 (1 study) Author:

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(2) JK Dale et al 1991: Chronic Fatigue Syndrome: Lack of Association With Hepatitis C Virus Infection Journal of Medical Virology, Vol. 34, pp. 119-121. Fatigue Study. U.S.A. Methods: This study was part of an ongoing investigation into the cause of chronic fatigue syndrome (CFS), which took place between 1980 - 89 and was originally comprised of 125 patients all of whom met centre for disease control criteria (USA) for CFS (Holmes et al., 1988). Patients with a past history of hepatic illness or blood transfusion were not excluded but HIV positive patients and intravenous drug users (IDU’s) were.

Fortunately stored, blood samples*, from these patients was available for analysis, when HCV antibody testing became available in 1991. In this study the stored blood samples of 36 of those patients were selected for HCV antibody testing (M=23, F=13; Mean age =37yrs) as well as those for 14 healthy volunteers matched for gender and age –and used as a control.

Note: * It is important to note that other researchers had an established diagnosis with CFS in these patients before this study was commenced.

Aim of Study: To determine whether there is an association between Chronic Fatigue Syndrome (CFS) and HCV infection (yes/no).

Results: Only one of the 36 patients complaining of fatigue tested positive on an HCV antibody test and none of the controls. In the absence of any association between CFS and any other assessment measures all 35 patients were diagnosed with CFS. The authors conclude that there appears to be no association between HCV and CFS. Commentary: There are two ways of interpreting this study. The first is that it is a simple look-back attempting to investigate an association between HCV infection and CFS. However, it can also be interpreted as a random estimate of the prevalence of chronic fatigue in HCV patients. Wessley & Pariante (2002) in their review chose the latter interpretation and claimed that this study provided evidence that chronic fatigue was not associated with HCV infection. In the same year Poynard et al. (2002), questioned the validity of these results. In Poynard’s study 53% of HCV patients fulfilled the published criteria for chronic fatigue syndrome. Only three other studies have looked at HCV infection and CFS (Younossi et al., 1998; Karatsune et al., 1998; Kalman et al., 2007) the first and third study claim to find CFS symptoms in HCV infected patients. In order to investigate these conflicting reports we examined the CFS criteria (Holmes et al 1988; Fukuda, 1994) used in the latter three studies. Apart for Karatsune’s study, the other two did not use established criteria for CFS diagnosis. Holmes specifically excluded hepatic illness and stipulated the presence of fever, sore throat and swollen lymph glands as essential criteria. Of note, is that none of the latter are reported to be associated with HCV infection. More importantly, Fukuda’s criteria specifically excluded patients with HCV when assessing CFS. As such, it is not surprising that the two positive studies report an association. All of the above mentioned studies are examined elsewhere in this review.

1993 (1 study) Author:

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(3) I Merican et al, 1993: Clinical, Biochemical and Histological features in 102 patients with chronic hepatitis C virus infection. Quarterly Journal of Medicine, 1993, Vol. 86: pp. 119-125. Clinical Description. England.

Methods: 102 consecutively referred people with chronic HCV (M=69, F=33, Mean age=49yrs), 10 of whom had an additional other liver disease were assessed using a number of clinical, biochemical and histological measures. It is not clear how fatigue was assessed it is simply reported as a prevalence rate (presumably yes/no). However, AST levels between those presenting with fatigue and those not presenting with fatigue were compared.

Aim of Study: Assessment of clinical, biochemical and histological features of chronic HCV. Results: Fatigue is reported as the most common presenting symptom. Fatigue was present in 36 (35%) of the total sample. Comparisons of AST levels of those with and without complaints of fatigue showed no significant difference.

Commentary: It is not clear why they used AST in this study as opposed to ALT, since ALT is liver specific and AST is not. A year before this study an Italian study (Alberti et al., 1992) showed how unreliable ALT and AST levels could be as indicators of liver damage.

1994 (2 studies) Author: (4) Davis et al, 1994: Assessing Health Related QOL in Chronic Hepatitis C using the Sickness Impact Profile. Clinical Therapeutics, March-April, Vol. 16, No. 2, pp. 335-342. Quality of Life Study. U.S.A Methods: For details of patients in this study see Davis, 1989. At baseline, and before randomization to either the 3 million units group, the 1 million units or the no-treatment group, all 160 HCV patients were administered the Sickness Impact Profile (SIP). Baseline scores for each group were compared with population norms. SIP, assessments for each group were also made at 6 months, and for the 3 million units group only, at end-point of study – 1 year. Statistical comparisons of SIP scores were made within the 3 million units group between each assessment point, and also between the 3 million units group and the no-treatment group at baseline and six months (the 1 million units group was not compared). At the end-point of the study SIP scores for responders and non-responders to interferon were also compared. Treatment response was based on normalisation of ALT Aim of Study: To measure the impact of treatment with interferon on the QoL of HCV patients.

Results: When the baseline SIP mean score for the total HCV infected group (i.e. 3million units, N=53; 1 million units, N=53; and no-treatment controls, N=54; total N=160) was compared with that for population norms (N=624), the HCV group were shown to have a significantly higher (worse) SIP mean score (HCV=9.0 Vs. Population Norms=3.6). When the baseline SIP mean score for the 3million units group was compared with that for the HCV no-treatment group there was no significant difference. When mean SIP scores for each of the 7 categories* were compared between baseline and end-point of study within the 3 million units group, only two categories Sleep/Rest and Recreation/Pastimes were significantly improved. Finally when total SIP mean scores were compared between responders and non-responders to interferon there was no significant difference.

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*There are 12 SIP scales but some were aggregated in the analyses.

Commentary: This was the first QoL study of HCV infected patients and although the SIP does not include fatigue as a category the study is frequently cited in HCV fatigue literature - so it was included. This study was part of an interferon trial (Davis et al., 1989), but remained un-published until 1995. Results showed that at the beginning of the study HCV patients (before being randomised to groups) had significantly abnormal QoL when compared to population norms. At the end of the study those who had a sustained response to interferon (i.e. normalisation of ALT) showed no significant improvement in QoL compared to those who did not respond. The authors state that the SIP is too generic a measure to detect treatment effects, however the outcome would always have been difficult to interpret because of the unreliability of ALT as a measure of treatment success - others have found it to be a poor indicator of viral activity (e.g.

Alberti, 1992). Only one other study in this review has used the SIP (Obhrai, 2001) but as a supplement to other standardised tests including a test of fatigue .

Author: (5) Desmet et al, 1994: Classification of CHC, Diagnosing, Grading and Staging. Hepatology. June, Vol.19, pp. 1513-1520. Classification of Liver Disease. Belgium.

The editor of Hepatology designated this article as a ‘special article’, as it was a proposal for a 'revised system of classifying chronic hepatitis'. It contains some interesting observations on the symptoms of viral hepatitis, including fatigue. In a section on ‘clinical assessment', Desmet describes the typical symptoms of viral hepatitis (not just HCV), in particular fatigue – for which he mentions a prevalence rate of 60%. The following quotations are two examples selected from that description: "Patients may claim to have no symptoms and to feel well but then admit to fatigue when questioned directly. Physicians may dismiss the complaints of fatigue as being unimportant or due to other causes. The term asymptomatic should not be used without a careful and fruitless search for symptoms". And "…Indeed in most studies of natural history or therapy, symptoms are not mentioned an unfortunate omission because quality of life is an important outcome in assessment of therapy". This is the first time anyone had described symptoms of chronic liver disease and included HCV; it was also the first time someone had criticized others for not mentioning fatigue and other symptoms. It is difficult to say how much influence this article may have had on later studies, but it was the first to delineate the importance of psychosocial factors in HCV.

1995 (2 studies) Author: (6) Shakil et al, 1995: Volunteer Blood Donors with Antibody to Hepatitis C Virus: Clinical, Biochemical, Virological and Histological Features. Annals of Internal Medicine, 1995; Vo. 123: pp. 330-337. Natural History Study. U.S.A. Methods: Sixty blood donors found to be HCV antibody positive during routine blood screening between 19911992. (M=25, F=35, Mean age=41yrs) were referred to this study after being informed of their diagnosis.

Only 1 patient was cirrhotic, 54 patients had evidence of mild liver damage. These patients were self selected from a larger group and split into 3 groups of 20 i.e. 1.Those with normal ALT levels. 2.Those with ALT levels less than twice the normal range. 3. Those with ALT levels elevated more than twice the normal range. All were required to complete a self-administered symptom questionnaire. Patients were also asked about route of transmission, duration of HCV infection and alcohol consumption.

Aim of Study: To examine the natural history of HCV infected volunteer blood donors and specifically evaluate the relationship between ALT levels and liver disease.

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Results: There was no difference between the three ALT groups on the following variables: symptom score (global score only), route of transmission, duration of illness, and alcohol consumption. Symptom results for the total sample (n=60) were: 61% fatigue, 54% headaches, 54% anxiety, 53% drowsiness, 46% muscle aches, 34% itching, 29% depression. Patients in this study also reported that their symptoms were mild and did not affect their daily activities.

Commentary: This study was conducted before PCR testing became available, hence the focus on ALT. By the time this study was published there was enough evidence to show that ALT levels were a poor indicator of liver damage (these studies are reviewed by Hoofnagle, 1997). Nevertheless, ALT would continue to be considered an important variable to measure at least until the early 2000s. Patients from this study and another HCV study (Di Bisceglie et al. 1995) were combined to form a larger group who were investigated for fatigue and other symptoms (Hoofnagle, 1997). Both these authors were a part of the research team in this study.

Author: (7) Tong et al.1995: Clinical Outcomes After Transfusion Associated Hepatitis C. New England Journal of Medicine. Vol. 332: No. 22, pp. 1463-1466. Natural History Study. U.S.A. Methods: 131 patients (F=81, M=50; Mean age=57 yrs at time of first visit) infected with HCV as a result of blood transfusion had their health status evaluated as part of a natural history study. Patients were seen between 1980 and 1994 and followed up after initial referral to a liver clinic. Evaluation was by physical examination, blood analysis and liver biopsy in 101 of the above patients - the other 30 could not be biopsied due to blood coagulation problems- all had clinical signs of cirrhosis. It is not clear how the data on symptoms was collected. Fatigue was a minor part of the study.

Aim of Study: “To elucidate the clinical course of post transfusion HCV infection”.

Results: The general results showed that initially 57 patients had from stages 1- 3, fibrosis; 67 cirrhosis and 7 had hepatocellular carcinoma. A further 7 developed hepatocellular carcinoma; by the end of the study 19 patients had died as a consequence of their HCV infection. For the total sample of 131 people 88 (67.2%) had fatigue. Fatigue was found to be present in: 50% of those with what would now be referred to as stage one to three fibrosis; 75% of those with cirrhosis and in 100% of those with hepatocellular carcinoma.

Commentary: This is the first of two companion studies by the same author who investigated the relationship between method of infection and liver disease progression. In this first study the focus was on post-transfusion patients: the second on intravenous drug users (IDU’s). It seems that the two studies were a response to previous studies which had found that post-transfusion patients had very little liver damage and that IDU’s had an even slower rate of progression towards cirrhosis than post-transfusion patients. In this study the prevalence rate for cirrhosis (N=50%) and death from liver disease (N=15%) was higher than any previous study and higher than that found in the second study (below) with IDU’s, i.e. cirrhosis (N=35%), death from liver disease (2%). However, when prevalence rates for fatigue are compared between the two studies for patients who do not have cirrhosis the results are similar – a little over 50%.

Subsequent studies of fatigue in both post –transfusion patients and IDU’s confirm these findings.

1996 (6 studies) 11

Author: (8) Tong et al, 1996: Clinical Sequelae of Hepatitis C Acquired From Injection Drug Use. Western Journal Of Medicine, Vol. 164, No. 5: pp. 399-404. Natural History Study. U.S.A. Methods: 125 IUDs, (F=37, M=88, Mean age=43.5yrs at time of initial assessment) with chronic HCV were referred to a liver centre and were assessed using clinical, biochemical and histological measures. This was part of a natural history study undertaken from 1980 until 1994. All patients were followed up after initial visit. There are no details of how symptoms were assessed only rates are given. Fatigue was a minor part of the study.

Aim of Study: To further investigate the natural history of HCV, by examining a group of Intravenous Drug Users (IDU’s), infected from injecting drug use Results: Fatigue was present in 63% of the total sample (N =125). In the 79 patients who had fibrosis from stage 1-3, 46 (58%) reported having fatigue. Of the remaining 46 patients all of whom were cirrhotic, except one who had hepatocellular carcinoma, 33 (72%) reported having fatigue.

Commentary: See commentary above for this study.

Author: (9) G Taruschio et al, 1996: Psychiatric disorders in HCV Related Chronic Liver Disease.

Gastroenterology, Vol. 110, No. 4: A1342. Abstract. Psychiatric Study. Italy.

Methods: 30 patients (M=18, F=12, Mean age=45.5yrs) with chronic HCV were psychiatrically assessed prior to treatment with interferon. Patients were interviewed as well as assessed on a number of instruments measuring anxiety, depression and personality. This was a simple prevalence study, which did not have a hypothesis nor make statistical comparisons between measured variables.

Aim of Study: To measure the prevalence of psychiatric symptoms in HCV patients prior to interferon treatment.

Results: Of the 30 patients assessed 20% had anxiety disorders 10% depression and 6.7% personality disorders. The authors conclude that these results are much higher than those in the general population and suggest that these psychiatric symptoms may appear due to a number of fears associated with being infected with an incurable illness. They also state that many of the symptoms that HCV patients complain about for example, loss of strength, muscle pains, and gastro-intestinal symptoms usually appear only when diagnosis of HCV is made and are therefore more than likely due to anxiety/depression rather than to HCV infection.

Commentary: This study was published only as an abstract so there is little detail. Its focus was on the screening of interferon candidates for psychiatric symptoms, which were likely to be made worse by such treatment.

This study was too small and poorly controlled to provide an accurate estimate of the prevalence of psychiatric symptoms in HCV infection; as for fatigue and other symptoms it relies too heavily on clinical observation, rather than empirical evidence. The author’s remark, that “symptoms usually appear after

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diagnosis with HCV is made”, would become the central focus of a controversial study conducted in Australia in 1999 (see Rodger, 1999).

Author: (10) TC Mahl et al, 1996: Fatigue in Patients With Chronic Hepatitis C Gastroenterology, Vol. 110, No. 4: A1254. Abstract. Fatigue Study. U.S.A. 2 Methods: Thirty-one (31) patients with chronic HCV (M= 71%, Mean age=45yrs) responded to a mail request and completed and returned the Fatigue Assessment Instrument (FAI), the Beck Depression Inventory (BDI) and the SCL-90-R (SCL), a measure of psychopathology. Results of these questionnaires were then compared to clinical data recorded in their hospital files e.g. ALT, severity of liver disease and statistical comparisons were then made.

Aim of Study: To investigate the severity and correlates of fatigue in Chronic HCV. Results: Most patients had only mild liver disease. 39% of patients had severe fatigue i.e. two standard deviations above the mean on the FAI. Fatigue was significantly correlated with depression and global measures of psychopathology. Fatigue was not correlated with any other measure e.g. severity of liver disease or ALT. Patients with fatigue scored in the mild range of depression on the BDI. While patients with no fatigue scored in the normal range i.e. no depression. Patients with fatigue also had clinically* relevant scores for psychopathology as measured by the SCL while non fatigued patients scores were within the normal range. The author’s conclusion was: fatigue may be due to psychological dysfunction rather than liver damage.

Commentary: This is the first of two very similar studies, both published as abstracts in the same edition of the Journal “Gastroenterology” – they were the first proper studies of fatigue in HCV infected patients and the first to have the word “fatigue” in their title. Other firsts were the use of standardised tests, the measurement of fatigue severity (as opposed to just the presence of fatigue), the use of cut-off scores on tests, the investigation of psychological influences on fatigue and the use of correlation analysis.

The main criticism of these two studies has been the way in which they recruited patients i.e. in one a postal study and the other a consecutive case study, and the fact that neither study had a control group.

Mahl’s study was also very small which probably prevented her from doing further statistical analyses.

Despite these weaknesses, the variables they examined were well chosen – their endeavours lifted the quality of symptom research in HCV.

Author: (11) S. Nelles et al, 1996: Fatigue Assessment in Patients With Hepatitis C. Gastroenterology, Vol. 110, No. 4: A1276. Fatigue Study. Canada.

Methods: Eighty-eight, (88) patients with HCV (no demo-graphic information supplied) were assessed on biochemical, virological and histological measures. They were also assessed on a number of questionnaires measuring: fatigue (using the Fatigue Severity Scale (FSS)), sleep quality, illness intrusiveness* and depression. There was no control group in this study. Mean scores were compared to general population norms. Route of infection was also examined. * Measures disability due to illness or treatment - similar to a QOL test.

Aim of Study:

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To identify factors that correlate with fatigue severity in HCV infected patients.

Results: The FSS scores for patients with self-reported fatigue were significantly higher than those reporting no fatigue (no prevalence rates given). There were no correlations between fatigue scores and disease activity, ALT or fibrosis scores. However, there were high and significant correlations between fatigue and illness intrusiveness, sleep quality and depression. Depression scores were also significantly correlated with sleep. There were no correlations between fatigue scores and ALT levels or route of infection.

Commentary: Nelles, study was much larger than Mahl’s and also included a sleep measure - sleep continues to be a much-ignored symptom in HCV symptom research. For some reason - it could hardly have been lack of space – there is no mention of the specific tests used to measure variables other than fatigue. This study together with Mahl's and an Italian study by Taruschio all published in the same issue of Gastroenterology in 1996 might have alerted future researchers to the importance of measuring depression and psychopathology in studies of fatigue in HCV, however, it did not. Since this study there have been only two similar studies (Dwight et al., 2000; Mc Donald et al., 2002).

Author: (12) Crowe J. et al, 1996: Presentation of Hepatitis C In A Unique Uniform Cohort 17 Years From Inoculation. Gastroenterology Vol 108, April, No. 4: A1054. Abstract. Natural History Study. Ireland.

Methods: 232 Irish women accidentally infected with HCV from inoculation with contaminated Anti-D immune globulin, 17 years before detection under went assessment on biochemical, histological and clinical measures.

Aim of Study: Not stated, but is clearly a natural history/ prevalence study.

Results: 26.5% of the women in this study reported having fatigue, 70.2% were asymptomatic. No other symptoms were recorded. Only 2.6% had early indicators of cirrhosis Commentary: This is the first of a series of studies all investigating the natural history of a large group of Irish women accidentally infected with HCV from inoculation with contaminated Anti- D immune globulin*, from a single donor, between 1977-8, and not discovered until some time between 1991-1994. This accident led to a government inquiry, a national screening programme of all women inoculated with Anti-D, and a HCV compensation tribunal. The women in these studies represent a unique cohort, they were all infected during the same short period, all were approximately the same age at time of infection, and all have the same genotype (1a or 1b). Such homogeneity is rare and almost impossible to find in a normal HCV population, hence there has been great interest in the natural history of HCV in these women. What is interesting about this and all subsequent studies of these women is the very slow rate of progression towards cirrhosis. * In 1979-80, a similar event took place in East Germany, resulting in the infection of N=2867 women all recipients of HCV contaminated Anti-D immune globulin, also traceable to a single blood donor. (Weise et al., 2005).

Author: (13) Carithers et al, 1996: A health Assessment For Chronic HCV infection: Results of QOL. A review of QOL instruments used in HCV research plus results from 2 HCV/QOL studies. Digestive Diseases and Sciences, Vol. 41,No. 12 (supp.), pp. 75S-80S. Quality of Life Study. U.S.A.

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Methods: 157 patients with chronic HCV infection were assessed on the SF-36 (a slightly modified version for use with HCV) prior to treatment with Interferon. Details of objective measures of disease activity and severity e.g. liver damage; are not given. These patients were not followed up.

Aim of Study: To validate the modified SF-36 as well as to provide an argument for the use of the SF-36 as a much faster, more efficient and cost effective method of obtaining data on the natural history and morbidity of HCV than large expensive prospective studies. The inclusion of the results of an unpublished study are meant to provide support for this argument.

Results: HCV patient scores were significantly worse on the SF-36 (on all 8 scales including the Vitality scale which measures fatigue) compared with those for the general population. There were no significant associations between QoL and other objective measures.

Commentary: This article is a preliminary report of a study by the same authors, which had been submitted, but was not published until 1998. The aim was to promote the use of the SF-36 as a measure of QoL in HCV natural history studies. The argument for using the SF-36 in these studies can be reduced to the following: 1. The perception that HCV has a mainly benign and asymptomatic course is based on the outcome of Seef’s, (1992) prospective natural history study. However other studies since then have found worse outcomes, which put in doubt these findings. 2. Seef et al. (1992) did not measure subjective symptoms (e.g. fatigue and depression), but only physical symptoms (e.g. fibrosis and cirrhosis) thus implying that subjective symptoms do not exist. 3. The SF-36 is a better measure of the total burden of illness than the SIP (used by Davis et al., 1994) and if researchers employ the SF-36 in natural history studies of HCV it will provide important information about the total burden of illness and reduce the need for expensive long-term natural history studies. We shall examine each part of this argument in turn. 1. At the time this article was written it was clear that outcomes could be worse or better than Seef’s, (Hoofnagle, 1997). 2. It is true that Seef, (1992), did not measure subjective symptoms, but being a careful scientist he is not likely to deny the existence of something he has not measured. 3. This final part is the most problematic, the least plausible and arises from a conflation of subjective with objective symptoms. The purpose of long-term prospective natural history studies is to record everything about the illness being studied on as wide a spectrum as possible, for as long as possible (ideally, up until death). In order for the SF-36 to reduce the necessity for long-term prospective studies it would need to be able to accurately predict not only subjective symptoms (which it purports to measure) but also liver histology scores (which it does not measure). There is no substitute for prospective studies and the notion that a simple generic test of disability could short cut this process is disingenuous to say the least. It could be easily argued that the employment of the SF-36 in HCV studies has actually arrested our knowledge of the natural history of HCV. Three authors have published articles drawing attention to the limitations of QoL measures, specifically the SF-36 (Koff, 1999; Owens, 1998; Forton et al., 2002).

1997 (5 studies) Author: (14) 1997 National Institutes of Health Consensus Statement Online 1997 March 24-26th; 15 (3).

Also in (Hepatitis Alert), News Letter of the Hepatitis Foundation International (800-891-0707), Summer 1997. (Occurrence of significant auto- antibodies). U.S.A. This consensus statement is set out in a question and answer format and says the following: In the first two decades after infection with HCV most people who are infected with the virus are likely to have few

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symptoms. However, after this time 20% of those infected are likely to develop symptoms including mild fatigue, which may lead to a decrease in quality of life. In response to the question ' why is fatigue associated with hepatitis C', the following answer is given.

"Much of the fatigue a person with HCV experiences is due to an activated immune system attempting to eliminate the virus. Despite the effective creation of antibodies against it, the hepatitis C virus can undergo frequent mutation allowing it to avoid being eliminated from the body in 85% of those who contract it. In an ongoing effort to rid the body of the virus, the immune system continues to create weapons against the virus including antibodies, interleukins and white blood cells. At times, the immune response leads to the production of immune complexes, collections of antibodies, that course through the body. Immune complexes may deposit in the joints, blood vessels in the skin, or in the kidney, leading to arthritis, rashes or glomerulonephritis (a form of kidney disease).

These conditions are referred to as 'extra-hepatic manifestations' of hepatitis. An immune system activated to fight a virus like HCV might also begin developing antibodies against other tissues in the body, including the thyroid. The resulting autoimmune illness, such as autoimmune thyroiditis, can result in still more symptoms of fatigue�

This statement also considers underlying conditions, which may contribute to fatigue e.g. iron deficiency, anaemia, hypothyroidism and depression. It suggests that these underlying conditions may be treated separately from HCV but the fatigue related to HCV may best be treated with interferon.

Finally, some very basic coping strategies for fatigue e.g. short naps and flexible work schedules are suggested. Because this is a consensus statement the authors are anonymous.

Author: (15) Lee et al., 1997: Morbidity of CHC As Seen In A Tertiary Care Medical Centre. Digestive Diseases and Sciences, Vol 42, No 1, Jan. pp. 186-191. Natural History Study. U.S.A. Methods: 500 consecutive patients with chronic HCV (M=299 (60%) F=201 (40%), Mean age 50.2 yrs) who attended a tertiary care centre had their medical records examined for biopsy results, signs & symptoms of liver disease, source of infection, duration of time since exposure, presence of extra-hepatic disease, presence of co-morbid disease and alcohol consumption. Of the 500, 64% had been transfused, 20% had a past history of IDU, and the source of infection was unclear in the remaining 16%. Both fatigue and depression were assessed but there are no details of how. The statistics used in this study were of the simplest kind- prevalence rates and bar graphs. There were no statistical comparisons.

Aim of Study: To assess the morbidity (amount of illness) of HCV and its relationship to duration of illness in HCV infected patients referred to a tertiary care medical centre.

Results: Results for 305 of the 500 who had been biopsied showed that 113 (37%) had mild hepatitis; 82 (26%) had moderate to severe hepatitis and 103 (34%) had cirrhosis. A history of chronic fatigue was recorded in 225 (45%) of patients. There was no consistent relationship between fatigue and duration of infection. The authors note that fatigue was the 'most common complaint' and 'tended to occur evenly at all stages'. They also found depression to be high at 24%.

Commentary: Consecutive case studies, such as this, are generally considered to be inferior to other types of study design, when compared to, for example, cross sectional studies in which all participants are assessed only once and at the same time, or prospective studies in which all participants are assessed at regular intervals over a period of many years. Since consecutive case design is retrospective it means that researchers are limited in their investigations to data recorded by others where assessments, if they exist at all, may vary in type and quality, depending on the individual skills and abilities of the original assessors. Because they tend to be imprecise, such studies generate

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only prevalence rates, which are not amenable to statistical manipulation. In their review of fatigue and depression studies in HCV infection Wessley and Pariante (2002) criticise this study for its poor measures, but given the design it would be hard to expect otherwise. Despite poor design this study nevertheless contains some very good observations on the relationship between fatigue and depression. Lee et al report that the frequency of depression was high in this study. They offer two explanations for this. The first is that the patients they studied may be suffering from a reactive depression because of the severity of their fatigue, and/or “…. concern for their long-term well being”.

The second explanation is that patients who suffer from depression (cause unknown) may be more likely to be IDU’s and therefore at greater risk of infection with HCV. However, since no evidence was found to support either explanation the authors conclude that viral infection, if not the sole cause of depression, fatigue and other symptoms in HCV infection “is a significant contributing factor”. They state that the relationship between fatigue and depression is a “co-dependent” one. Most of what this study found would later be confirmed. Their allusion to the impact of diagnosis on symptoms would soon become a controversial issue in future research on fatigue and other symptoms in HCV infection (Rodger, 1999; Cordoba, 2003).

Author: (16) Hoofnagel et al, 1997: Hepatitis C: The Clinical Spectrum of Disease. Hepatology Vol. 26, No. 3, Suppl. 1, June, pp. 1299-1301, Natural History. U.S.A. Methods: The study consisted of 108 patients with chronic HCV infection taken from two other studies, Shakil et al., (1995) in which all patients were blood donors; and a smaller study by Di Bisceglie et al., (1995) in which there were no blood donors. Patients were given a questionnaire about five symptoms: fatigue, itching, abdominal pain, dark urine, nausea, and asked to rate the presence and the level of these symptoms (i.e. severity) in terms of discomfort on a 5-point scale i.e. from 0-4, with 0 representing no discomfort and 4 representing extreme discomfort. Scores were then compared with those of 100 healthy blood donors. Cirrhosis, liver inflammation and ALT were also assessed and the latter two variables compared with fatigue.

Aim of Study: “To better define the clinical symptoms of chronic HCV “ Although this article is primarily a review of all that was known about the clinical course of the illness, up until the time it was published, there are four paragraphs embedded in the main text that describe this study, which was obviously completed two years earlier.

Results: Of 108 patients with HCV, 62% had fatigue, however, the healthy blood donors when assessed had an even higher percentage of people with fatigue i.e. 70%. Of the five symptoms investigated only abdominal pain, dark urine and itching were more significant in the HCV group however they were only present in a small minority. There were no correlations between presence of fatigue and ALT levels or liver inflammation in the HCV group. Seven patients all of whom were symptomatic were shown to have cirrhosis on biopsy; six of those had one or more symptoms ranging from moderate to severe. For some reason the severity of fatigue, although measured, is not reported for either the HCV group or the 100 healthy controls.

Commentary: This study was one of a series of three studies in which Hoofnagle had taken part – the data for this study comes from combining the results of the other two. Unlike the other two studies this study was never published as a full-length article; it takes up less than 350 words, which means a great deal of detail has been left out. The findings on fatigue in this study are difficult to accept on the grounds that they are highly counter-intuitive. One would not expect normal healthy people to have a higher prevalence rate for fatigue than people who have HCV, especially since fatigue is known to be associated with liver disease. Indeed, the author himself admits that he was surprised by these results,

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but offers no explanation for them. In 2002 Wessley & Pariante in their review of fatigue and depression in HCV infection, stated that this study carried more “weight” than any other HCV symptom study because the patients were blood donors* (in fact about two thirds were) and that the study therefore provided good evidence for fatigue not being associated with HCV infection: however, like Hoofnagle they did not explain why the healthy control group had worse fatigue than the HCV infected group. In 2002, Hassoun et al. attempted to explain these results by saying that since the study didn’t properly assess the severity of fatigue, it is likely that the high prevalence of fatigue in both patients and controls is due to the fact that the fatigue measure used could not discriminate between “normal” every day fatigue, which is inconsequential, and high levels of disabling fatigue - the study they undertook to show this, proved their point. This study has also come under sharp criticism from Jones (2004) who argues that it is inappropriate to use blood donors in HCV studies – he does not expand on this but we take it to mean that only patients who complain about symptoms should be assessed for them. While we take his point we cannot agree, as it is important to assess all HCV populations irrespective of how they were diagnosed otherwise we will have a skewed natural history of this disease. We have never been able to decide if Hoofnagle is a major strategist and agent provocateur for leaving us this little “cliff-hanger” hoping to get some good symptom research from the reaction, or whether he really believed in his own results – he was after all a contributor to the article by Desmet et al.,(1994). We would like to think of him in the former role. * Blood donors, who test positive for HCV, are assumed to be asymptomatic since they discover their HCV status accidentally and not from the investigation of complaints about symptoms.

Author: (17) Hunt C.M. et al. 1997: Effect of Interferon Alpha Treatment on Chronic Hepatitis C on Health Related Quality of Life. Digestive Diseases and Sciences Vol. 42, No. 12: pp. 2482-2486, December.

Quality of Life Study. USA. Methods: 38 patients with chronic HCV (M=67%, Mean age=35.8yrs) were treated with 3 million units of interferon per dose for 24wks with a 24-week follow-up. Patients were assessed on the Beck depression inventory (BDI); the hospital anxiety and depression scale (HADS) and the SF-36 QOL questionnaire, at baseline (pre-treatment), after 1 month of treatment, at 24 weeks end of treatment, and at 24 weeks follow-up.

Scores on the above 3 measures taken at each assessment point were compared with each other and with population norms. Comparisons of QoL, depression and anxiety scores were also made between cirrhosis* vs. no cirrhosis and treatment response** vs. no treatment response. * No prevalence rate given. ** Based on ALT levels. No prevalence rate is given.

Aim of Study: To assess the impact of interferon on QoL and depression.

Results: Results showed a 30% prevalence rate for depression on the BDI and a 25% prevalence rate for anxiety on the HADS at baseline. Although anxiety significantly reduced at 1 month and depression significantly increased at 6 months there were no significant differences between pre-treatment scores on these variables and those found at the end of follow-up. SF36 scores for the group before, during or six months after treatment were not significantly different when compared with those for U.S. population norms. When depression, anxiety and QoL scores were compared between cirrhosis vs. no cirrhosis and treatment response vs. no treatment response no significant differences were found.

Commentary: This study has the dubious distinction of being one of only two studies* that did not find any evidence of abnormal fatigue in HCV infected patients. The authors state that their results are the same as those of Davis et al. (1994), i.e. that treatment with interferon did not produce any significant improvements in QoL. However, Davis et al. found that the HCV patients in their study had significantly poorer QoL

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before and after treatment with interferon, whereas in this study patients had normal QoL before, during and after treatment. It is interesting to note that the prevalence rates for depression and anxiety found in patients at baseline were not significantly different six months after treatment – the same proportion still had abnormal depression, and there was only a slight reduction in the number of patients who had abnormal anxiety scores. This study was very small and was reduce by about a third by the end of follow up due to non-completed tests or non-completed treatment; this may explain its anomalous results. * Both used the SF-36.

1998 (7 studies) Author: (18) Sladden et al, 1998: Hepatitis C virus Infection: impacts on behaviours and lifestyle. Australia & New Zealand Journal of Public Health, Vol. 22, No. 4: pp. 509-511. Symptom Survey Study. Australia.

Methods: 467 people from a rural area notified with HCV over a 21-month period between 1993 and 1994 completed a questionnaire asking about source of infection, changes to behaviour, symptoms and treatment or therapies they were using. A separate questionnaire, asking only about symptoms was completed by their GP. Aim of Study: To investigate the personal impact of HCV infection, on symptoms, behaviour and life-style.

Results: Symptom results from the total sample showed that 45% had fatigue, 39% reduced daily activities, 11% nausea and 16% emotional disturbances. Symptom results from the GPs showed that 219 symptom questionnaires were completed (117 Male & 102 Female). Fatigue was the most commonly reported symptom - 78 (36%) other symptoms were e.g. nausea 21%, abdominal pain 21%, and loss of appetite 13%. The top three treatments reported by participants were: naturopathy (10.3%), anti-nausea (7.9%), analgesia (7.3%).

Commentary: This is the first of four community surveys, the only ones in this review and all from Australia. Although this study was published in 1998 it was conducted during 1993/94. It was prescient on the part of the investigators to have conducted such a study at the time they did i.e. only a few years after the first antibody test for HCV became available in Australia. It is interesting that they mention the possibility that the “initial shock of diagnosis” may have an effect on symptoms without realizing that this would soon be the focus of an intense debate.

Author: (19) Younossi Z.M. et al, 1998: Hepatitis C: Health Related QOL, Rheumatologic, Virologic and Histologic Outcomes. Gastroenterology, Vol. 114, No. 4: L0704. Abstract. Quality of Life Study. U.S.A. Methods: 30 patients (M=69%, Mean age not reported) with chronic HCV infection (a sample from a larger group of 100 prospective consecutively assessed HCV patients) were administered the: chronic fatigue

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syndrome screener, connective tissue disease screen questionnaire, the SF36 and the chronic liver disease questionnaire. Rheumatologic markers (cryoglobulin, soluble interlukin 2 receptors,) rheumatoid factor), ALT and liver histology were also assessed. Comparisons were made between HCV patients with and without rheumatological markers and with general population norms.

Aim of Study: “To determine the of prevalence of HRQL* rheumatologic and fatigue markers in HCV infected patients.” * Health Related Quality Of Life Results: Cirrhosis was found in 41%, fatigue in 76%, reduced activity due to fatigue in 50%, and loss of work due to fatigue in 12%. Only 12% of patients had life-long fatigue and 72% of patients reported relief of fatigue after resting. Arthralgia was the most common rheumatological symptom (no rate supplied).

QoL on the SF36 was significantly lower than that for population norms. QoL was significantly lower in those with fatigue than those without fatigue. It would appear that rheumatological markers did not make a significant difference to QoL, or fatigue.

Commentary: This was the first of a number of studies, which have investigated the relationship between autoimmune diseases* and fatigue in HCV infection. Autoimmune diseases are a result of the body’s immune system producing antibodies, which attack its healthy tissue and organs. In HCV infection it is thought that the virus may be responsible for triggering an autoimmune response; in this study they focussed on autoimmune diseases associated with muscle and joint inflammation that may be the cause of fatigue and arthralgia. The study found no relationship between rheumatologic (immunological) markers and fatigue in HCV infected patients. Subsequent studies have found similar results. This study assessed fatigue using chronic fatigue syndrome (CFS) criteria (See Dale et al., 1991) and the fatigue scales of two QoL measures. It is unusual and can be problematic to assess fatigue (or any subjective variable) on more than one measure during the same assessment – it can cause confounding. In HCV literature autoimmune diseases are generally referred to as “extra-hepatic manifestations” as they occur outside of the liver, but not all extra-hepatic manifestations are autoimmune disorders e.g. depression and anxiety.

