Estimating the Prevalence of over- and Under-Reporting in HIV Testing, Status and Treatment in Rural Northeast South Africa: A Comparison of a Survey and Clinic Records.

We assess the accuracy of self-reported testing, HIV status, and treatment responses compared to clinical records in Ehlanzeni District, South Africa. We linked a 2018 population-based survey of adults 18-49 years old with clinical data at local primary healthcare facilities from 2014 to 2018. We calculated self-reported testing, HIV status, and treatment, and triangulated findings with clinic record data. We adjusted testing estimates for known gaps in HIV test documentation. Of 2089 survey participants, 1657 used a study facility and were eligible for analysis. Half of men and 84% of women reported an HIV test in the past year. One third of reported tests could be confirmed in clinic data within 1 year and an additional 13% within 2 years; these fractions increased to 57% and 22% respectively limiting to participants with a verified clinic file. After accounting for gaps in clinic documentation, we found that prevalence of recent HIV testing was closer to 15% among men and 51% in women. Estimated prevalence of known HIV was 16.2% based on self-report vs. 27.6% with clinic documentation. Relative to clinical records among confirmed clinic users, self report of HIV testing and of current treatment were highly sensitive but non-specific (sensitivity 95.5% and 98.8%, specificity 24.2% and 16.1% respectively), while self report of HIV status was highly specific but not sensitive (sensitivity 53.0%, specificity 99.3%). While clinical records are imperfect, survey-based measures should be interpreted with caution in this rural South African setting.

The use of monitoring data and community feedback mechanisms to increase HIV testing among men during a cluster-randomised community mobilisation trial in South Africa.

This short communication describes the development and implementation of a programme monitoring and feedback process during a cluster-randomised community mobilisation intervention conducted in rural Bushbuckridge, Mpumalanga, South Africa. Intervention activities took place from August 2015 to July 2018 with the aim of addressing social barriers to HIV counselling and testing and engagement in HIV care, with a specific focus on reaching men. Multiple monitoring systems were put in place to allow for early and continuous corrective actions to be taken if activity goals, including target participation numbers in events or workshops, were not reached. Clinic data, intervention monitoring data, team meetings and community feedback mechanisms allowed for triangulation of data and creative responses to issues arising in implementation. Monitoring data must be collected and analysed carefully as they allow researchers to better understand how the intervention is being delivered and to respond to challenges and make changes in the programme and target approaches. An iterative process of sharing these data to generate community feedback on intervention approaches was critical to the success of our programme, along with engaging men in the intervention. Community mobilisation interventions to target the structural and social barriers impeding men's uptake of services are feasible in this setting, but must incorporate a continuous review of monitoring data and community collaboration to ensure that the target population is reached, and may need to also be supplemented by changes in the structure of care provision.

A community mobilisation intervention to improve engagement in HIV testing, linkage to care, and retention in care in South Africa: a cluster-randomised controlled trial.

