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Menzies, Nicolas

Background: The Xpert MTB/RIF test enables rapid detection of tuberculosis (TB) and rifampicin resistance. The World Health Organization recommends Xpert for initial diagnosis in individuals suspected of having multidrug-resistant TB (MDR-TB) or HIV-associated TB, and many countries are moving quickly toward adopting Xpert. As roll-out proceeds, it is essential to understand the potential health impact and cost-effectiveness of diagnostic strategies based on Xpert. Methods and findings: We evaluated potential health and economic consequences of implementing Xpert in five southern African countries—Botswana, Lesotho, Namibia, South Africa, and Swaziland—where drug resistance and TB-HIV coinfection are prevalent. Using a calibrated, dynamic mathematical model, we compared the status quo diagnostic algorithm, emphasizing sputum smear, against an algorithm incorporating Xpert for initial diagnosis. Results were projected over 10- and 20-y time periods starting from 2012. Compared to status quo, implementation of Xpert would avert 132,000 (95% CI: 55,000–284,000) TB cases and 182,000 (97,000–302,000) TB deaths in southern Africa over the 10 y following introduction, and would reduce prevalence by 28% (14%–40%) by 2022, with more modest reductions in incidence. Health system costs are projected to increase substantially with Xpert, by US$460 million (294–699 million) over 10 y. Antiretroviral therapy for HIV represents a substantial fraction of these additional costs, because of improved survival in TB/HIV-infected populations through better TB case-finding and treatment. Costs for treating MDR-TB are also expected to rise significantly with Xpert scale-up. Relative to status quo, Xpert has an estimated cost-effectiveness of US$959 (633–1,485) per disability-adjusted life-year averted over 10 y. Across countries, cost-effectiveness ratios ranged from US$792 (482–1,785) in Swaziland to US$1,257 (767–2,276) in Botswana. Assessing outcomes over a 10-y period focuses on the near-term consequences of Xpert adoption, but the cost-effectiveness results are conservative, with cost-effectiveness ratios assessed over a 20-y time horizon approximately 20% lower than the 10-y values. Conclusions: Introduction of Xpert could substantially change TB morbidity and mortality through improved case-finding and treatment, with more limited impact on long-term transmission dynamics. Despite extant uncertainty about TB natural history and intervention impact in southern Africa, adoption of Xpert evidently offers reasonable value for its cost, based on conventional benchmarks for cost-effectiveness. However, the additional financial burden would be substantial, including significant increases in costs for treating HIV and MDR-TB. Given the fundamental influence of HIV on TB dynamics and intervention costs, care should be taken when interpreting the results of this analysis outside of settings with high HIV prevalence. Please see later in the article for the Editors' Summary

Background: Governments and international donors have partnered to provide free HIV treatment to over 6 million individuals in low and middle-income countries. Understanding the determinants of HIV treatment costs will help improve efficiency and provide greater certainty about future resource needs. Methods and Findings: We collected data on HIV treatment costs from 54 clinical sites in Botswana, Ethiopia, Mozambique, Nigeria, Uganda, and Vietnam. Sites provided free HIV treatment funded by the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR), national governments, and other partners. Service delivery costs were categorized into successive six-month periods from the date when each site began HIV treatment scale-up. A generalized linear mixed model was used to investigate relationships between site characteristics and per-patient costs, excluding ARV expenses. With predictors at their mean values, average annual per-patient costs were $177 (95% CI: 127–235) for pre-ART patients, $353 (255–468) for adult patients in the first 6 months of ART, and $222 (161–296) for adult patients on ART for >6 months (excludes ARV costs). Patient volume (no. patients receiving treatment) and site maturity (months since clinic began providing treatment services) were both strong independent predictors of per-patient costs. Controlling for other factors, costs declined by 43% (18–63) as patient volume increased from 500 to 5,000 patients, and by 28% (6–47) from 5,000 to 10,000 patients. For site maturity, costs dropped 41% (28–52) between months 0–12 and 25% (15–35) between months 12–24. Price levels (proxied by per-capita GDP) were also influential, with costs increasing by 22% (4–41) for each doubling in per-capita GDP. Additionally, the frequency of clinical follow-up, frequency of laboratory monitoring, and clinician-patient ratio were significant independent predictors of per-patient costs. Conclusions: Substantial reductions in per-patient service delivery costs occur as sites mature and patient cohorts increase in size. Other predictors suggest possible strategies to reduce per-patient costs.

In this dissertation I assessed three distinct policy questions: the implications of introducing a new tuberculosis diagnostic in southern Africa, the potential value of research related to HIV treatment policy in South Africa, and the causal effect of state cigarette taxes imposed between 1996 and 2013 on health outcomes in the United States.

