Pediatric Infectious Diseases Revisited ed. by Horst Schroten and Stefan Wirth © 2007 Birkhäuser Verlag Basel/Switzerland
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New treatments for hepatitis B and C in children and adolescents Patrick Gerner Children’s Hospital, Heusnerstrasse 40, HELIOS Klinikum Wuppertal, Witten-Herdecke University, 42283 Wuppertal, Germany
Abstract The treatment of chronic viral hepatitis is a rapidly evolving field. Therapy for chronic hepatitis B is indicated at times of high viral replication, as long as the patient’s aminotransferase levels are increased by more than twice the norm, and when hepatitis B e antigen (HBeAg) is positive. The treatment options for chronic hepatitis B include interferon-alpha and the nucleoside analogues lamivudine and adefovir dipivoxil. Between 26% and 38% of patients respond to treatment with interferon-alpha and nucleoside analogues; from 17% to 36% respond with antibodies to HBeAg (anti-HBe) seroconversion after 1 year. With seroconversion, HBeAg disappears and there is a dramatic decrease in HBV-DNA and usually in the aminotransferases. Further development of nucleoside analogues promises to increase the effectiveness of the therapy. Complete recovery, with conversion to antibodies to hepatitis B surface antigen (anti-HBs), occurs in about 5% of patients only after interferon-alpha therapy. The success of treatment is influenced by factors such as the origins of infection, the viral load before therapy, and the intensity of liver inflammation. Without therapy, the rate of seroconversion to anti-HBe ranges from 2.5% to 11% a year. It is becoming evident that patients with fulminant hepatitis B benefit from treatment with lamivudine. In contrast to hepatitis B, the treatment goal for chronic hepatitis C is the patient’s full recovery. Currently, depending on the HCV genotype, the combination therapy of interferon-alpha and ribavirin administered for 6–12 months has proven effective. Approximately 80% of children are infected with genotype 1a or 1b. They have a recovery rate of 45%. Genotypes 2 or 3 respond much better to treatment. More than 84% of patients can be successfully treated. Genotype 4 is relatively rare and appears to respond to treatment like genotype 1. Under certain circumstances, unsuccessfully treated patients can be treated a second time, after a number of years, with another interferon-alpha, e.g., natural human alpha interferon (Multiferon®) or consensus interferon (Inferax®) plus ribavirin. In addition, new medications such as protease and polymerase inhibitors are currently being tested in adult patients and should be available in the next few years.
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Hepatitis B Epidemiology Worldwide, an estimated one million people die annually due to the consequences of hepatitis B virus (HBV) infection. Almost half of the world’s population will contract HBV, and approximately 350 million people are chronic virus carriers. The prevalence of chronic hepatitis B in children and young people ranges from 0.1% to 8%. In Europe and Northern America the prevalence of chronic hepatitis B in adults is about 0.4–0.8% but lower during childhood. Among adults in some ethnic groups, for example in Egypt, prevalence may be as high as 25% [1, 2].
Serological diagnosis With HBV infection the following parameters are relevant: hepatitis B surface antigen (HBsAg), antibodies to HBsAg (anti-HBs), hepatitis B e antigen (HBeAg), antibodies to HBeAg (anti-HBe), and antibodies to the hepatitis B core antigen (anti-HBc) (both IgG and IgM). Once infection is confirmed, quantitative measurement of HBV-DNA is also useful. These levels are not only an indicator of viral load, and therefore the degree of infectiousness, but also a help to determine the probability of therapy response. Under therapy, the decline in viral replication indicates a positive response. HBcAg is expressed on the membrane of hepatocytes and can therefore only be detected in liver tissue using special dyes. HBV-DNA is the most sensitive marker of HBV infection. It can often be detected before the rise in antibodies even after the disappearance of antigens. In most cases a liver biopsy for histological examination is unnecessary. In the future, determination of HBV genotypes may become more important as a marker of successful therapy.
