Antiretroviral Drug Use in a Cross-Sectional Population Survey in Africa: NIMH Project Accept (HPTN 043).

BACKGROUND: Antiretroviral (ARV) drug treatment benefits the treated individual and can prevent HIV transmission. We assessed ARV drug use in a community-randomized trial that evaluated the impact of behavioral interventions on HIV incidence. METHODS: Samples were collected in a cross-sectional survey after a 3-year intervention period. ARV drug testing was performed using samples from HIV-infected adults at 4 study sites (Zimbabwe; Tanzania; KwaZulu-Natal and Soweto, South Africa; survey period 2009-2011) using an assay that detects 20 ARV drugs (6 nucleoside/nucleotide reverse transcriptase inhibitors, 3 nonnucleoside reverse transcriptase inhibitors, and 9 protease inhibitors; maraviroc; raltegravir). RESULTS: ARV drugs were detected in 2011 (27.4%) of 7347 samples; 88.1% had 1 nonnucleoside reverse transcriptase inhibitors ± 1-2 nucleoside/nucleotide reverse transcriptase inhibitors. ARV drug detection was associated with sex (women>men), pregnancy, older age (>24 years), and study site (P < 0.0001 for all 4 variables). ARV drugs were also more frequently detected in adults who were widowed (P = 0.006) or unemployed (P = 0.02). ARV drug use was more frequent in intervention versus control communities early in the survey (P = 0.01), with a significant increase in control (P = 0.004) but not in intervention communities during the survey period. In KwaZulu-Natal, a 1% increase in ARV drug use was associated with a 0.14% absolute decrease in HIV incidence (P = 0.018). CONCLUSIONS: This study used an objective, biomedical approach to assess ARV drug use on a population level. This analysis identified factors associated with ARV drug use and provided information on ARV drug use over time. ARV drug use was associated with lower HIV incidence at 1 study site.

Determination of HIV Status in African Adults With Discordant HIV Rapid Tests.

BACKGROUND: In resource-limited settings, HIV infection is often diagnosed using 2 rapid tests. If the results are discordant, a third tie-breaker test is often used to determine HIV status. This study characterized samples with discordant rapid tests and compared different testing strategies for determining HIV status in these cases. METHODS: Samples were previously collected from 173 African adults in a population-based survey who had discordant rapid test results. Samples were classified as HIV positive or HIV negative using a rigorous testing algorithm that included two fourth-generation tests, a discriminatory test, and 2 HIV RNA tests. Tie-breaker tests were evaluated, including rapid tests (1 performed in-country), a third-generation enzyme immunoassay, and two fourth-generation tests. Selected samples were further characterized using additional assays. RESULTS: Twenty-nine samples (16.8%) were classified as HIV positive and 24 of those samples (82.8%) had undetectable HIV RNA. Antiretroviral drugs were detected in 1 sample. Sensitivity was 8.3%-43% for the rapid tests; 24.1% for the third-generation enzyme immunoassay; 95.8% and 96.6% for the fourth-generation tests. Specificity was lower for the fourth-generation tests than the other tests. Accuracy ranged from 79.5% to 91.3%. CONCLUSIONS: In this population-based survey, most HIV-infected adults with discordant rapid tests were virally suppressed without antiretroviral drugs. Use of individual assays as tie-breaker tests was not a reliable method for determining HIV status in these individuals. More extensive testing algorithms that use a fourth-generation screening test with a discriminatory test and HIV RNA test are preferable for determining HIV status in these cases.

Performance of the fourth-generation Bio-Rad GS HIV Combo Ag/Ab enzyme immunoassay for diagnosis of HIV infection in Southern Africa.

