Impact of adverse drug reactions on the incremental cost-effectiveness of bedaquiline for drug-resistant tuberculosis.

BACKGROUND: Adverse drug reactions (ADRs) are common during standard, long-course treatment for multidrug-resistant and rifampicin-resistant tuberculosis (MDR-/RR-TB). In particular, second-line injectables (SLIs) are associated with permanent hearing loss, acute renal injury and electrolyte imbalance. We adapted an established Markov model for ambulatory treatment to estimate the impact of the toxicity profile on the incremental cost-effectiveness ratio (ICER) for a proposed MDR-/RR-TB regimen replacing the SLI with bedaquiline (BDQ). METHODS: Treatment effectiveness was evaluated in disability-adjusted life-years (DALYs). Clinical outcomes and ingredient costs from a provider perspective were derived from the South African public-sector treatment program or extracted from the literature. Costs and effectiveness were discounted at 3% per year over 10 years. RESULTS: A BDQ-based MDR-/RR-TB regimen compared with the SLI regimen had a mean ICER of US$516 per DALY averted using the standard Markov model. Costs for both regimens increased and effectiveness decreased for the SLI regimen once adjusted for toxicity. The resulting ICER for the BDQ-based regimen was cost saving (US$96/patient) and more effective (0.96 DALYs averted) after adjusting for ADRs. CONCLUSION: Decision-analysis models of treatment for MDR-/RR-TB, including new drug regimens, should consider the costs of managing ADRs and their sequelae.

Cost and cost-effectiveness of transitioning to universal initiation of lifelong antiretroviral therapy for all HIV-positive pregnant and breastfeeding women in Swaziland.

OBJECTIVES: To assess the costs and cost-effectiveness of transitioning from antiretroviral therapy (ART) initiation based on CD4 cell count and WHO clinical staging ('Option A') to universal ART ('Option B+') for all HIV-infected pregnant and breastfeeding women in Swaziland. METHODS: We measured the total costs of prevention of mother-to-child HIV transmission (PMTCT) service delivery at public sector facilities with empirical cost data collected at three points in time: once under Option A and again twice after transition to the Option B+ approach. The cost per woman treated per month includes recurrent costs (personnel, overheads, medication and diagnostic tests) and capital costs (buildings, furniture, start-up costs and training). Cost-effectiveness was estimated from the health services perspective as the cost per woman retained in care through 6 months postpartum. This analysis is nested within a larger stepped-wedge evaluation, which demonstrated a 26% increase in maternal retention after the transition to Option B+. RESULTS: Across the five sites, the total cost for PMTCT during the study period (from August 2013 to October 2015, in 2015 US$) was $868,426 for Option B+ and $680 508 for Option A. The cost per woman treated per month was $183 for a woman on ART under Option B+, and $127 and $118 for a woman on ART and zidovudine (AZT), respectively, under Option A. The weighted average cost per woman treated on Option B+ was $826 compared to $525 under Option A. The main cost drivers were the start-up costs, additional training provided and staff time spent on PMTCT tasks for Option B+. The incremental cost-effectiveness ratio was estimated at $912 for every additional mother retained in care through six months postpartum. CONCLUSIONS: The cost and cost-effectiveness outcomes from this study indicate that there is a robust economic case for pursuing the Option B+ approach in Swaziland and similar settings such as South Africa. Furthermore, these costs can be used to aid decision making and budgeting, for similar settings transitioning to test and treat strategy.

Direct costs of managing adverse drug reactions during rifampicin-resistant tuberculosis treatment in South Africa.

