期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 22, 页码 9202-9207出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1105688108
关键词
mother-to-child transmission; nonnucleoside reverse transcriptase inhibitors
资金
- Kenya Medical Research Institute/Walter Reed Project Clinical Research Center, Kericho, Kenya [12501]
- National Institute of Allergy and Infectious Diseases [U01AI068636]
- National Institute of Mental Health and National Institute of Dental and Craniofacial Research
- Division of AIDS, National Institute of Allergy and Infectious Diseases [1U01 AI069494-01]
- AIDS Clinical Trials Group Central Group [204VC009, 1 U01AI068636-01]
- AIDS Clinical Trials Group Statistical and Data Management Center [1 U01-AI068634]
- National Cancer Institute [25XS119]
- F. M. Kirby Foundation
- [U01AI69463-03]
- [IAAY1AI8374]
- [5 U01AI069518]
- [AI69453]
- [AACTG 50.5208.07]
- [5U01AI069455-03]
- [3U01AI32775-13S5]
- [5U01AI069456-03]
- [AI-069501]
- [AI69426]
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.
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