The Effect of HIV on the Association of Hyperglycaemia and Active Tuberculosis in Zambia, a Case-Control Study.

OBJECTIVES: To determine if HIV modifies the association between hyperglycaemia and active tuberculosis in Lusaka, Zambia. METHODS: A case-control study among newly-diagnosed adult tuberculosis cases and population controls in three areas of Lusaka. Hyperglycaemia is determined by random blood glucose (RBG) concentration measured at the time of recruitment; active tuberculosis disease by clinical diagnosis, and HIV status by serological result. Multivariable logistic regression is used to explore the primary association and effect modification by HIV. RESULTS: The prevalence of RBG concentration ≥ 11.1 mmol/L among 3843 tuberculosis cases was 1.4% and among 6977 controls was 1.5%. Overall, the adjusted odds ratio of active tuberculosis was 1.60 (95% CI 0.91-2.82) comparing those with RBG concentration ≥ 11.1- < 11.1 mmol/L. The corresponding adjusted odds ratio among those with and without HIV was 5.47 (95% CI 1.29-23.21) and 1.17 (95% CI 0.61-2.27) respectively; p-value for effect modification by HIV = 0.042. On subgroup analysis, the adjusted odds ratio of smear/Xpert-positive tuberculosis was 2.97 (95% CI 1.49-5.90) comparing RBG concentration ≥ 11.1- < 11.1 mmol/L. CONCLUSIONS: Overall, no evidence of association between hyperglycaemia and active tuberculosis was found, though among those with HIV and/or smear/Xpert-positive tuberculosis there was evidence of association. Differentiation of hyperglycaemia caused by diabetes mellitus and stress-induced hyperglycaemia secondary to tuberculosis infection is important for a better understanding of these findings.

Integrating molecular and radiological screening tools during community-based active case-finding for tuberculosis and COVID-19 in southern Africa.

OBJECTIVES: To evaluate diagnostic yield and feasibility of integrating testing for TB and COVID-19 using molecular and radiological screening tools during community-based active case-finding (ACF). METHODS: Community-based participants with presumed TB and/or COVID-19 were recruited using a mobile clinic. Participants underwent simultaneous point-of-care (POC) testing for TB (sputum; Xpert-Ultra) and COVID-19 (nasopharyngeal swabs; Xpert-SARS-CoV-2). Sputum culture and SARS-CoV-2 RT-PCR served as reference standards. Participants underwent ultra-portable POC chest-radiography with computer-aided detection (CAD). TB infectiousness was evaluated using smear microscopy, cough aerosol sampling studies (CASS), and chest radiographic cavity detection. Feasibility of POC testing was evaluated via user-appraisals. RESULTS: 601 participants were enrolled, with 144/601 (24.0%) reporting symptoms suggestive of TB and/or COVID-19. 16/144 (11.1%) participants tested positive for TB, while 10/144 (6.9%) tested positive for COVID-19 (2/144 [1.4%] had concurrent TB/COVID-19). 7/16 (43.8%) individuals with TB were probably infectious. Test-specific sensitivity and specificity (95% CI) were: Xpert-Ultra 75.0% (42.8-94.5) and 96.9% (92.4-99.2); Xpert-SARS-CoV-2 66.7% (22.3-95.7) and 97.1% (92.7-99.2). Area-under-the-curve (AUC) for CAD4TB was 0.90 (0.82-0.97). User appraisals indicated POC Xpert to have 'good' user-friendliness. CONCLUSIONS: Integrating TB/COVID-19 screening during community-based ACF using POC molecular and radiological tools is feasible, has a high diagnostic yield, and can identity probably infectious persons.

The burden and natural history of cardiac pathology at TB diagnosis in a high-HIV prevalence district in Zambia: protocol for the TB-Heart study.

