ART Guidelines 2008
Guidelines for Use of Antiretroviral Therapy for Hiv Infected Individuals in India (ART Guidelines 2008)
Sanjay Pujari, Atul Patel, Shashank R Joshi, Raman Gangakhedkar, N Kumarasamy, and SB Gupta for the Expert Panel 2008
2008 Guidelines Committee
Chairs: Pujari Sanjay, Atul Patel
Co-Chair: Joshi Shashank, Gupta SB
Writing Committee
Chair : RR Gangakhedkar
Co-Chair : N Kumarasamy
Expert panel members : Subhasish Kamal Guha, Nalin Nag, Bharat Rewari, K Satish, Rajeev Soman, Jehangir Sorabjee, Soumya Swaminathan, Jaideep Gogtay, Ajay Wanchu
#See original API Guidelines Committee on Page 371
EXECUTIVE SUMMARY
With the rational use of antiretroviral therapy (ART),
human immunodeficiency virus (HIV) infection has been transformed into a chronic manageable illness like diabetes and hypertension. Since these guidelines were last published, there has been new evidence addressing ART strategies and efficacy of new combinations. Additionally, many new antiretroviral drugs are now available in India. These guidelines update the previous version and provide information on state of art, evidence based approach for use of ART in the Indian context.
When to initiate ART?
Antiretroviral therapy is indicated for all symptomatic HIV infected persons (Current WHO stage 4 and 3 conditions) regardless of CD4 counts and plasma Viral load (PVL) levels. In asymptomatic HIV infected individuals, ART is indicated if the CD4 count<350/mm3. Therapy is not recommended for asymptomatic individuals with CD4 count more than 350/mm3 except in HIV-HBV/HCV co-infected patients when treatment for HBV/HCV is indicated, HIV infected pregnant mothers for prevention of mother-to-child transmission of HIV and in patients receiving concomitant cytotoxic therapy (e.g. cancer chemotherapy). Involvement of the patient in all treatment decisions and assessing readiness is critical before initiating ART.
What to start with?
A non-nucleoside reverse transcriptase inhibitor (NNRTI) based regimen is recommended as initial therapy for antiretroviral naïve patients. The prevalence of primary NNRTI resistance amongst HIV infected patients in India is expected to be low. The choice between nevirapine and efavirenz is based on differences in adverse events profiles; cost, availability of convenient fixed-dose combinations and need for concomitant use of rifampicin. A backbone of 2-nucleoside reverse transcriptase inhibitors (NRTI’s) is combined with the NNRTI. In recognition of the short and long term toxicities of thymidine analog reverse transcriptase inhibitors (especially lipodystrophy, dyslipidemia, peripheral neuropathy, anemia and hyperlactataemia) and some evidence of inferior potency in the long term (mainly driven by treatment related toxicities) it is recommended that tenofovir or abacavir, in combination with lamivudine or emtricitabine, be preferred as the 2NRTI backbone. However, due to cost-related factors zidovudine may still be used as one of the NRTI backbone for initial treatment. Use of stavudine should be minimized in first line regimens and should be initiated if no other options can be accessed by the patient. Various combinations and ART strategies not to be used in clinical practice has been enlisted.
How to follow up?
Recommendations have been made for baseline evaluation and monitoring of patients on ART. These include guidelines on laboratory and clinical evaluation. A plasma viral load (PVL) at 6 months after initiation of first-line ART is strongly recommended. Furthermore PVL determination is recommended every six months (or at least yearly) to identify failure early and prevent development of broader cross resistance by persisting with a failing regimen. Twice-yearly estimation of lipid profile and blood sugar is recommended.
How to identify and manage ART failure?
The guidelines recognize the issue of identifying ART failure late if only CD4 counts/clinical markers are used for monitoring. Genotypic resistance testing, when available, should be used to determine resistance patterns, particularly if ART failure has been identified immunologically or clinically rather than virologically and if the patient has been continuing a failing regimen for a prolonged period of time. In the absence of resistance testing various second line regimens have been enlisted. A boosted protease-inhibitor based regimen is recommended in this situation to be combined with 2-NRTIs (with least likelihood of cross resistance to the initially used NRTIs).
Special situations
Recommendations have been made for use of ART in HIV-TB, HIV-HBV, and HIV-HCV co-infected patients. In patients with active TB and a CD4 count < 350/mm3, initiation of ART is recommended as soon as the anti-TB treatment is tolerated. Efavirenz is the only ARV drug, which can be safely and effectively used with rifampicin. In pregnancy use of single dose nevirapine for reducing the risk of mother to child transmission of HIV is not recommended, because of the risk of development of resistance that can compromise mothers ART treatment especially if initiated within six months of receipt of the NVP dose. For post exposure prophylaxis taking the ART treatment history of the source patient is crucial in designing an effective regimen.
