CROI: Efavirenz-based ART more effective than nevirapine-based ART as first-line therapy in Southern Africa

Efavirenz-based antiretroviral therapy (ART) appears to reduce HIV (viral load) more rapidly — and keep it suppressed for a longer time — than nevirapine-based regimens, according to a retrospective study conducted in a real world southern African setting presented on Monday at the Fourteenth Conference on Retroviruses and Opportunistic Infections in Los Angeles.

This was one of the largest population-based studies to date comparing the efficacy of efavirenz (Sustiva) versus nevirapine (Viramune), with over 2,800 HIV-infected participants. Importantly, the greater antiviral effect of efavirenz was shown to be independent of the effects of baseline viral load, baseline CD4 cell count or treatment adherence according to multivariate analyses.

“These findings may reflect either the superiority of efavirenz-based ART or it may just be that this is an observational study and [the results] could be due to the confounding effects of some unmeasured variable,” according to Dr Jean Nachega of Johns Hopkins University who presented the study findings.

Earlier comparisons of efavirenz vs nevirapine-based ART

A few other studies have previously addressed the relative efficacy of these two non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs) as the cornerstone of first-line ART.

For example, the 2NN trial indicated that the two drugs had roughly comparable efficacy, and yet it did not conclusively demonstrate that nevirapine was as potent as efavirenz; (in fact, the study reported a slight, but not statistically significant, advantage of efavirenz-based therapy over nevirapine-based treatment). Similarly, a study across Europe, the ART Cohort Collaboration, found that virological outcomes on nevirapine were inferior to efavirenz — and there was also some difference in mortality. A meta-analysis of efavirenz and nevirapine studies published in the Lancet in 2000 reported similar findings.

This is the first large study to look at the issue in sub-Saharan Africa, where these drugs are increasingly being used, and where there are other factors that could impact upon the relative potency of each drug.

The AIDS for AIDS study

The data for this study were drawn from the records of people receiving ART, between January 1999 and March 2003, via AIDS for AIDS (AfA), a private sector disease management programme based out of Cape Town, South Africa, but involving individuals from nine Southern African countries.

The primary study endpoint was viral load suppression to 400 copies/ml). Adherence was measured using pharmacy refill data (a validated surrogate measure of adherence). (Previously reported data from this same cohort had shown a clear dose-response relationship between higher adherence and better virological outcomes on NNRTI-based ART.)

At baseline, the average patient age was 38 and 97% of the patients were black. Individuals on nevirapine were more likely to be women (over 60%) while those on efavirenz were more likely to have higher baseline viral loads. Nearly 65% of the cohort was assigned to the efavirenz-based study arm.

The follow-up period was approximately 26 months (range 19 to 31 months).

Results

One of the first things to stand out was that patients were significantly more likely to be adherent on the efavirenz (taken once a day) than the nevirapine (twice a day) -based regimen. 38.2% (696 of 1,822 patients) maintained 100% adherence versus 30.1% (301 of 999 patients) in the nevirapine-based arm. At an adherence level of 70%, 69% of those patients in the efavirenz-based arm achieved 100% viral suppression versus 31% in the nevirapine-based arm.

Four predictors to shorter time to viral suppression were female gender 1.17 (1.06-1.28); baseline viral load ≤105 copies/ml 1.28 (1.18-1.40); efavirenz-based regimen 1.20 (1.10-1.32); and adherence levels of 100% versus 50% 3.79 (3.13-4.58) using multivariate analysis with a 95% CI.

After initial viral suppression, three predictors of shorter time to virologic failure were low baseline CD4+ counts, 160 cells/mm³ (1.22- 2.10 comparing those with ≤50 vs. >200 cells/mm³); baseline viral load >100,000 copies/ml 1.39 (1.14-1.70); being on a nevirapine -based regimen 1.43 (1.16-1.75); and poor adherence 1.42 (1.15-1.73 per 10% adherence decrease).

But in the multivariate analysis, after adjusting for other variables including adherence, people on efavirenz were still less likely to experience viral load rebounds. “This was quite significant,” said Dr Nachega.

“Patients on nevirapine were performing very badly,” he said. “It's clear that the rates of virologic failure are higher than what has been reported in clinical trials.“

Alternative explanations and potential confounders

Although it is possible that efavirenz could simply be the more potent drug, Dr Nachega stressed that the results could also be due to a number of other unmeasured underlying factors. For example, the prescribing patterns were in a state of flux during this period and were greatly influenced by the cost of drugs that changed from year to year. Some of the effect could be explained by drug interactions, such as those between nevirapine and rifampicin, which is commonly used in Southern African patients, who are often coinfected with tuberculosis (TB).

Some in the audience questioned whether the women had been previously exposed to nevirapine. However, Dr Nachega responded that only 5% had been.

Although adherence clearly had an impact as well, Dr Nachega placed more importance on the greater toxicity of nevirapine (nevirapine seems to have more serious side effects, particularly in women with more than 250 cells/mm³). “I would tend to say the second explanation,” he said.

Finally, given the contraindication of efavirenz in pregnancy (because it has the potential to cause pregnancy complications when taken during the first trimester in pregnancy), some questioned what should be the policy recommendations for using efavirenz in women of child-bearing potential. Dr Francois Venter, Head of the Southern African HIV Clinician Society and co-chair of the session, noted that “huge numbers of women in South Africa were becoming pregnant on efavirenz-based regimens.”

Yet, Dr Nachega said that clearly women who do not wish to become pregnant should be given the option to take what is best for their own health, and pointed out that these women can be given injectable contraceptives which are quite popular in South Africa.