Author: (20) Foster et al, 1998 Jan: Chronic Hepatitis C Virus Infection Causes a Significant Reduction in Quality of Life in the Absence of Cirrhosis. Hepatology. Vol. 27, No.1: pp. 209-212. Quality of Life (QoL study). England.

Methods: 72 patients (M=33, Mean age=39.3 yrs) with chronic HCV attending an outpatient clinic; 30 patients (M=20, Mean age=32yrs, with hepatitis B virus (HBV)) attending the same clinic; and 17 healthy controls were administered the SF-36 QoL instrument and their scores subsequently compared.

Patients with cirrhosis or other disorders that may be associated with fatigue were excluded from the study. To assess mode of infection SF-36 scores were compared between IDU's (N=36) versus 'never took drugs' (N=36), in the HCV group. Mode of presentation in the HCV group was assessed by comparing the SF-36 scores between those in whom the virus had been detected from investigation of symptoms (N=31) versus those in whom it had been detected by routine screening (N=41) i.e. blood donors or medical insurance examination. Finally, SF-36 scores for the HCV group were compared with virus activity, fibrosis and ALT scores.

Aim of Study: To assess quality of life in people with HCV who do not have cirrhosis using the SF-36 and comparing results with two control groups.

Results:

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To validate the SF36 scores for the 17 healthy controls they were compared to SF-36 UK population scores and found to be not significantly different. Comparisons between the SF-36 scores of the HCV group, the control group and the HBV groups showed the following: The HCV group had significantly worse quality of life scores on every SF-36 scale compared with population scores; the HBV control group however had significantly poorer scores than those for the normal population on only two scales i.e. mental health (MH) and general health perceptions (GH). Within the HCV group there were no significant differences in SF-36 scores for mode of transmission i.e. IDU's versus non-IDU's, except that the non-IDU's scores on the 'Vitality' scale were within normal range. Likewise there were no significant differences in the SF-36 scores for mode of presentation (symptoms versus no symptoms), virus activity, fibrosis or ALT scores.

Commentary: This study is very well written in precise and clear language (scientists are not always good writers).

What distinguishes this study from previous studies in this review is its well-considered design, aimed at controlling for bias and eliminating confounding variables, the following are good examples: referral bias was controlled by comparing different referral methods; confounding due to method of infection was controlled by comparing IDU’s with Non-IDU’s; confounding due to severity of liver disease (and possible encephalitis) was avoided by excluding patients with cirrhosis. It is difficult to explain why the non-IDU’s had normal fatigue, but abnormal scores on every other SF-36 scale, perhaps that particular scale is a poor discriminator of severity; conversely, perhaps IDU’s have more fatigue related psychopathology as a consequence of previous or current addiction – although in later studies there is little evidence to support this. In their review of this study Wessley and Pariante (2002) criticised it for failing to measure depression and for using patients who were aware of their HCV diagnosis. The first criticism is valid and in a later review Foster (1999) would acknowledge this. The second criticism is based on the view that it is the shock of being given a diagnosis with HCV (something akin to a reactive depression) that is the cause of fatigue rather than an effect of the virus. However, to insist that all HCV studies assess fatigue before the patient is given a diagnosis with HCV is an extremely hard requirement to fulfil – only two studies in twenty years have been able to do this (Rodger et al.1999; Cordoba et al., 2003); it would seem easier to control for the impact of diagnosis by excluding psychopathology (e.g. depression, anxiety, insomnia) from HCV studies (Hassoun et al., 2002), or not excluding psychopathology and measuring it (Dwight et al. 2000; Mc Donald et al., 2002). Despite not measuring depression this is a comparatively good study; it is frequently cited and most importantly it has influenced a number of other studies, for example, Rodger et al., (1999); Miller et al., (2001); Hassoun et al., (2002).

Author: (21) Bayliss M.S. et al. 1998: A questionnaire to assess the generic and disease specific health outcomes of patients with chronic hepatitis C. Quality of Life Research, Vol. 7, pp. 39-55. Quality of Life Study. U.S.A. Methods: 157 patients with chronic HCV (M=72%, Mean age = 44.2 yrs), candidates for Interferon treatment, were administered a modified version of the SF-36 comprised of the standard 8 scale SF-36 plus four augmented SF-36 scales (Role disability physical, Vitality, Social functioning, Role disability emotional), three additional generic scales (Positive well being, Sleep somnolence, Health distress) and two disease specific scales (Limitations due to CHC*, Health distress due to CHC). Statistical analyses were performed to assess the validity and reliability of these changes. Results for the 8 scales of the standardized SF-36 were compared with general population norms and those of other illnesses. Thirty five percent of patients had cirrhosis, and for mode of infection – 41% IDU, 36% transfusion and 23% other. ALT was also assessed.

Aim of Study: To develop and test a modified and augmented version of the SF36 which is more HCV specific than the standard eight-scale version.

Results:

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Results from statistical analyses confirmed the validity and reliability of the changes made to the SF-36 i.e. the additional items and scales correlated with the eight scales of the SF-36. When SF-36 scores (standard 8 scale version) for the 157 patients with HCV were compared with those for the general population the HCV group had significantly worse scores on all 8 scales of the SF-36, including the vitality (fatigue) scale. Because the additional items and scales have no population norms and are not specifically measures of fatigue we have not include the results here. No consistent relationship was found between fatigue scores and cirrhosis or elevated ALT. There were no reports of differences among different modes of infection.

Commentary: This is the second in a series of studies that used a modified version of the SF-36, which was designed to be more HCV specific. In the following year, three interferon trials, using the SF-36, also employed additional scales – since those studies only one other HCV study has used a modified version of the SF-36. However, the generic eight-scale version of the SF-36 has become almost a standard measure of QoL in HCV studies. There are only a few brief references to fatigue in this article and occasional statements about the burden of illness in HCV having been previously 'underestimated'. And that HCV is not a “silent” illness. As in their previous article (Carithers et al. 1996) the merits of the modified HCV specific SF-36 QoL measure are argued, but are no more convincing than previously.

Note: *CHC = chronic hepatitis C

Author: (22) Wollschlaeger et al. 1998: Assessment of quality of life (QOL) in hepatitis C. Hepatology Vol 28.

No 4: pt 2, p. 203A. Abstract. QOL Study. Germany.

Methods: 51 female patients (age not reported) infected with HCV for 19 years and only with mild liver damage; 31 female ‘cured [sic]' i.e. HCV, PCR negative patients; and 23 healthy female controls. They compared three German QOL measures; the FPI-R, the PLC and the FKV-LIS-SE and a 19, item questionnaire about HCV symptoms devised by the authors. Scores for the 3 different groups were tested for significant differences on each of the 3 questionnaires* Note: * The controls were also assessed on the authors HCV symptom questionnaire.

Aim of Study: To assess quality of life in a HCV positive and HCV negative group of women, using three different German measures of quality of life with the view to selecting the most valid measure.

Results: The authors found only the Freiburg Personality Inventory-Revised (FPI-R) to be sensitive enough to measure QoL in HCV. The PCR positive group were significantly different from controls on 5 of 6 scales of the FPI-R while the PCR negative group were significantly different from controls on only two scales. The FPI-R has only one scale likely to measure fatigue, 'physical complaints', and scores on this scale were significantly higher (worse) for the PCR negative (cured) group, but not for the PCR positive group, when both groups scores were compared with those of the control group. On the authors own symptom questionnaire the HCV, PCR positive group had more physical complaints than the healthy controls, but no more than the PCR negative group. The authors conclude that overall there was no correlation between improved quality of life and PCR negative status – in other words cured patients were still found to have abnormal QoL – which, they claim, needs to be more critically compared with outcomes in HCV treatment (i.e. interferon) trials.

Commentary: The word fatigue is not mentioned in this study though it is quite likely that it, or a correlate of fatigue, was included in the “physical complaints” scale of the FPI-R. We included this study only because it is

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the first German HCV study of QoL/symptoms published in English, and more importantly the first to include PCR negative patients. Because the study was published as an abstract only, there are the usual problems with insufficient detail, there is for example, no rationale provided for including PCR negative patients. They may have been included as a second control group with the expectation that they would have few symptoms, which seems to have been the case with Forton et al. (2002). It is also possible that they were included because they had complained about symptoms. The women in this study may have been part of the German Anti-D women’s group (Weise et al., 2005) as their demographics and clinical profile are very closely matched. Those particular women have been followed up annually since 1979-80, so they may have been referred to this study because they were known to be symptomatic. Whatever the reason for including PCR negative women, finding that they were symptomatic after clearing the virus was a contradiction to the then popularly held view that successful viral clearance should lead to a loss of symptoms (Foster et al.,1999). Later studies by Goh et al.

(1999), Forton et al. (2002) and Weissenborn et al. (2006) also included PCR negative patients in their studies and most found them to have significantly worse symptoms (including fatigue) and poorer QoL when compared to the general population. In 2006, Weissenborn et al. were able to explain the persistence of symptoms in HCV PCR negative patients in terms of the “Trojan Horse” theory of HCV brain infection.

Author: (23) Desmorat et al. 1998: Quality of life during chronic hepatitis C: Study of 466 patients before treatment. Hepatology, Vol. 28, October, p. 472A. QoL Study. France.

Methods: 466 untreated chronic HCV patients (M=61%, Mean age 41yrs, Cirrhosis = 10%), candidates for interferon treatment, were assessed for QoL using the SF-36. SF-36 scores for each of the 8 scales were compared with gender, age, ALT levels, genotype cirrhosis, Knodell score (a clinical measure of disease activity i.e. liver inflammation) and disease duration. Other variables examined in this study were: age, gender, cirrhosis, ALT, genotype, mode of infection and duration of infection. There was no control group in this study and comparison of SF-36 scores with population norms are not reported, or were not compared.

Aim of Study: To assess QoL in French chronic HCV patients and to investigate any associations with biochemical, histological, virological or clinical measures.

Results: Quality of life (QoL) scores in this study, as measured by the SF-36, were compared only within the total sample of HCV infected patients and not, additionally, with a control group or population norms as is usual in most studies. Results for SF-36 comparisons between HCV subgroups were as follows: Females had significantly poorer QoL on 5 scales i.e. physical functioning (PF), role physical (RP), role emotional (RE), body pain (BP) and mental health (MH), compared with males; older patients (46+yrs.), had significantly poorer QoL on 3 scales i.e. physical functioning (PF), body pain (BP) and general health (GH), compared with younger patients; finally, those with cirrhosis had significantly poorer QoL on 2 scales i.e. PF and BP, when compared to those without cirrhosis. None of the above comparisons or those between other variables showed a significant difference in the SF-36 vitality (VT) scale, which is a measure of fatigue. However when a correlation analysis was performed the VT scale showed an inverse correlation with Knodell score i.e. as liver inflammation increases, vitality decreases. Means and correlation coefficients are not reported.

Commentary:

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This is the first French study of QoL/symptoms in HCV infected patients to be published in English. The study is difficult to interpret as we know only about the differences in QoL between one HCV subgroup and another (e.g. male vs. female), but we do not know how they differ in QoL compared with healthy people. With regard to fatigue, since the mean SF-36 scores were not reported, comparison with other SF-36 studies is not possible, and because no correlation coefficients were reported for fatigue vs. liver inflammation, we cannot tell how strongly they were correlated. Most other studies have found no relationship between liver inflammation scores and fatigue scores.

Author: (24) Kuratsune, H. 1998: Low levels of serum acylcarnitine in chronic fatigue syndrome and chronic hepatitis type C, but not in other diseases. International Journal of Molecular Medicine, 2, pp. 51-56.

Experimental/CFS/HCV. Japan.

Methods: There were both Swedish and Japanese patients in this study. Apart from gender there are no demographics. The Swedish sample contained 57 (F) chronic fatigue syndrome (CFS) patients and 46 (F) controls. The Japanese sample was comprised of 146 patients with CFS; 27 patients with leukaemia, lymphoma, or myeloma; 10 patients with chronic pancreatitis or hyper-tension; 20 patients with depression/neurosis (anxiety); 56 patients with HCV 36(M) and 20(F); 22 patients with diabetes mellitus and 308 normal healthy controls. Most of the above groups were roughly equal in gender composition. All patients gave early morning i.e. pre-breakfast, blood samples and serum was assessed for differences in acylcarnitine levels (see last panel on the right for an explanation why they were interested in this hormone). To exclude whether raised acylcarnitine levels may be explained by liver inflammation they used a mouse model where they compared five with induced liver inflammation and five controls. There were no significant differences in acylcarnitine levels between the mice groups.

Thus suggesting that raised acylcarnitine levels are not indicative of fatigue arising from liver inflammation. Fatigue was assessed using either Holmes (1988), or Fakuda’s (1994) criteria. We can assume that only the first part of the major criteria was used in the non-CFS patients e.g. six months of disabling fatigue not improved by rest, as the second part of the criteria in both versions would automatically exclude HCV and each of the other illnesses included in this study.

Aim of Study: To examine whether a deficiency in acylcarnitine (ACR) is associated with Chronic Fatigue Syndrome (CFS)* by studying ACR levels in both Japanese and Swedish patients and to compare results with those of other chronic illnesses where fatigue is thought to be a symptom.

Note: * This study was principally about CFS. The inclusion of an HCV group was mainly for comparison. The inclusion of the mice was to rule out inflammation of the liver as a possible cause of decreased ACR in HCV patients. Carnitine is produced in the liver and kidneys.

Results: In the Swedish sample CFS patients had reduced ACR levels when compared to healthy controls. The same pattern was seen in Japanese CFS patients compared to healthy controls. However, when ACR levels were compared between the Swedish and Japanese healthy control groups the latter were shown to have significantly higher levels of carnitine, confirming a racial or geographic difference in ACR levels. All other illnesses were shown to have normal levels of ACR except HCV, which like CFS had significantly lower levels of ACR compared to healthy controls. ACR levels were lower in HCV patients compared with CFS patients but they were not tested for significance. The author mentions that in a previous study of ACR levels in CFS patients he also found a deficit in levels of the hormone DHEA-S or dehydroepiandrosterone sulphate, which is thought to be involved in regulating ACR. Commentary: This is the second CFS study in this review; it is not usually cited in the Fatigue/HCV literature. The study is much more sophisticated than any study that had so far been done in HCV fatigue research.

Carnitine is a substance (amino acid) found in the blood, which is responsible for transporting fat molecules to cells where they are converted into energy. Acylcarnitine is carnitine with fat molecules bound to it. Acylcarnitine deficits have been found in other illnesses, as well as liver diseases, and are thought to be associated with fatigue, myalgia, hypotonia and constant infections, and had previously

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been found in CFS patients. In 2003, Neri et al. used carnitine to treat a small group of HCV patients, but only in the context of improving fatigue during interferon treatment. In 2005, Piche et al., in a small treatment review, mention the possibility of treating HCV patients with carnitine. In 2008, Ahboucha et al. found deficits in DHEA-S in HCV patients.

1999 (11 studies) Author: (25) Nancy Lau et al. 1999: Role of body composition, resting energy and exercise tolerance in fatigue among patients with CHC. Hepatology, Vol. 30, p. 599A. Abstract. Fatigue Study. U.S.A. Methods: 27 patients with chronic HCV (M=18; Mean age=45yrs.), without cirrhosis, were assessed for fatigue, resting energy expenditure (REE), body composition (BCM) and exercise tolerance. These variables were measured, respectively, by the fatigue impact scale (FIS); indirect calorimetry; bioelectrical impedance analysis (BIA) and performance on a stationary bicycle machine. ALT levels were also assessed. Scores for each variable were correlated with fatigue scores. Alcoholics and those being treated with interferon were excluded.

Aim of Study: “To…. assess fatigue using the Fatigue Impact Scale (FIS) and to correlate fatigue with body composition, exercise tolerance, resting energy level and ALT levels”.

Results: Fatigue was correlated with nutritional depletion i.e. weight loss and reduction of body cell mass (BCM).

There was no correlation between fatigue and resting energy expenditure (REE); exercise tolerance results (as measured by the bicycle test); or ALT levels. The authors’ concluded that being thin and underweight was associated with subjective fatigue (the patients self-perception), in HCV infected patients, but that there was no relationship between subjective fatigue and exercise tolerance.

Commentary: This study was published only as an abstract, therefore no rationale is provided for its focus. However, it was clearly designed to answer some very basic questions about fatigue in HCV infection that had not been previously examined, mostly concerning whether fatigue in HCV infection is objective or subjective. There was only one subjective measure used, the FIS, which measures the severity, duration and the disabling impact of fatigue. The other measures were objective. Resting energy expenditure (REE), indicates whether a persons body is using more energy than it would normally (i.e. hyper-metabolism), when a person is resting; it is calculated by a chemical analysis of the atmosphere, enclosed in a canopy, surrounding the patient, whilst they are in a lying position. Hyper-metabolism is common in cirrhosis, but not at earlier stages of liver disease. Body composition, the proportion of fat, to muscle and bone, is usually measured in addition to REE. Reduced, body cell mass (BCM) is associated with anorexia (lack of appetite), which is also common in cirrhosis. The final measure, exercise performance on a stationary bicycle machine, we can assume, was included to examine whether peripheral fatigue (i.e. in the muscles) as opposed to subjective fatigue was the cause, or partial cause, of the fatigue typically seen in HCV patients. The results are interesting as they suggest that fatigue is not due to muscle weakness but is related to being nutritionally depleted. However, unless the correlation between nutritional depletion and fatigue was very strong the former is likely to produce only an additive effect on the latter. In a later study, using measures of REE and BCM, Piche et al. (2002) investigated the role of the hormone leptin (thought to be involved in the control of body weight), and its possible relationship to fatigue. There was no assessment of depression or anxiety in this study: the sample size was also very small, and there are no statistical comparisons with a healthy control group or cut-off scores for the FIS, making interpretation difficult.

Author:

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(26) M Sherman et al. 1999: Assessment of quality of life in patients with chronic hepatitis C using a range of subjective assessment tools. Hepatology, Vol. 30, p. 24A. Abstract. Quality of Life Study.

Canada.

Methods: 96 HCV infected patients (Age=42+7yrs.), 199 healthy controls (Age=38+8yrs) and 199 healthy fatigue simulators* (Age=40+9yrs.) were administered 21 self-report questionnaires to assess fatigue and its impact on sleep, mood, QoL, personality and illness intrusiveness.

Note: * The reason for including the fatigue simulator group was to artificially create a group with very high fatigue scores, to contrast, what one would expect to find i.e. much lower scores in the HCV group and even lower scores in the healthy controls. In order to qualify as an accurate measure of fatigue each of the 21 fatigue questionnaires was expected to show this pattern of scores i.e. discriminate between different levels of fatigue severity.

Aim of Study: “ To…. assess fatigue and its impact on sleep, quality of life, mood, personality, and illness intrusiveness in patients diagnosed with CHC.” * Note: * CHC = chronic hepatitis C Results: The simulators had the highest fatigue scores on 20 of the 21 measures; HCV patients had the next highest scores and the healthy controls the lowest. Patients with HCV had higher levels of depression and sleepiness than the two control groups. They also had reduced alertness and QoL compared to those groups. All of the assessment tools were able to discriminate between healthy controls or healthy fatigue simulators and HCV patients except the Vitality (fatigue) scale of the SF-36, QoL instrument.

The authors claim that the same results could be achieved by using only 7* of the 20 assessment tools: CES-D Depression Scale Fatigue Impact Scale (FIS), Illness Intrusiveness Ratings Scale, TWH Fatigue Scale, ZOGIM-A Alertness Scale, and the FACES Fatigues (this is a pain scale often used with children – they must have adapted it to measure fatigue).

Note: * The remaining 13 measures are not named.

Commentary: The authors of this study wanted to find the best measures of fatigue and other symptoms for use in symptoms studies with HCV patients. When the authors’ use the term “quality of life”, they tend to mean specific symptoms rather than measures of disability, it is easy to conflate the two but they are different.

The study selected 21 measures that contained a fatigue scale (many symptom measures such as depression tests, have a separate fatigue scale) and administered them to each of the three groups.

The inclusion of a group of healthy people told to pretend that they are fatigued was necessary to create a greater range of fatigue scores (i.e. very high) as an additional test measure in discriminating between different levels of fatigue severity. With this design you would expect to find either no or very low fatigue scores in the normal healthy control group; abnormally high fatigue scores in the HCV infected group; and extremely high fatigue scores in the fatigue simulators – which is what the study found for 20 of the 21 measures they examined. The only measure, which was not able to discriminate between each of the three groups, was the VT (fatigue) scale of the SF-36 QoL measure. The essential finding of the study was that seven measures were capable of accurately measuring fatigue and other symptoms in HCV infected patients. At the time this study was conducted it was probably too early to see that the fatigue impact scale (FIS) would become the preferred fatigue measure in HCV fatigue studies. This study was published as an abstract only and contains few details - it is surprising that no other study has followed it up with a validation study comparing the FIS with the SF-36 VT scale since both these measures are frequently used together in the same study. This study was the first in this review to use the term “labelling” in referring to possible causes of fatigue in HCV infected patients.

Author:

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(27) Jason Goh et al. 1999: Fatigue does not correlate with the degree or the presence of autoimmune disorders in chronic hepatitis C infection. European Journal of Gastroenterology & Hepatology. Vol. 11, pp. 833-838. Fatigue/Extra-hepatic Manifestations. Ireland.

Methods: Patients in this study were 66 women with chronic HCV infection (Mean age=47.7 yrs.) from the Irish anti D, Group of women; 50 healthy women controls (age matched) and 20 anti-D women who were HCV antibody positive, but were PCR negative i.e. they had cleared the virus either spontaneously or due to interferon treatment. All patients were administered the fatigue impact scale (FIS). Patients in the HCV group had previously been biopsied – none were cirrhotic. The HCV group was also tested for the presence of autoimmune disorders (extra hepatic-manifestations), these were: xerophthalmia (Sjorgen’s syndrome), cryoglobulinemia, sicca complex, kidney disorder, thyroid disorder and autoimmune disorders in general. FIS scores were compared between the HCV group and the two control groups Within the HCV group FIS scores were compared (using correlation analysis) with the following variables: results from autoimmune tests, previous treatment with interferon and Knodell (HAI) scores (liver inflammation).

Aim of Study: “To quantify fatigue in terms of its impact on quality of life in a homogeneous cohort and examine its relationship to the status of liver disease or associated auto-immunity”.

Results: Scores for the fatigue impact scale (FIS) were significantly higher in the PCR positive group compared to healthy controls but not significantly different from the HCV PCR negative group. Although autoimmune disease was found in a small number of patients e.g. cryoglobulinemia (N=10), xerophthalmia (N=6), sicca complex (N=6), there were no correlations between fatigue and autoimmune disease, liver inflammation, or previous treatment with interferon. The authors of this study claim that the prevalence rate for fatigue was 97% (64 of 66 patients), and 40% for arthralgia. However, they also claim that 17% of all patients in this group were asymptomatic, which would put the prevalence rate for fatigue at 83%. We can only assume that 97% was the rate for “reported “ fatigue rather than fatigue measured by the FIS. The “reported “ prevalence rate for fatigue in the HCV antibody positive, PCR negative group was 75%.

Commentary: This is an important study. It is the first full-length publication (as opposed to abstracts) of research on the Irish Anti-D women’s group and its central focus was on fatigue. It also had a number of other important features, for example: the FIS, probably the best measure of fatigue in HCV infected patients, was chosen; autoimmune diseases were examined – cryoglobulinemia, especially is thought to be a cause of fatigue; and finally the inclusion of the HCV anti-body positive, PCR negative women was fortuitous as would later be shown. The main weakness of the study, apart from not measuring depression, can be attributed to a lack of clear reporting on the use of cut-off scores with the FIS. The FIS does not have pre-determined cut off scores e.g. for mild, moderate or severe fatigue, so researchers must devise their own if they wish to report a prevalence rate for fatigue severity. The authors claim to have found a prevalence rate of 97% for fatigue but do not give a cut–off score. Later they make a contradictory claim that 17% of all patients were ”asymptomatic”, which would mean that only 83% had fatigue. To estimate which of the two rates was correct we recalculated the number of scores above FIS >35, the minimal cut-off score for fatigue used by Weissenborn et al. (2006), and found a prevalence rate of 82%, only one percent different from the lower of the two possible prevalence rates reported. We suggest the latter, 82% as being the best estimate and in the HCV PCR negative group we found 80%, only a little higher than the 75% “reported” prevalence rate for fatigue in this group. However, even an 82% prevalence rate for fatigue in the HCV positive group makes it the highest in this review. Only one study in this review has discussed the importance of measuring the individual severity of fatigue in HCV studies (Hassoun, 2002), partly as an explanation for Hoofnagle’s (1997) findings on fatigue, although severity and cut off scores have been briefly mentioned by others (Wessley and Pariante, 2002; Mc Andrews et al., 2005).

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Author: (28) Bonkovsky A.L. et al. 1999: Reduction in Health related QOL in chronic hepatitis C and improvement with interferon therapy. Hepatololgy Vol. 29, No. 1: pp. 264-270. Quality of Life & Treatment Response Study. U.S.A. Methods: Six hundred and forty two (642) patients with chronic HCV (M=73%; Mean age=43 yrs.) 358 with cirrhosis and 284 non-cirrhotic (they were approximately the same age and gender composition) were randomised to one of three interferon groups and treated for 24 weeks using either a different type or a different dosage of interferon. All were assessed for QoL on the SF-36 and 6 additional QoL scales* from the Medical Outcomes Study (MOS) at baseline and at follow-up i.e. 48 wks later (24 weeks posttreatment). FS-36 scores were compared to NSFHS ** (U.S.A.), population norms. Comparisons were made within and between groups e.g. Total HCV group versus population norms, sustained viral responders (SVR’s) versus non- viral responders, sustained viral responders (SVR’s) baseline scores versus their own end of follow-up scores, and SVR’s end of follow-up scores with population norms.

Exclusion criteria were rigorous and excluded a history of depression.

Note: * These were: appetite, cognitive function, perceptions of current health, feelings of health distress, sexual function and quality of sleep – none of these extra scales have norms. ** National Survey of Functional Health Status.

Aim of Study: To assess the impact of HCV on QoL in cirrhotic and non-cirrhotic patients and to assess the effect of successful interferon treatment i.e. viral clearance or ALT normalisation, on QoL Results: Prior to treatment, scores for the HCV group n=642 showed significantly reduced QoL compared to US population norms for all eight scales of the SF-36. Changes in SF-36 scores from baseline to end of follow-up were calculated for both viral responders (SVR’s), and non-SVR’s, (non-responders and relapsers) and compared. For SVR’s there was a significant improvement on five SF-36 scales (physical function, vitality (fatigue), social function, general health and role physical) when compared with nonSVR’s. Changes from base line to end of follow-up were also calculated for both SVR’s and non SVR’s on five additional QoL scales; SVR’s showed a significant improvement on three scales i.e. appetite, current perception of health and sexual function when compared with non-SVR’s. Finally when SVR’s end of follow-up SF-36 scores were compared to population norms, 7 out of 8 scales had normalised, only one scale, general health, was still significantly lower (worse). The authors state that the presence or absence of cirrhosis made no difference to treatment outcomes; they conclude that these results support previous findings that HCV patients suffer from significantly poorer QoL than the normal population. They also conclude that their findings indicate that HCV infection causes symptoms which, result in significant decreases in QoL. Commentary: This study and the following two studies by Neary et al. (1999) and Ware et al (1999) are interferon outcome studies that used the SF-36 quality of life (QoL) measure with additional HCV specific QoL scales. The first augmented version of the SF-36was developed by Bayliss et al. (1998) with the intention of creating a hepatitis C specific measure to be used in future interferon trials. The appearance of these three very similar studies within a few months of each other is unusual and they may have been a response to Foster’s (1998) hypothesis that if poor quality of life is caused by HCV, eradicating the virus by interferon treatment should lead to a reversal of symptoms i.e. normal SF-36 scores. The results of each of these studies are difficult to interpret because they do not give baseline or end of follow-up scores for sustained viral responders (SVR’s) that can be compared with SF-36 scores for the general population – in other words we cannot say whether those who cleared the virus, in these studies, still had abnormally low fatigue or other scales on the SF-36. Outcomes in these studies were based only on difference or change scores. A change score is what you have left when you subtract a baseline score from an end of follow-up score—in the case of the SF-36 it is the number of points

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gained or lost on each scale due to treatment: i.e. it is solely a measure of the treatment effect. In all three studies change scores for each scale were compared between SVR’s and Non-SVR’s for significant differences and in the present study SVR’s scores at end of follow-up were compared with their own baseline scores. Each study found that 6 months after treatment SVR’s (as opposed to NonSVR’s ) had improved on most SF-36 and additional scales and that approximately half of these had improved significantly.

Despite these gains, there are some difficulties in interpreting the findings. None of the three studies report the actual SF-36 scores for SVR’s at baseline or at follow-up. As such, it is difficult to ascertain how abnormal HCV patients QoL was before they were treated with interferon and if they normalised 6 months post-treatment. In Bonkovsky’s study we are informed that SVR’s baseline scores were abnormal at baseline and end of follow-up, and although scores improved, none of the scales had normalised. However, the scores are not reported. Without the SF-36 scores we are unable to say how close each scale may have been to that for the general population.

In an attempt to address the limitation identified above and in order to obtain an estimate of how abnormal fatigue was in SVR’s at follow-up in each of three studies, we took their difference scores on the vitality scale and added them to the reported scores for the vitality scale at baseline for the group as a whole (i.e. both responders and non-responders). We then compared this with the score for vitality reported for general population norms. Following this manipulation we found that fatigue had normalised in Bonkovsky’s and Ware et al.’s studies, but not Neary et al.’s study. However, we know from Bonkovsky et al. that the SVR’s were significantly different from the normal population on all SF-36 scales both at baseline and follow-up suggesting that none of the eight scales had normalised. We take this inconsistency to mean that our estimate was wrong, indicating that baseline scores at least in this study must have been lower for SVR’s than for non–SVR’s. We cannot be sure that the same was not the case in the other two studies. In the end we simply do not know how different the QoL of SVR’s was from that of normal healthy people, only that they had improved in comparison to those who remained PCR positive.

We have not discussed the extra scales used in these studies, as they do not have any general population norms with which they can be compared. Also, the lifespan of the HCV specific QoL measures were to be very brief and restricted to only one more study in 2001 by Fontana et al. before it disappeared along with the outcome studies that had used it.

In summary, these three studies failed to report the exact percentage of SVR’s assessed at follow-up and just as importantly, the number or percentage of those who had made no improvements in QoL even after successful treatment. Of the three studies the Bonkovsky’s study was the largest, the best controlled and the most detailed. The legacy of these studies has been the establishment of the SF-36 (without extra scales) as the predominant measure of QoL in HCV studies, however, in later studies it is generally used as only one measure among a number of other more specific assessment tools.

Author: (29) Neary, M. P. et al 1999: Sustained Virologic Response Is Associated With Improved Health Related Quality of Life in Relapsed Hepatitis C Patients. Seminars in Liver Disease. Vol. 19, Suppl. 1, pp. 77-85. Interferon/QOL study. U.S.A. Methods: 257 patients with chronic HCV who had relapsed within one year after previous interferon monotherapy, took part in an interferon trial comparing interferon alpha + ribavirin (I+R) - (N=125, Mean age=43, M=79 F=46) with interferon + placebo (I+P) - (N=132, Mean age=45, M=92 F=40). Patients were treated with Interferon for a total period of 24 weeks then followed up for another 24 weeks of observation. All patients were administered a modified version of the SF36 which included a substituted Mental Health Scale, the M18, plus four additional scales, sleep somnolence, health distress, HCV health distress and HCV specific limitations. SF36 assessments were made at baseline (pre-treatment), 12 weeks, 24 weeks (end of treatment), 12 weeks (follow-up) and 24 weeks (end of follow-up). Comparisons OF SF36 SCORES were made at baseline for interferon + ribavirin vs. interferon + placebo. At the end of 24 weeks follow up SF-36 comparisons were made for interferon + ribavirin vs. Interferon + placebo, for changes

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in scores between baseline and end of follow-up within both the I+R and I+P groups, and for the I+R, non-1 genotype group Vs. I+P non-1 genotype group i.e. any other genotype than 1a or 1b. At the end of follow-up differences in SF36 scores between baseline and follow up were calculated for overall sustained viral responders (PCR negative and reduction of 2 or more points in HAI score) and compared with those for non-viral responders (PCR+). Forty-four patients in this study had cirrhosis, 150 had genotype 1. No data supplied on mode of infection.

Aim of Study:

To examine the relationship between sustained viral response and QOL in two groups of former Interferon relapsers retreated with either, Interferon + Ribavirin or Interferon + placebo.

Results: SF-36 scores for the two groups were similar at baseline. At week, 24 (end of follow-up) the interferon + ribavirin group showed a significant improvement on 3 SF-36 scales and 3 additional scales* compared with the interferon + placebo group, however data for the “Vitality” scale was not calculated as it did not meet the criteria for the statistics that were used. Comparisons between baseline and week 24 follow-up scores within each group were not significant. Comparisons between genotype 1 and non-1 genotype are not reported. Comparison of SF-36 scores at week 24 for non-1 genotype and interferon + ribavirin treatment (N=48) vs. non-1 genotype and interferon + placebo (N=59) showed significant improvements in 4 SF-36 scales - including the “Vitality”(fatigue) scale. When differences in SF36 scores from baseline to end of follow up were calculated and compared between overall responders and non-responders to interferon treatment, the overall responders showed a significant improvement in 4 SF-36 scales (including Vitality) and 3 additional QoL scales.

Note: * The additional QoL scales have no population norms and very low significance levels were used in some of these comparisons (i.e. p =/< 0.1).

Commentary: Both in this study and the following companion study by Ware et al. (1999), the authors used the same dataset from an interferon trial by Davis et al. (1998), which compared mono with combination therapy.

In this study the modified SF-36 no longer had augmented items, but the additional scales were the same, with the exception that a second mental health (MH) scale was added. A major limitation in interpreting Nearys study is that statistical comparisons of SF-36 scores between SVR’s and general population norms were not made at any of the assessment points. Since this study did not provide general population norms for the SF-36, we compared the baseline SF-36 scores in this study for all HCV patients, with those for similar patients and general population norms in an earlier study by the same authors (Bayliss et al. 1998). We found that all the baseline scores for each of the eight SF-36 scales appeared to be significantly lower (worse) than those for the general population. When SF-36 change scores for SVR’s in this study were compared with those for non-SVR’s at follow-up, the SVR’s showed significant improvements on 4 scales i.e. physical function (PF), vitality (fatigue)(VT), general health (GH) and social function (SF). When we added SVR’s, SF-36 change scores to those for the total group at baseline (see comments in the review of Bonkovsky’s study) and compared them with general population norms, all eight SF-36 scales were well below normal values (i.e. worse). In Neary’s study as in Bonkovsky’s, SVR’s had made significant improvements six months after interferon treatment on some SF-36 scales including fatigue, but none of the eight scales appear to have normalised. We have not discussed the extra scales reported in Neary’s, article as they do not have general population norms.

Author: (30) JE Ware et al, 1999: Health Related Quality of Life in Hepatitis C; impact of disease and treatment response. Hepatology. August. Vol. 30, No. 2: pp. 550-555. Quality of Life / Treatment Response Study.

U.S.A. Methods: Three hundred and eight (308) patients, 152 from the U.S.A. and 156 from 9 other countries (demographics, not reported) with HCV who had previously responded to Interferon, but relapsed after

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treatment, were randomly assigned to 24 weeks treatment with either interferon + ribavirin or interferon + placebo. Treatment outcome at end of 24 weeks follow-up was defined as “overall responder” (PCR-, plus histological improvement); “responder” (PCR-); and non-responder (PCR+). A modified version of the SF-36 which included 4 extra QoL scales* was used to assess QoL on 5 occasions spaced equally from baseline to end of follow up (i.e. 48 weeks). SF-36 population norms were based on data from the National Survey of Functional Health Status (NSFHS), (U.S.A.). Statistical comparisons of SF-36 scores were as follows: U.S. and patients from other countries scores were compared with population norms; at end of follow-up, changes in scores from baseline to end of follow-up were compared for significance within the sustained viral responder group, the overall responder group, and the nonresponder group.