INTRODUCTION
Antiretroviral therapy (ART) has dramatically reduced morbidity and mortality rates in human immunodeficiency virus (HIV) disease in both the developed and developing world.1-3 Generic manufacturers of antiretrovirals (ARVs) from India have significantly reduced the cost of ART. Enhancing access to ARVs and ensuring quality care both in public or private sector in India is critical. In order to provide quality care, physicians need up to date and accurate information regarding ART including indications for its use, which drugs to choose and how to choose them, complications of therapy and managing special situations like HIV and tuberculosis (TB), HIV and pregnancy. Of the twenty-four antiretrovirals approved by US FDA, currently fourteen are available in India. Rational use of ART is critical for prevention of a possible epidemic of drug resistant HIV in India in future.
Most issues relating to use of ART in the Indian context will be addressed by the guidelines. The objectives of these guidelines are:
To develop evidence-based, state-of-the- art guidelines for use of ART in India
To develop guidelines which are simple to implement in clinical practice
The guidelines are designed to assist physicians in extending care to HIV infected individuals and establish a standard of clinical practice across India. HIV medicine is a rapidly changing field necessitating periodic updating. Physicians are encouraged to update themselves periodically. These guidelines will be reviewed on an annual basis.
WHEN TO INITIATE ART?
With use of available therapeutic options, eradication of HIV cannot be achieved.4 However, with the advent of potent ART, HIV infection has now been transformed into a chronic, manageable illness.
The goals of ART are:
1. To ensure maximal and durable suppression of the virus
2. To reconstitute and preserve immunologic quantity and function
3. To improve quality of life
4. To reduce morbidity and mortality due to HIV infection
Additionally, antiretroviral drugs can be used to reduce transmission of HIV in various situations, e.g. prevention of transmission of HIV from infected mother-to-child (pMTCT), after high risk occupational/non-occupational exposures: post exposure prophylaxis (PEP). There is increasing interest in use of ARV for pre-exposure prophylaxis (PrEP), however pending further evidence this is not recommended in clinical practice. A reduction in plasma viral load is likely to lead to reduction in the risk of sexual transmission of HIV.
Since the use of ART is life-long, and associated with long-term adverse events, not all patients diagnosed with HIV infection need to be started on treatment. The decision to initiate ART is made after weighing the risk of progression to AIDS and other important determinants such as the incidence of short and long-term toxicities, commitment to high levels of adherence, possible development of resistance to ARVs and affordability and accessibility and patient’s readiness for therapy. Figure 1 summarizes recommendations about when to initiate ART.
Antiretroviral treatment is indicated for all patients who are symptomatic with an AIDS defining illness, irrespective of CD4 counts or viral load levels (or current WHO stage 4 and 3 conditions). Patients with AIDS have higher rates of mortality unless treated with ART.5,6 Patients with WHO stage 3 conditions have functional immunodeficiency and have a risk of rapid progression, and therapy is recommended in these patients especially if CD4 count is <350/mm3 .7-9 Table 1 enlists the WHO clinical staging system.
Fig. 1: Algorithm for when to initiate ART.
The exact time for initiating ART in the presence of an acute OI is unclear. A recent randomized strategy trial (ACTG 5164) demonstrated higher rates of clinical progression and more deaths especially in the first 6 months in patients who initiated ART after completion of OI treatment as compared to patients who initiated it within 14 days of starting acute OI treatment.1 However, virologic and immunologic outcomes between the two arms were similar at 48 weeks in this trial. Furthermore CD4 counts increased more rapidly in the immediate treatment group. While consideration should be given to early initiation of ART in patients presenting with an active OI, physicians should closely monitor for drug-drug interactions, additive toxicities and the emergence of immune reconstitution inflammatory syndrome (IRIS). It should also be noted that patients with TB were not included in the study and recommendations for the appropriate timing for initiation of ART in HIV patients with active TB is discussed below.
Certain AIDS defining illness like cryptosporidial diarrhea, progressive multifocal leucoencephalopathy (PML) and non-infectious complications like idiopathic esophageal ulcers, thrombocytopenia may be most effectively treated with ART induced immune reconstitution.10,11
There is a limited data on natural history of HIV infection from India, especially the risk of progression to AIDS at various CD4 counts and viral load levels. A retrospective analysis demonstrated that Indian HIV infected patients with CD4 counts <200/mm3 were 19 times more likely to die than were those with CD4 counts> 350/mm3.12 Since the risk of developing OI’s is significant when CD4 counts drop to less than 200/mm3, therapy is indicated for these patients, even if they are currently asymptomatic.5 At the same time it should be remembered that ART is effective even in patients with advanced immunosuppression (CD4<50/mm3) and should be always be offered.13,14 However, the risk for development of IRIS and certain short and long term toxicities is higher if ART is initiated at this stage and close monitoring is recommended.
