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CROI Resistance Report 3: Nevirapine Effect & The Development of Drug Resistance in Preventing Mother to Child HIV Transmission
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Written for NATAP by Andrew Zolopa, MDStanford University
NNRTI Resistance after Single Dose Nevirapine: Negative Impact on Treatment Response
Perhaps one of the most important studies presented at this year's conference was a study from Thailand on the implications of single dose nevirapine used to prevent MTCT on subsequent treatment of the HIV-infected mother.[abstract 41LB] In this study, women who were exposed to SD-NVP (single-dose nevirapine) as part of the trial PHPT 2 were treated after delivery with a NNRTI-containing ARV regimen. Genotypic analysis from a plasma sample obtained 10 days postpartum, revealed NNRTI-related resistance in 18% of a random sample of women participating in this trial. 61 women had postpartum NVP plasma levels up to 24 days after delivery. 12 days postpartum 21% of women had the key NNRTI genotypic drug mutation, K103N.
Compared to a group of women who were not exposed to SD-NVP, the investigators found trends for decreased response rates at 3 and 6 months of ARV treatment in the women who had prior SD-NVP. Comparing response in the SD-NVP exposed women with detectable NNRTI-mutations to those who did not have detectable mutations after SD-NVP, the group with detectable mutations had poorer responses. Comparison of treatment response rates by the percent of subjects achieving viral loads of <50 copies at 6 months in the 3 groups (no SD-NVP, SD-NVP without mutations and SD-NVP with mutations), showed 75%, 53% and 34% had <50 copies/ml, respectively (p<0.01, trend). Thus, women exposed to single-dose nevirapine had lower response rates to NNRTI therapy. Another interesting observation from this study was that mothers who initiated treatment after a 6 month delay following SD-NVP exposure seemed to have better responses than those who initiated treatment earlier, although longer term follow up is required to substantiate this observation.
The obvious implication from this trial is the need to limit the development of NNRTI-resistance in women receiving ARV to prevent transmission of HIV to their newborns. Studies are now under way, looking at strategies which employ various combinations of ARV's to help decrease the substantial risk of NNRTI-resistance associated with SD- NVP. The study authors said "where or when HAART during pregnancy is not feasible or desirable, AZT-NVP regimen is the only regimen which matches the efficacy of HAART during pregnancy to prevent vertical transmission".
Note from Jules Levin: there were 3 studies presented in oral sessions at the conference on the use of single-dose nevirapine to prevent mother-to-child transmission. Martinson (abstract 38) reported on a study whose primary objective was to determine whether single dose NVP administered to both mother and infant leads to drug resistance, and secondarily to assess the effectiveness of the MTCT program. Nevirapine (NVP), given to mothers in labor and to neonates within 72 hours of delivery, is an effective, simple PMTCT regimen. The authors said the NVP regimen is operationally effective, transmission rate was 8.6% at weeks 4-10, but high level NVP resistance developed. 39% of women had NNRTI genotypic resistance: 21% had K103N mutation, 13% had K103N+Y181C, 5% had K103N+Y181C+G190A. 12% of infants had the K103N mutation and 30% of infants had the Y181C NNRTI mutation at 6 weeks after birth.
Lallemant reported on "A Randomized, Double-blind Trial Assessing the Efficacy of Single-dose Perinatal Nevirapine Added to a Standard Zidovudine Regimen for the Prevention of Mother-to-child Transmission of HIV-1 In Thailand" (abstract 40LB). The authors said that although zidovudine prophylaxis initiated at 28 weeks decreases in utero transmission of HIV to 1 to 2%, significant peripartum transmission still occurs. The hypothesis for the study is that without additional toxicity, logistical complications, or significant cost, perinatal NVP added to ZDV could further reduce intrapartum transmission. All study women received prophylaxis during the third trimester of pregnancy, and infants received 1 week of zidovudine and formula feeding. Mother-infant pairs were randomized into 3 groups: single nevirapine dose to the mother (200 mg) and infant (6 mg), Nevirapine-Nevirapine; Nevirapine-Placebo; and Placebo-Placebo. The study endpoint was virologically proven HIV infection of the infant. The study was primarily designed to test the superiority of NVP-NVP over PL-PL.
Transmission rates were 6.3% for PL-PL, 2.1% for NVP-PL, and 1.1% for NVP-NVP (ITT analysis: NVP-NVP vs PL-PL, p=0.00026). The transmission rate for NVP-PL was 2.8% vs 2.0% for NVP-NVP (ITT: non-inferior). 3.2% of mothers had skin rash within 10 days, and 15% had skin rash after 10 days. In a random sample of 90 women who received NVP intrapartum, and among women with detectable viral load at 12 days postpartum 20% of women had NVP genotypic resistance. The authors concluded: maternal and infant NVP+AZT prophylaxis decreases the risk of HIV perinatal transmission to levels comparable to HAART during pregnancy; NVP-NVP and NVP-PL were declared statistically equivalent, per protocol definition.
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