OBJECTIVE: To estimate the provider costs of managing adverse drug reactions (ADRs) to standard long-course treatment for multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) according to South African guidelines. METHODS: We parameterised a published Markov health state model for MDR/RR-TB with guidelines-based, bottom-up public-sector provider costing of ADR management. Frequency of ADR occurrence was extracted from the literature. Costs were estimated over 10 years, discounted 3% annually and tested using probabilistic sensitivity analysis. RESULTS: On average, guidelines-based costing of moderate ADRs weighted by the frequency of occurrence was US$135.76 (standard deviation [SD] US$17.18) and the cost of serious ADRs was US$521.29 (SD US$55.99). We estimated that the incremental costs of ADR management were US$380.17 annually per patient initiating MDR/RR-TB treatment. The incremental costs of ADR management for the public health sector in South Africa was US$4.76 million, 8.3% of the estimated cohort costs of MDR/RR-TB treatment ($57.55 million) for the 2015 cohort of 12 527 patients. CONCLUSIONS: Management of multiple ADRs and serious ADRs, which are common during the first 6 months of standard, long-course MDR/RR-TB treatment, substantially increases provider treatment costs. These results need to be taken into account when comparing regimen costs, and highlight the urgent need to identify drug regimens with improved safety profiles.

Persistently high early mortality despite rapid diagnostics for drug-resistant tuberculosis cases in South Africa.

OBJECTIVE: To describe the timing and predictors of mortality among multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) patients reported in the South African electronic drug-resistant TB register (EDRweb), 2012-2014. DESIGN: We present time-to-event survival analysis and Cox proportional hazards regression. Identity numbers were matched to the National Vital Statistics Register. RESULTS: Of the 20 653 patients included in the analysis (median age 35 years, interquartile range 28-43), over half were male (n = 10 944, 53.0%). Most were human immunodeficiency virus (HIV) positive (n = 14 174, 68.9%), most of whom were on antiretroviral therapy (ART; n = 12 471, 88.0%). At 24 months, 4689 patients had died (22.7%); 2072 deaths (44.2%) were reported within 12 weeks of initiating treatment for MDR/RR-TB. From week 12 to week 24, there were 717 deaths/18 048 persons; 59.5% of mortality occurred within the first 24 weeks. During the first 12 weeks, the adjusted hazard rate (aHR) for mortality was highest among patients with a missing baseline culture result (aHR 3.78, 95%CI 2.94-4.86) and among HIV-positive, ART-naïve patients (aHR 3.40, 95%CI 2.90-3.99). Patients initiating MDR/RR-TB treatment within 4 weeks of diagnosis had higher mortality than those with delayed initiation (aHR 1.57, 95%CI 1.41-1.75). CONCLUSION: In EDRweb, mortality is highest in the first few weeks after MDR/RR-TB treatment initiation.

Cost and cost-effectiveness of tuberculosis treatment shortening: a model-based analysis.

BACKGROUND: Despite improvements in treatment success rates for tuberculosis (TB), current six-month regimen duration remains a challenge for many National TB Programmes, health systems, and patients. There is increasing investment in the development of shortened regimens with a number of candidates in phase 3 trials. METHODS: We developed an individual-based decision analytic model to assess the cost-effectiveness of a hypothetical four-month regimen for first-line treatment of TB, assuming non-inferiority to current regimens of six-month duration. The model was populated using extensive, empirically-collected data to estimate the economic impact on both health systems and patients of regimen shortening for first-line TB treatment in South Africa, Brazil, Bangladesh, and Tanzania. We explicitly considered 'real world' constraints such as sub-optimal guideline adherence. RESULTS: From a societal perspective, a shortened regimen, priced at USD1 per day, could be a cost-saving option in South Africa, Brazil, and Tanzania, but would not be cost-effective in Bangladesh when compared to one gross domestic product (GDP) per capita. Incorporating 'real world' constraints reduces cost-effectiveness. Patient-incurred costs could be reduced in all settings. From a health service perspective, increased drug costs need to be balanced against decreased delivery costs. The new regimen would remain a cost-effective option, when compared to each countries' GDP per capita, even if new drugs cost up to USD7.5 and USD53.8 per day in South Africa and Brazil; this threshold was above USD1 in Tanzania and under USD1 in Bangladesh. CONCLUSION: Reducing the duration of first-line TB treatment has the potential for substantial economic gains from a patient perspective. The potential economic gains for health services may also be important, but will be context-specific and dependent on the appropriate pricing of any new regimen.

Patients' costs associated with seeking and accessing treatment for drug-resistant tuberculosis in South Africa.

