Kenya Medical Research Institute, Kisumu, Kenya Department of Global Health, Academic Medical Center of the University of Amsterdam, and Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands.
Centers for Disease Control and Prevention, Atlanta, GA, USA.
J Antimicrob Chemother. 2016 Jun;71(6):1619-26. doi: 10.1093/jac/dkw039. Epub 2016 Mar 6.
K65R is a relatively rare drug resistance mutation (DRM) selected by the NRTIs tenofovir, didanosine, abacavir and stavudine and confers cross-resistance to all NRTIs except zidovudine. Selection by other NRTIs is uncommon.
In this study we investigated the frequency of emergence of the K65R mutation and factors associated with it in HIV-1-infected infants exposed to low doses of maternal lamivudine, zidovudine and either nevirapine or nelfinavir ingested through breast milk, using specimens collected from the Kisumu Breastfeeding Study.
Plasma specimens with viral load ≥1000 copies/mL collected from HIV-infected infants at 0-1, 2, 6, 14, 24 and 36 weeks of age and maternal samples at delivery were tested for HIV drug resistance using Sanger sequencing of the polymerase gene. Factors associated with K65R emergence were assessed using Fisher's exact test and the Wilcoxon rank-sum test.
K65R was detected in samples from 6 of the 24 infants (25%) who acquired HIV-1 infection by the age of 6 months. K65R emerged in half of the infants by 6 weeks and in the rest by 14 weeks of age. None of the mothers at delivery or the infants with a positive genotype at first time of positivity had the K65R mutation. Infants with K65R had low baseline CD4 cell counts (P = 0.014), were more likely to have DRMs earlier (≤6 weeks versus ≥14 weeks, P = 0.007) and were more likely to have multiclass drug resistance (P = 0.035). M184V was the most common mutation associated with K65R emergence. K65R had reverted by 3 months after cessation of breastfeeding.
A high rate of K65R emergence may suggest that ingesting low doses of lamivudine via breast milk could select for this mutation. The presence of this mutation may have a negative impact on future responses to NRTI-based ART. More in vitro studies are, however, needed to establish the molecular mechanism for this selection.
K65R 是一种相对罕见的耐药突变（DRM），由 NRTIs 替诺福韦、地达诺辛、阿巴卡韦和司他夫定选择，对除齐多夫定以外的所有 NRTIs 具有交叉耐药性。其他 NRTIs 的选择并不常见。
本研究通过对 Kisumu 母乳喂养研究中采集的样本进行分析，调查了在接受低剂量母亲拉米夫定、齐多夫定和通过母乳摄入的奈韦拉平或奈非那韦的 HIV-1 感染婴儿中，与 K65R 突变相关的因素和该突变的出现频率。
从感染 HIV-1 的婴儿在 0-1、2、6、14、24 和 36 周龄时采集的病毒载量≥1000 拷贝/mL 的血浆样本和分娩时的母亲样本中，使用 Sanger 测序聚合酶基因检测 HIV 耐药性。使用 Fisher 精确检验和 Wilcoxon 秩和检验评估与 K65R 出现相关的因素。
在 24 名在 6 个月时感染 HIV-1 的婴儿中，有 6 名（25%）检测到 K65R。K65R 在一半的婴儿中在 6 周时出现，在其余婴儿中在 14 周时出现。在分娩时的母亲或首次阳性时具有阳性基因型的婴儿中，均未发现 K65R 突变。具有 K65R 的婴儿基线 CD4 细胞计数较低（P=0.014），更有可能较早（≤6 周与≥14 周，P=0.007）出现 DRM，并且更有可能具有多药耐药性（P=0.035）。与 K65R 出现相关的最常见突变是 M184V。在停止母乳喂养 3 个月后，K65R 已恢复。
高 K65R 出现率可能表明通过母乳摄入低剂量的拉米夫定可能选择了这种突变。这种突变的存在可能对未来基于 NRTI 的 ART 反应产生负面影响。然而，需要更多的体外研究来确定这种选择的分子机制。
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