HIV prevention for the next decade: Appropriate, person-centred, prioritised, effective, combination prevention.

UNAIDS and a broad range of partners have collaborated to establish a new set of HIV prevention targets to be achieved by 2025 as an intermediate step towards the sustainable development target for 2030.The number of new HIV infections in the world continues to decline, in part due to the extraordinary expansion of effective HIV treatment. However, the decline is geographically heterogeneous, with some regions reporting a rise in incidence. The incidence target that was agreed for 2020 has been missed.A range of exciting new HIV prevention technologies have become available or are in the pipeline but will only have an impact if they are accessible and affordable and delivered within systems that take full account of the social and political context in which most infections occur. Most new infections occur in populations that are marginalised or discriminated against due to structural, legal, and cultural barriers.The new targets imply a new approach to HIV prevention that emphasises appropriate, person-centred, prioritised, effective, combination HIV prevention within a framework that reduces existing barriers to services and acknowledges heterogeneity, autonomy, and choice.These targets have consequences for people working in HIV programmes both for delivery and for monitoring and evaluation, for health planners setting local and national priorities, and for funders both domestic and global. Most importantly, they have consequences for people who are at risk of HIV exposure and infection.Achieving these targets will have a huge impact on the future of the HIV epidemic and put us back on track towards ending AIDS as a public health threat by 2030.

Cash transfers for HIV prevention: A systematic review.

BACKGROUND: Given the success of cash programs in improving health outcomes and addressing upstream drivers of HIV risk such as poverty and education, there has been an increasing interest in their potential to improve HIV prevention and care outcomes. Recent reviews have documented the impacts of structural interventions on HIV prevention, but evidence about the effects of cash transfer programs on HIV prevention has not been systematically reviewed for several years. METHODS AND FINDINGS: We did a systematic review of published and unpublished literature to update and summarize the evidence around cash programs for HIV prevention from January 2000 to December 17, 2020. We included studies with either a cash transfer intervention, savings program, or program to reduce school costs. Included studies measured the program's impact on HIV infection, other sexually transmitted infections (STIs), or sexual behaviors. We screened 1,565 studies and examined 78 in full-text review to identify a total of 45 peer-reviewed publications and reports from 27 different interventions or populations. We did not do a meta-analysis given the range of outcomes and types of cash transfer interventions assessed. Most studies were conducted in sub-Saharan Africa (N = 23; South Africa, Tanzania, Malawi, Lesotho, Kenya, Uganda, Zimbabwe, Zambia, and eSwatini) followed by Mexico (N = 2), the United States (N = 1), and Mongolia (N = 1)). Of the 27 studies, 20 (72%) were randomized trials, 5 (20%) were observational studies, 1 (4%) was a case-control study, and 1 (4%) was quasi-experimental. Most studies did not identify a strong association between the program and sexual behaviors, except sexual debut (10/18 finding an association; 56%). Eight of the 27 studies included HIV biomarkers, but only 3 found a large reduction in HIV incidence or prevalence, and the rest found no statistically significant association. Of the studies that identified a statistically significant association with other STIs (N = 4/8), 2 involved incentives for staying free of the STI, and the other 2 were cash transfer programs for adolescent girls that had conditionalities related to secondary schooling. Study limitations include the small number of studies in key populations and examining interventions to reduce school costs and matched saving programs. CONCLUSIONS: The evidence base for large-scale impacts of cash transfers reducing HIV risk is limited; however, government social protection cash transfer programs and programs that incentivize school attendance among adolescent girls and young women show the greatest promise for HIV prevention.

Estimating HIV pre-exposure prophylaxis need and impact in Malawi, Mozambique and Zambia: A geospatial and risk-based analysis.

