Evaluating systematic targeted universal testing for tuberculosis in primary care clinics of South Africa: A cluster-randomized trial (The TUTT Trial).

BACKGROUND: The World Health Organization (WHO) recommends systematic symptom screening for tuberculosis (TB). However, TB prevalence surveys suggest that this strategy does not identify millions of TB patients, globally. Undiagnosed or delayed diagnosis of TB contribute to TB transmission and exacerbate morbidity and mortality. We conducted a cluster-randomized trial of large urban and rural primary healthcare clinics in 3 provinces of South Africa to evaluate whether a novel intervention of targeted universal testing for TB (TUTT) in high-risk groups diagnosed more patients with TB per month compared to current standard of care (SoC) symptom-directed TB testing. METHODS AND FINDINGS: Sixty-two clinics were randomized; with initiation of the intervention clinics over 6 months from March 2019. The study was prematurely stopped in March 2020 due to clinics restricting access to patients, and then a week later due to the Coronavirus Disease 2019 (COVID-19) national lockdown; by then, we had accrued a similar number of TB diagnoses to that of the power estimates and permanently stopped the trial. In intervention clinics, attendees living with HIV, those self-reporting a recent close contact with TB, or a prior episode of TB were all offered a sputum test for TB, irrespective of whether they reported symptoms of TB. We analyzed data abstracted from the national public sector laboratory database using Poisson regression models and compared the mean number of TB patients diagnosed per clinic per month between the study arms. Intervention clinics diagnosed 6,777 patients with TB, 20.7 patients with TB per clinic month (95% CI 16.7, 24.8) versus 6,750, 18.8 patients with TB per clinic month (95% CI 15.3, 22.2) in control clinics during study months. A direct comparison, adjusting for province and clinic TB case volume strata, did not show a significant difference in the number of TB cases between the 2 arms, incidence rate ratio (IRR) 1.14 (95% CI 0.94, 1.38, p = 0.46). However, prespecified difference-in-differences analyses showed that while the rate of TB diagnoses in control clinics decreased over time, intervention clinics had a 17% relative increase in TB patients diagnosed per month compared to the prior year, interaction IRR 1.17 (95% CI 1.14, 1.19, p < 0.001). Trial limitations were the premature stop due to COVID-19 lockdowns and the absence of between-arm comparisons of initiation and outcomes of TB treatment in those diagnosed with TB. CONCLUSIONS: Our trial suggests that the implementation of TUTT in these 3 groups at extreme risk of TB identified more TB patients than SoC and could assist in reducing undiagnosed TB patients in settings of high TB prevalence. TRIAL REGISTRATION: South African National Clinical Trials Registry DOH-27-092021-4901.

Yield of Facility-based Targeted Universal Testing for Tuberculosis With Xpert and Mycobacterial Culture in High-Risk Groups Attending Primary Care Facilities in South Africa.

BACKGROUND: We report the yield of targeted universal tuberculosis (TB) testing of clinic attendees in high-risk groups. METHODS: Clinic attendees in primary healthcare facilities in South Africa with one of the following risk factors underwent sputum testing for TB: human immunodeficiency virus (HIV), contact with a TB patient in the past year, and having had TB in the past 2 years. A single sample was collected for Xpert-Ultra (Xpert) and culture. We report the proportion positive for Mycobacterium tuberculosis. Data were analyzed descriptively. The unadjusted clinical and demographic factors' relative risk of TB detected by culture or Xpert were calculated and concordance between Xpert and culture is described. RESULTS: A total of 30 513 participants had a TB test result. Median age was 39 years, and 11 553 (38%) were men. The majority (n = 21734, 71%) had HIV, 12 492 (41%) reported close contact with a TB patient, and 1573 (5%) reported prior TB. Overall, 8.3% were positive for M. tuberculosis by culture and/or Xpert compared with 6.0% with trace-positive results excluded. In asymptomatic participants, the yield was 6.7% and 10.1% in symptomatic participants (with trace-positives excluded). Only 10% of trace-positive results were culture-positive. We found that 55% of clinic attendees with a sputum result positive for M. tuberculosis did not have a positive TB symptom screen. CONCLUSIONS: A high proportion of clinic attendees with specific risk factors (HIV, close TB contact, history of TB) test positive for M. tuberculosis when universal testing is implemented.

