Lessons learned from implementation of four HIV self-testing (HIVST) distribution models in Zambia: applying the Consolidated Framework for Implementation Research to understand impact of contextual factors on implementation.

BACKGROUND: Although Zambia has integrated HIV-self-testing (HIVST) into its Human Immunodeficiency Virus (HIV) regulatory frameworks, few best practices to optimize the use of HIV self-testing to increase testing coverage have been documented. We conducted a prospective case study to understand contextual factors guiding implementation of four HIVST distribution models to inform scale-up in Zambia. METHODS: We used the qualitative case study method to explore user and provider experiences with four HIVST distribution models (two secondary distribution models in Antenatal Care (ANC) and Antiretroviral Therapy (ART) clinics, community-led, and workplace) to understand factors influencing HIVST distribution. Participants were purposefully selected based on their participation in HIVST and on their ability to provide rich contextual experience of the distribution models. Data were collected using observations (n = 31), group discussions (n = 10), and in-depth interviews (n = 77). Data were analyzed using the thematic approach and aligned to the four Consolidated Framework for Implementation Research (CFIR) domains. RESULTS: Implementation of the four distribution models was influenced by an interplay of outer and inner setting factors. Inadequate compensation and incentives for distributors may have contributed to distributor attrition in the community-led and workplace HIVST models. Stockouts, experienced at the start of implementation in the secondary-distribution and community-led distribution models often disrupted distribution. The existence of policy and practices aided integration of HIVST in the workplace. External factors complimented internal factors for successful implementation. For instance, despite distributor attrition leading to excessive workload, distributors often multi-tasked to keep up with demand for kits, even though distribution points were geographically widespread in the workplace, and to a less extent in the community-led models. Use of existing communication platforms such as lunchtime and safety meetings to promote and distribute kits, peers to support distributors, reduction in trips by distributors to replenish stocks, increase in monetary incentives and reorganisation of stakeholder roles proved to be good adaptations. CONCLUSION: HIVST distribution was influenced by a combination of contextual factors in variable ways. Understanding how the factors interacted in real world settings informed adaptations to implementation devised to minimize disruptions to distribution.

Assessment of a screening tool to aid home-based identification of adolescents (aged 10-14) living with HIV in Zambia and South Africa: HPTN 071 (PopART) study.

INTRODUCTION: The HPTN071 (PopART) for Youth (P-ART-Y) study evaluated the acceptability and uptake of a community-level combination HIV prevention package including universal testing and treatment (UTT) among young people in Zambia and South Africa. We determined whether a four-question primary care level screening tool, validated for use in clinical settings, could enhance community (door-to-door) identification of undiagnosed HIV-positive younger adolescents (aged 10-14) who are frequently left out of HIV interventions. METHOD: Community HIV-care Providers (CHiPs) contacted and consented adolescents in their homes and offered them participation in the PopART intervention. CHiPs used a four question-screening tool, which included: history of hospital admission; recurring skin problems; poor health in last 3 months; and death of at least one parent. A "yes" response to one or more questions was classified as being "at risk" of being HIV-positive. Rapid HIV tests were offered to all children. Data were captured through an electronic data capture device from August 2016 to December 2017. The sensitivity, specificity, positive predictive value and negative predictive value were estimated for the screening tool, using the rapid HIV test result as the gold standard. RESULTS: In our 14 study sites, 33,710 adolescents aged 10-14 in Zambia and 8,610 in South Africa participated in the study. About 1.3% (427/33,710) and 1.2% (106/8,610) self-reported to be HIV positive. Excluding the self-reported HIV-positive, we classified 11.3% (3,746/33,283) of adolescents in Zambia and 17.5% (1,491/8,504) in South Africa as "at risk". In Zambia the estimated sensitivity was 35.3% (95% CI 27.3%-44.2%) and estimated specificity was 88.9% (88.5%-89.2%). In South Africa the sensitivity was 72.3% (26.8%-94.9%) and specificity was 82.5% (81.6-83.4%). CONCLUSION: The sensitivity of the screening tool in a community setting in Zambia was low, so this tool should not be considered a substitute for universal testing where that is possible. In South Africa the sensitivity was higher, but with a wide confidence interval. Where universal testing is not possible the tool may help direct resources to adolescents more likely to be living with undiagnosed HIV. TRIAL REGISTRATION: Clinical Trial Number: NCT01900977.

Tuberculosis prevalence after 4 years of population-wide systematic TB symptom screening and universal testing and treatment for HIV in the HPTN 071 (PopART) community-randomised trial in Zambia and South Africa: A cross-sectional survey (TREATS).

