03 HIV

SECTION 3

HIV 27.

HIV Epidemiology BB Rewari

123

28.

HIV & Diabetes – A Double Trouble PK Agrawal

128

29.

Bone Health in HIV AR Pazare

132

30.

Opportunistic Infections in HIV Partha S Karmakar, Tuhin Santra, Apu Adhikary

134

31.

Management of Failure of Antiretroviral Treatment Subhasish Kamal Guha, Dolanchampa Modak

139

HIV Epidemiology

C H A P T E R

27

BB Rewari

The terms HIV/AIDS were unknown just about three and half decades ago, yet it has emerged as one of the leading cause of death among young adults. In July 1981, the New York Times reported few cases of a rare form of cancer among gay men in Los Angeles which the Centre for Disease Control termed as “GRID” (Gay-Related Immune

Deficiency) which was later termed as “Acquired Immune Deficiency” Syndrome (AIDS) in 1982. Almost 6 years after the disease was identified, the first treatment that emerged was a huge step in fight against HIV/AIDS. The drug AZT (Zidovudine) was approved by the FDA, which was used in high doses to treat people infected with HIV.

Table 1: Global HIV Scenario: 20153

Global Asia and Pacific

People living with HIV (all age groups) in millions

New Infections (all age groups)

34.0- 39.8

1.8- 2.1

People living with AIDS related deaths ART (all age groups) 17 025 900

940 000- 1.3 million

4.4- 5.9

240 000- 380 000

2 071 900

150 000- 220 000

17.7- 20.5

830 000- 1.1 million

10 252 400

390 000- 560 000

Eastern Europe and Central Asia

1.4-1.7

170 000- 200 000

321 800

39 000- 55 000

Latin America and the Caribbean

1.7-2.3

86 000- 120 000

1 091 900

41 000- 59 000

160 000- 330 000

12 000- 37 000

38 200

8700- 16 000

Western and Central Africa

5.3- 7.8

310 000- 530 000

1 830 700

250 000- 430 000

Western and central Europe and North America

2.2- 2.7

89 000- 97 000

1 418 900

20 000- 24 000

Eastern and Southern Africa

Middle East and North Africa

Reference: UNAIDS 2016 Global AIDS Update

Fig. 1: Number of people living with HIV on antiretroviral therapy, global, 2010–20153.

Reference: UNAIDS 2016 Global AIDS Update

INDIA

In 1986, the first few cases of HIV were detected in sex workers in Chennai in the state of Tamil Nadu. India currently has an estimated 2.1 million people living with HIV (PLHIV), third highest globally after South Africa and Nigeria. The HIV epidemic in India is highly heterogeneous – it is concentrated in specific regions of the country and in high risk groups (HRGs) such as people who inject drugs (PWID), female sex workers (FSW), men

There has been a steady decline in the prevalence of HIV (both among men and women) at the National level from 25.0 20.0

Number of PLHIV (Lakhs)

Number of PLHA (Lakhs) 0.34

0.32

0.31 0.30

0.29

Adult HIV Prevalence (%) 0.40 0.35 0.28

0.27

0.27

21.2

21.3

21.4

21.5

21.6

10.0

21.7

15.0 22.0

HIV

Nearly 17 million people are receiving antiretroviral therapy (ART) worldwide (Figure 1). Nearly 68% of infections are in age group of 25 years and above (Figure 2). Globally the number of AIDS related annual deaths have decreased by 43% since 2003 while in eastern and southern Africa, the regions that are most affected by HIV, there has been a 36% reduction in AIDS related deaths since 2010.

EPIDEMIC PROFILE

The National adult (15–49 years) HIV prevalence as per the 2015 HIV surveillance estimates is 0.26% (0.22%– 0.32%) with 0.30% among males and at 0.22% among females (Figure 3). As per the state specific estimates, Manipur has the highest estimated adult HIV prevalence of 1.15%, followed by Mizoram (0.80%), Nagaland (0.78%), Andhra Pradesh & Telangana (0.66%), Karnataka (0.45%), Gujarat (0.42%) and Goa (0.40%). Andhra Pradesh and Telangana together have the highest estimated number of PLHIV (3.95 lakhs) followed by Maharashtra (3.01 lakhs), Karnataka (1.99 lakhs), Gujarat (1.66 lakhs), Bihar (1.51 lakhs) and Uttar Pradesh (1.50 lakhs). Infact these States together account for 64% of total estimated HIV infected people in India.

0.26

Fig. 2: Global Distribution of new adult HIV infections and population by age and sex, 20153. Reference: UNAIDS 2016 Global AIDS Update 2003

0.30 0.25 0.20 0.15 0.10

5.0 0.0

Adult HIV Prevalence (%)

GLOBAL SCENARIO

There are nearly 36 million people living with HIV Globally. Almost 2 million new infections occur every year and 1.2 million people die of HIV every year (Table 1).

who have sex with men (MSM) and transgender. HIV prevalence among adults (15-49 years) in the country has been declining steadily from 0.38% in 2001 to 0.26% in 2015. Prevalence among FSW, MSM, and PWID were 2.2%, 4.3%, and 9.9%, respectively. Overall, the estimated new HIV infections annually have reduced by 66% over 2000- 2015 and annual AIDS-related deaths have also decreased by 54% since 2007. In 2015, there were an estimated 86,000 new HIV infections and 68,000 AIDSrelated deaths in India.

21.2

Billions of dollars have been spent over the last three decades, a cure/vaccine is still not in sight. More than 70 million people have been infected with globally of whom 35 million people have already died because of HIV/AIDS and there is not a single country across the globe that has not reported cases of HIV infection.

22.3

124

0.05 2007 2008 2009 2010 2011 2012 2013 2014 2015

0.00

Fig. 4: HIV Prevalence and PLHIV Burden1. Reference: Technical Report India HIV Estimates 2015, NACO & NIMS

2006

2015

Fig. 3: State Wise HIV Prevalence (%) at ANC sites, HSS 2014-152. Reference: HSS 2014:15

an estimated peak of 0.38% in 2001-03 through 0.34% in 2007 and 0.28% in 2012 to 0.26% in 2015 (Figure 4).

The declining prevalence has been observed across all high prevalence States (Andhra Pradesh & Telangana, Karnataka, Maharashtra, Manipur, Nagaland and Tamil Nadu) and other States such as Goa, Odisha and West Bengal. There are also some states that continue to show a plateau like Bihar, Chhattisgarh, Gujarat, Mizoram, Rajasthan and Uttar Pradesh but the concern is with states like Assam, Chandigarh, Delhi, Jharkhand, Punjab, Tripura and Uttarakhand where there has been an increase in the prevalence.

125

MODES OF TRANSMISSION OF HIV

Unprotected heterosexual intercourse is the primary mode of transmission of HIV in India. Disease is affecting mainly the people in sexually active age group. The majority of the patients are in the age group of 15-49 years. As per the latest data from NACO, the predominant mode of transmission of infection in 2014-15 was through heterosexual contact (94%) followed by parent to child transmission (Figure 8).

Besides heterosexual transmission and parent to child transmission, Injecting drug use is also an important risk factor for HIV infection in the North-East (especially in the states of Manipur, Mizoram and Nagaland), and features increasingly in the epidemics of major cities elsewhere, Modes including of transmission of HIV: Mumbai and New Delhi. in Chennai,

CHAPTER 27

Almost 68,000 new infections occur every year with 54% decline over a decade (Figure 5), with states of AP, Telangana, Maharashtra, Karnataka and Tamil Nadu contributing 50% of cases (Figure 6) and ART scale up

has led to more than 30% decline in AIDS related deaths (Figure 7). Uttar Pradesh and West Bengal, account for 88% of all PPTCT needs in the country.

Unprotected heterosexual intercourse is the primary mode of transmission of HIV in affecting mainly the people in sexually active age group. The majority of the patien group of 15-49 years. As per the latest data from NACO, the predominant mode o infection in 2014-15 was through heterosexual contact (94%) followed by parent to c (Fig 8)

Besides heterosexual transmission and parent to child transmission, Injecting dru

Fig. 5: Annual New Infection in India (1999- 2015)1. Reference: important risk factor for HIV infection in the North-East (especially in the states of M India HIV Estimates: Technical Report 2015 and Nagaland), and features increasingly in the epidemics of major cities elsewh Madhya Odisha Pradesh 3% 2% Rajasthan 5% West Bengal 6%

Chennai, Mumbai and New Delhi.

Others 14%

7: ART Scale and HIVinrelated Deaths in India Figure 8: ModesFig. of Transmission of HIV India 2014-15

.

Reference: India HIV Estimates: Technical Report 2015 1

AP& Telangana 18%

Maharashtra 14% Uttar Pradesh 7% Bihar 7%

0.1% 1%

0.9%

3%

Hetero sexual

1%

Homo/Bisexual Blood & blood products

Gujarat 8%

Tamil Nadu 7%

Karnataka 9%

Infected syringe and needles Parent to child Not specified

94%

*Source : SIMS data 2014-15

Fig. 6: State wise New Infections in 2015 . Reference: India HIV Fig. 8: Modes of Transmission of HIV in India 2014-15.

