奈韦拉平耐药性与母乳中HIV传播：C亚型HIV感染婴儿单剂量和延长剂量奈韦拉平预防的效果
Nevirapine resistance and breast-milk HIV transmission: effects of single and extended-dose nevirapine prophylaxis in subtype C HIV-infected infants.
作者信息
Moorthy Anitha, Gupta Amita, Bhosale Ramesh, Tripathy Srikanth, Sastry Jayagowri, Kulkarni Smita, Thakar Madhuri, Bharadwaj Renu, Kagal Anju, Bhore Arvind V, Patil Sandesh, Kulkarni Vandana, Venkataramani Varadharajan, Balasubramaniam Usha, Suryavanshi Nishi, Ziemniak Carrie, Gupte Nikhil, Bollinger Robert, Persaud Deborah
机构信息
Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
出版信息
PLoS One. 2009;4(1):e4096. doi: 10.1371/journal.pone.0004096. Epub 2009 Jan 1.
BACKGROUND
Daily nevirapine (NVP) prophylaxis to HIV-exposed infants significantly reduces breast-milk HIV transmission. We assessed NVP-resistance in Indian infants enrolled in the "six-week extended-dose nevirapine" (SWEN) trial who received single-dose NVP (SD-NVP) or SWEN for prevention of breast-milk HIV transmission but who also acquired subtype C HIV infection during the first year of life.
METHODS/FINDINGS: Standard population sequencing and cloning for viral subpopulations present at > or =5% frequency were used to determine HIV genotypes from 94% of the 79 infected Indian infants studied. Timing of infection was defined based on when an infant's blood sample first tested positive for HIV DNA. SWEN-exposed infants diagnosed with HIV by six weeks of age had a significantly higher prevalence of NVP-resistance than those who received SD-NVP, by both standard population sequencing (92% of 12 vs. 38% of 29; p = 0.002) and low frequency clonal analysis (92% of 12 vs. 59% of 29; p = 0.06). Likelihood of infection with NVP-resistant HIV through breast-milk among infants infected after age six weeks was substantial, but prevalence of NVP-resistance did not differ among SWEN or SD-NVP exposed infants by standard population sequencing (15% of 13 vs. 15% of 20; p = 1.00) and clonal analysis (31% of 13 vs. 40% of 20; p = 0.72). Types of NVP-resistance mutations and patterns of persistence at one year of age were similar between the two groups. NVP-resistance mutations did differ by timing of HIV infection; the Y181C variant was predominant among infants diagnosed in the first six weeks of life, compared to Y188C/H during late breast-milk transmission.
CONCLUSIONS/SIGNIFICANCE: Use of SWEN to prevent breast-milk HIV transmission carries a high likelihood of resistance if infection occurs in the first six weeks of life. Moreover, there was a continued risk of transmission of NVP-resistant HIV through breastfeeding during the first year of life, but did not differ between SD-NVP and SWEN groups. As with SD-NVP, the value of preventing HIV infection in a large number of infants should be considered alongside the high risk of resistance associated with extended NVP prophylaxis.
TRIAL REGISTRATION
ClinicalTrials.gov NCT00061321.
背景
对暴露于HIV的婴儿每日给予奈韦拉平（NVP）预防可显著降低母乳传播HIV的风险。我们评估了参与“六周延长剂量奈韦拉平”（SWEN）试验的印度婴儿的NVP耐药情况，这些婴儿接受单剂量NVP（SD-NVP）或SWEN以预防母乳传播HIV，但在出生后第一年也感染了C型HIV。
方法/发现：对79名接受研究的感染印度婴儿中的94%，采用标准群体测序和对频率≥5%的病毒亚群进行克隆的方法来确定HIV基因型。根据婴儿血液样本首次检测出HIV DNA呈阳性的时间来定义感染时间。通过标准群体测序（12例中的92%对29例中的38%；p = 0.002）和低频克隆分析（12例中的92%对29例中的59%；p = 0.06），6周龄前被诊断为HIV感染的接受SWEN的婴儿中NVP耐药的患病率显著高于接受SD-NVP的婴儿。6周龄后感染的婴儿通过母乳感染NVP耐药HIV的可能性很大，但通过标准群体测序（13例中的15%对20例中的15%；p = 1.00）和克隆分析（13例中的31%对20例中的40%；p = 0.72），接受SWEN或SD-NVP的婴儿中NVP耐药的患病率没有差异。两组在NVP耐药突变类型和1岁时的持续模式相似。NVP耐药突变因HIV感染时间而异；与母乳后期传播期间的Y188C/H相比，Y181C变异在出生后前六周被诊断出的婴儿中占主导。
结论/意义：如果在出生后前六周发生感染，使用SWEN预防母乳传播HIV产生耐药的可能性很高。此外，在出生后第一年通过母乳喂养传播NVP耐药HIV的风险持续存在，但SD-NVP组和SWEN组之间没有差异。与SD-NVP一样，在考虑大量婴儿预防HIV感染价值的同时，也应考虑延长NVP预防带来的高耐药风险。
试验注册
ClinicalTrials.gov NCT00061321
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