BACKGROUND: Tuberculosis (TB) prevalence remains persistently high in many settings, with new or expanded interventions required to achieve substantial reductions. The HIV Prevention Trials Network (HPTN) 071 (PopART) community-randomised trial randomised 14 communities to receive the "PopART" intervention during 2014 to 2017 (7 arm A and 7 arm B communities) and 7 communities to receive standard-of-care (arm C). The intervention was delivered door-to-door by community HIV care providers (CHiPs) and included universal HIV testing, facilitated linkage to HIV care at government health clinics, and systematic TB symptom screening. The Tuberculosis Reduction through Expanded Anti-retroviral Treatment and Screening (TREATS) study aimed to measure the impact of delivering the PopART intervention on TB outcomes, in communities with high HIV and TB prevalence. METHODS AND FINDINGS: The study population of the HPTN 071 (PopART) trial included individuals aged ≥15 years living in 21 urban and peri-urban communities in Zambia and South Africa, with a total population of approximately 1 million and an adult HIV prevalence of around 15% at the time of the trial. Two sputum samples for TB testing were provided to CHiPs by individuals who reported ≥1 TB suggestive symptom (a cough for ≥2 weeks, unintentional weight loss ≥1.5 kg in the last month, or current night sweats) or that a household member was currently on TB treatment. Antiretroviral therapy (ART) was offered universally at clinics in arm A and according to local guidelines in arms B and C. The TREATS study was conducted in the same 21 communities as the HPTN 071 (PopART) trial between 2017 and 2022, and TB prevalence was a co-primary endpoint of the TREATS study. The primary comparison was between the PopART intervention (arms A and B combined) and the standard-of-care (arm C). During 2019 to 2021, a TB prevalence survey was conducted among randomly selected individuals aged ≥15 years (approximately 1,750 per community in arms A and B, approximately 3,500 in arm C). Participants were screened on TB symptoms and chest X-ray, with diagnostic testing using Xpert-Ultra followed by culture for individuals who screened positive. Sputum eligibility was determined by the presence of a cough for ≥2 weeks, or ≥2 of 5 "TB suggestive" symptoms (cough, weight loss for ≥4 weeks, night sweats, chest pain, and fever for ≥2 weeks), or chest X-ray CAD4TBv5 score ≥50, or no available X-ray results. TB prevalence was compared between trial arms using standard methods for cluster-randomised trials, with adjustment for age, sex, and HIV status, and multiple imputation was used for missing data on prevalent TB. Among 83,092 individuals who were eligible for the survey, 49,556 (59.6%) participated, 8,083 (16.3%) screened positive, 90.8% (7,336/8,083) provided 2 sputum samples for Xpert-Ultra testing, and 308 (4.2%) required culture confirmation. Overall, estimated TB prevalence was 0.92% (457/49,556). The geometric means of 7 community-level prevalence estimates were 0.91%, 0.70%, and 0.69% in arms A, B, and C, respectively, with no evidence of a difference comparing arms A and B combined with arm C (adjusted prevalence ratio 1.14, 95% confidence interval, CI [0.67, 1.95], p = 0.60). TB prevalence was higher among people living with HIV than HIV-negative individuals, with an age-sex-community adjusted odds ratio of 2.29 [95% CI 1.54, 3.41] in Zambian communities and 1.61 [95% CI 1.13, 2.30] in South African communities. The primary limitations are that the study was powered to detect only large reductions in TB prevalence in the intervention arm compared with standard-of-care, and the between-community variation in TB prevalence was larger than anticipated. CONCLUSIONS: There was no evidence that the PopART intervention reduced TB prevalence. Systematic screening for TB that is based on symptom screening alone may not be sufficient to achieve a large reduction in TB prevalence over a period of several years. Including chest X-ray screening alongside TB symptom screening could substantially increase the sensitivity of systematic screening for TB. TRIAL REGISTRATION: The TREATS study was registered with ClinicalTrials.gov Identifier: NCT03739736 on November 14, 2018. The HPTN 071 (PopART) trial was registered at ClinicalTrials.gov under number NCT01900977 on July 17, 2013.

Assessment of non-tuberculosis abnormalities on digital chest x-rays with high CAD4TB scores from a tuberculosis prevalence survey in Zambia and South Africa.

BACKGROUND: Chest X-rays (CXRs) have traditionally been used to aid the diagnosis of TB-suggestive abnormalities. Using Computer-Aided Detection (CAD) algorithms, TB risk is quantified to assist with diagnostics. However, CXRs capture all other structural abnormalities. Identification of non-TB abnormalities in individuals with CXRs that have high CAD scores but don't have bacteriologically confirmed TB is unknown. This presents a missed opportunity of extending novel CAD systems' potential to simultaneously provide information on other non-TB abnormalities alongside TB. This study aimed to characterize and estimate the prevalence of non-TB abnormalities on digital CXRs with high CAD4TB scores from a TB prevalence survey in Zambia and South Africa. METHODOLOGY: This was a cross-sectional analysis of clinical data of participants from the TREATS TB prevalence survey conducted in 21 communities in Zambia and South Africa. The study included individuals aged ≥ 15 years who had high CAD4TB scores (score ≥ 70), but had no bacteriologically confirmed TB in any of the samples submitted, were not on TB treatment, and had no history of TB. Two consultant radiologists reviewed the images for non-TB abnormalities. RESULTS: Of the 525 CXRs reviewed, 46.7% (245/525) images were reported to have non-TB abnormalities. About 11.43% (28/245) images had multiple non-TB abnormalities, while 88.67% (217/245) had a single non-TB abnormality. The readers had a fair inter-rater agreement (r = 0.40). Based on anatomical location, non-TB abnormalities in the lung parenchyma (19%) were the most prevalent, followed by Pleura (15.4%), then heart & great vessels (6.1%) abnormalities. Pleural effusion/thickening/calcification (8.8%) and cardiomegaly (5%) were the most prevalent non-TB abnormalities. Prevalence of (2.7%) for pneumonia not typical of pulmonary TB and (2.1%) mass/nodules (benign/ malignant) were also reported. CONCLUSION: A wide range of non-TB abnormalities can be identified on digital CXRs among individuals with high CAD4TB scores but don't have bacteriologically confirmed TB. Adaptation of AI systems like CAD4TB as a tool to simultaneously identify other causes of abnormal CXRs alongside TB can be interesting and useful in non-faculty-based screening programs to better link cases to appropriate care.