Epidemiological Factors Estimates: Technical Report 2015 Reference: SIMS data 2014-15 1

Reference: 12.00India HIV Estimates: Technical Report 2015

10.00

Figure 7: 8.00 6.00 4.00 2.00 0.00

High Risk Groups

The lifestyle of certain population groups increases their vulnerability to acquire H hence they1 are identified as high risk groups. e.g. long distance truck drivers, migrant ART Scale and HIV related Deaths in India MSMs, IDUs 0.8 etc. The 2014- 15, Integrated Biological and Behavioral Surveillance (IBBS the highest HIV positivity among the FSW samples was in Maharashtra (7.4%), fol 0.6 Pradesh (6.3%), Manipur, Mizoram, Nagaland (5.9%) and Karnataka (5.8%) while the 0.4MSM which is another group of people at high risk of acquiring HIV, 20 was 2.2%. shown that 0.2 the highest HIV positivity among MSM samples was highest in Andhra followed by Gujarat and Goa (6.8%), West Bengal, Odisha and Jharkhand (6.7%), Ma 0 and finally Karnataka national 4.3%. Among I 03-05 04-06 05-07 06-08 07-10 08-15 03- 05 (4.1%).

04-06 The 05-07 06-08average 07-10positivity 08-13 was 10-15 average was 9.9% with states like Manipur; Mizoram; Delhi and Rajasthan combine ANC FSW MSM IDU Uttarakhand combined and Chattisgarh and MP combined having more than the natio Figure 9: HIV Prevalence Trends

Fig. 9: HIV Prevalence Trends.1 Reference: India HIV Estimates: Technical Report 2015

Presence of STD

126

Exposure route

HIV

Amount of Virus

Table 2: Efficiency of HIV Transmission (Reference: NACO annual report 2014) HIV

Blood transfusion

90-95%

Perinatal (without any intervention)

15-40%

Sexual intercourse

0.1 to 10%

Vaginal

0.05 - 0.1%

Anal

0.065-0.5%

Oral

0.005-0.01%

Injecting drugs use

0.67%

Needle stick exposure

0.3%

Mucous membrane splash to eye, oronasal

0.09%

Note: Comparative risk after needle-stick injury for HBV is 9-30% and for HCV is 1-1.8%

EPIDEMIOLOGICAL FACTORS

High Risk Groups

The lifestyle of certain population groups increases their vulnerability to acquire HIV infection and hence they are identified as high risk groups. e.g. long distance truck drivers, migrant labourers, CSWs, MSMs, IDUs etc. The 2014- 15, Integrated Biological and Behavioral Surveillance (IBBS) has shown that the highest HIV positivity among the FSW samples was in Maharashtra (7.4%), followed by Andhra Pradesh (6.3%), Manipur, Mizoram, Nagaland (5.9%) and Karnataka (5.8%) while the national average was 2.2%. MSM which is another group of people at high risk of acquiring HIV, 2014- 15, IBBS has shown that the highest HIV positivity among MSM samples was highest in Andhra Pradesh (10.1%) followed by Gujarat and Goa (6.8%), West Bengal, Odisha and Jharkhand (6.7%), Maharashtra (4.9%) and finally Karnataka (4.1%).

The national average positivity was 4.3%. Among IDUs the national average was 9.9% with states like Manipur; Mizoram; Delhi and Rajasthan combined; Bihar, UP and Uttarakhand combined and Chattisgarh and MP combined having more than the national average.

Presence of STD

There is strong evidence that men and women with genital ulcer disease or urethral discharge are at increased risk of acquiring and transmitting HIV. The recent IBBS data shows that of the total IDUs sampled in the survey 15.9% had reported as having atleast one STI symptom in the last 12 months while among MSM It was 21% and in FSWs it was as high as 49%.

The Type of Sex Act

All unprotected acts of sexual penetration (anal, vaginal, and oral) carry a risk of HIV transmission because they bring sexual secretions directly into contact with exposed mucous membrane. Injury to the mucous membrane of the rectum, the vagina or the mouth may help the virus to enter into the bloodstream. ‘Receptive’ partners are thus at a greater risk than ‘insertive’ partners in acts of intercourse.

The amount of virus present in the blood or sexual secretions (semen, vaginal or cervical secretions) of the infected partner is an important determinant of infection.

Individuals with HIV infection become more infectious as they progress to HIV related diseases and AIDS. There is also an early period of high infectiousness around the time of sero-conversion.

Susceptibility of HIV

The HIV is a very fragile virus and is inactivated by a number of physical and chemical agents and extreme of pH. It is susceptible to heat. A temperature of 56°C for 30 minutes or boiling for a few seconds kills the virus.

Most of the chemical germicides used in hospital/ laboratories and health care settings kill HIV at much lower concentrations. Thus 0.2% sodium hypochlorite, 70% ethanol, 2% glutaraldehyde, acetone, ether, betapropiolactone (1:400 dilution) and sodium hydroxide (40 mmol/litre) inactivate the virus.

Transmission of Virus

The virus can be transmitted by following ways: unprotected sex with an infected person; use of unsterilized needles; transfusion of infected blood and blood products and from an infected mother to her child before, during or after birth (Table 2).

The mode of transmission of HIV is determined by the amount of infectious virus in a body fluid and the extent of contact. High concentrations of free infectious virus and virus-infected cells have been reported in blood, genital fluids and cerebrospinal fluid. Breast milk and saliva yield varying numbers, whereas, other body fluids have a low viral content. High levels of virus are always associated with symptoms and advanced disease.

Urine, sweat, saliva, faeces and tears have not been reported to transmit the virus unless contaminated with blood. Breast milk at the time of primary infection in a feeding mother has a high content of virus and may transmit the infection to the baby.

Progression of HIV Infection

Three dominant patterns of HIV disease progression have been described. These are based on the kinetics of immunologic and virologic events described above •

Almost 80-90% of HIV infected are ‘typical progressors’ with a median survival time of 11 years, approximately.

•

About 5-10% of HIV infected individuals are ‘rapid progressors’ with a median survival time of 3 years approximately.

CONCLUSION

Over the last two decades major achievements have been made in the field of HIV prevention and treatment.

Today HIV infected mothers are giving birth to healthy children, people are aware of HIV which has resulted in behavioral modifications resulting in a decline in the number of people exposing others or themselves getting

exposed to HIV and most importantly with access to ART, people are living longer and healthier. But with so much advancement clinical science, we still do not have a vaccine or a cure. Even today people continue to transmit the infection and those once infected have to live with it throughout their life.

127

REFERENCES

1.

India HIV Estimates 2015: Technical Report: National AIDS Control Organization. www.naco.gov.in

2.

HIV Sentinel Surveillance 2014-15: A Technical Report.

National AIDS Control Organization. www.naco.gov.in

3.

Global AIDS Update 2016: UNAIDS.www.unaids.org

4.

Consolidated Guidelines on: The Use of ART Drugs For Treating And Preventing HIV Infection: 2016, WHO.www. who.int

CHAPTER 27

Under the Sustainable Development Goals (SDGs) the indicator on HIV specifically mentions “Ends of AIDS” by 2030. Achieving this target requires major changes in the way we identify HIV infected individuals and link them to treatment services. The timeline is not very far and lot needs to be achieved. In order to ensure that our efforts are on the right track, the UNAIDS has set targets for 2020. By then if the countries can ensure that 90% of all people living with HIV will know their HIV status, 90% of all people with diagnosed HIV infection will receive sustained antiretroviral therapy and 90% of all people receiving antiretroviral therapy will have viral suppression then we could achieve the SDG targets in 2030. India, as mentioned earlier in the chapter has made significant

progress but HIV epidemic being a dynamic epidemic, new pockets and areas of concern keep emerging. It is necessary that the program keeps pace with the evolving nature of the epidemic and plans its interventions as per the behavior, needs and lifestyle of the present day young population who are the major drivers of the epidemic.

We cannot afford to relax now. It has to be ensured that people infected and affected by HIV live a normal life, minimum number of new infections occur and the efforts put in over the last two decades do not go waste.

C H A P T E R

28

HIV & Diabetes – A Double Trouble PK Agrawal

INTRODUCTION

Patients with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) are increasing in number, partly due to improved screening,earlier diagnosis, better methods of treatment, and greater accessibility to, as well as acceptance of therapy. The treatment of HIV-1 infection with combined antiretroviraltherapy (cART) has significantly altered the natural history of this life-threatening condition.

Immunocompetence has come at significant metabolic cost, however, because cART is associated with a range of metabolic complications, including insulin resistance, glucose intolerance, type 2 diabetes mellitus, dyslipidemia, and changes in body fat compartmentalization (lipodystrophy).1 cART-associated lipodystrophy in HIV infection is now the commonest form of lipodystrophy.

These metabolic complications have rapidly translated into increased risk for type 2 diabetes and cardiovascular disease.1 These diseases will present new challenges in the management of HIV infection.

EPIDEMIOLOGY

The prevalence of DM in HIV-infected patients has been reported to range from 2% to 14% and varies by the composition of the cohort studied, howDM diagnosis is ascertained, and how DM risk factors are accounted for in the analysis .2–5 There is conflicting evidence on whether HIV infection is an independent risk factor for DM, with some studies showing increased risk2,6,7 and others showing no independent effect of HIV on DM or showing an inverse effect.4,8,9 Despite the conflicting evidence on the independent role of HIV in DM, certain factors are clearly associated with DM, including increasing age, obesity, and genetic factors. Other factors influence DM incidence in the general population but are more common in HIVinfected patients: hepatitis C virus infection,10 use of certain medications (atypical antipsychotics, corticosteroids),

opiate use, and low testosterone.11 Furthermore, ARTassociated lipoatrophy4 and visceral fat accumulation/ lipohypertrophy3,12 and HIV-related inflammation (increased proinflammatory cytokines and/or free fatty acids)13,14 are DM risk factors in HIV-infected patients.