Note: * Sleep, health distress, HCV distress and HCV limitations

Aim of Study: To assess the impact of HCV on QoL and to assess whether a sustained viral response to treatment leads to an increase in QoL. Results: There were no significant differences between patients’ scores in terms of nationality, so the 2 samples were combined as one. HCV infected patients at baseline had significantly poorer QoL on 5 SF-36 scales i.e. physical functioning (PF), role physical (RP), general health (GH), vitality (fatigue) (VT), and social functioning (SF) when compared with population norms. Comparison of SF-36 scores between baseline and end of follow-up for overall responders, sustained responders and non-responders showed the following: overall responders -had improved on 3 SF-36 scales i.e. GH, VT (fatigue), SF, and 2 additional QoL scales i.e. health distress and HCV limitations; sustained responders – had a significant improvement on two SF-36 scales i.e. vitality, social functioning and one additional QoL scale, health distress; non-responders – had made no significant improvements on any SF-36 or other additional QoL scales Commentary: As in the previous study, the data in this study comes from the interferon trial by Davis et al. (1998) and presumably they used the same patient set. Ware’s study is different from the Neary’s study in that it focussed more on the SF-36 outcomes for SVR’s rather than different QoL outcomes for the two different kinds of interferon treatment. In addition this study used general population norms (at least at baseline) as well as standardised SF-36 scores—the latter make comparisons more accurate. At baseline 5 of 8 SF-36 scales were significantly lower (worse) than those for general population norms: i.e. physical function (PF), general health (GH), role emotional (RE) vitality (fatigue) (VT), and social function. At follow-up, SVR’s, as opposed to Non-SVR’s showed improvement on 3 of the latter scales: i.e. GH, VT (fatigue) and SF. However, similar to Neary’s study only SF-36 change scores are reported for SVR’s. As described earlier, we followed the same procedure and added the change scores to the appropriate scale scores reported for all patients at baseline to give us an estimated SF-36 means for SVR’s at follow-up. When we compared these with the same scales for SF-36 population norms we found that each of the 3 scales had normalised. This suggests that treatment was beneficial. The differences in results between this study and the study by Neary et al. (1999) i.e. the number of significant improvements on the SF-36, may be due to the data in this study being standardised while the data in the former study was not standardised.

Author: (31) Allison J Rodger et al, 1999: The Impact of Diagnosis of Hepatitis C Virus on Quality of Life.

Hepatology Vol. 30, Nov., No. 5: pp. 1299-1301. QoL Study. Australia.

Methods: Thirty-four (34) patients with a past history of IDU who had been hospitalised 25 yrs previously with acute symptoms from an unknown viral hepatitis, and for whom frozen blood samples were still available, took part in this study. The patients were thought to be at high risk for HCV infection given

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their history. Testing of the frozen blood samples by anti-body and PCR tests was under-taken prior to initial interview where patients were assessed on a number of clinical measures including the SF-36, QoL questionnaire using Australian norms. Of the 34 people in this study, 15 (M=10, F=5; Mean age=44yrs) were already aware (Mean=2yrs.) of their HCV status. The other 19 (M=10, F=9: Mean age= 42yrs) were unaware of their HCV status at their first interview and were not informed until after they had completed an assessment on the SF36. People with a history of depression, or who had previously complained of fatigue or depression, were excluded from this study as well as anyone with signs of liver damage or another illness that might affect QoL. Scores on the SF36 for both groups were compared with those for the general population on all 8 scales.

Aim of Study: To assess the impact of HCV diagnosis on QoL in HCV infected patients. The authors do not state a hypothesis but if they had it would have been that they expected to find that those who already knew they had HCV infection would have significantly worse QoL scores compared to those that did not and that at least part of the difference is due to the effects of 'labelling'*.

Note: *Labelling is an attribution theory and its origins are Sociological. It was popular in the 1960s and 70s, its appeal waned in the 1980s – it has been used a great deal by criminologists to explain social attitudes towards crime. It was also used as a critique of, particularly, psychiatric diagnoses. The term now appears to have been adopted by medical researchers. The theory in essence is that people who are given a label by the society in which they live are likely to take on that label irrespective of whether the label was accurate in the first place. It is a descriptive rather than an explanatory theory.

Results: There were no associations between QoL scores for either group on any clinical measure e.g. ALT or cirrhosis. Scores on each of the 8 scales of the SF36 were compared, for both groups, to population norms. The group who were aware of their HCV diagnosis had significantly worse scores than the normal population on 7 of 8 scales of the SF36, whereas the unaware group were significantly worse only on 3 scales. This suggests that both groups have impaired QoL but that the unaware group are much less impaired than the aware group. The authors suggest that the impairment of QoL in the unaware group is probably due to a physiological effect related to the virus, and in the aware group the even higher level of impairment is due to the additional burden of being given an HCV diagnosis i.e. a psychological effect. Both groups had abnormal fatigue.

Commentary: This small, well-designed and excellently written study is unique and would be very difficult to replicate.

It was the first study to measure QoL in people who were unaware that they had been infected with HCV. The study was only made possible because of the availability of frozen blood samples taken 22 to 26 years previously from a group of people (mostly IDU’s) who had been hospitalized with an unknown viral hepatitis, and at the time of this study were considered to be at high risk for HCV infection. The authors of the study used this rare opportunity to measure QoL in these patients while they were still unaware of their diagnosis – the patients were told of there diagnosis only after having first completed the SF36, QoL questionnaire. The aim of the study was to measure the effect of an HCV diagnosis on QoL by comparing the QoL scores of the “unaware” group of patients with another patient group (from the same original sample) who had accidently discovered they were HCV positive i.e. the “aware” group. The authors predicted that any difference found in the QoL between these two groups would represent the effect of the diagnosis. However to compare these two groups it was essential first to compare both groups QoL scores with population norms to ensure that at least one of the groups had abnormal QoL before going on to compare the two groups directly with each other.

Unfortunately because of the small size of the study there was insufficient statistical power for the authors to do the final comparisons. The study found that both the “unaware” and the “aware” group had significantly abnormal SF-36 scores on three (3), out of eight (8) scales, the fatigue, mental health and general health scales, when compared with population norms. However, the “aware” group also had significantly abnormal results on an additional four (4) SF-36 scales, the role limitation-physical, role limitation-emotional, social functioning and bodily pain scales. Rodger’s interpretation of her results was that poor mental health and fatigue scores in the “unaware” group may be due to an unknown effect of the virus or due to the impact of an IDU lifestyle, but she asserts that “What is clear from this study is that patients who have been diagnosed with HCV have a global and significant reduction in QoL compared with individuals with chronic HCV who have not yet been diagnosed”. This statement would

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have been true only if both groups had been compared with each other and found to be significantly different, but there was no direct comparison between the two groups as other reviewers have asserted (Forman, 2000; Wessley & Pariante, 2002). This study hypothesized a psychological impact for diagnosis but didn’t measure psychopathology, only QoL – it essentially found an additive effect which might just as easily be ascribed to a reactive depression or anxiety, making concepts such as “labeling“ unnecessary. In its unfinished state the most important and undisputed evidence from this study is that the group who were unaware of their HCV status had significantly abnormal fatigue and mental health scores when compared to those for a normal population. This study is cited frequently in the forthcoming literature and has clearly affected the design of some studies. In the year following its publication Forman (2000) queried Rodger’s findings, stating that, on viewing a graph in her study, the evidence did not suggest any significant difference between the two groups on any of the eight (8) SF36 scales – a summary of Forman’s (2000) letter and Rodger’s (2000) reply are to be found in this review under the appropriate name and year. There is also a comparative summary of this study in the discussion. Finally, credit must be given where it is due – there were a great many look-back programmes inaugurated after 1995, but this is the only one whose authors had the perspicacity to use such an opportunity to its fullest advantage.

Author: (32) G R Foster et al, 1999: Hepatitis C virus infection: QOL and side effects of treatment. Journal of Hepatology. Vol. 31: (Suppl. 1): pp.250 – 254. QOL Study. U.K. In this, as in his previous article, Foster writes elegantly. The review is in four parts. The first part is a rationale for using QoL studies in HCV research and is similar to those of previous studies except for two points. Firstly, he mentions that other researchers have criticised QoL measures as being “illdefined” and “imprecise” but he asserts that they are nevertheless “robust and well-validated”, this however is not an answer to the question being asked which is - what do QoL questionnaires actually measure? He further argues that using tests that measure specific symptoms can lead to an “overestimation” of the importance of these symptoms to that specific disease; however that is surely a consequence of not using enough specific measures. If every symptom thought to be related to HCV was measured by a specific test at one assessment, assuming the study was well controlled, the results would be far more accurate in terms of the relative importance of each symptom - QoL measures like the SF-36 do not cover the full range of HCV symptoms. By 1999 all of the symptoms of HCV had been previously assessed, but not all of them in one study; it took until 2006 (Lang et al.) before someone became curious enough about the symptoms of HCV to do the first comprehensive survey.

Part two is a review of eight QoL studies. Foster, states that these studies have shown significant reductions of QoL in HCV patients that are not due to liver disease. He also notes that depression seems to be higher in HCV patients than in the general population and should be further investigated.

Part three is a more comprehensive review of individual studies, for example, Foster acknowledges the findings of Rodger et al. (1999), but notes the difficulty in replicating such a study. Part two also includes an examination of criteria for confirming a disease association. Foster argues that any study wishing to confirm an association between HCV and symptoms would need to meet the following criteria: A. Be a controlled study taking confounding variables into account and showing a significant increase in symptoms in patients with HCV when compared with a control group. B. Eradication of HCV (from interferon treatment) should lead to a “reversal” of symptoms. Final comments are that there is already evidence, primarily from the interferon trial reported by Bonkovsky et al., (1999), that significantly reduced QoL is associated with HCV infection. It would seem Foster assumed that all SVR’s in the study by Bonkovsky et al. (1999) were symptom free at follow-up. Although he cites Wollschlaeger et al., (1998) he does not explain why there was no reversal of symptoms in the PCR negative women in that study.

And he could not have foreseen a theory of HCV brain infection, which might explain the persistence of symptoms after successful interferon treatment. Part four is about symptoms caused by Interferon.

Author:

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(33) Elizabeth Kenny-Walsh et al, 1999: Clinical outcomes after hepatitis C infection from contaminated Anti-D immune globulin. The New England Journal of Medicine, April 22, pp. 1228-1233.

Natural History Study Ireland.

Methods: All of the women in this study were infected between 1977 and 1978, as a consequence of being injected with HCV contaminated anti-D immunoglobulin*, a prophylactic, which prevents rhesus disease of the foetus in pregnant women. The contamination and its consequences remained undetected until 1994 when the Irish Blood Transfusion Board started screening blood donors for HCV and found that a high proportion of HCV, PCR positive women had formerly received anti-D injections. A screening programme of all women who had been treated with anti-D was soon established; women found to be HCV positive were referred for further observation, and an expert group was created to investigate the source of contamination. In a report by the expert group in 1995, a total of 62,667 women had been screened (estimated to be 94% of all anti-D recipients); of those, a total of 704 were found to be HCV antibody positive and of those 390 were also HCV PCR positive; the source of contamination was found to be from a single donor whose blood had been used to manufacture the anti D immunoglobulin preparation. In 1996 the Irish government set up a tribunal of inquiry and a compensation tribunal (no details of compensation criteria). This incident received a great deal of sensational and negative publicity in the Irish media. The present study examined 376 women (Mean age=45 yrs.), of the 390 found by the screening programme to be HCV positive -14 women declined to take part in the study. All women received a full medical examination as well as assessments of ALT, genotype, and liver histology (e.g. fibrosis, cirrhosis). Symptoms e.g. fatigue, arthralgia/myalgia, depression/anxiety, upper right quadrant pain and skin rashes were also assessed, but there are no details of how that was done, they are reported only as prevalence rates. The study did not include a normal control group. * It destroys antibodies in the mother, which are likely to attack the red blood cells of the unborn foetus.

Aim of Study: To assess clinical outcomes of a group of women who had been infected with HCV for 17* years. * At time assessment was made.

Results: 304 women (81%) reported one or more symptoms; fatigue 66%, arthralgia or myalgia 38%, anxiety/depression 16%, right upper quadrant pain 6%, rashes 5%. All women had either 1a or 1b HCV genotype. About half the women had fibrosis and only 7 (2%) had probable or definite cirrhosis Commentary: This is the first full text natural history study of the Irish anti-D women's group– an abstract had been published three years earlier (Crowe et al., 1996). The article is well written and has an excellent discussion. Although the events surrounding this study are unique it is not the only study of women who have been accidentally infected with HCV from contaminated anti-D injections - a similar out break took place at around the same time in the former GDR, it was however quickly detected (Weisse et al., 2004). The importance of these studies is in the rare opportunity provided to study a group of women who were all infected at the same time, with the same genotype, at a similar age, all in good health at time of infection and with few other risk factors. In most HCV studies the time of infection and sometimes the method of infection cannot be accurately assessed; genotype, age, method of infection and severity of liver damage are often mixed. When these variables are not taken into account they are referred to as “confounding variables” as they tend to distort outcomes, making the study results difficult or impossible to interpret. In the anti-D studies there are few confounding variables except the possibility of a negative reaction to being given a diagnosis with HCV, which might affect subjective (e.g. fatigue or depression), but not objective (e.g. fibrosis or cirrhosis) symptoms. The author of this study argues that the very low prevalence rate for cirrhosis that she found may reflect the very small amount of virus anti-D recipients are likely to be exposed to as compared with posttransfusion or IDU patients at time of infection. She also states that symptoms such as fatigue may have been influenced by negative publicity at the tim e the women were screened, but since she had no control group she cannot say how they are related to HCV infection. Both this study and its German counterpart reported subjective symptoms, but not how they were assessed and neither included a

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control group. However, in both studies the prevalence rate for fatigue was similar – around 60%, which is consistent with fatigue rates for other methods of infection e.g. post-transfusion and IDU, reported by other studies in this review.

Author: (34) E Anthony Jones, July 1999: Relief from profound fatigue associated with chronic liver disease by long-term ondansetron therapy. The Lancet, July 31st, Vol. 354, p. 397. Review of fatigue/report of single case Treatment Study. Holland.

Methods: This was a single case study of a woman with chronic HCV and profound fatigue. She was allocated to a double blind trial of 4 wks of 12mg daily ondansetron and 4 wks of placebo tablet .

Aim of Study: To investigate whether ondansetron (a drug which alters serotonin levels in the brain) is effective in the treatment of fatigue in a woman with chronic HCV and profound fatigue.

Results: For the first 4 weeks of placebo there was no change in the patients level of fatigue. In the 2nd fourweek period (ondansetron) her fatigue subsided. At the end of the trial when the ondansetron was ceased, her symptoms returned. Eventually she was treated long term on 8mg of ondansetron. The author notes that the patient’s symptoms would return within 24 hours of ceasing the drug.

Commentary: If part or all of the mechanism of fatigue is of central origin (i.e. in the brain and spinal chord) as opposed to being of peripheral origin (i.e. in the muscles) it must involve neurotransmitters. If neurotransmitters are involved in fatigue, then serotonin is the one most likely to be implicated since it is known to influence the sleep/wake cycle, mood and appetite. Two studies, one in rats the other in humans have shown that when serotonin levels are artificially increased by administration of SSRI antidepressants, the rats appear fatigued and humans have a marked reduction in physical endurance on a bicycle test. It follows then that if the amount of serotonin in the brain could be reduced this might result in the improvement or loss of fatigue. Such is the reasoning underpinning this single case study. Odansetron* is a 5 HT –type 3 serotonin receptor antagonist – it blocks serotonin at receptor sites. Ondansetron has been used for more than 20 years to control nausea and vomiting induced by chemotherapy. However, until this study no one seems to have considered using it to treat fatigue – in any disease. Single case studies usually do not carry much weight as evidence, but this study was different, its author was not just testing the benefits of a fatigue treatment but attempting to validate a very attractive theory – one which would become predominant 10 years later as part of the “Trojan Horse” theory of HCV brain infection. Jones published another 3 articles after this one, each of them explaining the possible role of serotonin in the mechanism of fatigue and also describing the results of this single case study. He also appealed to other researchers to replicate his findings using well-controlled ondansetron trials. In 2005, Piche et al., obliged him by conducting a randomised double blind placebo control trial of ondansetron in fatigued HCV infected patients. This article is frequently cited and ondansetron has been used in the treatment of fatigue in other illnesses. * Ondansetron has reduced in price in the last few years but it is still a very expensive drug.

Author: (35) A Barkhuizen et al, May 1999: Musculoskeletal pain and fatigue are associated with chronic hepatitis C. The American Journal of Gastroenterology, Vol 94; No. 5: p. A601. Prevalence Study.

U.S.A. Methods:

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There were 239 patients (mean age=47 years, M=52%) in this study, the total sample seen at a hepatology clinic over a period of seven months. Forty-four (18%) patients had HCV infection without another liver disease, 77(38%) had HCV infection plus another liver disease (5 are listed), mostly alcoholic liver disease and HBV. The remaining 50% of patients had other liver diseases (17 are listed), without having HCV and they were also mainly patients with alcoholic liver disease or HBV. Route of transmission was mostly IDU, followed by blood transfusion or unknown. Details of diagnosis of liver disease, liver histology (e.g. fibrosis, cirrhosis) and biochemical (e.g. ALT) results were based on evaluation of patients’ hospital records. All patients completed a questionnaire* that asked about “excessive fatigue” and bodily pain – they were also given a body pain diagram and asked to locate areas of pain. The statistics reported in this study are given as simple prevalence rates. Statistical comparisons of fatigue and musculo-skeletal pain were made between the following groups: HCV and HCV + another liver disease vs. all other liver diseases, HCV alone vs. alcoholic liver disease alone and HBV alone. Similar comparisons were made for route of transmission and current or past interferon treatment. *There are no details of these measures; they seem to be self-devised.

Aim of Study: “ The aim of this study was to identify the frequency of fatigue and musculoskeletal pain in hepatitis C compared with other liver diseases”.

Results: The authors found that in the presence of HCV either alone or including another illness i.e. Hepatitis B and/or alcoholic liver disease, there was a much greater association with fatigue and musculoskeletal pain than in those who had other liver diseases. For the 44 people who could be isolated as having only HCV, 91% reported musculoskeletal pain, 66% excessive fatigue and 27% diffuse pain. There was no association between fatigue or bodily pain and severity of liver disease, route of infection, or past or current interferon treatment.

Commentary: The hypothesis in this study was developed from three strands of evidence. The first is that HCV RNA is located in many parts of the body. The second, is that patients with HCV infection often meet many but not a sufficient number of the criteria to meet the diagnosis of an autoimmune disease especially cryoglobulinemia suggesting the presence of subthreshold autoimmune disorder. Thirdly, no study has so far been able to show an association between “full-blown” autoimmune disorder and HCV. The authors of this study argue that when all the evidence is taken together it is plausible that HCV infected patients will experience one or more autoimmune symptoms without experiencing the full range of symptoms. In this study the authors were particularly interested in assessing the prevalence rates of fatigue and musculo-skeletal pain; the latter being indicative of rheumatoid arthritic symptoms, such as myalgias (muscle pain) and arthralgias (joint pain). Their study shows that significantly more HCV patients, about twice as many, had fatigue and bodily pain, when compared with most other liver diseases. As well, having another liver disease plus HCV infection did not increase the prevalence rate.

In this study both fatigue and muscle and joint pain appear to have been measured on author-devised rather than standardised tests; there were no measures of cryoglobulins or immune factors; very few demographic details about the HCV group; no measure of depression and no normal control group.

However it should be noted that the study was based on initial data from an ongoing prospective study (although none has so far been forthcoming) and that the data by the authors own admission is by no means complete.

2000 (6 studies) Author: (36) Meagan M Dwight, 2000: Depression, fatigue & functional disability in patients with chronic hepatitis C Journal of Psychosomatic Research, Vol. 49, pp. 311-317. U.S.A. Methods:

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Fifty patients (Male=58%; Mean age=45yrs) with chronic HCV attending a tertiary care clinic were assessed for: psychiatric symptoms (depression, anxiety, panic disorder, somatization disorder, drug and alcohol abuse/dependence) using DSM IV* diagnostic criteria and the Beck depression inventory (BDI); hepatic disease severity (cirrhosis, fibrosis, liver inflammation, ALT and AST) using serology and biopsy results; fatigue, using the multiple assessment of fatigue (MAF) questionnaire; QoL using the SF36; and severity of co-morbid illness using the Duke Severity of Illness Scale. Based on the diagnosis of depression the 50 patients were divided into two groups, a depressed group (N=14) vs. a nondepressed group (N=36) and scores on each of the above mentioned variables for both groups were statistically compared. In order to determine which of these variables was the best predictor of fatigue or functional disability, both multiple and individual regression analyses were performed. Patients who were in the final stage of a terminal illness or had psychosis, mania, encephalopathy or dementia were excluded from the study. There are no details of mode of infection but due to comments in the discussion we can assume that most were IDU’s. *Diagnostic and Statistical Manual IV. The manual contains internationally accepted criteria for the diagnosis of all psychiatric illness.

Aim of Study: “To assess the extent to which fatigue and functional disability correlate with severity of depressive symptoms in patients with chronic hepatitis C”.

Results: 14 of the 50 patients (28%) had current depressive disorders – most of them had only mild fatigue when measured on the BDI. When this group was compared with the non-depressed group they had significantly more depression. When both groups were compared on all outcome variables there was no difference between the depressed and non-depressed patients on the following: MAF, SF-36, cirrhosis, fibrosis, liver inflammation, ALT, AST, severity of co-morbid illness, current treatment with interferon, drug or alcohol abuse/dependence and demographics (e.g. age, gender). Only functional disability (e.g. reduction in daily activities) due to fatigue as measured by the fatigue interference subscale of the MAF, and the number of somatic (medically unexplained) symptoms were significantly higher in the depressed group. The relationship between depression, fatigue and functional disability (in this analysis SF-36 scores) were further examined using regression analyses. Depression was significantly, and highly correlated with fatigue (i.e. best predictor). The amount of variance (overlap) in fatigue scores explained by the severity of depression scores was 31.4% - in other words about one third of the increase in the severity of fatigue was attributable to depression. Fatigue did not correlate with any other variable. Depression was also significantly correlated with three SF-36 Scales i.e. physical functioning (PF), vitality (VT), and general health perceptions (GH).

Commentary: The results of this study confirm those of two previous studies, Mahl et al. (1996) and Nelles et al.

(1996), which also found highly significant correlations between depression and fatigue. However, the main impetus for this study comes from much more widely based evidence from research in other illnesses, which has shown that depression amplifies already existing symptoms. The authors investigated whether this is also the case in HCV infected patients who had fatigue, and found the same results – as depression increased so did fatigue. However, the influence of depression on fatigue scores only explained 30% of the variance in fatigue, which indicates that other unknown variables – the remaining 70% - are somehow involved in fatigue severity. The authors recommend clinical treatment trials of antidepressants in order to reduce fatigue severity and improve functional disability in HCV infected patients; they cite evidence for the effectiveness of such treatment in other illnesses. This study did not exclude potential confounding variables such as, current interferon treatment, instead it included them, measured and statistically controlled for their confounding effects. The prevalence rates for a lifelong history of any psychiatric illness, or any depressive illness were high in this study 82% and 44% respectively; this was also the case for lifelong histories of: alcohol abuse/dependence (56%) and drug abuse/dependence (46%). The authors’ claim that such high levels of psychopathology are typical of patients seen in tertiary care settings and because of this and the small and preliminary nature of the study their results may not be representative of the larger population of HCV infected patients seen at primary care units or in community settings. That the study found fatigue and depression to be highly correlated is not a surprising result as fatigue is a common symptom of depression: Lee et al. (1997) have described the relationship as a “co-dependent” one. What is surprising is the paucity of studies,

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which have sought to rigorously examine this relationship. This is the only study in this review to have diagnosed depression and other psychopathology using DSM IV criteria as well as using a standardized depression test.

In 2003, Mc Donald et al. would take another look at this relationship. To date, there have been no trials of antidepressants as a treatment for fatigue in HCV infected patients.

Author: (37) Forman, L. et al., 2000: The Impact of Diagnosis of Hepatitis C Virus on Quality of Life.

Hepatology, April 2000. Letter to the Editor. p. 1029. Knowledge of diagnosis/QOL. U.S.A. This is a letter to the editor from Forman et al querying the results of Rodger’s (1999) well known controversial study. That study examined whether a significant proportion of the reduction in QoL seen in previous HCV studies is due to the negative psychological impact of being diagnosed with HCV. Rodger compared the SF-36 scores of people who knew their HCV diagnosis with those who were unaware that they were infected. She found that those who knew their diagnosis had significantly lower scores on seven out of eight SF-36 scales as opposed to only three scales in the “unaware” group when both group’s scores were compared with those of SF-36 general population norms. All of the participants in that study were former IDU’s who 25 years previously were hospitalized with an unidentified acute viral hepatic infection and their frozen sera from that time had become the focus of a Look-Back programme. The study is unique and can only ever be partly replicated. Forman’s queries are methodological and are mostly about, control of confounding variables, group size and significance, group comparison and significance. She begins by saying that there is insufficient information about demographics in Rodger’s study especially about recruitment and possible differences between those who chose to take part in the study and those who refused. She mentions a number of possible confounding variables which may not have been controlled for including co-infection with HIV, mild undetected symptoms, level of medical care, education level and alcohol consumption. Forman questions whether the group was representative because it was so small. She also queries whether the two groups were significantly different* from each other stating that the SF36 means given in Rodger’s study do not suggest a significant difference**. She ends her letter with a request that the previous unaware group, now aware, be followed up to monitor their QoL. *Rodger only compared the SF-36 scores of each group with general population norms and not with each other –this was due to a lack of statistical power. ** We came to the same conclusion as Forman – the means did not look very different.

Author: (38) Rodger et al, 2000: The Impact of Diagnosis of Hepatitis C Virus on Quality of Life. Hepatology, April 2000. Letter to the Editor. pp. 1029-1030. Knowledge of diagnosis/QoL. Australia.

In Rodger’s (2000) reply she responds to Forman’s (2000) queries by answering each one in the same order that they appeared in Forman’s letter. Questions of small group size, bias, chance results and possible confounding variables are all convincingly refuted by Rodger. The majority of Forman’s queries appear disingenuous as the answer to most of them was evident in Rodger’s (1999) original study and those which were not e.g. on statistical issues, might easily have been answered by a hospital statistician. It is perhaps not surprising then that she kept her most incisive query to the last – Rodger’s failure to statistically compare each of the eight scales of the SF-36, of both the “Aware” and “Unaware” groups with each other. Forman’s final query relates to a graph in Rodger’s study, which compares the means of each SF-36 scale, for the “Aware” and “Unaware” groups as well as those for the normal population. The essence of Forman’s letter and Rodger’s reply are perfectly contained in the following two quotations: “….the investigators purport to find a difference between the two groups of HCV patients. They do not present a comparison to substantiate this claim. On review of Fig.1 in their article, there is a suggestion that the SF -36 results for the two groups may not be significantly different”. (Forman, 2000) Rodger’s reply was:

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“…. On direct comparison significantly worse scores were seen for general health and social functioning (P< .05) in those aware of their serostatus compared with those unaware. Direct group comparisons, therefore, do not abolish differences between the two groups. (Rodger, 2000) Rodger goes on to say that the evidence from her study showed a potential causal effect for the impact of knowledge of diagnosis on QoL. However, Rodger does not interpret her post-hoc analysis (an analysis done after the study is complete and usually not reported) by explaining why only two scales, one measuring perceived functional ability, the other general health perceptions, were significantly different between the two groups while there were no differences on any of the symptom scales. We have spent a great deal of the readers time attempting to explain Rodger’s (1999) study – we have done so because it is has not been discussed at length, it has had a strong influence on other research, and it is easy to misinterpret and therefore misrepresent. The study has been cited by almost every study of symptoms in HCV since it was first published. Some studies in this review have sought to get around the problem of knowledge of diagnosis; by excluding psychopathology (Hassoun, 2002; Ahboucha, 2008); by explaining it away (Poynard, 2002; Miller, 2003), but most have ignored it. Only one study, albeit succinctly, put it in what we consider to be its proper perspective. Weissenborn (2006), comparing her own results with those of Roger (1999) wrote: “Patients scored significantly worse than healthy controls in the FIS, HADS, and SF-36. As these measures rely on self-report, the abnormal findings could result from anxiety due to knowledge of the infection rather than somatic alterations. However, a study analyzing HCV positive patients unaware of their diagnosis also found them to be impaired compared with HCV negative controls.”* (Weissenborn, 2006). * She means with population norms, not with people who have cleared the virus.

Author: (39) Gershon et al, 2000: "Serum cytokines values and fatigue in chronic hepatitis C infection" Journal of Viral Hepatitis, Vol. 7, pp. 397-402. Experimental Study. Canada.

Methods: The study examined the medical records of more than1000 HCV patients seen during a four-month period at a hepatology clinic. Exclusion criteria were unusually rigorous – anyone who had another illness or was taking medication or recreational drugs that might cause fatigue and/or fluctuations in cytokine levels was not admitted to the study. All but 149 patients were excluded; of those, sixty-two patients, for a variety of reasons, were not able to participate. The study finally examined 87 (around 9%) HCV infected patients (Mean age=46.3 yrs.; Male =62%) to create as the authors state a very “pure” population. A healthy control group (N=35) was included in the study. Fatigue was assessed using the fatigue assessment instrument (FAI). Severe/disabling fatigue was associated with an FAI score of > 4. Blood levels of cytokines, interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor (TNF) were assayed for both patients and controls. Cytokine levels more than 2 standard deviations above or below the mean for the control group were considered abnormal. The fatigue scores from the FAI were compared between those who had abnormal and those who had normal cytokine levels.

Aim of Study: The aim of our study was to examine whether there was an association between abnormal serum cytokine levels and fatigue in patients with compensated chronic hepatitis C”.

Results: Results showed that 19 (24%) of patients had abnormal elevations in IL-1, 24 (30%) abnormal elevations in IL-6, and 45 (56%) abnormal elevations in TNF, compared with only 2(6%) of healthy controls who had abnormal levels in one or more of those three cytokines. The study also found that 35 (45%)* of 78 HCV infected patients had a fatigue severity score of more than (> 4) on the FAI indicating severe clinical fatigue. When the FAI scores for those with abnormal cytokine levels were compared with those who had normal cytokine levels, no significant difference was found.

39

*The actual number of fatigued people in this study was 54 (70%), but 19(25%) had fatigue below an FAI score of four (< 4).

Commentary: This study is the first to examine the relationship between cytokines and fatigue in HCV infected patients. Cytokines* are blood borne immune messenger cells that communicate with both the brain and immune cells and play a role in coordinating the latter in response to infection. In the cytokine theory used in this study – the neuroendocrine hypothesis (Anisman et al., 1996) - cytokines are thought to act on the hypothalamic, pituitary, adrenal (HPA) axis activating the production of corticotropin releasing hormone eventually resulting in the release of cortisol from the adrenal gland which is then suppressed by the HPA axis - the final result being the onset of “illness behaviours” (i.e. such as fatigue, low mood, sleep disturbance and other symptoms (Anisman et al., 1996; Swain, 2000) Because this study found no relationship between abnormal cytokine levels and fatigue, it must be assumed that the fatigue found in HCV infected patients is due to some other cause -that at least is the view of the authors. They suggest, alternatively that it is also possible that cytokines may have a direct affect on the brain, in which case cytokine levels in the brain may be different to those found in the blood – this is different from the “Trojan Horse” theory of HCV brain infection later described by Forton et al. (2001, 2002), and Weissenborn et al. (2004, 2006 and 2009). However, this study was concerned only with examining the cytokine/corticotropin theory. The authors’ final conclusion is that depression and disordered sleep patterns rather than elevated blood cytokines may be a sufficient explanation for the cause of fatigue in HCV infected patients. In a previous study (Nelles et al., 1996) two researchers from this group found that both depression and disordered sleep correlated with fatigue. It seems surprising then, given their efforts to create a “pure” study population that they did not consider measuring both variables in this study – there is no evidence that they excluded them – antidepressants were only excluded, it seems, because they alter cytokine levels. It would appear that all patients had only mild liver disease, but no details are reported e.g. fibrosis scores, only ALT scores are reported, which at the time of the study was known to be a poor measure of the severity of liver disease. However these are minor criticisms - it was a very good study. * Interferon is a cytokine, but of a different type from those being investigated here. However, elevated interferon levels are also known to activate the HPA axis and treatment with interferon is known to cause a similar spectrum of symptoms.

Author: (40) L Kleinman et al, 2000: Psychometric evaluation of the fatigue severity scale for use in chronic hepatitis C. Quality of Life Research, Vol. 9, pp. 499-508. Validation Study. U.S.A. Methods: Using pooled data from three large interferon trials conducted in 11 different countries, 1225 interferon candidates (Male=69.4%, Mean age=45) were assessed on both the fatigue severity scale (FSS) and the SF-36 prior to commencement of treatment. This was not an outcome study, patients were assessed only twice: a few weeks before baseline and at baseline itself (day 1 of treatment). The FSS was then analysed for its psychometric properties and its scores compared to those of the SF36 for further validation. 32% of patients were cirrhotic. FSS scores were also compared between cirrhotic vs. non-cirrhotic, as well as ALT levels, viral load and liver inflammation scores. Patients with other liver disease or major illness, previous interferon treatment, pregnancy, or drug use (within one year) were excluded from these trials.

Aim of Study: To evaluate the psychometric properties of the Fatigue Severity Scale (FSS).

Results: The FSS was found to have excellent psychometric properties - Item performance and scaling characteristics, internal consistency and test-retest reliability. It was also found to correlate significantly with scores on the SF36 especially with the "Vitality" scale (a measure of fatigue). The authors found a significant correlation between FSS scores and cirrhosis and liver inflammation, but they were weak.

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No significant correlations were found between FSS scores and ALT levels, liver inflammation scores, or viral load. Compared to population norms the mean score on the FSS was higher (worse) for HCV infected patients, but the authors do not say whether it was a significant difference. When SF-36 scores for all HCV infected patients were compared with those for population norms, seven scales were significantly lower (worse), the single exception was the SF-36 “pain” scale.

Commentary: The authors of this study state that they wanted to find a fatigue measure (a brief one) to augment QoL measures, such as the SF-36, that had been previously used in interferon trials. They argue, persuasively, that consistent evidence shows very high prevalence rates (> 60%) for fatigue in HCV infected patients, but generic tests such as the SF-36 do not provide specific information about fatigue.

It seems that their decision to include the FSS in the three trials was a last minute one – and a fortunate one. The psychometric properties of the FSS were excellent. The study was not an outcome study, so they did not have a chance to test whether the FSS was sensitive enough to detect changes in fatigue over a longer period. It is not clear why they validated the results of the FSS, a specific measure of fatigue against the “vitality” scale of the FS-36 – a generic measure of fatigue. A comparison of the FSS with another validated fatigue measure e.g. the FIS, MAF or FAI would have been more reassuring.

Also in this study, there were no statistical comparisons between HCV patient scores on the FSS, and population norms, however, these comparisons (HCV vs. pop norms) were made for the SF-36 and the Vitality (fatigue) scale was significantly lower in HCV patients. After more than a decade of assessing fatigue in HCV infected interferon candidates it seemed at last that fatigue was being taken more seriously by those who conduct interferon trials, this study certainly seemed to indicate that: however, it was not to last. All previous QoL studies of data from HCV interferon trials (with only one exception) had been either conducted or funded by the same drug company who favoured the SF-36 as a symptom measure – the present study was funded by their competitor. A few months after this study was published, another interferon trial (Cotler et al., 2000), jointly funded by both companies, measured fatigue before and during treatment. Instead of using the SF-36, with additional scales, the FSS, or even both, a simple four-point severity scale adapted from the WHO grading system for symptoms was used – perhaps it was a compromise reached after failing to agree on whose measure of fatigue should be used. In the following decade HCV fatigue studies of interferon candidates would eventually all but disappear, we are not sure why, and with them the chances to, without much extra effort, develop better measures of all the symptoms of HCV.