Visual diagnosis of female genital schistosomiasis in Zambian women from hand-held colposcopy: agreement of expert image review.

Female genital schistosomiasis (FGS) can occur in S. haematobium infection and is caused by parasite egg deposition in the genital tract. Confirming a diagnosis of FGS is challenging due to the lack of a diagnostic reference standard. A 2010 expert-led consensus meeting proposed visual inspection of the cervicovaginal mucosa as an adequate reference standard for FGS diagnosis. The agreement of expert human reviewers for visual-FGS has not been previously described. Methods: In two Zambian communities, non-menstruating, non-pregnant, sexually-active women aged 18-31 years participating in the HPTN 071 (PopART) Population-Cohort were enrolled in a cross-sectional study. Self-collected genital swabs and a urine specimen were collected at a home visit; trained midwives performed CVL and hand-held colposcopy at a clinic visit. S. haematobium eggs and circulating anodic antigen (CAA) were detected from urine. Two expert reviewers independently diagnosed visual-FGS as the presence of sandy patches, rubbery papules or abnormal blood vessels in digital cervicovaginal images obtained by hand-held colposcopy. PCR-FGS was defined as Schistosoma DNA detected by real-time PCR in any genital specimen (CVL or genital swab). Results: Of 527 women with cervicovaginal colposcopic images, 468/527 (88.8%) were deemed interpretable by Reviewer 1 and 417/527 (79.1%) by Reviewer 2. Visual-FGS was detected in 35.3% (165/468) of participants by expert review of colposcopic images by Reviewer 1 and in 63.6% (265/417) by Reviewer 2. Cohen's kappa statistic for agreement between the two expert reviewers was 0.16, corresponding to "slight" agreement. The reviewers made concordant diagnoses in 38.7% (204/527) participants (100 negative, 104 positive) and discordant diagnoses in 31.8% (168/527) participants. Conclusions: The unexpectedly low level of correlation between expert reviewers highlights the imperfect nature of visual diagnosis for FGS based on cervicovaginal images obtained with a hand-held colposcope. This finding is a call to action for improved point-of-care diagnostics for female genital schistosomiasis.

The Presence of Hemoglobin in Cervicovaginal Lavage Is Not Associated With Genital Schistosomiasis in Zambian Women From the BILHIV Study.

Background: Female genital schistosomiasis (FGS) occurs when Schistosoma haematobium eggs are deposited in reproductive tissue. Female genital schistosomiasis in the cervical mucosa is associated with increased vascularity. If FGS is associated with the presence of hemoglobin in cervicovaginal lavage (CVL), the use of urinary reagent strips to detect hemoglobin in CVL could supplement FGS diagnosis. Methods: Nonmenstruating, nonpregnant, sexually active women aged 18-31 participating in the HPTN 071 (PopART) Population-Cohort were invited in 2 Zambian communities. Genital self-swabs and a urine specimen were collected at a home visit, and CVL and hand-held colposcopy were performed at a midwife led clinic visit. Urinary reagent strips were used to identify hemoglobin in CVL. Eggs and circulating anodic antigen (CAA) were detected from urine. Visual-FGS was defined as the presence of sandy patches, rubbery papules, or abnormal blood vessels. Polymerase chain reaction (PCR)-FGS was defined as Schistosoma deoxyribonucleic acid detected by real-time PCR on CVL or cervical or vaginal swab. Results: Of 209 women with home genital swabs and companion CVL specimens, 66% (138 of 209) had detectable CVL hemoglobin, 13.4% (28 of 209) had PCR-defined FGS, and 17.2% (36 of 209) had visual-FGS. Active Schistosoma infection, diagnosed by CAA or urine microscopy, was present in 21.0% (44 of 209) participants. Active Schistosoma infection (P = .4), PCR-FGS (P = 0.7), and visual-FGS (P = 0.3) were not associated with CVL hemoglobin presence. Results did not differ in subgroups with high infection burden (cycle threshold < 35 or 2-3 positive genital PCR). Conclusions: Polymerase chain reaction-FGS, visual-FGS, and active Schistosoma infection were not associated with the presence of CVL hemoglobin. Further research is needed to establish accessible community-based FGS diagnostics.

Evaluation of multi-assay algorithms for cross-sectional HIV incidence estimation in settings with universal antiretroviral treatment.