Therapy is not indicated in asymptomatic patients with CD4 counts >350/mm3. The risk of progression to AIDS in these patients is very low.15 Initiating ART at this stage would mean prolonged exposure to the drugs resulting in increased costs, potential for development of short and long term toxicities and development of drug resistance in cases of sub-optimal adherence. For example the risk of developing fatal hepatitis due to nevirapine is significantly higher at this stage. Exceptions include patients who are co-infected with HBV or HCV in whom hepatitis treatment is indicated,18,19 pregnant mothers for prevention of mother to child transmission of HIV and patients initiating cytotoxic therapy.
Initiation of antiretroviral therapy is recommended in asymptomatic patients with confirmed CD4 counts<350/mm3 or CD4%<15%.17 There are no randomized controlled studies supporting this recommendation. However, observational studies have demonstrated a significant decline in mortality and morbidity when ART is initiated in this range rather than waiting until CD4 counts drop to below 200/mm3.15,16,2 Furthermore improvement in CD4 counts are better if ART is initiated before the CD4 counts fall to <200/mm3.3 The risk of occurrence of certain non-AIDS defining conditions (hepatic, cardiovascular, renal disease and non-AIDS defining malignancies) is also higher as compared to development of AIDS defining illnesses as CD4 falls to <350/mm3.4 High rates of early mortality on ART (within 6 months of initiation) has been demonstrated from ART programs in Africa that may be associated with advanced clinical and immunological disease at baseline in these patients.5,6 Finally there is emerging evidence to suggest lower rates of long term toxicities (peripheral neuropathy, anemia and renal toxicities) amongst patients who initiate ART at higher CD4 counts.7 All of this argues for earlier initiation of ART rather than waiting till the CD4 counts drop to less than 200. It should be remembered that women with CD4 counts 250-350/mm3 cannot be initiated on NVP based regimen because of concerns of life threatening hepatic toxicity.
Other surrogate markers like the total lymphocyte count (TLC) have been recommended for initiation of ART by some guidelines. However, the sensitivity and specificity of TLC are not sufficiently high to replace CD4 counts.20 Additionally, the use of TLC in monitoring response to treatment is unproven. Hence TLC is not recommended as a marker for decisions about initiation of ART.
The role of ART in primary HIV infection is controversial. Till further data is available treatment of primary HIV infection with ART is not recommended in routine clinical practice and should be restricted to clinical trial settings only.
Apart from the biological indications for therapy, assessing patient readiness prior to ART initiation is crucial for long-term success.21 The following points should be discussed with the patient prior to initiation:
1. Treatment is life-long, since viral eradication is not achievable.
2. Treatment is expensive.
3. High levels of adherence are needed and negative consequences of low adherence.
4. Education about short and long term adverse events.
5. Education about drug-drug interactions including herbals.
6. Counseling about the importance of safer sex practices.
Therapy should never be initiated during the first visit (unless advanced HIV disease) and patients should be encouraged to involve at least one family member in care.
BASELINE EVALUATION
A standard clinical and laboratory evaluation is recommended prior to initiation of ART. It is necessary to establish the baseline status for future comparisons, individualize ART according to patient’s clinical status and preferences, and rule out active OI’s.
History
Points to be elicited in history taking:
1. HIV specific symptoms- present and past
2. Genital ulcers and other sexually transmitted diseases
3. Personal history- smoking, alcohol, drugs
4. Past history of any coronary artery disease
5. High risk behavior- partner’s HIV sero-status if known
6. Women- Gynecological history, past pregnancies, contraception
7. Family history of coronary disease, hypertension, diabetes and hyperlipidemia
8. Treatment history: any past or current use of ARVs (useful for designing an ART regimen), sexual partners ARV use, ARV use during pregnancy (e.g. single dose NVP) and the use of any alternative (e.g. herbal) preparations.
