Kaletra superior to nevirapine-based ART for women already exposed to single-dose nevirapine

An antiretroviral regimen based on the boosted protease inhibitor lopinavir/ritonavir (Kaletra, or Aluvia) was significantly more effective than a nevirapine-containing regimen in mothers previously exposed to single-dose nevirapine, according to results from the randomised OCTANE study presented on Tuesday at the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montreal.

However the difference in response to the two regimens was less pronounced among women who started treatment at a longer interval after exposure to single-dose nevirapine. There was no difference in the risk of treatment failure between the regimens among women who started antiretroviral therapy more than two years after exposure to single-dose nevirapine.

Background

Numerous studies have demonstrated that a large proportion of women who take single-dose nevirapine at delivery to prevent mother to child transmission of HIV develop resistance. Use of AZT (zidovudine) at the time of delivery and postpartum reduces the risk of developing nevirapine resistance somewhat, and results from a Thai study also presented at CROI on Tuesday show that if mothers take AZT and didanosine (ddI) for one month after delivery the risk of developing nevirapine resistance is almost completely eliminated.

Nevirapine resistance develops easily when the drug is dosed alone because it is eliminated very slowly from the body in comparison with other antiretroviral drugs. The presence of sub-optimal drug levels for up to a week after taking a single dose creates an environment in which resistance to the drug emerges easily, compromising the future treatment options for mothers when they need antiretroviral treatment to preserve their own health.

The emergence of nevirapine resistance in mothers exposed to single-dose nevirapine is particularly problematic because nevirapine-based ART is the first-line option in resource-limited settings. Furthermore, the mutations in HIV that cause resistance to nevirapine also cause resistance to efavirenz, the other affordable non-nucleoside reverse transcriptase inhibitor used in first-line treatment in resource-limited settings.

The Optimum Combination Therapy After Nevirapine Exposure (OCTANE) study was designed to determine whether nevirapine-based ART would be effective in women previously exposed to single-dose nevirapine, or whether a regimen based on a different drug class, using the boosted protease inhibitor lopinavir/ritonavir, would prove more effective. The study used a nucleoside backbone of tenofovir/emtricitabine (FTC), since some women were also exposed to AZT monotherapy before and after delivery. These drugs are active even when AZT-related mutations have developed.

The study

The OCTANE study enrolled 243 HIV-positive women in seven African countries. Enrolment criteria included receiving a single intrapartum dose of nevirapine at least six months earlier and having a CD4 cell count of less than 200 cells/mm³. The women were randomised into two arms: one receiving tenofovir and emtricitabine (as Truvada) and lopinavir/ritonavir (Kaletra) (n = 120), and the other receiving tenofovir, emtricitabine and nevirapine (n = 123).

Time from randomisation to either death or virologic failure was the primary study endpoint, or outcome, with virologic failure defined as plasma HIV RNA less than 1 log₁₀ below baseline after the first 12 weeks of treatment or ≥ 400 copies/ml at or after 24 weeks.

The study population had the following median values at entry: age, 31 years; CD4 cell count, 139 cells/mm³; HIV-1 RNA, 5.15 log₁₀; time since intrapartum dose of nevirapine, 17 months; and duration of follow-up, 73 weeks. All women recalled their earlier use of nevirapine, and 73% had written documentation that it was administered.

Significantly more women in the nevirapine arm than the lopinavir/ritonavir arm reached the primary study endpoint (26% versus 8%; an odds ratio of 3.55 [95% confidence intervals 1.71 – 7.34], p = 0.0007). There were 27 virologic failures in the nevirapine arm and nine in the lopinavir/ritonavir arm (22% vs 8%). Four women in the nevirapine arm and one woman in the lopinavir/ritonavir arm died without experiencing a preceding virologic failure; none of those deaths appeared to be treatment-related.

The difference between the two study arms appeared to decrease in proportion to the length of time between the administration of intrapartum nevirapine and the initiation of combination antiretroviral therapy. Among women who experienced the second event six to less than 12 months after the first, 37% of the nevirapine arm and 3% of the lopinavir/ritonavir arm reached the primary study endpoint (total number evaluable = 78) (p = 0.008). Among women who experienced the second event 12 to less than 24 months after the first, 26% of the nevirapine arm and 12% of the lopinavir/ritonavir arm reached the primary endpoint (n = 98)(p = 0.056). When more than two years had elapsed, 12% of the nevirapine arm reached the primary endpoint, compared to 10% of the lopinavir/ritonavir arm (n = 65) (p = 0.72).

The researchers retrospectively obtained baseline HIV genotypes for 239 women. Thirty-three women (14%) showed evidence of nevirapine resistance, with the K103N mutation occurring in 28 of these cases. Fifteen of the 33 women with nevirapine resistance were assigned to the nevirapine arm; eleven of the 15 reached the primary study endpoint. In contrast, among the 18 nevirapine-resistant women assigned to the lopinavir/ritonavir arm, only one (6%) reached the primary endpoint.

Further information about the impact of resistance, and in particular of low-level, or minority, populations of nevirapine-resistant virus will be presented at future meetings.

The researchers note that there were more treatment discontinuations due to adverse events in the nevirapine arm than in the lopinavir/ritonavir arm (12% versus 1%).

The researchers concluded that the lopinavir-based regimen was superior to the nevirapine-based regimen in women with prior exposure to single-dose nevirapine, but that the difference lessened as the interval between single-dose nevirapine and maternal antiretroviral therapy lengthened, suggesting that the compromising effect of nevirapine resistance does indeed wane over time.

Speaking at a press conference following the presentation of the results, Shahin Lockman of Brigham and Women’s Hospital, Boston, said that in the long term the best way of eliminating the problems caused by nevirapine resistance would be to treat mothers with three-drug antiretroviral therapy during pregnancy and postpartum. “We hope and anticipate that this problem will go away as more and more women receive HAART or receive other drugs alongside single-dose nevirapine,” she commented.

Until that is possible, she noted, the use of lopinavir/ritonavir is becoming increasingly practical as the heat-stable formulation Aluvia is being licensed in more and more countries at a price of $500 a year for least-developed countries.