Low-abundance drug-resistant HIV-1 variants in antiretroviral drug-naïve individuals: A systematic review of detection methods, prevalence, and clinical impact.

BACKGROUND: The presence of high-abundance drug-resistant HIV-1 jeopardizes the success of antiretroviral therapy (ART). Despite numerous investigations, the clinical impact of low-abundance drug-resistant HIV-1 variants (LA-DRVs) present at levels <15-25% of the virus population in antitretroviral (ARV) drug-naive individuals remains controversial. METHODS: We systematically reviewed 103 studies assessing the prevalence, detection methods, technical and clinical detection cut-offs, and the clinical significance of LA-DRVs in antiretroviral drug-naive adults. RESULTS: In total, 14,919 ARV drug-naive individuals were included. The prevalence of LA-DRVs, i.e., the proportion of individuals harboring LA-DRVs, varied between 0 and 100%. Technical detection cut-offs showed a 4 log range (0.001-10%). 42/103 (40.8%) studies investigating the impact of LA-DRVs on ART; 25 studies (67.6%) included only individuals on first-line NNRTI-based ART regimens. Eleven of those 25 studies (44.0%) reported a significantly association between pre-existing LA-DRVs and risk of virological failure whereas 14/25 (66.0%) did not. CONCLUSIONS: The comparability of the 103 studies is hampered by the high heterogeneity of the studies' designs and the use of different methods to detect LA-DRVs. Thus, evaluating the clinical impact of LA-DRVs on first-line ART remains challenging. We, the WHO HIVResNet working group, defined central areas of future investigations to guide further efforts to implement ultrasensitive resistance testing in routine settings.