BACKGROUND: Multi-assay algorithms (MAAs) are used to estimate population-level HIV incidence and identify individuals with recent infection. Many MAAs use low viral load (VL) as a biomarker for long-term infection. This could impact incidence estimates in settings with high rates of early HIV treatment initiation. We evaluated the performance of two MAAs that do not include VL. METHODS: Samples were collected from 219 seroconverters (infected < 1 year) and 4376 non-seroconverters (infected > 1 year) in the HPTN 071 (PopART) trial; 28.8% of seroconverter samples and 73.2% of non-seroconverter samples had VLs ≤ 400 copies/mL. Samples were tested with the Limiting Antigen Avidity assay (LAg) and JHU BioRad-Avidity assays. Antibody reactivity to two HIV peptides was measured using the MSD U-PLEX assay. Two MAAs were evaluated that do not include VL: a MAA that includes the LAg-Avidity assay and BioRad-Avidity assay (LAg + BR) and a MAA that includes the LAg-Avidity assay and two peptide biomarkers (LAg + PepPair). Performance of these MAAs was compared to a widely used MAA that includes LAg and VL (LAg + VL). RESULTS: The incidence estimate for LAg + VL (1.29%, 95% CI: 0.97-1.62) was close to the observed longitudinal incidence (1.34% 95% CI: 1.17-1.53). The incidence estimates for the other two MAAs were higher (LAg + BR: 2.56%, 95% CI 2.01-3.11; LAg + PepPair: 2.84%, 95% CI: 1.36-4.32). LAg + BR and LAg + PepPair also misclassified more individuals infected > 2 years as recently infected than LAg + VL (1.2% [42/3483 and 1.5% [51/3483], respectively, vs. 0.2% [6/3483]). LAg + BR classified more seroconverters as recently infected than LAg + VL or LAg + PepPair (80 vs. 58 and 50, respectively) and identified ~ 25% of virally suppressed seroconverters as recently infected. CONCLUSIONS: The LAg + VL MAA produced a cross-sectional incidence estimate that was closer to the longitudinal estimate than two MAAs that did not include VL. The LAg + BR MAA classified the greatest number of individual seroconverters as recently infected but had a higher false recent rate.

Sensitivity and specificity of OraQuick® HIV self-test compared to a 4th generation laboratory reference standard algorithm in urban and rural Zambia.

BACKGROUND: HIV self-testing (HIVST) has the potential to increase coverage of HIV testing, but concerns exist about intended users' ability to correctly perform and interpret tests, especially in poor communities with low literacy rates. We assessed the clinical performance of the 2016 prototype OraQuick® HIV Self-Test in rural and urban communities in Zambia to assess the sensitivity and specificity of the test compared to the national HIV rapid diagnostic test (RDT) algorithm and a laboratory reference standard using 4th generation enzyme immunoassays and HIV RNA detection. METHODS: Participants were recruited from randomly selected rural and urban households and one urban health facility between May 2016 and June 2017. Participants received a brief demonstration of the self-test, and then self-tested without further assistance. The research team re-read the self-test, repeated the self-test, drew blood for the laboratory reference, and conducted RDTs following the national HIV testing algorithm (Determine™ HIV1/2 (Alere) confirmed using Unigold™ HIV1/2 (Trinity Biotech)). Selected participants (N = 85) were videotaped whilst conducting the testing to observe common errors. RESULTS: Initial piloting showed that written instructions alone were inadequate, and a demonstration of self-test use was required. Of 2,566 self-test users, 2,557 (99.6%) were able to interpret their result. Of participants who were videoed 75/84 (89.3%) completed all steps of the procedure correctly. Agreement between the user-read result and the researcher-read result was 99.1%. Compared to the RDT algorithm, user-conducted HIVST was 94.1% sensitive (95%CI: 90.2-96.7) and 99.7% specific (95%CI: 99.3-99.9). Compared to the laboratory reference, both user-conducted HIVST (sensitivity 87.5%, 95%CI: 82.70-91.3; specificity 99.7%, 95%CI: 99.4-99.9) and the national RDT algorithm (sensitivity 93.4%, 95%CI: 89.7-96.1%; specificity 100% (95%CI: 99.8-100%) had considerably lower sensitivity. CONCLUSIONS: Self-testers in Zambia who used OraQuick® HIV Self-Test achieved reasonable clinical performance compared to the national RDT algorithm. However, sensitivity of the self-test was reduced compared to a laboratory reference standard, as was the national RDT algorithm. In-person demonstration, along with the written manufacturer instructions, was needed to obtain accurate results. Programmes introducing self-care diagnostics should pilot and optimise support materials to ensure they are appropriately adapted to context.

Closing the gap: did delivery approaches complementary to home-based testing reach men with HIV testing services during and after the HPTN 071 (PopART) trial in Zambia?

INTRODUCTION: The HPTN 071 (PopART) trial demonstrated that universal HIV testing-and-treatment reduced community-level HIV incidence. Door-to-door delivery of HIV testing services (HTS) was one of the main components of the intervention. From an early stage, men were less likely to know their HIV status than women, primarily because they were not home during service delivery. To reach more men, different strategies were implemented during the trial. We present the relative contribution of these strategies to coverage of HTS and the impact of community hubs implemented after completion of the trial among men. METHODS: Between 2013 and 2017, three intervention rounds (IRs) of door-to-door HTS delivery were conducted in eight PopART communities in Zambia. Additional strategies implemented in parallel, included: community-wide "Man-up" campaigns (IR1), smaller HTS campaigns at work/social places (IR2) and revisits to households with the option of HIV self-testing (HIVST) (IR3). In 2018, community "hubs" offering HTS were implemented for 7 months in all eight communities. Population enumeration data for each round of HTS provided the denominator, allowing for calculation of the proportion of men tested as a result of each strategy during different time periods. RESULTS: By the end of the three IRs, 65-75% of men were reached with HTS, primarily through door-to-door service delivery. In IR1 and IR2, "Man-up" and work/social place campaigns accounted for ∼1 percentage point each and in IR3, revisits with the option of self-testing for ∼15 percentage points of this total coverage per IR. The yield of newly diagnosed HIV-positive men ranged from 2.2% for HIVST revisits to 9.9% in work/social places. At community hubs, the majority of visitors accepting services were men (62.8%). In total, we estimated that ∼36% (2.2% tested HIV positive) of men resident but not found at their household during IR3 of PopART accessed HTS provided at the hubs after trial completion. CONCLUSIONS: Achieving high coverage of HTS among men requires universal, home-based service delivery combined with an option of HIVST and delivery of HTS through community-based hubs. When men are reached, they are willing to test for HIV. Reaching men thus requires implementers to adapt their HTS delivery strategies to meet men's needs. CLINICAL TRIAL NUMBER: NCT01900977.

