Highly active antiretroviral therapy (HAART) has changed dramatically the morbidity and mortality profile of the HIV epidemic in the developed world [1]. Over the last few years, prolonged survival of HIV-infected individuals has been attributed to the widespread use of HAART, and has been reported even in a developing country situation [2].

HAART normally consists of a combination of three or more antiretroviral (ARV) drugs taken together. The goal of therapy is to maximize viral suppression, thus limiting and reversing immune damage, leading to decline in opportunistic infections. The durability of response depends on viral-, drug-and patient-related factors. Viral factors include the genetic barrier to resistance development, the capacity to remain latent in reservoirs, and on-going replication in sanctuary sites like the nervous system, genital tissue and kidneys. Drug-related factors include the potency, tolerability and convenience of a regimen and pharmacologic barriers to resistance as a function of trough concentrations achieved by these drugs. The most important patient-related factor is adherence, but toxicities, quality of life, and psychosocial issues also need to be addressed to ensure success of therapy.

Several studies have documented the efficacy and safety of nevirapine (NVP)-based HAART in ARV-naïve HIV-infected patients [3,4,5]. NVP-based HAART has been found to be superior to a combination of two nucleosides alone and also had similar efficacy to a protease-inhibitor or efavirenz-based regimen. In a randomized controlled trial of NVP versus efavirenz with a backbone of stavudine(d4T)/lamivudine(3TC), NVP was found to have similar efficacy, but was associated with more hepatitis and rash [6]. Hence in terms of potency, NVP-based HAART is as effective as a protease-inhibitor or efavirenz-based HAART.

Adherence

Adherence is critical for success of HAART. Numerous studies have documented that a high level of adherence is needed to ensure maximal and durable suppression of the virus [7]. Various factors influence adherence: Drug combinations, which are difficult to take because of pill burden or due to food restrictions [8]; treatment costs, in situations where patients have to pay for their own treatment; and difficulties in accessing care, and unavailability of drugs in remote places, may all contribute.

Since eradication of HIV is unlikely with currently-available HAART and since the evidence for structured treatment interruption seems disappointing [9], HIV therapy needs to be life-long. Coupled with high levels of adherence needed to ensure response, this is a demanding task for HIV-infected patients. Studies have shown that adherence to prescribed drugs over long treatment periods is generally poor [8]. Non-adherence to HAART can lead to rebound in viral replication and, in presence of sub-optimal drug concentrations, rapid development of drug resistance. The development of drug resistance can be disastrous because of the complexity and cost associated with second-line regimens and the potential for transmission of drug-resistant virus in the community.

Fixed-dose combinations (FDCs)

The cost of antiretroviral drugs has been reduced dramatically because of generic manufacturing in some countries across the world. This has contributed significantly to improving access to ARV drugs. Apart from lowering drug costs, generic manufacturing has also led to development of FDCs and once daily combo-packs of ARVs. FDCs have been available for treatment of other diseases and have long been regarded as a standardized, simpler and potentially more reliable way of treating tuberculosis (TB). Guidelines from WHO and many other international bodies recommend the use of FDC formulations as a step to facilitate the optimal treatment of TB [10]. However, unlike TB treatment, HIV therapy, being life-long, is more demanding. Hence, the use of FDCs to treat HIV infection for long periods of time is crucial.

Development of FDCs

Development of FDCs has not been possible in countries where the component drugs are under patent because different companies manufacture the drugs used in these formulations. The only patented FDC formulation available is trizivir, a single pill combining zidovudine (ZDV)/3TC/abacavir (ABC). Generic companies have been successful in developing two three-drug FDC formulations for use in HIV infection: ZDV/3TC/NVP and d4T/3TC/NVP (Table 1).

Formulation of FDCs

Developments of FDC formulations essentially concentrate on ensuring the physico-chemical compatibility of drugs in combination. Furthermore, the in-vitro dissolution profile of individual drugs and the formulation should be similar to the patented products. Drug compatibility studies [pers comm] have shown physical incompatibility for 3TC with d4T, and NVP with d4T. However, 3TC and NVP were compatible. Hence the formulation of d4T/3TC/NVP is a bilayered tablet, where d4T is one layer and 3TC and NVP another layer and thus the physical incompatibility has been minimized. Excipient compatibility studies, carried out with the chosen excipients from the individual formulated drugs, did not reveal any interactions with any of the excipients, indicating compatibility with the drug combination

A similar approach has been used for manufacturing a FDC of AZT/3TC/NVP. However, in this case no incompatibility was observed between any of the individual drugs. Therefore all drugs can be combined into a single pill.

Table 1: Anti-HIV FDC formulations available in India

Safety, efficacy and quality of FDCs

There are limited data on the safety and efficacy of FDC formulations in treatment of HIV disease. Although there have been anecdotal reports of lack of active ingredients in some generic antimicrobials [11], in one study of NVP in generic formulations, drug content in both individual tablets and in combinations was found to be satisfactory [12]. In a clinico-pharmacological study from India [Gogaty et al. unpublished], FDC formulations were found to be bioequivalent to the reference loose drugs given in similar doses. Many of the generic drugs are listed in WHO’s supplier’s and formulary list.

The quality of FDC formulations available in India has also been evaluated in pharmacokinetic studies. In a randomized, two-treatment, two-period, two-sequence, single dose, crossover bioavailability study in healthy volunteers, the FDC formulation was compared with the individual reference drugs. The FDC formulation met all the requisite criteria for proving bioequivalence with regards to rate and extent of absorption. The ratios of AUC 0-t and AUC 0-x for the three drugs ranged from 96.6% to 104.8% [Gogaty; unpublished].

Advantages and disadvantages of FDCs

There are distinct advantages and some disadvantages associated with the use of FDC formulations for treatment of HIV infection. An obvious advantage is the convenience associated with taking these formulations, as patients prefer taking one pill twice a day as compared to three pills twice a day. Convenience increases adherence, which will lead to durable response to therapy.

Another advantage is easier delivery of treatment with FDCs. Using FDCs simplifies the physician’s job, leading to reduction in prescription errors.

FDCs also reduce the risk of giving the wrong dose (high or low) of individual drugs. While high doses can lead to development of serious adverse events, low doses can lead to sub-optimal drug concentrations and development of drug resistance. Ingestion of proper dosages through FDC formulation can help prevent development of drug resistance; missing a dose of a FDC tablet maybe more “forgiving” than erratic missing of doses of the individual drugs when taken separately. However, sufficiently irregular intake of FDCs can also lead to drug resistance; in an NVP-based regime, drug resistance may easily develop because of NVP’s long half life. Any missing dose in this context can lead to persistence of NVP in the plasma beyond that of the backbone nucleosides, rendering it as monotherapy.

There are also some disadvantages associated with the use of FDCs, particularly for NVP-based HAART. Many physicians may initiate these regimes without the lead-in dose, thus increasing the risk of development of adverse events like rash and hepatitis.

This study

The efficacy of FDCs can be assessed by determining virological, immunological and clinical responses amongst HIV-infected patients. A randomized controlled trial comparing FDCs with treatment regimens based on loose drugs has not been carried out and may not be required if bioequivalence studies show comparable plasma concentrations. Here, we report the results of the largest study carried out to date to assess the clinical and immunological effectiveness and the safety of NVP-based FDCs in ARV-naïve HIV-1-infected patients in India.