HIV has fuelled increasing tuberculosis (TB) incidence in sub-Saharan Africa. Better control of TB in this region may be achieved directly through TB programme improvements and indirectly through expanded use of antiretroviral therapy (ART) among those with HIV. We used a mathematical model of TB and HIV in South Africa to examine the potential epidemiological impact in scenarios involving improvements in three dimensions of TB programmes: coverage, diagnosis and treatment effectiveness, as well as expanded ART use through broadened eligibility. We projected the effect of alternative scenarios on TB prevalence, incidence and TB-related mortality over 20 years. Of the three dimensions of TB programme improvement, expanding coverage would produce the greatest reduction in TB burden. Compared with current performance, combined TB programme improvements were projected to decrease TB incidence by 30% over 5 years and 46% over 20 years, and decrease TB-related mortality by 45% over 5 years and 69% over 20 years. Expanded ART eligibility was projected to decrease TB incidence by 22% over 5 years and 45% over 20 years, and TB-related mortality by 22% over 5 years and 50% over 20 years. We found that over a 20-year horizon, TB-specific and HIV-specific programme changes contribute equally to incidence reductions, whereas the TB-specific changes produce a majority of the mortality benefits. An aggressive expansion of ART alongside traditional TB-specific control measures has the potential to greatly reduce TB burden, with the different elements of a combined approach having a synergistic effect in reducing long-term TB incidence and mortality.

The costs of delivering routine immunization services in India vary widely across facilities, districts and states. Understanding the factors influencing this cost variation could help predict future immunization costs and suggest approaches for improving the efficiency of service provision. We examined determinants of facility cost for immunization services based on a nationally representative sample of sub-centres and primary health centres (99 and 89 facilities, respectively) by regressing logged total facility costs, both including and excluding vaccine cost, against several explanatory variables. We used a multi-level regression model to account for the multi-stage sampling design, including state- and district-level random effects. We found that facility costs were significantly associated with total doses administered, type of facility, salary of the main vaccinator, number of immunization sessions, and the distance of the facility from the nearest cold chain point. Use of pentavalent vaccine by the state was an important determinant of total facility cost including vaccine cost. India is introducing several new vaccines including some supported by Gavi. Therefore, the government will have to ensure that additional resources will be made available after the support from Gavi ceases.

Background: Evidence on immunization costs is a critical input for cost-effectiveness analysis and budgeting, and can describe variation in site-level efficiency. The Expanded Program on Immunization Costing and Financing (EPIC) Project represents the largest investigation of immunization delivery costs, collecting empirical data on routine infant immunization in Benin, Ghana, Honduras, Moldova, Uganda, and Zambia. Methods: We developed a pooled dataset from individual EPIC country studies (316 sites). We regressed log total costs against explanatory variables describing service volume, quality, access, other site characteristics, and income level. We used Bayesian hierarchical regression models to combine data from different countries and account for the multi-stage sample design. We calculated output elasticity as the percentage increase in outputs (service volume) for a 1% increase in inputs (total costs), averaged across the sample in each country, and reported first differences to describe the impact of other predictors. We estimated average and total cost curves for each country as a function of service volume. Results: Across countries, average costs per dose ranged from $2.75 to $13.63. Average costs per child receiving diphtheria, tetanus, and pertussis ranged from $27 to $139. Within countries costs per dose varied widely—on average, sites in the highest quintile were 440% more expensive than those in the lowest quintile. In each country, higher service volume was strongly associated with lower average costs. A doubling of service volume was associated with a 19% (95% interval, 4.0–32) reduction in costs per dose delivered, (range 13% to 32% across countries), and the largest 20% of sites in each country realized costs per dose that were on average 61% lower than those for the smallest 20% of sites, controlling for other factors. Other factors associated with higher costs included hospital status, provision of outreach services, share of effort to management, level of staff training/seniority, distance to vaccine collection, additional days open per week, greater vaccination schedule completion, and per capita gross domestic product. Conclusions: We identified multiple features of sites and their operating environment that were associated with differences in average unit costs, with service volume being the most influential. These findings can inform efforts to improve the efficiency of service delivery and better understand resource needs. Electronic supplementary material The online version of this article (doi:10.1186/s12916-017-0942-1) contains supplementary material, which is available to authorized users.