BACKGROUND: Fourth-generation HIV assays detect both antigen and antibody, facilitating detection of acute/early HIV infection. The Bio-Rad GS HIV Combo Ag/Ab assay (Bio-Rad Combo) is an enzyme immunoassay that simultaneously detects HIV p24 antigen and antibodies to HIV-1 and HIV-2 in serum or plasma. OBJECTIVE: To evaluate the performance of the Bio-Rad Combo assay for detection of HIV infection in adults from Southern Africa. STUDY DESIGN: Samples were obtained from adults in Soweto and Vulindlela, South Africa and Dar es Salaam, Tanzania (300 HIV-positive samples; 300 HIV-negative samples; 12 samples from individuals previously classified as having acute/early HIV infection). The samples were tested with the Bio-Rad Combo assay. Additional testing was performed to characterize the 12 acute/early samples. RESULTS: All 300 HIV-positive samples were reactive using the Bio-Rad Combo assay; false positive test results were obtained for 10 (3.3%) of the HIV-negative samples (sensitivity: 100%, 95% confidence interval [CI]: 98.8-100%); specificity: 96.7%, 95% CI: 94.0-98.4%). The assay detected 10 of the 12 infections classified as acute/early. The two infections that were not detected had viral loads<400 copies/mL; one of those samples contained antiretroviral drugs consistent with antiretroviral therapy. CONCLUSIONS: The Bio-Rad Combo assay correctly classified the majority of study specimens. The specificity reported here may be higher than that seen in other settings, since HIV-negative samples were pre-screened using a different fourth-generation test. The assay also had high sensitivity for detection of acute/early infection. False-negative test results may be obtained in individuals who are virally suppressed.

Effect of community-based voluntary counselling and testing on HIV incidence and social and behavioural outcomes (NIMH Project Accept; HPTN 043): a cluster-randomised trial.

BACKGROUND: Although several interventions have shown reduced HIV incidence in clinical trials, the community-level effect of effective interventions on the epidemic when scaled up is unknown. We investigated whether a multicomponent, multilevel social and behavioural prevention strategy could reduce HIV incidence, increase HIV testing, reduce HIV risk behaviour, and change social and behavioural norms. METHODS: For this phase 3 cluster-randomised controlled trial, 34 communities in four sites in Africa and 14 communities in Thailand were randomly allocated in matched pairs to receive 36 months of community-based voluntary counselling and testing for HIV (intervention group) or standard counselling and testing alone (control group) between January, 2001, and December, 2011. The intervention was designed to make testing more accessible in communities, engage communities through outreach, and provide support services after testing. Randomisation was done by a computer-generated code and was not masked. Data were collected at baseline (n=14 567) and after intervention (n=56.683) by cross-sectional random surveys of community residents aged 18-32 years. The primary outcome was HIV incidence and was estimated with a cross-sectional multi-assay algorithm and antiretroviral drug screening assay. Thailand was excluded from incidence analyses because of low HIV prevalence. This trial is registered at ClinicalTrials.gov, number NCT00203749. FINDINGS: The estimated incidence of HIV in the intervention group was 1.52% versus 1.81% in the control group with an estimated reduction in HIV incidence of 13.9% (relative risk [RR] 0.86, 95% CI 0.73-1.02; p=0.082). HIV incidence was significantly reduced in women older than 24 years (RR=0.70, 0.54-0.90; p=0.0085), but not in other age or sex subgroups. Community-based voluntary counselling and testing increased testing rates by 25% overall (12-39; p=0.0003), by 45% (25-69; p<0·0001) in men and 15% (3-28; p=0.013) in women. No overall effect on sexual risk behaviour was recorded. Social norms regarding HIV testing were improved by 6% (95% CI 3-9) in communities in the intervention group. INTERPRETATION: These results are sufficiently robust, especially when taking into consideration the combined results of modest reductions in HIV incidence combined with increases in HIV testing and reductions in HIV risk behaviour, to recommend the Project Accept approach as an integral part of all interventions (including treatment as prevention) to reduce HIV transmission at the community level. FUNDING: US National Institute of Mental Health, the Division of AIDS of the US National Institute of Allergy and Infectious Diseases, and the Office of AIDS Research of the US National Institutes of Health.

Mixture models for calibrating the BED for HIV incidence testing.

A number of antibody biomarkers have been developed to distinguish between recent and established Human Immunodeficiency Virus (HIV) infection and used for HIV incidence estimation from cross-sectional specimens. In general, a cut-off value is specified, and estimates of the following parameters are needed: (i) the mean time interval .w/ between seroconversion and reaching that cut-off; (ii) the probability of correctly identifying individuals who became infected in the last w years (sensitivity); and (iii) the probability of correctly identifying individuals who have been infected for more than w years (specificity). We develop two statistical methods to study the distribution of a biomarker and derive a formula for estimating HIV incidence from a cross-sectional survey. Both methods allow handling interval censored data and basically consist of using a generalized mixture model to model the growth of the biomarker as a function of time since infection. The first uses data from all followed-up individuals and allows incidence estimation in the cohort, whereas the second only uses data from seroconverters. We illustrate our methods using repeated measures of the IgG capture BED enzyme immunoassay. Estimates of calibration parameters, that is, mean window period, mean recency period, sensitivity, and specificities obtained from both models are comparable. The formula derived for incidence estimation gives the maximum likelihood estimate of incidence which, for a given window period, depends only on sensitivity and specificity. The optimal choice of the window period is discussed. Numerical simulations suggest that data from seroconverters can provide reasonable estimates of the calibration parameters.