Author: (41) Cotler, S.J. et al., 2000: Pre-treatment symptoms and dosing regimen predict side effects of interferon therapy for Hepatitis-C. Journal of Viral Hepatitis, 2000, Vol.7, pp. 211-217.

Interferon/adverse effects study. USA. Methods: Patients were 222 with chronic HCV who were enrolled in a 6-month interferon treatment trial. 120 patients were from the USA, and 102 France. (F=76, Mean age=44), (M= 144, Mean age=41). Patients were randomly assigned to either a control group or a dose intensification group. The control group were treated with 3 MU of Interferon t.i.w. (Three times a week) for the entire duration of the six month study. The dose intensification group was divided into two further groups, the first group received 3MU of Interferon t.i.w. (The same dosage as the control group) and the second group received 5 MU of interferon t.i.w. However after 3 months those patients in either of the dose intensification groups who did not show a significant viral response to treatment had the frequency of their dosing regimen increased from t.i.w. to daily dosing for the remaining 3 months of the study. All patients were assessed at baseline and at six months for fatigue, malaise, myalgia, arthralgia, depression and a number of other symptoms using a modified World Health Organization grading scheme i.e. none, mild, moderate (disabling), severe (disabling). Participants were also asked about source of infection (IDU in 50%) and alcohol status. Cirrhosis was more common in the U.S group (22%) as compared to the French group (1%). Statistical comparisons were made between symptom scores and other variables. Results are given as prevalence rates and correlations.

Aim of Study:

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“….to evaluate symptoms in patients with chronic hepatitis C and to identify factors that might predict development of debilitating IFN side-effects”. They also wanted to investigate daily dosing on interferon might be better tolerated than three times a week dosing.

Results: Comparison of baseline data for debilitating symptoms with that of end of treatment symptoms showed significant increases as a result of treatment for most symptoms e.g. fatigue was 25% at baseline and 38% after 6 months interferon treatment. Generally it was found that an increase in the amount of interferon and number of doses given per week are significantly related to an increase in fatigue and other symptoms. A regression analysis showed that moderate or severe fatigue at 6 months of interferon treatment can be predicted by the presence of fatigue before treatment; higher dosing in the last three months of treatment; and past history of IDU. There was a gender and national difference with US females having significantly worse debilitating arthralgia at 6 months of treatment than the French group. Finally there were no significant differences in fatigue scores between those who cleared the virus and those who did not.

Commentary: The purpose of this study was to generate information that would allow researchers to predict, before treatment with interferon, those patients who were likely to withdraw from interferon treatment due to the development of intolerable symptoms. From the beginning of treatment to the end, at 6 months, the number of patients with moderate/severe fatigue increased by 13%, from 25% to 38% - all of the 13% had only mild fatigue when measured at baseline. The study used modified world health organization (WHO) grading scheme criteria, normally used only for classification, as a method of assessing disabling symptoms: which resulted in a very simple 4 item scale for each symptom e.g. (1. No fatigue; (2. Fatigue, but no reduction in daily functioning; (3. Fatigue with moderate reduction in daily functioning; (4. Fatigue with severe reduction in daily functioning. Similar measures of fatigue have been used by other studies in this review (Hoofnagle et al., 1997: Poynard et al., 2002), but how valid and reliable they are is difficult to say – most experts on the measurement of fatigue recommend the use of multi dimensional measures of fatigue as opposed to a uni-dimensional measure such as the one used in this study. The measuring of depression with such a simple scale is clearly inadequate and probably explains why the study found such a low prevalence rate of only 2% at baseline. The authors state that no significant differences in symptom scores were found between those who cleared the virus and those who did not. However, improvements in symptoms due to interferon treatment may not be evident until many months after treatment.

Author: (42) Wolf, D. C. et al, 2000: Ritalin improves chronic fatigue symptoms in patients with cirrhosis. st American Journal of Gastroenterology. Abstract, Volume 95, Number 9, 1 . September 2000: p. 2523.

Fatigue Treatment Study. U.S.A. Methods: This was a small treatment study total N = 15. Patients were (no demographics), 12 with HCV (1 chronic, 11 cirrhosis), two with primary biliary cirrhosis (PBC) and one with alcoholic cirrhosis. Patients were treated with Ritalin (methylphenidate hydrochloride) a neuro-stimulant, 10-20 mgs once or twice a day for 5 days with a 2-day break (to avoid dependence) each week for periods up to 24 months (median 6 months). Four patients were treated with Ritalin for 18 months or longer. Five patients were treated concurrently with an anti-depressant and five with lactulose (for encephalitis). A questionnaire was used to assess fatigue (no details).

Aim of Study: To assess whether long-term treatment with Ritalin reduces fatigue in HCV infected patients with cirrhosis.

Results: Fatigue relief was mild in 27% of patients, moderate in 53% and high in 20%. There was a reduction in the need to take naps (73%) improvement in performing household chores (67%) and improvement in

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family interactions (55%). The authors conclude that Ritalin can be safely and effectively used to reduce fatigue in HCV patients (chronic & cirrhotic) for up to two years – no one in the study developed drug dependence. They also suggest augmenting Ritalin use with physical and nutritional therapy.

Commentary: This is the second treatment study of fatigue in HCV infected patients - it was published only as an abstract. It was unfortunately very small only having 12 patients with HCV. It is difficult to interpret because there are no details about the measurement of fatigue or a baseline assessment to compare improvement against, and it had no control group. Nearly all patients had cirrhosis and were being treated with either antidepressants or a drug that reduces the symptoms of encephalitis – both may influence fatigue. Neuro-stimulants like Ritalin, because they produce drug dependency over time may not be an ideal treatment for fatigue in HCV infected patients.

First Eleven Years of Fatigue Research in HCV Infection (Dec.1989 – Dec. 2000): Results, Discussion, Summary & Conclusions In the first five years of this review from December 1989 to the end of 1995 only five studies examined HCV infection and fatigue; the interferon trial by Davis et al., and four natural history studies. These studies were mostly concerned with the level of liver disease in HCV. To a lesser degree they examined subjective symptoms including fatigue where the focus was more on the frequency than quality of symptoms i.e. data is limited to prevalence rates. Of note is that in these early studies standardized measures were not used to assess symptoms. Taken together these early findings revealed that fatigue had the highest prevalence rate of any subjective symptom followed by psychiatric symptoms such as depression and anxiety and then physical symptoms such as nausea, itching and pain.

The realisation that the symptoms of patients with liver disease and by extension those with HCV might be better studied if adequate measures were employed has been a consistent criticism of research in this field since Desmet et al. drew attention to this limitation in 1994. Although subsequent studies have employed more robust instruments this criticism remains relevant to this day. Several explanations have been given for the lack of adequate symptom studies in HCV infection. These include: that subjective symptoms are difficult to measure; that the early findings from studies of Non-A/Non-B hepatitis patients, which were later re-diagnosed as HCV, indicated an asymptomatic course of illness; and the devaluing of subjective complaints in medical research. Despite these reservations it is evident that researchers have taken an interest in HCV symptoms with the frequency of publications increasing substantially from 1996. A further explanation for the increased interest in HCV symptoms may be the advent of PCR testing in 1995 allowing for HCV status to be ascertained and this patient group to be more clearly defined.

In assembling the articles for this review we sourced all the publications from peer reviewed publications that examined fatigue and HCV. We identified 43 articles published between 1989 and 2000. The majority of these studies (33) examined HCV infected patients, the remainder were reviews or commentaries. Of the 33 research studies only 12 specifically focused on fatigue and included the word ‘fatigue’ in their title or abstract. The remaining 21 studies included fatigue data secondary to the main focus of the study especially in conjunction with an assessment of quality-of-life (QoL). Given these differing focuses we divided the studies into three categories for discussion: A) Fatigue as a secondary focus: i.e. studies, which, looked at fatigue and other symptoms, but where fatigue was not the main focus.

B) Fatigue and QoL: i.e. QoL studies (all used the SF-36), which reported results of the SF-36 Vitality (fatigue) scale.

C) Fatigue as a primary focus: i.e. studies with the word “fatigue” in their title, or in which, fatigue was of central focus and with which all other variables were compared.

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The first category consisted of 11 studies (this includes the 5 studies conducted before 1996). All these studies report fatigue prevalence rates but no other details (See Table A below). Interpreting these results are complicated by the lack of details in some studies on how fatigue was assessed and the different criteria used to classify fatigue. As can be seen in Table A, prevalence rates for fatigue varied from 25 - 77%. Of note is that all these studies report a higher than expected frequency of fatigue with six studies reporting a prevalence of more than 60%.

Table A. Fatigue prevalence rates from studies where fatigue was not of central focus.

Year /Author

% With Fatigue

Comment

1989 Davis et al.

77

Used untreated HCV controls

1993 Merican et al.

35

1995 Shakil et al.

61

1995 Tong et al.

67

1996 Tong et al.

63

1996(A) Crowe et al.

26

A=abstract

1997 Hoofnagle

62

70% Fatigue in control group

1997 Lee et al.

45

1998 Sladden et al.

45

1999 Kenny-Walsh et al.

66

2000 Cotler et al.

25

Unsurprisingly the 11 fatigue prevalence studies tell us little about fatigue severity. Only two included a control group. Davis et al. compared untreated and treated HCV patients, both had similar prevalence rates at baseline. In a brief report Hoofnagle (1997) compared HCV patients (blood donors detected through screening) and healthy blood donor controls and unexpectedly found higher fatigue in healthy blood donors (62% and 70% respectively). However, as discussed by Hassoun et al (2002) although severity was collected (4-point scale; 0 = not at all to 4 = severe) the results were not fully reported and that while the prevalence of fatigue may be lower it remains possible that they had higher fatigue severity scores and were therefore more disabled by the burden of fatigue. It is also possible that the blood donor group may have been an atypical subpopulation and not typical healthy controls. Problems in interpretation such as this are less likely to arise when standardised multi-dimensional fatigue measures are used. This has been the case in subsequent studies with the majority using the Fatigue Impact Scale (FIS). Overall studies in this category indicate high prevalence rates for fatigue in HCV patients, much higher than might be expected in a healthy population, but how many of these patients had disabling fatigue is unknown.

The second group of studies, 10 in all (See Table B), used a quality of life measure (QoL), the SF-36, which has three symptom scales: fatigue, mental health and pain, as well as 5 other scales measuring the disability arising from those three symptoms, giving a total number of eight scales. Five studies used only the SF-36 and five used the SF-36, with additional QoL scales that were especially created to be â&#x20AC;&#x153;hepatitis C specificâ&#x20AC;? (up to 9 extra scales were constructed in some studies). Two of the latter studies were questionnaire validation studies (Carithers et al,. 1996; Bayliss et al., 1998) and three examined QoL before and six months after interferon treatment (Bonkovsky et al., 1999; Neary et al., 1999; Dale et al., 1999). All five of the extended SF-36 studies report that compared with SF-36 U.S. population norms the HCV infected patients prior to treatment had significantly higher fatigue and lower QoL. The three interferon trial studies all showed that most of the standard SF-36 and several additional QoL scales significantly improved post-treatment in patients who had cleared the virus compared with those who did not. In sum, fatigue was significantly reduced in those patients who responded to treatment.

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However although interferon quite clearly improved the symptoms and disabilities of the HCV infected patients they did not return them to normal levels.

Five QoL studies only collected standard SF-36 scales scores. The study by Hunt et al., (1997), was the first published interferon outcome trial to use the SF-36 and the only SF-36 study in the first ten years of this review to report no significant differences between the baseline SF-36 scales scores of HCV infected patients and those for U.S. population norms including the SF-36 Vitality (fatigue) scale. The same study, however, did find that 30% of HCV patients had mild depression (Beck Depression Inventory) and 25% had anxiety (Hospital Anxiety and Depression Scale) at baseline. Of note is that the frequency of depression and anxiety remained unchanged six months after treatment. Hunt’s study examined 38 patients and the failure to find any treatment gains may be explained by the small subject numbers.

Table B. Summary data from QOL studies using the SF-36 Vitality Scale.

Article (Author & Date)

Measure

Nß Index

Mean (SD) Control

Index

Comment Control

Carithers et al. (1996)

SF36 VT scale

157

PN

53* (NR)

72*(NR)

*Estimate from graph

Hunt et al. (1997) INT.

SF36 VT scale

38

PN

50* (35-60)

65*(50-75)

* Non-significant difference

Foster et al. (1998)

SF36 VT scale

71

PN

48.3(24.2)

64 (18.2)

Desmorat et al. 1998 Abstract

SF36 VT scale

466

NA

NR

NA

Bayliss et al. (1998)

SF36 VT scale

157

PN

53.3 (SE 2)

70.8 (SE 1)

Younossi 1998(A)

SF36 VT scale

30

NA

NR

NA

Bonkovsky et al. (1999) INT.

SF36 VT scale

642

PN

52.4 (23.6)

67.4 (17.9)

Neary et al. (1999) INT.

SF36 VT scale

257

PN

54 (SE 2)

PN

Ware et al. (1999) INT.

SF36 VT scale

324

PN

46.46 (SE .64)

50.62 (SE .3)

The scores are lower because they are standardized i.e. t-scores.

Rodger et al. (1999)

SF36 VT scale

15/19*

PN

49 (20)/60(21)*

PN 66(0.5)

*See below

(A) = Abstract

Page 53

NR = not reported NA = not appropriate PN = Population norms SD = standard deviation SE = standard error INT = interferon trial *Rodger compared two HCV groups: respectively, those “aware” and those ”unaware” of their HCV status.

The second study by Younossi et al. (1998) in addition to the SF-36 QoL scores also examined fatigue using the chronic fatigue syndrome screener (CFSS) and the chronic liver disease questionnaire (CLDQ). Rheumatologic symptoms and autoimmune disease were also assessed and the latter compared with fatigue and QoL scores. Details of the study are limited as it was only published as an abstract. Younossi’s group report that all seventy-eight of their patients had elevated fatigue. Further, the second most common symptom was arthralgia (i.e. muscle weakness and fatigue). For the group as a whole, SF-36 QoL (including the Vitality scale) and CLDQ scores was significantly lower when compared with U.S. population norms. There was no relationship between autoimmune disease (e.g. cryoglobulinemia and rheumatoid factor) and reduced QoL. Of note is that while the CFSS does assess the presence of fatigue it does not provide a measure of severity.

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The study by Desmorat et al. (1998) was the first French SF-36 study of HCV patients. The study examined a large number of patients and compared SF-36 scores with a number of variables e.g. age, gender, method of infection, Knodell (liver inflammation) score and cirrhosis. However, these comparisons appear to have been made only between subgroups e.g. female vs. male, cirrhotic vs. non-cirrhotic, without determining first whether the total group score was significantly different when compared with French population norms. The only mention of the SF-36, Vitality scale in this study was that it was negatively correlated with liver inflammation (Knodell score) i.e. the higher the liver inflammation score the lower the vitality score.

In the same year as Desmorat, Foster et al (1998) published the first UK SF-36 study of HCV infected patients. In this well designed study Foster controlled for many of the confounding variables evident in previous studies, except depression. Unlike previous studies a normal healthy control group and also a HBV control group were also employed. The most salient feature of the study was that no HCV patient had cirrhosis nor did any have more than mild fibrosis. The study found significantly reduced QoL on all eight scales of the SF-36 (including the vitality scale) for the HCV infected group, who also had poorer QoL than the HBV group. In addition, they found that while there was no difference in SF-36 Vitality scores between intravenous drug users (IDU’s) and non-IDU’s, the remainder of the SF-36 QoL scores were worse in IDU patients. The import of this study seemed clear – fatigue and other symptoms are not a consequence of liver damage, but may be better explained by an as yet unknown effect of the hepatitis C virus. Unfortunately, as later acknowledged by Foster (1999) in his QoL review, his earlier study did not assess psychopathology, the inclusion of which would have allowed for most of the problematic confounds to be controlled for in the one study. This desirable goal remains to be undertaken. Foster’s study had an important influence on future studies; one in particular was the final QoL study in this review of the first eleven years of HCV fatigue research.

The study by Rodger et al. (1999) only examined a small number of patients. However, it is unique in that through the convergence of unrepeatable circumstances the authors were able to assess a small group of HCV infected patients on the SF-36, while they were still unaware of their HCV infection. This group was compared with a similar group who had been infected at the same time, twenty-five years previously, but who had accidentally discovered their HCV status a few years before the study took place. Rodger hypothesized in her study that the group who knew that they were infected, the “aware” group would have worse QoL than the group who were “unaware” of their HCV infection. The study was well designed, rigorously conducted and excellently written. The study found that compared to Australian population norms both groups had significant reductions on three SF-36 scales, the VT (fatigue), MH (mental health) and GH (general health) scales. However, the “aware” group also had significant reductions on another four SF-36 scales, the BP (bodily pain), RP (role physical), RE (role emotional) and SF (social functioning) scales. The authors interpretation of their results is that fatigue and mental health problems as reflected by low scores on the VT and MH, SF-36 scales are most likely to due to some unknown effect of the virus since they were statistically significant in the “unaware” as well as the “aware” group, but they argue that the “aware” group had much poorer QoL overall and that this was due to the impact of diagnosis, which they attribute to labelling, a self-attribution theory. This interpretation has been challenged by a number of authors (Forman et al., 2000; Wessley & Pariante, 2002)) who have drawn attention to the small numbers of patients in the study and, by implication, the effects of this on the validity of the statistical analyses. In most studies when two groups are individually compared to a third as a reference of abnormality they are afterwards compared with each other to see whether one group is more abnormal. In Roger’s study the second comparison could not be made because of a statistical rule that limits whether a comparison is allowed or not, namely, one needs a sufficient number of subjects to undertake the analyses which was not the case in Roger’s study. There has been much controversy about the interpretation of Roger’s results. This is discussed elsewhere in this review. However, one thing that can be said with certainty is that the group who had no knowledge of their HCV infection had significantly abnormal fatigue and mental health problems compared with local population norms.

If taken together the evidence from these SF-36 QoL studies shows that patients with HCV infection have abnormal fatigue: evidence from the study by Roger et al. further suggests that this is also true for people unaware of their HCV status. There is little evidence to show a relationship between fatigue as measured by the SF-36 vitality scale and the following variables: cirrhosis, fibrosis, liver inflammation (except in the study by Desmorat et al. 1998), mode of infection (e.g. blood transfusion or IDU), duration of infection, viral load, genotype, ALT or autoimmune disease (e.g. immunological markers). Only one study (Bonkovsky et al. 1999) found correlations between fatigue and age and fatigue and gender, but it is clear that these are additive and not the cause of fatigue.

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While the authors of each of the studies discussed above seem to be confident (sometimes with proselytizing zeal) that the SF-36 is a good measure of QoL and by implication, fatigue, this is by no means a consensus view. Foster (1998) in his review of HCV QoL studies (almost all SF-36 studies) mentions anecdotally, the criticisms of other researchers who consider generic measures of symptoms as inaccurate – although he personally discounts this view. Sherman et al. (1999) found that compared to other measures of fatigue the vitality scale of the SF-36 is a poor discriminator, suggesting that it may be an insensitive measure of fatigue severity. Other authors have challenged the psychometric validity of the SF-36 (Owens, 1998; Koff, 1999) and others its relevance in HCV studies (Forton et al., 2002).

If there is no consensus on the quality of the SF-36 vitality scale there is at least tacit agreement that the mental health scale (MH) is not a valid measure of depression or anxiety – which it purports to be – since no HCV SF-36 study has ever claimed to have found those two symptoms on the basis of abnormally low MH scale scores. HCV SF-36 studies, which have reported depression or anxiety, have always used standardized depression or anxiety tests. Because depression is a symptom of HCV and fatigue is a symptom of depression it is important that when one is measured the other is also measured. In the QoL studies reported here only one study (Hunt et al. 1997) simultaneously measured depression.

Further criticisms of the SF-36 are not so much about the test itself but the way in which it is used, for example, there is a tendency to rely only on population norms rather than comparing scores with a normal control group. It would be possible to give prevalence rates for fatigue by standardising the data and using cut-off scores, for example, identifying cases above the 95%ile or some other cut-off. This approach as yet has not been undertaken. Although the SF-36 would remain the most popular QoL measure in future HCV studies, its usage would change; in the future it is used in conjunction with a battery of other tests. It is also notable that HCV specific versions of the SF-36, which were supported only by drug companies, would disappear after 2001 at the same time that HCV interferon outcome studies based solely on the examination of symptoms or QoL also ceased.

Finally we come to the third category of studies that directly examined fatigue as an independent factor and not just part of QoL (Table C). These studies can be further divided into four broad groupings: those that examined fatigue and psychopathology, fatigue and its measurement, fatigue and causality and fatigue and treatment outcomes.

We shall first consider the studies, which compared fatigue with psychopathology. The first two studies that included fatigue in their title were by Nelles et al. (1996) and Mahl et al. (1996). Both of the latter studies were published as abstracts in the same edition of the journal Hepatology and, therefore, details are limited. These studies only examined a small number of subjects, but did measure fatigue and psychopathology using standardised psychometrically validated measures. Both report elevated levels of fatigue. Mahl et al. (1996) found that 35% of their patients had severe/disabling fatigue and while Nelles et al. (1996) reports elevated levels they do not provide details. Both studies found that patients with more severe fatigue also had more severe depression, but neither study report any association between fatigue and cirrhosis, method of infection or ALT. Both studies have been criticised for not using controls and problems with patient recruitment, however, they were the first to examine psychopathology and its relationship with fatigue in HCV infection.

The study by Dwight et al., (2000) also used standardised measures of fatigue and psychopathology, as well as psychiatric diagnosis. Dwight’s group also found a correlation between elevated fatigue and elevated depression, while regression analysis revealed that 30% of the variance in fatigue scores could be explained by depression scores; i.e. about one third of all fatigue in the group could be attributed to the additive effect of depression. Although Dwight’s study did not include a control group and many of the HCV patients had a previous history of psychiatric illness affecting the generalizability of the findings the authors do demonstrate that depression amplifies fatigue i.e. depression makes fatigue worse even if the cause of either is unknown. As to whether depression causes fatigue remains an open question.

The second category consists of just two studies that were mainly concerned with the measurement of fatigue.

Sherman et al. (1999) wanted to find the best QoL measures to use with HCV patients. More precisely they wanted to know about specific symptoms rather than their disabling effects and they were particularly interested in fatigue. They used twenty-one different measures all of which included fatigue

47

items. These were administered to three groups: an HCV infected group, a healthy control group and a second healthy control group who were instructed to fake-fatigue. The latter group were included in order to test whether which measures were best at distinguishing patients with ‘real’ fatigue form those who were ‘stimulating-fatigue’. This was undertaken to test of the discriminant validity of the measures.

As predicted, they found that fatigue simulators had the highest fatigue scores followed by HCV patients and then healthy controls. Further, apart for one exception the measures were able to discriminate between the groups. The one exception was the SF-36 Vitality scale. This raises doubt as to the validity of this scale as measure of fatigue in previous studies. The authors state that a statistical comparison of the 21 measures showed that the same results could be achieved by using only seven. The FIS is the only measure of those seven to subsequently become widely accepted in HCV fatigue research.

Unfortunately, this study was published as an abstract and there are insufficient details to expand further upon their findings.

The study by Kleinman et al. (2000) was the first interferon trial to use a standardized fatigue measure other than the SF-36 “Vitality” scale—it was essentially a validation study of the fatigue severity scale (FSS). They compared the FSS with the SF-36 Vitality scale as well as the other seven SF-36 scales.

The study was international (11countries), large (N=1225), and compared FSS scores with other variables, e.g. ALT, viral load, cirrhosis and liver inflammation. The study found the FSS to be a valid measure of fatigue and correlated well with the SF-36 Vitality scale. Cirrhosis and liver inflammation correlated weakly with FSS scores. Compared to population norms both the FSS and the SF-36 vitality scale showed HCV infected patients had higher fatigue than normal healthy people, but only on the SF36 vitality score reached a significant level of difference.

The third category of studies investigated whether fatigue in patients with HCV might be explained by causes other than liver disease or depression.

The study by Karatsune et al. (1998) was not focussed on HCV patients but on chronic fatigue syndrome (CFS) patients. They included patients with HCV as well as other patient groups with illnesses known to be associated with fatigue as comparison groups and, as well, healthy controls. The purpose of the study was to measure carnitine levels (a transporter of energy to body cells) and explore for differences between the three groups. In all three groups, they further examined whether they met the diagnostic criteria for CFS. Compared to the healthy controls and all other patient groups, the carnitine levels were significantly reduced in patients with HCV and even more reduced in patients with CFS.

Lau et al. (1999) in a brief abstract report the results of a study where they examined the association between FIS fatigue scores with measures of resting energy expenditure (REE), body mass index (BMI) and physical endurance (bicycle-machine test). An association was only observed between fatigue and lower body mass index (BMI). The author’s argue that this is indicative of “nutritional depletion”. Of note is that no association was observed between fatigue and physical endurance. Taken together it can be argued that these finding suggest that while underfed and thin patients with HCV report fatigue this is not associated with reduced physical output. Unfortunately, they did not explore the different dimensions of fatigue, i.e. the cognitive, physical and social components of the FIS, thereby precluding an analysis of which component was associated with BMI and not physical endurance.

Barkhuisen et al. (1999) were interested in whether fatigue in HCV patients might reflect an underlying immune disorder, in particular were interested in assessing for the presence of rheumatological symptoms. They assessed fatigue (no details of measure) and compared scores with biological markers of immune disease (cryoglobulinemia and rheumatoid factor (RF)) as well as diagnostic measures of joint and body pain. They found a 66% prevalence rate for fatigue and a 91% prevalence rate for musculo-skeletal pain, but no relationship between either of these variables and cryoglobulinemia or RF levels. To date, despite a large number of studies only Stefanova-Petrova

48

(2008) have ever found a relationship between markers of immune disease and fatigue in HCV infected patients.

The study by Goh et al. (1999) examined a cohort of Irish women who were accidentally infected with HCV contaminated Anti D immunoglobulin (a prophylactic used to prevent rhesus birth). The women were infected at around the same time (1972-4), and the contamination was traced to a single blood donor. The study compared fatigue (FIS) with markers of immune disease, cryoglobulinemia, rheumatoid factor (RF) and arthralgia. The prevalence rate for arthralgia was moderately high (40%) while abnormal fatigue was very high (97%). No relationship was found between fatigue and any of the immune markers or other variables. The study already notable for its unique population is also notable for including a control group of women who were HCV antibody positive but PCR negative. These women were probably assumed to be symptom free, but surprisingly they also had a high prevalence rate of abnormal fatigue (75%). The authors remark on the negative press, the legal and compensation issues surrounding this “medical crisis” which may have had a negative psychological impact on these women. Although this might explain their high level of fatigue and other symptoms, later research by Weissenborn et al. (2006) would offer a very compelling answer.

Gershon et al. (2000) investigated abnormal cytokine levels and their relationship with fatigue in HCV infected patients. Cytokines are messenger cells produced by immune cells, they communicate with both the brain and immune cells and play a role in coordinating the latter in response to infection; when there are abnormal fluctuations in cytokine levels they are thought to produce symptoms such as, swelling, fatigue, nausea and insomnia. Interferon is a cytokine, but of a different type from those being investigated here. Gershon and colleagues found abnormal cytokine levels in 56% of their patients.

Despite the elevated levels, no association was observed between fatigue scores (FAI) and levels of interleukin 1, interleukin 6, and tumour necrosis factor (TNF)– all cytokines. The authors state that cytokines are difficult to measure and also note that it is possible for cytokine levels to be normal in circulating blood but abnormal in the brain. Although the latter sounds similar to the “Trojan Horse” theory of brain infection, it is based on a different theory (although there may be connections). The study screened up to 1000 HCV patients and excluded all but 149 patients, of those, 62, for a variety of reasons were not able to participate. The study finally examined 87 patients (around 9%) to create as the authors state a very “pure” population. The study was careful to exclude people taking psychiatric drugs but of note is that they do not appear to have formally assessed depression. Only a standardised measure of fatigue the FAI was used, a healthy control group was employed, the study used correlation analysis and also, unusually, and much to our delight, they used cut-off scores, so we know exactly how many patients had severe, disabling fatigue, as opposed to levels of fatigue that might be found in a normal healthy population: fatigue like height and weight is normally distributed in the general population. The study found that 45% of 78 HCV infected patients had a fatigue severity score of more than 4 on the FAI - indicating severe clinical fatigue. The authors suggest that sleep and depression are just as likely to be the cause of fatigue since the study found no relationship with fatigue and abnormal cytokines, however for some reason they didn’t measure those two variables. Nevertheless, this is probably the best study in this first part of our review. The general quality of HCV fatigue research coming from Canada has been exceptionally high – it remains so.

The last category is treatment studies of fatigue in HCV infected patients – there were two. The first study (Wolf et al., 2000), published only as an abstract, treated a very small group of patients (n = 13) with the stimulant Ritalin (methylphenidate). Although treatment gains were found, the long-term efficacy of treating HCV patients with a neurostimulant remains controversial. Many of the patients in this study also had severe enough liver damage to warrant treatment with anti-encephalitic drugs raising questions as to the viability of such a treatment. Interpretation of the findings are further limited by the lack of information on how fatigue was assessed and the failure to include a placebo condition.

The final study in this category by Jones (1999) was a single case study of a HCV infected woman with severe disabling fatigue who was successfully treated with the anti-emetic drug ondansetron a serotonin 5 HT 3 receptor antagonist. This study was inspired by the findings of a study which found that compared to a placebo the SSRI antidepressant paroxetine significantly reduced the physical performance of athletes. Paroxetine increases the availability of the neurotransmitter, serotonin. Jones postulated that elevated levels of the serotonin might underlie fatigue. Evidence from single case studies do not normally carry much weight, but this study was cutting edge in terms of theory and treatment and the author, cleverly, kept it under the nose of other researchers for as long as possible. In 2005 Piche et al., conducted a well-controlled HCV study comparing ondansetron vs. placebo in

49

fatigued HCV patients and found that it significantly reduced fatigue in one third of treated patients (it also significantly reduced depression). Ondansetron is commonly used to control nausea induced by chemotherapy and is a very expensive drug (although there are now generic brands available at half its former cost). Despite the expense and its side-effects (especially severe constipation), the idea of a single drug which is effective in treating nausea, fatigue, depression and possibly severe itching may be of great benefit in the treatment of HCV symptoms.

From the above description of each of the twelve fatigue studies it is apparent that there were variations in the aim, design and method of assessing fatigue. This makes it difficult to generalise the results.

Further factors affecting our understanding include the following limitations: most of the studies used small subject numbers, were either abstracts (n=5) or preliminary studies (n=2), and only two study employed a normal control group who also completed fatigue measures. Four of the twelve studies (Karatsune et al., 1998; Jones, 1999; Barkhuisen et al., 1999; Wolf, et al., 2000) did not mention how they measured fatigue further affecting the interpretation of the results. For example, although Karatsune et al. found reduced carnitine levels in fatigued HCV patients, and Barkhuisen found a high prevalence rate for muscle and joint pain in fatigued patients it is hard to quantify the severity of fatigue in these studies and without this knowledge it is difficult to interpret what relationship fatigue might have with either rheumatologic symptoms or reduced carnitine levels. Similarly, while the two treatment studies by Jones (1999) and Wolf et al. (2000) both showed gains in the improvement of fatigue their results are difficult to interpret for the same reason â&#x20AC;&#x201C; neither study used a standardised fatigue measure. One further study by Lau et al. (1999) who examined the relationship between fatigue and energy expenditure, BMI and effort was difficult to interpret not because they failed to include standardised fatigue measures but because they report only limited results.

Seven studies did use standardised fatigue measures. Not surprisingly, these studies provide more information about fatigue than any of the other studies in this review. In addition to using standard measures and thereby allowing for more reliable measures each of the studies also chose to examine the relationship between fatigue and other measures of importance allowing for meaningful conclusions to be made about the impact of fatigue on function. All seven studies used correlation and/or regression analyses, statistical procedures which can control for factors other than the presence of the HCV virus, such as depression, which help in identifying additional causes of fatigue. Taken together the findings from the seven studies suggest the following: (i) HCV infected patients have significantly higher fatigue when compared to normal control groups, (ii) a greater number of HCV patients have scores above the clinical cut-off for significant fatigue and (iii) and mean scores for HCV patient groups are higher than those for population norms. However, of note only two studies reported prevalence rates for severe/disabling fatigue, which varied in range: i.e. 39% - 45%. Investigation of factors that may further contribute to fatigue revealed that the only variable to consistently correlate with fatigue was depression.

This is not surprising. Apart for a few isolated relationships, fatigue was not systematically associated with age, gender, cirrhosis, fibrosis, liver inflammation, viral load, ALT, resting energy expenditure (REE) (hyper-metabolism), cytokine levels, autoimmune disease, co-morbid illness or method of infection.

Table C. Summary data for studies with the word â&#x20AC;&#x153;Fatigueâ&#x20AC;? in their title.

Article (Author & Date)

Fatigue Measure

N

Mean (SD)

Fatigue

Comments

Rate Index

Control

Index

Control

Index

Mahl et al. (1996) Abstract

FAI

31

NA

4.08 (NR)

NA

39%

Nelles et al. (1996) Abstract

FSS

88

NA

4.7 (NR)

2.53 (NR)*

NR

*Population norms only

50

Karatsune (1998)

CFS criteria

NA

NA

NA

NA

NR

HCV group abnormal carnitine levels

Lau et al. (1999) Abstract

FIS

27

NA

NR

NA

NR

Sherman et al.

(1999) Abstract

21 fatigue measures

96

199/199

NR

NR

NR

HCV group significantly abnormal on 7 measures

Jones (1999)

NR*

1

NA

NA

NA

NA

*Single case study

Barkhuisen et al.

(1999)

NR

44

NA

NA

NA

66%

Goh et al. (1999)

FIS

66

50

78 (36)

31 (24)

97%*

Kleinman et al.

(2000)

FSS

1223

PN

3.8 (1.7)

2.3 (NR)

NR

Dwight et al.

(2000)

MAF

36

NA

23.76 (NR)

NA

NR

Gershon et al.

(2000)

FAI

87

35

>4

2.53 (1.18)*

45%

*Population norms only

Wolf et al. (2000) Abstract

NR

12

NA

NA

NA

100%*

*Treatment trial

*We calculated 82%

NR = not reported NA = not appropriate FAI = fatigue assessment instrument FSS = fatigue severity scale FIS = fatigue impact scale MAF = multiple assessment of fatigue

51

Conclusion: The following conclusions can be drawn from a review of the HCV and fatigue literature 1989-2000:   





Severe disabling fatigue is common in HCV infected patients as well as milder forms of fatigue.

Although it is not possible to give an accurate estimate for the prevalence of fatigue in HCV infected patients at this time, an approximate estimate would be about 60% - in 2009, it was estimated to be roughly 50%. The range for severe/disabling fatigue was 39% - 45%.

Successful interferon treatment appears to improve fatigue but falls short of normalizing it.

Treatment studies of fatigue showed improvement gains, but these results need confirming with larger subject numbers and need to have longer follow-up periods to assess whether gains are maintained for more than six months.

Depression is the only variable that consistently correlates with fatigue severity and it may make fatigue worse by about 30%, but does not appear to be the cause. Anxiety and sleep have also been found to correlate with fatigue but there is not enough evidence to draw any clear conclusions. There was no other evidence suggestive of a cause for fatigue in HCV infected patients at this time but the evidence from Jones (1999) ondansetron study, if statistically meaningless, was nevertheless compelling and it was at least theoretically sound – it was the first indicator of a change of focus in HCV fatigue research.

Abnormal fatigue is a common experience for at least half of all HCV infected patients, irrespective of how they became infected, the degree of liver damage sustained, or evidence of abnormal test results from biochemical measures e.g. ALT.