BACKGROUND: Tuberculosis (TB) continues to be a major cause of death across sub-Saharan Africa (SSA). In parallel, non-communicable disease and especially cardiovascular disease (CVD) burden has increased substantially in the region. Cardiac manifestations of TB are well-recognised but the extent to which they co-exist with pulmonary TB (PTB) has not been systematically evaluated. The aim of this study is to improve understanding of the burden of cardiac pathology in PTB in those living with and without HIV in a high-burden setting. METHODS: This is a cross-sectional and natural history study to evaluate the burden and natural history of cardiac pathology in participants with PTB in Lusaka, Zambia, a high burden setting for TB and HIV. Participants with PTB, with and without HIV will be consecutively recruited alongside age- and sex-matched TB-uninfected comparators on a 2:1 basis. Participants will undergo baseline assessments to collect clinical, socio-demographic, functional, laboratory and TB disease impact data followed by point-of-care and standard echocardiography. Participants with PTB will undergo further repeat clinical and functional examination at two- and six months follow-up. Those with cardiac pathology at baseline will undergo repeat echocardiography at six months. DISCUSSION: The outcomes of the study are to a) determine the burden of cardiac pathology at TB diagnosis, b) describe its association with patient-defining risk factors and biochemical markers of cardiac injury and stretch and c) describe the natural history of cardiac pathology during the course of TB treatment.

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.

Self-reported uptake of STI testing services among adolescents and young people aged 15-24 years: Findings from the Yathu Yathu cluster randomized trial in Lusaka, Zambia.

There is little evidence regarding community-based delivery of STI testing and treatment for youth aged 15-24 (AYP) in Zambia. In a cluster-randomised trial, we evaluated whether offering syndromic STI screening through community-based, peer-led sexual and reproductive health services (Yathu Yathu) with referral to a local health facility for testing, increased self-reported testing for STIs (other than HIV) among AYP. Two communities in Lusaka were divided into 10 zones each (20 zones in total); by community, zones were randomly allocated (1:1) to Yathu Yathu or control. Monitoring data were used to describe syndromic STI screening through Yathu Yathu and an endline cross-sectional survey used to evaluate the impact of Yathu Yathu on self-reported ever and recent (last 12 months) STI testing. 10,974 AYP accessed Yathu Yathu; 66.6% (females-67.7%; males-64.7%) were screened for STIs, 6.2% reported any STI symptoms. In the endline survey, 23.3% (n = 350/1501) of AYP who ever had sex ever STI tested; 13.5% (n = 174/1498) who had sex in the last 12 months recently STI tested. By trial arm, there was no difference in self-reported ever or recent STI testing among all AYP. Among men aged 20-24, there was evidence that ever STI testing was higher in the Yathu Yathu compared to control arm (24.1% vs 16.1%; adjPR = 1.67 95%CI = 1.02, 2.74; p = 0.04). Among AYP who ever STI tested, 6.6% (n = 23) reported ever being diagnosed with an STI. Syndromic STI management through community-based, peer-led services showed no impact on self-reported STI testing among AYP. Research on community-based delivery of (near) point-of-care diagnostics is needed. Trial registration number(s): NCT04060420 https://clinicaltrials.gov/ct2/show/NCT04060420; and ISRCTN75609016; https://doi.org/10.1186/ISRCTN75609016.

Evaluation of COVID-19 antigen rapid diagnostic tests for self-testing in Lesotho and Zambia.