BACKGROUND: Community mobilisation, engaging communities in a process to collectively enact change, could improve HIV testing and care engagement. In South Africa, current rates fall below those needed for epidemic control. We assessed whether community mobilisation increased HIV testing, linkage to care, and retention in care over time in intervention relative to control communities. METHODS: We conducted a cluster-randomised controlled trial in villages in the Agincourt sub-district of the rural Mpumalanga Province in South Africa. 15 villages were randomly assigned to either a community mobilisation intervention engaging residents to address social barriers to HIV testing and treatment (intervention arm) or to a control arm using balanced randomisation. Villages were eligible if they had been fully enumerated in 2014, had not been included in previous mobilisation activities, and included over 500 permanent adult residents aged 18-49 years. Primary outcomes included quarterly rates of HIV testing, linkage to care, and retention in care documented from health facility records among residents of the intervention and control communities over the 3-year study period. Intention-to-treat analyses employed generalised estimating equations stratified by sex. This trial is registered with ClinicalTrials.gov, NCT02197793. FINDINGS: Between Aug 1, 2015, and July 31, 2018, residents in eight intervention communities (n=20 544 residents) and seven control communities (n=17 848) contributed data; 92 residents contributed to both arms. Among men, HIV testing increased quarterly by 12·1% (relative change [RC] 1·121, 95% CI 1·099 to 1·143, p<0·0001) in the intervention communities and 9·5% (1·095, 1·075 to 1·114, p=0·011) in the control communities; although increases in testing were greater in the intervention villages, differences did not reach significance (exponentiated interaction coefficient 1·024, 95% CI 0·997 to 1·052, p=0·078). Among women, HIV testing increased quarterly by 10·6% (RC 1·106, 95% CI 1·097 to 1·114, p<0·0001) in the intervention communities and 9·3% (1·093, 1·084 to 1·102, p=0·053) in the control communities; increases were greater in intervention communities (exponentiated interaction coefficient 1·012, 95% CI 1·001 to 1·023, p=0·043). Quarterly linkage increased significantly among women in the intervention communities (RC 1·013, 95% CI 1·002 to 1·023, p=0·018) only. Quarterly linkage fell among men in both arms, but decreased significantly among men in the control communities (0·977, 0·954 to 1·002, p=0·043). Quarterly retention fell among women in both arms; however, reductions were tempered among women in the intervention communities (exponentiated interaction coefficient 1·003, 95% CI <1·000 to 1·006, p=0·062). Retention fell significantly among men in both arms with difference in rates of decline. INTERPRETATION: Community mobilisation was associated with modest improvements in select trial outcomes. The sum of these incremental, quarterly improvements achieved by addressing social barriers to HIV care engagement can impact epidemic control. However, achieving optimal impacts will probably require integrated efforts addressing both social barriers through community mobilisation and provision of improved service delivery. FUNDING: US National Institutes of Health, National Institute of Mental Health, and United States President's Emergency Plan for AIDS Relief through Right to Care and Project SOAR.

Health Care Providers' Challenges to High-Quality HIV Care and Antiretroviral Treatment Retention in Rural South Africa.

Provision of high-quality HIV care is challenging, especially in rural primary care clinics in high HIV burden settings. We aimed to better understand the main challenges to quality HIV care provision and retention in antiretroviral treatment (ART) programs in rural South Africa from the health care providers' perspective. We conducted semi-structured qualitative interviews with 23 providers from nine rural clinics. Using thematic and framework analysis, we found that providers and patients face a set of complex and intertwined barriers at the structural, programmatic, and individual levels. More specifically, analyses revealed that their challenges are primarily structural (i.e., health system- and microeconomic context-specific) and programmatic (i.e., clinic- and provider-specific) in nature. We highlight the linkages that providers draw between the challenges they face, the motivation to do their job, the quality of the care they provide, and patients' dissatisfaction with the care they receive, all potentially resulting in poor retention in care.

Gaining traction: Promising shifts in gender norms and intimate partner violence in the context of a community-based HIV prevention trial in South Africa.

BACKGROUND: HIV and violence prevention programs increasingly seek to transform gender norms among participants, yet how to do so at the community level, and subsequent pathways to behavior change, remain poorly understood. We assessed shifts in endorsement of equitable gender norms, and intimate partner violence (IPV), during the three-year community-based trial of Tsima, an HIV 'treatment as prevention' intervention in rural South Africa. METHODS: Cross-sectional household surveys were conducted with men and women ages 18-49 years, in 8 intervention and 7 control communities, at 2014-baseline (n = 1,149) and 2018-endline (n = 1,189). Endorsement of equitable gender norms was measured by the GEM Scale. Intent-to-treat analyses assessed intervention effects and change over time. Qualitative research with 59 community members and 38 staff examined the change process. RESULTS: Nearly two-thirds of men and half of women in intervention communities had heard of the intervention/seen the logo; half of these had attended a two-day workshop. Regression analyses showed a 15% improvement in GEM Scale score over time, irrespective of the intervention, among men (p<0.001) and women (p<0.001). Younger women (ages 18-29) had a decreased odds of reporting IPV in intervention vs. control communities (aOR 0.53; p<0.05). Qualitative data suggest that gender norms shifts may be linked to increased media access (via satellite TV/smartphones) and consequent exposure to serial dramas modeling equitable relationships and negatively portraying violence. Tsima's couple communication/conflict resolution skills-building activities, eagerly received by intervention participants, appear to have further supported IPV reductions. CONCLUSIONS: There was a population-level shift towards greater endorsement of equitable gender norms between 2014-2018, potentially linked with rapid escalation in media access. There was also an intervention effect on reported IPV among young women, likely owing to improved couple communication. Societal-level gender norm shifts may create enabling environments for interventions to find new traction for violence and HIV-related behavior change.