Evaluation of multi-assay algorithms for identifying individuals with recent HIV infection: HPTN 071 (PopART).

BACKGROUND: Assays and multi-assay algorithms (MAAs) have been developed for population-level cross-sectional HIV incidence estimation. These algorithms use a combination of serologic and/or non-serologic biomarkers to assess the duration of infection. We evaluated the performance of four MAAs for individual-level recency assessments. METHODS: Samples were obtained from 220 seroconverters (infected <1 year) and 4,396 non-seroconverters (infected >1 year) enrolled in an HIV prevention trial (HPTN 071 [PopART]); 28.6% of the seroconverters and 73.4% of the non-seroconverters had HIV viral loads ≤400 copies/mL. Samples were tested with two laboratory-based assays (LAg-Avidity, JHU BioRad-Avidity) and a point-of-care assay (rapid LAg). The four MAAs included different combinations of these assays and HIV viral load. Seroconverters on antiretroviral treatment (ART) were identified using a qualitative multi-drug assay. RESULTS: The MAAs identified between 54 and 100 (25% to 46%) of the seroconverters as recently-infected. The false recent rate of the MAAs for infections >2 years duration ranged from 0.2%-1.3%. The MAAs classified different overlapping groups of individuals as recent vs. non-recent. Only 32 (15%) of the 220 seroconverters were classified as recent by all four MAAs. Viral suppression impacted the performance of the two LAg-based assays. LAg-Avidity assay values were also lower for seroconverters who were virally suppressed on ART compared to those with natural viral suppression. CONCLUSIONS: The four MAAs evaluated varied in sensitivity and specificity for identifying persons infected <1 year as recently infected and classified different groups of seroconverters as recently infected. Sensitivity was low for all four MAAs. These performance issues should be considered if these methods are used for individual-level recency assessments.

Does community-based distribution of HIV self-tests increase uptake of HIV testing? Results of pair-matched cluster randomised trial in Zambia.

OBJECTIVES: Ending HIV by 2030 is a global priority. Achieving this requires alternative HIV testing strategies, such as HIV self-testing (HIVST) to reach all individuals with HIV testing services (HTS). We present the results of a trial evaluating the impact of community-based distribution of HIVST in community and facility settings on the uptake of HTS in rural and urban Zambia. DESIGN: Pair-matched cluster randomised trial. METHODS: In catchment areas of government health facilities, OraQuick HIVST kits were distributed by community-based distributors (CBDs) over 12 months in 2016-2017. Within matched pairs, clusters were randomised to receive the HIVST intervention or standard of care (SOC). Individuals aged ≥16 years were eligible for HIVST. Within communities, CBDs offered HIVST in high traffic areas, door to door and at healthcare facilities. The primary outcome was self-reported recent testing within the previous 12 months measured using a population-based survey. RESULTS: In six intervention clusters (population 148 541), 60 CBDs distributed 65 585 HIVST kits. A recent test was reported by 66% (1622/2465) in the intervention arm compared with 60% (1456/2429) in SOC arm (adjusted risk ratio 1.08, 95% CI 0.94 to 1.24; p=0.15). Uptake of the HIVST intervention was low: 24% of respondents in the intervention arm (585/2493) used an HIVST kit in the previous 12 months. No social harms were identified during implementation. CONCLUSION: Despite distributing a large number of HIVST kits, we found no evidence that this community-based HIVST distribution intervention increased HTS uptake. Other models of HIVST distribution, including secondary distribution and community-designed distribution models, provide alternative strategies to reach target populations. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02793804).

ART initiations following community-based distribution of HIV self-tests: meta-analysis and meta-regression of STAR Initiative data.

INTRODUCTION: Measuring linkage after community-based testing, particularly HIV self-testing (HIVST), is challenging. Here, we use data from studies of community-based HIVST distribution, conducted within the STAR Initiative, to assess initiation of antiretroviral therapy (ART) and factors driving differences in linkage rates. METHODS: Five STAR studies evaluated HIVST implementation in Malawi, Zambia and Zimbabwe. New ART initiations during the months of intervention at clinics in HIVST and comparison areas were presented graphically, and study effects combined using meta-analysis. Meta-regression was used to estimate associations between the impact of community-based HIVST distribution and indicators of implementation context, intensity and reach. Effect size estimates used (1) prespecified trial definitions of ART timing and comparator facilities and (2) exploratory definitions accounting for unexpected diffusion of HIVST into comparison areas and periods with less distribution of HIVST than was expected. RESULTS: Compared with arms with standard testing only, ART initiations were higher in clinics in HIVST distribution areas in 4/5 studies. The prespecified meta-analysis found positive but variable effects of HIVST on facility ART initiations (RR: 1.14, 95% CI 0.93 to 1.40; p=0.21). The exploratory meta-analysis found a stronger impact of HIVST distribution on ART initiations (RR: 1.29, 95% CI 1.08 to 1.55, p=0.02).ART initiations were higher in studies with greater self-reported population-level intensity of HIVST use (RR: 1.12; 95% CI 1.04 to 1.21; p=0.02.), but did not differ by national-level indicators of ART use among people living with HIV, number of HIVST kits distributed per 1000 population, or self-reported knowledge of how to link to care after a reactive HIVST. CONCLUSION: Community-based HIVST distribution has variable effect on ART initiations compared with standard testing service alone. Optimising both support for and approach to measurement of effective and timely linkage or relinkage to HIV care and prevention following HIVST is needed to maximise impact and guide implementation strategies.