INTRODUCTION: The use of antigen rapid tests (Ag-RDTs) for self-testing is an important element of the COVID-19 control strategy and has been widely supported. However, scale-up of self-testing for COVID-19 in sub-Saharan Africa is still insufficient and there is limited evidence on the acceptability of self-testing and agreement between Ag-RDT self-testing and Ag-RDT testing by professional users. A joint collaboration (Botnar Research Centre for Child Health-European & Developing countries Clinical Trials Partnership)was established between Lesotho and Zambia to address these gaps in relation to Ag-RDT self-testing and contribute to increasing its use in the region. METHODS: A cross-sectional study was conducted with qualitative and quantitative data analysis. Firstly, 14 in-depth cognitive interviews (5 in Zambia and 9 in Lesotho) were performed to assess the participants' understanding of the instructions for use (IFU) for self-testing. In a second step, evaluation of test agreement between Ag-RDT self-testing and Ag-RDT testing by professional user using SD Biosensor STANDARD Q COVID-19 Ag-RDT was performed. In Zambia, usability and acceptability of self-testing were also assessed. RESULTS: Cognitive interviews in Lesotho and Zambia showed overall good understanding of IFU. In Zambia, acceptability of self-testing was high, though some participants had difficulties in conducting certain steps in the IFU correctly. Agreement between Ag-RDT self-test and Ag-RDT by professional users in Lesotho (428 participants) and Zambia (1136 participants) was high, 97.3% (403/414, 95% CI: 95.3-98.7) and 99.8% (1116/1118, 95% CI: 99.4-100) respectively. CONCLUSION: Findings from this study support the use of Ag-RDT self-testing within COVID-19 control strategies in sub-Saharan Africa, contributing to increase the testing capacity and access in hard-to reach settings.

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.

Demographics of sources of HIV-1 transmission in Zambia: a molecular epidemiology analysis in the HPTN 071 PopART study.

BACKGROUND: In the last decade, universally available antiretroviral therapy (ART) has led to greatly improved health and survival of people living with HIV in sub-Saharan Africa, but new infections continue to appear. The design of effective prevention strategies requires the demographic characterisation of individuals acting as sources of infection, which is the aim of this study. METHODS: Between 2014 and 2018, the HPTN 071 PopART study was conducted to quantify the public health benefits of ART. Viral samples from 7124 study participants in Zambia were deep-sequenced as part of HPTN 071-02 PopART Phylogenetics, an ancillary study. We used these sequences to identify likely transmission pairs. After demographic weighting of the recipients in these pairs to match the overall HIV-positive population, we analysed the demographic characteristics of the sources to better understand transmission in the general population. FINDINGS: We identified a total of 300 likely transmission pairs. 178 (59·4%) were male to female, with 130 (95% CI 110-150; 43·3%) from males aged 25-40 years. Overall, men transmitted 2·09-fold (2·06-2·29) more infections per capita than women, a ratio peaking at 5·87 (2·78-15·8) in the 35-39 years source age group. 40 (26-57; 13·2%) transmissions linked individuals from different communities in the trial. Of 288 sources with recorded information on drug resistance mutations, 52 (38-69; 18·1%) carried viruses resistant to first-line ART. INTERPRETATION: HIV-1 transmission in the HPTN 071 study communities comes from a wide range of age and sex groups, and there is no outsized contribution to new infections from importation or drug resistance mutations. Men aged 25-39 years, underserved by current treatment and prevention services, should be prioritised for HIV testing and ART. FUNDING: National Institute of Allergy and Infectious Diseases, US President's Emergency Plan for AIDS Relief, International Initiative for Impact Evaluation, Bill & Melinda Gates Foundation, National Institute on Drug Abuse, and National Institute of Mental Health.

Factors associated with use of community-based, peer-led sexual and reproductive health services by adolescent boys and young men aged 18-24 in Lusaka, Zambia: A case control study nested in the Yathu Yathu trial.

