The Cost-Effectiveness of the BEAT-TB Regimen for Pre-Extensively Drug-Resistant TB.

OBJECTIVE: To measure the economic impacts of the longer pre-XDR-TB treatment regimen and the shorter BEAT-TB India regimen. METHODS: In the current study, the economic impacts of the current 18-month pre-XDR-TB treatment regimen and the 6-9 month BEAT-TB regimen were evaluated using an economic model via a decision tree analysis from a societal perspective. The incremental costs and quality-adjusted life years (QALYs) gained from the introduction of the BEAT-TB regimen for pre-XDR-TB patients were estimated. RESULTS: For a cohort of 1000 pre-XDR-TB patients, we found that the BEAT-TB India regimen yielded higher undiscounted life years (40,548 vs. 21,009) and more QALYs gained (27,633 vs. 15,812) than the 18-month regimen. The BEAT-TB India regimen was found to be cost-saving, with an incremental cost of USD -128,651 when compared to the 18-month regimen. The current analysis did not consider the possibility of reduced TB recurrence after use of the BEAT-TB regimen, so it might have under-estimated the benefits. CONCLUSION: As a lower-cost intervention with improved health outcomes, the BEAT-TB India regimen is dominant when compared to the 18-month regimen.

One year of COVID-19 and its impact on private provider engagement for TB: A rapid assessment of intermediary NGOs in seven high TB burden countries.

The COVID-19 pandemic has impacted health systems and health programs across the world. For tuberculosis (TB), it is predicted to set back progress by at least twelve years. Public private mix (PPM)has made a vital contribution to reach End TB targets with a ten-fold rise in TB notifications from private providers between 2012 and 2019. This is due in large part to the efforts of intermediary agencies, which aggregate demand from private providers. The COVID-19 pandemic has put these gains at risk over the past year. In this rapid assessment, representatives of 15 intermediary agencies from seven countries that are considered the highest priority for PPM in TB care (the Big Seven) share their views on the impact of COVID-19 on their programs, the private providers operating under their PPM schemes, and their private TB clients. All intermediaries reported a drop in TB testing and notifications, and the closure of some private practices. While travel restrictions and the fear of contracting COVID-19 were the main contributing factors, there were also unanticipated expenses for private providers, which were transferred to patients via increased prices. Intermediaries also had their routine activities disrupted and had to shift tasks and budgets to meet the new needs. However, the intermediaries and their partners rapidly adapted, including an increased use of digital tools, patient-centric services, and ancillary support for private providers. Despite many setbacks, the COVID-19 pandemic has underlined the importance of effective private sector engagement. The robust approach to fight COVID-19 has shown the possibilities for ending TB with a similar approach, augmented by the digital revolution around treatment and diagnostics and the push to decentralize health services.

Realizing the "40 by 2022" Commitment from the United Nations High-Level Meeting on the Fight to End Tuberculosis: What Will It Take to Meet Rapid Diagnostic Testing Needs?

The potential gains from full adoption of World Health Organization (WHO)-recommended rapid diagnostics (WRDs) for tuberculosis (TB) are significant, but there is no current analysis of the additional investment needed to reach this goal. We sought to estimate the necessary investment in instruments, tests, and money, using Xpert MTB/RIF (Xpert), which detects Mycobacterium tuberculosis (MTB) and tests for resistance to rifampicin (RIF), as an example. An existing calculator for TB diagnostic needs was adapted to estimate the Xpert needs for a group of 24 countries with high TB burdens. This analysis assumed that countries will achieve the case-finding commitments agreed to at the recent United Nations High-Level Meeting on the Fight to End Tuberculosis, and that countries would adopt the WHO-recommended algorithm in which all people with signs and symptoms of TB receive an Xpert test. When compared to the current investments in these countries, this baseline model revealed that countries would require a 4-fold increase in the number of Xpert modules and a 6-fold increase in the number of Xpert test cartridges per year to meet their full testing needs. The incremental cost of the additional instruments for these countries would total approximately US$474 million, plus an incremental cost each year of cartridges of approximately $586 million, or a 5-fold increase over current investments. A sensitivity analysis revealed a variety of possible changes under alternative scenarios, but most of these changes either do not meet the global goals, are unrealistic, or would result in even greater investment needs. These findings suggest that a major investment is needed in WRD capacity to implement the recommended diagnostic algorithm for TB and reach the case-finding commitments by 2022.

