Pharmacokinetics of Nevirapine in Human Immunodeficiency Virus Type 1-Infected Pregnant Women and Their Neonates

Mirochnick, Mark; Fenton, Terry; Gagnier, Paul; Pav, Joseph W.; Gwynne, Meg; Siminski, Sue; Sperling, Rhoda; Beckerman, Karen; Jiménez, Eleanor; Yogev, Ram; Spector, Stephen A.; Sullivan, John L.

doi:10.1086/515641

Cited by 187 publications

(114 citation statements)

References 12 publications

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“…Following sdNVP, high drug concentrations and slow drug clearance (13) result in the selection of NVP-resistant mutants that become the dominant virus population in most women. Although this resistant virus population decays to lower levels over time (4), resistant mutants can still be detected in a substantial fraction of patients after 1 y and persist in some women for longer (6,7).…”

Section: Discussionmentioning

confidence: 99%

Role of low-frequency HIV-1 variants in failure of nevirapine-containing antiviral therapy in women previously exposed to single-dose nevirapine

Boltz

Zheng

Lockman

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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In the OCTANE/A5208 study of initial antiretroviral therapy (ART) in women exposed to single-dose nevirapine (sdNVP) ≥6 mo earlier, the primary endpoint (virological failure or death) was significantly more frequent in the NVP-containing treatment arm than in the lopinavir/ritonavir-containing treatment arm. Detection of NVP resistance in plasma virus at study entry by standard population genotype was strongly associated with the primary endpoint in the NVP arm, but two-thirds of endpoints occurred in women without NVP resistance. We hypothesized that low-frequency NVP-resistant mutants, missed by population genotype, explained excess failure in the NVP treatment arm. Plasma samples from 232 participants were analyzed by allele-specific PCR at study entry to quantify NVP-resistant mutants down to 0.1% for 103N and 190A and to 0.3% for 181C. Of 201 women without NVP resistance by population genotype, 70 (35%) had NVP-resistant mutants detected by allele-specific PCR. Among these 70 women, primary endpoints occurred in 12 (32%) of 38 women in the NVP arm vs. 3 (9%) of 32 in the lopinavir/ritonavir-containing arm (hazard ratio = 3.84). The occurrence of a primary endpoint in the NVP arm was significantly associated with the presence of K103N or Y181C NVP-resistant mutations at frequencies >1%. The risk for a study endpoint associated with NVP-resistant mutant levels did not decrease with time. Therefore, among women with prior exposure to sdNVP, low-frequency NVP-resistant mutants were associated with increased risk for failure of NVP-containing ART. The implications for choosing initial ART for sdNVP-exposed women are discussed.mother-to-child transmission | nonnucleoside reverse transcriptase inhibitors S ingle-dose nevirapine (sdNVP) administered at the onset of labor to pregnant HIV-infected women can reduce the risk for mother-to-child transmission (MTCT) of HIV by ∼50% (1-3), but NVP-resistant HIV-1 mutants emerge in the majority of women who have received sdNVP alone (4, 5). These mutants most commonly encode K103N, Y181C, or G190A mutations in HIV-1 RT, conferring resistance to NVP and efavirenz. With the use of sensitive drug resistance assays, such as allele-specific PCR (ASP), resistant mutants can be detected in the majority of women after NVP exposure and can persist for years (6, 7).In resource-limited settings, NVP in combination with lamivudine (3TC) and zidovudine (AZT) or tenofovir disoproxil fumarate (TDF) is recommended as the standard of care for first-line antiretroviral therapy (ART) (8). This recommendation is potentially problematic for women who have been previously exposed to sdNVP (9-11). The A5208/OCTANE trials were designed to compare protease inhibitor-based therapy using lopinavir/ritonavir (LPV/r) with NVP-based therapy in ART-naive women with or without prior sdNVP. A5208 trial 1, which will be the focus of this report, showed that LPV/r + TDF and emtricitabine (FTC) was superior to NVP + TDF/FTC (P = 0.001) for initial therapy of women with prior sdNVP ≥6 mo earlier and a CD4 cell...

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Section: Discussionmentioning

confidence: 99%

Role of low-frequency HIV-1 variants in failure of nevirapine-containing antiviral therapy in women previously exposed to single-dose nevirapine

Boltz

Zheng

Lockman

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, sdNVP has been demonstrated to be more effective than zidovudine chemoprophylaxis alone, and to be equivalent to NVP plus zidovudine in preventing MTCT (9)(10)(11)(12). The efficacy of sdNVP in preventing MTCT is attributed to its potent antiviral activity, rapid absorption, placental transfer, and long half-life (13,14). As a result, its use has been recommended by the World Health Organization as one of several options to reduce MTCT in resource-limited countries [Joint UNAIDS͞WHO press release (2000) (WHO, Geneva)].…”

mentioning

confidence: 99%

Persistence of nevirapine-resistant HIV-1 in women after single-dose nevirapine therapy for prevention of maternal-to-fetal HIV-1 transmission