SETTING: South Africa is one of the world's 22 high tuberculosis (TB) burden countries, with the second highest number of notified rifampicin-resistant TB (R(R)-TB) and multidrug-resistant TB (MDR-TB) cases. OBJECTIVE: To estimate patient costs associated with the diagnosis and treatment of R(R)-TB/MDR-TB in South Africa. DESIGN: Patients diagnosed with R(R)-TB/MDR-TB and accessing care at government health care facilities were surveyed using a structured questionnaire. Direct and indirect costs associated with accessing R(R)-TB/MDR-TB care were estimated at different treatment durations for each patient. RESULTS: A total of 134 patients were surveyed: 84 in the intensive phase and 50 in the continuation phase of treatment, 82 in-patients and 52 out-patients. The mean monthly patient costs associated with the diagnosis and treatment of R(R)-TB/MDR-TB were higher during the intensive phase than the continuation phase (US$235 vs. US$188) and among in-patients than among out-patients (US$269 vs. US$122). Patients in the continuation phase and those accessing care as out-patients reported higher out-of-pocket costs than other patients. Most patients did not access social protection for costs associated with R(R)-TB/MDR-TB illness. CONCLUSION: Despite free health care, patients bear high costs when accessing diagnosis and treatment services for R(R)-TB/MDR-TB; appropriate social protection mechanisms should be provided to assist them in coping with these costs.

Impact of reduced hospitalisation on the cost of treatment for drug-resistant tuberculosis in South Africa.

SETTING: The cost of multidrug-resistant tuberculosis (MDR-TB) treatment is a major barrier to treatment scale-up in South Africa. OBJECTIVE: To estimate and compare the cost of treatment for rifampicin-resistant tuberculosis (RR-TB) in South Africa in different models of care in different settings. DESIGN: We estimated the costs of different models of care with varying levels of hospitalisation. These costs were used to calculate the total cost of treating all diagnosed cases of RR-TB in South Africa, and to estimate the budget impact of adopting a fully or partially decentralised model vs. a fully hospitalised model. RESULTS: The fully hospitalised model was 42% more costly than the fully decentralised model (US$13,432 vs. US$7753 per patient). A much shorter hospital stay in the decentralised models of care (44-57 days), compared to 128 days of hospitalisation in the fully hospitalised model, was the key contributor to the reduced cost of treatment. The annual total cost of treating all diagnosed cases ranged from US$110 million in the fully decentralised model to US$190 million in the fully hospitalised model. CONCLUSION: Following a more decentralised approach for treating RR-TB patients could potentially improve the affordability of RR-TB treatment in South Africa.

Key issues in the clinical development and implementation of TB vaccines in South Africa.

Significant progress has been made in advancing the development pipeline for a new and more effective TB vaccine with some candidate vaccines now in late stage clinical evaluation. However, progress has been hampered by an incomplete understanding of the components of a protective immune response and limited animal models, rendering the field unable to reliably predict vaccine efficacy earlier in preclinical development, including by evaluation in animal models, and limiting the predictive utility of comparing immunogenic effects across vaccine candidates in phase I/II studies. Consequently, new candidate vaccines have to be evaluated for efficacy in large-scale phase II/III trials using clinical endpoints. Apart from the technical challenges of characterising TB incidence in target populations at high risk of acquiring TB disease and standardising case definitions in order to improve both the sensitivity and more importantly the specificity of trial endpoints, there is an urgency in expanding and supporting the considerable trial infrastructure that will be required to evaluate and ultimately license a new TB vaccine. In the longer term, implementation strategies are dependent on what policy makers most value. Economic analyses will be essential to guide policy and implementation. This paper outlines the gaps and challenges and identifies solutions for effectively developing and efficiently introducing a new TB vaccine.

The role of health economics research in implementation research for health systems strengthening.

It has long been recognised that the health-related Millennium Development Goals cannot be achieved without strengthened health systems. This article presents the most recent World Health Organization framework for strengthening health systems and considers how health economics research can be used to measure achievements against each of the goals of the framework. Benefits to health systems strengthening of incorporating health economics tools into operational research are highlighted. Finally, health economic tools are placed within an impact assessment framework that facilitates the capture of health systems considerations in implementation research for innovations in tuberculosis diagnosis.

Quality of tuberculosis care provided in different models of public-private partnerships in South Africa.