Prevalence and Associations, by Age Group, of IPV Among AGYW in Rural South Africa.

The prevalence of intimate partner violence (IPV) is alarmingly high among South African adolescent girls and young women (AGYW). Limited data exist exploring how IPV prevalence and its risk factors differ by age. Study data were from the baseline visit of HPTN 068, a randomized controlled trial (RCT) conducted from 2011 to 2015 in Mpumalanga, South Africa. A cohort of 2,533 AGYW, aged 13 years to 20 years, answered survey questions on demographics and behaviors, including their experiences of physical and sexual violence ever and in the past 12 months. We calculated the prevalence of IPV and related risk factors, as well as prevalence ratios with 95% confidence intervals, stratified by age. Nearly one quarter (19.5%, 95% CI = [18.0, 21.2]) of AGYW experienced any IPV ever (physical or sexual) by a partner. The prevalence of any IPV ever among AGYW aged 13 years to 14 years, 15 years to 16 years, and 17 years to 20 years was 10.8%, 17.7%, and 32.1%, respectively. Key variables significantly associated with any IPV ever across all age groups included borrowing money from someone outside the home in the past 12 months, ever having had vaginal sex, ever having had anal sex, and consuming any alcohol. Few statistically significant associations were unique to specific age groups. The history of IPV among the youngest AGYW is a critical finding and should be a focus of prevention efforts.

Does Partner Selection Mediate the Relationship Between School Attendance and HIV/Herpes Simplex Virus-2 Among Adolescent Girls and Young Women in South Africa: An Analysis of HIV Prevention Trials Network 068 Data.

OBJECTIVE: School attendance prevents HIV and herpes simplex virus-2 (HSV-2) in adolescent girls and young women, but the mechanisms to explain this relationship remain unclear. Our study assesses the extent to which characteristics of sex partners, partner age, and number mediate the relationship between attendance and risk of infection in adolescent girls and young women in South Africa. DESIGN: We use longitudinal data from the HIV Prevention Trials Network 068 randomized controlled trial in rural South Africa, where girls were enrolled in early adolescence and followed in the main trial for more than 3 years. We examined older partners and the number of partners as possible mediators. METHODS: We used the parametric g-formula to estimate 4-year risk differences for the effect of school attendance on the cumulative incidence of HIV/HSV-2 overall and the controlled direct effect (CDE) for mediation. We examined mediation separately and jointly for the mediators of interest. RESULTS: We found that young women with high attendance in school had a lower cumulative incidence of HIV compared with those with low attendance (risk difference = -1.6%). Partner age difference (CDE = -1.2%) and the number of partners (CDE = -0.4%) mediated a large portion of this effect. In fact, when we accounted for the mediators jointly, the effect of schooling on HIV was almost removed, showing full mediation (CDE = -0.3%). The same patterns were observed for the relationship between school attendance and cumulative incidence of HSV-2 infection. CONCLUSION: Increasing school attendance reduces the risk of acquiring HIV and HSV-2. Our results indicate the importance of school attendance in reducing partner number and partner age difference in this relationship.

Effect of Schooling on Age-Disparate Relationships and Number of Sexual Partners Among Young Women in Rural South Africa Enrolled in HPTN 068.

BACKGROUND: Attending school may have a strong preventative association with sexually transmitted infections among young women, but the mechanism for this relationship is unknown. One hypothesis is that students who attend school practice safer sex with fewer partners, establishing safer sexual networks that make them less exposed to infection. SETTING: We used longitudinal data from a randomized controlled trial of young women aged 13-20 years in the Bushbuckridge district, South Africa, to determine whether the percentage of school days attended, school dropout, and grade repetition are associated with having a partner 5 or more years older (age-disparate) and with the number of sexual partners in the previous 12 months. METHODS: Risks of having an age-disparate relationship and number of sexual partners were compared using inverse probability of exposure weighted Poisson regression models. Generalized estimating equations were used to account for repeated measures. RESULTS: Young women who attended fewer school days (<80%) and who dropped out of school were more likely to have an age-disparate relationship (risk difference 9.9%, 95% confidence interval [CI]: 3.9% to 16.0%; risk difference (%) dropout 17.2%, 95% CI: 5.4% to 29.0%) and those who dropped out reported having fewer partners (count difference dropout 0.343, 95% CI: 0.192 to 0.495). Grade repetition was not associated with either behavior. CONCLUSION: Young women who less frequently attend school or who drop out are more likely to have an age-disparate relationship. Young women who drop out have overall more partners. These behaviors may increase the risk of exposure to HIV infection in young women out of school.