The next decade 2001-2011 In the first few years of the next decade the annual number of studies which, examined fatigue in HCV infection continued to increase, i.e. 8 studies in 2001, 8 studies in 2002, 9 studies in 2003 and 8 studies in 2005 - but then dropped to only a few studies each year thereafter. These studies are much more varied in focus than their predecessors, more experimental, complex and generally of a higher standard.

The most noticeable change is in the number of neuropsychological and neurological studies of fatigue, in particular a small number of studies using brain-imaging procedures, which reflect the growing interest in the brain as a site of HCV infection. This change in focus can be attributed to two researchers Forton et al (2001, 2004) and Weissenborn et al., (2004, 2006 and 2009) and their efforts to find evidence for HCV infection of the brain – the “Trojan Horse” theory. This continues to be the most promising area of HCV symptom research. These studies will be examined in a forthcoming review (Part 2).

52

Acknowledgements

We would like to thank Kerry Paterson, (Executive Officer) and Cecilia Lim, (Co-ordinator, Information and Resources) at the Hepatitis C Council of SA Inc; Kerry for being the catalyst for this review and Cecilia for helping us to get access to the necessary journal articles we needed. We would also like to thank the library staff of the South Australian Department of Health, in particular ( Wanda Dillon, Brenda Daly & Robyn Davis) for their helpful instruction in improving our search techniques and for providing us with journal articles not held by the local university libraries. Finally we would like to thank Dr Kurt Lushington, Associate Professor of Psychology at the University of South Australia, for his advice, and his editing and correcting of this document, without his help and inspiration it is doubtful that we would have completed it.

All correspondence should be sent to Doug Mellors at : dougmellors@hotmail.com

53

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Kalman, J., O’Neil, M.M., & Z.M. Younossi. (2007). Fatigue and health related quality of life (HRQL) in chronic hepatitis C virus infection. Digestive Diseases and Sciences, 52(10), 2531-2539.

McDonald, J., Jayasuriya, R., & Gluseska, S. (2002). Fatigue and psychological disorders in chronic hepatitis C. Journal of Gastroenterology and Hepatology, 17, 171-176.

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McAndrews, P., Farcnik, K., & Heathcoat, E.J. (2005). Prevalence and significance of neurocognitive dysfunction in hepatitis C in the absence of correlated risk factors. Hepatology, 41(4), 801-808.

Miller, E.R., Hiller, J.E., Shaw, D.R. (2001). Quality of life in HCV infection: lack of association with ALT levels. Australian and New Zealand Journal of Public Health, 25(4), 355-361.

Obhrai, J., Hall, Y., & Anand, B.S. (2001). Assessment of fatigue and psychologic disturbances in patients with hepatitis C virus infection. Journal of Clinical Gastroenterology, 32(5), 413-417.

Piche, T., Vanbiervliet, G., Cherikh, F., Antoun, Z., Huet, P.M., Gelsi, E., …Tran, A. (2005). Effect of ondansetron, a 5-HT3 receptor antagonist, on fatigue in chronic hepatitis C: a randomized, double blind, placebo controlled study. Gut, 54, 1169-1173.

Poynard, T., Cacoub, P., Ratziu, V., Myers, R.P., Dezailles, M.H., Mercadier, A., …Moussalli, J. (2002).

Fatigue in patients with chronic hepatitis C. Journal of Viral Hepatitis, 9, 295-303.

Weise, M., Grüngreiff, K., & Porst, H. (2005). Outcome in a hepatitis C (genotype 1b) single source outbreak in Germany – a 25 year multicenter study. Journal of Hepatology, 43(4), 590-598.

Weissenborn, K., Krause, J., Bokemeyer, M., Hecker, H., Schuler, A., Ennen, J. … Boker, K. W. (2004).

Hepatitis C virus infection affects the brain-evidence from psychometric studies and magnetic resonance spectroscopy. Journal of Hepatology, 41(5), 845-851.

Weissenborn, K .,Ennen, J.C., Bokemeyer, M., Ahl, B., Wurster, U.,Tillman, H. … Berding, G. (2006).

Monoaminergic neurotransmission is altered in hepatitis C virus infected patients with chronic fatigue and cognitive impairment. Gut, 55, 1624-1630. * Weissenborn, K., Tyc, A.B., Heeren, M., Worthman, H., Pflugrad, H., Berding, G., Bokemeyer, M., Goldbecker, A. (2009). Hepatitis C virus infection and the brain, Metabolic Brain Disease, 24, 197-210.

Wessely, S., & Pariante, C. (2002). Fatigue, depression and chronic hepatitis C infection. Psychological Medicine, 32, 1-10.

References Outside Review Alberti, A., Morisca, G., & Ruol, A. (1992). Hepatitis C viraemia and liver disease in symptom free individuals with anti-HCV. Lancet, 340, pp. 697-698.

Anisman, H., Baines M.G., Berczi, I., Bernstein, C.N., Blennerhasset, M.G., Gorczynski, R.M., …

Warrington, R.J. (1996). Neuroimmune mechanisms in health and disease: 1. Health. Canadian Medical Association Journal, 155(7), pp. 867–874.

Barofsky, I., & Legro, M.W. (1991). Definition and measurement of fatigue, Reviews of Infectious Diseases, 13(Suppl. 1), pp. S94-S97.

Di Bisceglie, A.M., Conjeevaram, H.S., Fried, M.W., Sallie, R., Park, Y., Yuradin, C., … Hoofnagle, J.H. (1995). Ribavirin as therapy for chronic hepatitis C: a randomized, double-blind, placebo-controlled trial.

Annals of Internal Medicine, 123(12), pp. 897-903.

Chaudhuri, A., & Behan, P.O. (2004). Fatigue in neurological disorders. Lancet, 363, pp. 378-988.

Cavalheiro, N.P. (2007). Sexual transmission of hepatitis ,. Revista do Instituto de Medicina Tropical de São Paulo, 49(5), pp. 271-277.

Fisk, J.D., Rito, P.G., & Schlech, W.F. (1994). Measuring the functional impact of fatigue: initial validation of the Fatigue Impact Scale. Clinical Infectious Diseases, 18(Suppl. 1), pp. S79-S83.

Forton, D.M., Taylor-Robinson, S.D., & Thomas, H.C. (2002) Reduced quality of life in hepatitis C – is it all in the head? Journal of Hepatology, 36, pp. 435-438.

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Fukuda, K., Straus, S.E., & Komaroff, A. (1994). The chronic fatigue syndrome: a comprehensive approach to its definition and study. Annals of Internal Medicine, 121, pp. 953-959.

Holmes, G.P., Kaplan, J.E., Gantz, N.M., Komaroff, A.L., Schonberger, L.B., Straus, S.E., … Brus, I. (1988). Chronic fatigue syndrome: a working case definition. Annals of Internal Medicine, 108, pp. 387389.

Jones, E.A. (2004). Fatigue complicating chronic liver disease. Metabolic Brain Disease, 19(3/4), pp.

421-429.

Koff, R.S., (1999). Impaired health-related quality of life in chronic hepatitis C: the how, but not the why.

Hepatology, 29(1), pp. 277-279.

Owens, D.K., (1998). In the eye of the beholder: assessment of health-related quality of life.

Hepatology, 27(1), pp. 292-293.

Perillo, R.P., Schiff, E.R., Davis, G.L., Bodenheimer, H.C., Lindsay, K., Payne, J., … Dienstag, J.L. (1990). A randomized controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of hepatitis B. New England Journal of Medicine, 323, pp. 295-301.

Seef, L.B., Buskell-Bales, Z., Wright, E.C., Durako, S.J., Alter, H.J., Iber, F.L., … Hollingsworth C.D.G. (1992). Long-term mortality after transfusion-associated non-A, non-B hepatitis. New England Journal of Medicine, 327, pp. 1906-1911.

Shepard, C.W., Finelli, L., Alter, M. J. (2005). Global epidemiology of hepatitis C virus infection. Lancet Infectious Diseases, 5, pp. 558-567 Swain, M.G. (2000). Fatigue in chronic disease.

Clinical Science, 99, pp. 1–8.

Ware, J.E. (1993). SF-36 health survey: manual and interpretation guide. Boston, MA. The Health Institute. New England Medical Center.

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2001 Author: (43) Fontana, R. J. et al, 2001: Co-morbidities and Quality of Life in Patients with Interferon Refractory Hepatitis C. American Journal of Gastroenterology. Vol. 9, No.1, pp. 170-178 QoL/Co-morbidities. U.S.A. Methods: 107 patients with chronic HCV infection (Mean age - 44.5yrs, Male - 72%) who had failed previous Interferon (monotherapy) treatment were recruited as candidates for Interferon + Ribavirin treatment. Patients who had ceased interferon treatment within three months prior to the study were excluded. QoL was assessed using both the SF36 (a modified HCV version – see Bayliss et al., 1998) and the Health Utilities Index (HUI) Mark 3, a generic QoL measure which does not have a fatigue scale. All patients were assessed for, presence of a coexisting (comorbid) illness or illnesses, history of alcohol or drug abuse, ALT, cirrhosis, viral load, genotype, route of infection and mental health status - SF36 & HUI scores were compared with the resulting data. To assess the impact of the different number and types of comorbidities on QoL, SF36 scores were grouped under different categories and compared with SF36 scores for the general population. The following comparisons of SF36 scores were made: HCV with no co-morbidities (N=46) vs. HCV + one or more comorbidities (N=61) (Total N=107); HCV with no history of depression (N=80) vs. HCV + history of depression (N=27) (Total N=107); No painful comorbidities (N=85) vs. one painful comorbidity (N=22) (Total N=107). Risk factors (possible routes of infection) were intranasal cocaine 64%, IDU 51%, high risk sexual behaviour 42%*, blood transfusion 32%, tattoo 20% and unknown 9%, 14% of patients had cirrhosis (compensated).

Aim of Study: To assess whether differences in QoL in a group of HCV patients, who had previously failed Interferon treatment, may partly be explained by co-morbid illness, past abuse of drugs or alcohol, or both these variables.

Results: SF36 and HUI scores for the 107 patients were significantly lower (worse) than those for people in the general population – this included the SF-36, VT (fatigue) scale. Scores on the SF36 appeared to correlate well with those of the HUI. There were no significant associations between SF36 or HUI scores and ALT levels. HCV RNA levels (viral load), genotype, liver histology, route of infection or a past history of drug or alcohol abuse Significantly lower scores on the SF36 and the HUI were associated with co-morbidities, particularly with a painful co-existing illness or depression (see comments). Although not specifically mentioned by the authors the lowest scores on the “Vitality”(fatigue) subscale of the SF36 were for the HCV+ painful comorbidity group with a mean score of 30 SF36 points below the general population norm – a very large difference.

Commentary: There are a number of obvious problems in this study. From what is known about the symptoms of interferon treatment, assessing patients for symptoms less than six months after treatment is to risk serious confounding of the cause of those symptoms – this has an effect on the generalizability of the results. The study also suffers from a problem common to most Interferon studies in this review: a lack of clear information relating to the exact composition of the groups being compared—in this study there appears to be an overlap between the “no comorbidities” and “depression” groups. There was also a large amount of unexplained missing data (N=19). Depression was assumed to be present where a patient had a history of depression or if they were currently being treated with antidepressants; neither of these methods of ascertaining a patient’s depression status qualifies as a valid form of assessment.

A patients psychiatric history cannot tell you if a person is currently depressed only a standardized depression test or a psychiatric interview can do that and the same is true with anti-depressant medication—indeed, if the treatment is efficacious there should be no

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depression. However even if the assessment for depression were valid there would still be a problem with confounding i.e. was the depression a symptom of HCV or interferon induced?

There were a number of other problems in this study, but the above are the most important and consequential. It is true that this study found strong correlations consistent with those of other studies of QoL and co-morbidities but in the context of this particular study it is not possible to explain them. * HCV infection is not classified as a sexually transmitted disease although many researchers throughout the 1990s mainly in the U.S.A. assumed that it was sexually transmitted.

Cavalheiro (2007) who has comprehensively reviewed this area has stated that if sexual transmission of HCV does indeed exist it must be considered a rare event.

Author: (44) E Anthony Jones et al, 2001: Altered central seretonergic neurotransmission; a potential mechanism for profound fatigue complicating chronic hepatitis C. Medical Hypothesis, Vol 57, No. 2: pp 133-134. Review /Theoretical. Holland.

The information in this article is very similar to that found in the 1999 article by the same author, in that it describes a theoretical model for fatigue in HCV infection based on alterations in the transmission of the neurotransmitter serotonin. The author uses the same three studies to support his theory and his conclusion is the same, fatigue in HCV infection should be treated with drugs that block serotonin transmission e.g. the use of ondansetron in controlled clinical trials.

Author: (45) J Obhrai et al, 2001: Assessment of fatigue and psychologic disturbances in patients with hepatitis C virus infection Journal of Clinical Gastroenterology, Vol 32, No 5: p.p.413417. Comparative assessment of fatigue across different liver diseases. U.S.A. Methods: This study was comprised of three groups and two control groups. The three study groups were an HCV alone group (no co-morbidities) (N = 24, Mean Age â&#x20AC;&#x201C; 51.3 years), Gender â&#x20AC;&#x201C; predominantly male); a group with both HCV and alcohol related liver disease (N =32, Mean Age = 45.8 years; Gender = predominantly male) and a group with alcohol related liver disease alone (N = 22; Mean Age = 51 years; Gender = predominantly male) The control groups were: a group with chronic illness not related to liver disease (N = 40; Mean Age = 46 years; Gender = predominantly male); and a healthy control group (N = 24; Mean Age = 51 years; Gender = predominantly male) All participants were assessed using the Fatigue Assessment Instrument (FAI) and the Sickness Impact Profile (SIP; a generic quality of life measure).

Aim of Study: 1. To assess whether fatigue experienced by people with HCV is more severe than that in people with other liver diseases and other types of chronic illness. 2. To assess the association of fatigue with psychological impairments.

Results: Fatigue scores were higher in the HCV alone group than in any of the other groups. Fatigue was significantly higher in all illness groups compared to healthy controls but not significantly different between the three study groups. However, fatigue experienced by those with liver disease was less responsive to rest and sleep than in the non-liver disease and healthy control groups - the difference was significant. Scores for depression, anger and hostility were also significantly greater in patients with liver disease compared to those in the non-liver disease and normal (healthy) control groups.

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Commentary: The authors’ conclusion in this study was that there is something particular to HCV infection that makes the experience of fatigue worse than in other illnesses. However, given the design of the study and the results one might have expected that those who had both HCV and alcoholic liver disease would have had the worst fatigue scores but that was not what they found. Although a standardized fatigue measure, the FAI was used in this study, depression and anxiety as well as hostility were measured using the sickness impact profile (SIP), which was the first QoL measure ever to be used with HCV patients (Davis et al., 1994) and quickly abandoned as an inadequate measure of QoL in this population. This is one of the very few studies in this review where the authors have accepted the results of a depression scale from a QoL measure as being valid; not using a well validated depression measure may have resulted in a confounding of their fatigue results. An interesting finding of this study was significantly higher scores on anger and hostility scales for the HCV group.

Author: (46) E A Dunn and E Quayle, 2001: The impact of iatrogenically acquired hepatitis C infection on the wellbeing and relationships of a group of Irish Women. Journal of Health Psychology, Vol 6: No 6: pp 679-692. Qualitative Study. Ireland.

Methods: 32 women who were part of a large group of Irish women accidently infected with HCV in1977 when they were inoculated with contaminated anti-D immunoglobulin to prevent RH haemolytic disease. These women were volunteers from a support group called "positive action" which was formed in 1997 when the source of their infection was disclosed to them.

This is a qualitative study so there are no tests or assessment instruments and no statistics.

Duration of infection = 24yrs and age range = 40-50yrs Aim of Study: To describe the impact of HCV on the well being, familial and other close relationships of 32 Irish women.

Results: The study found that these women as a group suffered from profound fatigue, reactive depression, and deterioration in cognitive functioning. Problems with marital relationships, friends and children were common. Work either inside or outside the home was severely affected. In general, results suggested that the impact of HCV on these women’s health was affecting their sense of identity.

Commentary: Qualitative studies are not easy to summarise as they are usually comprised of descriptions of illness in the patient’s own words. Also, because they do not generate statistics thereby allowing comparisons with other like conducted studies they are difficult to compare and contrast and make generalisations difficult. Nevertheless, these reports are rich in the kinds of information that all humans can relate to and are invaluable for gaining a deeper insight into the impact of an illness. What is interesting about this study is that most of the participants were already suffering from profound fatigue many years before they were diagnosed with HCV and most of them had actively pursued a diagnosis or explanation for how they felt during those intervening years.

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Author: (47) Daniel M Forton et al, 2001: Evidence for a cerebral effect of the hepatitis C virus.

Lancet, Vol. 358: pp 38-39. Experimental Study. England.

Methods: The study consisted of 30 randomly selected HCV infected patients (Male = 47%; combined mean age = 44yrs), with minimal fibrosis and no cirrhosis; 12 patients (Male = 92%; combined mean age = 35yrs) with hepatitis B infection and a control group of 29 healthy controls (Male = 52%; combined mean age = 42yrs). All participants were assessed for abnormalities in cerebral choline/creatine levels using proton magnetic resonance spectroscopy. Results for cerebral levels of these two metabolites were compared for each group. Sixty-seven percent of the HCV group were former IDUâ&#x20AC;&#x2122;s.

Aim of Study: To test the hypothesis that fatigue and other symptoms of hepatitis C may be the result of viral infection of the brain, since it has been shown in other illnesses that alterations in cerebral choline/creatine levels are an index of inflammation or infection of the brain.

Results: Results showed a significant elevation of choline/creatine in the white matter and basal ganglia area in the brains of HCV patients compared to patients with HBV and healthy controls. There were no important differences in choline/creatine ratios between former IDUâ&#x20AC;&#x2122;s and non-IDUâ&#x20AC;&#x2122;s in the HCV group. The authors conclude that this study provides evidence that HCV can infect the brain directly and may therefore explain the "brain fog" described by HCV patients. They also note that other possible causes such as encephalitis (found in cirrhotic patients) or IDU life style were controlled for in this study and found not to be associated with elevated choline/creatine levels excluding these factors as possible explanations.

Commentary: This was the first study to show that it is possible for HCV to permeate the brain blood barrier and directly influence chemicals in the brain; a first, but important step towards a biological association between HCV and fatigue. Although fatigue was not measured and hardly mentioned in this study we decided to include it as it had an important influence on later studies which did look at fatigue, i.e. Forton (2002), Kramer (2002; 2005) and Weissenborn (2004, 2006).

Author: (48) Thomas Riley et al, 2001: Is Nausea Associated With Chronic Hepatitis C Infection.

The American Journal of Gastroenterology. Vol. 96, No. 12, p.p. 3356 - 3360. Prevalence Study. U.S.A. Methods: 64 HCV patients (Mean age = 45.5 years; Female = 43.8%), 53 liver disease controls (Mean age = 49.8 years; Female = 60.4%) and 64 normal controls (Mean age = 38 years, Female = 43.8%) took part in this study. Nausea, fatigue and other symptoms were measured using the Nausea Profile questionnaire (NP). This is described by the authors as a three dimensional checklist of the symptoms associated with nausea: GI (gastrointestinal) distress, Somatic (bodily) distress and Emotional distress. The NP questionnaire contains 17 questions including one on fatigue scored from 0-9 (0 = no fatigue to 9 = severe fatigue).

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Aim of Study: To assess the frequency of nausea in patients with hepatitis C infection compared to controls A second aim was to compare other symptoms e.g. fatigue and abdominal pain.

Results: Using linear regression the study found that higher nausea scores were significantly independently correlated with a diagnosis of hepatitis C, fatigue and abdominal pain. The prevalence of nausea (43.8%) and fatigue (71.9%) in the HCV group were much higher than that for both the liver disease controls, nausea (18.9%), fatigue 43%) and the normal controls, nausea (29%) and fatigue (34.4%).

Commentary: There have been very few studies of nausea in HCV patients and it is certainly one of the least reported symptoms; even in large symptom studies, such as, Poynard’s (2002) study there is no mention of nausea. It is surprizing therefore to find a study with equal focus on nausea and fatigue. This was a simple prevalence study of nausea in HCV infection, using a single measure of subjective symptoms albeit a multidimensional one. The study suggests that a relationship exists between nausea and fatigue, but since the prevalence rate for fatigue is much higher - which means that some patients had fatigue but no nausea - the relationship is not clear.

Author: (49) Barrett S et al, 2001: The Natural Course of Hepatitis C Virus Infection after 22 years in a unique homogenous cohort: spontaneous viral clearance and chronic HCV infection.

Natural History Study. Gut, Vol 49, Sept, pp: 423-430. Ireland.

Methods: 87 PCR positive and 68 PCR negative Irish women all of whom had been infected in 1977-78 from HCV contaminated anti–D globulin injections (for history and demographic variables see Kenny-Walsh, 1999) took part in a long term study for a duration of 5 years for the PCR positive group and 4 years for the PCR negative group. Both groups were assessed using histological, biochemical and clinical measures. Symptoms were assessed in 62 (71%) of the PCR positive and 52 (76%) of the PCR negative groups (no details on how fatigue was measured are provided). Psychological and QoL measures were assessed using the HADS and the Goldberg General Health Questionnaire GHQ) and the UK SF36 QoL measure in 43 (49%) of the PCR positive group and 23 (34%) of the PCR negative group. Statistical comparisons were made between each group.

Aim of Study: To assess the natural history of a group of Irish women who in 1977 were accidently infected with HCV through contaminated anti-D globulin.

Results: No one in this study had cirrhosis and all patients had only mild histology. Fatigue and arthralgia were the most commonly reported symptoms. Fatigue was reported in 15 (24%) of the PCR positive group and in 23 (44%) of the PCR negative group—a statistically significant difference. Arthralgia was reported in 6 (10%) of the PCR positive group and 20 (39%) of the PCR negative group—also a significant difference. No differences were found between the PCR negative and PCR positive groups on psychological wellbeing, anxiety or depression.

However, results for the total sample (n=60) showed that 51 (77%) had signs of psychological distress, 23% had depression and 43% anxiety. Social functioning appeared to be the best predictor of the variance in scores on QoL and psychological measures.

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Commentary: This is a very thorough natural history study, but for some unknown reason there is almost no information on how fatigue was measured, which is surprizing since a previous study by the same authors’ (see Goh et al, 1999) had used a well-validated fatigue measure (i.e. the FIS).

Fatigue in this study is reported only as a prevalence rate.

When the authors’ of this study found that the prevalence rate for fatigue was twice as high in the PCR negative group (who had cleared the virus) than the PCR positive group they were surprised and suspected that it may have been caused by the psychological impact of negative media reportage on HCV at the time of assessment. The media reports first appeared in 1995 when the majority of the PCR negative women were first assessed, however, most of the PCR positive women had been first assessed in 1994 prior to any negative press reports or the government inquiry, which ensued.

In order to investigate whether the media reports were a possible cause of the rise in the prevalence of fatigue an odds ratio was calculated (for the whole group i.e. PCR+ and PCRgroups combined) which showed the odds of a report of fatigue in 1995 were six times higher than that for 1994. When this confounding effect (i.e. the year of diagnosis) was statistically controlled for no differences were found in the prevalence rates for fatigue between the HCV positive and HCV negative groups – which means that the PCR negative group’s prevalence rate for fatigue would be similar to the PCR positive group of 24%.

The authors’ interpretation of their results is that the increase in reporting of fatigue in 1995 was probably due to the psychological impact of the negative media attention on HCV but, that fatigue is clearly a symptom of HCV infection caused by some unknown mechanism.

It’s hard to know what to make of this study because they don’t mention how they measured fatigue. In the study by Goh et al., (1999) the prevalence rate in women from the same anti-D population, using the FIS* was 97% or four times higher than the prevalence rate given in this study. * FIS – Fatigue impact scale.

Author: (50) Miller, E.R. et al, 2001: Quality of Life in HCV Infection: Lack of association with ALT levels. QoL Study. Australia & New Zealand Journal of Public Health, Vol.25, No4 pp:355361. Australia Methods: This was a mixed methods study. It comprised of 95 patients with chronic HCV; 73 attending an infectious disease clinic (M=45, median age 41 yrs) and 22 a liver diseases clinic (M=14, median age 40.5 yrs). All, patients took part in stage one of a two-stage study. None of these patients had been treated with interferon or had other illnesses, which might affect QoL. All patients were assessed on the SF36, the social support questionnaire (shortened version), methadone use, alcohol use and mode of infection. In addition they were asked a number of questions regarding their understanding and concerns about ALT levels. Stage two (qualitative interviews) involved 9 volunteers from stage 1 who were asked to discuss the social impact of HCV and the significance of ALT levels in their lives. Mode of transmission in this group was as follows: lifestyle e.g. IDU (n=56), medical/work related e.g. transfusion (n=11), unknown, n=6.

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Aim of Study: To assess the impact of HCV infection on QoL and investigate associations between burden of illness, psychosocial factors and ALT. Results: For stage 1 there were no significant differences on any of the measures used between the liver clinic and infectious diseases clinics groups. So, for the purpose of statistical comparison the two groups were considered as one. Scores on the SF36 were significantly reduced on all 8 scales (this includes the VT or fatigue scale) when compared with local population norms.

Significant differences in summary SF-36 scores were also found for gender (women under forty had lower that is worse scores); mode of infection (IDUs had lower scores); alcohol intake (scores were lower for those who consumed alcohol); methadone use (those using methadone (20%) had lower scores); and satisfaction with social support (those who had lower satisfaction also had lower scores). No significant differences in SF36 scores were found for any other variable. While more than half the patients indicated they were worried about ALT levels this did not appear to be related to whether their ALT levels were high or low. From the nine interviews at Stage 2, qualitative analyses revealed four major themes: social stigma, social loss, fear of disease prognosis and negative responses from medical or health professionals. The first two themes (social stigma and social loss or fear of social loss) were the most prevalent.

Commentary: The first part of this study was a fairly typical SF-36 QoL study in which, there is little information about fatigue except that it was significantly higher in HCV patients when compared with local norms. Unfortunately all the comparisons made were with summary SF36 scores, and not with each of the eight SF-36 scales, so although we know that the HCV patients were fatigued we don’t know what their fatigue was associated with. We also do not know if the poor QoL scores were due, or partly due, to depression, as it wasn’t assessed.

The inclusion of questions related to patients perceptions of the importance of ALT was not typical of previous studies but was important to confirm what was anecdotally known at the time, which was, from an Australian perspective, that a majority of HCV patients who attended clinics had negative and overvalued ideas about the importance of ALT results. This perception is perhaps not surprizing when one considers that many clinicians at that time also shared these views. The second part of the study by contrast was a qualitative study. The themes that emerged are similar to those found by both earlier and later qualitative studies in this review and provide an interesting insight into the experience of HCV symptoms from the perspective of the patient. Combining empirical with qualitative methods in a study can sometimes produce results that are not mutually supportive but in this study the combination worked well.

2002 Author: (51) T. Piche et al, 2002: Fatigue is associated with high circulating leptin levels in chronic hepatitis C. Gut, Vol. 51, p.p. 434 - 439. Experimental Study. France.

Methods: The study consisted of 78 HCV patients (44 Males Mean age = 40 years and 34 females, Mean age = 42.5 years) without cirrhosis; 13 patients with Primary Biliary Cirrhosis* (PBC), (9 females and 4 males, Mean age - 63.8 years) also without cirrhosis and 22 healthy controls matched for age and other demographics with the HCV group. Fatigue was assessed in each group with a French version of the Fatigue Impact Scale (FIS). Resting energy expenditure (REE) a measure of hyper-metabolism was calculated by measuring oxygen and CO2 levels in the breath. Fat free mass (FFM) and fat mass (FM) were measured by electrical impedance analysis. REE and FFM were reported as a ratio i.e. REE/FFM. Leptin* levels were ascertained by blood analysis and reported as “absolute’ and “corrected for fat mass”.

Tumour necrosis factor (TNF), a correlate of leptin (e.g. when one is high so is the other) was

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also measured in the blood. For each of the above variables statistical comparisons of scores were made between: HCV vs. Controls, PBC vs. Controls, then HCV vs. PBC. Due to leptin levels being naturally higher in women than in men, comparisons of scores for each variable were also made between: HCV infected females vs female controls and HCV infected males and male controls. Correlations between fatigue and each variable were also performed for both the HCV and PBC group. Exclusions in this study were rigorous, however, depression was not formally assessed. Mode of infection e.g. IDU and blood transfusion, is not reported in this study. *PBC is an autoimmune disease of the liver i.e. liver damage is caused by the immune system attacking liver cells because they have been incorrectly identified by immune cells as alien. PBC generally has a poor prognosis and symptoms tend to be more severe than in HCV infection, including fatigue. **Leptin is a hormone thought to control fat and energy levels in the body and women in the general population have higher levels than men.

Aim of Study: To measure fatigue in hepatitis C patients and to determine whether there is an association with disease activity, resting energy expenditure (REE), circulating leptin and tumour necrosis factor (TNF).

Results: 38 of 78 HCV patients considered fatigue as their worst or initial symptom. Compared to healthy controls fatigue was significantly higher in the HCV group and within the HCV group, significantly higher in females compared to males. The severity of fatigue in PBC was comparable to that of the HCV group. Both the HCV and PBC groups’ leptin levels were significantly higher compared to controls. HCV females when compared to female controls had significantly higher absolute (circulating) leptin levels but when corrected for fat mass there was no significant difference. HCV males had normal circulating leptin, even after controlling for fat mass. REE/FFM was significantly higher in both the HCV and PBC groups’ compared to controls and within the HCV group was significantly higher in females when compared to males. Tumor necrosis factor levels were significantly higher in HCV females when compared to female controls, but normal in HCV males. PBC patients had significantly higher TNF level compared to both controls and HCV patients. In both the HCV group (females and males combined) and the PBC group there was a significant correlation between fatigue and leptin levels, but fatigue did not correlate with any other measures, such as, age, weight, BMI, REE/FFM, FM, ALT viral load or Metavir score. The authors conclude that fatigue is more pronounced in females and be may be partly mediated by leptin Commentary: This study had all the makings of excellence, for example, it was well conceived, theoretically interesting, not too small, looked at mostly objective measures, used one of the best fatigue measures and required a huge investment in time and effort on behalf of the researchers.

However, and most unfortunately, this study is incomplete because it did not fully take account of the natural differences in leptin levels between females and males, this at least is the contention of Romero-Gomez et al., (2003) in a letter to the editor of Gut. As those authors’ point out circulating leptin is three times higher in normal females than it is in normal males even after adjusting for fat mass. They suggest that to control for the confounding effect of gender Piche and colleagues should have used multivariate analysis. Their final statement is that the correlation between fatigue and leptin found in this study cannot be confirmed. While we agree with Romero-Gomez’s conclusions we would like to add that even using the same statistical analysis Piche could have controlled for the gender differences in leptin by treating the scores as coming from two different populations (i.e. covarying the data).

In a subsequent and even more elegant study Piche et al. (2005) made the same mistake again of not covarying the data on baseline fatigue for groups with dissimilar scores, fortunately, in that study it did not matter and had little effect on the final results, which is just

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as well, because it is one of the best studies in this review indeed his assessment of depression in the 2005 study is exemplary.

Author: (52) Daniel M Forton et al, 2002: Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease. Hepatology, Vol. 35: p.p. 433-439. Experimental Study.

England. * Methods: All the patients in this study were referred to a hepatology clinic. There were three groups in this study, an HCV, PCR positive group (N=27; Mean age = 44.5; Male = 59%) an HCV, PCR negative group* (N=16; Mean age = 42.3; Male = 38%) and a group of healthy controls (N = 29; Mean age = 42; Male = 52%). There were three stages of assessment. At stage one both the HCV positive and HCV negative groups were assessed for cognitive impairments (brain fog) on a battery of computerized and written cognitive tests. The results of these tests were factor analyzed which revealed a four-factor solution. The 4 factors (i.e. categories of cognitive function) were: power of concentration, memory speed, quality of working memory and ability to sustain attention. At stage two of the study, 19 of the PCR, positive and all of the PCR negative group were assessed on the Chalder fatigue scale; the BDI (depression), HADS (depression and anxiety) and the SF36, QoL questionnaire. At stage three of the study, 17 of the PCR positive group and the healthy control group were assessed for abnormalities in brain choline/creatine levels using H-MRS (Magnetic Resonance Spectroscopy). Comparisons were made between the PCR positive & PCR negative groups on each of the four factors (and also compared to population norms), choline/creatine levels and, fatigue scale, BDI, HADS and SF36 scores. Finally, choline/creatine levels compared between those in the PCR positive group (N=17) who had deficits on 2 or more cognitive tests (N=11) and those who had no cognitive deficits (N=11). Both groupsâ&#x20AC;&#x2122; choline/creatine levels were compared to those of the healthy control group (N=29). All HCV patients had only mild fibrosis and approximately half were IDUs, while the remainder were infected by either blood products or an unknown source.

Aim of Study: To test the hypothesis (generated by his earlier study) that HCV infection can: (A) result in brain metabolite abnormalities; (B) to assess whether cognitive impairments exist in patients with mild liver disease (this is a way of excluding encephalitis); (C) to assess whether brain metabolite abnormalities are associated with cognitive impairment (Brain Fog); and (D) to assess whether cognitive impairments or brain metabolite abnormalities are associated with fatigue, depression, QoL or previous history of injecting drug use (IDU).

Results: HCV positive patients (N=27) were significantly impaired on two of the four cognitive factors i.e. power of concentration and working memory when compared with HCV patients who had cleared the virus (N=16) and population norms (N=362). There were no significant differences in fatigue scores between the HCV positive (N=19) and HCV cleared patients (N=16), (but no report of whether they were abnormal or not). Likewise there were no significant differences in anxiety between the two groups. The HCV positive group had significantly lower (worse) scores on the SF36 Physical Summary Scale (this does not contain the VT (vitality) scale and were significantly more depressed on both the BDI (depression) and HADS (depression) questionnaires than the HCV cleared group. However, the level of depression in the HCV positive group was less than mild i.e. still within normal range. When choline/creatine levels were compared between the HCV positive group (N=17) and those of a healthy control group (N=29) the HCV positive groups choline/creatine levels were significantly higher, but they were not significantly correlated with any of the four cognitive factors. However, when the HCV positive group was divided into those who were impaired on two or more computer-based cognitive tests (N=11) and those who showed no impairment (N=6), the cognitively impaired group had significantly higher choline/creatine

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levels than both the cognitively unimpaired group and the healthy controls. Finally, there were no associations between choline/creatine levels and fatigue, depression, anxiety, QoL (SF36 scores) or IDU status.

Commentary: This is an important theoretical study and was a natural progression of an earlier study by the same author also looking at evidence for HCV infection of the brain known as the “Trojan Horse” Theory (Forton et al., 2001). The aim in this study was to investigate cognitive impairments (brain fog) and their relationship with two chemicals in the brain: choline, which is thought to be elevated in inflammatory conditions or infection; and creatine which is a measure of cellular energy status. Similar elevations have been found in other chronic illness e.g. HIV. This study showed clearly that there is a significant relationship between elevated choline/creatine levels and cognitive deficits in HCV patients, but no associations were found with any other variable, including fatigue. It is difficult to determine what the fatigue status of patients was in this study because of insufficient data. It is reported that there was a trend towards increasing fatigue in the PCR positive group when compared with the PCR negative group, but that the difference was not significant. However, mean scores for the Chalder fatigue scale (all groups) were not reported, nor was there any report of comparisons between the two study groups and normal controls. In addition, no prevalence rate is given for fatigue in any group. Given the thoroughness of the study and the amount of space given to the discussion of depression, it is quite possible that the results for fatigue were unremarkable and were therefore not reported. The finding that the PCR negative/HCV antibody positive group who had cleared the virus had no evidence of cognitive deficits is interesting, mostly because this is in contrast to what others would later find (e.g. Weissenborn et al., 2006).

Author: (53) S. Wessely & C. Pariante, 2002: Fatigue, Depression and Chronic Hepatitis C Infection Psychological Medicine, Vol. 32, p.p. 1-10. Review of Fatigue Studies in HCV. England. A review of the literature on hepatitis C, fatigue and depression.