INTRODUCTION: Adolescents and young people (AYP) aged 15-24 years have the least access to facility-based sexual and reproductive health (SRH) services, including HIV services. The Yathu-Yathu cluster-randomized trial (CRT) in Zambia tested whether a novel peer-led community-based approach increased knowledge of HIV status amongst AYP. In this nested case-control study, we aimed to identify factors associated with non-attendance to the Yathu Yathu hubs by adolescent boys and young men (ABYM) aged 18-24-years. METHODS: Yathu Yathu was a CRT conducted in two communities in Lusaka, Zambia, with 10 intervention and 10 control zones. AYP in all zones were offered prevention points cards (PPC), which incentivized and tracked service use at the hubs and health facility. In intervention zones, services were provided to AYP through community-based spaces (hubs) led by peer support workers. In these zones, cases were defined as those not having accessed any service at a hub and controls as those that accessed at least one service. Data were collected from October 2020 to January 2021 and analysed using methods appropriate for unmatched case-control studies. RESULTS: 161 cases and 160 controls consented to participate in the study. Participants aged 20-24 years (adjOR 1.99, 95%CI 1.26-3.12, p = 0.003), who were educated up to college level (adjOR 8.47,95%CI 2.08-34.53, p = 0.001) or who reported being employed in the last 12 months (adjOR 2.15, 95%CI 1.31-3.53, p = 0.002) were more likely to not attend the hubs. ABYM who had a friend with a PPC were more likely to attend the hubs (adjOR 0.18 95%CI 0.09-0.35, p<0.001). Most cases reported having their last HIV test at the local government health facility (58%) while most controls reported HIV-testing at a Yathu Yathu hub (82%). Among the controls, 84% (134/160) rated the hub experience as excellent. Among cases, 65% (104/161) stated they didn't visit the hubs "due to employment". CONCLUSIONS: Despite Yathu Yathu services being community-based and more accessible compared to health facilities, we found age, education and employment were associated with not attending hubs. Strategies are needed to reach employed young men who may not have access to SRH/HIV services during conventional working hours and to better utilise peer networks to increase service use.

Population-level analysis of natural control of HIV infection in Zambia and South Africa: HPTN 071 (PopART).

INTRODUCTION: HIV controllers have low viral loads (VL) without antiretroviral treatment (ART). We evaluated viraemic control in a community-randomized trial conducted in Zambia and South Africa that evaluated the impact of a combination prevention intervention on HIV incidence (HPTN 071 [PopART]; 2013-2018). METHODS: VL and antiretroviral (ARV) drug testing were performed using plasma samples collected 2 years after enrolment for 4072 participants who were HIV positive at the start of the study intervention. ARV drug use was assessed using a qualitative laboratory assay that detects 22 ARV drugs in five drug classes. Participants were classified as non-controllers if they had a VL ≥2000 copies/ml with no ARV drugs detected at this visit. Additional VL and ARV drug testing was performed at a second annual study visit to confirm controller status. Participants were classified as controllers if they had VLs <2000 with no ARV drugs detected at both visits. Non-controllers who had ARV drugs detected at either visit were excluded from the analysis to minimize potential confounders associated with ARV drug access and uptake. RESULTS: The final cohort included 126 viraemic controllers and 766 non-controllers who had no ARV drugs detected. The prevalence of controllers among the 4072 persons assessed was 3.1% (95% confidence interval [CI]: 2.6%, 3.6%). This should be considered a minimum estimate, since high rates of ARV drug use in the parent study limited the ability to identify controllers. Among the 892 participants in the final cohort, controller status was associated with biological sex (female > male, p = 0.027). There was no significant association between controller status and age, study country or herpes simplex virus type 2 (HSV-2) status at study enrolment. CONCLUSIONS: To our knowledge, this report presents the first large-scale, population-level study evaluating the prevalence of viraemic control and associated factors in Africa. A key advantage of this study was that a biomedical assessment was used to assess ARV drug use (vs. self-reported data). This study identified a large cohort of HIV controllers and non-controllers not taking ARV drugs, providing a unique repository of longitudinal samples for additional research. This cohort may be useful for further studies investigating the mechanisms of virologic control.

Comprehensive profiling of pre-infection antibodies identifies HIV targets associated with viremic control and viral load.

