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Prevention of mother-to-child transmission and nevirapine resistance
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12th CROI Feb 2005
Reported for NATAP by David Margolis, MD
Univ of Texas, Southwestern Medical Center Dallas; VA Dallas; ACTG
The burning international issue of the use of nevirapine in MTCT prevention was beautifully covered in a plenary talk by James McIntyre of the University of the Witwatersrand and Chris Hani Baragwanath Hosp, Johannesburg
(view at: http://www.retroconference.org/2005/Pages/webcasts.htm). He summarized well the value of single-dose nevirapine (sdNVP) prophylaxis, its problems, the recent distractions created by an NIH whistleblower, the recent advancements in strategies that improve on single dose nevirapine, and the need for continued advances in both strategies for and access to prophylaxis to prevent MTCT.
Several groups presented elegant and sensitive assays that documented the extent and persistence of NNRTI-resistant HIV after exposure to sdNVP. Sarah Palmer (abstr. 101) of the NCI-Frederick group used an allele-specific RT-PCR assay to quantify non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant variants 103N and 181C at frequencies < 0.1% in longitudinal samples from HIV-1 subtype-C-infected women who received sdNVP. Mothers with subtype C HIV appear to be at greater risk of developing NNRTI resistance after sdNVP, and prior studies had found 30-50% prevalence on such mutations after exposure.
Palmer and coworkers studied samples from women participating in a South African mother-to-child HIV-1 transmission trial. Patients were separated into 2 groups based on detection of NNRTI-resistance mutations by standard genotyping. Group 1 had NNRTI-resistance mutations detected at 6 weeks and 6 months but not at 12 months after sdNVP. Group 2 had NNRTI-resistance mutations detected at 6 weeks but not thereafter. Group 3 had no mutations detected at 6 weeks after sdNVP.
The natural frequency of such mutations in drug-naï
ve individuals is thought to be ca. 1%. 12-months after sdNVP, 103N or 181C mutants were detected in 7 of 8 (88%) of group 1, at frequencies ranging from 0.25% to 16%. Similarly, 6 months after sdNVP mutants were found in 7 of 9 (78%) of group 2 at frequencies ranging from 0.9% to 10%. The rate of detection declined towards the natural frequency in group 2 by 12 months. In group 3, up to 10% had mutations detected at 4 months by single genome sequencing. In total, up to 69% of women exposed to sdNVP had NNRTI resistance detected 1-4 months later, and about 25% of women had mutants detected at 1 year.
The following presentation (abstr. 102) from Shayne Loubser of Johannesburg reported concordant results. Comparing real-time PCR and direct population sequencing, 103N mutants were detected in 16 of 18 (89%) samples by real-time PCR and in 9 of 18 (50%) by population sequencing. 3 women had no evidence of 103N and amplified only wild type virus at all time-points tested; 4 had the 103N mutation at > 60% within 12 weeks of NVP exposure, which declined to 10 to 40% within 7 to 12 months; 6 had 103N at levels ranging from 5 to 40% at 12 weeks and in 4 cases declined to below the threshold of detection by 7 to 12 months. At 1 year 103N was still detectable at low levels in 4 of 16 (25%).
However, preliminary studies suggest that the use of sdNVP in a first pregnancy does not seriously jeopardize the efficacy of sdNVP in a second pregnancy (abstr. 103). In this study reported by Martinson, 106 women given sdNVP for the first time, and 212 given it for the second time were enrolled. Data on 64 and 128 mothers, respectively was presented. The transmission rate was 3.8% in the first-time mothers, and 10.7% in the second-time mothers. This difference is not statistically significant, and the data should be considered preliminary at this time.
Ed note from Jules Levin:we know that HIV drug resistance can be archived. So as an attendee at the 12th CROi made this point at the microphone during these oral resistance sessions regarding nevirapine, just because nevirapine resistance or resistance to any drug appears to become Ônon-detectableÕ after being detectable this does not mean it is gone. HIV drug resistance is archived and it is thought does not necessarily go away. Often after stopping & starting therapy when resistance was present it reappears; restarting drugs brings back the resistance to detection. Although studies have been conducted to better understand the clinical implications of the presence of undetectable HIV drug resistance, our understanding is limited & needs further study. By the way, when single dose nevirapine was first starting to be used it was clear to many that resistance would develop. These developments are not surprising. Use of any single dose NNRTI would lead to resistance.
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