SETTING: Free State, North West and Western Cape provinces, South Africa. OBJECTIVE: To evaluate quality of care for the treatment of tuberculosis (TB) provided in different public-private partnerships. DESIGN: Quality of care analysis comparing three different models of directly observed treatment (DOT) provision: purely public, public-private workplace partnership (PWP), and public non-governmental organisation (NGO) partnership (PNP). For each type of provision model, two sites were selected. Three dimensions of quality of TB care--structure, process and outcome--were assessed. RESULTS: The PWP sites had the highest score in all three aspects of quality of care. In terms of process quality, the sites achieved similar scores, reflecting a very good knowledge of the treatment guidelines for both private and public providers. Patients supervised in the public clinics generally had lower treatment completion rates than those supervised in the occupational health clinics in the workplace and in the community. CONCLUSION: Partnerships with community-based NGOs and employer-based medical services should be established when the government does not have the capacity to provide services. The capacity of the public sector to monitor the quality of care provided in the partnerships is therefore crucial.

Cost analysis of ELISA, solid-phase extraction, and solid-phase microextraction for the monitoring of pesticides in water.

The implementation of a pesticide water monitoring program in South Africa is limited by a lack of financial and analytical resources. A cost analysis of three analytical methods, enzyme-linked immunosorbent assays (ELISA), solid-phase microextraction (SPME), and traditional solid-phase extraction methods (SPE), was conducted. The cost analysis assumed a hypothetical scenario in terms of the sampling area (a grape farming rural region in the Western Cape province of South Africa), sample collection (weekly grab samples collected from eight sites by an environmental health officer in a nearby town), transport of samples (via courier), and analysis (endosulfan and chlorpyrifos analysis conducted by a local higher educational institution laboratory in Cape Town). The cost per sample for the three analytical methods was determined by estimating the annual capital costs, including building and equipment, and recurrent costs, including transport, personnel, supplies, and building operating costs. At the optimal utility of resources, SPME had the lowest cost per sample (US $37), followed by SPE (US $48.50) and ELISA (US $60). Recurrent costs formed the bulk of the costs of all three methods (91-97%). The cost of supplies was particularly high for ELISA (US $34 per sample). The cost per sample estimated for all three methods is substantially lower than those quoted by other laboratories in South Africa. The low cost of SPME is particularly important because of the sensitivity and reliability of this method and the faster output compared to SPE, and SPME is recommended for the long-term monitoring of pesticide pollution.

Cost and cost-effectiveness of community-based care for tuberculosis in Cape Town, South Africa.

SETTING: Guguletu and Nyanga areas of Cape Town, South Africa. OBJECTIVE: To evaluate the affordability and cost-effectiveness of community involvement in tuberculosis (TB) care. DESIGN: A cost-effectiveness analysis comparing treatment for new smear-positive pulmonary and retreatment TB patients in two similar townships, one providing clinic-based-care with community-based observation options available for its TB patients (Guguletu) and one providing clinic-based care only, with no community-based observation of treatment (Nyanga). Costs were assessed from a societal perspective in 1997 US dollars, and cost-effectiveness was calculated as the cost per patient successfully treated. RESULTS: TB treatment in Guguletu was more cost-effective than TB treatment in Nyanga for both new and retreatment patients (dollars 726 vs. dollars 1201 and dollars 1419 vs. dollars 2058, respectively). This reflected both lower costs (dollars 495 vs. dollars 769 per patient treated for new cases; dollars 823 vs. dollars 1070 per patient treated for retreatment cases) and better treatment outcomes (successful treatment rate 68% vs. 64% and 58% vs. 52% for new and retreatment patients, respectively). Within Guguletu, community-based care was more than twice as cost-effective as clinic-based care (dollars 392 vs. dollars 1302 per patient successfully treated for new patients, and dollars 766 vs. dollars 2008 for retreatment patients), for similar reasons (e.g., for new cases, dollars 314 vs. dollars 703 per patient treated, successful treatment rate 80% vs. 54%). CONCLUSION: Community involvement in TB care can improve the affordability and cost-effectiveness of TB treatment in urban South Africa. Expansion in the Western Cape and in similar areas of the country is worthy of serious consideration by planners and policy-makers.