Household Contact Tracing With Intensified Tuberculosis and Human Immunodeficiency Virus Screening in South Africa: A Cluster-Randomized Trial.

BACKGROUND: Household contact tracing for tuberculosis (TB) may facilitate diagnosis and access to TB preventive treatment (TPT). We investigated whether household contact tracing and intensive TB/human immunodeficiency virus (HIV) screening would improve TB-free survival. METHODS: Household contacts of index TB patients in 2 South African provinces were randomized to home tracing and intensive HIV/TB screening or standard of care (SOC; clinic referral letters). The primary outcome was incident TB or death at 15 months. Secondary outcomes included tuberculin skin test (TST) positivity in children ≤14 years and undiagnosed HIV. RESULTS: From December 2016 through March 2019, 1032 index patients (4459 contacts) and 1030 (4129 contacts) were randomized to the intervention and SOC arms. Of intervention arm contacts, 3.2% (69 of 2166) had prevalent microbiologically confirmed TB. At 15 months, the cumulative incidence of TB or death did not differ between the intensive screening (93 of 3230, 2.9%) and SOC (80 of 2600, 3.1%) arms (hazard ratio, 0.90; 95% confidence interval [CI], .66-1.24). TST positivity was higher in the intensive screening arm (38 of 845, 4.5%) compared with the SOC arm (15 of 800, 1.9%; odds ratio, 2.25; 95% CI, 1.07-4.72). Undiagnosed HIV was similar between arms (41 of 3185, 1.3% vs 32 of 2543, 1.3%; odds ratio, 1.02; 95% CI, .64-1.64). CONCLUSIONS: Household contact tracing with intensive screening and referral did not reduce incident TB or death. Providing referral letters to household contacts of index patients is an alternative strategy to home visits. CLINICAL TRIALS REGISTRATION: ISRCTN16006202.

Community-led cross-sectional study of social and employment circumstances, HIV and associated factors amongst female sex workers in South Africa: study protocol.

BACKGROUND: In South Africa, female sex workers (FSWs) are perceived to play a pivotal role in the country's HIV epidemic. Understanding their health status and risk factors for adverse health outcomes is foundational for developing evidence-based health care for this population. OBJECTIVE: Describe the methodology used to successfully implement a community-led study of social and employment circumstances, HIV and associated factors amongst FSWs in South Africa. METHOD: A community-centric, cross-sectional, survey of 3,005 adult FSWs was conducted (January-July 2019) on 12 Sex Work (SW) programme sites across nine provinces of South Africa. Sites had existing SW networks and support programmes providing peer education and HIV services. FSWs were involved in the study design, questionnaire development, and data collection. Questions included: demographic, sexual behaviour, HIV testing and treatment/PrEP history, and violence exposure. HIV rapid testing, viral load, CD4 count, HIV recency, and HIV drug resistance genotypic testing were undertaken. Partner organisations provided follow-up services. RESULTS: HIV Prevalence was 61.96%, the median length of selling sex was 6 years, and inconsistent condom use was reported by 81.6% of participants, 88.4% reported childhood trauma, 46.2% reported physical or sexual abuse by an intimate partner and 57.4% by a client. More than half of participants had depression and post-traumatic stress disorder (52.7% and 54.1%, respectively). CONCLUSION: This is the first national survey of HIV prevalence amongst FSWs in programmes in South Africa. The data highlight the vulnerability of this population to HIV, violence and mental ill health, suggesting the need for urgent law reform. Based on the unique methodology and the successful implementation alongside study partners, the outcomes will inform tailored interventions. Our rapid rate of enrolment, low rate of screening failure and low proportion of missing data showed the feasibility and importance of community-centric research with marginalised, highly vulnerable populations.

Using information on ART costs and benefits to mobilise resources - comparing different methods and contexts.