Commentary: This review covers most of the same studies as Part 1, of the present review, but reaches different conclusions. Wessely and Pariante argue that because high prevalence rates for fatigue have been found in HCV infected patients that doesn’t mean that fatigue is necessarily related to HCV. They point out that fatigue is very common in the general population and may be as high as 20% for males and 30% for females, although they do not say how fatigue was measured in these reference studies. They mention that fatigue is also common in many illnesses and can persist even after successful treatment of those illnesses. The authors propose that depression, anxiety, IDU status, lack of exercise and especially the psychological impact of being diagnosed with HCV infection are more likely to be the cause of fatigue in HCV patients than the virus or liver damage.

Their main criticism of HCV fatigue research therefore, is that none of the studies they examined, with the exception of Rodger et al., 1999, had controlled for the impact of diagnosis in HCV infected patients. Other criticisms made by the authors are that many of the studies which they examined were published as abstracts or preliminary reports, were poorly controlled and had important biases which were not controlled for in the analyses, e.g. referral bias, depression and IDU status. Their general conclusion is that there is no evidence of an association between HCV infection and fatigue (they collectively refer to the evidence as “anecdotal”) and some evidence of an absence of a relationship.

The three studies which Wessely and Pariante claim show no evidence of relationship between fatigue and HCV include the studies by Dale (1991), Hoofnagle (1997) Rodger (1999). If the reader has read Part 1 of this review they will be aware that these are the three most controversial studies of the HCV research literature up until that time.

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We argued in Part 1 of this review that Dale’s testing for HCV infection in chronic fatigue syndrome patients (CFS), did not provide any information about fatigue in HCV infection.

We also argued that the results of Hoofnagel’s study, because they showed that a so called normal control group had a fatigue prevalence rate of 70%, while HCV patients had only a 60% prevalence rate, indicated serious problems either with the health of the control group or with the measurement of fatigue and hence the validity of the study. Hoofnagle’s study is described by W&P as “carrying the most weight” of all the studies they reviewed.

Finally in Rodger’s study, which we have earlier discussed at great length, there was very little difference between the fatigue scores of those who knew their diagnosis and those who did not (they were both abnormal), but Wessely and Pariante interpret fatigue found in the patients who did not know their diagnosis as probably caused by their IDU status, however there is no evidence from the HCV fatigue literature to support the view that IDU is the cause of fatigue and a number of studies which show that it is not.

Wessely and Pariante’s insistence that only those studies, which have measured fatigue prior to disclosure of HCV diagnosis, should be accepted as valid is not realistic and very difficult to achieve even in blood donors whom Wessely and Pariante think are the most suitable candidates for such studies. The fact is that Rodger’s study and Cordoba’s (2003), study, are the only studies that ever managed to fulfil Wessely and Pariante’s major criteria for validity.

However, it is, possible to control for the confounding effects of diagnosis, for example, one way is to exclude all patients with a psychiatric diagnosis from HCV fatigue studies. This is what Hassoun (2002) did in a part replication of Hoofnagle’s study and found that fatigues were elevated in HCV non-depressed patients with no comorbid psychiatric history. This would challenge Wessely and Pariante’s conclusion.

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Author: (54) T Poynard et al, 2002: Fatigue In Patients With Chronic Hepatitis C. Journal of Viral Hepatitis, Vol 9, 2002, pp 295-303. Long-term Prevalence Study of Fatigue in HCV. France.

Methods: Patients were 1614 (Male = 876 (54%); Mean age = 46.7 yrs) with chronic HCV, assessed between 1993 -1997. Due to the large number of participants in this study the authors were able to assess many variables thought to be linked with fatigue: age, gender, mode of infection, duration of infection, alcohol intake, viral load, genotype, fibrosis stage, cirrhosis and ALT levels. In addition, other extrahepatic manifestations, less frequently assessed, were also investigated and compared with fatigue: depression, renal insufficiency, purpura, arthralgia, myalgia, paresthesia, sicca syndrome, pruritus, cryoglobulinemia, diabetes, benzodiazepine use, liver inflammation, thyroid stimulating hormone, thyroxine level and antithyroid antibodies. Fatigue was measured by a simple questionnaire that included other symptoms and was rated as none, moderate (not impairing activity), severe (impairing activity). Mode of infection was: transfusion 42%, IDU 23%, and the remaining 35% unknown.

Aim of Study: To assess the prevalence of fatigue in patients with chronic HCV and to determine whether there is an association with other clinical and biological extra hepatic manifestations, associations between fatigue and liver disease (fibrosis stage and activity grade), viral characteristics (mode of infection, genotype and viral load) and alcohol consumption Results: Fatigue was present in 861 (53%) and severe fatigue in 276 (17%). There was a significant association between fatigue and age (50+ years), female gender, fibrosis stage 3 (precirrhotic), cirrhosis, depression and purpura. Independent of these associations fatigue was associated with arthralgia, myalgia, parasthesia, sicca syndrome and pruritus. When moderate fatigue was compared to severe fatigue there were more people in the latter group who were over 50 years and who had a higher prevalence of renal insufficiency, arthralgia, myalgia and pruritus. There were no significant associations between fatigue and viral load, genotype, alcohol consumption, cryoglobulinaemia or abnormal thyroid function. Depression was significantly associated with fatigue in 5%, only 2% had depression and no fatigue.

Poynard notes that 53% of the total sample fulfilled the criteria for Chronic Fatigue Syndrome.

This is in contrast to the findings of an earlier study (Dale, 1991 â&#x20AC;&#x201C; see this study for CFS criteria). Poynard cites Barkhuizen, Carithers, Foster, Rodger, Bonkovsky, Ware and Forton's studies as each providing evidence for an as yet unknown, biological process underlying fatigue in HCV (all of these studies are reported in this review).

Commentary: This is the largest study of fatigue in this review; it is also the most comprehensive. In addition to those variables most usually examined by HCV fatigue studies e.g. fibrosis, ALT, method of infection, this study examined a large number of extrahepatic manifestations of HCV infection and compared them with fatigue. The study was highly prescient It was begun in December 1993, and continued until the end of 1997. Apart from an abstract published in 1999* it took almost 5 years for the study to be published. By the time the study was published, 9 years after it was begun, much more was known about fatigue in HCV infection and the assessment methods were much more sophisticated than the simple self-devised fatigue test used by Poynard back in 1993, in particular depression was poorly assessed.

Unfortunately, Poynard had little choice about which fatigue test to use as there were no validated fatigue tests in France in 1993, and once he had started the study he was locked in to using the same assessment measures until its end. Although the study found a significant association between fatigue and liver disease i.e. stage 3 fibrosis and cirrhosis, it by no means suggests that fibrosis is the cause of fatigue as a number of other variables were also

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associated with fatigue and because correlations were not performed it’s not possible to say what the amount of explained variance for each symptom was i.e. their percentage contribution to fatigue. Poynards statement that everyone in his study fulfilled the criteria for chronic fatigue syndrome (CFS) seems unlikely, but he may have just been referring to the first part of the criteria i.e. the presence of continual fatigue for six months or longer. Although the study may have seemed a little dated when it first appeared it provided important new information about the relationship between fatigue and a large number of extrahepatic manifestations; it also confirmed the findings of a number of other studies. Poynard and his fellow researchers have been among the foremost pioneers in the investigation of many aspects of HCV infection – the amount of observation, thought and effort they put into this study, and their other studies, is salutary. *We did not include this abstract in the review as the results of the statistical analysis in the abstract showed an association between alcohol and fatigue, which was not found by a later analysis i.e. the one used in this full text version.

Author: (55) Cacoub, P. et al., 2002: “Impact of treatment on extra hepatic manifestations in patients with chronic hepatitis C.” Journal of Hepatology, Vol. 36, Issue 6, June, p.p. 812-818.

Methods: This study was a treatment arm of Poynard’s (2002) study of fatigue and extrahepatic manifestations. In this study the same research team but different first author focus on the impact of Interferon treatment on fatigue and extra-hepatic manifestations. The study began in 1994 and ended in December 1997. Of the original 1614 patients, most were excluded due to missing assessment data. Of the 431 HCV infected patients (Female = 189; combined Mean age = 49 years) who took part in the study, 76 were untreated, the remaining 355 received Interferon treatment. The measures used in this study were identical to those used in the earlier study for fatigue and extrahepatic manifestations. All 431 patients were assessed at baseline, every six months and at end of follow-up (a period of18 months).

Prevalence rates for fatigue and extrahepatic manifestations for each of the four groups, untreated, SVRs, relapsed patients and non-responders were compared at baseline and at 18 months; an additional comparison was made between the fatigued vs. non-fatigued SVRs. The author states that those who took part in this study had more liver damage, were older, and had more symptoms than the original group.

Aim of Study: “The aim of this study was to assess the prevalence of fatigue and other extrahepatic manifestations in a large single-centre cohort of patients with chronic hepatitis C before any treatment and to evaluate the effect of a sustained virological response to anti-viral therapy.

Factors associated with these extrahepatic manifestations prior to treatment and during longterm follow-up in treated and untreated patients were also investigated.”

Results: At baseline (N=431) there was no significant difference in fatigue or any other extra-hepatic manifestations between the four groups, no-treatment (N=76), SVRs (N=83), relapsers (N=47) and non-responders (N=225). At the end of follow-up all those treated with Interferon, irrespective of whether they had cleared the virus or not had a reduction in all extrahepatic manifestations. However, when prevalence rates for the end of follow-up were compared to baseline prevalence rates for each group only those with a sustained viral response (SVR) showed a significant improvement, but on two variables only, fatigue (baseline, N=58% vs. month 18, N=31%) and cryoglobulinemia (baseline, N=48% vs. month 18, N=6%). There was no significant improvement in any other extra-hepatic manifestation in any of the three treatment groups. When severity of fatigue was compared between each of the treatment groups, 35% of SVRs showed a reduction in one grade or more of fatigue, whereas in the other treated groups it was only 22%. To determine what effect depression had on the

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fatigue prevalence rates of SVRs, baseline and end of follow-up fatigue prevalence rates were compared between depressed (baseline fatigue, N=77% vs. month 18, N=54%) and non-depressed patients (baseline fatigue, N=54% vs. month 18, N=27%), even in those who were depressed there was still a significant reduction in the prevalence of fatigue. The final comparison was between SVRs (N=26) who remained fatigued at month 18 and SVRs (N=57) who were without fatigue at month 18. SVRs who remained fatigued had significantly more extra-hepatic manifestations including arthralgia and myalgia while depression was higher but not significantly; the proportion of women in this group was also significantly higher when compared with the non-fatigued SVRs. Commentary: Cacoub and colleagues admit that the interpretation of their results are speculative. They note that the reduced fatigue and cryoglobulinemia in the SVR group can be ascribed to liver damage (see explanation of this theory in Poynard, 2002). However, in the SVRs who remained fatigued, Cacoub attributes the cause of their fatigue to the high baseline levels of fatigue in the community (cause unknown), citing a single study by Wessley (2001) as support for this explanation. He discounts depression as a possible cause of fatigue as only 10% of his patients were depressed. Cacoub and colleagues expected a complete reduction in extrahepatic manifestations and were surprised that it was only partial. They further speculate that the follow-up period may not have been long enough for symptoms to completely resolve. They cites Ware (1999), and Bonkovskyâ&#x20AC;&#x2122;s (1999) Interferon/QoL studies, which produced results similar to their own, but note that the SF-36 used in the latter studies is a generic instrument, while they specifically measured fatigue.

This study is an anomaly, begun in 1993, finished in 1997, but not published until 2002. In the interim 1997-2002, the nature of fatigue studies had changed. These later studies were better designed, used standardised fatigue tests, found no association between fatigue and fibrosis/cirrhosis and did not favour a liver damage theory of fatigue. The evidence since 2002 also does not support a liver damage theory of fatigue. Cacoub and colleagues propose two alternative explanations for their results. The first is that the test used to measure fatigue may not have been sensitive enough to discriminate between different levels of fatigue; secondly the presence of depression was assessed on the basis of antidepressant use rather than direct assessment. Both these factors may have distorted the final results. It is interesting to note that Cacoub and colleagues mention the possibility that symptoms may be due to HCV infection of the brain (Forton, 2001), but do not apply this theory as an explanation for the partial but not complete disappearance of extrahepatic manifestations in patients who had a sustained viral response to Inteferon. Although this study, as we have shown, had a number of problems, in the final analysis it is still worthy of our admiration given that this was first study to examine fatigue and report the measure used. It also predates Desmetâ&#x20AC;&#x2122;s (1994) article criticising researchers for ignoring fatigue and other symptoms in viral hepatitis.

Author: (56) Hassoun Z. et al, 2002: Assessment of fatigue in patients with chronic HCV using the Fatigue Impact Scale. Digestive Diseases and Sciences. Vol. 47, No. 12, Dec 2002, p.p.

2674-268. Fatigue/Validation Study. Quebec, Canada.

Methods: The study was composed of ninety-two patients with chronic HCV infection, 42% with mild to moderate fibrosis and 38% with severe fibrosis or early cirrhosis (Female = 39, Male = 53; combined Mean age = 46.32 yrs). Of the 92 patients, 62 were liver unit patients who had complained of fatigue. The remaining 30 were blood donors who had been screened for HCV and were found to be antibody positive and not complaining of symptoms. All HCV patients were screened for coinfection and other factors that may influence fatigue. There were 2

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control groups, a primary biliary cirrhosis (PBC) control group of 116 patients (Female = 103, Male = 3; combined Mean age = 52.7 yrs) and a healthy blood donor control group (Female = 108, Male = 105; combined Mean age = 40.8 yrs) both were assessed on the FIS and their scores compared. Severity of fatigue on the FIS was compared within the HCV group to age, gender, symptomatic versus asymptomatic, IDU, alcohol, ALT liver inflammation, work status, duration of disease, fibrosis and viral load. Psychological disorders, as well as treated depression were excluded from this study.

Aim of Study: The aims were several; further validation of the French version of the FIS as an assessment tool of fatigue in HCV; to examine whether there is a relationship between fatigue severity and those variables mentioned in the previous column i.e. age, gender, viral load etc; to compare FIS scores between the HCV group and two control groups i.e. a group of healthy blood donors and a group of patients with PBC. The study was also a part replication of the study by Hoofnagle et al. (1997).

Results: Statistical analyses of the French version of the fatigue impact scale (FIS) showed it to have excellent validity and reliability. All the FIS scale score inter-correlations were statistically significant. Comparison of fatigue scores between the HCV group and the two control groups showed that the HCV group had significantly higher levels of fatigue than the healthy blood donors group and significantly lower levels of fatigue than the PBC group. In order to establish a cut-off point for disabling fatigue the author’s used the 90th percentile* of the FIS scores for the healthy blood donors group. Scores above FIS = 1.24 were considered disabling fatigue while scores lower than FIS = 1.24 were considered as normal fatigue. Thirty eight (41%) of the total HCV group had FIS scores higher than 1.24 and could be thus considered as having disabling fatigue. It should be noted that the 38 patients either came from the original 62 patients who had complained of fatigue or the 30 HCV positive blood donors. By contrast, the non-symptomatic group had FIS scores lower than 1.24 (i.e. normal fatigue). When FIS scores for the HCV group were compared with age, gender, symptomatic vs. non-symptomatic**, IDU vs. non-IDU, alcohol use, ALT levels, liver inflammation scores, duration of infection, fibrosis scores and work status only the latter was significantly associated with fatigue. Specifically, those who were not working had significantly worse fatigue than those who were working. Four of the 40 questions in the FIS were found to predict disabling fatigue: “normal day-to-day events are stressful to me”, “I am less able to provide financial support for myself and family”, “I require more frequent or longer periods of rest” and “I am more irritable and easily angered”. th

*The 90 percentile of the FIS for healthy blood donors means that 90% of that group had scores below that score i.e. 1.24, and the remaining 10% all had higher scores. It is a convention among clinical researchers to accept scores in a normal population which are th higher than the 75 percentile as being in the “clinical range” i.e. abnormal. Hassoun et al., in th using the 90 percentile are being quite conservative. **We had a problem with the means reported for these two groups – see Appendix.

Commentary: This is an excellent study. What distinguishes it from previous HCV fatigue studies is that firstly, it excluded psychopathology thereby avoiding the problem of ”knowledge of diagnosis” mentioned by other authors (Rodger, 1999; Wessley & Pariante, 2002); secondly, the severity of fatigue was measured and compared with a normal healthy control and a PBC control group; and thirdly to avoid the problem of “referral bias”, recently diagnosed blood donors with HCV who had not complained of fatigue were included in the study. In addition, fatigue was compared with most variables thought to be a potential “confounders” in previous studies.

Hassoun et al.’s conclusions conflict with those reported by Hoofnagle et al. (2002). Hassoun suggests that Hoofnagle’s (2002) findings may be explained by the large numbers of people with “normal fatigue” in both HCV patients and healthy volunteers. This is similar to what Hassoun et al. also found in their own study, but is obscured in Hoofnagle et al.’s study

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because fatigue severity was not reported. Although Hassoun et al.â&#x20AC;&#x2122;s research design was excellent nonetheless close examination of the results reveals several statistical errors. In particular, a mistake is evident in the calculation of the means of the symptomatic and nonsymptomatic sub-groups which may explain the reporting of no statistically significant difference in fatigue severity between the two groups. If the error is corrected then a large difference is evident and likely to be significant (see Appendix). If there were a difference in the severity of fatigue between the symptomatic vs. non-symptomatic groups it would not alter the main findings of the study, and would lend further support to the findings of Foster et al, (1999) who found that recently diagnosed HCV patients had significantly less fatigue than patients who had been infected for some time.

Author: (57) Jennifer McDonald et al 2002: Fatigue and psychological disorders in chronic hepatitis C. Journal of Gastroenterology and Hepatology (2002) 17, 171-176 Psychological study.

Australia.

Methods: 115 patients (Male = 76, Female = 39, combined Mean age = 37yrs) with chronic HCV referred to a hepatology unit were assessed using the fatigue impact scale (FIS) and 50 questions from the symptom check list 90R (SCL-90-R) measuring depression, anxiety, somatization, interpersonal sensitivity and hostility. Scores from these two questionnaires were first compared with historical norms, then entered into a multiple regression analyses that also included IDU, ALT, present and past alcohol use and fibrosis results. Five patients had cirrhosis, mode of infection was IDU = 36, transfusion = 6, tattooing = 7 & unknown = 13. The remaining 66 patients had 2 or more possible modes of infection.

Aim of Study: "â&#x20AC;Ś.to examine the relationship between fatigue and biological/psychological measures".

Results: 100 (83%) of patients reported fatigue as their main symptom. Scores on the FIS were about the same as for those with multiple sclerosis, so we can assume that they were significantly worse than for a normal population. FIS scores were significantly correlated with all 5 items on the SCL-90-R, with depression showing the strongest correlation. Fibrosis score (n=65) and past IDU were also significantly but weakly correlated with fatigue. No other measures were significantly correlated with fatigue.

Commentary: This study is quite similar to its predecessors i.e. Mahl et al (1996), Nelles et al (1996) and Dwight et al (2000). All of these three studies used validated fatigue measures and investigated the relationship between fatigue and depression. However, both of these earlier studies were reported only as abstracts and the study by Dwight et al. was less concerned with non-psychiatric variables e.g. mode of infection. In this study correlations were performed between the five variables taken from the SCL-90R i.e. depression, anxiety, hostility, interpersonal sensitivity, somatization (complaining about bodily symptoms for which no clinical evidence can be found) and also, ALT levels, alcohol abuse, IDU and fibrosis score. When all 7 variables were entered into a regression analysis it was found that 3 variables accounted for 70% of the variance in fatigue scores i.e. depression 62%, somatization 5% and interpersonal sensitivity 3%. However, when a second regression analysis was performed with the depression scores removed, somatization and interpersonal sensitivity accounted for 68% of the variance in fatigue scores. The statistical approach used by this study makes interpretation of the relationship between the various predictors and fatigue complex. They imply that depression is less important than either somatization or interpersonal sensitivity in predicting fatigue. However, the statistical approach used in this study does not warrant this conclusion.

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Author: (58) Cordoba, J. et al. 2003: Labelling May Be an Important Cause of Reduced Quality of Life in Chronic Hepatitis C. American Journal of Gastroenterology, Jan. 2003. Letters to the Editor. P.p. 226-227. Knowledge of diagnosis/QoL. Spain.

Methods: This study consisted of 2 groups of HCV patients all of whom were blood donors identified at the same blood bank and referred to a liver unit. Group A (N=17, combined mean age=40 yrs, Male = 14, Female =3) were recent referees who were assessed for QoL on the SF36 at the same clinical interview at which they were first informed of their HCV diagnosis. Group B (N=72, combined Mean age = 58, Male = 28, Female = 44) consisted of HCV patients who had been identified and diagnosed more than 2 years previously (Mean = 5yrs) who were assessed on the SF36 during the same time period as group A. Total SF36 scores for the 2 groups were compared with scores for general population norms and also with scores for histological and biochemical variables.

Aim of Study: Not stated, but would be to test the hypothesis stated in the title of this study.

Results: Total SF-36 Scores for Group A (unaware of diagnosis) were not significantly different from those for Spanish SF-36 general community norms. However, total SF-36 scores for group B (aware of diagnosis) were significantly lower those for general population norms. No scores or comparisons are reported for the 8 SF-36 scales which make specific symptoms and their contribution to lowered QoL impossible to assess. This study contains some important clinical observations, namely that the researchers report witnessing the decline of QoL in asymptomatic HCV patients over time as a consequence not only of HCV diagnosis, but as a part of the “medical process” e.g. blood tests, biopsies, which are a corollary of diagnosis.

However, it is not clear that these observations were measured in any systematic way that could be used as evidence in this study.

Commentary: This study was reported only as a letter to the editor, which is surprising given the importance of its aim and the difficulties involved in assessing symptoms in patients prior to them being informed of their diagnosis. Unfortunately only overall QoL scores are given and it is not possible to say anything specifically about fatigue.

Author: (59) R. Hogg et al, 2003: Health and socioeconomic status differences among antibody hepatitis C positive and negative transfusion recipients, 1986 -1990. Canadian Journal of Public Health. Issue 2, pp.130-134. Survey. Canada.

Methods: 241 patients antibody positive for HCV (Male = 52%, Median age = 50yrs) and 222 patients antibody negative for HCV (Male = 52%, Median age = 65yrs) were assessed on measures of health and socio-economic status. All patients had been transfused sometime between 1986 and 1990. This survey was part of an HCV look-back campaign carried out in the Canadian province of British Columbia involving 38,989 patients; of these1,948 were found to be HCV antibody positive and the patients in this study are a subset of that population. The HCV antibody positive patients were part of a class action lawsuit and had been referred to ‘the study by lawyers’. The HCV antibody negative patients, i.e. those who had been transfused during the same period but who had not been infected with HCV, were recruited as volunteers for

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the control group. The study was conducted during October 1998 and February 1999. The survey elicited information for the 12-month period before assessment (consisting of demographic measures, health status measures and the following 4 subjective measures: The Fatigue Severity Scale (FSS), the Rand 36* Item Health Survey, the Epworth Sleepiness Scale and the Illness Intrusiveness Rating Scale). Scores from each of the above assessment measures were compared between the HCV group and controls. For the HCV group a regression analysis was performed to ascertain which variables, were likely to be associated with HCV infection *Essentially the same as the SF-36 QoL measure Aim of Study: “…. was to characterize the health status, socioeconomic and disease symptoms of anti HCV positive and negative transfusion recipients.”

Results: Scores on all 4 subjective measures, including the Fatigue Severity Scale, showed a significantly poorer outcome for the HCV group compared with the normal control group. The regression analysis revealed that being HCV antibody positive was associated with having 2 or more clinical symptoms (physiological rather than subjective), being male, being of younger age, having a deterioration in health status compared to 10 years previously and having high scores on illness intrusiveness.

Commentary: This was a Canadian government sponsored initiative and therefore the focus was more on demographic and physiological symptoms rather than subjective symptoms. However, for some unknown reason there was no assessment of liver pathology and also no assessment of psychiatric symptoms. With regard to subjective symptoms, which included fatigue, no prevalence rates or mean scores were reported. We know only that the HCV group was significantly more fatigued than controls. The study may have had an important potential bias, noted by the authors, which was that patients in the study were not recruited randomly (i.e. those who were first to come forward to claim compensation may have had worse health status than those who came later). However, the authors also note that they had no control over the referral process, which was entirely in the hands of lawyers involved in the compensation claims. Furthermore, while there may have been a potential bias the authors’ state that it was most likely very small since other demographic and clinical data suggest that the participants in their study appear to be a representative sample of HCV infected blood transfusion recipients. It’s not clear if the results of this study were used as evidence in the compensation claim, but if the study participants thought that it might be, this may have tempted them to exaggerate their symptoms thus introducing another bias in the study.

Author: (60) Cordoba, J. et al., 2003: “Quality of life and cognitive function in hepatitis C at different stages of liver disease.” Journal of Hepatology, Vol. 39, p.p. 231- 238.

Methods: Participants in this study were 120 HCV infected patients, all interferon candidates, selected from a hospital outpatient clinic and allocated to one of three groups: a chronic HCV group (without cirrhosis) (N=40): a group with compensated cirrhosis (N=40); and a group with decompensated cirrhosis (N=40). There was a high percentage of newly diagnosed blood donors in each group, e.g. in the chronic HCV group 83%. The mean age for all groups was

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56 ± 6 years with an age range of 45 to 65 years; gender was balanced in each group (i.e. 20 females and 20 males in each group). Patients were excluded if they had disorders or symptoms likely to affect cognition with the exception of 9 patients in the compensated and 31 in the de-compensated cirrhosis groups who were being treated with beta-blockers e.g. propanalol or diuretics. This study also included a group of healthy controls (N=40), matched for age, gender and level of education. Patients and controls were assessed on the following measures: neuropsychological measures consisted of the Rey Auditory Verbal Learning Test (RAVLT), the Trail-making Test, the Symbol Digit Test, the Stroop Test, Grooved Pegboard, Judgment of Line, Hooper Visual Organization and controlled Word Association Tests.

Depression was measured on the BDI and anxiety on the State/Trait Anxiety Test. QoL was measured on the SF-36. Statistical comparisons of scores on the above measures were made between each of the 3 HCV groups and between each group and controls.

Aim of Study: “Our aim was to investigate the influence of cognitive function on HRQoL and explore possible associations between HRQoL and the clinical characteristics of the patients.”

Results: Neuropsychological results were normal in the chronic HCV and compensated cirrhotic groups when compared to controls. The de-compensated cirrhosis group, however, showed significant cognitive deficits in attention, motor and executive functioning. Similarly with depression and anxiety, only the de-compensated cirrhosis group showed significantly worse scores on those two measures compared with controls. SF-36 scores became worse with increasing liver disease severity. However, only the compensated and de-compensated groups had significantly different SF-36 scores compared with controls and, as well, with each other. The chronic HCV infected group had only one SF-36 scale, role physical (RP), which was significantly worse compared with controls. The fatigue scores were within normal range.

When only those FS-36 scores that measured physical function (as opposed to psychological) were compared for each of the three groups with those of controls, all three groups scores were significantly lower (worse). In order to determine which variables best predicted poor SF-36 scores a multiple regression analysis*was performed which showed that treatment with beta-blockers or diuretics was significantly correlated with poor SF-36 scores in the de-compensated but not the compensated cirrhosis group. The author’s interpretation of his results is that poor QoL is more likely caused by some unknown mechanism of the virus rather than liver disease by itself (although progressive liver damage tends to further reduce QoL). Cognitive deficits, depression, and anxiety were found only in patients with de-compensated cirrhosis; however, these do not appear to be related to poor QoL. Only treatment with beta-blockers or diuretics was significantly correlated with poor SF36 scores. *This was a post-hoc analysis. (See Rodger’s Reply to Forman (2000), for an example) Commentary: This is the second HCV QoL study by the same authors and was published only a few months after their first study. In the earlier study there was no assessment of cognitive deficits and the QoL results of that study are inconsistent with what was found in this study. Previous cognitive studies in HCV infection, have found significant cognitive deficits, fatigue and depression in the absence of cirrhosis. However, in this study the results of the chronic HCV infected group (i.e. non-cirrhotic) showed no evidence of significant cognitive deficits and neither reductions in QoL (including fatigue on SF-36*, VT scale), depression nor anxiety. The reasons for these findings are unclear but may be due to one or more of the following: the cognitive tests used were different from those of previous studies which have found deficits; as acknowledged by the authors themselves the study was statistically underpowered reducing the likelihood of finding a statistical difference when one may in reality exist. Other authors have commented on the failure of this study to find cognitive deficits in HCV patients.

In her 2004 cognitive study, McAndrews cites this study but makes no attempt to explain the inconsistency. Weissenborn (2006, 2009) reviews the findings of this study twice. In her 2006 study, Weissenborn suggests that the results may be explained the use of different cognitive tests. In her 2009 review, however, her explanation is more elaborate. She states

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that a subgroup of this study were newly diagnosed blood donors who may not have been infected long enough to develop cognitive and other symptoms of HCV infection. However, Foster (1998), found significantly worse SF-36 scores in a similar group, i.e. all blood donors with only mild liver disease when compared to a healthy control group. Since “duration of symptoms”, as far as we are aware, has never been examined by any study of HCV infected patients there is no way of ascertaining how long it takes symptoms to manifest after infection. * Only one previous study had found no significant difference in QoL scores (including fatigue) between HCV patients and controls (Hunt, 1997).

Author: (61) Sandra M Gifford et al., 2003: Australian Women’s experiences of living with hepatitis C virus: Results from a cross sectional study. Journal of Gastroenterology and Hepatology, Vol 18, p.p., 841-850. Community Survey. Australia.

Methods: 400 women living in the community contacted through a range of recruitment strategies completed questionnaires with 123 items looking at a number of issues e.g. medical care, treatment disclosure, discrimination, concerns about sexual relationships and symptoms.

They were also asked to complete the SF12 Health Related QoL and 3 items from the Hepatitis Quality of Life Instrument (HQLI). Approximately half of these 400 women were current IDUs. Aim of Study: To provide the first social study of Australian women’s experiences living with HCV. The author states that in most previous studies of HCV current women IDUs have been ignored.

For that reason she made sure that they were well represented in her sample.

Results: 58% of women reported having experienced symptoms of HCV: 204 (44%) had fatigue, 114 (25%) had nausea, 66 (14%), had emotional/psychological problems. Almost half the women in the sample had received poor treatment by a health professional because of their HCV. Their health status was significantly lower than that for normal women in the local community.

Scores on the SF12 for physical and mental health were highly correlated suggesting significant impairment in these areas due to their HCV. Commentary: As the author says this is a descriptive social study and not an epidemiological survey.

However, she separated her sample into different categories when describing health care and treatment. We are specifically referring to IDU status but unfortunately she did not do this for symptoms for the SF12 or the items from the HRQL scores. The sample was large and it would have been easy to do this. Since no other HCV study has assessed currently intravenous drug using women with hepatitis C we would have learned more about them as a specific group if the author had done so.

Author: (62) Robin Hilsabeck et al, 2003: Cognitive functioning and psychiatric symptomatology in patients with chronic hepatitis C. Journal of the International Neuropsychological Society, Vol 9, pp 847-854. Neuropsychological Study. U.S.A.

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Methods: 21 patients with chronic HCV, (F = 9; Mean age = 46 yrs), were assessed on a battery of neuropsychological tests measuring visuo-construction, learning, memory, visual memory, psychomotor speed and mental flexibility. Also assessed were depression (BDI*), subjective cognitive function (MOS Cognitive Scale), anxiety (BAI*) and fatigue (FSS*). The assessment of fatigue involved splitting the group (using a median split) into two groups i.e. those with “less fatigue” and those with “more fatigue”, and comparing both groups fatigue scores with scores for subjective cognitive deficits, depression and anxiety. * BDI – Beck Depression inventory, BAI – Beck Anxiety Inventory, FSS – Fatigue Severity Scale.

Aim of Study: To replicate Forton's (2002) study by comparing performance on neuropsychological tests with depression, anxiety, subjective cognitive dysfunction and fatigue scores.

Results: Of the 21 patients 47% showed one or more cognitive deficit. The highest percentage of cognitive deficits was 38%, on tasks involving visual scanning and tracking, psychomotor speed and working memory. The lowest percentage of cognitive deficits 9.5% was on tasks involving copying and recognition. Higher fibrosis scores were associated with greater cognitive dysfunction. Objective measures of cognitive dysfunction were not related to patients’ own ratings of cognitive dysfunction i.e. no significant differences on objective cognitive measures were found between those patients who had complained about cognitive deficits and those patients who had not. There were significant differences between the “less fatigue” group (N=10) and the “more fatigue” group (N=11) with the latter having higher scores on self-assessed cognitive dysfunction, depressive and anxious symptoms.

Commentary: This study had only 21 subjects, no control group and a very long list of known confounding variables that were not controlled for in the analyses, e.g. 9.5% were co-infected with HIV; 14.3% had type 2 diabetes; 4.8% had fibromyalgia; 19.1% a history of alcohol abuse and 23.8% were currently on interferon and ribavirin treatment during this study. In addition 55% were taking psychiatric medication and 82% of these were taking anti-depressants. Apart from a worrying lack of exclusion criteria it is highly unusual to test patients for depression while they are on antidepressant medication. We found the study impossible to interpret, as did Mc Andrews (2005), who sharply criticised the study for its lack of control. However as the author exhorts, the participants are typical of the sort of patients generally seen in veteran’s clinics.

Author: (63) M. Glacken et al, 2003: The experience of fatigue for people living with hepatitis C. A qualitative grounded theory. Journal of Clinical Nursing, March 1, Vol. 12, Issue 2. p.p. 244252. Qualitative Fatigue Study. Ireland.

Methods: 28 participants with HCV (Male = 8, Age range 36 – 64 years, PCR+ = 24) undertook in-depth interviewing (average 80 minutes) using a ‘grounded theory' approach*. Most of the participants were either from the Irish women’s Anti–D group or they had been infected through IDU. This was a qualitative study so the data, unlike the data in empirical studies, is not amenable to statistical manipulation. The interviewers sought to elicit comprehensive descriptions of fatigue as they apply to its nature, its physical, cognitive, and affective dimensions and its severity.

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* Grounded Theory is a Sociological Theory, developed in the late 1960s, from data based on dying hospital patients, Aim of Study: The research question was "what is the nature of the fatigue that individuals with hepatitis C experience". The aim of the study was to use the descriptions generated as a resource for practitioners, which might aid in the development of future interventions for fatigue.

Results: The authors note that most of the participants in this study were unable to articulate nominal descriptions of fatigue and could only describe their experiences through using metaphors, comparisons or the effect of fatigue on their daily activities. From an analysis of the interview data the most important finding was that there are two distinct types of fatigue in HCV infection, namely, chronic and idiopathic fatigue, the latter being the term given by the authors to fatigue that over time remits and then reappears, often without warning. In general the study found that the fatigue experienced by people with HCV whether chronic or idiopathic appears to be on more than one dimension. Below are examples of descriptions of chronic fatigue each of the three dimensions of fatigue and its severity.

Chronic Fatigue: “I am permanently tired. It is present even on wakening every morning. I am like an old engine trying to get started in the morning, trying to stoke myself up. It could take me 2 or 3 hours to get going.”

Physical Dimension: “It’s a feeing of heaviness. I just feel I am going to collapse with the weight of my body. It’s like having something continually dragging out of you.”

Cognitive Dimension: “Stupid is the only word for it. Thick kinda. A bit forgetful as well. It is very annoying. I have no concentration. I cannot learn during that time. I cannot read for any length of time, because. I just sort of lose it a bit” Affective Dimension: “Something comes upon me (when I am tired). People say I get a bit of a temper. Sometimes I am so bad tempered….what would come out of my mouth would shock me, myself.”

Severity: “You know I could put up with this fatigue every day, if I knew it would only be there for an hour or two. I could manage to do things around it but it’s when it comes and doesn’t lift for days. I really feel defeated. Everything has to be shelved. I just feel everything is beyond my reach, beyond my control, I suppose.”

Commentary: Excellent review of the literature and very well written. We thought the descriptions do not require any further explanation or commentary. This article is free on the Internet.