Physical examination
A routine physical examination is essential prior to initiating ART. The following evaluation is recommended:
1. Body weight and BMI
2. Temperature
3. Blood pressure
4. Lymphadenopathy
5. Oral cavity: oral candidiasis, oral hairy leukoplakia
6. Dermatological
7. Genital
8. Systemic examination
Laboratory evaluation
The purpose of baseline laboratory evaluation is to stage HIV disease, rule out opportunistic infections and determine baseline safety parameters. The following tests are recommended:
Essential
1. Confirm HIV infection: A pre-requisite prior to ART initiation. This can be done by a supplemental ELISA or a Western Blot. A rapid HIV antibody test is recommended to rule out HIV-2 infection. Non-nucleoside reverse transcriptase inhibitor’s (NNRTIs) have no activity against HIV-2.22
2. Specific investigations to rule out OI’s
3. CD4 counts: Determined by flow-cytometry. Alternative low cost technologies are becoming available, however further evidence is needed to recommend its routine use in clinical practice.23
4. CBC: Baseline Hemoglobin and WBC counts are needed to monitor possible hematological toxicity due to Zidovudine (ZDV) use.
5. LFT’s: Necessary in evaluation of possible hepatitis, particularly when NVP use is contemplated; should be done if patient is co-infected with HBV/HCV.
6. Urine routine: To evaluate proteinuria and glycosuria (necessitate estimation of blood glucose)
7. Creatinine: Doses of nucleoside reverse transcriptase inhibitors (NRTI’s) except abacavir has to be adjusted according to Creatinine clearance. It is also essential to determine baseline creatinine prior to initiating tenofovir based regimens.
8. HbsAg: To rule out concomitant hepatitis B infection, this influences the choice of the ARV regimen. Abrupt stopping of anti-HBV drugs like lamivudine, emtrictabine and tenofovir is not recommended in patients with chronic hepatitis B co- infection since it may result in hepatitis B flare.24
9. Chest X-ray: to rule out TB or other pulmonary infections only if the patient is symptomatic
10. VDRL/TPHA
11. Pap smear
Optional
1. Fasting lipid profile: May be recommended in patients with established coronary artery disease risk factors or if stavudine, zidovudine, efavirenz, protease inhibitor (PI) use is contemplated.
2. Plasma viral load (PVL): A baseline PVL is not mandatory. With optimum adherence and a potent regimen, undetectable levels at 6 months after ART initiation should be achieved.25
3. Pregnancy test: EFV is contraindicated in first trimester of pregnancy and most ARVs are in FDA category B/C.
4. Anti HCV antibodies: The prevalence of HCV is low in HIV infected patients except, such as in northeastern states of India where the prevalence of injection drug use is high. It is also recommended in HIV infected hemophiliacs and thalassaemics or in HIV patients having any history of exposure to blood or blood products in the past.
5. Genotypic resistance testing: This is recommended in a patient with current history of sub-optimal exposure to ARVs (e.g. 2 drug therapy). Routine baseline genotypic resistance testing is not recommended at this time because it is presumed that the prevalence of transmitted baseline drug resistance may be low in the HIV-infected population in India.
Cautions with interpretation of CD4 counts and PVL
Standard methods
CD4 counts: Flow cytometry
PVL: Amplicor 1.5 , Branched DNA assay. NASBA and Real time PCR
The laboratory should have a quality assurance program
Inter-current illnesses, concomitant steroid use, vaccinations may influence the CD4 counts and PVL values.
Some evidence to suggest that CD4 counts in normal north Indians is significantly lower than the western population.26
Physiologic variations
CD4 counts:
30% changes especially at higher CD4 counts
Diurnal variations: The CD4 count is lowest at around 12.30 PM and highest at about 8.30 PM in the evening. A practice to draw blood for CD4 counts around the same time during follow up testing is necessary.
PVL: 0.3-0.5 log (2-3 fold change)
Specimen processing
CD4 counts: within 18-24 hours of specimen withdrawal, ideally as soon as possible.27
PVL: plasma separated within half an hour of specimen withdrawal and store/transport at -20o, -70o Celsius.
PVL: Currently available for HIV-1, not for HIV-2
WHAT TO START?
Antiretroviral agents of five classes are approved by US FDA for use in HIV infected patients (Table 2). These five classes include the nucleoside and nucleotide reverse transcriptase inhibitors (NRTI/NtRTI), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PI’s), entry inhibitors (fusion and chemokine inhibitors) and integrase inhibitors.
The terminology “highly active antiretroviral therapy” (HAART) refers to use of combinations of antiretroviral agents that achieve maximal and durable suppression of HIV. To date, most clinical experience with use of HAART in treatment-naïve individuals has been based on three types of combination regimens: NNRTI-based (1 NNRTI + 2 NRTI), PI-based (Ritonavir boosted PI + 2 NRTI), and triple NRTI-based regimens. There is emerging data about the use of raltegravir and maraviroc in initial treatment, however these drugs are not available at this time in India and will not be discussed.
Most experience in India is with use of NNRTI based regimens.