Serological and clinical course Serologically, chronic hepatitis B can be divided into three major phases (Fig. 1). In the first phase, HBeAg is positive and anti-HBe is negative. Typically, there is a high level of viral replication and the transferases can also be increased. The second phase begins once seroconversion to antiHBe has occurred; HBeAg is then no longer detectable. This seroconversion is not predictable in the individual case and usually occurs together with a dramatic reduction in the viral load and the transferases return to normal. The seroconversion to anti-HBs signals the third phase of infection and is generally equated with recovery from hepatitis. However, highly sensitive polymerase chain reactions (PCR) can detect HBV-DNA sequences in
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Figure 1. Three phases (I–III) of chronic hepatitis B.
roughly 10% of these patients [3]. HBV-DNA is detectable in liver tissue in as many as 30–80% of patients. Whether these low viral levels are clinically relevant is still unclear. However, it is known that the infection may be reactivated in the case of immune suppression.
Therapy Three drugs are available for the treatment of hepatitis B in childhood: these include interferon-alpha, the nucleoside analogue lamivudine (Zeffix®), and adefovir dipivoxil (Hepsera®). The therapeutic goal is complete recovery from hepatitis. However, this occurs in roughly 5% of those patients treated with interferon-alpha. Thus, the primary goal becomes prevention of life-threatening complications such as liver cirrhosis and hepatocellular carcinoma. Most importantly, this is achieved through a reduction in the histological inflammatory activity in liver tissue. A favorable prerequisite therefore is seroconversion to anti-HBe and reduction in viral replication. Treatment of chronic hepatitis is indicated when aminotransferase levels are more than double upper normal limits, and when HBeAg is detectable in serum. If the transaminases remain high in spite of anti-HBe seroconversion and the loss of HBeAg, treatment can still prove to be helpful. It is important that every HBV-infected patient has been tested, to rule out a co-infection with hepatitis C or D virus, especially if the patient exhibits anti-HBe seroconversion and still has high transaminase levels.
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Figure 2. Seroconversion to anti-HBe after therapy with IFN-_ (black column) or without therapy (gray column) in percentages. Columns from left to right: (1)+(2) [5] (n = 29); (3)+(4) [6] (n = 149); (5) [4] (n = 107); (6)+(7) [7] (n = 166); (8)+(9) [8] (n = 74).
Interferon-_ Interferon-_ (IFN-_) has immune-modulating, anti-proliferating, and antiviral properties. There are a variety of genetically manufactured as well as naturally derived IFN-_ preparations available, and all need to be injected subcutaneously. During a 6-month treatment period, seroconversion to antiHBe, and with it the transition from the first to the second phase of infection, is achieved in 26–38% of children (see Figs 1 and 2). The spontaneous rate of seroconversion is clearly exceeded with this therapy. Seroconversion to anti-HBs is achieved in approximately 5% of children. The success of anti-HBe or anti-HBs-seroconversion is influenced by a series of factors (Tab. 1). Prognostically, the most important as well as the most favorable factor is a high level of inflammatory activity in the liver. New research suggests that the HBV genotype may influence response to therapy in a way similar to that for hepatitis C. Genotypes A and B also respond better than genotypes C and D [2]. However, with HBV genotypes, especially the genotypes A and D predominant in Europe and North America, treatment success is only marginal.
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Table 1. Predictors for therapy response Positive predictors
Negative predictors
Horizontal transmission
Vertical transmission
Transaminases increased > 2 Ă—
Normal transaminases
Clear evidence of inflammatory activity in liver tissue
Minimal hepatitis
HBV-DNA < 1000 pg/ml serum
Immune suppression
HBV genotypes A and B
HBV-DNA > 1000 pg/ml HBV genotypes C and D
Although the rate of anti-HBe seroconversion using IFN-_ is significantly higher in comparison to the spontaneous course of development, it must be noted that according to a number of long-term studies, seroconversion is probably just delayed in those who do not receive treatment. According to a study conducted by Bortolotti et al. [4], there was no difference (in a second study only a small difference) between those who received treatment and those who did not after 5 years (Fig. 2). Further studies following patients over the long-term course after therapy do not exist. In most studies the combination of IFN-_ with lamivudine, in comparison to monotherapy with IFN-_ does not improve anti-HBe seroconversion and is thus not worthy of consideration [2]. In conclusion, successful treatment accelerates anti-HBe seroconversion in the individual patient but does not increase the overall rate by a statistical significant proportion. To date there are no data in children with PEG-interferon-alpha therapy. According to recent data from adults it seems quite reasonable to assume that the treatment results are comparable.