Background: High HIV viral load (VL) is associated with increased transmission risk and faster disease progression. HIV controllers achieve viral suppression without antiretroviral (ARV) treatment. We evaluated viremic control in a community-randomized trial with >48,000 participants. Methods: A massively multiplexed antibody profiling system, VirScan, was used to quantify pre- and post-infection antibody reactivity to HIV peptides in 664 samples from 429 participants (13 controllers, 135 viremic non-controllers, 64 other non-controllers, 217 uninfected persons). Controllers had VLs <2,000 copies/mL with no ARV drugs detected at the first HIV-positive visit and one year later. Viremic non-controllers had VLs 2,000 copies/mL with no ARV drugs detected at the first HIV-positive visit. Other non-controllers had either ARV drugs detected at the first HIV-positive visit (n=47) or VLs <2,000 copies/mL with no ARV drugs detected at only one HIV-positive visit (n=17). Results: We identified pre-infection HIV antibody reactivities that correlated with post-infection VL. Pre-infection reactivity to an epitope in the HR2 domain of gp41 was associated with controller status and lower VL. Pre-infection reactivity to an epitope in the C2 domain of gp120 was associated with non-controller status and higher VL. Different patterns of antibody reactivity were observed over time for these two epitopes. Conclusion: These studies suggest that pre-infection HIV antibodies are associated with controller status and modulation of HIV VL. These findings may inform research on antibody-based interventions for HIV treatment.

Prevalence and risk factors of M tuberculosis infection in young people across 14 communities in Zambia and South Africa.

BACKGROUND: From 2018-2021 the TB Reduction through Expanded Antiretroviral Treatment and TB Screening (TREATS) project took place in 21 Zambian and South African communities. The TREATS Incidence of TB Infection Cohort Study was conducted in adolescents and young people (AYP), aged 15-24 years in 14 communities. We describe the baseline prevalence and risk factors of Mycobacterium tuberculosis (M. tuberculosis) infection among this cohort and explore the quantitative QFT-Plus interferon gamma (IFN-γ) responses. METHODS AND FINDINGS: A random sample of approximately 300 AYP per community were recruited and information on TB/HIV risk factors, TB symptoms and social mixing patterns collected. QuantiFERON TB Gold Plus assay (QFT-Plus) was used to detect M. tuberculosis infection, following manufacturer's instructions. Logistic regression was used to determine factors associated with infection. 5577 eligible AYP were invited to participate across both countries, with 4648 enrolled. QFT-Plus results were available for 4529: 2552(Zambia) and 1977(South Africa). Overall, 47.6% (2156/4529) AYP had positive QFT-Plus results, the prevalence of infection in South Africa being twice that in Zambia (64.7% (1280/1977) vs 34.3% (867/2552) p<0.001). Infection was associated with age, household contact with TB and alcohol in Zambia but showed no associations in South Africa. The antigen tube differential (TB2-TB1>0.6 IU/ml) of the assay at baseline showed no evidence of association with recent TB exposure. CONCLUSION: The high prevalence of infection in AYP warrants urgent action to address TB control, especially in South Africa. Further research is required to delineate antigen tube responses of the QFT-Plus assay more precisely to fully realise the benefit of the additional TB2 tube in high TB/HIV burden settings.

Protocol-driven primary care and community linkage to reduce all-cause mortality in rural Zambia: a stepped-wedge cluster randomized trial.