Cash transfers for HIV prevention: what do young women spend it on? Mixed methods findings from HPTN 068.

BACKGROUND: Social grants have been found to have an impact on health and wellbeing in multiple settings. Who receives the grant, however, has been the subject of discussion with regards to how the money is spent and who benefits from the grant. METHODS: Using survey data from 1214 young women who were in the intervention arm and completed at least one annual visit in the HPTN 068 trial, and qualitative interview data from a subset of 38 participants, we examined spending of a cash transfer provided to young women conditioned on school attendance. RESULTS: We found that spending was largely determined and controlled by young women themselves and that the cash transfer was predominately spent on toiletries, clothing and school supplies. In interview data, young women discussed the significant role of cash transfers for adolescent identity, specifically with regard to independence from family and status within the peer network. There were almost no negative consequences from receiving the cash transfer. CONCLUSIONS: We established that providing adolescents access to cash was not reported to be associated with social harms or negative consequences. Rather, spending of the cash facilitated appropriate adolescent developmental behaviours. The findings are encouraging at a time in which there is global interest in addressing the structural drivers of HIV risk, such as poverty, for young women. TRIAL REGISTRATION: Clinicaltrials.gov NCT01233531 (1 Nov 2010). First participant enrolled 5 March 2011.

The effect of school attendance and school dropout on incident HIV and HSV-2 among young women in rural South Africa enrolled in HPTN 068.

OBJECTIVE: To estimate the association between school attendance, school dropout, and risk of incident HIV and herpes simplex virus type 2 (HSV-2) infection among young women. DESIGN: We used longitudinal data from a randomized controlled trial in rural Mpumalanga province, South Africa, to assess the association between school days attended, school dropout, and incident HIV and HSV-2 in young women aged 13-23 years. METHODS: We examined inverse probability of exposure weighted survival curves and used them to calculate 1.5, 2.5, and 3.5-year risk differences and risk ratios for the effect of school attendance on incident HIV and HSV-2. A marginal structural Cox model was used to estimate hazard ratios for the effect of school attendance and school dropout on incident infection. RESULTS: Risk of infection increased over time as young women aged, and was higher in young women with low school attendance (<80% school days) compared with high (≥80% school days). Young women with low attendance were more likely to acquire HIV [hazard ratio (HR): 2.97; 95% confidence interval (CI): 1.62, 5.45] and HSV-2 (HR: 2.47; 95% CI: 1.46, 4.17) over the follow-up period than young women with high attendance. Similarly, young women who dropped out of school had a higher weighted hazard of both HIV (HR 3.25 95% CI: 1.67, 6.32) and HSV-2 (HR 2.70; 95% CI 1.59, 4.59). CONCLUSION: Young women who attend more school days and stay in school have a lower risk of incident HIV and HSV-2 infection. Interventions to increase frequency of school attendance and prevent dropout should be promoted to reduce risk of infection.

Evaluation of the Tsima community mobilization intervention to improve engagement in HIV testing and care in South Africa: study protocol for a cluster randomized trial.