Sustaining HIV and AIDS responses depends on a mix of donor, government and private funders. Their decisions about investing in HIV treatment may be informed by various types of economic evaluations, which may be more or less useful for different contexts. This paper benchmarks methods against each other. Epidemiological and demographic impacts of HIV and antiretroviral therapy (ART) from 1996-2015 were quantified using country- specific spectrum files. The study compared societal benefits of ART using the full income (FI) methodology with "conventional" benefit, utility and effectiveness estimates produced with the same data. The FI estimates suggested $3.50 in benefits per dollar spent on ART globally, 2.6 times larger than productivity-related measures of benefits, of $1.33 in benefits per dollar. Higher benefit-cost ratios are mainly because FI reflects value of life beyond what people produce at work and in non-working age groups, and allocates the future stream of benefits in the year that death is avoided. ART costs were 0.78 times per capita GDP per quality-adjusted life-years gained globally. FI benefit-cost ratios are considerably higher in upper- and lower-middle-income countries than in low- or high-income countries. Productivity-based benefits also exceeded costs in all but one region but had smaller ratios and different regional patterns. Per capita GDP per quality-adjusted life-years ratios were below 1.2 for all regions and country income bands, suggesting cost effectiveness. The fact that FI returns of ART are higher than productivity returns, helps to quantify developmental benefits of interventions that directly extend life and its quality, arguably the objective of development. They provide an important argument to increase budget allocations to health sectors for ART scale-up, and not just reallocate existing health resources. Benchmarking FI returns against cost per quality- adjusted life-years may allow comparison to other "cost effective" health interventions. However, caution should be taken in extrapolations between measures, because they produce different rankings across country categories.

Intensified household contact tracing, prevention and treatment support versus enhanced standard of care for contacts of tuberculosis cases in South Africa: study protocol for a household cluster-randomised trial.

BACKGROUND: Household contact tracing of index TB cases has been advocated as a key part of TB control for many years, but has not been widely implemented in many low-resource setting because of the current dearth of high quality evidence for effectiveness. Innovative strategies for earlier, more effective treatment are particularly important in contexts with hyper-endemic levels of HIV, where levels of TB infection remain extremely high. METHODS: We present the design of a household cluster-randomised controlled trial of interventions aimed at improving TB-free survival and reducing childhood prevalence of Mycobacterium tuberculosis infection among household contacts of index TB cases diagnosed in two provinces of South Africa. Households of index TB cases will be randomly allocated in a 1:1 ratio to receive either an intensified home screening and linkage for TB and HIV intervention, or enhanced standard of care. The primary outcome will compare between groups the TB-free survival of household contacts over 15 months. All participants, or their next-of-kin, will provide written informed consent to participate. DISCUSSION: Evidence from randomised trials is required to identify cost-effective approaches to TB case-finding that can be applied at scale in sub-Saharan Africa. TRIAL REGISTRATION: ISRCTN16006202 (01/02/2017: retrospectively registered) and NHREC4399 (11/04/2016: prospectively registered). Protocol version: 4.0 (date: 18th January 2018).

Feasibility of community-based HIV self-screening in South Africa: a demonstration project.

BACKGROUND: HIV diagnosis is a critical step in linking HIV-infected individuals to care and treatment and linking HIV-uninfected persons to prevention services. However, the uptake of HIV testing remains low in many countries. HIV self-screening (HIVSS) is acceptable to adults, but there is limited data on HIVSS feasibility in community programmes. This study aimed to evaluate the feasibility of HIVSS in South Africa. METHODS: We conducted a prospective study that enrolled participants through mobile site, homebased, workplace and sex worker programmes in two townships from May to November 2017. Following an information session on HIVSS, interested participants were offered one of three methods of HIVSS testing: supervised, semi-supervised, and unsupervised. Participants who opted for unsupervised testing and those who tested HIV positive after semi- or supervised HIVSS were followed up telephonically or with a home visit one week after receipt of the test kit to confirm results and linkages to care. Follow-up visits were concluded when the participant indicated that they had used the kit or had accessed a confirmatory HIV test. RESULTS: Of the 2061 people approached, 88.2% (1818/2061) received HIV testing information. Of this group, 89% (1618/1818) were enrolled in the study and 70.0% (1133/1618) were tested for HIV with the kit. The median age was 28 (IQR:23-33) years with an even gender distribution. Of those enrolled, 43.0% (696/1618) were identified through homebased outreach, 42.5% (687/1618) through mobile sites, 7.3% (118/1618) at their workplace and 7.2% (117/1618) from sex worker programmes. A total of 68.7% (1110/1616) selected unsupervised HIVSS, whereas 6.3% (101/1616) opted for semi-supervised and 25.0% ((405/1616) chose supervised HIVSS. Overall, the HIV prevalence using the HIVSS test was 8.2% (93/1129). Of those newly diagnosed with HIV, 16% (12/75) were initiated on ART. Almost half (48.0%; 543/1131) of those tested were linked to a primary HIV test as follows: supervised (85.2%; 336/394); semi-supervised (93.8%; 91/97) and unsupervised (18.1%; 116/640). CONCLUSION: Unsupervised HIVSS was by far the most selected and utilised HIVSS method. Linkages to primary and confirmatory testing for the unsupervised HIVSS and further care were low, despite home visits and telephonic reminders.

