Antiretroviral Therapies in Women After Exposure to Nevirapine

Only one in three HIV positive pregnant women worldwide receives antiretroviral drugs to prevent mother-to-child transmission. The most frequently used prophylactic medication in resource-limited settings for these women is nevirapine, which is typically administered in a single dose. Many women who receive nevirapine around the time of delivery develop an HIV virus that is resistant to nevirapine, even when other accompanying antiretrovirals are administered in order to lower this risk of resistance. Though nevirapine resistance declines over time, low-level resistance can remain. This trial was performed to assess whether non-pregnant women being started on maintenance antiretrovirals for the woman’s health who had received nevirapine during a past pregnancy to decrease risk of mother-to-child transmission were more likely to die or experience persistently high viral loads if their maintenance regimen included nevirapine compared to a non-nevirapine based regimen.

The primary focus of the OCTANE study (optimal combination therapy after nevirapine exposure) was 241 HIV positive non-pregnant women in 10 different African sites with CD4 counts less than 200 who had previously received single-dose nevirapine 6 or more months ago during a past pregnancy. All women were started on the antiretroviral medication Truvada (tenofovir/emtricitabine). In addition to Truvada, all women were randomly assigned to take either twice daily nevirapine or twice daily lopinavir/ritonavir. Participants who did not tolerate a regimen could switch to the other regimen, or begin additional antiretroviral therapies as required. Women were followed for at least 48 weeks. At enrollment, patient blood samples were collected; these samples were eventually subjected to resistance testing, but the testing results were not factored into the treatment arm to which the patients were assigned. Patients were seen on average every 4 weeks for the first 24 weeks, and every 12 weeks thereafter. HIV-1 RNA viral levels were drawn at study entry and every 12 weeks thereafter.

The investigators found that among the previously nevirapine exposed women, 26% of women in the group randomized to a maintenance regimen containing nevirapine reached one of the two endpoints (i.e. death or persistently high viral levels), versus 8% in the group receiving maintenance therapy containing lopinavir/ritonavir. This statistically significant difference means that women in the maintenance nevirapine group were between 3 and 4 times more likely to experience persistently high viral levels or death when compared to women in the group receiving lopinavir/ritonavir. This difference was apparent by week 12 in half of women, and the trial was stopped early because of the clear superiority of the lopinavir/ritonavir maintenance over the nevirapine-based regimen. Approximately 14% of the women who had previously received nevirapine around the time of delivery displayed evidence of nevirapine resistance when their HIV strains were tested. Though the superiority of the lopinavir/ritonavir regimen was much greater in women with viruses resistant to nevirapine, even among women without baseline nevirapine resistance, more women in the nevirapine group died or experienced persistently high viral loads. Both groups of women experienced similar increases in their CD4 counts and had greater than 80% of women adhere to the therapy they were assigned, though more women in the nevirapine group were discontinued from their treatment than women in the lopinavir/ritonavir group. As a means of comparison, an additional study was performed by the same investigators among women who had never been exposed to nevirapine. In this second trial, the researchers found that among women receiving Truvada based maintenance regimens, there was no difference in the number of women with persistently high viral loads or death when women were randomized to additional treatment with nevirapine or lopinavir/ritonavir.

The OCTANE study demonstrates that a maintenance regimen of lopinavir/ritonavir plus Truvada is superior to nevirapine plus Truvada among non-pregnant HIV women with CD4 counts less than 200 who had received nevirapine at the time of delivery 6 months or more in the past. This relationship remained even among women without evidence of viral resistance at the start of the maintenance regimen. On the other hand, there was no difference in the rate of persistently high viral loads or death among women who had not been exposed to nevirapine in the past.
This data supports pretreatment testing for drug resistance among women with prior exposure to single-dose nevirapine when practical and in settings where a non-nevirapine based maintenance regimen is available. The rigorous methodology with which this study was carried out suggests that these findings are real and largely free from bias. An important question that must be asked is how to incorporate these findings into practice here in the United States, where many women who receive single dose nevirapine also receive other antiretroviral medications around the time of delivery and postpartum, in contrast to more resource-limited settings in other countries. Additionally, domestically many women have a much less advanced disease state, with CD4 counts which often are substantially higher than 200. Finally, whether any maintenance regimen other than a nevirapine-based one would result in similar improvements in outcome as the lopinavir/ritonavir regimen studied in OCTANE is an additional area open to speculation. That said, this study represents a gargantuan contribution to the existing knowledge base regarding initiation of maintenance antiretroviral therapy in HIV positive women previously exposed to nevirapine at the time of delivery. It will dramatically alter antiretroviral prescribing patterns internationally.

The OCTANE study confirms that women in whom therapy is initiated 6 months or more after exposure to single-dose nevirapine have a diminished response to nevirapine-based antiretroviral maintenance regimens, as compared with lopinavir/ritonavir regimens, and that the difference in failure rates is largest among women with resistance mutations at initiation.
Within the United States, OCTANE should prompt providers caring for HIV positive women who have emigrated from Africa and other resource-limited settings to thoroughly look into their patients’ pregnancy and medication histories prior to initiating antiretroviral maintenance regimen. OCTANE also emphasizes the importance of prescribing pregnant patients receiving single-dose nevirapine “tails”—which are antiretroviral medications taken in the immediate wake of nevirapine that help decrease the development of resistance-- and educating women regarding the importance of “tail” adherence.
--Summarized by Barrett Robinson, MD, MPH

Barrett Robinson is a Maternal-Fetal Medicine Fellow at Northwestern Memorial Hospital, where he participates in the ongoing care of one of Illinois’ largest clinics exclusively servicing HIV-positive pregnant patients

Lockman S, et al. Antiretroviral therapies in women after single-dose nevirapine exposure.” New England Journal of Medicine 2010. 363:1499-1509.
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