Initial Regimen for ART-naïve HIV-1 infected patients in India
Regimen selection should be individualized, taking into consideration a number of factors including: co-morbidity or conditions such as tuberculosis, liver disease, depression or mental illness, cardiovascular disease, adherence potential; cost of treatment and affordability, dosing convenience including pill burden, dosing frequency, storage requirement, and food and fluid considerations; potential adverse events; drug-drug interactions, gender; and pregnancy potential.
An NNRTI based regimen is recommended as first line therapy for most ART-naïve HIV infected patients. NNRTI- based regimens are potent and have shown comparable efficacy to ritonavir boosted PI based regimens and are superior to 3 NRTI based regimens.31-33 NNRTI-based regimens have the advantage of a lower pill burden, no strict storage requirement and are cheaper when compared to PI-based regimens. Use of NNRTI-based regimens as initial therapy can preserve the PI’s for later use and reduce or delay patient exposure to some of the adverse events more commonly associated with PI’s. These regimens can still be positioned as first line treatment because the prevalence of primary resistance to NNRTIs may be presumed to be low in India.
The major disadvantage of currently available NNRTI’s is their low genetic barrier for development of resistance. These agents only require a single mutation to confer high level resistance (mutations at codons 103, 106, 181, 190 see section on treatment failure), and cross-resistance often develops across the entire class.34 As a result, patients who fail these initial regimens may lose the utility of other NNRTI’s and/or may transmit NNRTI-resistant virus. When patients fail an NNRTI based regimen 2 –class resistance is more frequently seen, with accumulation of some mutations responsible for drug resistance to the NRTIs in the backbone.35 Furthermore, patients continuing on a failing NNRTI- based regimen may accumulate further resistance mutations that may compromise utility of second generation NNRTIs i.e. etravirine.36
The major short-term adverse event associated with efavirenz is CNS disturbances. Usually these are self-limiting and wane of within two to four weeks of therapy and do not warrant discontinuation of efavirenz.37 Patients should be forewarned about these before initiating treatment. Pre-existent psychiatric illness is not a contraindication for EFV use. Efavirenz should be avoided during pregnancy (especially during the first trimester) or in women who are planning to conceive or women who are not using effective and consistent contraception, because of concerns relating to teratogenecity.
Nevirapine may be used as an alternative to efavirenz for the initial NNRTI-based regimen in females with pre-treatment CD4+ T cell counts <250 cells/mm3 or males with pre-treatment CD4+ T cell counts <400 cells/mm3.38 Symptomatic, sometimes serious or life-threatening hepatic events were observed with greater frequency in patient with higher CD4 ranges than that mentioned above.39 Nevirapine should be used with caution in patients already having background liver disease like chronic hepatitis B and C co-infection. When starting nevirapine, a 14-day lead-in period at a dose of 200 mg once daily should be prescribed before increasing to the maintenance dose of 200 mg twice daily.
Efavirenz is the only NNRTI (and the only ARV drug), which can be effectively and safely used with rifampicin. Initiation with an efavirenz-based regimen is recommended in patients receiving rifampicin based antituberculous therapy (see section on drug-drug interactions and HIV and TB).
A large randomized controlled trial has shown similar efficacy of nevirapine and efavirenz based first line regimens, although there were differences in safety profile.40 Recently published Indian data also support the above finding.40a Hence the choice between using NVP and EFV is based on toxicity concerns41 with EFV having a better safety profile. Table 3 summarizes characteristics of EFV and NVP.
Patients Intolerant to both NNRTIs
Patients who develop severe adverse events to both nevirapine and efavirenz should be treated with ritonavir boosted protease inhibitors (IDV/r, SQV/r, LPV/r, ATV/r) combined with 2NRTIs. Nelfinavir as a PI is not recommended due to concerns about sub-optimal potency.
Selection of Dual Nucleoside/Nucleotide “Backbone” as Part of Initial Combination Therapy
Six nucleoside/nucleotide HIV-1 reverse transcriptase inhibitors (NRTI’s/NtRTIs) are currently available in India. Lamivudine is a common second agent in these combinations because of its tolerability. Though lamivudine has a low genetic barrier to resistance (a single mutation M184V/I causes high level resistance), this mutation renders the virus less fit, renders the virus hypersusceptible to ZDV and TDF (see section: When to change) and delays development of thymidine-associated mutations (TAMs) which are associated with ZDV and d4T resistance.42 Emtricitabine is similar to lamivudine except that it can be taken once daily and hyper pigmentation is an adverse event associated with its use. However, it is not available as a single agent but as a fixed dose combination with TDF or TDF/EFV (Table 4).
