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Objective: We sought to evaluate the utility of a point-of-care (POC) urine tenofovir (TFV) assay, developed to objectively assess adherence, to predict HIV drug resistance (HIVDR) in people failing first-line antiretroviral therapy (ART)., Design: We retrospectively analyzed TFV levels as a biomarker of adherence in urine specimens collected during a clinical trial that enrolled adults with virologic failure on first-line ART in Uganda and South Africa., Methods: Urine specimens were analyzed from participants on TFV-containing regimens who had a viral load >1000 copies/ml and paired genotypic resistance test (GRT) results. We assessed recent ART TFV adherence with a qualitative POC lateral flow urine assay with a cut-off value of 1500 ng/ml. We then calculated performance characteristics of the POC urine TFV assay to predict HIVDR, defined as intermediate or high-level resistance to any component of the current ART regimen., Results: Urine specimens with paired plasma GRT results were available from 283 participants. The most common ART regimen during study conduct was emtricitabine, tenofovir disoproxil fumarate, and efavirenz. The overall prevalence of HIVDR was 86% ( n = 243/283). Of those with TFV detected on the POC assay, 91% ( n  = 204/224) had HIVDR, vs. only 66% ( n  = 39/59) among those with no TFV detected ( P- value < 0.001). Positive and negative predictive values of the assay to predict HIVDR were 91% and 34%, respectively., Conclusions: In populations with a high prevalence of HIVDR, the POC urine TFV assay can provide a low-cost, rapid method to guide requirements for confirmatory resistance testing and inform the need for regimen change., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Prolonged virologic failure on 2nd-line protease inhibitor (PI)-based antiretroviral therapy (ART) without emergence of major protease mutations is well recognized and provides an opportunity to study within-host evolution in long-term viremic individuals. Using next-generation sequencing and in silico haplotype reconstruction, we analyzed whole-genome sequences from longitudinal plasma samples of eight chronically infected HIV-1-positive individuals failing 2nd-line regimens from the French National Agency for AIDS and Viral Hepatitis Research (ANRS) 12249 Treatment as Prevention (TasP) trial. On nonsuppressive ART, there were large fluctuations in synonymous and nonsynonymous variant frequencies despite stable viremia. Reconstructed haplotypes provided evidence for selective sweeps during periods of partial adherence, and viral haplotype competition, during periods of low drug exposure. Drug resistance mutations in reverse transcriptase (RT) were used as markers of viral haplotypes in the reservoir, and their distribution over time indicated recombination. We independently observed linkage disequilibrium decay, indicative of recombination. These data highlight dramatic changes in virus population structure that occur during stable viremia under nonsuppressive ART. IMPORTANCE HIV-1 infections are most commonly initiated with a single founder virus and are characterized by extensive inter- and intraparticipant genetic diversity. However, existing literature on HIV-1 intrahost population dynamics is largely limited to untreated infections, predominantly in subtype B-infected individuals. The manuscript characterizes viral population dynamics in long-term viremic treatment-experienced individuals, which has not been previously characterized. These data are particularly relevant for understanding HIV dynamics but can also be applied to other RNA viruses. With this unique data set we propose that the virus is highly unstable, and we have found compelling evidence of HIV-1 within-host viral diversification, recombination, and haplotype competition during nonsuppressive ART.

Female children and adults typically generate more efficacious immune responses to vaccines and infections than age-matched males, but also suffer greater immunopathology and autoimmune disease. We here describe, in a cohort of > 170 in utero HIV-infected infants from KwaZulu-Natal, South Africa, fetal immune sex differences resulting in a 1.5-2-fold increased female susceptibility to intrauterine HIV infection. Viruses transmitted to females have lower replicative capacity (p = 0.0005) and are more type I interferon-resistant (p = 0.007) than those transmitted to males. Cord blood cells from females of HIV-uninfected sex-discordant twins are more activated (p = 0.01) and more susceptible to HIV infection in vitro (p = 0.03). Sex differences in outcome include superior maintenance of aviraemia among males (p = 0.007) that is not explained by differential antiretroviral therapy adherence. These data demonstrate sex-specific innate immune selection of HIV associated with increased female susceptibility to in utero infection and enhanced functional cure potential among infected males.