DIAGNOSIS OF DIABETES

Table 1 shows the current American Diabetes Association (ADA) definitions of DM and prediabetes.15 Data are accumulating that HbA1c may underestimate glycemia in HIV-infected individuals. Although the degree of discordance has varied, higher mean corpuscular volume, nucleoside reverse transcriptase inhibitor use (specifically abacavir), and lower CD4 count have been associated with discordance.16-20

DIABETES AND HIV: CLASSIFICATION

Three subgroups of patients with diabetes and HIV can be identified: 1.

Patients with preexisting diabetes who contract HIV,

2.

Those who are diagnosed to have diabetes at onset of HIV infection, and

3.

Others who develop hyperglycemia after start of therapy.

These subgroups need to be managed differently, as the mechanisms of metabolic dysregulation vary in them.

Aetiopathogenesis

Impaired glucose tolerance, and insulin resistance are noted to precede weight loss in patients with HIV.21-25 Insulin resistance, rather than insulin deficiency, is usually implicated in the pathogenesis of diabetes in HIV-infected patients. According to earlier reports, evidence of islet cell autoimmunity, or beta cell destruction has not been seen in HIV patients.26 Autoimmune diabetes, however, has recently been reported to develop in some HIV-infected

Table 1: Definitions of Prediabetes and Diabetes Diabetes Prediabetes Normal

HbA1c

FBS

RBS

OGTT

>=6.5%

>=126mg/dL(>=7.0mmol/L)

>=200mg/ dL(>=11.1mmol/L) with polyuria & polydipsia

>=200mg/ dL(>=11.1mmol/L)

5.7%-6.4%

100-125mg/dL(5.66.9mmol/L)

-

140-199mg/dL(7.811.1mmol/L)

<5.7%

<=99mg/dL(<=5.5mmol/L)

-

<=139mg/dL(<=7.7mmol/L)

patients after immune restoration during HAART. The postulate is that recovery of immune function predisposes to autoimmune disease, in the form of type 1 diabetes (T1DM).27 The type of diabetes associated with HIV may be classified as type 2 diabetes (T2DM), rather than T1DM, in the vast majority of patients.

Viral factors which contribute to diabetes risk are an increase in viral burden of 0.5 log over a 6 month period, a lower CD4 count, and longer duration of HIV infection.21 In general, people with severe, long-standing HIV infection are more prone to developing diabetes

HIV is also associated with various endocrine abnormalities. These include deficiency of growth hormone, as well as growth hormone resistance. Growth hormone deficiency may contribute to insulin resistance in HIV-infected patients.31 The increased accumulation of visceral fat, with wasting of subcutaneous fat, noted in these patients, creates higher levels of inflammatory cytokines such as TNF α. This in turn leads to diabetes or impaired glucose tolerance by increasing insulin resistance.32 HIV-infected subjects with metabolic syndrome show disturbances in inflammation and adipokines: they have higher CRP (5.5 ± 7.0 vs. 3.9 ± 6.0 mg/l) and leptin (9 ± 9 vs. 4 ± 6 ng/ml) and lower adiponectin(12 ± 8 vs. 15 ± 10 μg/ml) levels. This may contribute to the pathogenesis of diabetes.33 The major contributor to hyperglycemia in HIV/AIDS, however, is iatrogenic. A recent analysis has found that diabetes is four fold more common in HIV-infected men exposed to highly active anti retroviral therapy (HAART) than in HIV seronegative men.34 HAART based on the use of Class of drugs Protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) have been linked with development of diabetes mellitus.

PIs have been shown to increase insulin resistance and reduce insulin secretion, by interfering with GLUT-4 mediated glucose transport. Risk factors for development of diabetes with PI therapy include positive family history of diabetes, weight gain, lipodystrophy, old age and hepatitis C infection.35 PIs interfere with cellular retinoic

The other class of drugs which is used is the nucleoside analogs (reverse transcriptase inhibitors) (NRTIs). The risk is highest with stavudine, but is also significant with zidovudine and didanosine. Proposed mechanisms include insulin resistance, lipodystrophy, and mitochondrial dysfunction.37 These mechanisms may be evident only in HIV-infected persons treated for long periods of time with NRTIs.37 This does not mean that HAART should not be prescribed to patients with HIV and diabetes. One should be aware of the adverse metabolic effects of these drugs, and take proactive steps to prevent and manage these.

Anti-retroviral drugs are not the only iatrogenic culprits in HIV-associated diabetes. Drugs used to manage comorbid conditions associated with AIDS may also cause diabetes. Pentamidine, which is used to prevent and treat P. carinii associated pneumonia, can cause β-cell toxicity, with acute hypoglycemia followed by later diabetes. Megesterol acetate, which is used as an appetite stimulant, predisposes to diabetes because of its intrinsic glucocorticoid like activity, increased caloric intake and weight gain.38

Screening for Diabetes

Patients with HIV should be screened for diabetes at diagnosis, at onset of HAART therapy, and three to six months after HAART. While certain professional bodies advise fasting blood glucose as a screening tool,39 the predominant role of insulin resistance in the development of the illness implies that postprandial glucose values, or an oral glucose tolerance test, should also be performed as part of screening procedures.A1c has not been recommended as a diagnostic test in HIV/AIDS.

DIABETES MANAGEMENT

Initial Management

Lifestyle modification have a meaningful impact on glucose control and the course of DM.

Medication Therapy

Oral- Hypoglycaemic Drugs The first-line medication for DM is metformin . Special caution should be used when metformin is coadministered with dolutegravir, as dolutegravir increases metformin

129

CHAPTER 28

Coexistent hepatitis C virus (HCV) infection with HIV infection seems to increase diabetes risk in some but not in all studies. HCV infection is associated with increased insulin resistance.28 A retrospective study of 1230 HIVinfected Cart recipients (50% coinfected with HCV) offers valuable insights. Diabetes mellitus prevalence was doubled in those coinfected with HCV, 5.9% compared with 3.3% in subjects with HIV infection alone.29 Incident cases of diabetes mellitus were more common in those with HCV coinfection: 5.8% vs 2.8%; the incidence of hyperglycemia per 100 person-years was 4.9 in those with HCV coinfection vs 2.3 in those with treated HIV infection alone.29 In contrast, the Swiss HIV Cohort Study of 6513 subjects did not find HCV coinfection a risk factor incident diabetes mellitus.30

acid-binding protein type 1 (CRABP 1) that interacts with peroxisomal proliferator-activated receptor (PPAR) γ.

Inhibition of PPAR-γ promotes adipocyte inflammation, release of free fatty acids and insulin resistance.36 Hyperglycemia resolves in almost all patients when PIs are discontinued.36 All PIs do not have the same metabolic effects. Indinavir induces insulin resistance with no effect on lipid metabolism, whereas lopinavir and ritonavir increase fasting triglycerides and free fatty acids, but do not worsen insulin sensitivity. Indinavir and retonavir both block GLUT -4, but no such effect is noted with amprenavir, and atazanzvir. This implies that there is no class effect of PIs on diabetes, and that various PIs should be studied individually with respect to their metabolic effects.36

130

concentration.40

HIV

After lifestyle modification and metformin, if a patient is still not at goal, there are multiple treatment options like sulfonylureas, thiazolidinediones, incretins (GLP1 analogues and DPP 4 inhibitors) gliflozins and meglitinides.

Levels of thiazolidinediones may increase when used with CYP2C8 inhibitors (many PIs). It should monitor carefully. Concern regarding gliptin use in HIV infected individuals was raised, as gliptins have molecular targets on immune cells; however, a small study revealed no changes in CD4 or HIV RNA among treated HIVinfected patients taking sitagliptin.41 Of note, saxagliptin interacts with strong cytochrome P450 3A4/5 inhibitors (eg, ritonavir), and saxagliptin dose should be reduced when used in combination.42 No interactions between ART and dapagliflozin are expected; however, if UDPglucuronosyltransferase enzyme inducers (eg, ritonavir) must be coadministered with canagliflozin, clinicians could consider increasing the dose to 300 mg.43 When used with CYP3A4/CYP2C8 inhibitors (many PIs), meglitinides (repaglinide/ nateglinide) levels may increase. Monitor carefully. Efavirenz (EFV) and Etravirine (ETR) may increase nateglinide .

Insulin

Insulin is the preferred choice for management of diabetes with HIV. Insulin has an anabolic effect, is known to reduce inflammatory markers such as TNFalpha, does not have any interactions with antiretroviral or other drugs, is not contraindicated with renal or hepatic dysfunction, does not reduce appetite or cause gastrointestinal side effects, can correct both insulin deficiency and resistance when given in appropriate doses, and does not increase the risk of cardiovascular disease.44

Changes in HAART

PI-based regimes should be avoided in patients at high risk of developing diabetes, e.g., those with a history of gestational diabetes, a positive family history of diabetes, or impaired glucose tolerance on screening. Indinavir should be avoided, and replaced with less toxic drug.

Management of Pre-Existing Diabetes

Pre-existing T2DM may continue to be managed, after diagnosis of HIV, with the same drug therapy that was being used prior to detection of HIV. Patients should be informed about the chances of worsening hyperglycemia, and educated about the features of ketosis and lactic acidosis. In case glycemic control deteriorates, insulin should be initiated, rather than increasing dosage or number of OADs.

