Modeling the impact of universal tuberculosis molecular testing and timing of tuberculosis preventive treatment during antiretroviral therapy initiation in South Africa.

OBJECTIVES: Targeted universal tuberculosis (TB) testing can improve TB detection among people with HIV. This approach is being scaled up in South Africa through Xpert MTB/RIF Ultra testing for individuals starting antiretroviral therapy and annually thereafter. Clarity is needed on how Universal Xpert testing may affect TB preventive treatment (TPT) provision, and on whether TPT should be delayed until TB is ruled out. DESIGN: State-transition microsimulation. METHODS: We simulated a cohort of South African patients being screened for TB while entering HIV care. We compared clinical and cost outcomes between four TB screening algorithms: symptom-based, C-reactive protein-based, and Universal Xpert testing with either simultaneous or delayed TPT initiation. RESULTS: Prompt TB treatment initiation among simulated patients with TB increased from 26% (24-28%) under symptom screening to 53% (50-56%) with Universal Xpert testing. Universal Xpert testing led to increased TPT uptake when TPT initiation was simultaneous, but to approximately 50% lower TPT uptake if TPT was delayed. Universal Xpert with simultaneous TPT prevented incident TB compared to either symptom screening (median 17 cases averted per 5000 patients) or Universal Xpert with delayed TPT (median 23 averted). Universal Xpert with Simultaneous TPT cost approximately $39 per incremental TPT course compared to Universal Xpert with delayed TPT. CONCLUSIONS: Universal Xpert testing can promote timely treatment for newly diagnosed people with HIV who have active TB. Pairing universal testing with immediate TPT will improve the promptness, uptake, and preventive effects of TPT. Simultaneous improvements to TB care cascades are needed to maximize impact.

Pragmatic cluster-randomized trial of home-based preventive treatment for TB in Ethiopia and South Africa (CHIP-TB).

BACKGROUND: Each year, 1 million children develop TB resulting in over 200,000 child deaths. TB preventive treatment (TPT) is highly effective in preventing TB but remains poorly implemented for household child contacts. Home-based child contact management and TPT services may improve access to care. In this study, we aim to evaluate the effectiveness and cost-effectiveness of home-based contact management with TPT initiation in two TB high-burden African countries, Ethiopia and South Africa. METHODS: This pragmatic cluster randomized trial compares home-based versus facility-based care delivery models for contact management. Thirty-six clinics with decentralized TB services (18 in Ethiopia and 18 in South Africa) were randomized in a 1:1 ratio to conduct either home-based or facility-based contact management. The study will attempt to enroll all eligible close child contacts of infectious drug-sensitive TB index patients diagnosed and treated for TB by one of the study clinics. Child TB contact management, including contact tracing, child evaluation, and TPT initiation and follow-up, will take place in the child's home for the intervention arm and at the clinic for the control arm. The primary outcome is the cluster-level ratio of the number of household child contacts less than 15 years of age in Ethiopia and less than 5 years of age in South Africa initiated on TPT per index patient, comparing the intervention to the control arm. Secondary outcomes include child contact identification and the TB prevention continuum of care. Other implementation outcomes include acceptability, feasibility, fidelity, cost, and cost-effectiveness of the intervention. DISCUSSION: This implementation research trial will determine whether home-based contact management identifies and initiates more household child contacts on TPT than facility-based contact management. TRIAL REGISTRATION: NCT04369326 . Registered on April 30, 2020.

Human resource time commitments and associated costs of Community Caregiver outreach team operations in South Africa.

INTRODUCTION: In South Africa, Community Caregivers (CCGs) visit households to provide basic healthcare services including those for tuberculosis and HIV. However, CCG workloads, costs, and time burden are largely unknown. Our objective was to assess the workloads and operational costs for CCG teams operating in different settings in South Africa. METHODS: Between March and October 2018, we collected standardized self-reported activity time forms from 11 CCG pairs working at two public health clinics in Ekurhuleni district, South Africa. CCG workloads were assessed based on activity unit times, per-household visit time, and mean daily number of successful household visits. Using activity-based times and CCG operating cost data, we assessed CCG annual and per-household visit costs (USD 2019) from the health system perspective. RESULTS: CCGs in clinic 1 (peri-urban, 7 CCG pairs) and 2 (urban, informal settlement; 4 CCG pairs) served an area of 3.1 km2 and 0.6 km2 with 8,035 and 5,200 registered households, respectively. CCG pairs spent a median 236 minutes per day conducting field activities at clinic 1 versus 235 minutes at clinic 2. CCG pairs at clinic 1 spent 49.5% of this time at households (versus traveling), compared to 35.0% at clinic 2. On average, CCG pairs successfully visited 9.5 vs 6.7 households per day for clinics 1 and 2, respectively. At clinic 1, 2.7% of household visits were unsuccessful, versus 28.5% at clinic 2. Total annual operating costs were higher in clinic 1 ($71,780 vs $49,097) but cost per successful visit was lower ($3.58) than clinic 2 ($5.85). CONCLUSIONS: CCG home visits were more frequent, successful, and less costly in clinic 1, which served a larger and more formalized settlement. The variability in workload and cost observed across pairs and clinics suggests that circumstantial factors and CCG needs must be carefully assessed for optimized CCG outreach operations.