Introduction: While tremendous progress has been made in recent years to improve the health of people living in low- and middle-income countries (LMIC), significant challenges remain. Chief among these are poor health systems, which are often ill-equipped to respond to current challenges. It remains unclear whether intensive intervention at the health system level will result in improved outcomes, as there have been few rigorously designed comparative studies. We present results of a complex health system intervention that was implemented in Zambia using a cluster randomized design. Methods: BHOMA was a complex health system intervention comprising intensive clinical training and quality improvement measures, support for commodities procurement, improved community outreach, and district level management support. The intervention was introduced as a stepped wedge cluster-randomized trial in 42 predominately rural health centers and their surrounding communities in Lusaka Province, Zambia. Baseline survey was conducted between January-May 2011, mid-line survey was conducted February-November, 2013 and Endline survey, February-November 2015.The primary outcome was all-cause mortality among those between 28 days and 60 years of age and assessed through community-based mortality surveys. Secondary outcomes included post-neonatal under-five mortality and service coverage scores. Service coverage scores were calculated across five domains (child preventative services; child treatment services; family planning; maternal health services, and adult health services). We fit Cox proportional hazards model with shared frailty at the cluster level for the primary analysis. Mortality rates were age-standardized using the WHO World Standard Population. Results: Mortality declined substantially from 3.9 per 1,000 person-years in the pre-intervention period, to 1.5 per 1,000 person-years in the post intervention period. When we compared intervention and control periods, there were 174 deaths in 49,230 person years (age-standardized rate = 4.4 per 1,000 person-years) in the control phase and 277 deaths in 74,519 person years (age-standardized rate = 4.6 per 1,000 person-years) in the intervention phase. Overall, there was no evidence for an effect of the intervention in minimally-adjusted [hazard ratio (HR) = 1.18; 95% confidence interval (CI): 0.88, 1.56; value of p = 0.265], or adjusted (HR = 1.12; 95% CI: 0.84, 1.49; value of p = 0.443) analyses.Coverage scores that showed some evidence of changing with time since the cluster joined the intervention were: an increasing proportion of children sleeping under insecticide treated bed-net (value of p < 0.001); an increasing proportion of febrile children who received appropriate anti-malarial drugs (value of p = 0.039); and an increasing proportion of ever hypertensive adults with currently controlled hypertension (value of p = 0.047). No adjustments were made for multiple-testing and the overall coverage score showed no statistical evidence for a change over time (value of p = 0.308). Conclusion: We noted an overall reduction in post-neonatal under 60 mortality in the study communities during the period of our study, but this could not be attributed to the BHOMA intervention. Some improvements in service coverage scores were observed. Clinical Trial Registration: clinicaltrials.gov, Identifier NCT01942278.

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.

The effect of universal testing and treatment for HIV on health-related quality of life - An analysis of data from the HPTN 071 (PopART) cluster randomised trial.

Background: HIV treatment has clear Health-Related Quality-of-Life (HRQoL) benefits. However, little is known about how Universal Testing and Treatment (UTT) for HIV affects HRQoL. This study aimed to examine the effect of a combination prevention intervention, including UTT, on HRQoL among People Living with HIV (PLHIV). Methods: Data were from HPTN 071 (PopART), a three-arm cluster randomised controlled trial in 21 communities in Zambia and South Africa (2013-2018). Arm A received the full UTT intervention of door-to-door HIV testing plus access to antiretroviral therapy (ART) regardless of CD4 count, Arm B received the intervention but followed national treatment guidelines (universal ART from 2016), and Arm C received standard care. The intervention effect was measured in a cohort of randomly selected adults, over 36 months. HRQoL scores, and the prevalence of problems in five HRQoL dimensions (mobility, self-care, performing daily activities, pain/discomfort, anxiety/depression) were assessed among all participants using the EuroQol-5-dimensions-5-levels questionnaire (EQ-5D-5L). We compared HRQoL among PLHIV with laboratory confirmed HIV status between arms, using adjusted two-stage cluster-level analyses. Results: At baseline, 7,856 PLHIV provided HRQoL data. At 36 months, the mean HRQoL score was 0.892 (95% confidence interval: 0.887-0.898) in Arm A, 0.886 (0.877-0.894) in Arm B and 0.888 (0.884-0.892) in Arm C. There was no evidence of a difference in HRQoL scores between arms (A vs C, adjusted mean difference: 0.003, -0.001-0.006; B vs C: -0.004, -0.014-0.005). The prevalence of problems with pain/discomfort was lower in Arm A than C (adjusted prevalence ratio: 0.37, 0.14-0.97). There was no evidence of differences for other HRQoL dimensions. Conclusions: The intervention did not change overall HRQoL, suggesting that raising HRQoL among PLHIV might require more than improved testing and treatment. However, PLHIV had fewer problems with pain/discomfort under the full intervention; this benefit of UTT should be maximised during roll-out.

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.

Community- and individual-level correlates of HIV incidence in HPTN 071 (PopART).