The choice of another NRTI to be combined with lamivudine depends on cost, short and long term adverse event profiles and availability of fixed dose combinations, which potentially improves adherence. Another important issue would be the sequencing potential and availability of other NRTI’s to be used in second line regimens. Randomized controlled trials have shown no difference in the potency between zidovudine + lamivudine and stavudine + lamivudine along with a PI.43,44 However, stavudine is associated with significant long-term toxicities and is recommended only as an alternative in patients who cannot be initiated on ZDV (due to anemia) and cannot afford tenofovir or abacavir.
Another strategy may be to start with stavudine + lamivudine backbone (in patients who are anemic) and then switch to zidovudine + lamivudine at 12-24 weeks, when hemoglobin improves. However, no randomized controlled trials have been undertaken to assess this strategy.
Thymidine analog NRTIs (i.e. ZDV and d4T) are associated with short and long term toxicities. Hence in patients who can afford, a non-thymidine analog NRTI/NtRTI (ABC, TDF) is recommended in combination with 3TC/FTC. Tenofovir is an NtRTI with the convenience of once daily dosing and a good safety profile. When combined with lamivudine/emtricitabine it has shown comparable efficacy with d4T/3TC based NNRTI regimen and had better long term safety profile.45 In a randomized controlled trial (Gilead 934) at 96 weeks TDF/FTC/EFV was virologically and immunologically superior to ZDV/3TC/EFV. The difference in efficacy was driven mostly due to toxicity related discontinuations in the ZDV/3TC arm. The rates of body fat changes were also higher in the ZDV/3TC arm.46 The only important concern about TDF is renal toxicity although the incidence of the same is very low even at 4-5 years of treatment.47,48 Tenofovir has to be used cautiously in patients with background renal disease or potential for the same (e.g. diabetes, hypertension) and in patient on concomitant nephrotoxic medications e.g. amphotericin B, streptomycin. Creatinine clearance (calculated) and urinalysis is recommended to be done prior to and on TDF treatment. TDF/FTC/EFV is available as once a day pill which simplifies treatment.
Other non-thymidine based backbones using ABC, and ddI have the advantage of not being associated with long-term adverse events like lipodystrophy and dyslipidemia. ABC/3TC has shown similar virologic and immunologic efficacy as ZDV/3TC and TDF/FTC.49 However, physicians should watch for abacavir hypersensitivity reaction (HSR), which is more common in patients harboring the HLA B5071 genotype. A test to check for the presence of HLA-B5701 prior to ABC initiation is currently not available in India. Additionally, combining ABC with NVP during initiation is not recommended because of difficulty in identifying the offending agent should a hypersensitivity reaction occur. Didanosine is associated with pancreatitis and hyperlactataemia and is recommended as an alternative NRTI. One advantage is its availability as once a day kit along with 3TC and EFV.50,51 Recently the DAD study reported that current use of ABC and ddI may be linked to an increased risk of myocardial infarction. Further studies are needed to confirm this observation, and this should not preclude the use of ABC or ddI in HIV infected patients.8
Use of TDF or ABC in the initial regimen also provides for better sequencing options after treatment failure. Even if failure is identified late, K65R (with TDF) and L74V (with ABC) may be selected. Thymidine analogs would be effective backbone for second line regimens. Additionally further accumulation of mutations associated with cross resistance to other NRTIs seems to be less likely if a patient continues on a failing TDF based regimen.52 However if failure is identified late with ZDV or d4T based regimens, thymidine associated mutations (TAMs) may accumulate which can compromise use of all NRTIs in the second line regimen.53
When NVP and EFV based regimens are contemplated, consideration should be given to using fixed dose combinations (FDCs) of ZDV/d4T+ 3TC + NVP and TDF/FTC/EFV respectively which improves adherence due to low pill burden. It also reduces prescription errors and has demonstrated effectiveness and safety in large cohort study from India.54 A combination of NVP with TDF/FTC will have a higher pill burden, but potentially a better safety profile. However NVP should not be used once daily with this combination because of higher incidence of unexplained virological failure.55
Though boosted protease inhibitors based regimens are extremely potent as first line therapy, they are only recommended in patients who cannot tolerate both NVP and EFV. Boosted PI based regimens are costly, complex, with high pill burden, associated with long term adverse events like lipodystrophy, dyslipidemia and diabetes. The advantage in using boosted PI based regimens is their high genetic barrier to resistance and patients failing these regimens usually do not have PI resistant mutations thus restricting resistance to 1 class (i.e. to the backbone nucleosides).35 Recommended regimens for initial therapy in treatment naïve patients are summarized in Table 5.