BACKGROUND: Pre-exposure prophylaxis (PrEP), a WHO-recommended HIV prevention method for people at high risk for acquiring HIV, is being increasingly implemented in many countries. Setting programmatic targets, particularly in generalised epidemics, could incorporate estimates of the size of the population likely to be eligible for PrEP using incidence-based thresholds. We estimated the proportion of men and women who would be eligible for PrEP and the number of HIV infections that could be averted in Malawi, Mozambique, and Zambia using prioritisation based on age, sex, geography, and markers of risk. METHODS AND FINDINGS: We analysed the latest nationally representative Demographic and Health Surveys (DHS) of Malawi, Mozambique, and Zambia to determine the proportion of adults who report behavioural markers of risk for HIV infection. We used prevalence ratios (PRs) to quantify the association of these factors with HIV status. Using a multiplier method, we combined these proportions with the number of new HIV infections by district, derived from district-level modelled HIV estimates. Based on these numbers, different scenarios were analysed for the minimum number of person-years on PrEP needed to prevent 1 HIV infection (NNP). An estimated total of 38,000, 108,000, and 46,000 new infections occurred in Malawi, Mozambique, and Zambia in 2016, corresponding with incidence rates of 0.43, 0.63, and 0.57 per 100 person-years. In these countries, 9%-20% of new infections occurred among people with a sexually transmitted infection (STI) in the past 12 months and 40%-42% among people with either an STI or a non-regular sexual partner (NP) in the past 12 months (STINP). The models estimate that around 50% of new infections occurred in districts with incidence rates ≥1.0% in Mozambique and Zambia and ≥0.5% in Malawi. In Malawi, Mozambique, and Zambia, 35.1%, 21.9%, and 12.5% of the population live in these high-incidence districts. In the most parsimonious scenario, if women aged 15-34 years and men 20-34 years with an STI in the past 12 months living in high-incidence districts were to take PrEP, it would take a minimum of 65.8 person-years on PrEP to avert 1 HIV infection per year in Malawi, 35.2 in Mozambique, and 16.4 in Zambia. Our findings suggest that 3,300, 5,200, and 1,700 new infections could be averted per year in the 3 countries, respectively. Limitations of our study are that these values are based on modelled estimates of HIV incidence and self-reported behavioural risk factors from national surveys. CONCLUSIONS: A large proportion of new HIV infections in these 3 African countries were estimated to occur among people who had either an STI or an NP in the past year, providing a straightforward means to set PrEP targets. Greater prioritisation of PrEP by district, sex, age, and behavioural risk factors resulted in lower NNPs thereby increasing PrEP cost-effectiveness, but also diminished the overall impact on reducing new infections.

Modeling the epidemiological impact of the UNAIDS 2025 targets to end AIDS as a public health threat by 2030.

BACKGROUND: UNAIDS has established new program targets for 2025 to achieve the goal of eliminating AIDS as a public health threat by 2030. This study reports on efforts to use mathematical models to estimate the impact of achieving those targets. METHODS AND FINDINGS: We simulated the impact of achieving the targets at country level using the Goals model, a mathematical simulation model of HIV epidemic dynamics that includes the impact of prevention and treatment interventions. For 77 high-burden countries, we fit the model to surveillance and survey data for 1970 to 2020 and then projected the impact of achieving the targets for the period 2019 to 2030. Results from these 77 countries were extrapolated to produce estimates for 96 others. Goals model results were checked by comparing against projections done with the Optima HIV model and the AIDS Epidemic Model (AEM) for selected countries. We included estimates of the impact of societal enablers (access to justice and law reform, stigma and discrimination elimination, and gender equality) and the impact of Coronavirus Disease 2019 (COVID-19). Results show that achieving the 2025 targets would reduce new annual infections by 83% (71% to 86% across regions) and AIDS-related deaths by 78% (67% to 81% across regions) by 2025 compared to 2010. Lack of progress on societal enablers could endanger these achievements and result in as many as 2.6 million (44%) cumulative additional new HIV infections and 440,000 (54%) more AIDS-related deaths between 2020 and 2030 compared to full achievement of all targets. COVID-19-related disruptions could increase new HIV infections and AIDS-related deaths by 10% in the next 2 years, but targets could still be achieved by 2025. Study limitations include the reliance on self-reports for most data on behaviors, the use of intervention effect sizes from published studies that may overstate intervention impacts outside of controlled study settings, and the use of proxy countries to estimate the impact in countries with fewer than 4,000 annual HIV infections. CONCLUSIONS: The new targets for 2025 build on the progress made since 2010 and represent ambitious short-term goals. Achieving these targets would bring us close to the goals of reducing new HIV infections and AIDS-related deaths by 90% between 2010 and 2030. By 2025, global new infections and AIDS deaths would drop to 4.4 and 3.9 per 100,000 population, and the number of people living with HIV (PLHIV) would be declining. There would be 32 million people on treatment, and they would need continuing support for their lifetime. Incidence for the total global population would be below 0.15% everywhere. The number of PLHIV would start declining by 2023.