Twenty Years Of Antiretroviral Therapy For People Living With HIV: Global Costs, Health Achievements, Economic Benefits.

Since the introduction of azidothymidine in 1987, significant improvements in treatment for people living with HIV have yielded substantial improvements in global health as a result of the unique benefits of antiretroviral therapy (ART). ART averted 9.5 million deaths worldwide in 1995-2015, with global economic benefits of $1.05 trillion. For every $1 spent on ART, $3.50 in benefits accrued globally. If treatment scale-up achieves the global 90-90-90 targets of the Joint United Nations Programme on HIV/AIDS, a total of 34.9 million deaths are projected to be averted between 1995 and 2030. Approximately 40.2 million new HIV infections could also be averted by ART, and economic gains could reach $4.02 trillion in 2030. Having provided ART to 19.5 million people represents a major human achievement. However, 15.2 million infected people are currently not receiving treatment, which represents a significant lost opportunity. Further treatment scale-up could yield even greater health and economic benefits.

Readmission and death following hospitalization among people with HIV in South Africa.

BACKGROUND: Additional approaches are needed to identify and provide targeted interventions to populations at continued risk for HIV-associated mortality. We sought to describe care utilization and mortality following an index hospitalization for people with HIV in South Africa. METHODS: We conducted a prospective cohort study among hospitalized patients admitted to medicine wards at a single hospital serving a large catchment area. Participants were followed to 6 months post-discharge. Hospital records were used to describe overall admission numbers and inpatient mortality. Poisson regression was used to assess for associations between readmission or death and independent variables. RESULTS: Of 124 enrolled participants, 121 lived to hospital discharge. At the time of discharge the median length of stay of sampled patients was 5.5 days and 105 (87%) participants were referred for follow-up, most within 2 weeks of discharge. By 6 months post-discharge, only 18% of participants had attended the clinic to which they were referred and within the referred timeframe; 64 (53%) had been readmitted at least once and 31 (26%) had died. Self-reported skipping care due to difficulty in access (relative risk 1.3, p = 0.02) and not attending follow-up care on time or at the scheduled clinic or not attending clinic at all (relative risk 1.8 and 2.4, respectively, p = 0.001) were associated with readmission or mortality. CONCLUSIONS: The post-hospital period is a period of medical vulnerability and high mortality. Improving post-hospital retention in care may reduce post-hospital mortality.

Incorporating costing study results into district and service planning to enhance immunization programme performance: a Zambian case study.

Donors, researchers and international agencies have made significant investments in collection of high-quality data on immunization costs, aiming to improve the efficiency and sustainability of services. However, improved quality and routine dissemination of costing information to local managers may not lead to enhanced programme performance. This study explored how district- and service-level managers can use costing information to enhance planning and management to increase immunization outputs and coverage. Data on the use of costing information in the planning and management of Zambia's immunization programme was obtained through individual and group semi-structured interviews with planners and managers at national, provincial and district levels. Document review revealed the organizational context within which managers operated. Qualitative results described managers' ability to use costing information to generate cost and efficiency indicators not provided by existing systems. These, in turn, would allow them to understand the relative cost of vaccines and other resources, increase awareness of resource use and management, benchmark against other facilities and districts, and modify strategies to improve performance. Managers indicated that costing information highlighted priorities for more efficient use of human resources, vaccines and outreach for immunization programming. Despite decentralization, there were limitations on managers' decision-making to improve programme efficiency in practice: major resource allocation decisions were made centrally and planning tools did not focus on vaccine costs. Unreliable budgets and disbursements also undermined managers' ability to use systems and information. Routine generation and use of immunization cost information may have limited impact on managing efficiency in many Zambian districts, but opportunities were evident for using existing capacity and systems to improve efficiency. Simpler approaches, such as improving reliability and use of routine immunization and staffing indicators, drawing on general insights from periodic costing studies, and focusing on maximizing coverage with available resources, may be more feasible in the short-term.

