Clinical Experience with Non-Nucleoside Reverse Transcriptase Inhibitors: L-697,661 and Nevirapine

Kilby, J Michael; Saag, Michael S.

doi:10.1007/978-1-4757-9209-6_26

Cited by 4 publications

(1 citation statement)

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“…NVP is a potent nonnucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 (15)(16)(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).…”

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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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