Ending AIDS as a public health threat by 2030: Time to reset targets for 2025.

Paul De Lay and co-authors introduce a Collection on the design of targets for ending the AIDS epidemic.

Interpretation of serial interferon-gamma test results to measure new tuberculosis infection among household contacts in Zambia and South Africa.

BACKGROUND: A more stringent QuantiFERON-TB Gold In-Tube (QFT) conversion (from negative to positive) definition has been proposed to allow more definite detection of recent tuberculosis (TB) infection. We explored alternative conversion definitions to assist the interpretation of serial QFT results and estimate incidence of TB infection in a large cohort study. METHODS: We used QFT serial results from TB household contacts aged ≥15 years, collected at baseline and during two follow-up visits (2006-2011) as part of a cohort study in 24 communities in Zambia and South Africa (SA). Conversion rates using the manufacturers' definition (interferon-gamma (IFN-g) < 0.35 to ≥0.35, 'def1') were compared with stricter definitions (IFN-g < 0.2 to ≥0.7 IU/ml, 'def2'; IFN-g < 0.2 to ≥1.05 IU/ml, 'def3'; IFN-g < 0.2 to ≥1.4 IU/ml, 'def4'). Poisson regression was used for analysis. RESULTS: One thousand three hundred sixty-five individuals in Zambia and 822 in SA had QFT results available. Among HIV-negative individuals, the QFT conversion rate was 27.4 per 100 person-years (CI:22.9-32.6) using def1, 19.0 using def2 (CI:15.2-23.7), 14.7 using def3 (CI:11.5-18.8), and 12.0 using def4 (CI:9.2-15.7). Relative differences across def1-def4 were similar in Zambia and SA. Using def1, conversion was less likely if HIV positive not on antiretroviral treatment compared to HIV negative (aRR = 0.7, 95%CI = 0.4-0.9), in analysis including both countries. The same direction of associations were found using def 2-4. CONCLUSION: High conversion rates were found even with the strictest definition, indicating high incidence of TB infection among household contacts of TB patients in these communities. The trade-off between sensitivity and specificity using different thresholds of QFT conversion remains unknown due to the absence of a reference standard. However, we identified boundaries within which an appropriate definition might fall, and our strictest definition plausibly has high specificity.

Epidemiological metrics and benchmarks for a transition in the HIV epidemic.

Peter Godfrey-Faussett and colleagues present six epidemiological metrics for tracking progress in reducing the public health threat of HIV.

Socio-economic gradients in prevalent tuberculosis in Zambia and the Western Cape of South Africa.