BACKGROUND: HIV transmission can be decreased substantially by reducing the burden of undiagnosed HIV infection and expanding early and consistent use of antiretroviral therapy (ART). Treatment as prevention (TasP) has been proposed as key to ending the HIV epidemic. To activate TasP in high prevalence countries, like South Africa, communities must be motivated to know their status, engage in care, and remain in care. Community mobilization (CM) has the potential to significantly increase uptake testing, linkage to and retention in care by addressing the primary social barriers to engagement with HIV care-including poor understanding of HIV care; fear and stigma associated with infection, clinic attendance and disclosure; lack of social support; and gender norms that deter men from accessing care. METHODS/DESIGN: Using a cluster randomized trial design, we are implementing a 3-year-theory-based CM intervention and comparing gains in HIV testing, linkage, and retention in care among individuals residing in 8 intervention communities to that of individuals residing in 7 control communities. Eligible communities include 15 villages within a health and demographic surveillance site (HDSS) in rural Mpumalanga, South Africa, that were not exposed to previous CM efforts. CM activities conducted in the 8 intervention villages map onto six mobilization domains that comprise the key components for community mobilization around HIV prevention. To evaluate the intervention, we will link a clinic-based electronic clinical tracking system in all area clinics to the HDSS longitudinal census data, thus creating an open, population-based cohort with over 30,000 18-49-year-old residents. We will estimate the marginal effect of the intervention on individual outcomes using generalized estimating equations. In addition, we will evaluate CM processes by conducting baseline and endline surveys among a random sample of 1200 community residents at each time point to monitor intervention exposure and community level change using validated measures of CM. DISCUSSION: Given the known importance of community social factors with regard to uptake of testing and HIV care, and the lack of rigorously evaluated community-level interventions effective in improving testing uptake, linkage and retention, the proposed study will yield much needed data to understand the potential of CM to improve the prevention and care cascade. Further, our work in developing a CM framework and domain measures will permit validation of a CM conceptual framework and process, which should prove valuable for community programming in Africa. TRIAL REGISTRATION: NCT02197793 Registered July 21, 2014.

A novel isoform of the Ly108 gene ameliorates murine lupus.

Studies of human systemic lupus erythematosus patients and of murine congenic mouse strains associate genes in a DNA segment on chromosome 1 with a genetic predisposition for this disease. The systematic analysis of lupus-prone congenic mouse strains suggests a role for two isoforms of the Ly108 receptor in the pathogenesis of the disease. In this study, we demonstrate that Ly108 is involved in the pathogenesis of lupus-related autoimmunity in mice. More importantly, we identified a third protein isoform, Ly108-H1, which is absent in two lupus-prone congenic animals. Introduction of an Ly108-H1-expressing transgene markedly diminishes T cell-dependent autoimmunity in congenic B6.Sle1b mice. Thus, an immune response-suppressing isoform of Ly108 can regulate the pathogenesis of lupus.

Homotypic interactions mediated by Slamf1 and Slamf6 receptors control NKT cell lineage development.

Commitment to the T and natural killer T (NKT) cell lineages is determined during alphabeta T cell receptor (TCR)-mediated interactions of common precursors with ligand-expressing cells in the thymus. Whereas mainstream thymocyte precursors recognize major histocompatibility complex (MHC) ligands expressed by stromal cells, NKT cell precursors interact with CD1d ligands expressed by cortical thymocytes. Here, we demonstrated that such homotypic T-T interactions generated "second signals" mediated by the cooperative engagement of the homophilic receptors Slamf1 (SLAM) and Slamf6 (Ly108) and the downstream recruitment of the adaptor SLAM-associated protein (SAP) and the Src kinase Fyn, which are essential for the lineage expansion and differentiation of the NKT cell lineage. These receptor interactions were required during TCR engagement and therefore only occurred when selecting ligands were presented by thymocytes rather than epithelial cells, which do not express Slamf6 or Slamf1. Thus, the topography of NKT cell ligand recognition determines the availability of a cosignaling pathway that is essential for NKT cell lineage development.

CD48 controls T-cell and antigen-presenting cell functions in experimental colitis.