Development of methods for cross-sectional HIV incidence estimation in a large, community randomized trial.

BACKGROUND: Accurate methods of HIV incidence determination are critically needed to monitor the epidemic and determine the population level impact of prevention trials. One such trial, Project Accept, a Phase III, community-randomized trial, evaluated the impact of enhanced, community-based voluntary counseling and testing on population-level HIV incidence. The primary endpoint of the trial was based on a single, cross-sectional, post-intervention HIV incidence assessment. METHODS AND FINDINGS: Test performance of HIV incidence determination was evaluated for 403 multi-assay algorithms [MAAs] that included the BED capture immunoassay [BED-CEIA] alone, an avidity assay alone, and combinations of these assays at different cutoff values with and without CD4 and viral load testing on samples from seven African cohorts (5,325 samples from 3,436 individuals with known duration of HIV infection [1 month to >10 years]). The mean window period (average time individuals appear positive for a given algorithm) and performance in estimating an incidence estimate (in terms of bias and variance) of these MAAs were evaluated in three simulated epidemic scenarios (stable, emerging and waning). The power of different test methods to detect a 35% reduction in incidence in the matched communities of Project Accept was also assessed. A MAA was identified that included BED-CEIA, the avidity assay, CD4 cell count, and viral load that had a window period of 259 days, accurately estimated HIV incidence in all three epidemic settings and provided sufficient power to detect an intervention effect in Project Accept. CONCLUSIONS: In a Southern African setting, HIV incidence estimates and intervention effects can be accurately estimated from cross-sectional surveys using a MAA. The improved accuracy in cross-sectional incidence testing that a MAA provides is a powerful tool for HIV surveillance and program evaluation.

Estimation of HIV incidence in a large, community-based, randomized clinical trial: NIMH project accept (HIV Prevention Trials Network 043).

BACKGROUND: National Institute of Mental Health Project Accept (HIV Prevention Trials Network [HPTN] 043) is a large, Phase III, community-randomized, HIV prevention trial conducted in 48 matched communities in Africa and Thailand. The study intervention included enhanced community-based voluntary counseling and testing. The primary endpoint was HIV incidence, assessed in a single, cross-sectional, post-intervention survey of >50,000 participants. METHODS: HIV rapid tests were performed in-country. HIV status was confirmed at a central laboratory in the United States. HIV incidence was estimated using a multi-assay algorithm (MAA) that included the BED capture immunoassay, an avidity assay, CD4 cell count, and HIV viral load. RESULTS: Data from Thailand was not used in the endpoint analysis because HIV prevalence was low. Overall, 7,361 HIV infections were identified (4 acute, 3 early, and 7,354 established infections). Samples from established infections were analyzed using the MAA; 467 MAA positive samples were identified; 29 of those samples were excluded because they contained antiretroviral drugs. HIV prevalence was 16.5% (range at study sites: 5.93% to 30.8%). HIV incidence was 1.60% (range at study sites: 0.78% to 3.90%). CONCLUSIONS: In this community-randomized trial, a MAA was used to estimate HIV incidence in a single, cross-sectional post-intervention survey. Results from this analysis were subsequently used to compare HIV incidence in the control and intervention communities. TRIAL REGISTRATION: ClinicalTrials.gov NCT00203749.

Mobile VCT: reaching men and young people in urban and rural South African pilot studies (NIMH Project Accept, HPTN 043).

Mounting evidence exists that mobile voluntary counselling and testing (VCT) is able to extend coverage to new localities and populations. We describe two feasibility and acceptability pilot studies conducted in rural and urban South Africa in preparation for the larger NIMH Project Accept HIV prevention trial. A total of 1,015 individuals participated in the pilot studies. Participants in rural Vulindlela were younger (median 22 years) compared to urban Soweto (p < 0.001). Young people were more likely to be first time testers in both sites (p = 0.01 in Vulindlela, p < 0.001 in Soweto), with significantly more men likely to be first time testers than women (p = 0.01 in Vulindlela, p < 0.001 in Soweto). User satisfaction with mobile VCT was extremely high in both sites. Our study shows that providing mobile, high-quality and easy to access services in a high prevalence context is a feasible way to engage youth, men and more rural populations in HIV counselling and testing.