OBJECTIVE: To describe the associations between socio-economic position and prevalent tuberculosis in the 2010 ZAMSTAR Tuberculosis Prevalence Survey, one of the first large tuberculosis prevalence surveys in Southern Africa in the HIV era. METHODS: The main analyses used data on 34 446 individuals in Zambia and 30 017 individuals in South Africa with evaluable tuberculosis culture results. Logistic regression was used to estimate adjusted odds ratios for prevalent TB by two measures of socio-economic position: household wealth, derived from data on assets using principal components analysis, and individual educational attainment. Mediation analysis was used to evaluate potential mechanisms for the observed social gradients. RESULTS: The quartile with highest household wealth index in Zambia and South Africa had, respectively, 0.55 (95% CI 0.33-0.92) times and 0.70 (95% CI 0.54-0.93) times the adjusted odds of prevalent TB of the bottom quartile. College or university-educated individuals in Zambia and South Africa had, respectively, 0.25 (95% CI 0.12-0.54) and 0.42 (95% CI 0.25-0.70) times the adjusted odds of prevalent TB of individuals who had received only primary education. We found little evidence that these associations were mediated via several key proximal risk factors for TB, including HIV status. CONCLUSION: These data suggest that social determinants of TB remain important even in the context of generalised HIV epidemics.

Impact of Point-of-Care Xpert MTB/RIF on Tuberculosis Treatment Initiation. A Cluster-randomized Trial.

RATIONALE: Point-of-care (POC) diagnostics have the potential to reduce pretreatment loss to follow-up and delays to initiation of appropriate tuberculosis (TB) treatment. OBJECTIVES: To evaluate the effect of a POC diagnostic strategy on initiation of appropriate TB treatment. METHODS: We conducted a cluster-randomized trial of adults with cough who were HIV positive and/or at high risk of drug-resistant TB. Two-week time blocks were randomized to two strategies: (1) Xpert MTB/RIF test (Cepheid, Sunnyvale, CA) performed at a district hospital laboratory or (2) POC Xpert MTB/RIF test performed at a primary health care clinic. All participants provided two sputum specimens: one for the Xpert test and the other for culture as a reference standard. The primary outcome was the proportion of participants with culture-positive pulmonary tuberculosis (PTB) initiated on appropriate TB treatment within 30 days. MEASUREMENTS AND MAIN RESULTS: Between August 22, 2011, and March 1, 2013, 36 two-week blocks were randomized, and 1,297 individuals were enrolled (646 in the laboratory arm, 651 in the POC arm), 159 (12.4%) of whom had culture-positive PTB. The proportions of participants with culture-positive PTB initiated on appropriate TB treatment within 30 days were 76.5% in the laboratory arm and 79.5% in the POC arm (odds ratio, 1.13; 95% confidence interval, 0.51-2.53; P = 0.76; risk difference, 3.1%; 95% confidence interval, -16.2 to 10.1). The median time to initiation of appropriate treatment was 7 days (laboratory) versus 1 day (POC). CONCLUSIONS: POC positioning of the Xpert test led to more rapid initiation of appropriate TB treatment. Achieving one-stop diagnosis and treatment for all people with TB will require simpler, more sensitive diagnostics and broader strengthening of health systems. Clinical trial registered with www.isrctn.com (ISRCTN 18642314) and www.sanctr.gov.za (DOH-27-0711-3568).

A trial of mass isoniazid preventive therapy for tuberculosis control.

BACKGROUND: Tuberculosis is epidemic among workers in South African gold mines. We evaluated an intervention to interrupt tuberculosis transmission by means of mass screening that was linked to treatment for active disease or latent infection. METHODS: In a cluster-randomized study, we designated 15 clusters with 78,744 miners as either intervention clusters (40,981 miners in 8 clusters) or control clusters (37,763 miners in 7 clusters). In the intervention clusters, all miners were offered tuberculosis screening. If active tuberculosis was diagnosed, they were referred for treatment; if not, they were offered 9 months of isoniazid preventive therapy. The primary outcome was the cluster-level incidence of tuberculosis during the 12 months after the intervention ended. Secondary outcomes included tuberculosis prevalence at study completion. RESULTS: In the intervention clusters, 27,126 miners (66.2%) underwent screening. Of these miners, 23,659 (87.2%) started taking isoniazid, and isoniazid was dispensed for 6 months or more to 35 to 79% of miners, depending on the cluster. The intervention did not reduce the incidence of tuberculosis, with rates of 3.02 per 100 person-years in the intervention clusters and 2.95 per 100 person-years in the control clusters (rate ratio in the intervention clusters, 1.00; 95% confidence interval [CI], 0.75 to 1.34; P=0.98; adjusted rate ratio, 0.96; 95% CI, 0.76 to 1.21; P=0.71), or the prevalence of tuberculosis (2.35% vs. 2.14%; adjusted prevalence ratio, 0.98; 95% CI, 0.65 to 1.48; P=0.90). Analysis of the direct effect of isoniazid in 10,909 miners showed a reduced incidence of tuberculosis during treatment (1.10 cases per 100 person-years among miners receiving isoniazid vs. 2.91 cases per 100 person-years among controls; adjusted rate ratio, 0.42; 95% CI, 0.20 to 0.88; P=0.03), but there was a subsequent rapid loss of protection. CONCLUSIONS: Mass screening and treatment for latent tuberculosis had no significant effect on tuberculosis control in South African gold mines, despite the successful use of isoniazid in preventing tuberculosis during treatment. (Funded by the Consortium to Respond Effectively to the AIDS TB Epidemic and others; Thibela TB Current Controlled Trials number, ISRCTN63327174.).