Antiretroviral Regimens Not Recommended
Some antiretroviral regimens or components are not recommended for HIV-1 infected patients due to sub-optimal antiviral potency, unacceptable toxicity, or pharmacological concerns. These are summarized below:
1. Mono-therapy and Dual nucleoside therapy: These regimens are not recommended because they have not demonstrated potent and sustained antiviral activity.56
2. Tenofovir + ddI + NNRTI is not recommended as an initial regimen due to reports of early virological and immunological failure.57 Additionally a combination of TDF +ddI is usually avoided unless there are no options due to concerns of virologic and immunologic failure.9 The mechanism for this interaction is still unclear though intracellular antagonism has been postulated. When used concomitantly the 250 mg dose of ddI is recommended for use.
3. 3-NRTI regimens of abacavir + tenofovir + lamivudine and didanosine + tenofovir + lamivudine should be avoided due to high rates of virological failure.58
4. NRTI sparing regimens (i.e. NNRTI+PI) is not recommended for initiation due to pharmacokinetic interactions, toxicities and resistance issues.
5. Boosted PI monotherapy esp. LPV/r is not recommended due to lower rates of virologic suppression.10
6. Didanosine + stavudine: The combined use of didanosine and stavudine as a 2-NRTI backbone can result in a high incidence of toxicities, particularly peripheral neuropathy, pancreatitis, and lactic acidosis. A combination containing didanosine and stavudine should be avoided unless other 2-NRTI combinations have failed or have caused unacceptable toxicities, and where potential benefits outweigh the risks of toxicities.59
7. Stavudine + zidovudine: Combination regimens containing these two NRTIs should be avoided due to the demonstration of antagonism in vitro and in vivo
8. Unboosted PI’s should be avoided due to poor bioavailability and higher pill burden.
9. Altering dosages or schedules of ARV drugs is not recommended. However, recently a meta-analysis has demonstrated equivalent efficacy of low dose stavudine (30 mg) for patients with > 60 kg weight.60 The World Health Organization has also recommended use of stavudine 30 mg bid for all patients needing ART irrespective of weight.
10. Efavirenz should be avoided in pregnancy or in women with pregnancy potential.
11. Tenofovir should be avoided during pregnancy because of possible risk of fetal bone loss.
12. Nevirapine should be avoided in women with CD4 count>250/mm3 and in men with CD4 count>400/mm3.
Antiretroviral strategies that are not recommended
1. Induction-maintenance: Initiation of three drug regimens and then reducing it to a combination of two ARV drugs is not recommended.
2. Sequential addition of drugs: A third drug, especially NNRTI should not be added to an on-going two drug regimen, as it can lead to rapid selection of resistance.
3. Structured treatment interruptions: Any form of treatment interruptions is not recommended in clinical practice unless a patient develops severe toxicities. CD4 guided treatment interruption as studied in the SMART trial was associated with more adverse outcomes (disease progression and non-AIDS events) in the treatment discontinuation (drug conservation) arm as compared to patients in the continuous therapy arm.61
FOLLOW UP AFTER INITIATING ART
Table 6 depicts the recommended follow up scheme after initiating ART.
Frequent follow up during the initial months is necessary to diagnose and efficiently manage acute adverse events, work with the patient on adherence issues, and diagnose clinical conditions like IRIS and acute OI’s. Most morbidity and mortality on ART in the developing world tend to occur within the first 3-6 months of initiation.62 Once a patient is on an effective and stable regimen at 6 months, quarterly follow up is recommended.
Determination of CD4 count is recommended initially at 6 months to document immunological improvement on ART and every six months thereafter. A caveat in following up with only CD4 counts is the risk of delayed detection of treatment failure (see section on identifying and managing failure).
A PVL at 6 months is essential to determine efficacy of the ARV regimen. With optimal adherence and a potent regimen PVL should be below the limits of quantification (undetectable) at 6 months.63,64 The lower limit of detection of PVL can be 400 copies/ml or 50 copies/ml depending on the assay used.
A PVL estimation at 6 months helps in the following:
1. Assess potency of the regimen
2. Assess adherence to the regimen: Objective marker to assess whether a patient has been taking medicines regularly as recommended
3. Past history of ARV treatment taken by the patient or by their sexual partners may not be always known. In either instance primary resistance may be present which can compromise efficacy of the ARV regimen
4. Ensure pharmacokinetics and pharmacodynamics of the regimen is optimal, particularly interaction with herbals (many patients may not disclose concomitant use of herbals)
Determination of viral load is recommended subsequently every 6 months (or at least once a year) since it can identify failure earlier and reduce accumulation of resistance mutations. This is more important if a patient is on ZDV or d4T based regimen to prevent ongoing accumulation of TAMs.
