Safety of nevirapine in HIV-infected pregnant women initiating antiretroviral therapy at higher CD4 counts: A systematic review and meta-analysis

Abstract

United States (US) Food and Drug Administration (FDA) issued a public health advisory recommending against initiating nevirapine (NVP) in HIV-infected women (including pregnant women) with CD4 counts >250 cells/µl. 1 The NVP package insert was revised accordingly to warn about risks, with further revision in November 2011 to comply with FDA recommendations on product labelling safety. 2The initial warning followed a meta-analysis of hepatotoxicity in over 600 women, stratified by CD4 count (risk ratio 9.8 with a CD4 count ≥250 cells/µl).3 However, results from several subsequent studies with larger datasets demonstrated no association between CD4 count and NVP toxicity. [4][5][6] Current World Health Organization (WHO) guidelines recommend NVP as part of first-line antiretroviral therapy (ART) for pregnant women with CD4 ≤350 cells/µl, 7 based on their own analysis of 836 pregnant women, which showed no increased hepatotoxicity risk at CD4 ≥250 cells/µl (relative risk 1.04; 95% confidence interval (CI) 0.22 -4.93). 9 In contrast, the 2011 perinatal guidelines from the US Department of Health and Human Services recommend a protease inhibitor as part of the ART regimen for pregnant women with a CD4 count ≥250 cells/µl, while cautioning against starting NVP above this count. 10 The British HIV Association 2012 draft guidelines recommend either efavirenz (EFV) or NVP (with a CD4 count <250 cells/µl) or a boosted protease inhibitor as the third drug for pregnant women requiring ART for their own health. 11 The recommendation of EFV is a departure from previous guidelines discouraging its use in pregnancy. Furthermore, women who conceived on EFV-based ART need not switch to another drug in the first trimester, following analysis of recent data showing no increased risk of birth defects after first-trimester EFV exposure. 11Reports of NVP-related maternal deaths have surfaced in South Africa, generating renewed concerns about the drug's safety, notably among ART-naive pregnant women. The Eastern Cape Province recently amended its PMTCT guidelines following an analysis of 45 HIV-related maternal deaths, 6 due to liver failure and StevensJohnson Syndrome (SJS). The use of NVP in pregnancy since then has been limited to a single dose at delivery (M Shweni, personal communication).To address the uncertainty about the safety of initiating NVPbased ART in pregnancy, we aimed to determine whether ART-naive pregnant women initiating NVP at higher CD4 counts experience greater toxicity. MethodsThe Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) guidelines were followed.12 All studies except case reports were evaluated for inclusion without consideration of their results. ART-naive pregnant women initiating NVP-based ART during the index pregnancy for maternal health or infant prophylaxis were included. For studies that included both ART-naive and -experienced pregnant women, only the data of ART-naive participants were extracted. ART-experienced pregnant women were excluded, including those naive to N...

Safety and effectiveness of antiretroviral therapies for HIV-infected women and their infants and children: protocol for a systematic review and network meta-analysis

“…Most children acquire HIV from mother-to-child transmission and many of these cases are preventable. Effective antiretroviral therapy is available, yet safety concerns during pregnancy have been raised, including major congenital abnormalities, preterm delivery, anemia, and low birth weight [8,12-17]. Our findings regarding the comparative safety and effectiveness of these agents will be of great importance to policy-makers, healthcare providers, and patients.…”

“…This is due to increased risk of major congenital abnormalities, preterm delivery, anemia, and low birth weight [2,8,12-17]. As such, our objective is to evaluate the comparative safety and effectiveness of antiretroviral drugs in HIV-infected pregnant women and their infants who were exposed to HIV in-utero , during delivery or while breastfeeding, through performance of a systematic review and network meta-analysis.…”

Adverse drug reactions associated with antiretroviral therapy during pregnancy

“…There are continued concerns about the chronic use of NVP in women with HIV with CD4 cell counts above 250 cells/ mm 3 , with some studies showing an increased relative risk for severe hepatic and skin reactions in pregnant women using NVP at higher CD4 cell counts [69][70][71][72][73][74]. A systematic review [75] of the risk of NVP-associated toxicity in pregnant women suggests that the frequency of adverse events is elevated but no higher than that observed in the general adult population.…”

Non-AIDS Morbidity among HIV Patients

“…Because of concerns about the increased risk of toxicity of NVP among pregnant women with higher CD4 counts (132)(133)(134), the recommended regimens for pregnant women who did not require treatment for their own health and who were receiving triple ARV regimens for PMTCT were AZT + 3TC or TDF + 3TC (or FTC) + EFV as the preferred NNRTI regimens. Alternative regimens were AZT + 3TC plus either LPV/r or ABC, rather than NVP.…”