HIV surveillance in a large, community-based study: results from the pilot study of Project Accept (HIV Prevention Trials Network 043).

BACKGROUND: Project Accept is a community randomized, controlled trial to evaluate the efficacy of community mobilization, mobile testing, same-day results, and post-test support for the prevention of HIV infection in Thailand, Tanzania, Zimbabwe, and South Africa. We evaluated the accuracy of in-country HIV rapid testing and determined HIV prevalence in the Project Accept pilot study. METHODS: Two HIV rapid tests were performed in parallel in local laboratories. If the first two rapid tests were discordant (one reactive, one non-reactive), a third HIV rapid test or enzyme immunoassay was performed. Samples were designated HIV NEG if the first two tests were non-reactive, HIV DISC if the first two tests were discordant, and HIV POS if the first two tests were reactive. Samples were re-analyzed in the United States using a panel of laboratory tests. RESULTS: HIV infection status was correctly determined based on-in country testing for 2,236 (99.5%) of 2,247 participants [7 (0.37%) of 1,907 HIV NEG samples were HIV-positive; 2 (0.63%) of 317 HIV POS samples were HIV-negative; 2 (8.3%) of 24 HIV DISC samples were incorrectly identified as HIV-positive based on the in-country tie-breaker test]. HIV prevalence was: Thailand: 0.6%, Tanzania: 5.0%, Zimbabwe 14.7%, Soweto South Africa: 19.4%, Vulindlela, South Africa: 24.4%, (overall prevalence: 14.4%). CONCLUSIONS: In-country testing based on two HIV rapid tests correctly identified the HIV infection status for 99.5% of study participants; most participants with discordant HIV rapid tests were not infected. HIV prevalence varied considerably across the study sites (range: 0.6% to 24.4%). TRIAL REGISTRATION: ClinicalTrials.gov registry number NCT00203749.

Recent HIV type 1 infection among participants in a same-day mobile testing pilot study in Zimbabwe.

We estimated HIV-1 incidence and characterized risk factors associated with recent infection among participants of a mobile HIV voluntary counseling and testing (VCT) pilot program in two communities in Zimbabwe (N = 1096). HIV-1 infection was diagnosed using a parallel rapid testing algorithm. Recent HIV-1 infections were characterized using the BED immunoglobulin G capture enzyme immunoassay (BED-CEIA). HIV prevalence was 28.9% overall and nearly twice as high in women compared to men (39.5% vs. 21.4%, p < 0.001). HIV-1 incidence was 1.91% and was comparable between men and women (1.99% vs.1.88%; p = 0.626). Although not significant, the proportion of recent infections among all infections was highest among persons ages 25 to 34 years old (10.5%) for both men (11.9%) and women (9.2%). Persons recently infected compared to those with long-term infections were more likely to report STD symptoms (33% vs. 13%; OR = 3.2; p = 0.075) and prior STD treatment (13% vs. 6%; OR = 3.4; p = 0.187) in the previous 6 months. There were no associations found between recent versus long-term HIV infection status and perceived risk or expectation of negative test results. Recent HIV-1 infection detection among mobile VCT participants is a valuable measure for tracking the spread of the epidemic among persons who might otherwise not have access to HIV testing due to practical and logistical barriers. Mobile VCT presents opportunities to expand HIV testing services and evaluate at-risk populations within community settings. Given the challenges of longitudinal cohort studies, recent infection may be a practical endpoint for community-based prevention intervention trials employing mobile testing.

Can HIV incidence testing be used for evaluating HIV intervention programs? A reanalysis of the Orange Farm male circumcision trial (ANRS-1265).