After initiation of a NVP based regimen ALT measurement is recommended in patients with clinical suspicion of hepatitis. With a ZDV based regimen it is important to monitor CBC for earlier detection of hematological toxicity. The prevalence of lipid abnormalities is significant on ART, particularly if a patient is on ZDV/d4T, EFV or PI’s. In these patients and in patients with significant coronary artery disease risk factors; a fasting lipid profile and blood sugar estimation should be done every 6 months.
Discontinuation of OI prophylaxis on ART
With ART induced immune reconstitution, the incidence of most OI’s have reduced dramatically. It is possible to discontinue primary and secondary prophylaxis for most OI’s when CD4 counts improve and sustain for > 200/mm3 at least 3-6 months.65, 66 Table 7 summarizes indications for starting and discontinuation of OI prophylaxis.
ADHERENCE TO ART
One of the most important determinants of success with ART is optimal adherence to drugs. The prevention of resistance to ARV drugs depends on adherence to and potency of the ARV drug regimen. Low levels of adherence to a standard regimen rapidly selects for drug resistant virus leading to therapy failure. There is strong evidence to suggest association of lower adherence with virological, immunological and clinical failure of ART.67,68
Adherence is the ability to take prescribed drugs in the recommended dosages and schedules and following any special instructions e.g. empty stomach. Adherence rate is calculated according the following formula:
Adherence rate = number of pills expected to be taken –
number of pills missed x 100
Number of pills expected to be taken
During the era of unboosted PI’s an adherence rate of more than 95% was recommended for successful ART outcome.67 However with use of more potent drugs (e.g. boosted PI’s) in regimens, this cut off of 95% may be too strict (making a regimen more forgiving). There is evidence to suggest that at least for an intermediate level of adherence (adherence rate 76%-99%), NNRTI based regimens may be more forgiving than PI based regimens.69 Nevertheless, physicians should encourage patients to achieve high rates of adherence to ART and work towards achieving the same. The patient should understand that more than 95% adherence for NVP based regimen would mean that he should ensure that s/he does not miss even two doses of fixed combination pills during a month.
Measuring adherence in clinical practice is difficult. Self-report is the easiest and cheapest method of assessing the same, they may be quite reliable.70 Pill counts and other objective markers of adherence measurement like MEMS caps are rarely possible in clinical set ups. Following up regularly (keeping clinic appointments) may also be an marker of good adherence. Patients should be asked whether they have missed doses over the last 4-7 days and over the last follow up period, rather than asking whether they have been taking drugs regularly. If a patient reports missing doses then the reasons for doing the same should be explored and addressed. Indirect markers of good adherence are keeping appointments and getting prescription refills. Another marker of adherence on a thymidine analog based regimen (ZDV or d4T) is development of macrocytosis, although it is not uniformly seen in all patients.
The physician should use various strategies to achieve good adherence. One of the most important aspects is developing a trusting relationship and rapport with the patient. Some of the strategies to achieve adherence are the following:
Careful screening before starting: It is very important to screen for patient readiness before initiating ART. Cost is a major barrier to adherence in India and financial status of the patient should be assessed prior to prescribing ART.71 It may be worthwhile not to initiate therapy at the first visit and give some time to understand the commitment that a regimen would require, implications of being on treatment and to think about the strategies that s/he needs to evolve to overcome the challenges.
Emphasize adherence before starting: Explaining to the patient that a high level of adherence is needed, and that the treatment is lifelong is crucial. Patient’s comprehension about drug adherence must be ascertained.
Demonstrate how to take drugs (e.g. NVP): Many patients make mistakes during the initial lead-in dose of nevirapine. Demonstrating how to take the regimen and ensure that the patient has understood the same may be by asking him/her to repeat what has been explained.
Using fixed dose combinations pills or combination packs: Using fixed dose combination of ARV drugs reduces the pill burden, potentially improving adherence. Additionally, using these combinations is associated with fewer prescription errors, and ensures that the patient takes all drugs in a regimen.
Advice patients to buy monthly packs: Patients are more likely to take drugs regularly if they buy monthly packs. Buying loose pills on an as needed basis has a higher risk of missing doses.
Follow up before supplies exhaust: One of the common reasons for missing doses is following up after the drug supplies are over. Patients should be encouraged to consult 3-4 days before their drug stocks are exhausted.
Reminders every time during follow up: During follow up apart from assessing adherence the importance of achieving good adherence should be re-emphasized. This is also a good opportunity to reinforce safer sex messages.
Using once daily regimens/user friendly regimens: There is evidence to suggest that adherence rates are higher if patients are prescribed once daily or twice daily drugs as compared to thrice per day or higher frequencies.
The physician should work out dose schedule in consultation with the patient. Instead of explaining a dose as twice a day (bd), it should be explained as 12 hourly doses. This approach emphasizes