Field performance and cost-effectiveness of a point-of-care triage test for HIV virological failure in Southern Africa.

INTRODUCTION: Antiretroviral therapy (ART) monitoring using viral load (VL) testing is challenging in high-burden, limited-resources settings. Chemokine IP-10 (interferon gamma-induced protein 10) strongly correlates with human immunodeficiency virus (HIV) VL. Its determination could serve to predict virological failure (VF) and to triage patients requiring VL testing. We assessed the field performance of a semi-quantitative IP-10 lateral flow assay (LFA) for VF screening in South Africa, and the cost-effectiveness of its implementation in Mozambique. METHODS: A cross-sectional study was conducted between June and December 2021 in three primary health clinics in the Western Cape. Finger prick capillary blood was collected from adults on ART for ≥1 year for direct application onto the IP-10 LFA (index test) and compared with a plasma VL result ≤1 month prior (reference test). We estimated the area under the receiver operating characteristic curves (AUC), sensitivity and specificity, to evaluate IP-10 LFA prediction of VF (VL>1000 copies/ml). A decision tree model was used to investigate the cost-effectiveness of integrating IP-10 LFA combined with VL testing into the current Mozambican ART monitoring strategy. Averted disability-adjusted life years (DALYs) and HIV acquisitions, and incremental cost-effectiveness ratios were estimated. RESULTS: Among 209 participants (median age 38 years and 84% female), 18% had VF. Median IP-10 LFA values were higher among individuals with VF compared to those without (24.0 vs. 14.6; p<0.001). The IP-10 LFA predicted VF with an AUC = 0.76 (95% confidence interval (CI) 0.67-0.85), 91.9% sensitivity (95% CI 78.1-98.3) and 35.1% specificity (95% CI 28.0-42.7). Integrating the IP-10 LFA in a setting with 20% VF prevalence and 61% VL testing coverage could save 13.0% of costs and avert 14.9% of DALYs and 55.7% new HIV acquisitions. Furthermore, its introduction was estimated to reduce the total number of routine VL tests required for ART monitoring by up to 68%. CONCLUSIONS: The IP-10 LFA is an effective VF triage test for routine ART monitoring. Combining a highly sensitive, low-cost IP-10 LFA-based screening with targeted VL confirmatory testing could result in significant healthcare quality improvements and cost savings in settings with limited access to VL testing.

Antiretroviral Drug Detection in a Community-Randomized Trial of Universal HIV Testing and Treatment: HPTN 071 (PopART).

Background: Antiretroviral therapy (ART) reduces human immunodeficiency virus (HIV) transmission risk. The primary aim of this study was to evaluate ART uptake in a trial in Zambia and South Africa that implemented a community-wide universal testing and treatment package to reduce HIV incidence. Methods: Study communities were randomized to 3 arms: A, combination-prevention intervention with universal ART; B, combination-prevention intervention with ART according to local guidelines; and C, standard of care. Samples were collected from people with HIV (PWH) during a survey visit conducted 2 years after study implementation: these samples were tested for 22 antiretroviral (ARV) drugs. Antiretroviral therapy uptake was defined as detection of ≥1 ARV drug. Resistance was evaluated in 612 randomly selected viremic participants. A 2-stage, cluster-based approach was used to assess the impact of the study intervention on ART uptake. Results: Antiretroviral drugs were detected in 4419 of 6207 (71%) samples (Arm A, 73%; Arm B, 70%; Arm C, 60%); 4140 (94%) of samples with ARV drugs had viral loads <400 copies/mL. Drug resistance was observed in 237 of 612 (39%) viremic participants (95 of 102 [93%] with ARV drugs; 142 of 510 [28%] without drugs). Antiretroviral therapy uptake was associated with older age, female sex, enrollment year, seroconverter status, and self-reported ART (all P < .001). The adjusted risk ratio for ART uptake was similar for Arm A versus C (1.21; 95% confidence interval [CI], .94-1.54; P = .12) and Arm B versus C (1.14; 95% CI, .89-1.46; P = .26). Conclusions: At the 2-year survey, 71% of PWH were on ART and 94% of those participants were virally suppressed. Universal testing and treatment was not significantly associated with increased ART uptake in this cohort.

HIV drug resistance in a community-randomized trial of universal testing and treatment: HPTN 071 (PopART).