Guidance for the Evaluation of Tuberculosis Diagnostics That Meet the World Health Organization (WHO) Target Product Profiles: An Introduction to WHO Process and Study Design Principles.

Existing high-priority target product profiles (TPPs) of the World Health Organization (WHO) establish important needs for tuberculosis (TB) diagnostic development. Building on this earlier work, this guidance series aims to provide study guidance for performing accuracy studies of novel diagnostic products that may meet the 4 high-priority WHO TPPs and thus enable adequate evidence generation to inform a WHO evidence review process. Diagnostic accuracy studies represent a fundamental step in the validation of all tests. Unfortunately, such studies often have limitations in design, execution, and reporting, leading to low certainty of the evidence about true test performance, which can delay or impede policy and scale-up decisions. This introductory paper outlines the following: (1) the purpose of this series of papers on study guidance; (2) WHO evidence needs and process for the development of policy guidelines for new TB diagnostic tests; and (3) study design considerations, ie, general diagnostic study considerations, intended use of test and role in the clinical pathway, choice of population and setting, index-test specific issues, suitable reference standard and comparators, study flow and specimen issues, and finally key issues beyond accuracy that should be considered. The other 4 papers in this series will provide more detailed guidance for each of the 4 WHO high-priority TPPs. By increasing the clarity around the clinical evaluation needs for tests that have the potential to meet the TPP specifications, we hope to support harmonized evidence generation and enable the WHO review process towards meeting the WHO End TB Strategy targets for reducing the incidence and mortality associated with TB.

Guidance for Studies Evaluating the Accuracy of Sputum-Based Tests to Diagnose Tuberculosis.

Tests that can replace sputum smear microscopy have been identified as a top priority diagnostic need for tuberculosis by the World Health Organization. High-quality evidence on diagnostic accuracy for tests that may meet this need is an essential requirement to inform decisions about policy and scale-up. However, test accuracy studies are often of low and inconsistent quality and poorly reported, leading to uncertainty about true test performance. Here we provide guidance for the design of diagnostic test accuracy studies of sputum smear-replacement tests. Such studies should have a cross-sectional or cohort design, enrolling either a consecutive series or a random sample of patients who require evaluation for tuberculosis. Adults with respiratory symptoms are the target population. The reference standard should at a minimum be a single, automated, liquid culture, but additional cultures, follow-up, clinical case definition, and specific measures to understand discordant results should also be included. Inclusion of smear microscopy and Xpert MTB/RIF (or MTB/RIF Ultra) as comparators is critical to allow broader comparability and generalizability of results, because disease spectrum can vary between studies and affects relative test performance. Given the complex nature of sputum (the primary specimen type used for pulmonary TB), careful design and reporting of the specimen flow is essential. Test characteristics other than accuracy (such as feasibility, implementation considerations, and data on impact on patient, population and health systems outcomes) are also important aspects.

Genetic sequencing for surveillance of drug resistance in tuberculosis in highly endemic countries: a multi-country population-based surveillance study.

BACKGROUND: In many countries, regular monitoring of the emergence of resistance to anti-tuberculosis drugs is hampered by the limitations of phenotypic testing for drug susceptibility. We therefore evaluated the use of genetic sequencing for surveillance of drug resistance in tuberculosis. METHODS: Population-level surveys were done in hospitals and clinics in seven countries (Azerbaijan, Bangladesh, Belarus, Pakistan, Philippines, South Africa, and Ukraine) to evaluate the use of genetic sequencing to estimate the resistance of Mycobacterium tuberculosis isolates to rifampicin, isoniazid, ofloxacin, moxifloxacin, pyrazinamide, kanamycin, amikacin, and capreomycin. For each drug, we assessed the accuracy of genetic sequencing by a comparison of the adjusted prevalence of resistance, measured by genetic sequencing, with the true prevalence of resistance, determined by phenotypic testing. FINDINGS: Isolates were taken from 7094 patients with tuberculosis who were enrolled in the study between November, 2009, and May, 2014. In all tuberculosis cases, the overall pooled sensitivity values for predicting resistance by genetic sequencing were 91% (95% CI 87-94) for rpoB (rifampicin resistance), 86% (74-93) for katG, inhA, and fabG promoter combined (isoniazid resistance), 54% (39-68) for pncA (pyrazinamide resistance), 85% (77-91) for gyrA and gyrB combined (ofloxacin resistance), and 88% (81-92) for gyrA and gyrB combined (moxifloxacin resistance). For nearly all drugs and in most settings, there was a large overlap in the estimated prevalence of drug resistance by genetic sequencing and the estimated prevalence by phenotypic testing. INTERPRETATION: Genetic sequencing can be a valuable tool for surveillance of drug resistance, providing new opportunities to monitor drug resistance in tuberculosis in resource-poor countries. Before its widespread adoption for surveillance purposes, there is a need to standardise DNA extraction methods, recording and reporting nomenclature, and data interpretation. FUNDING: Bill & Melinda Gates Foundation, United States Agency for International Development, Global Alliance for Tuberculosis Drug Development.