Age- and Sex-Specific Social Contact Patterns and Incidence of Mycobacterium tuberculosis Infection.

We aimed to model the incidence of infection with Mycobacterium tuberculosis among adults using data on infection incidence in children, disease prevalence in adults, and social contact patterns. We conducted a cross-sectional face-to-face survey of adults in 2011, enumerating "close" (shared conversation) and "casual" (shared indoor space) social contacts in 16 Zambian communities and 8 South African communities. We modeled the incidence of M. tuberculosis infection in all age groups using these contact patterns, as well as the observed incidence of M. tuberculosis infection in children and the prevalence of tuberculosis disease in adults. A total of 3,528 adults participated in the study. The reported rates of close and casual contact were 4.9 per adult per day (95% confidence interval: 4.6, 5.2) and 10.4 per adult per day (95% confidence interval: 9.3, 11.6), respectively. Rates of close contact were higher for adults in larger households and rural areas. There was preferential mixing of close contacts within age groups and within sexes. The estimated incidence of M. tuberculosis infection in adults was 1.5-6 times higher (2.5%-10% per year) than that in children. More than 50% of infections in men, women, and children were estimated to be due to contact with adult men. We conclude that estimates of infection incidence based on surveys in children might underestimate incidence in adults. Most infections may be due to contact with adult men. Treatment and control of tuberculosis in men is critical to protecting men, women, and children from tuberculosis.

Comparison of indoor contact time data in Zambia and Western Cape, South Africa suggests targeting of interventions to reduce Mycobacterium tuberculosis transmission should be informed by local data.

BACKGROUND: In high incidence settings, the majority of Mycobacterium tuberculosis (M.tb) transmission occurs outside the household. Little is known about where people's indoor contacts occur outside the household, and how this differs between different settings. We estimate the number of contact hours that occur between adults and adult/youths and children in different building types in urban areas in Western Cape, South Africa, and Zambia. METHODS: Data were collected from 3206 adults using a cross-sectional survey, on buildings visited in a 24-h period, including building function, visit duration, and number of adults/youths and children (5-12 years) present. The mean numbers of contact hours per day by building function were calculated. RESULTS: Adults in Western Cape were more likely to visit workplaces, and less likely to visit shops and churches than adults in Zambia. Adults in Western Cape spent longer per visit in other homes and workplaces than adults in Zambia. More adults/youths were present at visits to shops and churches in Western Cape than in Zambia, and fewer at homes and hairdressers. More children were present at visits to shops in Western Cape than in Zambia, and fewer at schools and hairdressers. Overall numbers of adult/youth indoor contact hours were the same at both sites (35.4 and 37.6 h in Western Cape and Zambia respectively, p = 0.4). Child contact hours were higher in Zambia (16.0 vs 13.7 h, p = 0.03). Adult/youth and child contact hours were highest in workplaces in Western Cape and churches in Zambia. Compared to Zambia, adult contact hours in Western Cape were higher in workplaces (15.2 vs 8.0 h, p = 0.004), and lower in churches (3.7 vs 8.6 h, p = 0.002). Child contact hours were higher in other peoples' homes (2.8 vs 1.6 h, p = 0.03) and workplaces (4.9 vs 2.1 h, p = 0.003), and lower in churches (2.5 vs 6.2, p = 0.004) and schools (0.4 vs 1.5, p = 0.01). CONCLUSIONS: Patterns of indoor contact between adults and adults/youths and children differ between different sites in high M.tb incidence areas. Targeting public buildings with interventions to reduce M.tb transmission (e.g. increasing ventilation or UV irradiation) should be informed by local data.