Costs of integrating HIV self-testing in public health facilities in Malawi, South Africa, Zambia and Zimbabwe.

INTRODUCTION: As countries approach the UNAIDS 95-95-95 targets, there is a need for innovative and cost-saving HIV testing approaches that can increase testing coverage in hard-to-reach populations. The HIV Self-Testing Africa-Initiative distributed HIV self-test (HIVST) kits using unincentivised HIV testing counsellors across 31 public facilities in Malawi, South Africa, Zambia and Zimbabwe. HIVST was distributed either through secondary (partner's use) distribution alone or primary (own use) and secondary distribution approaches. METHODS: We evaluated the costs of adding HIVST to existing HIV testing from the providers' perspective in the 31 public health facilities across the four countries between 2018 and 2019. We combined expenditure analysis and bottom-up costing approaches. We also carried out time-and-motion studies on the counsellors to estimate the human resource costs of introducing and demonstrating how to use HIVST for primary and secondary use. RESULTS: A total of 41 720 kits were distributed during the analysis period, ranging from 1254 in Zimbabwe to 27 678 in Zambia. The cost per kit distributed through the primary distribution approach was $4.27 in Zambia and $9.24 in Zimbabwe. The cost per kit distributed through the secondary distribution approach ranged from $6.46 in Zambia to $13.42 in South Africa, with a wider variation in the average cost at facility-level. From the time-and-motion observations, the counsellors spent between 20% and 44% of the observed workday on HIVST. Overall, personnel and test kit costs were the main cost drivers. CONCLUSION: The average costs of distributing HIVST kits were comparable across the four countries in our analysis despite wide cost variability within countries. We recommend context-specific exploration of potential efficiency gains from these facility-level cost variations and demand creation activities to ensure continued affordability at scale.

Community-based active case-finding interventions for tuberculosis: a systematic review.

BACKGROUND: Community-based active case-finding interventions might identify and treat more people with tuberculosis disease than standard case detection. We aimed to assess whether active case-finding interventions can affect tuberculosis epidemiology in the wider community. METHODS: We did a systematic review by searching PubMed, Embase, Scopus, and Cochrane Library for studies that compared tuberculosis case notification rates, tuberculosis disease prevalence, or tuberculosis infection prevalence or incidence in children, between populations exposed and unexposed to active case-finding interventions. We included studies published in English between Jan 1, 1980, and April 13, 2020. Studies of active case-finding in the general population, in populations perceived to be at high risk for tuberculosis, and in closed settings were included, whereas studies of tuberculosis screening at health-care facilities, among household contacts, or among children only, and studies that screened fewer than 1000 people were excluded. To estimate effectiveness, we extracted or calculated case notification rates, prevalence of tuberculosis disease, and incidence or prevalence of tuberculosis infection in children, and compared ratios of these outcomes between groups that were exposed or not exposed to active case-finding interventions. RESULTS: 27 883 abstracts were screened and 988 articles underwent full text review. 28 studies contributed data for analysis of tuberculosis case notifications, nine for prevalence of tuberculosis disease, and two for incidence or prevalence of tuberculosis infection in children. In one cluster-randomised trial in South Africa and Zambia, an active case-finding intervention based on community mobilisation and sputum drop-off did not affect tuberculosis prevalence, whereas, in a cluster-randomised trial in Vietnam, an active case-finding intervention based on sputum tuberculosis tests for everyone reduced tuberculosis prevalence in the community. We found inconsistent, low-quality evidence that active case-finding might increase the number of cases of tuberculosis notified in populations with structural risk factors for tuberculosis. INTERPRETATION: Community-based active case-finding for tuberculosis might be effective in changing tuberculosis epidemiology and thereby improving population health if delivered with high coverage and intensity. If possible, active case-finding projects should incorporate a well designed, robust evaluation to contribute to the evidence base and help elucidate which delivery methods and diagnostic strategies are most effective. FUNDING: WHO Global TB Programme.

Cervicovaginal Immune Activation in Zambian Women With Female Genital Schistosomiasis.