Estimating the Impact of Tuberculosis Case Detection in Constrained Health Systems: An Example of Case-Finding in South Africa.

Mathematical models are increasingly being used to compare strategies for tuberculosis (TB) control and inform policy decisions. Models often do not consider financial and other constraints on implementation and may overestimate the impact that can be achieved. We developed a pragmatic approach for incorporating resource constraints into mathematical models of TB. Using a TB transmission model calibrated for South Africa, we estimated the epidemiologic impact and resource requirements (financial, human resource (HR), and diagnostic) of 9 case-finding interventions. We compared the model-estimated resources with scenarios of future resource availability and estimated the impact of interventions under these constraints. Without constraints, symptom screening in public health clinics and among persons receiving care for human immunodeficiency virus infection was predicted to lead to larger reductions in TB incidence (9.5% (2.5th-97.5th percentile range (PR), 8.6-12.2) and 14.5% (2.5th-97.5th PR, 12.2-16.3), respectively) than improved adherence to diagnostic guidelines (2.7%; 2.5th-97.5th PR, 1.6-4.1). However, symptom screening required large increases in resources, exceeding future HR capacity. Even under our most optimistic HR scenario, the reduction in TB incidence from clinic symptom screening was 0.2%-0.9%-less than that of improved adherence to diagnostic guidelines. Ignoring resource constraints may result in incorrect conclusions about an intervention's impact and may lead to suboptimal policy decisions. Models used for decision-making should consider resource constraints.

Application of provincial data in mathematical modelling to inform sub-national tuberculosis program decision-making in South Africa.

South Africa has the highest tuberculosis (TB) disease incidence rate in the world, and TB is the leading infectious cause of death. Decisions on, and funding for, TB prevention and care policies are decentralised to the provincial governments and therefore, tools to inform policy need to operate at this level. We describe the use of a mathematical model planning tool at provincial level in a high HIV and TB burden country, to estimate the impact on TB burden of achieving the 90-(90)-90 targets of the Stop TB Partnership Global Plan to End TB. "TIME Impact" is a freely available, user-friendly TB modelling tool. In collaboration with provincial TB programme staff, and the South African National TB Programme, models for three (of nine) provinces were calibrated to TB notifications, incidence, and screening data. Reported levels of TB programme activities were used as baseline inputs into the models, which were used to estimate the impact of scale-up of interventions focusing on screening, linkage to care and treatment success. All baseline models predicted a trend of decreasing TB incidence and mortality, consistent with recent data from South Africa. The projected impacts of the interventions differed by province and were greatly influenced by assumed current coverage levels. The absence of provincial TB burden estimates and uncertainty in current activity coverage levels were key data gaps. A user-friendly modelling tool allows TB burden and intervention impact projection at the sub-national level. Key sub-national data gaps should be addressed to improve the quality of sub-national model predictions.

Empirical estimation of resource constraints for use in model-based economic evaluation: an example of TB services in South Africa.