The association of hyperglycaemia with prevalent tuberculosis: a population-based cross-sectional study.

BACKGROUND: Systematic reviews suggest that the incidence of diagnosed tuberculosis is two- to- three times higher in those with diabetes mellitus than in those without. Few studies have previously reported the association between diabetes or hyperglycaemia and the prevalence of active tuberculosis and none in a population-based study with microbiologically-defined tuberculosis. Most have instead concentrated on cases of diagnosed tuberculosis that present to health facilities. We had the opportunity to measure glycaemia alongside prevalent tuberculosis. A focus on prevalent tuberculosis enables estimation of the contribution of hyperglycaemia to the population prevalence of tuberculosis. METHODS: A population-based cross-sectional study was conducted among adults in 24 communities from Zambia and the Western Cape (WC) province of South Africa. Prevalent tuberculosis was defined by the presence of a respiratory sample that was culture positive for M. tuberculosis. Glycaemia was measured by random blood glucose (RBG) concentration. Association with prevalent tuberculosis was explored across the whole spectrum of glycaemia. RESULTS: Among 27,800 Zambian and 11,367 Western Cape participants, 4,431 (15.9%) and 1,835 (16.1%) respectively had a RBG concentration ≥7.0 mmol/L, and 405 (1.5%) and 322 (2.8%) respectively had a RBG concentration ≥11.1 mmol/L. In Zambia, the prevalence of tuberculosis was 0 · 5% (142/27,395) among individuals with RBG concentration <11.1 mmol/L and also ≥11.1 mmol/L (2/405); corresponding figures for WC were 2 · 5% (272/11,045) and 4 · 0% (13/322). There was evidence for a positive linear association between hyperglycaemia and pulmonary prevalent tuberculosis. Taking a RBG cut-off 11.1 mmol/L, a combined analysis of data from Zambian and WC communities found evidence of association between hyperglycaemia and TB (adjusted odds ratio = 2 · 15, 95% CI [1 · 17-3 · 94]). The population attributable fraction of prevalent tuberculosis to hyperglycaemia for Zambia and WC combined was 0.99% (95% CI 0 · 12%-1.85%) for hyperglycaemia with a RBG cut-off of 11.1 mmol/L. CONCLUSIONS: This study demonstrates an association between hyperglycaemia and prevalent tuberculosis in a large population-based survey in Zambia and Western Cape. However, assuming causation, this association contributes little to the prevalence of TB in these populations.

The Second Zambian National Tuberculosis Drug Resistance survey - a comparison of conventional and molecular methods.