HIV-1 infection disproportionately affects women in sub-Saharan Africa, where areas of high HIV-1 prevalence and Schistosoma haematobium endemicity largely overlap. Female genital schistosomiasis (FGS), an inflammatory disease caused by S. haematobium egg deposition in the genital tract, has been associated with prevalent HIV-1 infection. Elevated levels of the chemokines MIP-1α (CCL-3), MIP-1ß (CCL-4), IP-10 (CXCL-10), and IL-8 (CXCL-8) in cervicovaginal lavage (CVL) have been associated with HIV-1 acquisition. We hypothesize that levels of cervicovaginal cytokines may be raised in FGS and could provide a causal mechanism for the association between FGS and HIV-1. In the cross-sectional BILHIV study, specimens were collected from 603 female participants who were aged 18-31 years, sexually active, not pregnant and participated in the HPTN 071 (PopART) HIV-1 prevention trial in Zambia. Participants self-collected urine, and vaginal and cervical swabs, while CVLs were clinically obtained. Microscopy and Schistosoma circulating anodic antigen (CAA) were performed on urine. Genital samples were examined for parasite-specific DNA by PCR. Women with FGS (n=28), defined as a positive Schistosoma PCR from any genital sample were frequency age-matched with 159 FGS negative (defined as negative Schistosoma PCR, urine CAA, urine microscopy, and colposcopy imaging) women. Participants with probable FGS (n=25) (defined as the presence of either urine CAA or microscopy in combination with one of four clinical findings suggestive of FGS on colposcope-obtained photographs) were also included, for a total sample size of 212. The concentrations of 17 soluble cytokines and chemokines were quantified by a multiplex bead-based immunoassay. There was no difference in the concentrations of cytokines or chemokines between participants with and without FGS. An exploratory analysis of those women with a higher FGS burden, defined by ≥2 genital specimens with detectable Schistosoma DNA (n=15) showed, after adjusting for potential confounders, a higher Th2 (IL-4, IL-5, and IL-13) and pro-inflammatory (IL-15) expression pattern in comparison to FGS negative women, with differences unlikely to be due to chance (p=0.037 for IL-4 and p<0.001 for IL-5 after adjusting for multiple testing). FGS may alter the female genital tract immune environment, but larger studies in areas of varying endemicity are needed to evaluate the association with HIV-1 vulnerability.

Social response to the delivery of HIV self-testing in households: experiences from four Zambian HPTN 071 (PopART) urban communities.

BACKGROUND: Door-to-door distribution of HIV self-testing kits (HIVST) has the potential to increase uptake of HIV testing services (HTS). However, very few studies have explored the social response to and implications of door-to-door including secondary distribution of HIVST on household relations and the ability of individuals to self-test with or without supervision within households. METHODS: A CRT of HIVST distribution was nested within the HPTN 071 (PopART) trial, in four Zambian communities randomised to receive the PopART intervention. The nested HIVST trial aimed to increase knowledge of HIV status at population level. Between February 1 and April 30, 2017, 66 zones (clusters) within these four communities were randomly allocated to either the PopART standard of care door-to-door HTS (33 clusters) or PopART standard of care door-to-door HTS plus oral HIVST (33 clusters). In clusters randomised to HIVST, trained Community HIV care provider (CHiPs) visited households and offered individuals aged ≥ 16 and eligible for an offer of HTS the choice of HIV testing using HIVST or routine door-to-door HTS (finger-prick RDT). To document participants' experiences with HIVST, Interviews (n = 40), observations (n = 22) and group discussions (n = 91) with household members and CHiPs were conducted. Data were coded using Atlas.ti 7 and analysed thematically. RESULTS: The usage and storage of HIVST kits was facilitated by familiarity with and trust in CHiPs, the novelty of HIVST, and demonstrations and supervision provided by CHiPs. Door-to-door distribution of HIVST kits was appreciated for being novel, convenient, private, empowering, autonomous and easy-to-use. Literacy and age influenced accurate usage of HIVST kits. The novelty of using oral fluids to test for HIV raised questions, some anxiety and doubts about the accuracy of HIVST. Although HIVST protected participants from experiencing clinic-based stigma, it did not address self-stigma. Within households, HIVST usually strengthened relationships but, amongst couples, there were a few reports of social harms. CONCLUSION: Door-to-door distribution of HIVST as a choice for how to HIV test is appreciated at community level and provides an important testing option in the sub-Saharan context. However, it should be accompanied by counselling to manage social harms and by supporting those testing HIV-positive to link to care.

HIV testing and treatment coverage achieved after 4 years across 14 urban and peri-urban communities in Zambia and South Africa: An analysis of findings from the HPTN 071 (PopART) trial.