Abstract Little information exists on the cost structure of routine infant immunization services in low- and middle-income settings. Using a unique dataset of routine infant immunization costs from six countries, we estimated how costs were distributed across budget categories and programmatic activities, and investigated how the cost structure of immunization sites varied by country and site characteristics. The EPIC study collected data on routine infant immunization costs from 319 sites in Benin, Ghana, Honduras, Moldova, Uganda, Zambia, using a standardized approach. For each country, we estimated the economic costs of infant immunization by administrative level, budget category, and programmatic activity from a programme perspective. We used regression models to describe how costs within each category were related to site operating characteristics and efficiency level. Site-level costs (incl. vaccines) represented 77–93% of national routine infant immunization costs. Labour and vaccine costs comprised 14–69% and 13–69% of site-level cost, respectively. The majority of site-level resources were devoted to service provision (facility-based or outreach), comprising 48–78% of site-level costs across the six countries. Based on the regression analyses, sites with the highest service volume had a greater proportion of costs devoted to vaccines, with vaccine costs per dose relatively unaffected by service volume but non-vaccine costs substantially lower with higher service volume. Across all countries, more efficient sites (compared with sites with similar characteristics) had a lower cost share devoted to labour. The cost structure of immunization services varied substantially between countries and across sites within each country, and was related to site characteristics. The substantial variation observed in this sample suggests differences in operating model for otherwise similar sites, and further understanding of these differences could reveal approaches to improve efficiency and performance of immunization sites.

Summary Background: In high-incidence settings, recurrent disease among previously treated individuals contributes substantially to the burden of incident and prevalent tuberculosis. The extent to which interventions targeted to this high-risk group can improve tuberculosis control has not been established. We aimed to project the population-level effect of control interventions targeted to individuals with a history of previous tuberculosis treatment in a high-incidence setting. Methods: We developed a transmission-dynamic model of tuberculosis and HIV in a high-incidence setting with a population of roughly 40 000 people in suburban Cape Town, South Africa. The model was calibrated to data describing local demography, TB and HIV prevalence, TB case notifications and treatment outcomes using a Bayesian calibration approach. We projected the effect of annual targeted active case finding in all individuals who had previously completed tuberculosis treatment and targeted active case finding combined with lifelong secondary isoniazid preventive therapy. We estimated the effect of these targeted interventions on local tuberculosis incidence, prevalence, and mortality over a 10 year period (2016–25). Findings: We projected that, under current control efforts in this setting, the tuberculosis epidemic will remain in slow decline for at least the next decade. Additional interventions targeted to previously treated people could greatly accelerate these declines. We projected that annual targeted active case finding combined with secondary isoniazid preventive therapy in those who previously completed tuberculosis treatment would avert 40% (95% uncertainty interval [UI] 21–56) of incident tuberculosis cases and 41% (16–55) of tuberculosis deaths occurring between 2016 and 2025. Interpretation In this high-incidence setting, the use of targeted active case finding in combination with secondary isoniazid preventive therapy in previously treated individuals could accelerate decreases in tuberculosis morbidity and mortality. Studies to measure cost and resource implications are needed to establish the feasibility of this type of targeted approach for improving tuberculosis control in settings with high tuberculosis and HIV prevalence. Funding National Institutes of Health, German Research Foundation.

Summary Background: The economic burden on households affected by tuberculosis through costs to patients can be catastrophic. WHO's End TB Strategy recognises and aims to eliminate these potentially devastating economic effects. We assessed whether aggressive expansion of tuberculosis services might reduce catastrophic costs. Methods: We estimated the reduction in tuberculosis-related catastrophic costs with an aggressive expansion of tuberculosis services in India and South Africa from 2016 to 2035, in line with the End TB Strategy. Using modelled incidence and mortality for tuberculosis and patient-incurred cost estimates, we investigated three intervention scenarios: improved treatment of drug-sensitive tuberculosis; improved treatment of multidrug-resistant tuberculosis; and expansion of access to tuberculosis care through intensified case finding (South Africa only). We defined tuberculosis-related catastrophic costs as the sum of direct medical, direct non-medical, and indirect costs to patients exceeding 20% of total annual household income. Intervention effects were quantified as changes in the number of households incurring catastrophic costs and were assessed by quintiles of household income. Findings: In India and South Africa, improvements in treatment for drug-sensitive and multidrug-resistant tuberculosis could reduce the number of households incurring tuberculosis-related catastrophic costs by 6–19%. The benefits would be greatest for the poorest households. In South Africa, expanded access to care could decrease household tuberculosis-related catastrophic costs by 5–20%, but gains would be seen largely after 5–10 years. Interpretation Aggressive expansion of tuberculosis services in India and South Africa could lessen, although not eliminate, the catastrophic financial burden on affected households. Funding Bill & Melinda Gates Foundation.