CONCLUSION

Diabetes mellitus is a prevalent chronic condition with many deleterious effects, which may be accentuated among patients with both DM and HIV. Clinicians should perform regular DM screening in HIV-infected patients. The effective management of diabetes in HIVinfected patients requires a thorough understanding of

pathophysiology and pharmacology. The choice should be based on the etiopathogenesis of the disease. In treating DM, lifestyle changes are critical, as a 5%-10% weight loss can have important metabolic effects. If drug treatment is required, metformin is first line therapy.

Decisions regarding second and third line drugs should be individualized. Insulin is a safe and effective method of treating all these patients irrespective of type of diabetes.

REFERENCES

1. Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med 2005; 352:48–62.

2. Brown TT, Cole SR, Li X, et al. Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. Arch Intern Med 2005; 165:1179–84.

3. De Wit S, Sabin CA, Weber R, et al. Incidence and risk factors for new-onset diabetes in HIV-infected patients.

Diabetes Care 2008; 31:1224–9.

4. Rasmussen LD, Mathiesen ER, Kronborg G, Gerstoft J, Obel N. Risk of diabetes mellitus in persons with and without HIV: a Danish nationwide population-based cohort study.

PLoS One 2012; 7:e44575.

5. Polsky S, Floris-Moore M, Schoenbaum EE, Klein RS, Arnsten JH, Howard AA. Incident hyperglycaemia among older adults with or atrisk for HIV infection. Antivir Ther 2011; 16:181–8 6. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab 2007; 92:2506–12.

7. Galli L, Salpietro S, Pellicciotta G, et al. Risk of type 2 diabetes among HIV-infected and healthy subjects in Italy.

Eur J Epidemiol 2012; 27:657–65.

8. Howard AA, Hoover DR, Anastos K, et al. The effects of opiate use and hepatitis C virus infection on risk of diabetes mellitus in the Women’s Interagency HIV Study. J Acquir Immune Defic Syndr 2010; 54:152–9.

9. Butt AA, McGinnis K, Rodriguez-Barradas MC, et al. HIV infection and the risk of diabetes mellitus. AIDS 2009; 23:1227–34.

10. Mehta SH, Moore RD, Thomas DL, Chaisson RE, Sulkowski MS. The effect of HAART and HCV infection on the development of hyperglycemia among HIV-infected persons. J Acquir Immune Defic Syndr 2003; 33:577–84.

11. Monroe AK, Dobs AS, Xu X, et al. Sex hormones, insulin resistance, and diabetes mellitus among men with or at risk for HIV infection. J Acquir Immune Defic Syndr 2011; 58:173– 80.

12. Ledergerber B, Furrer H, Rickenbach M, et al. Factors associated with the incidence of type 2 diabetes mellitus in HIV infected participants in the Swiss HIV Cohort Study.

Clin Infect Dis 2007; 45:111–9.

13. Brown TT, Tassiopoulos K, Bosch RJ, Shikuma C, McComsey GA. Association between systemic inflammation and incident diabetes in HIV-infected patients after initiation of antiretroviral therapy. Diabetes Care 2010; 33:2244–9.

14. Meininger G, Hadigan C, Laposata M, et al. Elevated concentrations of free fatty acids are associated with increased insulin response to standard glucose challenge

in human immunodeficiency virus-infected subjects with fat redistribution. Metabolism 2002; 51:260–6.

HIV-infected participants in the Swiss HIV Cohort Study.

Clin Infect Dis 2007; 45:111–119.

15. American Diabetic Association. Standards of medical care in diabetes—2014. Diabetes Care 2014; 37(suppl. 1):S14–80.

31. Smith JC, Evans LM, Wilkinson I, et al: Effects of GH replacement on endothelial function and large artery stiffness in GH-deficient adults: a randomized, doubleblind, placebo-controlled study. Clinical Endocrinology 2002; 56:493-501.

16. Kim PS, Woods C, Georgoff P, et al. Hemoglobin A1c underestimates glycemia in HIV infection. Diabetes Care 2009; 82:1591–8.

17. Diop M-E, Bastard J-P, Meunier N, et al. Inappropriately low glycated hemoglobin values and hemolysis in HIVinfected patients. AIDS Res Hum Retroviruses 2006; 22:1242– 7.

19. Glesby MJ, Hoover DR, Shi Q, et al. Glycated hemoglobin in diabetic women with and without HIV infection: data from the women’s interagency HIV study. Antivir Ther 2010; 15:571–7.

20. Slama L, Palella F, Abraham A, et al. Inaccuracy of hemoglobin A1c among HIV-infected: effects of CD4 cell count, antiretroviral therapies, and hematologic parameters. J Antimicrob Chemother 2014; doi:10.1093/jac/ dku295.

21. Fichtenbaum CJ, Hadigan CM, Kotler DP, et al: Treating morphologic and metabolic complications in HIV-infected patients on antiretroviral therapy. IAPAC Monthly 2005, 38-46.

22. Norris A, Dreher HM: Lipodystrophy syndrome: the morphologic and metabolic effects of antiretroviral therapy in HIV infection. J Assoc of Nurses in AIDS Care 2004; 15:4646.

23. Gkarnia-Klotsas E, Klotsas AE: HIV and HIV Treatment: effects on fats, glucose and lipids. BMB 2007, 1093:1-20.

24. Vaidya D, Szklo M, Liu K, Schreiner PJ, Bertoni AG, Ouyang P: Defining the metabolic syndrome construct: multi-ethnic study of atherosclerosis cross-sectional analysis. Diabetes Care 2007; 30:2086-2090.

25. Mondy K, Oovertan ET, Grubb J, et al: Metabolic syndrome in HIV-infected patients from an urban, Midwestern US outpatient population. Clin Infec Dis 2007; 44:726-734.

26. Dagogo-Jack S: HIV therapy and diabetes risk. Diabetes Care 2008; 31:1267-1268.

27. Takarabe D, Rokukawa Y, Takahashi Y, Goto A, Takaichi M, Okamoto M, Tsujimoto T, Noto H, Kishimoto M, Kaburagi Y, Yasuda K, Yamamoto- Honda R, Tsukada K, Honda M, Teruya K, Kajio H, Kikuchi Y, Oka S, Noda M: Autoimmune diabetes in HIV-infected patients on highly active antiretroviral therapy. Journal of Clin Endocrinol Metab 2010; 95:4056-4060.

28. Yazicioglu G, Isitan F, Altunbas H, et al. Insulin resistance in chronic hepatitis C. Int J Clin Pract 2004; 58:1020–1022.

29. Mehta SH, Moore RD, Thomas DL, et al. The effect of HAART and HCV infection on the development of hyperglycemia among HIV-infected persons. J Acquir Immune Defic Syndr 2003; 33:577–584.

30. Ledergerber B, Ferrer H, Rickenbach M, et al. Factors associated with the incidence of type 2 diabetes mellitus in

32. Vigouroux C, Maachi M, Nguyen TH, et al: Serum adipocytokines are related to lipodystrophy and metabolic disorder in HIV-infected men under antiretroviral therapy.

AIDS 2003; 17:1503-1511.

33. Samaras K, Wand H, Law M, Emery S, Cooper D, Carr A: Prevalence of metabolic syndrome in HIV-infected patients receiving highly active antiretroviral therapy using International Diabetes Federation and Adult treatment Panel III criteria. Diabetes Care 2007; 30:113-115.

34. Brown TT, Cole SR, Kingsley LA, Palella FJ, Riddler SA, Visscher BR, Margoluck JB, Dobs AS: Antiretroviral Therapy and the prevalence and incidence of diabetes in a multicenter AIDS Cohort study. Arch Interm Med 2005; 165:1179-1184.

35. Woerle HJ, Marivz PR, Meyer C, Reichman RC, PFAEM, Dostou JM, Welle SL, Gerich JE: Mechanisms for the deterioration in glucose tolerance associated with protease inhibitor regumem. Diabetes 2003; 52:918-925.

36. Lee GA, Rao M, Greenfeld C: The effects of HIV Protease inhibitors on carbohydrate and lipid metabolism. Curr Infect Dis Resp 2004; 6:471-482.

37. Fleishman A, Johnsen S, Systrom DM, et al: Effects of a nucleoside reverse transcriptase inhibitor, stavudine, on glucose disposal and mitochondrial function in muscle of healthy adults. Am J Physiol Endocrinol Metab 2007; 292:E1666-E673.

38. Henry K, Rathgaber S, Sullivan C, McCabe K: Diabetes mellitus induced by megesterol acetate in patients with AIDS and cachexia. Ann Intern Med 1992; 116:53-54.

39. Schambelan M, Benson CA, Carr A, et al: Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA Panel. J Acquir Immune Defic Syndr 2002; 33:257-275.

40. Tivicay (dolutegravir) prescribing information. Available at: http://www.viivhealthcare.com/media/58599/us_ tivicay.pdf. Accessed 21 March 2014.

41. Goodwin SR, Reeds DN, Royal M, Struthers H, Laciny E, Yarasheski KE. Dipeptidyl peptidase IV inhibition does not adversely affect immune or virological status in HIV infected men and women: a pilot safety study. J Clin Endocrinol Metab 2012; 98:743–51.

42. Onglyza (saxagliptin) prescribing information. Available at: http://packageinserts.bms.com/pi/pi_onglyza.pdf.

Accessed 21 March 2014.