BACKGROUND: In 2014, the Joint United Nations Programme on HIV/AIDS (UNAIDS) set the 90-90-90 targets: that 90% of people living with HIV know their HIV status, that 90% of those who know their HIV-positive status are on antiretroviral therapy (ART), and that 90% of those on treatment are virally suppressed. The aim was to reach these targets by 2020. We assessed the feasibility of achieving the first two targets, and the corresponding 81% ART coverage target, as part of the HIV Prevention Trials Network (HPTN) 071 Population Effects of Antiretroviral Therapy to Reduce HIV Transmission (PopART) community-randomized trial. METHODS AND FINDINGS: The study population was individuals aged ≥15 years living in 14 urban and peri-urban "PopART intervention" communities in Zambia and South Africa (SA), with a total population of approximately 600,000 and approximately 15% adult HIV prevalence. Community HIV care providers (CHiPs) delivered the PopART intervention during 2014-2017. This was a combination HIV prevention package including universal home-based HIV testing, referral of HIV-positive individuals to government HIV clinic services that offered universal ART (Arm A) or ART according to national guidelines (Arm B), and revisits to HIV-positive individuals to support linkage to HIV care and retention on ART. The intervention was delivered in 3 "rounds," each about 15 months long, during which CHiPs visited all households and aimed to contact all individuals aged ≥15 years at least once. In Arm A in Round 3 (R3), 67% (41,332/61,402) of men and 86% (56,345/65,896) of women in Zambia and 56% (17,813/32,095) of men and 71% (24,461/34,514) of women in SA participated in the intervention, among 193,907 residents aged ≥15 years. Following participation, HIV status was known by 90% of men and women in Zambia and by 78% of men and 85% of women in SA. The median time from CHiP referral of HIV-positive individuals to ART initiation was approximately 3 months. By the end of R3, an estimated 95% of HIV-positive women and 85% of HIV-positive men knew their HIV status, and among these individuals, approximately 90% of women and approximately 85% of men were on ART. ART coverage among all HIV-positive individuals was approximately 85% in women and approximately 75% in men, up from about 45% at the start of the study. ART coverage was lowest among men aged 18 to 34 and women aged 15 to 24 years, and among mobile individuals/in-migrants. Findings from Arm B were similar. The main limitations to our study were that estimates of testing and treatment coverage among men relied on considerable extrapolation because, in each round, approximately one-third of men did not participate in the PopART intervention; that our findings are for a service delivery model that was relatively intensive; and that we did not have comparable data from the 7 "standard-of-care" (Arm C) communities. CONCLUSIONS: Our study showed that very high HIV testing and treatment coverage can be achieved through persistent delivery of universal testing, facilitated linkage to HIV care, and universal treatment services. The ART coverage target of 81% was achieved overall, after 4 years of delivery of the PopART intervention, though important gaps remained among men and young people. Our findings are consistent with previously reported findings from southern and east Africa, extending their generalisability to urban settings with high rates of in-migration and mobility and to Zambia and SA. TRIAL REGISTRATION: ClinicalTrials.gov NCT01900977.

Who Accepts and Who Uses Community-Based Secondary Distribution HIV Self-Testing (HIVST) Kits? Findings From the Intervention Arm of a Cluster-Randomized Trial of HIVST Distribution Nested in Four HPTN 071 (PopART) Communities in Zambia.

BACKGROUND: HPTN 071 (PopART) was a community-randomized trial of a universal testing-and-treatment intervention on HIV incidence at population level in Zambia and South Africa. In Zambia, a trial of community-based distribution of HIV self-testing (HIVST) kits, including secondary distribution, as an option for HIV-testing was nested within 4 PopART intervention communities. We used data from the intervention arm of the nested trial to measure levels of and factors associated with acceptance and use of secondary distribution HIVST kits. METHODS: Community HIV care providers offered the PopART combination HIV-prevention intervention door-to-door, systematically visiting all households and enumerating all household members. From 1 February to 30 April 2017, individuals aged 16 years and older consenting to PopART were offered the option to HIV self-test, if eligible for HIV-testing services. Individuals aged 18 years and older who reported a partner absent during household visits were offered an HIVST kit for secondary distribution to this partner. We used two data sources to measure acceptance and use of secondary distribution HIVST kits. RESULTS: Among 9105 individuals aged 18 years and older consenting to PopART, 9.1% (n = 825) accepted an HIVST kit for secondary distribution. Approximately 55.8% reported that the kit had been used. Women were more likely to accept, and men more likely to use, secondary distribution HIVST kits. Kits were more likely to be used by individuals aged 30+ and who had not participated in a previous round of PopART. Approximately 6.8% had a reactive result. CONCLUSIONS: Community-based secondary distribution of HIVST kits reached men absent during community HIV care provider household visits and is a complement to facility- and community-based HIV-testing services, which often miss men.

What do the Universal Test and Treat trials tell us about the path to HIV epidemic control?

INTRODUCTION: Achieving HIV epidemic control globally will require new strategies to accelerate reductions in HIV incidence and mortality. Universal test and treat (UTT) was evaluated in four randomized population-based trials (BCPP/Ya Tsie, HPTN 071/PopART, SEARCH, ANRS 12249/TasP) conducted in sub-Saharan Africa (SSA) during expanded antiretroviral treatment (ART) eligibility by World Health Organization guidelines and the UNAIDS 90-90-90 campaign. DISCUSSION: These three-year studies were conducted in Botswana, Zambia, Uganda, Kenya and South Africa in settings with baseline HIV prevalence from 4% to 30%. Key observations across studies were: (1) Universal testing (implemented via a variety of home and community-based testing approaches) achieved >90% coverage in all studies. (2) When coupled with robust linkage to HIV care, rapid ART start and patient-centred care, UTT achieved among the highest reported population levels of viral suppression in SSA. Significant gains in population-level viral suppression were made in regions with both low and high baseline population viral load; however, viral suppression gains were not uniform across all sub-populations and were lower among youth. (3) UTT resulted in marked reductions in community HIV incidence when universal testing and robust linkage were present. However, HIV elimination targets were not reached. In BCPP and HPTN 071, annualized HIV incidence was approximately 20% to 30% lower in the intervention (which included universal testing) compared to control arms (no universal testing). In SEARCH (where both arms had universal testing), incidence declined 32% over three years. (4) UTT reduced HIV associated mortality by 23% in the intervention versus control communities in SEARCH, a study in which mortality was comprehensively measured. CONCLUSIONS: These trials provide strong evidence that UTT inclusive of universal testing increases population-level viral suppression and decreases HIV incidence and mortality faster than the status quo in SSA and should be adapted at a sub-country level as a public health strategy. However, more is needed, including integration of new prevention interventions into UTT, in order to reach UNAIDS HIV elimination targets.