Value stream mapping to characterize value and waste associated with accessing HIV care in South Africa.

INTRODUCTION: Inefficient clinic-level delivery of HIV services is a barrier to linkage and engagement in care. We used value stream mapping to quantify time spent on each component of a clinic visit while receiving care following a hospital admission in South Africa. METHODS: We described time for each clinic service ("process time") and time spent waiting for that service ("lead time"). We also determined time and patient costs associated with travel to the clinic and expenditures during the clinic visits for 15 clinic visits in South Africa. Participants were selected consecutively based on timing of scheduled clinic visit from a cohort of HIV-positive patients recently discharged from inpatient hospital care. During the mapping we asked the participants to assess challenges faced at the clinic visit. We subsequently conducted in depth interviews and included themes from the care experience in this analysis. RESULTS: The 15 clinic visits occurred at five clinics; four primary care and one hospital-based specialty clinic. Nine (64%) of the participants were women, the median age was 44 years (IQR: 32-49), three of the participants had one or more clinic visit in the prior 14 days, all but one participant was on antiretroviral therapy (ART) at the time of the clinic visit (ART was stopped following the hospital visit for that participant). The median time since hospital discharge was 131 days (interquartile range; IQR: 121-183) for the observed visits. The median travel time to and from the clinic to a place of residence was 60 minutes. The median time spent at the clinic was 3.5 hours (IQR: 2.5-5.3) of which 2.9 hours was lead time and 25 minutes was process time (registration, vital signs, clinician assessment, laboratory, and check-out). The median patient cost for transport and food while at the clinic was ZAR43/USD2.8 (median monthly household income in the district was ZAR2450/USD157). Participants highlighted long queues, repeat clinic visits, and multiple queues during the visit (median of 5 queues) as challenges. CONCLUSIONS: Accessing HIV care in South Africa is time consuming, complicated by multiple queues and frequent visits. A more patient-centered approach to care may decrease the burden of receiving care and improve outcomes.

Costs of introducing pneumococcal, rotavirus and a second dose of measles vaccine into the Zambian immunisation programme: Are expansions sustainable?

BACKGROUND: Introduction of new vaccines in low- and lower middle-income countries has accelerated since Gavi, the Vaccine Alliance was established in 2000. This study sought to (i) estimate the costs of introducing pneumococcal conjugate vaccine, rotavirus vaccine and a second dose of measles vaccine in Zambia; and (ii) assess affordability of the new vaccines in relation to Gavi's co-financing and eligibility policies. METHODS: Data on 'one-time' costs of cold storage expansions, training and social mobilisation were collected from the government and development partners. A detailed economic cost study of routine immunisation based on a representative sample of 51 health facilities provided information on labour and vaccine transport costs. Gavi co-financing payments and immunisation programme costs were projected until 2022 when Zambia is expected to transition from Gavi support. The ability of Zambia to self-finance both new and traditional vaccines was assessed by comparing these with projected government health expenditures. RESULTS: 'One-time' costs of introducing the three vaccines amounted to US$ 0.28 per capita. The new vaccines increased annual immunisation programme costs by 38%, resulting in economic cost per fully immunised child of US$ 102. Co-financing payments on average increased by 10% during 2008-2017, but must increase 49% annually between 2017 and 2022. In 2014, the government spent approximately 6% of its health expenditures on immunisation. Assuming no real budget increases, immunisation would account for around 10% in 2022. Vaccines represented 1% of government, non-personnel expenditures for health in 2014, and would be 6% in 2022, assuming no real budget increases. CONCLUSION: While the introduction of new vaccines is justified by expected positive health impacts, long-term affordability will be challenging in light of the current economic climate in Zambia. The government needs to both allocate more resources to the health sector and seek efficiency gains within service provision.

Cost analysis of routine immunisation in Zambia.