OBJECTIVE: The prevalence of MDR-TB in Zambia was estimated to be 1.8% in 2001. A second drug resistance survey was conducted in 2008 to determine trends; the use of the Genotype MTBDRplus assay was applied to compare results to the gold standard. METHOD: A two-stage cluster sampling, with health facilities as primary sampling units. Processed sputum specimens were inoculated on solid media for culture; heat-inactivated bacterial suspensions from sputum samples were tested on a commercial line probe assay for the identification of rifampicin and isoniazid resistance. RESULTS: A total of 917 patients with TB were enrolled and 883 (96.3%) analysed. A total of 574 (65%) had LJ results and 824 (93.3%) had results from MTBDRplus assay. The median age was 32, and 63.3% were males. MDR-TB according to LJ-based DST was 1.1% (CI 0.1-2.4) whereas according to MDTBDRplus assay was 1.6% (CI 0.6-2.6). Isoniazid monoresistance in new cases was 2.4% (CI 0.613-4.26) based on LJ results and 5.0% (CI 3.2-6.7) based on the MTBDRplus; in retreatment cases, it was 4.4% (CI 0.3-8.6) and 2.40% (CI <0.1-5.1) on LJ and MTBDRplus, respectively. Rifampicin monoresistance in new cases was 0.1% (CI <0.1-0.4) based on LJ and 0.6% (CI 0.01-1.1) based on the MTBDRplus; in retreatment cases, it was 0% (CI 0-3.8) and 1.8% (CI <0.1-4.0) on LJ and MTBDRplus, respectively. There were no XDR-TB cases found and no association between MDR-TB and HIV. CONCLUSION: There was no increase in MDR-TB prevalence in Zambia from 2001 to 2008; results from the two methods were similar. Molecular methods were quicker and simpler to use.

Effect of household and community interventions on the burden of tuberculosis in southern Africa: the ZAMSTAR community-randomised trial.

BACKGROUND: Southern Africa has had an unprecedented increase in the burden of tuberculosis, driven by the HIV epidemic. The Zambia, South Africa Tuberculosis and AIDS Reduction (ZAMSTAR) trial examined two public health interventions that aimed to reduce the burden of tuberculosis by facilitating either rapid sputum diagnosis or integrating tuberculosis and HIV services within the community. METHODS: ZAMSTAR was a community-randomised trial done in Zambia and the Western Cape province of South Africa. Two interventions, community-level enhanced tuberculosis case-finding (ECF) and household level tuberculosis-HIV care, were implemented between Aug 1, 2006, and July 31, 2009, and assessed in a 2×2 factorial design between Jan 9, 2010, and Dec 6, 2010. All communities had a strengthened tuberculosis-HIV programme implemented in participating health-care centres. 24 communities, selected according to population size and tuberculosis notification rate, were randomly allocated to one of four study groups using a randomisation schedule stratified by country and baseline prevalence of tuberculous infection: group 1 strengthened tuberculosis-HIV programme at the clinic alone; group 2, clinic plus ECF; group 3, clinic plus household intervention; and group 4, clinic plus ECF and household interventions. The primary outcome was the prevalence of culture-confirmed pulmonary tuberculosis in adults (≥18 years), defined as Mycobacterium tuberculosis isolated from one respiratory sample, measured 4 years after the start of interventions in a survey of 4000 randomly selected adults in each community in 2010. The secondary outcome was the incidence of tuberculous infection, measured using tuberculin skin testing in a cohort of schoolchildren, a median of 4 years after a baseline survey done before the start of interventions. This trial is registered, number ISRCTN36729271. FINDINGS: Prevalence of tuberculosis was evaluated in 64,463 individuals randomly selected from the 24 communities; 894 individuals had active tuberculosis. Averaging over the 24 communities, the geometric mean of tuberculosis prevalence was 832 per 100,000 population. The adjusted prevalence ratio for the comparison of ECF versus non-ECF intervention groups was 1·09 (95% CI 0·86-1·40) and of household versus non-household intervention groups was 0·82 (0·64-1·04). The incidence of tuberculous infection was measured in a cohort of 8809 children, followed up for a median of 4 years; the adjusted rate ratio for ECF versus non-ECF groups was 1·36 (95% CI 0·59-3·14) and for household versus non-household groups was 0·45 (0·20-1·05). INTERPRETATION: Although neither intervention led to a statistically significant reduction in tuberculosis, two independent indicators of burden provide some evidence of a reduction in tuberculosis among communities receiving the household intervention. By contrast the ECF intervention had no effect on either outcome. FUNDING: Bill & Melinda Gates Foundation.

High treatment success in children treated for multidrug-resistant tuberculosis: an observational cohort study.