Author: (64) Gallegos-Orozoco, J. F. et al, 2003: Health–Related Quality of Life and Depression in Patients with Chronic Hepatitis–C. QoL Study: Archives of Medical Research Vol. 34 (2), p.p.

124-9. 2003 Mar-Apr. Mexico.

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Methods: 157 patients with chronic HCV, (F=71%, Age= 23.5% below age 45) seen at a referral Centre in Mexico City were assessed on their first visit and prior to interview (although they were aware of their diagnosis), on the SF36, the Zung Depression Scale and a self- devised 10 item questionnaire measuring illness understanding. All patients were interferon naïve.

Exclusion criteria were rigorous e.g. Interferon treatment, co-existing illness or disorder, alcohol or substance abuse and use of anti-depressant medication. Ninety-seven (61.8%) of the 157 patients had cirrhosis, Child-Pugh class: A=54, B=25 and C=18. Statistical comparisons were made between the scores of the 3 assessment measures. There was no control group in this study.

Aim of Study: “The aim of the present study was to evaluate HRQL and depression in a sample of Mexican patients naïve to treatment attending a tertiary-referral centre as well as to determine patient illness understanding and knowledge of disease.”

Results: When compared with scores for the general Mexican population QoL was significantly lower for HCV patients in all eight scales of the SF36, including the vitality scale (i.e. fatigue).

HCV patients who had cirrhosis Child-Pugh class B & C had significantly lower scores on SF36 scales that measure physical health than those who were Child-Pugh class A, or who did not have cirrhosis. Ninety-two (58.6%) patients were depressed on the Zung, and 9 (5.7%) had severe depression. There were no significant differences in depression scores when those with cirrhosis were compared with those without cirrhosis. When QoL scores were compared between depressed (N=92) and non-depressed (N=65), the depressed group had significantly poorer QoL than the non-depressed group. Results from the 10 item questionnaire assessing illness knowledge showed that 72.6% of patients had a poor knowledge of basic HCV information and their QoL scores were significantly lower on six domains compared to those who had some knowledge about HCV. There were no significant differences between the scores of those with cirrhosis versus those without cirrhosis on “knowledge of illness”. No association was found between QoL and gender, age or educational level.

Commentary: This study was well considered, rigorously controlled and well written. There are two notable findings. Firstly, the prevalence rate for depression (N=58.6) was surprisingly high and much higher than previous studies reported in this review. This may be specific to the Mexican environment but is noteworthy. The second finding was that HCV infected patients who had little knowledge of the disease, had significantly poorer QoL (including the vitality scale i.e. fatigue) than those who knew some basic facts about the course and treatment of HCV infection. The authors’ interpretation of the latter finding is that those who had little knowledge of HCV infection were more “psychologically distressed” as a result of their lack of knowledge and this was likely to impact on their QoL. The results would also suggest that the “psychological distress” might be due to the impact of diagnosis, which those who had some basic knowledge of HCV, managed to reduce by developing better coping skills from the information they had. However, because these patients were aware of their diagnosis when they took part in this study it is not possible to accurately assess how much of their symptomatology (including fatigue) may have been due to the negative psychological impact of diagnosis, which is probably why the authors say little about this topic. If the authors had compared depression scores between these two groups and found the group with little knowledge were significantly more depressed than the group with more knowledge of HCV, this would have added weight to the possibility of an “impact of diagnosis” effect, but they compared only QoL between the two groups. The idea of testing for knowledge of HCV before assessing patients, though it may seem obvious, was clever and it is surprising that no other study has done the same.

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Author: (54) T Poynard et al, 2002: Fatigue In Patients With Chronic Hepatitis C. Journal of Viral Hepatitis, Vol 9, 2002, pp 295-303. Long-term Prevalence Study of Fatigue in HCV. France.

Methods: Patients were 1614 (Male = 876 (54%); Mean age = 46.7 yrs) with chronic HCV, assessed between 1993 -1997. Due to the large number of participants in this study the authors were able to assess many variables thought to be linked with fatigue: age, gender, mode of infection, duration of infection, alcohol intake, viral load, genotype, fibrosis stage, cirrhosis and ALT levels. In addition, other extrahepatic manifestations, less frequently assessed, were also investigated and compared with fatigue: depression, renal insufficiency, purpura, arthralgia, myalgia, paresthesia, sicca syndrome, pruritus, cryoglobulinemia, diabetes, benzodiazepine use, liver inflammation, thyroid stimulating hormone, thyroxine level and antithyroid antibodies. Fatigue was measured by a simple questionnaire that included other symptoms and was rated as none, moderate (not impairing activity), severe (impairing activity). Mode of infection was: transfusion 42%, IDU 23%, and the remaining 35% unknown.

Aim of Study: To assess the prevalence of fatigue in patients with chronic HCV and to determine whether there is an association with other clinical and biological extra hepatic manifestations, associations between fatigue and liver disease (fibrosis stage and activity grade), viral characteristics (mode of infection, genotype and viral load) and alcohol consumption Results: Fatigue was present in 861 (53%) and severe fatigue in 276 (17%). There was a significant association between fatigue and age (50+ years), female gender, fibrosis stage 3 (precirrhotic), cirrhosis, depression and purpura. Independent of these associations fatigue was associated with arthralgia, myalgia, parasthesia, sicca syndrome and pruritus. When moderate fatigue was compared to severe fatigue there were more people in the latter group who were over 50 years and who had a higher prevalence of renal insufficiency, arthralgia, myalgia and pruritus. There were no significant associations between fatigue and viral load, genotype, alcohol consumption, cryoglobulinaemia or abnormal thyroid function. Depression was significantly associated with fatigue in 5%, only 2% had depression and no fatigue.

Poynard notes that 53% of the total sample fulfilled the criteria for Chronic Fatigue Syndrome.

This is in contrast to the findings of an earlier study (Dale, 1991 â&#x20AC;&#x201C; see this study for CFS criteria). Poynard cites Barkhuizen, Carithers, Foster, Rodger, Bonkovsky, Ware and Forton's studies as each providing evidence for an as yet unknown, biological process underlying fatigue in HCV (all of these studies are reported in this review).

Commentary: This is the largest study of fatigue in this review; it is also the most comprehensive. In addition to those variables most usually examined by HCV fatigue studies e.g. fibrosis, ALT, method of infection, this study examined a large number of extrahepatic manifestations of HCV infection and compared them with fatigue. The study was highly prescient It was begun in December 1993, and continued until the end of 1997. Apart from an abstract published in 1999* it took almost 5 years for the study to be published. By the time the study was published, 9 years after it was begun, much more was known about fatigue in HCV infection and the assessment methods were much more sophisticated than the simple self-devised fatigue test used by Poynard back in 1993, in particular depression was poorly assessed.

Unfortunately, Poynard had little choice about which fatigue test to use as there were no validated fatigue tests in France in 1993, and once he had started the study he was locked in to using the same assessment measures until its end. Although the study found a significant association between fatigue and liver disease i.e. stage 3 fibrosis and cirrhosis, it by no means suggests that fibrosis is the cause of fatigue as a number of other variables were also

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associated with fatigue and because correlations were not performed it’s not possible to say what the amount of explained variance for each symptom was i.e. their percentage contribution to fatigue. Poynards statement that everyone in his study fulfilled the criteria for chronic fatigue syndrome (CFS) seems unlikely, but he may have just been referring to the first part of the criteria i.e. the presence of continual fatigue for six months or longer. Although the study may have seemed a little dated when it first appeared it provided important new information about the relationship between fatigue and a large number of extrahepatic manifestations; it also confirmed the findings of a number of other studies. Poynard and his fellow researchers have been among the foremost pioneers in the investigation of many aspects of HCV infection – the amount of observation, thought and effort they put into this study, and their other studies, is salutary. *We did not include this abstract in the review as the results of the statistical analysis in the abstract showed an association between alcohol and fatigue, which was not found by a later analysis i.e. the one used in this full text version.

Author: (55) Cacoub, P. et al., 2002: “Impact of treatment on extra hepatic manifestations in patients with chronic hepatitis C.” Journal of Hepatology, Vol. 36, Issue 6, June, p.p. 812-818.

Methods: This study was a treatment arm of Poynard’s (2002) study of fatigue and extrahepatic manifestations. In this study the same research team but different first author focus on the impact of Interferon treatment on fatigue and extra-hepatic manifestations. The study began in 1994 and ended in December 1997. Of the original 1614 patients, most were excluded due to missing assessment data. Of the 431 HCV infected patients (Female = 189; combined Mean age = 49 years) who took part in the study, 76 were untreated, the remaining 355 received Interferon treatment. The measures used in this study were identical to those used in the earlier study for fatigue and extrahepatic manifestations. All 431 patients were assessed at baseline, every six months and at end of follow-up (a period of18 months).

Prevalence rates for fatigue and extrahepatic manifestations for each of the four groups, untreated, SVRs, relapsed patients and non-responders were compared at baseline and at 18 months; an additional comparison was made between the fatigued vs. non-fatigued SVRs. The author states that those who took part in this study had more liver damage, were older, and had more symptoms than the original group.

Aim of Study: “The aim of this study was to assess the prevalence of fatigue and other extrahepatic manifestations in a large single-centre cohort of patients with chronic hepatitis C before any treatment and to evaluate the effect of a sustained virological response to anti-viral therapy.

Factors associated with these extrahepatic manifestations prior to treatment and during longterm follow-up in treated and untreated patients were also investigated.”

Results: At baseline (N=431) there was no significant difference in fatigue or any other extra-hepatic manifestations between the four groups, no-treatment (N=76), SVRs (N=83), relapsers (N=47) and non-responders (N=225). At the end of follow-up all those treated with Interferon, irrespective of whether they had cleared the virus or not had a reduction in all extrahepatic manifestations. However, when prevalence rates for the end of follow-up were compared to baseline prevalence rates for each group only those with a sustained viral response (SVR) showed a significant improvement, but on two variables only, fatigue (baseline, N=58% vs. month 18, N=31%) and cryoglobulinemia (baseline, N=48% vs. month 18, N=6%). There was no significant improvement in any other extra-hepatic manifestation in any of the three treatment groups. When severity of fatigue was compared between each of the treatment groups, 35% of SVRs showed a reduction in one grade or more of fatigue, whereas in the other treated groups it was only 22%. To determine what effect depression had on the

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fatigue prevalence rates of SVRs, baseline and end of follow-up fatigue prevalence rates were compared between depressed (baseline fatigue, N=77% vs. month 18, N=54%) and non-depressed patients (baseline fatigue, N=54% vs. month 18, N=27%), even in those who were depressed there was still a significant reduction in the prevalence of fatigue. The final comparison was between SVRs (N=26) who remained fatigued at month 18 and SVRs (N=57) who were without fatigue at month 18. SVRs who remained fatigued had significantly more extra-hepatic manifestations including arthralgia and myalgia while depression was higher but not significantly; the proportion of women in this group was also significantly higher when compared with the non-fatigued SVRs. Commentary: Cacoub and colleagues admit that the interpretation of their results are speculative. They note that the reduced fatigue and cryoglobulinemia in the SVR group can be ascribed to liver damage (see explanation of this theory in Poynard, 2002). However, in the SVRs who remained fatigued, Cacoub attributes the cause of their fatigue to the high baseline levels of fatigue in the community (cause unknown), citing a single study by Wessley (2001) as support for this explanation. He discounts depression as a possible cause of fatigue as only 10% of his patients were depressed. Cacoub and colleagues expected a complete reduction in extrahepatic manifestations and were surprised that it was only partial. They further speculate that the follow-up period may not have been long enough for symptoms to completely resolve. They cites Ware (1999), and Bonkovskyâ&#x20AC;&#x2122;s (1999) Interferon/QoL studies, which produced results similar to their own, but note that the SF-36 used in the latter studies is a generic instrument, while they specifically measured fatigue.

This study is an anomaly, begun in 1993, finished in 1997, but not published until 2002. In the interim 1997-2002, the nature of fatigue studies had changed. These later studies were better designed, used standardised fatigue tests, found no association between fatigue and fibrosis/cirrhosis and did not favour a liver damage theory of fatigue. The evidence since 2002 also does not support a liver damage theory of fatigue. Cacoub and colleagues propose two alternative explanations for their results. The first is that the test used to measure fatigue may not have been sensitive enough to discriminate between different levels of fatigue; secondly the presence of depression was assessed on the basis of antidepressant use rather than direct assessment. Both these factors may have distorted the final results. It is interesting to note that Cacoub and colleagues mention the possibility that symptoms may be due to HCV infection of the brain (Forton, 2001), but do not apply this theory as an explanation for the partial but not complete disappearance of extrahepatic manifestations in patients who had a sustained viral response to Inteferon. Although this study, as we have shown, had a number of problems, in the final analysis it is still worthy of our admiration given that this was first study to examine fatigue and report the measure used. It also predates Desmetâ&#x20AC;&#x2122;s (1994) article criticising researchers for ignoring fatigue and other symptoms in viral hepatitis.

Author: (56) Hassoun Z. et al, 2002: Assessment of fatigue in patients with chronic HCV using the Fatigue Impact Scale. Digestive Diseases and Sciences. Vol. 47, No. 12, Dec 2002, p.p.

2674-268. Fatigue/Validation Study. Quebec, Canada.

Methods: The study was composed of ninety-two patients with chronic HCV infection, 42% with mild to moderate fibrosis and 38% with severe fibrosis or early cirrhosis (Female = 39, Male = 53; combined Mean age = 46.32 yrs). Of the 92 patients, 62 were liver unit patients who had complained of fatigue. The remaining 30 were blood donors who had been screened for HCV and were found to be antibody positive and not complaining of symptoms. All HCV patients were screened for coinfection and other factors that may influence fatigue. There were 2

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control groups, a primary biliary cirrhosis (PBC) control group of 116 patients (Female = 103, Male = 3; combined Mean age = 52.7 yrs) and a healthy blood donor control group (Female = 108, Male = 105; combined Mean age = 40.8 yrs) both were assessed on the FIS and their scores compared. Severity of fatigue on the FIS was compared within the HCV group to age, gender, symptomatic versus asymptomatic, IDU, alcohol, ALT liver inflammation, work status, duration of disease, fibrosis and viral load. Psychological disorders, as well as treated depression were excluded from this study.

Aim of Study: The aims were several; further validation of the French version of the FIS as an assessment tool of fatigue in HCV; to examine whether there is a relationship between fatigue severity and those variables mentioned in the previous column i.e. age, gender, viral load etc; to compare FIS scores between the HCV group and two control groups i.e. a group of healthy blood donors and a group of patients with PBC. The study was also a part replication of the study by Hoofnagle et al. (1997).

Results: Statistical analyses of the French version of the fatigue impact scale (FIS) showed it to have excellent validity and reliability. All the FIS scale score inter-correlations were statistically significant. Comparison of fatigue scores between the HCV group and the two control groups showed that the HCV group had significantly higher levels of fatigue than the healthy blood donors group and significantly lower levels of fatigue than the PBC group. In order to establish a cut-off point for disabling fatigue the author’s used the 90th percentile* of the FIS scores for the healthy blood donors group. Scores above FIS = 1.24 were considered disabling fatigue while scores lower than FIS = 1.24 were considered as normal fatigue. Thirty eight (41%) of the total HCV group had FIS scores higher than 1.24 and could be thus considered as having disabling fatigue. It should be noted that the 38 patients either came from the original 62 patients who had complained of fatigue or the 30 HCV positive blood donors. By contrast, the non-symptomatic group had FIS scores lower than 1.24 (i.e. normal fatigue). When FIS scores for the HCV group were compared with age, gender, symptomatic vs. non-symptomatic**, IDU vs. non-IDU, alcohol use, ALT levels, liver inflammation scores, duration of infection, fibrosis scores and work status only the latter was significantly associated with fatigue. Specifically, those who were not working had significantly worse fatigue than those who were working. Four of the 40 questions in the FIS were found to predict disabling fatigue: “normal day-to-day events are stressful to me”, “I am less able to provide financial support for myself and family”, “I require more frequent or longer periods of rest” and “I am more irritable and easily angered”. th

*The 90 percentile of the FIS for healthy blood donors means that 90% of that group had scores below that score i.e. 1.24, and the remaining 10% all had higher scores. It is a convention among clinical researchers to accept scores in a normal population which are th higher than the 75 percentile as being in the “clinical range” i.e. abnormal. Hassoun et al., in th using the 90 percentile are being quite conservative. **We had a problem with the means reported for these two groups – see Appendix.

Commentary: This is an excellent study. What distinguishes it from previous HCV fatigue studies is that firstly, it excluded psychopathology thereby avoiding the problem of ”knowledge of diagnosis” mentioned by other authors (Rodger, 1999; Wessley & Pariante, 2002); secondly, the severity of fatigue was measured and compared with a normal healthy control and a PBC control group; and thirdly to avoid the problem of “referral bias”, recently diagnosed blood donors with HCV who had not complained of fatigue were included in the study. In addition, fatigue was compared with most variables thought to be a potential “confounders” in previous studies.

Hassoun et al.’s conclusions conflict with those reported by Hoofnagle et al. (2002). Hassoun suggests that Hoofnagle’s (2002) findings may be explained by the large numbers of people with “normal fatigue” in both HCV patients and healthy volunteers. This is similar to what Hassoun et al. also found in their own study, but is obscured in Hoofnagle et al.’s study

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because fatigue severity was not reported. Although Hassoun et al.â&#x20AC;&#x2122;s research design was excellent nonetheless close examination of the results reveals several statistical errors. In particular, a mistake is evident in the calculation of the means of the symptomatic and nonsymptomatic sub-groups which may explain the reporting of no statistically significant difference in fatigue severity between the two groups. If the error is corrected then a large difference is evident and likely to be significant (see Appendix). If there were a difference in the severity of fatigue between the symptomatic vs. non-symptomatic groups it would not alter the main findings of the study, and would lend further support to the findings of Foster et al, (1999) who found that recently diagnosed HCV patients had significantly less fatigue than patients who had been infected for some time.

Author: (57) Jennifer McDonald et al 2002: Fatigue and psychological disorders in chronic hepatitis C. Journal of Gastroenterology and Hepatology (2002) 17, 171-176 Psychological study.

Australia.

Methods: 115 patients (Male = 76, Female = 39, combined Mean age = 37yrs) with chronic HCV referred to a hepatology unit were assessed using the fatigue impact scale (FIS) and 50 questions from the symptom check list 90R (SCL-90-R) measuring depression, anxiety, somatization, interpersonal sensitivity and hostility. Scores from these two questionnaires were first compared with historical norms, then entered into a multiple regression analyses that also included IDU, ALT, present and past alcohol use and fibrosis results. Five patients had cirrhosis, mode of infection was IDU = 36, transfusion = 6, tattooing = 7 & unknown = 13. The remaining 66 patients had 2 or more possible modes of infection.

Aim of Study: "â&#x20AC;Ś.to examine the relationship between fatigue and biological/psychological measures".

Results: 100 (83%) of patients reported fatigue as their main symptom. Scores on the FIS were about the same as for those with multiple sclerosis, so we can assume that they were significantly worse than for a normal population. FIS scores were significantly correlated with all 5 items on the SCL-90-R, with depression showing the strongest correlation. Fibrosis score (n=65) and past IDU were also significantly but weakly correlated with fatigue. No other measures were significantly correlated with fatigue.

Commentary: This study is quite similar to its predecessors i.e. Mahl et al (1996), Nelles et al (1996) and Dwight et al (2000). All of these three studies used validated fatigue measures and investigated the relationship between fatigue and depression. However, both of these earlier studies were reported only as abstracts and the study by Dwight et al. was less concerned with non-psychiatric variables e.g. mode of infection. In this study correlations were performed between the five variables taken from the SCL-90R i.e. depression, anxiety, hostility, interpersonal sensitivity, somatization (complaining about bodily symptoms for which no clinical evidence can be found) and also, ALT levels, alcohol abuse, IDU and fibrosis score. When all 7 variables were entered into a regression analysis it was found that 3 variables accounted for 70% of the variance in fatigue scores i.e. depression 62%, somatization 5% and interpersonal sensitivity 3%. However, when a second regression analysis was performed with the depression scores removed, somatization and interpersonal sensitivity accounted for 68% of the variance in fatigue scores. The statistical approach used by this study makes interpretation of the relationship between the various predictors and fatigue complex. They imply that depression is less important than either somatization or interpersonal sensitivity in predicting fatigue. However, the statistical approach used in this study does not warrant this conclusion.

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Author: (58) Cordoba, J. et al. 2003: Labelling May Be an Important Cause of Reduced Quality of Life in Chronic Hepatitis C. American Journal of Gastroenterology, Jan. 2003. Letters to the Editor. P.p. 226-227. Knowledge of diagnosis/QoL. Spain.

Methods: This study consisted of 2 groups of HCV patients all of whom were blood donors identified at the same blood bank and referred to a liver unit. Group A (N=17, combined mean age=40 yrs, Male = 14, Female =3) were recent referees who were assessed for QoL on the SF36 at the same clinical interview at which they were first informed of their HCV diagnosis. Group B (N=72, combined Mean age = 58, Male = 28, Female = 44) consisted of HCV patients who had been identified and diagnosed more than 2 years previously (Mean = 5yrs) who were assessed on the SF36 during the same time period as group A. Total SF36 scores for the 2 groups were compared with scores for general population norms and also with scores for histological and biochemical variables.

Aim of Study: Not stated, but would be to test the hypothesis stated in the title of this study.

Results: Total SF-36 Scores for Group A (unaware of diagnosis) were not significantly different from those for Spanish SF-36 general community norms. However, total SF-36 scores for group B (aware of diagnosis) were significantly lower those for general population norms. No scores or comparisons are reported for the 8 SF-36 scales which make specific symptoms and their contribution to lowered QoL impossible to assess. This study contains some important clinical observations, namely that the researchers report witnessing the decline of QoL in asymptomatic HCV patients over time as a consequence not only of HCV diagnosis, but as a part of the “medical process” e.g. blood tests, biopsies, which are a corollary of diagnosis.

However, it is not clear that these observations were measured in any systematic way that could be used as evidence in this study.

Commentary: This study was reported only as a letter to the editor, which is surprising given the importance of its aim and the difficulties involved in assessing symptoms in patients prior to them being informed of their diagnosis. Unfortunately only overall QoL scores are given and it is not possible to say anything specifically about fatigue.

Author: (59) R. Hogg et al, 2003: Health and socioeconomic status differences among antibody hepatitis C positive and negative transfusion recipients, 1986 -1990. Canadian Journal of Public Health. Issue 2, pp.130-134. Survey. Canada.

Methods: 241 patients antibody positive for HCV (Male = 52%, Median age = 50yrs) and 222 patients antibody negative for HCV (Male = 52%, Median age = 65yrs) were assessed on measures of health and socio-economic status. All patients had been transfused sometime between 1986 and 1990. This survey was part of an HCV look-back campaign carried out in the Canadian province of British Columbia involving 38,989 patients; of these1,948 were found to be HCV antibody positive and the patients in this study are a subset of that population. The HCV antibody positive patients were part of a class action lawsuit and had been referred to ‘the study by lawyers’. The HCV antibody negative patients, i.e. those who had been transfused during the same period but who had not been infected with HCV, were recruited as volunteers for

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the control group. The study was conducted during October 1998 and February 1999. The survey elicited information for the 12-month period before assessment (consisting of demographic measures, health status measures and the following 4 subjective measures: The Fatigue Severity Scale (FSS), the Rand 36* Item Health Survey, the Epworth Sleepiness Scale and the Illness Intrusiveness Rating Scale). Scores from each of the above assessment measures were compared between the HCV group and controls. For the HCV group a regression analysis was performed to ascertain which variables, were likely to be associated with HCV infection *Essentially the same as the SF-36 QoL measure Aim of Study: “…. was to characterize the health status, socioeconomic and disease symptoms of anti HCV positive and negative transfusion recipients.”

Results: Scores on all 4 subjective measures, including the Fatigue Severity Scale, showed a significantly poorer outcome for the HCV group compared with the normal control group. The regression analysis revealed that being HCV antibody positive was associated with having 2 or more clinical symptoms (physiological rather than subjective), being male, being of younger age, having a deterioration in health status compared to 10 years previously and having high scores on illness intrusiveness.

Commentary: This was a Canadian government sponsored initiative and therefore the focus was more on demographic and physiological symptoms rather than subjective symptoms. However, for some unknown reason there was no assessment of liver pathology and also no assessment of psychiatric symptoms. With regard to subjective symptoms, which included fatigue, no prevalence rates or mean scores were reported. We know only that the HCV group was significantly more fatigued than controls. The study may have had an important potential bias, noted by the authors, which was that patients in the study were not recruited randomly (i.e. those who were first to come forward to claim compensation may have had worse health status than those who came later). However, the authors also note that they had no control over the referral process, which was entirely in the hands of lawyers involved in the compensation claims. Furthermore, while there may have been a potential bias the authors’ state that it was most likely very small since other demographic and clinical data suggest that the participants in their study appear to be a representative sample of HCV infected blood transfusion recipients. It’s not clear if the results of this study were used as evidence in the compensation claim, but if the study participants thought that it might be, this may have tempted them to exaggerate their symptoms thus introducing another bias in the study.

Author: (60) Cordoba, J. et al., 2003: “Quality of life and cognitive function in hepatitis C at different stages of liver disease.” Journal of Hepatology, Vol. 39, p.p. 231- 238.

Methods: Participants in this study were 120 HCV infected patients, all interferon candidates, selected from a hospital outpatient clinic and allocated to one of three groups: a chronic HCV group (without cirrhosis) (N=40): a group with compensated cirrhosis (N=40); and a group with decompensated cirrhosis (N=40). There was a high percentage of newly diagnosed blood donors in each group, e.g. in the chronic HCV group 83%. The mean age for all groups was

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56 ± 6 years with an age range of 45 to 65 years; gender was balanced in each group (i.e. 20 females and 20 males in each group). Patients were excluded if they had disorders or symptoms likely to affect cognition with the exception of 9 patients in the compensated and 31 in the de-compensated cirrhosis groups who were being treated with beta-blockers e.g. propanalol or diuretics. This study also included a group of healthy controls (N=40), matched for age, gender and level of education. Patients and controls were assessed on the following measures: neuropsychological measures consisted of the Rey Auditory Verbal Learning Test (RAVLT), the Trail-making Test, the Symbol Digit Test, the Stroop Test, Grooved Pegboard, Judgment of Line, Hooper Visual Organization and controlled Word Association Tests.

Depression was measured on the BDI and anxiety on the State/Trait Anxiety Test. QoL was measured on the SF-36. Statistical comparisons of scores on the above measures were made between each of the 3 HCV groups and between each group and controls.

Aim of Study: “Our aim was to investigate the influence of cognitive function on HRQoL and explore possible associations between HRQoL and the clinical characteristics of the patients.”

Results: Neuropsychological results were normal in the chronic HCV and compensated cirrhotic groups when compared to controls. The de-compensated cirrhosis group, however, showed significant cognitive deficits in attention, motor and executive functioning. Similarly with depression and anxiety, only the de-compensated cirrhosis group showed significantly worse scores on those two measures compared with controls. SF-36 scores became worse with increasing liver disease severity. However, only the compensated and de-compensated groups had significantly different SF-36 scores compared with controls and, as well, with each other. The chronic HCV infected group had only one SF-36 scale, role physical (RP), which was significantly worse compared with controls. The fatigue scores were within normal range.

When only those FS-36 scores that measured physical function (as opposed to psychological) were compared for each of the three groups with those of controls, all three groups scores were significantly lower (worse). In order to determine which variables best predicted poor SF-36 scores a multiple regression analysis*was performed which showed that treatment with beta-blockers or diuretics was significantly correlated with poor SF-36 scores in the de-compensated but not the compensated cirrhosis group. The author’s interpretation of his results is that poor QoL is more likely caused by some unknown mechanism of the virus rather than liver disease by itself (although progressive liver damage tends to further reduce QoL). Cognitive deficits, depression, and anxiety were found only in patients with de-compensated cirrhosis; however, these do not appear to be related to poor QoL. Only treatment with beta-blockers or diuretics was significantly correlated with poor SF36 scores. *This was a post-hoc analysis. (See Rodger’s Reply to Forman (2000), for an example) Commentary: This is the second HCV QoL study by the same authors and was published only a few months after their first study. In the earlier study there was no assessment of cognitive deficits and the QoL results of that study are inconsistent with what was found in this study. Previous cognitive studies in HCV infection, have found significant cognitive deficits, fatigue and depression in the absence of cirrhosis. However, in this study the results of the chronic HCV infected group (i.e. non-cirrhotic) showed no evidence of significant cognitive deficits and neither reductions in QoL (including fatigue on SF-36*, VT scale), depression nor anxiety. The reasons for these findings are unclear but may be due to one or more of the following: the cognitive tests used were different from those of previous studies which have found deficits; as acknowledged by the authors themselves the study was statistically underpowered reducing the likelihood of finding a statistical difference when one may in reality exist. Other authors have commented on the failure of this study to find cognitive deficits in HCV patients.

In her 2004 cognitive study, McAndrews cites this study but makes no attempt to explain the inconsistency. Weissenborn (2006, 2009) reviews the findings of this study twice. In her 2006 study, Weissenborn suggests that the results may be explained the use of different cognitive tests. In her 2009 review, however, her explanation is more elaborate. She states

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that a subgroup of this study were newly diagnosed blood donors who may not have been infected long enough to develop cognitive and other symptoms of HCV infection. However, Foster (1998), found significantly worse SF-36 scores in a similar group, i.e. all blood donors with only mild liver disease when compared to a healthy control group. Since “duration of symptoms”, as far as we are aware, has never been examined by any study of HCV infected patients there is no way of ascertaining how long it takes symptoms to manifest after infection. * Only one previous study had found no significant difference in QoL scores (including fatigue) between HCV patients and controls (Hunt, 1997).

Author: (61) Sandra M Gifford et al., 2003: Australian Women’s experiences of living with hepatitis C virus: Results from a cross sectional study. Journal of Gastroenterology and Hepatology, Vol 18, p.p., 841-850. Community Survey. Australia.

Methods: 400 women living in the community contacted through a range of recruitment strategies completed questionnaires with 123 items looking at a number of issues e.g. medical care, treatment disclosure, discrimination, concerns about sexual relationships and symptoms.

They were also asked to complete the SF12 Health Related QoL and 3 items from the Hepatitis Quality of Life Instrument (HQLI). Approximately half of these 400 women were current IDUs. Aim of Study: To provide the first social study of Australian women’s experiences living with HCV. The author states that in most previous studies of HCV current women IDUs have been ignored.

For that reason she made sure that they were well represented in her sample.

Results: 58% of women reported having experienced symptoms of HCV: 204 (44%) had fatigue, 114 (25%) had nausea, 66 (14%), had emotional/psychological problems. Almost half the women in the sample had received poor treatment by a health professional because of their HCV. Their health status was significantly lower than that for normal women in the local community.

Scores on the SF12 for physical and mental health were highly correlated suggesting significant impairment in these areas due to their HCV. Commentary: As the author says this is a descriptive social study and not an epidemiological survey.

However, she separated her sample into different categories when describing health care and treatment. We are specifically referring to IDU status but unfortunately she did not do this for symptoms for the SF12 or the items from the HRQL scores. The sample was large and it would have been easy to do this. Since no other HCV study has assessed currently intravenous drug using women with hepatitis C we would have learned more about them as a specific group if the author had done so.

Author: (62) Robin Hilsabeck et al, 2003: Cognitive functioning and psychiatric symptomatology in patients with chronic hepatitis C. Journal of the International Neuropsychological Society, Vol 9, pp 847-854. Neuropsychological Study. U.S.A.

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Methods: 21 patients with chronic HCV, (F = 9; Mean age = 46 yrs), were assessed on a battery of neuropsychological tests measuring visuo-construction, learning, memory, visual memory, psychomotor speed and mental flexibility. Also assessed were depression (BDI*), subjective cognitive function (MOS Cognitive Scale), anxiety (BAI*) and fatigue (FSS*). The assessment of fatigue involved splitting the group (using a median split) into two groups i.e. those with “less fatigue” and those with “more fatigue”, and comparing both groups fatigue scores with scores for subjective cognitive deficits, depression and anxiety. * BDI – Beck Depression inventory, BAI – Beck Anxiety Inventory, FSS – Fatigue Severity Scale.

Aim of Study: To replicate Forton's (2002) study by comparing performance on neuropsychological tests with depression, anxiety, subjective cognitive dysfunction and fatigue scores.

Results: Of the 21 patients 47% showed one or more cognitive deficit. The highest percentage of cognitive deficits was 38%, on tasks involving visual scanning and tracking, psychomotor speed and working memory. The lowest percentage of cognitive deficits 9.5% was on tasks involving copying and recognition. Higher fibrosis scores were associated with greater cognitive dysfunction. Objective measures of cognitive dysfunction were not related to patients’ own ratings of cognitive dysfunction i.e. no significant differences on objective cognitive measures were found between those patients who had complained about cognitive deficits and those patients who had not. There were significant differences between the “less fatigue” group (N=10) and the “more fatigue” group (N=11) with the latter having higher scores on self-assessed cognitive dysfunction, depressive and anxious symptoms.

Commentary: This study had only 21 subjects, no control group and a very long list of known confounding variables that were not controlled for in the analyses, e.g. 9.5% were co-infected with HIV; 14.3% had type 2 diabetes; 4.8% had fibromyalgia; 19.1% a history of alcohol abuse and 23.8% were currently on interferon and ribavirin treatment during this study. In addition 55% were taking psychiatric medication and 82% of these were taking anti-depressants. Apart from a worrying lack of exclusion criteria it is highly unusual to test patients for depression while they are on antidepressant medication. We found the study impossible to interpret, as did Mc Andrews (2005), who sharply criticised the study for its lack of control. However as the author exhorts, the participants are typical of the sort of patients generally seen in veteran’s clinics.

Author: (63) M. Glacken et al, 2003: The experience of fatigue for people living with hepatitis C. A qualitative grounded theory. Journal of Clinical Nursing, March 1, Vol. 12, Issue 2. p.p. 244252. Qualitative Fatigue Study. Ireland.

Methods: 28 participants with HCV (Male = 8, Age range 36 – 64 years, PCR+ = 24) undertook in-depth interviewing (average 80 minutes) using a ‘grounded theory' approach*. Most of the participants were either from the Irish women’s Anti–D group or they had been infected through IDU. This was a qualitative study so the data, unlike the data in empirical studies, is not amenable to statistical manipulation. The interviewers sought to elicit comprehensive descriptions of fatigue as they apply to its nature, its physical, cognitive, and affective dimensions and its severity.

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* Grounded Theory is a Sociological Theory, developed in the late 1960s, from data based on dying hospital patients, Aim of Study: The research question was "what is the nature of the fatigue that individuals with hepatitis C experience". The aim of the study was to use the descriptions generated as a resource for practitioners, which might aid in the development of future interventions for fatigue.

Results: The authors note that most of the participants in this study were unable to articulate nominal descriptions of fatigue and could only describe their experiences through using metaphors, comparisons or the effect of fatigue on their daily activities. From an analysis of the interview data the most important finding was that there are two distinct types of fatigue in HCV infection, namely, chronic and idiopathic fatigue, the latter being the term given by the authors to fatigue that over time remits and then reappears, often without warning. In general the study found that the fatigue experienced by people with HCV whether chronic or idiopathic appears to be on more than one dimension. Below are examples of descriptions of chronic fatigue each of the three dimensions of fatigue and its severity.

Chronic Fatigue: “I am permanently tired. It is present even on wakening every morning. I am like an old engine trying to get started in the morning, trying to stoke myself up. It could take me 2 or 3 hours to get going.”

Physical Dimension: “It’s a feeing of heaviness. I just feel I am going to collapse with the weight of my body. It’s like having something continually dragging out of you.”

Cognitive Dimension: “Stupid is the only word for it. Thick kinda. A bit forgetful as well. It is very annoying. I have no concentration. I cannot learn during that time. I cannot read for any length of time, because. I just sort of lose it a bit” Affective Dimension: “Something comes upon me (when I am tired). People say I get a bit of a temper. Sometimes I am so bad tempered….what would come out of my mouth would shock me, myself.”