BACKGROUND: This study aimed to inform planning and funding by providing updated, detailed information on total and unit costs of routine immunisation (RI) in Zambia, a GAVI-eligible lower middle-income country with a population of 13 million. METHODS: The exercise was part of a multi-country study on costs and financing of routine immunisation (EPIC) that utilized a common, ingredients-based approach to costing. Data on inputs, prices and outputs were collected in a stratified, random sample of 51 facilities in nine districts between December 2012 and March 2013 using a pre-tested questionnaire. Shared inputs were allocated to RI costs on the basis of tracing factors developed for the study. A comprehensive set of costs were analysed to obtain total and unit costs, at facility and above-facility levels. RESULTS: The total annual economic cost of RI was $38.16 million, equivalent to approximately 10% of government health spending. Government contributed 83% of finances. Labour accounted for the lion's share (49%) of total costs followed by vaccines (16%) and travel allowances (12%). Analysis of specific activity costs showed that outreach and facility-based services accounted for half of total economic costs. Costs for managing the program at district, provincial and national levels (above-facility costs) represented 24% of total costs. Average unit costs were $7.18 per dose, $59.32 per infant and $65.89 per DPT3 immunised child, with markedly higher unit costs in rural facilities. Analyses suggest that greater efficiency is associated with higher utilisation levels and urban facility type. CONCLUSIONS: Total and unit costs, and government's contribution, were considerably higher than previous Zambian estimates and international benchmarks. These findings have substantial implications for planners, efficiency improvement and sustainable financing, particularly as new vaccines are introduced. Variations in immunisation costs at facility level warrant further statistical analyses.

Mapping financial flows for immunisation in Uganda 2009/10 and 2010/11: New insights for methodologies and policy.

BACKGROUND: The Global Vaccine Action Plan highlights the need for immunisation programmes to have sustainable access to predictable funding. A good understanding of current and future funding needs, commitments, and gaps is required to enhance planning, improve resource allocation and mobilisation, and to avoid funding bottlenecks, as well as to ensure that co-funding arrangements are appropriate. This study aimed to map the resource envelope and flows for immunisation in Uganda in 2009/10 and 2010/11. METHODS: To assess costs and financing of immunisation, the study applied a common methodology as part of the multi-country Expanded Program on Immunisation Costing (EPIC) study (Brenzel et al., 2015). The financial mapping developed a customised extension of the System of Health Accounts (SHA) codes to explore immunisation financing in detail. Data were collected from government and external sources. The mapping was able to assess financing more comprehensively than many studies, and the simultaneous costing of routine immunisation collected detailed data about human resources costs. RESULTS: The Ugandan government contributed 56% and 42% of routine immunisation funds in 2009/10 and 2010/11, respectively, higher than previously estimated, and managed up to 90% of funds. Direct delivery of services used 93% of the immunisation financial resources in 2010/11, while the above service delivery costs were small (7%). Vaccines and supplies (41%) and salaries (38%) absorbed most funding. There were differences in the key cost categories between actual resource flows and the estimates from the comprehensive multi-year plan (cMYP). CONCLUSIONS: Results highlight that governments and partners need to improve systems to routinely track immunisation financing flows for enhanced accountability, performance, and sustainability. The modified SHA coding allowed financing to be mapped to specific immunisation activities, and could be used for standardised, resource tracking compatible with National Health Accounts (NHA). Recommendations are made for refining routine resource mapping approaches.

Macroeconomic and household-level impacts of HIV/AIDS in Botswana.

OBJECTIVE: To measure the impact of HIV/AIDS on economic growth and poverty in Botswana and estimate how providing treatment can mitigate its effects. METHODS: Demographic and financial projections were combined with economic simulation models, including a macroeconomic growth model and a macro-microeconomic computable general equilibrium and microsimulation model. RESULTS: HIV/AIDS significantly reduces economic growth and increases household poverty. The impact is now severe enough to be affecting the economy as a whole, and threatens to pull some of the uninfected population into poverty. Providing antiretroviral therapy can partly offset this negative effect. Treatment increases health's share of government expenditure only marginally, because it increases economic growth and because withholding treatment raises the cost of other health services. CONCLUSION: Botswana's treatment programme is appropriate from a macroeconomic perspective. Conducting macroeconomic impact assessments is important in countries where prevalence rates are particularly high.