Second line treatment The majority of patients do not respond to treatment with IFN-_ and retreatment has not proven to be effective. Instead, after unsuccessful treatment with interferon, and if the transaminases are increased by at least 1.5 times upper normal limit, treatment with nucleoside analogues is indicated. Personal experience and the still unpublished results of a double-blind study indicate an increased anti-HBe seroconversion after 4 months of treatment with vitamin E (200â&#x20AC;&#x201C;600 IE/day according to body weight). From a total of 92 patients treated with vitamin E, 23% seroconverted to antiHBe, seroconversion occurred in only 8% of the placebo group. However, the difference between the two groups is not significant and represents a trend that must be tested on a larger group of patients. A second treatment with IFN-_ is not useful.
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Treatment IFN-_ for 24 weeks, 5 MU/m2 3 ×/week s.c. or PegIntron* 1.5 +g/kg 1 ×/week s.c. is used for treatment (* as of yet there are no published data regarding treatment of hepatitis B in childhood).
Complications The following are complications in IFN-_ treatment of hepatitis B : – Flu symptoms – Loss of hair (often minimal and reversible) – Depression (seldom) – Neutropenia, thrombopenia – Delayed growth (usually compensated for once therapy ends) – Autoimmune thyroiditis.
Contraindications The following are contraindications for treatment : – Leukopenia, thrombopenia – Autoimmune illnesses (autoimmune hepatitis, thyroiditis) – Decompensated liver cirrhosis – Acute psychosis, depression – Epilepsy – Immune suppression
Nucleoside analogues The second best choice for therapy or when the side effects of IFN-_ cannot be tolerated or the patient has advanced liver cirrhosis, are the nucleoside analogues. Based on many years of experience, currently lamivudine is the best choice for children. Under certain circumstances, adefovir dipivoxil can be given, especially as resistance is less likely to develop under this drug. Essentially, nucleoside analogues are effective due to the misarranged inclusion of a nucleoside during viral replication. Initially, in 50–80% of patients the HBV-DNA level drops and may no longer be detectable in conventional PCR, and in 50–70% the transaminase levels return to normal. In addition, liver inflammation is suppressed in over 50% of patients. However, these improvements appear to be restricted to the period of therapy, and 17–36% of those who do not receive treatment achieve anti-HBe seroconversion (Fig. 3). In the largest published trial [12], it was evident that anti-
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Figure 3. Seroconversion to anti-HBe (%) after 1 year of treatment with lamivudine (black column) or without therapy (gray column). Columns from left to right: (1)+(2) [9] (n = 58); (3)+(4) [10] (n = 106); (5) [11] (n = 20); (6)+(7) [12] (n = 288).
HBe seroconversion under lamivudine treatment strongly correlated with the pre-treatment aminotransferase levels, which is very similar to that seen for IFN-_ treatment. Beside patients with chronic infection, there is now strong evidence that patients with fulminant hepatitis B benefit from treatment with lamivudine. One disadvantage in treatment is the selection of resistant mutations. This occurs in approximately 19% of patients over the course of 1 year and often corresponds to an increase in transaminases. However, studies in adults show that long-term therapy with lamivudine over 5 years increases the rate of seroconversion to approximately 60%. On the other hand, 70% of these patients develop resistant mutations [7]. In the USA, lamivudine has been approved for the treatment of chronic hepatitis B in children. In addition to lamivudine, there are other nucleoside analogues, including adefovir dipivoxil, and most recently, entecavir or telbivudine. An international multi-centered study is currently considering whether or not to approve the treatment of children with adefovir. Adefovir does not appear to be more effective than lamivudine, but induces significantly fewer resistant mutations. According to a study by Hadziyannis et al. (unpublished), no resistant mutations arose in the first year of treatment, only 3% in the second, and at most, 18% after 4 years.