INTRODUCTION: Universal HIV testing and treatment aims to identify all people living with HIV and offer them treatment, decreasing the number of individuals with unsuppressed HIV and thus reducing HIV transmission. Longitudinal follow-up of individuals with and without HIV in a cluster-randomized trial of communities allowed for the examination of community- and individual-level measures of HIV risk and HIV incidence. METHODS: HPTN 071 (PopART) was a three-arm cluster-randomized trial conducted between 2013 and 2018 that evaluated the use of two combination HIV prevention strategies implemented at the community level to reduce HIV incidence compared to the standard of care. The trial, conducted in 21 communities in Zambia and South Africa, measured HIV incidence over 36 months in a population cohort of ∼2000 randomly selected adults per community aged 18-44. Multilevel models were used to assess the association between HIV incidence and community- and individual-level socio-demographic and behavioural risk factors, as well as prevalence of detectable virus (PDV) defined as the estimated proportion of the community with unsuppressed viral load. RESULTS: Overall HIV incidence was 1.49/100 person-years. Communities with less financial wealth and communities with more individuals reporting having sex partners outside of the community or two or more sexual partners had higher HIV incidence. PDV at 2 years of study was 6.8% and was strongly associated with HIV incidence: for every 50% relative reduction in community PDV, there was a 49% (95% confidence interval [CI]: 37%-58%, p < 0.001) relative decrease in HIV incidence. At the individual level; socio-economic status, AUDIT score, medical male circumcision and certain sexual behaviours were associated with HIV risk. CONCLUSIONS: Using data from the PopART randomized trial, we found several associations of HIV incidence with community-level measures reflecting the sexual behaviour and socio-economic make-up of each community. We also found a strong association between community PDV and HIV incidence supporting the use of PDV as a tool for monitoring progress in controlling the epidemic. Lastly, we found significant individual-level factors of HIV risk that are generally consistent with previous HIV epidemiological research. These results have the potential to identify high high-incidence communities, inform structural-level interventions, and optimize individual-level interventions for HIV prevention. CLINICAL TRIAL NUMBER: ClinicalTrials.gov number, NCT01900977, HPTN 071 [PopArt].

Creating access to SARS-CoV-2 screening and testing through community-based COVID-19 case-finding, observations from cross-sectional studies in Lesotho and Zambia.

BACKGROUND: The health impact of the COVID-19 pandemic largely depends on the ability of the healthcare systems to develop effective and adaptable preparedness and mitigation strategies. A collaborative initiative (BRCCH-EDCTP COVID-19 Initiative) was set up between Lesotho and Zambia early on in the pandemic, to jointly conduct a project to investigate creating access to SARS-CoV-2 screening and testing through community-based COVID-19 case-finding. METHODS: Two different community case-finding strategies were deployed. In Lesotho, an approach was implemented whereby a community (village) health worker screened community members at their home or during community gatherings for COVID-19 signs and symptoms. All community members who screened positive were then offered SARS-CoV-2 testing. In Zambia, so-called community hubs, staffed by community health care workers, were set up at different locations in the community for people to walk in and get tested for SARS-CoV-2. Hubs changed location from week-to-week and targeted transmission hotspots. All persons visiting the hubs were offered testing for SARS-CoV-2 irrespective of self-reported signs and symptoms of COVID-19 though information was collected on occurrence of these. Testing in both approaches was done using SARS-CoV-2 rapid antigen tests. RESULTS: Setting up testing in the community setting was feasible in both countries. In Lesotho in the village health worker approach, over a period of 46 weeks, 7221 persons were screened, and 49 (11.4%) SARS-COV-2 cases identified among 428 COVID-19 screen positive participants. In the community hubs among 3150 people tested, 166 (5.3%) SARS-CoV-2 cases were identified in a period of 26 weeks. From the community hubs approach, where all seen were offered COVID-19 testing it was learned that people screening positive for COVID-19 signs and symptoms were more likely to test SARS-COV-2 positive, especially those reporting classic COVID-19 symptoms like loss of sense/smell for a short period of time (1-3 days). CONCLUSIONS: In conclusion, in this project we learned that implementing COVID-19 screening and testing by lay health workers in the community is possible. Characteristics of the population screened, tested, and identified to have SARS-CoV-2 are described to help guide development of future testing strategies.