43. Invokana (canagliflozin) prescribing information. Available at: http://www.invokanahcp.com/prescribing-information. pdf. Accessed 21 March 2014.

44. Rao PV: Persons with type 2 diabetes and co-morbid active tuberculosis should be treated with insulin. Int J Diab Dev Countries 1999; 19:79-86.

CHAPTER 28

18. Polgreen PM, Putz D, Stapleton JT. Inaccurate glycosylated hemoglobin A1C measurements in human immunodeficiency virus—positive patients with diabetes mellitus. Clin Infect Dis 2003; 37:e53–6.

131

Bone Health in HIV

C H A P T E R

29

INTRODUCTION

Although the prevalence of HIV infection is gradually decreasing, the numbers of patients living with HIV are increasing which has been attained due to various government program and free antiretroviral therapy (ART).

In India, at present more than 1 million people are living with a various drug regimes provided through ART centers and private set up. Many patients are on ART since more than a decade, which poses typical problems due to longstanding HIV disease or drugs used for ART. This includes metabolic syndrome, lipodystrophy, bone marrow suppression, nephrotoxicity, cardiomyopathy, metabolic bone diseases and many more.

The major bone lesions detectable in these patients are due to demineralization which includes osteopenia, osteoporosis, osteomalacia, avascular necrosis of neck of femur and very rarely fractures. These bone abnormalities may occur because of HIV disease itself or as a side effect of ART drugs. Studies from western countries showed relation between ART drugs and abnormal bone lesions.

However in India nutritional status may also play a role in abnormal bone lesions in addition to side effects of ART drugs. Thus in Indian population, ART may actually improve bone mineral density by improving appetite, decreasing the incidence of vitamin D deficiency.1 Other risk factors for osteoporosis are gender (women are more susceptible for osteoporosis), age (risk of osteoporosis increases with age), body size (thin person are at greater risk), ethnicity (White and Asian are at highest risk), hormones (low estrogen at menopause and low testosterone in men), low calcium and vitamin D intake, lack of exercise, smoking and alcohol intake and prolong use of certain drugs like glucocorticoids, protease inhibitors, cyclosporine, tacrolimus, heparin, lithium, methotrexate, anticonvulsants and medroxyprogesterone.2 Osteoporosis is estimated to affect 200 million women worldwide and 1 in 3 women and 1 in 5 men over age of 50 years will experience osteoporotic fractures. In a study among Indian women aged 30-60 years from low income groups, BMD at all the skeletal sites were much lower than values reported from developed countries, with a high prevalence of osteopenia (52%) and osteoporosis (29%) thought to be due to inadequate nutrition.3 Meta-analysis showed that, the prevalence of osteoporosis

AR Pazare

was 3 times higher among HIV infected patients compared to HIV negative controls. Several studies have shown that BMD decreases by 2% - 6% within the first 2 years of various ART regimens. In a Turkish study osteopenia and osteoporosis were diagnosed in 53.9% and 23.8%, in HIV positive patients. There is an increase in fracture rates in the HIV infected population and it is 30%-70% higher than those among matched uninfected control subjects.4

MECHANISMS OF HIV ASSOCIATED OSTEOPENIA/ OSTEOPOROSIS

The pathogenesis of reduced BMD in HIV infected patients is probably multifactorial. The sum of traditional risk factors with HIV infection, and HAART side effects can determine the onset of these bone lesions in HIV infected patients.

DIRECT EFFECT OF HIV ON BONE

Bone might be considered an HIV reservoir where limited blood flow and the particular anatomical structure may also induce a poor antiretroviral drug concentration to tackle the HIV infection. Moreover, the infection of osteoblasts may be closely related to the incomplete refilling of bone lacunae during bone remodelling with subsequent bone loss. The apoptosis process plays a major role in HIV pathogenesis. The loss of CD4 cell is also related to the apoptosis activated by the interaction between HIV gp120 and the CD4 receptor by causing an increase in TNF-α which has direct inhibitory effect on osteoblasts function.5,6

ROLE OF VITAMIN D

Vitamin D deficiency is common in HIV infected patients.

Hypovitaminosis D is due to poor dietary intake and effect of ART on vitamin D metabolism.

EFFECT OF ART

HAART has been suspected of influencing bone turnover independently of the bone loss associated with HIV-1 infection itself, although it has been suggested that this effect may be relatively modest in relation to the loss of BMD associated with other established osteoporosis risk factors. Initiation of HAART has been consistently associated with up to a 6% reduction in hip BMD, a common site of fracture, over the first 48–96 weeks of therapy. In a recent meta-analysis of cross-sectional studies, protease inhibitors (PI’s) had a higher prevalence of osteoporosis compared to those receiving non protease inhibitor regimens.7,8

In vitro studies have illustrated that protease inhibitors inhibit the 25-hydroxylase and 1-α hydroxylase. The net effect of Pls on vitamin D is a reduction in the production of the active form of vitamin D 1, 25(OH) 2D which causes decrease in calcium absorption and decrease in bone density. Also protease inhibitors increase osteoclast activity through the abrogation of a physiological block to RANKL signaling represented by interferon gamma mediated proteosomal degradation of TNF receptor associated factor 6 (TRAF – 6) and also inhibit osteoblastogenesis.9

In contrast to studies in western countries, our study demonstrated that bone attrition is seen in HIV positive patients but it is not altered by ART. This difference may be due to nutritional status of Indian population. ART increases appetite which may improve nutritional status hence there is improvement in bone health and ART may deteriorate it. Thus a balance in bone health is maintained in Indian population. Other reason may be the use of different ART regimes in Indian population (NRTI + NNRTI) compared to western countries (NRTI+PI). And as per literature PI is blamed for deterioration of bone health.

REFERENCES

1.

Mithal A, Kaur P, Osteoporosis in Asia: A call to action.

Curr Osteoporos Rep 2012; 10:245–247.

2.

National Osteoporosis Foundation Clinician’s Guide to Prevention and Treatment of Osteoporosis. Available at http://www.nof.org/professionals/clinical-guidelines.

Accessed January 13, 2011.

3.

Melton LJ, Chrischilles EA, Cooper C, et al Perspective.

How many women have osteoporosis? J Bone Miner Res 1992; 7:1005-1006.

4.

Negredo E et al. Peak bone mass in young HIV-infected patients compared with healthy controls. J Acquir Immune Defic Syndr, online edition, doi: 10.1097/1. qai.0000435598.20104.d6, 2013.

5.

Annapoorna N, Rao GV, Reddy NS et al. An Increased Risk of Osteoporosis during Acquired Immunodeficiency Syndrome. International Journal of Medical Sciences 2004; 1:152-164.

6.

Yin M, Dobkin J, Brudney K, et al. Bone mass and mineral metabolism in HIV+ postmenopausal women. Osteoporos Int 2005; 16:1345–1352.

7.

Gallant JE, Staszewski S, Pozniak AL, et al, Efficacy and safety of tenofovir DF vs. stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. J Am Med Assoc 2004; 292:191–201.

IN OUR STUDY AT KEM HOSPITAL:

120 subjects in 2 groups were studied (ART naïve, n=60 and ART experienced, N=60). Prevalence of low BMD in HIV positive subjects was 85% (osteopenia and osteoporosis found to be 75% and 10% respectively).

The high prevalence of low BMD in our study can be attributed to lower socioeconomic status, malnutrition, vitamin D deficiency and delay in seeking medical care in Indian population.

In ART-naive group prevalence of osteopenia was seen in 76.7% and osteoporosis in 3.3% whereas in ARTexperienced group it was seen in 73.3% and 16.7% respectively. When ART-naive and ART-experienced group were compared there was no statistically significant change seen in osteopenia (p= 0.12) but osteoporosis was significantly higher in ART-experienced group (p=0.014). Thus bone attrition is seen in HIV positive patients irrespective of ART or no ART. And ART doesn’t significantly increase the rate of bone loss in HIV positive patients. This finding is similar to study by C Amiel et al in France which compared BMD in ART naïve and PI based ART experienced group in 81 subjects which concluded that there is no deleterious effect of the ART on BMD but does indicate a decrease in bone density in HIV patients irrespective of the treatment.10

8. Mallon PW, Miller J, Cooper DA, Carr A, Prospective evaluation of the effects of antiretroviral therapy on body composition in HIV-1-infected men starting therapy. AIDS 2003; 17:971–979.

9.

McComsey, Tebas P, Shane E, et al, Bone disease in HIV infection: a practical review and recommendations for HIV care providers. Clin Infect Dis 2010; 51:937-46.

10. C Amiel, A Ostertag,L Slama et al,BMD Is Reduced in HIVInfected Men Irrespective of Treatment. Journal of Bone and Mineral Research 2004; 19:402–409.

133

CHAPTER 29

NRTI’s inhibit the DNA polymerase the enzyme involved in the replication of mitochondrial DNA, leading to mitochondrial damage and dysfunction, which in turn leads to lactic acidaemia and causes osteopenia. There is a calcium hydroxyapatite loss as the bone tries to buffer chronic acidosis and hence osteoporosis.9

CONCLUSION

Opportunistic Infections in HIV

C H A P T E R

30

Partha S Karmakar, Tuhin Santra, Apu Adhikary

INTRODUCTION

An opportunistic infection may be caused by various pathogens - bacteria, viruses, fungi, or protozoa.

Many people living with HIV(PLHIV) may remain asyptomatic and first diagnosed when they face serious health threats from opportunistic infections (OIs). OIs are responsible as important contributing factor for mortility in PLHIV.