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Course of therapy Lamivudine is given for 12 months, 15 mg/kg per day p.o. (max. 100 mg/ 100 ml). Adefovir dipivoxil is given for 12 months 0.3–0.5 mg/kg per day p.o., max. 10 mg.
Side effects Problems with kidney function are rare.
Contraindications Renal insufficiency/failure.
Summary of treatment options (Tab. 2) Summarizing treatment options in chronic hepatitis B in children and adolescents, it can be stated that both IFN-_ and nucleoside analogues have no very high effectivity in terms of induction of anti-HBe seroconversion. IFN-_ exceeds nucleoside analogues by roughly 10%. Effectivity increases with pre-treatment aminotransferases levels of more than 80– 100 U/l. It has to be pointed out that the drugs are not generally approved for this age group (e.g., in Europe) and they have to be used “off label” in most cases.
The future In the coming years, further development of nucleoside analogues (e.g., entecavir, telbivudine, emtricitabine, clevudine) should expand treatment options. In adults, more patients are undergoing long-term treatment with nucleoside analogues. To date it remains open whether these developments prove to be useful in the treatment of children.
Hepatitis C Epidemiology Chronic hepatitis C occurs only infrequently in childhood. Based on our own research, the estimated rate is about 1/2000 children in Germany [13]. Many of these patients were found to have received blood or blood prod-
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Table 2. Advantages and disadvantages of antiviral medications for chronic hepatitis B
IFN-_
Advantages
Disadvantages
Anti-HBs seroconversion ~5%
Significant side effects
Anti-HBe seroconversion 26–38% Expensive Lamivudine
Adefovir
Few if any complications In most patients HBV-DNA and GPT decrease during therapy Available in juice form Resistance development
No anti-HBs seroconversion Anti-HBe seroconversion only 10–15%
Like lamivudine but fewer resistances
More expensive and little experience with children
Higher than spontaneous development Less long-term experience
ucts, in other words a treatment via parenteral injection in countries where inadequate measures of sterilization were practiced. While this method of infection is becoming increasingly less important, the vertical route of infection for HCV is steadily increasing.
Serological diagnosis Screening tests to determine the levels of anti-HCV antibodies are conducted using commercial tests, whereas HCV-RNA is detected via PCR. Usually a PCR is conducted to quantify the “viral-load”, which provides the number of circulating HCV genomes. A positive finding is followed by HCV genotyping. Characteristically, the transaminases progress in an often unsteady and fluctuating manner, and the discovery of normal levels is not unusual. A liver biopsy is usually not necessary and should only be performed if there is any reason to suspect significant liver damage or as a means of ruling out other liver diseases.
Transmission The risk of vertical infection is 3–8%. The method of birth does not influence the risk of transmission. Transmission via blood or blood products still occurs, and remains an important consideration. Blood transmissions took place either before the introduction of screening tests for HCV in the early 1990s, or the child originated from a country without adequate screening methods. Although transmission is possible during sexual intercourse, it seldom occurs. With monogamous partners, the transfer of HCV is so rare that a concern about such transmission does not even justify condom use [14].
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Figure 4. Continuing response to therapy (%) (HCV-RNA negative 6 months after end of treatment). Black, genotype 1; gray, genotype 2 or 3. Columns from left to right: (1)+(2): [15], review (n = 366); (3)+(4) [16] (n = 41); (5)+(6) [17] (n = 61); (7)+(8) [18] (n = 118).
