Almost a third of Indian patients make changes to first-line treatment regimen because of side-effects or cost

Background

A number of studies have demonstrated that generic antiretrovirals are well tolerated and effective in the developing world, but there are few data on the long-term experience. Little is known about the durability of generic ART, and what factors may lead people to change the drugs or regimens that they are taking.

Confounding matters, in many settings, people have to pay ‘‘out of pocket’’ for their own healthcare. In India, where nearly half the population lives on less than $1 per day, the least expensive triple-drug ART regimen costs around $20 per month. In addition, most people in India have to pay the cost of their own laboratory tests. Viral load tests are too expensive to be routinely used.

A study of over 1400 people in southern India paying to take generic antiretroviral therapy (ART) has found that 29% end up modifying or quitting their first-line treatment regimen according to a report in January 1^st issue of JAIDS. 20% of those switched one or more drugs in their ART regimens because of adverse events, but another 9% discontinued treatment — in some cases permanently, mostly because of the cost of care.

This observational study followed its subjects over variable lengths of time so this report may not accurately reflect what will happen to the study cohort with more follow-up. Even so, the study does make a number of interesting observations — including a high rate of nevirapine (Viramune)-related liver toxicity in persons also taking TB treatment (see more below).

The study

Researchers at a large tertiary HIV care and research institution in Chennai, India assessed reasons for treatment modification in previously ART-naive people with AIDS (defined by symptoms or CD4 cell counts

The median CD4 cell count at entry was 108 cells/mm³.A total of 82% of the cohort were men (95% were purportedly heterosexual). Noting this, the investigators wrote “it is likely that this disparity between the number of male and female patients on therapy [is] to do with the social and economic standing of women within the family unit and in society at large.”

Nevirapine-based regimens were the most commonly used first-line therapy because they were the cheapest and most widely available. Efavirenz (Sustiva)-based therapies were almost twice as expensive, and PI-based regimens seven times as expensive.

Regimens

Nevirapine toxicity

A total of 156 (13%) of those taking nevirapine switched therapy because of adverse events. Rash was the most common, in 41 subjects (26%) and liver toxicity accounted for 33 (21%) of the adverse events. The median time to development of liver toxicity on nevirapine was 34 days (range: 2–575 days).

The nevirapine-related liver toxicity occurred in individuals with fairly low CD4 cell counts (~65 at baseline) — which is peculiar because nevirapine-induced hepatitis usually affects people with higher CD4 cell counts (over 250).

The investigators note that the vast majority with nevirapine liver toxicity, 27 (82%) were also concurrently taking rifampicin-based anti-TB medications.

This may be one of this study’s most interesting observations. Rifampicin cuts nevirapine blood levels by half — which, if anything, would make one expect a lower incidence of liver toxicity. However, because of this drug interaction, nevirapine and rifampicin are not commonly prescribed together. However, in this study, those patients who could not afford efavirenz but who needed to be on both HIV and TB treatment, had no option but to take a nevirapine-based regimen.

While a recent study suggests that the rifampicin-nevirapine interaction is not great enough to significantly alter nevirapine’s anti-HIV effect — there isn’t much actual clinical experience using TB treatment with nevirapine. There would seem to be a real possibility for additive liver toxicity. These cases deserve closer study.

Results

A total of 285 (20%) patients modified therapy and 126 (9%) discontinued their first-line regimen (over a follow-up of 2330 person-years). Those on nevirapine-based regimens were significantly more likely to switch treatment because of side-effects, while those on efavirenz or PIs were significantly more likely to change or discontinue treatment because of cost. However, no significant differences in the rate of treatment failure have yet been observed.

Study limitations

Although the study notes median times to treatment modification or discontinuation, thus far; these figures will change with longer follow-up. In fact, to be included in the analysis, participants only had to have had one follow-up visit (at three months). Subjects in the study are at a variety of different time points and the investigators don’t mention the average length of follow-up in the cohort — only the total 2330 person years for the cohort as whole.

Nevertheless, it is hard to disagree with the investigators conclusion that despite the availability of lower cost generic ART, “even less expensive and more tolerable first-line regimens and cost-effective treatment monitoring tools need to be introduced to achieve better treatment outcomes and access in resource-constrained settings.”

d4T toxicity

d4T (stavudine, Zerit) toxicity caused 27 (15%) of the 183 patients to change treatments. However, the investigators noted that “despite the high incidence of d4T-related toxicities, including lipoatrophy and peripheral neuropathy, d4T continues to be widely used because of its low cost.”