Alpert Medical School, Brown University, Providence, RI 02912, USA.
Academic Model Providing Access to Healthcare (AMPATH), Eldoret 30100, Kenya.
Viruses. 2023 Jun 22;15(7):1416. doi: 10.3390/v15071416.
Drug resistance remains a global challenge in children and adolescents living with HIV (CALWH). Characterizing resistance evolution, specifically using next generation sequencing (NGS) can potentially inform care, but remains understudied, particularly in antiretroviral therapy (ART)-experienced CALWH in resource-limited settings. We conducted reverse-transcriptase NGS and investigated short-and long-term resistance evolution and its predicted impact in a well-characterized cohort of Kenyan CALWH failing 1st-line ART and followed for up to ~8 years. Drug resistance mutation (DRM) evolution types were determined by NGS frequency changes over time, defined as evolving (up-trending and crossing the 20% NGS threshold), reverting (down-trending and crossing the 20% threshold) or other. Exploratory analyses assessed potential impacts of minority resistance variants on evolution. Evolution was detected in 93% of 42 participants, including 91% of 22 with short-term follow-up, 100% of 7 with long-term follow-up without regimen change, and 95% of 19 with long-term follow-up with regimen change. Evolving DRMs were identified in 60% and minority resistance variants evolved in 17%, with exploratory analysis suggesting greater rate of evolution of minority resistance variants under drug selection pressure and higher predicted drug resistance scores in the presence of minority DRMs. Despite high-level pre-existing resistance, NGS-based longitudinal follow-up of this small but unique cohort of Kenyan CALWH demonstrated continued DRM evolution, at times including low-level DRMs detected only by NGS, with predicted impact on care. NGS can inform better understanding of DRM evolution and dynamics and possibly improve care. The clinical significance of these findings should be further evaluated.
耐药性仍然是儿童和青少年艾滋病毒感染者（CALWH）面临的全球性挑战。通过下一代测序（NGS）来描述耐药性的演变，尤其是耐药性的演变，有可能为治疗提供信息，但在资源有限的环境中，对接受过抗逆转录病毒治疗（ART）的 CALWH 患者，这方面的研究仍然很少。我们对逆转录酶 NGS 进行了研究，并对肯尼亚表现出一线抗逆转录病毒治疗失败的特征明确的 CALWH 队列中进行了短期和长期耐药性演变及其预测影响的研究，这些患者的随访时间长达约 8 年。耐药突变（DRM）的演变类型是通过随时间变化的 NGS 频率来确定的，定义为正在演变（呈上升趋势并超过 20% NGS 阈值）、逆转（呈下降趋势并超过 20%阈值）或其他。探索性分析评估了少数耐药变异体对进化的潜在影响。在 42 名参与者中，93%的参与者检测到了耐药性的演变，包括 91%的短期随访者、100%的无治疗方案改变的长期随访者、95%的长期随访者中有治疗方案改变。60%的参与者检测到了正在演变的 DRMs，17%的参与者检测到了少数耐药变异体，探索性分析表明，在药物选择压力下，少数耐药变异体的进化速度更快，而且在存在少数 DRMs 的情况下，耐药预测评分更高。尽管存在高水平的预先存在的耐药性，但对肯尼亚这个小型但独特的 CALWH 队列的基于 NGS 的纵向随访表明，DRM 仍在不断演变，有时包括仅通过 NGS 检测到的低水平 DRMs，这对治疗有预测影响。NGS 可以帮助更好地了解 DRM 的演变和动态，并可能改善治疗。这些发现的临床意义应进一步评估。