INTRODUCTION: Universal HIV testing and treatment (UTT) has individual and public health benefits. HPTN 071 (PopART), a community-randomized trial in Zambia and South Africa, demonstrated that UTT decreased HIV incidence. This endpoint was assessed in a cohort of >48,000 randomly selected adults in the study communities. We evaluated the impact of UTT on HIV drug resistance in this cohort and compared other resistance-related outcomes in participants with recent versus non-recent HIV infection. METHODS: Two years after the start of HPTN 071 (2016-2017), 6259 participants were HIV positive and 1902 were viremic (viral load >400 copies/ml). HIV genotyping and antiretroviral (ARV) drug testing were performed for viremic participants in three groups: seroconverters (infected <1 year), non-seroconverters (infected >1 year, random subset) and participants with unknown duration of infection (random subset). A two-stage cluster-based approach was used to assess the impact of the study intervention on drug resistance. Treatment failure was defined as being viremic with ARV drugs detected. Participants were classified as ARV naïve based on self-report and ARV drug testing. RESULTS: Genotyping results were obtained for 758 participants (143 seroconverters; 534 non-seroconverters; and 81 unknown duration of infection). The estimated prevalence of resistance in the study communities was 37% for all viremic persons and 11% for all HIV-positive persons. There was no association between UTT and drug resistance. Resistance was detected in 14.0% of seroconverters and 40.8% of non-seroconverters (non-nucleoside reverse transcriptase inhibitor resistance: 14.0% and 39.9%; nucleoside/nucleotide reverse transcriptase inhibitor resistance: 0.7% and 15.5%; protease inhibitor resistance: 0% and 1.9%; multi-class resistance: 0.7% and 16.1%, respectively). ARV drugs were detected in 2/139 (1.4%) of seroconverters and 94/534 (17.6%) of non-seroconverters tested. These participants were classified as failing ART; 88 (93.6%) of the non-seroconverters failing ART had resistance. Mutations used for surveillance of transmitted drug resistance were detected in 10.5% of seroconverters and 15.1% of non-seroconverters who were ARV naive. CONCLUSIONS: UTT was not associated with an increase in drug resistance in this cohort. Higher rates of drug resistance and multi-class resistance were observed in non-seroconverters compared to seroconverters.

Understanding low sensitivity of community-based HIV rapid testing: experiences from the HPTN 071 (PopART) trial in Zambia and South Africa.

INTRODUCTION: Population-wide HIV testing services (HTS) must be delivered in order to achieve universal antiretroviral treatment (ART) coverage. To accurately deliver HTS at such scale, non-facility-based HIV point-of-care testing (HIV-POCT) is necessary but requires rigorous quality assurance (QA). This study assessed the performance of community-wide HTS in Zambia and South Africa (SA) as part of the HPTN 071 (PopART) study and explores the impact of quality improvement interventions on HTS performance. METHODS: Between 2014 and 2016, HIV-POCT was undertaken within households both as part of the randomly selected HPTN 071 research cohort (Population Cohort [PC]) and as part of the intervention provided by community HIV-care providers. HIV-POCT followed national algorithms in both countries. Consenting PC participants provided a venous blood sample in addition to being offered HIV-POCT. We compared results obtained in the PC using a laboratory-based gold standard (GS) testing algorithm and HIV-POCT. Comprehensive QA mechanisms were put in place to support the community-wide testing. Participants who were identified as having a false negative or false positive HIV rapid test were revisited and offered retesting. RESULTS: We initially observed poor sensitivity (45-54%, 95% confidence interval [CI] 31-69) of HIV-POCT in the PC in SA compared to sensitivity in Zambia for the same time period of 95.8% (95% CI 93-98). In both countries, specificity of HIV-POCT was >98%. With enhanced QA interventions and adoption of the same HIV-POCT algorithm, sensitivity in SA improved to a similar level as in Zambia. CONCLUSIONS: This is one of the first reports of HIV-POCT performance during wide-scale delivery of HTS compared to a GS laboratory algorithm. HIV-POCT in a real-world setting had a lower sensitivity than anticipated. Appropriate choice of HIV-POCT algorithms, intensive training and supervision, and robust QA mechanisms are necessary to optimize HIV-POCT test performance when testing is delivered at a community level. HIV-POCT in clients who did not disclose that they were on ART may have contributed to false negative HIV-POCT results and should be the topic of future research.