BACKGROUND & AIMS: The cell-surface receptor CD48 is a lipid-anchored protein expressed on all antigen-presenting cells and T cells. CD2 and 2B4 are known ligands for CD48, which themselves are expressed on the surface of hematopoietic cells. Here we examine the effect of CD48 in the development of chronic experimental colitis and how CD48 affects adaptive and innate immune functions. METHODS: The role of CD48 in experimental colitis was first assessed by transferring CD4(+)CD45RB(hi) cells isolated from either wild-type or CD48(-/-) mice into either Rag-2(-/-) or CD48(-/-) x Rag-2(-/-) mice. Development of chronic colitis in these adoptively transferred mice was assessed by disease activity index, histology, and production of interferon-gamma in mesenteric lymph nodes. Relevant functions of CD48(-/-)CD4(+) T cells and CD48(-/-) macrophages were examined using in vitro assays. In a second set of experiments, the efficacy of anti-CD48 in prevention or treatment of chronic colitis was determined. RESULTS: CD48(-/-)CD4(+) cells induced colitis when transferred into Rag-2(-/-) mice, but not when introduced into CD48(-/-) x Rag-2(-/-) recipients. However, both recipient mouse strains developed colitis upon adoptive transfer of wild-type CD4(+) cells. Consistent with a CD4(+) T-cell defect was the observation that in vitro proliferation of CD48(-/-)CD4(+) T cells was impaired upon stimulation with CD48(-/-) macrophages. In vitro evidence for a modest macrophage functional defect was apparent because CD48(-/-) macrophages produced less tumor necrosis factor alpha and interleukin 12 than wild-type cells upon stimulation with lipopolysaccharide. Peritoneal macrophages also showed a defect in clearance of gram-negative bacteria in vitro. Treatment of the CD4(+)CD45RB(hi)-->Rag-2(-/-) mice or the wild-type BM-->tg26 mice with anti-CD48 (HM48-1) ameliorated development of colitis, even after its induction. CONCLUSIONS: Both CD48-dependent activation of macrophages and CD48-controlled activation of T cells contribute to maintaining the inflammatory response. Consequently, T cell-induced experimental colitis is ameliorated only when CD48 is absent from both T cells and antigen-presenting cells. Because anti-CD48 interferes with these processes, anti-human CD48 antibody treatment may represent a novel therapy for inflammatory bowel disease patients.

Cutting edge: the SLAM family receptor Ly108 controls T cell and neutrophil functions.

Ly108, a glycoprotein of the signaling lymphocytic activation molecule family of cell surface receptors expressed by T, B, NK, and APCs has been shown to have a role in NK cell cytotoxicity and T cell cytokine responses. In this study, we describe that CD4(+) T cells from mice with a targeted disruption of exons 2 and 3 of Ly108 (Ly108(DeltaE2+3)) produce significantly less IL-4 than wild-type CD4(+) cells, as judged by in vitro assays and by in vivo responses to cutaneous infection with Leishmania mexicana. Surprisingly, neutrophil functions are controlled by Ly108. Ly108(DeltaE2+3) mice are highly susceptible to infection with Salmonella typhimurium, bactericidal activity of Ly108(DeltaE2+3) neutrophils is defective, and their production of IL-6, IL-12, and TNF-alpha is increased. The aberrant bactericidal activity by Ly108(DeltaE2+3) neutrophils is a consequence of severely reduced production of reactive oxygen species following phagocytosis of bacteria. Thus, Ly108 serves as a regulator of both innate and adaptive immune responses.

Defective B cell responses in the absence of SH2D1A.

More than half of patients with X-linked lympho-proliferative disease, which is caused by a defect in the intracellular adapter protein SH2D1A, suffer from an extreme susceptibility to Epstein-Barr virus. One-third of these patients, however, develop dysgammaglobulenemia without an episode of severe mononucleosis. Here we show that in SH2D1A(-/-) mice, both primary and secondary responses of all Ig subclasses are severely impaired in response to specific antigens. Because germinal centers were absent in SH2D1A(-/-) mice upon primary immunization, and because SH2D1A was detectable in wt germinal center B cells, we examined whether SH2D1A(-/-) B cell functions were impaired. Using the adoptive cotransfer of B lymphocytes from hapten-primed SH2D1A(-/-) mice with CD4(+) T cells from primed wt mice into irradiated wt mice provided evidence that signal transduction events controlled by SH2D1A are essential for B cell activities resulting in antigen specific IgG production. Defects in naive SH2D1A(-/-) B cells became evident upon cotransfer with non-primed wt CD4(+) cells into Rag2(-/-) recipients. Thus, both defective T and B cells exist in the absence of SH2D1A, which may explain the progressive dysgammaglobulinemia in a subset of X-linked lympho-proliferative disease patients without involvement of Epstein-Barr virus.