Palmer

Boltz

Martinson

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

137

114

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Single-dose nevirapine (sdNVP) for prevention of mother-to-child transmission of HIV-1 can select nevirapine (NVP)-resistant variants, but the frequency, duration, and clinical significance of this resistance is not well defined. We used a sensitive allele-specific PCR assay to assess the emergence and persistence of NVPresistant variants in plasma samples from 22 women with HIV-1 subtype C infection who participated in a study of sdNVP for prevention of mother-to-child transmission of HIV-1. The women were categorized into three groups on the basis of detection of NVP resistance by standard genotype analysis. Group 1 (n ‫؍‬ 6) had NVP resistance detected at 2 and 6 mo after sdNVP, but not at 12 mo. Group 2 (n ‫؍‬ 9) had NVP resistance detected at 2 mo, but not 6 mo. Group 3 (n ‫؍‬ 7) had no NVP resistance detected at any time point. Allele-specific PCR analysis for the two most common NVP resistance mutations (K103N and Y181C) detected NVP-resistant variants in most (16 of 21) samples that were negative for NVP resistance by standard genotype, at levels ranging from 0.1% to 20% 1 yr after treatment. The frequency of NVP-resistant mutations decreased over time, but persisted above predose levels for more than 1 yr in >23% of the women. These findings highlight the urgent need for studies assessing the impact of sdNVP on the efficacy of subsequent antiretroviral therapy containing NVP or other nonnucleoside reverse transcriptase inhibitors.allele-specific PCR ͉ resistance ͉ low-frequency mutants T he treatment of pregnant women with antiretroviral therapy, in combination with zidovudine chemoprophylaxis administered to newborns, has dramatically reduced vertical transmission of HIV in developed countries (1-5). However, perinatal transmission of HIV-1 remains a major problem in developing countries because of limited access to antiretroviral therapy (6-8). In this latter setting, the simple regimen of maternal single-dose intrapartum nevirapine (NVP) and single-dose NVP (sdNVP) for the newborn reduces the risk of mother-to-child HIV-1 transmission (MTCT) by 41% through age 18 mo (9). Moreover, sdNVP has been demonstrated to be more effective than zidovudine chemoprophylaxis alone, and to be equivalent to NVP plus zidovudine in preventing MTCT (9-12). The efficacy of sdNVP in preventing MTCT is attributed to its potent antiviral activity, rapid absorption, placental transfer, and long half-life (13, 14). As a result, its use has been recommended by the World Health Organization as one of several options to reduce MTCT in resource-limited countries [Joint UNAIDS͞WHO press release (2000) (WHO, Geneva)].NVP is a potent nonnucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 (15-17). If administered as monotherapy, NVP selects for resistant variants within 1 wk, commonly those variants with the K103N and͞or Y181C mutations in reverse transcriptase, which confer cross-resistance to other approved drugs in the NNRTI class (18)(19)(20). The K103N mutation appears to have little effect on the replicative capacity o...

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“…The most information about use of ARV combinations in neonates is available for ZDV in combination with single-dose nevirapine [17][18][19][20][21][22] and the dual combination of ZDV and lamivudine, [23][24][25][26][27] which has been combined with daily nevirapine (although there are no published data on this last approach). Careful infant monitoring is needed if combination drugs are provided, because there may be enhanced hematologic toxicity from the combination of ZDV and lamivudine compared with ZDV alone.…”

Section: Infant Arv Prophylaxismentioning

confidence: 99%

Evaluation and Management of the Infant Exposed to HIV-1 in the United States

Havens¹,

Mofenson²

2009

Pediatrics

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The pediatrician plays a key role in the prevention of mother-to-child transmission of HIV-1 infection. For infants born to women with HIV-1 infection identified during pregnancy, the pediatrician ensures that antiretroviral prophylaxis is provided to the infant to decrease the risk of acquiring HIV-1 infection and promotes avoidance of postnatal HIV-1 transmission by advising HIV-1–infected women not to breastfeed. The pediatrician should perform HIV-1 antibody testing for infants born to women whose HIV-1 infection status was not determined during pregnancy or labor. For HIV-1–exposed infants, the pediatrician monitors the infant for early determination of HIV-1 infection status and for possible short- and long-term toxicity from antiretroviral exposures. Provision of chemoprophylaxis for Pneumocystis jiroveci pneumonia and support of families living with HIV-1 by providing counseling to parents or caregivers are also important components of care.

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Pharmacokinetics of Nevirapine in Human Immunodeficiency Virus Type 1-Infected Pregnant Women and Their Neonates

Cited by 187 publications

References 12 publications

Role of low-frequency HIV-1 variants in failure of nevirapine-containing antiviral therapy in women previously exposed to single-dose nevirapine

Role of low-frequency HIV-1 variants in failure of nevirapine-containing antiviral therapy in women previously exposed to single-dose nevirapine

Persistence of nevirapine-resistant HIV-1 in women after single-dose nevirapine therapy for prevention of maternal-to-fetal HIV-1 transmission

Evaluation and Management of the Infant Exposed to HIV-1 in the United States

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