Severity: “You know I could put up with this fatigue every day, if I knew it would only be there for an hour or two. I could manage to do things around it but it’s when it comes and doesn’t lift for days. I really feel defeated. Everything has to be shelved. I just feel everything is beyond my reach, beyond my control, I suppose.”

Commentary: Excellent review of the literature and very well written. We thought the descriptions do not require any further explanation or commentary. This article is free on the Internet.

Author: (64) Gallegos-Orozoco, J. F. et al, 2003: Health–Related Quality of Life and Depression in Patients with Chronic Hepatitis–C. QoL Study: Archives of Medical Research Vol. 34 (2), p.p.

124-9. 2003 Mar-Apr. Mexico.

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Methods: 157 patients with chronic HCV, (F=71%, Age= 23.5% below age 45) seen at a referral Centre in Mexico City were assessed on their first visit and prior to interview (although they were aware of their diagnosis), on the SF36, the Zung Depression Scale and a self- devised 10 item questionnaire measuring illness understanding. All patients were interferon naïve.

Exclusion criteria were rigorous e.g. Interferon treatment, co-existing illness or disorder, alcohol or substance abuse and use of anti-depressant medication. Ninety-seven (61.8%) of the 157 patients had cirrhosis, Child-Pugh class: A=54, B=25 and C=18. Statistical comparisons were made between the scores of the 3 assessment measures. There was no control group in this study.

Aim of Study: “The aim of the present study was to evaluate HRQL and depression in a sample of Mexican patients naïve to treatment attending a tertiary-referral centre as well as to determine patient illness understanding and knowledge of disease.”

Results: When compared with scores for the general Mexican population QoL was significantly lower for HCV patients in all eight scales of the SF36, including the vitality scale (i.e. fatigue).

HCV patients who had cirrhosis Child-Pugh class B & C had significantly lower scores on SF36 scales that measure physical health than those who were Child-Pugh class A, or who did not have cirrhosis. Ninety-two (58.6%) patients were depressed on the Zung, and 9 (5.7%) had severe depression. There were no significant differences in depression scores when those with cirrhosis were compared with those without cirrhosis. When QoL scores were compared between depressed (N=92) and non-depressed (N=65), the depressed group had significantly poorer QoL than the non-depressed group. Results from the 10 item questionnaire assessing illness knowledge showed that 72.6% of patients had a poor knowledge of basic HCV information and their QoL scores were significantly lower on six domains compared to those who had some knowledge about HCV. There were no significant differences between the scores of those with cirrhosis versus those without cirrhosis on “knowledge of illness”. No association was found between QoL and gender, age or educational level.

Commentary: This study was well considered, rigorously controlled and well written. There are two notable findings. Firstly, the prevalence rate for depression (N=58.6) was surprisingly high and much higher than previous studies reported in this review. This may be specific to the Mexican environment but is noteworthy. The second finding was that HCV infected patients who had little knowledge of the disease, had significantly poorer QoL (including the vitality scale i.e. fatigue) than those who knew some basic facts about the course and treatment of HCV infection. The authors’ interpretation of the latter finding is that those who had little knowledge of HCV infection were more “psychologically distressed” as a result of their lack of knowledge and this was likely to impact on their QoL. The results would also suggest that the “psychological distress” might be due to the impact of diagnosis, which those who had some basic knowledge of HCV, managed to reduce by developing better coping skills from the information they had. However, because these patients were aware of their diagnosis when they took part in this study it is not possible to accurately assess how much of their symptomatology (including fatigue) may have been due to the negative psychological impact of diagnosis, which is probably why the authors say little about this topic. If the authors had compared depression scores between these two groups and found the group with little knowledge were significantly more depressed than the group with more knowledge of HCV, this would have added weight to the possibility of an “impact of diagnosis” effect, but they compared only QoL between the two groups. The idea of testing for knowledge of HCV before assessing patients, though it may seem obvious, was clever and it is surprising that no other study has done the same.

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Author: (78) P. Braitstein et al, 2006: Differences in access to care among IDU's infected either with HIV and HCV or Hepatitis C alone. Aids Care. October 2006. Vol. 18, No.7, p.p. 690-693.

Health Survey. Canada.

Methods: The data used in this study comes from a long-term community study of IDUs i.e. The Vancouver Injection Drug User Study (VIDUS) begun in 1996. All of the participants were current injecting drug users. 239 HIV/HCV (F =109, Mean age 39yrs) co-infected IDUs and 464 HCV (F = 169, Mean age=41.7), mono-infected IDUs completed a questionnaire relating to their health status (including symptoms) and their use of health care facilities. The questions on symptoms were related only to HCV and included a list of 8 symptoms namely, fatigue, liver pain, nausea, night sweats, stomach pain and one "other symptoms?" question.

Statistical analysis in this study consisted mostly of comparisons of prevalence rates between the two groups.

Aim of Study: To describe the self reported health status of both HIV/HCV co-infected IDUs and HCV monoinfected IDUs and to describe and compare their access to HCV health care facilities.

Results: Fatigue was the most commonly reported symptom for both groups: HIV/HCV=32% and HCV=42%. For most of the symptoms listed the HCV group tended to have much higher prevalence rates than the HIV/HCV group. However, when asked whether they thought their HCV was affecting them or not the co-infected group had a much higher "yes" response than the HCV alone group. The co-infected group were also much more likely to report having received HCV related care.

Commentary: The purpose of this study was to provide evidence that would hopefully result in better access to treatment and healthcare for HCV infected intravenous drug users. The main focus of the study was the investigation of differences in health care access between those who had both HIV and HCV infection and those with only HCV. The study found that those co-infected with HIV/HCV had better access to HCV care as a consequence of their HIV status, although the extent of that care was quite limited. There are few details about how symptoms were assessed (e.g. how they measured fatigue) and they are reported only as prevalence rates and depression was not assessed. This was a descriptive study, so there is little interpretation of the studies results e.g. there is no attempt to explain the cause of the differences in access between the two groups? Although Gifford et al., (2003, 2004) had conducted similar studies with HCV infected current injecting drug users, comparing them with HCV infected non-IDUs, they did not separate the fatigue scores for the two groups, so there was no fatigue prevalence rate reported specifically for current IDUs, which makes it impossible to compare those studies with this study. This is the only study, as far as we are aware, to have reported the symptoms of HCV in current injecting drug users as a discrete group. It is also the first to have compared HCV symptoms between current IDUs with HCV infection alone and current IDUs with both HCV and HIV infection.

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Author: (79) Carolyn A. Lang et al, 2006: Symptom Prevalence and Clustering of Symptoms in People Living with Chronic Hepatitis C Infection. Journal of Pain and Symptom Management, Vol 31, No. 4, April 2006. Symptom Survey. Australia.

Methods: This study had 2 phases i.e. qualitative and quantitative. In phase 1, a community advisory group of 14 stakeholders generated a list of 14 QoL questions. 73 people with HCV infection (Female = 25; combined Mean age = 38yrs) were asked to respond to the 14 questions and their responses were taped. The tapes were then analysed and generated a list of 21 symptoms. In phase 2 of the study a group of 188 people with HCV (Female 62 and 1 transgender, combined Mean age = 42yrs) were asked about the severity and prevalence of these 21 symptoms. The data from phase 2 was then subjected to factor analysis, which revealed 4 factors or clusters of related symptoms from the original 21 symptoms.

Aim of Study: "Our aim was to describe the type, prevalence, and severity of symptoms in people living with HCV. In phase one of this study, the aim was to determine the diversity of symptoms using a qualitative approach. The aim of phase two was to examine symptom severity in a broad based sample in people living with hepatitis C and to delineate the types of symptom clusters that occur".

Results: Of the 21 symptoms, the symptom with the highest prevalence was physical tiredness (85.6%) followed by irritability (74%), depression (69.5%), mental tiredness (69.5%) and abdominal pain (68.4%). The symptoms with the highest reported severity were sleep disturbance, physical tiredness, mental tiredness and joint pain. Eighty three percent of the people in this study had experienced 6 or more symptoms in the last 3 months and 62% of the whole sample reported that at times they experienced the effects of more than one symptom. Prevalence rates for most symptoms, including fatigue, were significantly higher in females than in males. The factor analysis identified 4 factors or groups of related symptoms: a neurological/fatigue factor, containing 7 symptoms e.g. Physical tiredness, mental tiredness, depression, irritability, poor concentration, forgetfulness and sleep problems; a gastrointestinal factor containing a group of gastrointestinal symptoms; a pain factor with a related group of symptoms and a dyesthetic or heightened sensitivity factor with a related group of symptoms. Statistical analysis revealed that the first 3 factors but not the fourth, i.e. dyesthetic, had good internal consistency and reliability suggesting that these measured valid constructs and could be summed to generate meaningful scale scores.

Commentary: This is an excellent study which, logically should have been conducted in the first few years after the virus was discovered because its focus was solely on creating a comprehensive list of symptoms associated with HC infection, as well as the prevalence and severity of those symptoms and their relationship to each other. Without a study like this, it is difficult to take into account the full burden of illness associated with HCV infection, despite numerous QoL studies, which claim to have done so. Most previous researchers would no doubt be surprised to find “irritability” as the second most prevalent symptom, and that noise and light sensitivity were also frequently reported. The clustering and factor analysis showed that some symptoms have a strong relationship with each other suggesting that each group of symptoms may be activated by a similar causal mechanism. This study was long overdue but a very welcome addition to the literature examining the natural history of HCV infection. This study might be of especial interest to those with HCV infection—it is available free online in PDF format.

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Author: (80) K. Weissenborn et al, 2006: Monoaminergic neurotransmission is altered in hepatitis C virus infected patients with chronic fatigue and cognitive impairment. GUT, 2006, Vol., 55, p.p. 1624-1630.

Methods: This study consisted of twenty people with chronic HCV infection (F = 13, M = 7; combined Mean age = 48.8yrs) who had been referred for investigation of disabling fatigue and cognitive decline. Four of the 20 were PCR negative, 2 had cleared the virus spontaneously and 2 cleared the virus as a response to interferon treatment. All 20 were subjected to a range of assessments to exclude other reasons for their symptoms (none of the sample had cirrhosis). The study assessed cognitive dysfunction using a battery of neuropsychological tests, which were mostly measures of attention. Depression was assessed using the Beck Depression Inventory (BDI) and the Hospital Depression and Anxiety Scale (HADS). Fatigue was assessed using the fatigue impact scale (FIS), and QoL on the SF-36. To assess alterations in the brain of the neurotransmitters serotonin and dopamine they used SPECT or Single Photon Emission Computerised Tomography. Two groups of healthy controls were used to compare SPECT results, one for serotonin (N=16) and the other for dopamine (N=20).

Aim of Study: This is not precisely stated, but was clearly to investigate fluctuations in the levels of the two neurotransmitters serotonin and dopamine in HCV patients and to establish their relationship with cognitive deficits, fatigue and depression. A further aim was to investigate the same in the small group of 4 HCV patients who had cleared the virus but remained symptomatic.

Results: On the fatigue impact scale (FIS) all patients showed significantly higher levels of fatigue* than that found in healthy controls. Two thirds of all patients showed significant attention deficits on neuropsychological tests. The entire group showed significantly reduced QoL on the SF-36. Scores on the BDI and the HADS showed more than 50% suffered from depression.

Compared to controls, the HCV patients showed significantly reduced binding of serotonin (50% of patients), dopamine (60% of patients) and both dopamine and serotonin** (30%).

This was also the case in 3 out of 4 of the PCR negative patients. Patients with decreased dopamine and serotonin binding scored significantly lower on most attention tests compared to healthy controls leading to the conclusion that these two domains are related. Since SIF scores did not significantly differ between those with reduced serotonin and dopamine binding and those with normal levels the authors conclude that fatigue seems to be caused by "additional factors" other than reduced serotonin or dopamine levels in the brain. * Higher than any previous HCV study using the FIS. ** Only two patients had a reduction in serotonin binding alone, so their cognitive scores were not compared with controls. Those patients with reduced dopamine binding alone had only mild cognitive deficits compared with those who had reduced binding of both neurotransmitters.

Commentary: This study has the distinction of being the first to examine neurotransmitter activity in HCV infected patients; a crucial step towards proving both a central theory of the origin of fatigue in HCV infection and a Trojan Horse theory of HCV brain infection (proving the first theory is a prerequisite for proving the second). This is the second HCV symptom study by the same

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group of researchers (Weissenborn et al., 2004) and like the first study it was well designed, carefully controlled and is exceptionally well written—a pleasure to read.

The results, however, are surprising; only cognitive deficits (brain fog) were significantly correlated with reduced levels of the neurotransmitters “serotonin” and “dopamine”. One might have expected that fatigue, depression and anxiety would also correlate with reductions in these two neurotransmitters, especially “serotonin”, but that was not the case*. To explain the theoretical relevance of these results we shall examine them firstly from the perspective of a Central theory** and then from the Trojan Horse theory***.

The essential lines of evidence to prove the central theory of fatigue in HCV infection is firstly to show that neurotransmission has been significantly altered and cannot be explained by any other factor than hepatitis C viral infection; and second that altered neurotransmission is significantly correlated with fatigue. If we accept that this study had no confounding variables, used the correct methodology/statistics and made no errors, then the evidence strongly suggests that “brain fog” is quite likely caused by reductions in the neurotransmitters “serotonin” and “dopamine”. That these reductions are a result of HCV infection, through some unknown mechanism, can be taken as a given. However this evidence does not prove that fatigue is of central origin and is insufficient to confirm the Trojan Horse theory of HCV brain infection.

To prove the Trojan Horse theory of HCV brain infection is extremely difficult. Although we know from an autopsy study conducted by Forton et al. (2004) that HCV infection of the brain is possible it is difficult to demonstrate this in live subjects, at best we can only infer this from indirect evidence, which rules out alternative explanations. In this study the strongest indirect evidence comes from the four HCV patients who had cleared the virus, i.e. they were PCR negative. It is the results of those four patients that the authors hoped would shed more light on the viability of the Trojan Horse theory. Two of these patients had been treated successfully with interferon (the other two had cleared the virus spontaneously) yet they remained symptomatic and had reduced “serotonin” and “dopamine levels”, which correlated with brain fog. Although the Trojan Horse theory does not speculate on the effects of interferon on brain quasi species, in the autopsy study by Forton et al (2004) the authors state that because the HCV quasi species in the brain are of a different viral sequence from those in the blood they may be less influenced by the effects of interferon treatment. In other words someone who has been successfully treated with interferon (i.e. PCR negative) may still have HCV infection of the brain. Forton’s statement is reiterated almost word for word in Weissenborn’s interpretation of the results observed in the two of the four HCV PCR negative patients who had been successfully treated with interferon but still had symptoms. Although we have no reason to dispute this interpretation, nevertheless, it remains unclear how interferon is able to cross the blood brain barrier as it is commonly accepted that interferon cannot cross the blood brain barrier. If interferon does affect brain quasi-species then it must be through some unknown mechanism. The evidence from the four PCR negative patients while strongly supporting the relevance of the Trojan Horse theory does not prove it.

This is a very elegant study and one of the best in this review—its high quality is a hallmark of all the HCV research undertaken by this group. *Unfortunately this study cannot address the question of whether reduced neurotransmission is associated with fatigue. Had the sample size of this study been larger, allowing more statistical comparisons to be made, it is possible that a correlation between fatigue and reduced neurotransmission may have been found. If this was the case then it would support the position that reduced neurotransmission is the cause of fatigue, in those who were found to have reduced neurotransmission, but not the cause of fatigue in those who had normal neurotransmission. It would suggest that there may be more than a single cause of fatigue. ** Central fatigue can be defined as fatigue originating from the central nervous system (CNS) whilst, peripheral fatigue can be defined as originating in the nerves muscles and neuromuscular junctions. *** The Trojan Horse theory assumes that the HCV virus manages to cross the blood brain barrier, which it would not normally be able to penetrate, by infecting immune cells (e.g.

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monocytes and macrophages) present in circulating blood. These infected immune cells (which literally hide the virus) eventually end up crossing the blood brain barrier undetected and infect the brain. The corollary of this theory is that once inside the brain the virus, which is now encapsulated, begins to mutate – these mutations of the original virus or quasi species as they are known are thought to replicate very slowly and are assumed to be different from HCV quasi species in the blood. Through some unknown mechanism of these HCV quasispecies in the brain, possibly involving the infection of astrocytes, neurotransmitter levels are though to be reduced giving rise to most of the symptoms typically found in HCV infected patients e.g. fatigue, cognitive deficits, depression, anxiety and sleep problems.

Author: (81) Karaivazoglou, K. et al., 2007: Neuropsychological function in Greek patients with chronic hepatitis C. Liver International, ISSN 1478 – 3223,p.p. 798 – 805.

Methods: Patients in this study were, 32 with chronic HCV (Male = 55%, combined Mean age = 48.6 years); 29 with HBV (Male = 83%, combined Mean age = 49.7 years); and 20 healthy controls (Male = 50%, combined Mean age = 49.7 years) selected from hospital records. In the HCV group 21% had compensated cirrhosis and in the HBV group 22% of patients. Patients with conditions likely to cause cognitive deficits were excluded from the study. Both patient groups and controls were assessed on the following measures: neuropsychological tests consisting of the Rey Auditory Verbal Learning Test (RAVLT), the Greek Verbal Fluency Test, the Trail-making Test and the Symbol Digit Modalities Test (SDMT). Fatigue was measured using the Functional Assessment of Cancer Therapy-Anaemia Scale (FACT-An). Depression was measured on the BDI-2. Statistical comparisons of results on the above measures were made between the two patient groups and with controls. Comparisons were also made within the HCV and HBV groups between those with mild liver disease and those with cirrhosis.

Finally, a correlation analysis was performed comparing scores for fatigue, depression, ALT, AST, and fibrosis stage with scores on cognitive tests.

Aim of Study: “ The main purpose was to assess the degree and type of neuropsychological deficits observed in patients with chronic hepatitis C. We further address the issue of whether cognitive impairment is HCV specific, by comparing neurocognitive performance of chronic hepatitis C (HCV) and chronic hepatitis B (HBV) patients.”

Results: No significant differences were found between the three groups, HCV, HBV and controls, on measures of fatigue or depression. Both HCV and HBV groups were equally and significantly impaired on only one cognitive measure, the RAVLT, a test of verbal learning and memory.

No differences were found between those with cirrhosis and those without cirrhosis on cognitive measures. Correlation analysis (HCV group only) showed that fibrosis and fatigue severity were significantly correlated with cognitive deficits (though in the case of fatigue this was limited to only three trials on the RAVLT). The authors interpretation of their results is that they that they support a physiological cause of cognitive deficits, i.e. fibrosis. However, because there were no differences in cognitive deficits between those with cirrhosis and those without cirrhosis, the authors hypothesise that cognitive deficits might develop in the early stage of liver disease. Although fatigue severity was correlated with some of the learning and memory trials, because of the failure to find differences in fatigue (or depression) between the HCV group and controls, the authors argue that fatigue is unlikely to explain the learning/memory deficits. Her conclusion is that cognitive deficits are caused by some unspecified mechanism of viral hepatitis (as opposed to HCV alone) on brain function. In other words fibrosis is the cause of cognitive deficits in both HCV and HBV.

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Commentary: The results of the cognitive measures in this study are similar to those of McAndrews (2004), who found only verbal memory and learning impairments in HCV infected patients; and different from the majority of other studies which found deficits in attention and reaction time.

However, Karaivazoglou, like McAndrews, used different tests than those employed in earlier studies, she also used fewer tests – only three cognitive tests. This study is one of three in this review that did not find abnormal fatigue in HCV infected patients. Karaivazoglou used a fatigue scale designed to measure fatigue in patients with cancer whereas other two fatigue studies that failed to find fatigue used the SF-36. It is interesting to note that Karaivazoglou found no effect for depression which is also anomalous. In her review of HCV cognitive studies, Weissenborn (2009), while not specifically mentioning fatigue results, questions Karaivazoglou’s conclusion that cognitive deficits are a result of an unspecified mechanism of viral hepatitis (B or C). She states that this hypothesis cannot explain why one third of HCV patients with a SVR to interferon remain symptomatic despite remaining PCR negative.

Elsewhere in her review she provides convincing evidence that cognitive deficits and other symptoms, including fatigue, are significantly worse in HCV patients compared to those with HBV. Karaivazoglou’s theory as to the cause of cognitive deficits is similar to that proposed by the 1997 NIMH Online Consensus Statement, Poynard (2002) and Cacoub (2002), based on the view that symptoms are caused by damage to the structure and functioning of the liver affecting the brain and central nervous system. However, the bulk of the evidence is against such a theory for symptoms such as fatigue and depression and only one other cognitive HCV study has found a correlation between “brain fog” and fibrosis (Hilsabeck, 2003). A study which Karaivazoglou also admits was “poorly controlled”. Weissenborn’s (2006) article, which Karaivazoglou could not have read, as the publication dates were too close, strongly suggests that the Trojan Horse theory has relevance and has backed that up with further evidence (Weissenborn, 2009).

Author: (82) J. Kallman et al., 2007: Fatigue and Health-Related Quality of Life (HRQL) in Chronic Hepatitis C Virus Infection. Digestive Diseases and Sciences, October Vol. 52, No. 10. p.p.

2531-2539. QoL Study. U.S.A. Methods: 130 patients with chronic HCV infection (Male - 64%; combined Mean age = 45yrs) who were referred to an outpatient clinic and 61 healthy controls (demographics not reported) were assessed on the SF-36 and the Chronic Liver Disease Questionnaire (CLDQ; a liver disease specific QoL measure). Ninety-five of the 130 HCV patients were also assessed for autoimmune markers: Cryoglobulin (Cr), Soluble IL-2 receptors (SIL-2) and Rheumatoid Factor (RF). The same 95 patients as well as 53 of the 61 controls were assessed for fatigue on the chronic fatigue screener* and divided into 3 categories i.e. no fatigue, chronic fatigue and chronic fatigue plus CFS like symptoms. Statistical comparisons of scores on both QoL measures were made for each of the three categories within and between both groups.

In addition, for the HCV group, data from rheumatologic (i.e. Cr, SIL-2 and RF), virologic (e.g. genotype), biochemical (e.g. ALT), histological (e.g. severity of liver disease) and demographic (e.g. method of infection) assessments was statistically compared with SF-36 scores, CLDQ scores and fatigue category. * Based on the diagnostic criteria for chronic fatigue syndrome as defined by Fukuda et al., (1994).

Aim of Study: “To assess systematically Health Related Quality of Life (HRQL) in patients with chronic hepatitis-C and to determine if any clinical, biochemical, virologic, demographic and histological features are associated with HRQL status.”

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Results: Scores on the chronic fatigue screener showed that 67 (71%) of HCV patients had chronic fatigue (defined as lasting longer than 6 months) and 26 (27%) fulfilled the criteria for Chronic Fatigue Syndrome (CFS). For controls chronic fatigue was experienced by 13 (25%) and Chronic Fatigue Syndrome like fatigue symptoms in 6 (11%). Loss of usual activity was reported in 61% of those with HCV and chronic fatigue and 69% of controls with chronic fatigue. Chronic fatigue was not significantly associated with IDU, age, gender, cirrhosis or any of the immune factors.

Scores on the chronic fatigue screener, the SF-36 and the CLDQ were significantly abnormal compared to those for controls. Within the HCV group, fatigue scores on the CLDQ for females and those with cirrhosis were significantly worse than those for the remainder of the group, by contrast on the SF-36, no differences in fatigue scores were found for either gender or liver disease severity.

When the HCV group and control group were divided into no-fatigue, chronic fatigue and Chronic Fatigue Syndrome (CFS) categories those in the CFS group had the lowest scores on both the SF-36 and the CLDQ. The authors conclude that the most important contributor to reduction in QoL is disabling fatigue.

Commentary: This is the final part of a prospective study first published nine years before as an abstract (Younossi et al., 1998), which reported initial results for a sample of 30 patients, from the total sample of 130 patients in this study. The results of the initial study are similar to those reported here. Both studies found that HCV patients had a high prevalence rate for fatigue; that fatigue was significantly worse for HCV patients when compared with controls and that no relationship was found between fatigue and either QoL or immune factors. Also in this study as in the earlier one, the chronic fatigue screener—a questionnaire based on Fukuda’s (1994) criteria—was used to assess fatigue and Chronic fatigue symptoms. In other studies that have used published criteria to assess chronic fatigue syndrome, in HCV patients (e.g.

Dale et al., 1991) we questioned* the clinical utility of using such criteria. Both authors’ of extant CFS criteria (Holmes, 1988; Fukuda, 1994) preclude the use of CFS criteria with chronic liver disease patients, since CFS is a diagnosis arrived at by excluding all other possible reasons for chronic fatigue and all liver diseases including HCV are known to be associated with chronic fatigue. There is no rationale provided either in the 1998 abstract or in this study explaining why CFS criteria were being used and we cannot think of any reason to use CFS criteria with HCV patients other than in a study similar to the one conducted by Karatsune et al. (1998), where carnitine levels in CFS patients were compared with those of patients with other diseases known to be associated with chronic fatigue i.e. an HCV infected group. Kallman et al. must have been aware that after a lapse of 9 years their focus on CFS symptoms might seem a little outdated, and that their rheumatologic data would be old information. Since much of the results and discussion are taken up in comparison of the CLDQ (which the authors’ developed) with the SF-36, we suspect that they may have wanted to introduce the CLDQ, in a full length HCV study. The study ends with an interesting and pertinent conclusion: the authors’ state that whilst a great deal of resources are spent on finding a treatment for HCV infection too little has been spent on investigating the symptoms of HCV. * We seem to have missed commenting on the use of CFS criteria in that study.

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Author: (83) Stefanova-Petrova, D. et al., 2007: Chronic Hepatitis C Infection: Prevalence of extrahepatic manifestations and association with cryoglobulinemia in Bulgarian patients.

Gastroenterology. Dec 28th; 13(48): p.p. 6518-6528. Prevalence Study, Bulgaria.

Methods: 136 patients (Female = 72; combined Mean age = 50yrs) with chronic HCV infection referred to a gastroenterology clinic had their records reviewed to assess the presence of extrahepatic manifestations which included two subjective symptoms, i.e. fatigue and arthralgia.

Alcohol use, duration of infection, liver histology, genotype and mode of infection were also assessed. Mode of infection was as follows: IDU (14.7%); surgical procedures (27.2%); dental procedures (13.2%); needle stick injury (8.1%) and blood transfusion (36.8%). All patients with extrahepatic manifestations were examined for the presence or absence of cryoglobulin. The effect of gender, age, duration of infection, histological data and alcohol usage on extrahepatic manifestations were statistically explored. Fatigue was a minor focus in this study and there is no mention of how it was assessed. Depression was not assessed.

Aim of Study: "To assess the prevalence of extrahepatic manifestations in Bulgarian patients with chronic hepatitis C virus (HCV) infection and identify the clinical and biological manifestations associated with cryoglobulinemia".

Results: Fatigue was present in 81 of 136 patients i.e. 59.6% and for each of these it was their initial or worst symptom. Fatigue was present in 92.2% of the cryoglobulin positive patients and in 40% of the cryoglobulin negative patients. When fatigue scores were compared between the two groups, the cryoglobulin positive group had significantly more fatigue and, using odds ratio, were 17 times more likely to be fatigued than the cryoglobulin negative group. Using multivariate analysis only duration of infection and cirrhosis were significantly associated with the presence of extra hepatic manifestations.

Commentary: This study is quite similar* to that of Poynard et al. (2002) inasmuch as both studies sought to establish prevalence rates for HCV extra-hepatic manifestations in their respective countries i.e. Bulgaria and France. However in Poynardâ&#x20AC;&#x2122;s study the focus of attention was on fatigue and its relationship with other extra-hepatic manifestations, whereas in this study cryoglobulins levels were the main focus. Patients were divided into two groups, based on cryoglobulin levels, a cryoglobulin positive group and a cryoglobulin negative group and prevalence rates for extrahepatic manifestations were statistically compared between the two.

This is the only study so far in this review that has found a significant relationship between cryoglobulinemia and fatigue. Since most of the earlier studies used standardised fatigue tests and this study provides no information regarding the assessment of fatigue, the fatigue results are incomplete. * Both studies also favour a liver damage theory as an explanation for the presence of extrahepatic manifestations in HCV infected patients.

Author: (84) Ahboucha, S. et al. 2008: Neuro active steroids and fatigue severity in patients with primary biliary cirrhosis and hepatitis C. Neourogastroenterology and Motility. Feb., 2008, Vol.20, Issue 2, p.p. 671-679. Experimental study/fatigue study. Canada Methods: Twelve patients (Female = 5; combined Median age = 49yrs) with chronic HCV, 16 patients with primary biliary cirrhosis (PBC) (Female =15; combined Median age = 55yrs) and 11

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healthy controls (Female = 5; combined Median age = 53yrs) were assessed for plasma levels of five progesterone metabolites (neuroactive steroids), these were: 3 alpha, 5 alpha THP or allopregnanolone; 3 alpha, 5 beta THP or pregnanolone; 3 beta, 5 alpha THP or isopregnanolone; 3 alpha, 5 alpha THDOC or THDOC and 3 beta, 5 beta THP or epipregnanolone. They were also assessed on the fatigue impact scale (FIS). Patients (but not controls) were also assessed on biochemical, histologic and demographic measures.

Patients who were currently taking psychiatric drugs were excluded from this study.

Statistical comparisons of scores on the FIS and neuroactive steroid levels were made between each of the three groups and for the two treatment groups only, further comparisons were made between those two variables and scores on biochemical, histologic and demographic measures. Finally comparisons of neuroactive steroids were made between those with and without fatigue in both patient groups after the HCV and PBC groups’ scores had been combined.

Aim of Study: “We hypothesize that THP metabolites might be associated with fatigue commonly observed in chronic liver diseases."

Results: Both HCV and PBC patients had significantly higher FIS scores than controls. Abnormal fatigue (in this study higher than FIS ratio 1.24) was present in 62% of the PBC group, 42% of the HCV group and none of the control group. Fatigue did not correlate with cirrhosis, fibrosis, biological markers, menopausal status or gender. Only two of five neuroactive steroids were significantly increased in both HCV and PBC patients compared with controls: 3 alpha, 5 alpha THP and 3 alpha, 5 beta THP or allopregnanolone and pregnanolone. When patients were divided into two groups i.e. no-fatigue (N = 15, 10 PBC and 5 HCV) vs. fatigue (N = 13, 6 PBC and 7HCV) those in the fatigued group showed significantly higher concentrations of these two neuroactive steroids than the non-fatigued group whose levels were not significantly different from those of the control group. There were no correlations between an increase in either neuroactive steroids and fibrosis scores or cirrhosis severity.

Commentary: This is an excellent study and very well written—especially the discussion. In the introduction the authors describe many of the theories that have been put forward to explain the cause of fatigue in HCV patients and they examine the evidence from those studies that have based their investigations on those theories. Their conclusion is that no study so far has provided any clear-cut evidence of a causal link between HCV infection and fatigue. However, they note that in fatigue studies of PBC and CFS patients’ abnormal levels of metabolites of the female steroid hormone “progesterone” have been significantly associated with fatigue.

Metabolites, such as allopregnanolone and pregnanolone* are positive modulators of GABAA** receptors in the brain. These receptors are assumed to be involved in both the sleep/wake cycle and fatigue. It is therefore possible that high levels of neuroactive steroids may be related to sleep dysfunction and fatigue severity in HCV patients. The aim of this study was to test this hypothesis. The results show that abnormally high levels of two out of five neuroactive steroids investigated, namely allopregnanolone and pregnanolone were significantly related to fatigue. What causes neuroactive steroids to accumulate in circulating blood is not known, however the authors of this study speculate that liver damage or viral interference with their production or regulation may be the cause in HCV and PBC patients.

The authors also mention dehydroepiandrosterone sulphate (DHEAS) another neurosteroid, which they appear to have measured but did not include in their results, DHEAS is a negative modulator of GABA-A receptors. Low levels of DHEAS are also thought to be related to dysfunction of the sleep/wake cycle and fatigue severity. The authors note that when allopregnanolone and pregnanolone are high and the DHEAS low it is possible to get a synergistic effect i.e. the two combine to cause an increased effect. The authors claim to have found abnormally low levels of DHEAS in PBC, but not HCV patients, which they say may explain why PBC patients have worse fatigue. The theoretical importance of this study is that

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it returns the focus of fatigue research back to neurotransmitters, which had looked so unlikely after Weissenborn had failed to find any association between fatigue and either of the two neurotransmitters serotonin or dopamine. * These are classified as neuroactive steroids because they are known to effect neurotransmission ** GABA-A receptors are one of two types of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA). GABA is the main inhibitory neurotransmitter in the central nervous system.

Author: (85) Seef, L. et al. 2008: Herbal Product Use by Persons Enrolled in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT C Trial) Survey/Symptoms/Herbal Products.

Hepatology, Feb. 2008, Vol. 47, No. 2, p.p. 605-612. Survey/Symptoms/Herbal Products.

USA. Methods: 1145 patients with chronic HCV, candidates for Interferon treatment who were enrolled in the HALT-C* programme at one of ten health centres across the U.S.A. were asked whether they took herbal products: 641(56%) said they had never used them; 235 (21%) reported past, but not current use; and 269 (23%) stated that they currently used herbal products. From the responses of the 269 current herbal product users 60 herbal products were identified. The most commonly reported herbal product was Silymarin, taken by 195 patients (Female = 43; combined Mean age, 50.8yrs). Scores for virological, biochemical, and QoL assessments, as well as scores for physical and psychological symptoms were statistically compared between those taking Silymarin at their initial visit and those who had never taken herbal products The study contains no description or details of the measures used to assess fatigue and QoL in this study (the reader is referred to the original HALT-C trial which also fails to include a description of the measures). * A preventative programme aimed at treating non-responders to interferon treatment, who have evidence of fibrosis, with long-term interferon treatment before they develop cirrhosis.

Patients who had no response to Interferon/Ribavirin treatment were offered 3.5 years of Interferon treatment or observation for 3.5 years without treatment.

Aim of Study: “…to examine the use and potential effects of Silymarin as a treatment for symptoms in patients with chronic HCV infection.”

Results: There were no significant differences between the Silymarin group and the non-Silymarin group in terms of age, virological or biochemical data. However, there was a highly significant difference in fatigue, nausea, liver pain, anorexia and muscle pain between the two groups with the Silymarin group showing much lower scores on these variables. The depression scores on the BDI were also significantly lower for the Silymarin group. With regard to QoL, only one scale, general health (GH), was significantly higher for the Silymarin group otherwise no statistically significant differences in QoL were observed in the remaining scales between the two groups * There is no mention of which QOL measure was used in this study. Referral to the methods section of the original HALT-C trial is no more illuminating.

Commentary: This is the first scientific investigation of the use of herbal remedies as a treatment for the symptoms of HCV. We were surprised to note that the first author of this study is Leonard

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Seef who was criticized in the mid-nineties for ignoring symptoms and QoL in his HCV studies. It is interesting to speculate why he changed his viewpoint. However, despite this apparent change in view Seef still manages to tell the reader a lot about the usage of herbal remedies without telling them much about symptoms or essential details, such as the names of the measures they used*. The author makes it quite clear that this study was provisional and that the results should not be taken as evidence of a Silymarin effect on the symptoms of HCV until this can be substantiated using a standardised preparation of Silymarin in a prospective, randomized controlled trial—which the author states is “currently underway” (results not published at the time of this review).

The emphasis on getting things right in the next study (as this was a preliminary study) is exemplary, but there is no discussion about the type and quality of the symptom assessment measures that had been employed in what is otherwise a well controlled study**, which remains incomplete i.e. “currently underway”. One hopes in the subsequent study that the assessment and reporting of symptoms are given more careful attention. * The fatigue measure appears to be self-devised and probably had a severity scale of between zero and five. The QoL measure appears to be the SF-36 minus two scales i.e. role physical (RP) and role emotional (RE) substituted by two other scales i.e. a physical summary scale and a sexual summary scale, both probably taken from the original Medical Outcomes Study (MOS), from where the SF-36, is derived. ** In this preliminary study Seef’s main concern was that he had no control over the quality or dosage of the Sylimarin used by HCV patients, this and the lack of randomization of patients as well as the retrospective design were things he wanted to avoid in the next study.

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