Antiretroviral therapy in Indian setting: when & what to start with, when & what to switch to?

With the rapid scale-up of antiretroviral therapy, there is a dramatic decline in HIV related morbidity and mortality in both developed and developing countries. Several new safe antiretroviral, and newer class of drugs and monitoring assays are developed recently. As a result the treatment guideline for the management of HIV disease continue to change. This review focuses on evolving science on Indian policy--antiretroviral therapy initiation, which drugs to start with, when to change the initial regimen and what to change.

Highly active antiretroviral therapy (HAART) is the cornerstone of management of patients with HIV infection. Initiation of widespread use antiretroviral therapy marked declines in the incidence of most AIDS defining conditions and mortality both in the developed and developing world12. Suppression of HIV replication is an important component to prevent HIV associated morbidity and mortality as well as in improving the quality of life in patients with HIV infection. Adequate suppression requires strict adherence of antiretroviral therapy. This has been facilitated by the co-formulation of antiretroviral drugs and the development of once daily regimens. This review focuses on issues like when to initiate antiretroviral therapy, what drugs to start with, when to change the initial regimen and what to change to in Indian settings.

When to initiate ART? (Table I)

Strong evidence based on randomized controlled trials exists for initiating ART amongst asymptomatic patients with CD4<350/mm31213. Large observational studies have demonstrated the effectiveness of ART amongst patients with CD4<500mm3 in reducing mortality and clinical events including non-AIDS defining events1415. There is limited evidence about the prevalence of non-AIDS defining events from resource limited settings (RLS). Studies have also consistently demonstrated the usefulness of ART in preventing sexual transmission of HIV and this can be considered for the decision of when to initiate ART1617. The benefit of initiating ART in the setting of acute HIV infection is limited and consequently this has to be done only in the context of clinical trial18–20.

Assessing patient readiness prior to initiating ART

Although no readiness measure has accurately predicted adherence, it is essential to prepare a patient prior to initiating ART50–52. Issues that need to be discussed include conceptual understanding of treatment and its benefits, the importance of high level lifelong adherence to drugs and the consequences of sub-optimal adherence (more expensive second line regimens, progression of clinical disease) .Only after ensuring that patient has understood the consequences of initiating and being on ART, should treatment be initiated.

What to start with? (Table II)

An non nucleoside reverse transcriptase inhibitor (NNRTI) based regimen is preferred over protease inhibitors (PI/r) based regimens considering similar potency, convenience, lesser expense and lower prevalence of primary resistance in the population53–55. Efavirenz (EFV) is preferred over nevirapine (NVP) when concomitant use of rifampicin is indicated, patients preference for once daily (lower pill burden) regimen and if pre-therapy CD4 count is >250/mm3 and >400/mm3 in women and men respectively56–60. Nevirapine is preferred over EFV in women planning pregnancy and those with underlying severe psychiatric illness.

Tenofovir/Emtricitabine or Lamivudine is the preferred backbone because it has similar virologic response as compared to zidovudine/lamivudine (AZT/3TC) but has been associated with lower toxicity particularly in women61–64. Further advantages associated with TDF/XTC include low pill burden (one pill once a day when combined with EFV), better sequencing options after failure of first line regimen, concomitant treatment of underlying undiagnosed HBV infection, and it has been proven to be cost-effective in an analysis in India65–67. Tenofovir use has been associated with renal toxicity (although clinical effect is modest) and bone toxicity, and further research to characterize the incidence and risk factors for these need to be carried out in India68–72.

AZT/3TC is preferred in women who plan pregnancy/or are pregnant but has been associated with higher short-term haematological and long term morphologic and metabolic toxicities73–79. Stavudine (d4T) should be avoided because of long term toxicity concerns that are often irreversible80–82.

Boosted protease inhibitors need to be used as the third drug in first line regimen along with nucleoside reverse transinptases (NRTs) backbone in certain clinical situations (Table III).

Table III

Clinical situations for use of protease inhibitors/ritonavir (PI/r) in first line regimens

Certain antiretroviral combinations are less potent or can interact with other medications (Table IV). Various laboratory assays are performed before initiating therapy to choose appropriate drug regimen and on follow up to identify early toxicities and efficacy of the regimens. Table V describes various assays to be performed on patients initiating ART.

