Department of Medicine.
Department of Medical Microbiology, College of Health Sciences, University of Zimbabwe.
AIDS. 2019 Sep 1;33(11):1729-1737. doi: 10.1097/QAD.0000000000002284.
The integrase strand inhibitor dolutegravir (DTG) combined with tenofovir and lamivudine (TLD) is a single tablet regimen recommended for 1st, 2nd and 3rd-line public health antiretroviral therapy (ART). We determined drug resistance mutations (DRMs) and evaluated the predictive efficacy of a TLD containing regimen for viremic adolescents and young adults in Harare, Zimbabwe.
We sequenced plasma viral RNA from HIV-1-infected adolescents and young adults on 1st and 2nd-line ART with confirmed virologic failure (viral load >1000 copies/ml) and calculated total genotypic susceptibility scores to current 2nd, 3rd line and DTG regimens.
A total of 160 participants were genotyped; 112 (70%) on 1st line and 48 (30%) on 2nd line, median (interquartile range) age 18 (15-19) and duration of ART (interquartile range) was 6 (4-8) years. Major DRMs were present in 94 and 67% of 1st and 2nd-line failures, respectively (P < 0.001). Dual class resistance to nucleotide reverse transcriptase inhibitors and nonnucleotide reverse transcriptase inhibitors was detected in 96 (60%) of 1st-line failures; protease inhibitor DRMs were detected in a minority (10%) of 2nd-line failures. A total genotypic susceptibility score of 2 or less may risk protease inhibitor or DTG monotherapy in 11 and 42% of 1st-line failures switching to 2nd-line protease inhibitor and TLD respectively.
Among adolescents and young adults, current protease inhibitor-based 2nd-line therapies are poorly tolerated, more expensive and adherence is poor. In 1st-line failure, implementation of TLD for many adolescents and young adults on long-term ART may require additional active drug(s). Drug resistance surveillance and susceptibility scores may inform strategies for the implementation of TLD.
整合酶抑制剂多替拉韦（DTG）联合替诺福韦和拉米夫定（TLD）是一种单一片剂方案，推荐用于一线、二线和三线公共卫生抗逆转录病毒治疗（ART）。我们确定了耐药突变（DRMs），并评估了 TLD 方案在津巴布韦哈拉雷接受病毒血症的青少年和年轻成年人中的预测疗效。
我们对在一线和二线 ART 中治疗失败（病毒载量>1000 拷贝/ml）的 HIV-1 感染的青少年和年轻成年人的血浆病毒 RNA 进行了测序，并计算了当前二线、三线和 DTG 方案的总基因型敏感性评分。
共对 160 名参与者进行了基因分型；112 名（70%）在一线，48 名（30%）在二线，中位（四分位间距）年龄为 18（15-19），ART 时间（四分位间距）为 6（4-8）年。一线和二线失败者中分别有 94%和 67%存在主要耐药突变（P<0.001）。核苷酸逆转录酶抑制剂和非核苷酸逆转录酶抑制剂双重耐药在一线失败者中占 96%（60%）；少数（10%）二线失败者检测到蛋白酶抑制剂耐药突变。在转换为二线蛋白酶抑制剂和 TLD 的一线失败者中，有 11%和 42%的总基因型敏感性评分为 2 或更低，可能面临蛋白酶抑制剂或 DTG 单药治疗的风险。
在青少年和年轻成年人中，目前基于蛋白酶抑制剂的二线治疗方案耐受性差、费用更高，且依从性差。在一线失败的情况下，许多接受长期 ART 治疗的青少年和年轻成年人实施 TLD 可能需要额外的活性药物。耐药监测和敏感性评分可能为 TLD 的实施提供策略。