BACKGROUND: Few studies have described the management of multidrug-resistant (MDR) tuberculosis (TB) in children and evidence-based guidance on management is lacking. We describe the presentation, treatment and outcome in children treated for severe and non-severe MDR-TB in Cape Town, South Africa. METHODS: We conducted an observational cohort study of all children (<15 years) treated for MDR-TB if routinely initiated on treatment between January 2009 and December 2010. Treatment was based on local standard of care, based on international guidelines. Data were collected through family interviews and folder review. Standardised definitions were used for diagnosis, severity of disease, adverse events and outcome. RESULTS: Of 149 children started on MDR-TB treatment, the median age was 36 months (IQR 16-66), 32 (22%; of 146 tested) had HIV infection and 59 (40%) had a confirmed diagnosis. Ninety-four (66%) children were treated with an injectable drug and the median total duration of treatment was 13 months (IQR 11-18). Thirty-six (24%) children were cured, 101 (68%) probably cured, 1 (1%) was transferred out, 8 (5%) were lost to follow-up and 3 (2%) died. Children with severe disease were older (54 months (IQR 18-142) vs 31.5 months (IQR 17.5-53.5); p=0.012), more commonly had HIV infection (OR 6.25; 95% CI 2.50 to 15.6; p<0.001) and were more likely to die (p=0.008). DISCUSSION: A confirmed diagnosis of MDR-TB is not possible in all cases but this should not impede the treatment of MDR-TB in children. More than 90% of children with MDR-TB can be successfully treated. Non-severe disease could be successfully treated with reduced treatment duration.

Effect of home-based interventions on virologic outcomes in adults receiving antiretroviral therapy in Africa: a meta-analysis.

BACKGROUND: The success of adherence to combination antiretroviral therapy (ART) in sub-Saharan Africa is hampered by factors that are unique to this setting. Home based interventions have been identified as possible strategies for decentralizing ART care and improving access and adherence to ART. There is need for evidence at individual- or community-level of the benefits of home-based interventions in improving HIV suppression in African patients receiving ART. METHODS: We conducted a systematic review and meta-analysis of the literature to assess the effect of home-based interventions on virologic outcomes in adults receiving ART in Africa. RESULTS: A total of 260 publications were identified by the search strategy, 249 were excluded on initial screening and 11 on full review, leaving 5 publications for analysis. The overall OR of virologic suppression at 12 months after starting ART of home-based interventions to standard of care was 1.13 (95% CI: 0.51-2.52). CONCLUSIONS: There was insufficient data to know whether there is a difference in HIV suppression at 12 months in the home-based arm compared with the standard of care arm in adults receiving ART in Africa. Given the few trials conducted from Africa, there is need for further research that measures the effects of home-based models on HIV suppression in African populations.

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.

Longitudinal population-level HIV epidemiologic and genomic surveillance highlights growing gender disparity of HIV transmission in Uganda.

HIV incidence in eastern and southern Africa has historically been concentrated among girls and women aged 15-24 years. As new cases decline with HIV interventions, population-level infection dynamics may shift by age and gender. Here, we integrated population-based surveillance of 38,749 participants in the Rakai Community Cohort Study and longitudinal deep-sequence viral phylogenetics to assess how HIV incidence and population groups driving transmission have changed from 2003 to 2018 in Uganda. We observed 1,117 individuals in the incidence cohort and 1,978 individuals in the transmission cohort. HIV viral suppression increased more rapidly in women than men, however incidence declined more slowly in women than men. We found that age-specific transmission flows shifted: whereas HIV transmission to girls and women (aged 15-24 years) from older men declined by about one-third, transmission to women (aged 25-34 years) from men that were 0-6 years older increased by half in 2003 to 2018. Based on changes in transmission flows, we estimated that closing the gender gap in viral suppression could have reduced HIV incidence in women by half in 2018. This study suggests that HIV programmes to increase HIV suppression in men are critical to reduce incidence in women, close gender gaps in infection burden and improve men's health in Africa.