Population-level viremia predicts HIV incidence at the community level across the Universal Testing and Treatment Trials in eastern and southern Africa.

Universal HIV testing and treatment (UTT) strategies aim to optimize population-level benefits of antiretroviral treatment. Between 2012 and 2018, four large community randomized trials were conducted in eastern and southern Africa. While their results were broadly consistent showing decreased population-level viremia reduces HIV incidence, it remains unclear how much HIV incidence can be reduced by increasing suppression among people living with HIV (PLHIV). We conducted a pooled analysis across the four UTT trials. Leveraging data from 105 communities in five countries, we evaluated the linear relationship between i) population-level viremia (prevalence of non-suppression-defined as plasma HIV RNA >500 or >400 copies/mL-among all adults, irrespective of HIV status) and HIV incidence; and ii) prevalence of non-suppression among PLHIV and HIV incidence, using parametric g-computation. HIV prevalence, measured in 257 929 persons, varied from 2 to 41% across the communities; prevalence of non-suppression among PLHIV, measured in 31 377 persons, from 3 to 70%; population-level viremia, derived from HIV prevalence and non-suppression, from < 1% to 25%; and HIV incidence, measured over 345 844 person-years (PY), from 0.03/100PY to 3.46/100PY. Decreases in population-level viremia were strongly associated with decreased HIV incidence in all trials (between 0.45/100PY and 1.88/100PY decline in HIV incidence per 10 percentage points decline in viremia). Decreases in non-suppression among PLHIV were also associated with decreased HIV incidence in all trials (between 0.06/100PY and 0.17/100PY decline in HIV incidence per 10 percentage points decline in non-suppression). Our results support both the utility of population-level viremia as a predictor of incidence, and thus a tool for targeting prevention interventions, and the ability of UTT approaches to reduce HIV incidence by increasing viral suppression. Implementation of universal HIV testing approaches, coupled with interventions to leverage linkage to treatment, adapted to local contexts, can reduce HIV acquisition at population level.

The impact of a combined TB/HIV intervention on the incidence of TB infection among adolescents and young adults in the HPTN 071 (PopART) trial communities in Zambia and South Africa.

BACKGROUND: HPTN071 (PopART) was a cluster randomized trial conducted in Zambian and South African (SA) communities, between 2013-2018. The PopART intervention (universal HIV-testing and treatment (UTT) combined with population-level TB symptom screening) was implemented in 14 communities. The TREATS study (2017-2021) was conducted to evaluate the impact of the PopART intervention on TB outcomes. We report on the impact of the combined TB/HIV intervention on the incidence of TB infection in a cohort of adolescents and young adults (AYA) aged 15-24 years. METHODS: A random sample of AYA was enrolled between July 2018 and July 2019 in 7 intervention vs 7 standard-of-care communities. We collected questionnaire data on risk factors for TB, and blood for measuring TB infection using QuantiFERON (QFT) Plus. AYA were seen at months 12 and 24 with all procedures repeated. Primary outcome was incidence of TB infection comparing intervention and standard-of-care communities. An incident case was defined as a participant with QFT interferon-gamma response of < 0.2 IU/ml plasma ('negative') at baseline and a QFT interferon-gamma response of > = 0.7 IU/ml ('positive') at follow up. RESULTS: We enrolled 4,648 AYA, 2,223 (47.8%) had a negative QFT-plus result at baseline, 1,902 (85.6%) had a follow up blood sample taken at 12 months or 24 months. Among the 1,902 AYA, followed for 2,987 person-years, 213 had incident TB infection giving (7.1 per 100 person-years). TB infection incidence rates were 8.7 per 100 person-years in intervention communities compared to 6.0 per 100 person-years in standard-of-care communities. There was no evidence the intervention reduced the transmission of TB (incidence-rate-ratio of 1.45, 95%CI 0.97-2.15, p = 0.063). CONCLUSION: In our trial setting, we found no evidence that UTT combined with TB active case finding reduced the incidence of TB infection at population level. Our data will inform future modelling work to better understand the population level dynamics of HIV and TB.