Table IV

Antiretrovirals (ARVs)* not recommended for use

Table V

Mnitoring patients on ART

The utility of virologic monitoring has been debated. Trials have shown no advantage in using viral loads to monitor treatment response (especially disease progression and mortality) as compared to immunological and clinical monitoring91–93. Additionally, using CD4 criteria for failure to identify virologic failure has poor positive predictive value and low sensitivity94. However, not monitoring virologically is associated with identification of failure late as the gap between virologic and immunologic failure can be many years. This leads to exposure of the virus to a failing regimen amplifying resistance and further cross resistance can compromise future regimens95–102134. Hence after achieving virologic suppression, viral load may be monitored at least once a year. In patients in whom virologic monitoring can be done more frequently (e.g. every 3-6 months), CD4 counts may be monitored on an yearly basis after achieving good immunologic response.

Complications in the use of ART

Immune reconstitution inflammatory syndrome (IRIS)

Occurring in a sub-population of HIV infected individuals after initiation of ART, IRIS is associated with inflammatory response to clinical or sub-clinical pathogens or non-pathogenic antigens103. Definitions for diagnosis of TB and cryptococcal IRIS have been proposed, however for most other no clear definitions exist104105. Two types have been described: paradoxical IRIS is the worsening of well controlled underlying infection while unmasking IRIS is the occurrence of new manifestations in a patient apparently well prior to initiation of ART35106–113. The major risk factor for development of IRIS is a low pre-therapy CD4 count (usually<50/mm3)35114–117. Differential diagnosis includes anti-microbial resistance, ARV toxicity or progression of underlying OI. No clear strategies exist for management of IRIS, however, 4 wk of steroids treatment (1.5 mg/kg/day for 2 wk followed by 0.75 mg/kg/day for 2 wk) has been found to be effective for treatment of mild to moderate paradoxical TB IRIS.

ARV toxicities

A range of toxicities is associated with use of ART6869 Table VI. Some of these toxicities are acute and also certain medications can cause chronic toxicities (Tables VII & VIII). While some are mild and self-limited, some can be fatal and irreversible. It is important to forewarn the patients about the same and a discussion on these issues should be part of the discussion prior to initiating ART.

Table VI

Spectrum of adverse events to antiretrovirals and the management plan

Table VII

Managing ARV toxicities: acute

Table VIII

Managing ARV toxicities: Long term

Immunologic and/or clinical failure is an indication to determine viral load (targeted viral load) to identify disconnect or true failure. The disadvantage of immunologic/clinical monitoring is late identification of failure causing increased accumulation of drug resistant mutations that can compromise efficacy of future regimens100134. Patients on failing regimen should be switched to secondline regimens (Table IX). Antiretroviral resistance testing should be used to guide the second line regimens if the patient has access.

Table IX

Choice of second line regimens

Preferred choice of PI/r in second line includes ATV/r, DRV/r159, and alternative is LPV/r.

The essential principle of constructing an effective second/third line regimen is to combine at least two or preferably three fully active drugs. These drugs should ideally include one from a new class (e.g. PI/r if NNRTI based first line regimen) or those drugs from the same class of drugs with the least likelihood of resistance as determined by genotypic resistance testing (GRT). Choosing an active drug using GRT has better outcomes than based on expert opinion alone160–163. Genotypic resistance testing has to be performed when the patient is on or within 2 wk of discontinuation of a failing regimen.

An expert consultation is advisable. Early identification of second line regimen failure is critical (e.g. virologic failure) to preserve effective ARV options. CCR5 inhibitors, second generation NNRTIs and entry inhibitors are available in resource rich settings to construct salvage regimens164–167.

Clinical investigators, industry, federal government, patient advocates and clinical trial networks are involved in the process of drug development and clinical trials. As a result, new HIV therapies and new therapeutic strategies are continually emerging and makes this disease as yet another chronic manageable disease.

Table I

Indications and conditions to initiate antiretroviral therapy

Table II

Various antiretroviral drugs (ARVs)* approved for therapeutic use