BACKGROUND: Evidence on the relative costs and effects of interventions that do not consider 'real-world' constraints on implementation may be misleading. However, in many low- and middle-income countries, time and data scarcity mean that incorporating health system constraints in priority setting can be challenging. METHODS: We developed a 'proof of concept' method to empirically estimate health system constraints for inclusion in model-based economic evaluations, using intensified case-finding strategies (ICF) for tuberculosis (TB) in South Africa as an example. As part of a strategic planning process, we quantified the resources (fiscal and human) needed to scale up different ICF strategies (cough triage and WHO symptom screening). We identified and characterised three constraints through discussions with local stakeholders: (1) financial constraint: potential maximum increase in public TB financing available for new TB interventions; (2) human resource constraint: maximum current and future capacity among public sector nurses that could be dedicated to TB services; and (3) diagnostic supplies constraint: maximum ratio of Xpert MTB/RIF tests to TB notifications. We assessed the impact of these constraints on the costs of different ICF strategies. RESULTS: It would not be possible to reach the target coverage of ICF (as defined by policy makers) without addressing financial, human resource and diagnostic supplies constraints. The costs of addressing human resource constraints is substantial, increasing total TB programme costs during the period 2016-2035 by between 7% and 37% compared to assuming the expansion of ICF is unconstrained, depending on the ICF strategy chosen. CONCLUSIONS: Failure to include the costs of relaxing constraints may provide misleading estimates of costs, and therefore cost-effectiveness. In turn, these could impact the local relevance and credibility of analyses, thereby increasing the risk of sub-optimal investments.

The patient costs of care for those with TB and HIV: a cross-sectional study from South Africa.

BACKGROUND: This study describes the post-diagnosis care-seeking costs incurred by people living with TB and/or HIV and their households, in order to identify the potential benefits of integrated care. METHODS: We conducted a cross-sectional study with 454 participants with TB or HIV or both in public primary health care clinics in Ekurhuleni North Sub-District, South Africa. We collected information on visits to health facilities, direct and indirect costs for participants and for their guardians and caregivers. We define 'integration' as receipt of both TB and HIV services at the same facility, on the same day. Costs were presented and compared across participants with TB/HIV, TB-only and HIV-only. Costs exceeding 10% of participant income were considered catastrophic. RESULTS: Participants with both TB and HIV faced a greater economic burden (US$74/month) than those with TB-only (US$68/month) or HIV-only (US$40/month). On average, people with TB/HIV made 18.4 visits to health facilities, more than TB-only participants or HIV-only participants who made 16 and 5.1 visits, respectively. However, people with TB/HIV had fewer standalone TB (10.9) and HIV (2.2) visits than those with TB-only (14.5) or HIV-only (4.4). Although people with TB/HIV had access to 'integrated' services, their time loss was substantially higher than for other participants. Overall, 55% of participants encountered catastrophic costs. Access to official social protection schemes was minimal. CONCLUSIONS: People with TB/HIV in South Africa are at high risk of catastrophic costs. To some extent, integration of services reduces the number of standalone TB and HIV of visits to the health facility. It is however unlikely that catastrophic costs can be averted by service integration alone. Our results point to the need for timely social protection, particularly for HIV-positive people starting TB treatment.

Feasibility of achieving the 2025 WHO global tuberculosis targets in South Africa, China, and India: a combined analysis of 11 mathematical models.

BACKGROUND: The post-2015 End TB Strategy proposes targets of 50% reduction in tuberculosis incidence and 75% reduction in mortality from tuberculosis by 2025. We aimed to assess whether these targets are feasible in three high-burden countries with contrasting epidemiology and previous programmatic achievements. METHODS: 11 independently developed mathematical models of tuberculosis transmission projected the epidemiological impact of currently available tuberculosis interventions for prevention, diagnosis, and treatment in China, India, and South Africa. Models were calibrated with data on tuberculosis incidence and mortality in 2012. Representatives from national tuberculosis programmes and the advocacy community provided distinct country-specific intervention scenarios, which included screening for symptoms, active case finding, and preventive therapy. FINDINGS: Aggressive scale-up of any single intervention scenario could not achieve the post-2015 End TB Strategy targets in any country. However, the models projected that, in the South Africa national tuberculosis programme scenario, a combination of continuous isoniazid preventive therapy for individuals on antiretroviral therapy, expanded facility-based screening for symptoms of tuberculosis at health centres, and improved tuberculosis care could achieve a 55% reduction in incidence (range 31-62%) and a 72% reduction in mortality (range 64-82%) compared with 2015 levels. For India, and particularly for China, full scale-up of all interventions in tuberculosis-programme performance fell short of the 2025 targets, despite preventing a cumulative 3·4 million cases. The advocacy scenarios illustrated the high impact of detecting and treating latent tuberculosis. INTERPRETATION: Major reductions in tuberculosis burden seem possible with current interventions. However, additional interventions, adapted to country-specific tuberculosis epidemiology and health systems, are needed to reach the post-2015 End TB Strategy targets at country level. FUNDING: Bill and Melinda Gates Foundation.

Cost-effectiveness and resource implications of aggressive action on tuberculosis in China, India, and South Africa: a combined analysis of nine models.

