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Nevirapine Combo May Work for Some Kids Exposed to Single-Dose Nevirapine
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5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 19-22, 2009, Cape Town
Mark Mascolini
A nevirapine-based antiretroviral combination generally maintained control of HIV after initial suppression with lopinavir/ritonavir in South African children exposed to single-dose nevirapine (sdNVP) at birth [1].
If these findings are confirmed, they could mean at least some sdNVP-exposed children can start a nevirapine-containing combination after a regimen containing protease inhibitors (PIs) like lopinavir/ritonavir stops HIV replication.
A separate randomized trial at 10 sites in 7 countries found that nevirapine did not work as well as lopinavir/ritonavir in children starting their first antiretroviral regimen after exposure to sdNVP [2]. Using nevirapine in a first regimen after getting sdNVP can be risky because sdNVP often engenders nevirapine-resistant virus that persists for months and sometimes for more than a year. As a result, pediatric antiretroviral guidelines in countries that use sdNVP to prevent mother-to-child transmission of HIV often recommend lopinavir/ritonavir as first-line therapy. But nevirapine-based combinations are cheaper and easier to administer because they are formulated as generic triple-drug combinations in a single pill. And nevirapine regimens probably have fewer long-term side effects than ritonavir-boosted PIs.
The South African study involved 322 children under 2 years old who started lopinavir/ritonavir (or only ritonavir if they had TB) plus stavudine and lamivudine at Johannesburg's Coronation Hospital after receiving sdNVP [1]. Of the 195 children who reached and maintained a viral load below 400 copies for at least 3 months, the researchers randomized 99 to stay with lopinavir/ritonavir and 96 to switch to nevirapine. All children were 2 years old or younger, had received sdNVP, and met South African criteria for antiretroviral therapy. To be randomized they needed a viral load below 400 copies for at least 3 months and normal liver function tests, and they could not be taking anti-TB drugs.
Median age of the study group stood at 11 months (interquartile range [IQR] 7 to 16) when they began lopinavir/ritonavir and at 20 months (IQR 16 to 25 months) at randomization. At that point about two thirds of each treatment group had a viral load below 50 copies, and the remaining viral loads were between 50 and 400 copies. Two children in the nevirapine group and 2 in the lopinavir group died. Only 8 other children failed to complete the study, all because they had to start drugs for TB.
An intention-to-treatment analysis determined that 56.2% in the nevirapine group and 42.4% in the lopinavir group reached and consistently maintained a viral load below 50 copies for 24 weeks after randomization, a significant difference (P = 0.01). However, 73% of children in each group reached a sub-50 viral load and had only one 50-plus reading after that. While 98% in the lopinavir group consistently maintained a viral load below 1000 copies through 24 weeks, 80% in the nevirapine group achieved that benchmark, also a significant difference (P = 0.001).
The investigators believe their study "provides proof of concept that re-use of nevirapine following successful suppression on lopinavir/ritonavir-based therapy is possible under some circumstances for HIV-infected children exposed to nevirapine prophylaxis." But they cautioned that further study is needed "to determine the circumstances and interventions required to safely re-use this agent."
The 7-country trial of first-line nevirapine versus lopinavir/ritonavir (both with zidovudine/lamivudine) has two groups: children exposed to sdNVP and children never exposed to sdNVP [2]. The trial's Data and Safety Monitoring Board halted the study in sdNVP-exposed children after a median follow-up of 48 weeks when it became clear that treatment was failing significantly more often in nevirapine-treated children.
The primary endpoint was virologic failure, treatment discontinuation, or death by week 24, with virologic failure defined as less than a 10-fold drop in viral load between treatment weeks 12 and 24 or a load above 400 copies at week 24 or above 4000 copies after week 24. By those criteria, the failure rate in 164 randomized children was 39% with nevirapine-based therapy versus 22% with lopinavir/ritonavir, a significant difference (P = 0.015).
Looking at 24-week virologic failure alone, the investigators measured a 24% failure rate with nevirapine versus 7% with lopinavir/ritonavir, also a significant difference (P = 0.009). Virologic failure rates were similar in infants beginning treatment before or after 12 month of age.
Among 115 children tested for resistance mutations before starting therapy, 16 (14%) had nevirapine-related mutations. Four of those 16 children were older than 1 year. Virologic failure was more frequent in the 16 children with pretreatment resistance (57%) than in those without pretreatment resistance (17%).
The investigators concluded that "there is a need for next-generation strategies for prevention of mother-to-child transmission including postpartum antiretroviral tails [drugs given for a specified short period after sdNVP to prevent emergence of resistance] and maternal HAART."
References
1. Coovadia A, Abrams E, Strehlau R, et al. Randomized clinical trial of switching to nevirapine-based therapy for infected children exposed to nevirapine prophylaxis. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract MOAB103.
2. Violari A, Palumbo P, Lindsey J, et al.. Nevirapine vs lopinavir-ritonavir based antiretroviral therapy in single dose nevirapine (sdNVP) exposed HIV infected infants: preliminary results from the IMPAACT P1060 trial. 1st International Conference on HIV Pediatrics. July 17-19, 2009. Cape Town. Abstract O_08.
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