BACKGROUND: The objective of this study was to estimate the effect of male circumcision (MC) on HIV acquisition estimated using HIV incidence assays and to compare it to the effect measured by survival analysis. METHODS: We used samples collected during the MC randomized controlled trial (ANRS-1265) conducted in Orange Farm (South Africa) among men aged 18 to 24. Among the 2946 samples collected at the last follow-up visit, 194 HIV-positive samples were tested using two incidence assays: Calypte HIV-EIA (BED) and an avidity assay based on the BioRad HIV1/2+O EIA (AI). The results of the assays were also combined (BED-AI). The samples included the 124 participants (4.2% of total) who were HIV-positive at randomization. The protective effect was calculated as one minus the intention-to-treat incidence rate ratio in an uncorrected manner and with correction for misclassifications, with simple theoretical formulae. Theoretical calculations showed that the uncorrected intention-to-treat effect was approximately independent of the value of the incidence assay window period and was the ratio of the number tested recent seroconverters divided by the number tested HIV-negative between the randomization groups. We used cut-off values ranging from 0.325 to 2.27 for BED, 31.6 to 96 for AI and 0.325-31.6 to 1.89-96 for BED-AI. Effects were corrected for long-term specificity using a previously published formula. 95% Confidence intervals (CI) were estimated by bootstrap resampling. RESULTS: With the highest cut-off values, the uncorrected protective effects evaluated by BED, AI and BED-AI were 50% (95%CI: 27% to 66%), 50% (21% to 69%) and 63% (36% to 81%). The corrections for misclassifications were lower than 50% of the number of tested recent. The corrected effects were 53% (30% to 70%), 55% (25% to 77%) and 67% (38% to 86%), slightly higher than the corresponding uncorrected values. These values were consistent with the previously reported protective effect of 60% (34% to 76%) obtained with survival analysis. CONCLUSIONS: HIV incidence assays may be employed to assess the effect of interventions using cross-sectional data.

Refocusing and prioritizing HIV programmes in conflict and post-conflict settings: funding recommendations.

Conflict and post-conflict settings pose specific challenges to HIV prevention and care efforts. Whereas armed conflicts have decreased very considerably in number, the interactions between HIV epidemiology and conflict remain problematic. This review describes factors that affect HIV in conflict and post-conflict settings, identifies challenges to addressing HIV, and presents actionable and measurable programming and funding recommendations that can be implemented immediately. Funding priorities include prevention and care efforts such as the provision and monitoring of universal precautions for HIV infection, health services for sexual violence and antiretroviral therapy. Policy efforts should prioritize enforcing appropriate conduct by peacekeepers and aid workers, interventions targeted at specific phases and contexts of conflicts, supporting the continuity of programmes from emergency to post emergency and reconstruction efforts and simplifying and accelerating funding mechanisms.

Removing barriers to knowing HIV status: same-day mobile HIV testing in Zimbabwe.

OBJECTIVES: We developed a mobile HIV voluntary counseling testing (VCT) strategy. Our aims were (1) to describe those using the services, (2) to assess the acceptability of such services, (3) to assess reasons for not testing previously, and (4) to compare those who used the services with those who did not to determine how to increase acceptability. METHODS: We provided free anonymous mobile VCT using 2 rapid HIV tests in 12 marketplaces in Epworth and Seke, Zimbabwe. Qualitative interviews were conducted to assess motivations for and barriers to testing. A subsample of HIV testers and individuals near testing vans who declined testing (nontesters) completed a questionnaire. RESULTS: A total of 1099 individuals participated in mobile VCT between March 2002 and August 2003. The proportion of participants infected with HIV was 29.2%. Overall, 98.8% of participants elected to receive HIV test results the same day. Reasons for not testing previously were often logistic (eg, inconvenience of hours [25.6%] and location [20.7%] or cost [8%]). Those who used the same-day mobile testing services (testers vs. nontesters) perceived themselves at higher risk for HIV infection (adjusted odds ratio [AOR] = 1.8) but were less likely to have known people with HIV (AOR = 0.49) or where to get tested (AOR = 0.57). CONCLUSIONS: Same-day HIV testing in community settings seems to be acceptable in sub-Saharan Africa. Barriers to HIV testing are often logistic and can be overcome with community-based strategies. These strategies need to be refined to address the needs of those not using mobile testing services.

Heterosexual anal intercourse increases risk of HIV infection among young South African men.

Data from a nationally representative household survey of South African youth aged 15-24 years found that sexually active men reporting anal intercourse were nearly twice as likely to be HIV infected as men reporting only vaginal sex (OR 1.7, 95% CI 1.0-3.0). The associated risk was more pronounced among men aged 15-19 years (OR 4.3, 95% CI 1.5-12.1). The association among women was not significant (OR 1.2, 95% CI 0.7-2.0).