Therapy In comparison to hepatitis B, at least 50% of patients with chronic hepatitis C can be cured. IFN-_-2b (Intron A速) plus ribavirin (Rebetol速) is the approved treatment for children. Ribavirin can be obtained in capsule form as well as in juice form for smaller children. Based on numerous studies conducted in pediatric patients, successful treatment is assured with these two drugs. With the combination therapy of IFN-_ and ribavirin, approximately 45% of patients infected with genotype 1 and 4 and about 90% of those with genotypes 2 and 3, can be cured (Fig. 4). The rate of successfully treated pediatric patients therefore corresponds to those of adults [19]. To avoid late complications and to reduce the chances of contagion, and to maintain the high rates of success, treatment for all chronically infected children should be considered. Treatment with IFN-_ is much better tolerated in childhood than in adulthood and, therefore, it is best to think about treatment before puberty, as long as there are no contraindications. Children also experience the typical side effects of interferon, (see above), but usually they are significantly milder than in adults. Side effects are particularly present in the early phase of treatment, and can be treated
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with paracetamol given as a prophylaxis before each injection. After the first weeks many children get used to the side effects of interferon, which is a further argument for the treatment during childhood. In about 10% of children, specific thyroid antibodies are produced, which may cause hypothyroidism and in some instances must be treated (yet unpublished).
Therapy regimen IFN-_ is given over 12 weeks, 3 MU/m2 3 ×/week s.c. plus ribavirin 15 mg/kg per day. In the eventuality that HCV-RNA decreases by more than 99% after 3 months, treatment should either be continued for the total of 48 weeks or ceased. Treatment must be terminated if HCV-RNA continues to rise in spite of treatment. PegIntron® is given over 12 weeks 1.5 +g/kg 1 ×/week s.c. plus ribavirin 15 mg/kg per day. In case that HCV-RNA decreases by more than 99% after 3 months treatment should either be continued for the total of 48 weeks or ceased. Treatment must be terminated if HCV-RNA continues to rise in spite of treatment. Due to good response to therapy, patients with genotypes 2 and 3 need only be treated for 6 months as a whole.
Contraindications and side effects The most common side effects are flu-like symptoms, which often subside after a few weeks. For the most part they arise after an injection with IFN-_ and can be mitigated by paracetamol given as a prophylaxis (for details see Tab. 3). Side effects are definitively less pronounced before puberty. The induction of autoimmune thyroiditis is possible. Ribavirin may induce an anemia, which has little clinical relevance in most cases.
Second line treatment Basically, unsuccessful treatment can be re-attempted at a later time with another interferon (for example, Multiferon® or consensus interferon). However, no experience has been documented on repetition of treatment in children. We are currently conducting a study in previously treated children who are now receiving Multiferon® plus ribavirin. It is expected that patients who were free of the virus for a short time and became positive again during or after treatment, could profit from re-treatment. For patients who did not become HCV RNA negative during the first treatment period, re-treatment will most likely have less benefit. In any case, the rate of recovery with re-treatment is expected not to exceed 20% for patients infected with genotype 1.
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Table 3. Side effects of interferon-alpha therapy plus ribavirin [19] Side effect
%
Serious %
Headaches
69
3
Fever
61
Abdominal pain
39
Vomiting
42
Myalgia
32
2
Diarrhea
25
<1
Pharyngitis
27
Weight loss
25
Alopecia
23
Inflammation at place of injection
19
Emotional instability
16
Depression
13
Pruritis
12
Arthralgia
15
<1
<1
The future High hopes for the treatment of chronic hepatitis C are being pinned on two new groups of substances: protease inhibitors and polymerase inhibitors that suppress HCV replication. These have been around for a number of years. Some are presently being tested in Phase II studies on patients. The most promising drugs are SCH 503034, VX 950 and valopicitabine (NM 283). It is expected that at least one of these substances will be employed for the treatment of chronic hepatitis C in adults, at least in drug trials. Presumably, these new drugs will be used in combination with other antiviral substances.
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