WHAT IS OPPORTUNISTIC INFECTION (OI)

Some infections are called “opportunistic” because they usually do not infect people of healthy immune system but take advantage of weakened immune system of the affected person. We all know HIV is the most important cause of compromised immunity.

ARE OIS UNIQUE FOR PLHIV?

HIV infection is definitely very important cause for immune suppression but there are many other clinical conditions where a non-HIV person may fall prey to opportunistic infections. Following conditions are some examples not uncommon to be associated with opportunistic infections

• Chemotherapy for cancer • Immunosuppressing transplant recipients

agents

for

organ

• Genetic predisposition • Pregnancy • Ageing • Malnutrition PLHIV can face serious health threats from opportunistic infections (OIs). OIs usually occur when CD4 count is below 200. However, certain OIs in HIV infected person indicate the person is having AIDS irrespective of the CD4 count.

In general, OIs are treated first before initiation of anti retroviral therapy (ART).

OIS IN HIV

There are host of OIs - viral, bacterial, fungal,protozoal & description of all is beyond scope here. Important aspects of some selected OIs are described here.

Majority of OIs (asteric ones) here are AIDS defining diseases also according to CDC.1

Viral •

Cytomegalovirus (CMV): CMV retinitis*, colitis, esophagitis, pneumonitis.

•

Herpes simplex virus (HSV): chronic ulcer >1 month’s duration, bronchitis, pneumonia, esophagitis.

•

Human herpes virus 8 (HHV-8): Kaposi’s sarcoma.*

•

Human papillomavirus cancer(Invasive).

•

Epstein barr virus (EBV): Primary CNS lymphoma*, HIV associated Burkitt’s lymphoma.

(HPV):

• JC virus: PML (progressive leukoencephalopathy).*

Bacterial

Cervical

multifocal

•

Mycobacterium tubercrulosis extrapulmonary)*.

(pulmonary

or

•

Mycobacterium avium complex (MAC)* or other species, disseminated or extrapulmonary.

•

Recurrent pneumonia.

•

Recurrent Salmonella septicaemia*

Fungal

• Candida: oropharyngeal thrush, esophageal candidiasis ,* candidiasis of bronchi, trachea and lungs.

•

Pneumocystis jirovecii pneumonia.*

•

Cryptococcosis, extrapulmonary*

•

Histoplasmosis, disseminated or extrapulmonary*

• Coccidioidomycosis, extrapulmonary*

disseminated

or

• Microsporidiosis.

Protozoal

• Toxoplasmosis of brain.* • Cryptosporidiosis: chronic intestinal >1 month duration* • Isosporiasis: chronic intestinal >1 month duration*

VIRAL INFECTIONS

Cytomegalovirus disease (CMV) •

Causes retinitis, colitis, esophagitis, pneumonitis

•

Retinitis is the commonest manifestation. Patients with CD4 <100/µL are at higher risk. 1

•

•

Clinical features of CMV retinitis :- Painless progressive irreversible loss of vision (due to necrotic inflammatory process) but patients may also complain of blurred vision, floaters, scintillations. The disease is usually bilateral but typically asymmetric.

Fundoscopy :- Perivascular hemorrhage and exudate. When in doubt, vitreous or aqueous humor sampling with molecular diagnosis technique may be of value.

Treament :

Oral valganciclovir, IV ganciclovir, or IV foscarnet, with cidofovir as an alternative.

A 3-week induction course is followed by maintenance therapy with oral valganciclovir.

Maintenance therapy is continued until the CD4 count remains >100–150/µL for >6 months.

KAPOSI’S SARCOMA (KS)

•

HHV-8 has been implicated in the pathogenesis of KS.

•

May be seen at any stage of HIV infection, even in the presence of a normal CD4 count.1

•

It is a multicentric neoplasm consisting of multiple vascular nodules appearing in the skin, mucous membranes, and viscera. Lesions often appear in sun-exposed areas and shows Koebner phenomenon (tends to occur in areas of trauma)

•

Clinical features:

Depends upon according to organ involvement.

Disease limited to the lymph nodes show good prognosis.

Pulmonary involvemrnt may cause dyspnoea.

Chest x-ray may show bilateral lower lobe infiltrates and pleural effusion.

Gastrointestinal (GI) involvement may cause bleeding due to mucosal involveement or may cause GI obstruction.

•

JC virus related disease and unlike other OI it can occur even when CD4 count >100-200/µL and in patients on ART.2

•

Demyelination occurs in subcortical white matter that eventually coalesce. The cerebral hemispheres, cerebellum, and brainstem may all be involved.

•

Patients may have seizure, ataxia, hemiparesis, visual field defects, aphasia and sensory defects with or without changes in mental status.

•

MRI reveals multiple, nonenhancing white matter lesions that may coalesce and have a predilection for the occipital and parietal lobes. Measurement of JC virus DNA levels in CSF has diagnostic value.

No definitive treatment available. Favourable prognosis occurs when CD4 count >100/µL

BACTERIAL INFECTION

Mycobacterium tuberculosis (Pulmonary & extra-pulmonary) infection

We Indians go through discussions on tuberculosis in various forams and here only some important points are mentioned: •

Leading cause of isolated fever or fever with respiratory symptoms 3

•

Patients with HIV infection are more likely to have active TB by a factor of 100 when compared with an HIV negative population. 3

•

Levels of plasma HIV RNA increase in the setting of active TB. In patients with lower CD4 counts, disseminated disease is more common.

•

Patient may be asymptomatic. Thus screening for TB should be part of tlhe initial evaluation of every patient with HIV infection.

•

Management : Important points to be kept in mind in the management -

-

ART is delayed for a period of 2-8 weeks following initiation of antitubercular therapy (ATT) to prevent IRIS (Immune reconstitution inflammatory syndrome).

-

Nevirapine is substituted with efavirenz in a patient receiving ATT.

-

However, adjusted doses of rifabutin should be substituted for rifampin in patients receiving the HIV protease inhibitors.

Infiltration of the gallbladder and biliary tract may lead to obstructive jaundice.

•

Diagnosis - by biopsy of a suspicious lesion.

• Treatment

ART has been associated with the spontaneous regression of KS lesions.

In single/a few lesions that are causing significant discomfort or cosmetic problems can be treated with localized radiation, intralesional vinblastine or cryotherapy.

Extensive disease can be treated with IFN-α, liposomal daunorubicin, liposomal doxorubicin and paclitaxel with a varying response rate.

Mycobacterium avium complex disease •

Occurs in patients with CD4 count <50/µL and average CD4 count at the time of diagnosis is 10/ µL. 1

•

Prior infection with tuberculosis decreases the risk of MAC infection.

135

CHAPTER 30

•

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)

HIV

136

severe disease (Pa O2 <70 mmHg or a- A oxygen gradient ≥ 35 mmHg).

•

Clinical features & Diagnosis:

The disease is disseminated with multi organ involvement.

Presents with fever, wight loss, night sweats, abdominal pain, diarrhoea, lymphadenopathy.

•

Causative organism - C. Neoformans occurs in patients with CD4 <100/µL.1

Anemia and elevated liver alkaline phosphatase are common. Chest x-ray is abnormal in 25% of cases and may show bilateral lower lobe infiltrate.

•

Clinical features - Commonly manifests as subacute meningitis or meningoencephalitis, cryptococcoma, cranial nerve involvement.

Diagnosis is made by culture of blood or involved tissue.

•

Treatment :-

Patient usually presents with fever, headache, nausea, vomiting, altered mental status, personality changes, ± neck stiffness.

Macrolide (usually clarithromycin) with ethambutol.

Third drug (in extensive disease) – Rifabutin/ Ciprofloxacin/or Amikacin

Raised ICT due to impaired resorption CSF caused by debris from Cryptoccal polysaccharide capsule.

3 So subacute presentation with worsening of headache is usally initial manifestation.

Therapy may be stopped when CD4 count is >100/ µL for 3-6 months.

Approximately one-third pulmonary disease.

•

Investigations :

-

CSF analysis : Investigation of choice for diagnosis.



Modest rise in leucocytes (usually ≤ 20) and protein and decrease in glucose. These parameters may remain normal. 3



Confirmation is by identification of organism in spinal fluid with India ink preparation (less sensitive) or by detection of cryptococcal antigen(far more sensitive).3

FUNGAL

Pneumocystis Pneumonia (PCP) •

Caused by Pneumocystis jirovecii.

•

CD4 count <200/µL & previous history of PCP are risk factors for developing PCP. 1

Cryptococcosis

of

patients

have

•

Clinical features :- fever, nonproductive cough, dyspnoea, night sweats, unexplained weight loss and thrush.

•

Investigations :

-

Blood culture for fungus is often positive.

-

Chest x-ray may be normal at early stage or shows faint bilateral interstitial infiltrate rather than classic dense peri-hilar infiltrate in patients with AIDS.

-

Biopsy may be needed rarely to diagnose CNS cryptococcoma.

•

Treatment :

-

Amphotericin B ( 0.7 mg/kg) but preferably liposomal amphotericin( 4–6 mg/kg) daily, with flucytosine 25 mg/kg qid for at least 2 weeks and, if possible, until the CSF culture turns negative

-

HRCT (Chest) - Shows diffuse ground-glass opacities. Cysts and pneumothoraces are common radiological finding.

-

ABG - decline in PaO2, increase in the arterialalveolar (a–A) oxygen gradient. Blood - lactate dehydrogenase is elevated.