BACKGROUND: The post-2015 End TB Strategy sets global targets of reducing tuberculosis incidence by 50% and mortality by 75% by 2025. We aimed to assess resource requirements and cost-effectiveness of strategies to achieve these targets in China, India, and South Africa. METHODS: We examined intervention scenarios developed in consultation with country stakeholders, which scaled up existing interventions to high but feasible coverage by 2025. Nine independent modelling groups collaborated to estimate policy outcomes, and we estimated the cost of each scenario by synthesising service use estimates, empirical cost data, and expert opinion on implementation strategies. We estimated health effects (ie, disability-adjusted life-years averted) and resource implications for 2016-35, including patient-incurred costs. To assess resource requirements and cost-effectiveness, we compared scenarios with a base case representing continued current practice. FINDINGS: Incremental tuberculosis service costs differed by scenario and country, and in some cases they more than doubled existing funding needs. In general, expansion of tuberculosis services substantially reduced patient-incurred costs and, in India and China, produced net cost savings for most interventions under a societal perspective. In all three countries, expansion of access to care produced substantial health gains. Compared with current practice and conventional cost-effectiveness thresholds, most intervention approaches seemed highly cost-effective. INTERPRETATION: Expansion of tuberculosis services seems cost-effective for high-burden countries and could generate substantial health and economic benefits for patients, although substantial new funding would be required. Further work to determine the optimal intervention mix for each country is necessary. FUNDING: Bill & Melinda Gates Foundation.

Outcomes of on-site antiretroviral therapy provision in a South African correctional facility.

We evaluated a novel on-site antiretroviral therapy (ART) programme in a South African correctional facility using routinely collected programme data, from a retrospective cohort of adult inmates starting ART between 03/2007 and 03/2009 followed-up to 09/2009. We report (1) mortality (using survival analysis); (2) retention in the programme (to 09/2009); and (3) virological suppression at six and 12 months (<400 copies/ml) following ART initiation. In total, 404 started ART (median age 33 years; 91.3% men; median baseline CD4 cell count 152 cells/µl [interquartile range 85-225]). Among 299 starting ART for the first time (ART-naïve), 23 deaths occurred during 252 person-years (median follow-up nine months). Mortality rates were 17.2 at 0-6 months (95% confidence interval 10.9-26.9) and 2.8 at >6 months (95% confidence interval 1.1-7.5)/100 person-years; p < 0.001. At 09/2009, 35.6% (144/404) remained in the correctional facility, with 94.4% (136/144) retained in the programme; 38.4% (155/404) were released; and 20.0% (81/404) transferred to another facility. ART-naïve patients in care six and 12 months after ART initiation, 94.7% (124/131) and 92.5% (74/80) were virologically suppressed, respectively. High early mortality warrants the early identification and management of HIV-positive inmates. The high mobility of inmates necessitates systems for facilitating continuity of care. Good virological responses and retention supports decentralising HIV care to correctional facilities.

A novel HIV treatment model using private practitioners in South Africa.

OBJECTIVES: The extent of the HIV epidemic in South Africa may render the public sector capacity inadequate to manage all patients requiring antiretroviral treatment (ART). Private practitioners are an underutilised resource. METHODS: The authors developed a model of care using 72 private practitioners in five provinces in urban and rural areas of South Africa with centralised clinical support, training, pharmacy control and data management. The authors describe the programme, its quality control measures and patient outcomes using a cohort analysis. RESULTS: Between January 2005 and December 2008, 9102 individuals were started on ART, 62% female, median age 34 years, median viral load 50,655 copies/ml and median baseline CD4 count 123 cells/µl. Retention (alive and in care) after 12 months was 63% in the 2005 cohort (646 of 1026) and remained similar in the other calendar years, 58%, 68% and 64% in 2006, 2007 and 2008, respectively. After 36 months, retention was 50% and 41% for those enrolled in 2005 and 2006, respectively. The percentage virally suppressed remained similar at 6 months, 82% vs 84%, 84% and 85% from 2005, 2006, 2007 to 2008, respectively, p=0.66; but improved slightly at 12 months, 78% vs 83%, 83% and 84% from 2005 to 2008, p=0.05. At 36 months, it was 84% and 82% for the 2005 and 2006 cohorts, respectively. CONCLUSIONS: The results show that a well-managed private practitioner model can achieve comparable results to public services, although long-term retention needs further evaluation. This model of ART delivery can be used to expand access to ART in areas where the public sector is unable to meet the demand.