-

-

 Followed by

Fluconazole 400 mg/d PO for 8 weeks  Then

Definitive diagnosis - By showing organism in sputum, broncho-alveolar lavage, lung biopsy (with methenamine silver, toluidine blue O or Giemsa staining).

Fluconazole 200 mg/d until the CD4+ T cell count has increased to >200 cells/L for 6 months in response to ART.

DNA PCR for P.jirovecii (may be used when histology is non-confirmatory).

-

Fluconazole 800-1200 mg / day is to be given with Amphotericin B, if Flucytocine is intolerable/ unavailable (as in India)4 ICT is usually elevated & failure to relieve it satisfactorily with therapy is important underlying pathophysiology for morbidity & mortality.4

• Treatment

Trimethoprim (5mg/kg) + sulfamethoxazole (25mg/ kg) orally or IV for 14-21 days. Skin rash, cytopenia, hepatitis may occur. Alternatively

-

Dapsone/ Trimethoprim, clindamycin/primaquine, atovaquone or IV pentamidine may be used alternatively.

Histoplasmosis •

Caused by H. Capsulatum (dimorphic fungus) in persons with CD4 count <150/µL.5

Glucocorticoids improve survival in moderate to

•

Clinical features & diagnosis :-

for a minimum of 4–6 weeks.

137

-

Alternative regimens include

Infection

When to Give Prophylaxis

Agent

-

Clindamycin+ Pyrimethamine,

Pneumocystis jirovecii

CD4 < 200 cells/mm3 or oropharyngeal candidasis (thrush)

TMP-SMX

-

Atovaquone+ Pyrimethamine, and

-

Azithromycin+ Pyrimethamine+ Rifabutin.

-

Toxoplasma gondii

CD4 < 100 cells/ mm3 and positive Toxoplasma gondii IgG immunoassay

TMP-SMX

Maintenance therapy with sulfadiazine, pyrimethamine and leucovorin is required to prevent relapse as long as CD4 count is <200/µL.

-

Mycobacterium avium complex

CD4 < 50

Azithromycin

Response to therapy is usually prompt & satisfactory clinical improvement is within 1 week , otherwise alternative diagnosis is suggested.3

-

Disseminated disease with common features are fever, weight loss, hepatosplenomegaly, lymphadenopathy.

-

Maculopapular rash of skin and oral ulcer develops in 7% of patients.

-

Cytopenia occurs in 33% of patients.

•

Diagnosis :

-

By culturing the organisms from blood/bone marrow/tissue

-

By detecting antigen in blood or urine 3

•

Treatment :

Liposomal amphotericin B followed by maintenance therapy with oral itraconazole until the serum histoplasma antigen is < 2 units, the patient has been on antiretrovirals for at least 6 months and the CD4 count is >150 cells/µL.

PROTOZOAL

Cerebral Toxoplasmosis •

Caused by T.Gondii and occurs in patients with CD4 <200/µL.1

•

Occurs due to reactivation of latent T.Gondii cysts in the brain.

•

Clinical features - Usually fever, headache and focal neurologic deficit.

•

Common differentials : Primary CNS lymphoma, TB, fungal or bacterial abscess.

•

Investigations :

•

Caused by various species of Cryptosporidium which infect small bowel mucosa.

•

Persons with CD4<100/µL3 are at greater risk of developing severe manifestation. Common presenting features are diarrhoea accompanied by abdominal cramps, nausea, vomiting.

•

This was important cause for mortality before initiation of HAART

•

Therapy is supportive and improvement occurs in the setting of ART. Nitazoxamide upto 2000 mg/ day is effective in reducing symptoms.

•

This infection could be prevented to a great extent if water is boiled before drinking 6

PREVENTION OF OIS IN HIV

Much emphasis is to be put to prevent Ois in HIV as it may cause rapid deterioration of patients clinical status and ultimately death in many cases. This preventive approach may be addressed under following heading

Immune System Restoration •

Starting antiretroviral therapy is a very important step to reduce OIs incidence.7,8 It helps immune reconstitution to a great extent & may provide near normal life-span in PLHIV

To Reduce Exposures to microorganisms for Ois9 One has to avoid •

Cat feces & firm animals with diarrhoea (source of Toxoplasma gondii, Bartonella spp)

•

Eating undercooked meat or eggs, unpasteurized dairy products (M. tuberculosis)

MRI of brain - multiple ring enhancing lesions

•

Serum for IgG and IgM antibodies to Toxoplasma – simultaneous elevation of both helps diagnosis of acute infection.

Soil/dust mixed with bird (Histoplasmosis, Coccidiomycosis)

•

Brain biopsy – the definitive diagnostic procedure, only considered after failure of 2-4 weeks of emperical therapy.

Reptiles, chicks, ducklings: source of Salmonella spp.- Recurrent Salmonella septicaemia is a AIDS defining disease

Prophylactic Medications

• Treatment -

Cryptosporidiosis

Sulfadiazine and pyrimethamine with leucovorin

•

droppings

A patient’s risk stratification for developing an opportunistic infection is approximated according to patient’s CD4 T-cell count

CHAPTER 30

Table 1: Prophylactic Medications which are commonly in use in HIV patients

138

•

Prophylactic treatments are commonly in use as shown in the Table 1. 10

HIV

CLINICAL PEARLS: OPPORTUNISTIC INFECTIONS IN HIV

1.

Opportunistic Infection (OI) take advantage of weakened immune system of the affected person.

2.

Though HIV infection is classical example for weakened immune system to contract OIs, some other clinical conditions (eg.: Cancer chemotherapy, ageing, malnutrition) are not uncommon to be associated with opportunistic infections.

3.

In general, OIs are treated first before initiation of anti retroviral therapy (ART)

4.

Cytomegalovirus disease (CMV): Retinitis is the commonest manifestation. The disease is usually bilateral but typically asymmetric.

5.

Kaposis Sarcoma can occur even in the presence of a normal CD4 count. It is a rare manifestation of HIV in India.

6.

Patients with HIV infection are 100 times more likely to have active TB(Pulmonary/Extrapulmonary)

7.

Cryptococcus meningitis : Raised ICT is (due to organism debris induced impairment in CSF resorption) is usually responsible for morbidity & mortality of patients.

8.

Toxoplasma Gondaii: Response to therapy is usually prompt & if satisfactory clinical improvement is not seen within 1 week, alternative diagnosis is suggested.

REFERENCES

1.

Fauci AS, Lane HC. Human Immunodeficiency Virus Disease: AIDS and Related Disorders. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. (eds).

Harrison’s principles of internal medicine. 19th ed. New York: McGraw Hill Inc 2015; pp: 1215- 85.

2. Kean JM, Rao S, Wang M, Garcea RL. Seroepidemiology of human polyomaviruses. PLoS Pathog 2009; 5:e1000363.

3. Hoffmann CJ, Chaisson RE. HIV/AIDS and Oppurtunistic Illnesses. In: Cook GC, Zumla AI. (editors). Manson’s Tropical Diseases. 22nd ed. Saunders Elsevier.2009:379-85 4. Shelburne SA, Hamill RJ. Mycotic Infections. In: Papadakis MA, McPhee SJ. (editors), RabowM W(assoc. editors).

Current Medical Diagnosis & Treatment. 55th ed. McGraw Hill. 2016:1524-37 5. Antinori S, Magni C, Nebuloni M et al. Histoplasmosis among human immunodeficiency virus-infected people in Europe: report of 4 cases and review of the literature.

Medicine (Baltimore) 2006; 85:22-36.

6. Maartens G. HIV infection and AIDS. In: Walker BR, Colledge NR, Ralston SH, Penman ID (editors). Davidson’s Principle & Practice of Medicine. 22nd ed. Churchill Livingston. 2014: 388-410.

7. Ledergerber, B.; Egger, M.; Erard, V.; Weber, R.; Hirschel, B.; Furrer, H.; Battegay, M.; Vernazza, P.; Bernasconi, E. “AIDS-related opportunistic illnesses occurring after initiation of potent antiretroviral therapy: the Swiss HIV Cohort Study”. JAMA 1999; 282:2220–2226.

8. Brooks, John T.; Kaplan, Jonathan E.; Holmes, King K.; Benson, Constance; Pau, Alice; Masur, Henry. “HIVassociated opportunistic infections--going, going, but not gone: the continued need for prevention and treatment guidelines”. Clinical Infectious Diseases 2009; 48:609–611.

9. Jump up^ “AIDSinfo: Recommendations to Help HIVinfected Patients Avoid Exposure to, or Infection from, Opportunistic Pathogens”. 5/7/2013. Retrieved 2015-05-09.

10. Jump up “AIDS info: Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents” (PDF). 2013-06-17. Retrieved 201505-09.

Management of Failure of Antiretroviral Treatment

C H A P T E R

31

Subhasish Kamal Guha, Dolanchampa Modak

INTRODUCTION

There has been significant increase of universal access to antiretroviral therapy (ART) over the last three decades resulting in substantial reductions of morbidity and mortality and increase in life expectancy of people living with HIV/AIDS (PLHIV). While most of the present day guidelines (WHO, DHHS) recommend initiation of ART regardless of clinical stage and CD4 count, the current NACO guideline (2016) advocates the start of ART in patients with clinical stage 3 & 4 (irrespective of CD4 count) and in PLHIV with CD4 ≤ 500 cells/mm3 in clinical stage 1 & 2. Following initiation of ART, in most of the patients, the plasma HIV-1 viral load becomes undetectable by 4-6 months associated with substantial rise of CD4 count. A sustained high degree of adherence is required to maintain long-term viral suppression. However, because of very high rate of HIV replication and errorprone reverse transcription, mutations and consequent development of HIV drug resistance is inevitable - leading to virologic rebound, immunologic decline and clinical disease progression. While HIV genotypic drug resistance testing is mandatory in the developed world prior to ART initiation and switch, in public health programs of middle & low income countries such testing facility is largely unavailable. Patients in the western world are monitored routinely by plasma HIV viral load & CD4 count every 3 - 6 months. In the National ART Program of India, the patients are monitored clinically every month and by CD4 tests every 6 months.

DEFINITION OF ANTIRETROVIRAL TREATMENT FAILURE

Failure on antiretroviral treatment can be categorized as virological failure, immunological failure and clinical failure.

Virological Failure

It is defined as HIV RNA viral load of 1000 copies/ml on two consecutive occasions after at least 6 months of ART (WHO) or repeated detection of HIV RNA level > 200 copies/ml (DHHS).Virologic failure should be differentiated from viremia ‘blips’ which is defined as viral suppression followed by transient/isolated low level detectable HIV RNA (typically < 200 copies/ml) and subsequent return to undetectable levels. Blips probably represent statistical variations and are not associated with the risk of subsequent virologic failures.

Immunological Failure

It is defined as suboptimal immunologic response to therapy or an immunologic decline while on therapy. The

decrease in CD4 cell count to pre-therapy baseline level, or >50% fall from on-treatment peak value or persistently low CD4 cell counts of < 100 cells/mm3 even after 6-12 months of ART, constitute immunologic failure.

Clinical Failure

It is defined as occurrence or recurrence of a WHO stage 3 or 4 condition while on antiretroviral treatment. The progression of clinical disease should be differentiated from immune reconstitution inflammatory syndrome (IRIS).

Typically, virologic failure is the first even followed by immunologic & clinical failure.

While routine virologic monitoring is the standard of care in industrialized countries, targeted viral load testing is still practiced in resource-restricted settings to confirm immunologic &/or clinical failure before switching to second or third-line treatment. Although the targeted viral load approach is cost-saving, but it is associated with late diagnosis of treatment failure.

Causes of virologic failure are protean and include patient-related as well as regimen-related factors.

Patient-related factors include non-adherence, high baseline HIV RNA, low baseline or nadir CD4 count, comorbidities (active substance use, psychiatric illness, and neurocognitive disorders), transmitted/acquired drug resistance, prior treatment failure.

Among the ARV related factors the important ones are drug side-effects, sub-optimal pharmacokinetics, suboptimal virologic potency, functional monotherapy, food requirement/restriction, pill burden & frequency, adverse drug-drug interactions with co-administered drugs and cost & affordability.

Evaluation of virologic failure should include an assessment of patient-related as well as ARV-related factors. Adherence is a key determinant of the degree and duration of virologic suppression. Considering the fact that non-adherence to ART is the strongest predictor for failure to achieve viral suppression, assessment of adherence is crucial and all attempts need to be taken to identify the cause of non-adherence and initiate focused adherence support measures. 7 Drug toxicities, drug-drug interaction, depression, and active substance use need to be looked for and addressed specifically. Assessment of recent clinical history and physical examination, adherence, remaining treatment options, potential resistance pattern from previous therapies and patient’s

140

Table 1: Preferred second-line ART regimens for adults & adolescents (WHO) First-line regimen

Second-line Regimen

Alternative second-line regimen

Zidovudine/stavudine + lamivudine + nevirapine/efavirenz

Tenofovir + lamivudine + ritonavirboosted atazanavir or lopinavir

2 NRTIs + ritonavir-boosted darunavir

Tenofovir /abacavir + lamivudine + nevirapine/efavirenz

Zidovudine + lamivudine + ritonavir-boosted atazanavir or lopinavir

2 NRTIs + ritonavir-boosted darunavir

HBV-HIV co-infected patients failing tenofovir + lamivudine/emtricitabine + efavirenz based regimen should receive zidovudine + tenofovir + lamivudine/emtricitabine + ritonavir boosted atazanavir / lopinavir.

HIV

* Raltegravir + ritonavir-boosted Lopinavir can be an alternative second-line regimen for selected patients with NRTI toxicities or resistance to all NRTIs.

Table 2: Preferred second-line & third-line ART regimens for adults & adolescents (NACO) First-line regimen

Second-line Regimen

Third-line Regimen

Zidovudine/stavudine + lamivudine + nevirapine/efavirenz

Tenofovir + lamivudine + ritonavirboosted atazanavir or lopinavir

Raltegravir + ritonavir-boosted darunavir*

Tenofovir /abacavir + lamivudine + nevirapine/efavirenz

Zidovudine + lamivudine + ritonavir-boosted atazanavir or lopinavir

Raltegravir + ritonavir-boosted darunavir*

* In patients failing second-line ART with plasma HIV viral load > 100,000 copies/ml or CD4 count < 200 cells/mm3, in addition to raltegravir + ritonavir-boosted darunavir, the NRTI backbone of Zidovudine + lamivudine or Tenofovir + lamivudine need to be recycled.

understanding of consequences of new regimen are important before taking decisions regarding switching of ART regimen.

drugs of the same class. Maraviroc can only be used in patients harbouring CCR5 tropic virus as ascertained by genotypic/phenotypic co-receptor tropism assay.

HIV drug Resistance (DR) testing should be done while the patient is still on the failing therapy or within 4 weeks of discontinuance of the same. If the test is done beyond 4 weeks of treatment discontinuation, some of the key HIV DR mutations may be missed. For most of the HIV DR assays, a minimal viral load of 500 â&#x20AC;&#x201C; 1,000 copies/ml is essential.

According to WHO, the preferred third-line regimen should include new drugs with minimal risk of crossresistance to previously used regimens, e.g. integrase inhibitors like dolutegravir or raltegravir, secondgeneration NNRTI (etravirine) and PI (darunavir). It also recommends if a patient is failing on a second-line regimen with no new ARV drug option, s/he should continue with a tolerated ARV regimen.

Further treatment decision (Tables 1 & 2)

The goal of second/ third line regimen is to achieve an undetectable HIV viraemia. Ideally, the new ART regimen should contain at least two, preferably three fully active antiretroviral drugs. These active drugs are usually identified by HIV DR testing, patientâ&#x20AC;&#x2122;s past ARV history, CCR5 tropism assay etc. As a rule single active drug should never be added to a failing regimen. In absence of HIV DR results, the ARV history, knowledge of the genetic barrier & common mutations associated with different classes as well as specific ARV drugs, help in formulating the subsequent (2nd/3rd line) regimens. The heavily treatment experienced patients, failing multiple classes with very few treatment options with the available drugs, may benefit from HIV phenotypic resistance test results.

For patients failing non-nucleoside reverse-transcriptase inhibitor-based first-line ART, it is recommended to switch to boosted protease inhibitor (PI)-based regimens with unused NRTI backbone. Some ARVs despite having drug resistance (e.g. NRTIs) contribute partial activity in new regimen, while others are not (e.g. NNRTI, INSTI, and Enfuvirtide). Of note, a new/unused drug may not be fully active due to potential cross resistance among

ISOLATED CENTRAL NERVOUS SYSTEM VIROLOGIC FAILURE

A rare form of virologic failure has been documented in a subset of patients having HIV breakthrough in CSF in presence of suppressed plasma HIV. They usually present with sub-acute onset of new CNS symptoms & signs. MRI brain usually shows abnormalities and CSF demonstrates lymphocytic pleocytosis. CSF HIV RNA is typically higher than plasma HIV RNA. The CSFvirus often demonstrates drug resistance. Antiretroviral regimens need to be switched according to the CSF HIV drug resistance report, if available. In absence of CSF HIV resistance testing, the regimen may be changed based on patientâ&#x20AC;&#x2122;s ARV drug history and by selecting drugs with higher CNS Penetration Effectiveness (CPE) Score.

SUMMARY

Management of treatment-experienced patients requires judicious selection of subsequent regimens to achieve durable suppression of HIV. Review of past ARV history, side-effects & toxicities, drug-drug and drug-food interactions and assessment of adherence are crucial before switching to a new regimen. Identification of

barriers to adherence and adoption of remedial measures to improve adherence are of utmost importance.

REFERENCES

1.

Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents. http://aidsinfo.nih.gov/ guidelines accessed on 12/15/2015

2.

Consolidated Guidelines on The Use of Antiretroviral Drugs For Treating and Preventing HIV Infection. Second edition (2016).

3.

Canestri A, Lescure FX, Jaureguiberry S, Moulignier A, Amiel C, Marcelin AG et al. Discordance between cerebral

spinal fluid and plasma HIV replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy. Clin Infect Dis 2010; 50:773-778.

4.

Peluso MJ, Ferretti F, Peterson J, Lee E, Fuchs D, Boschini A et al. Cerebrospinal fluid HIV escape associated with progressive neurologic dysfunction in patients on antiretroviral therapy with well controlled plasma viral load. AIDS 2012; 26:1765-1774.

5.

Calcagno A, Di Perri G, Bonora S. Pharmacokinetics and pharmacodynamics of antiretrovirals in the central nervous system. Clin Pharmacokinet. 2014; 53:891-906.

141

CHAPTER 31