Mandatory tuberculosis case notification in high tuberculosis-incidence countries: policy and practice.

Mandatory tuberculosis (TB) notification is an important policy under the End TB Strategy, but little is known about its enforcement especially in high TB incidence countries. We undertook a literature search for selected high-incidence countries, followed by a questionnaire-based survey among key informants in countries with high-, intermediate- and low-TB incidence. Published literature on TB notification in high-incidence countries was limited, but it did illustrate some of the current barriers to notification and the importance of electronic systems to facilitate reporting by private providers. Required survey data were successfully gathered from 40 out of 54 countries contacted. TB is notifiable in 11 out of 15 high-incidence countries, all 16 intermediate-incidence countries, and all nine low-incidence countries contacted. TB case notification by public sector facilities is generally systematised, but few high-incidence countries had systems and tools to facilitate notification from private care providers. In the context of the new End TB Strategy aimed at eventual TB elimination, all countries should have TB on their national list of notifiable diseases. Enhancing the ease of notification by private providers is essential for effective implementation. To that effect, investing in strengthening disease surveillance systems and introducing digital tools to simplify notification are logical ways forward.

Population-based resistance of Mycobacterium tuberculosis isolates to pyrazinamide and fluoroquinolones: results from a multicountry surveillance project.

BACKGROUND: Pyrazinamide and fluoroquinolones are essential antituberculosis drugs in new rifampicin-sparing regimens. However, little information about the extent of resistance to these drugs at the population level is available. METHODS: In a molecular epidemiology analysis, we used population-based surveys from Azerbaijan, Bangladesh, Belarus, Pakistan, and South Africa to investigate resistance to pyrazinamide and fluoroquinolones among patients with tuberculosis. Resistance to pyrazinamide was assessed by gene sequencing with the detection of resistance-conferring mutations in the pncA gene, and susceptibility testing to fluoroquinolones was conducted using the MGIT system. FINDINGS: Pyrazinamide resistance was assessed in 4972 patients. Levels of resistance varied substantially in the surveyed settings (3·0-42·1%). In all settings, pyrazinamide resistance was significantly associated with rifampicin resistance. Among 5015 patients who underwent susceptibility testing to fluoroquinolones, proportions of resistance ranged from 1·0-16·6% for ofloxacin, to 0·5-12·4% for levofloxacin, and 0·9-14·6% for moxifloxacin when tested at 0·5 µg/mL. High levels of ofloxacin resistance were detected in Pakistan. Resistance to moxifloxacin and gatifloxacin when tested at 2 µg/mL was low in all countries. INTERPRETATION: Although pyrazinamide resistance was significantly associated with rifampicin resistance, this drug may still be effective in 19-63% of patients with rifampicin-resistant tuberculosis. Even though the high level of resistance to ofloxacin found in Pakistan is worrisome because it might be the expression of extensive and unregulated use of fluoroquinolones in some parts of Asia, the negligible levels of resistance to fourth-generation fluoroquinolones documented in all survey sites is an encouraging finding. Rational use of this class of antibiotics should therefore be ensured to preserve its effectiveness. FUNDING: Bill & Melinda Gates Foundation, United States Agency for International Development, Global Alliance for Tuberculosis Drug Development.

Shortened first-line TB treatment in Brazil: potential cost savings for patients and health services.

BACKGROUND: Shortened treatment regimens for tuberculosis are under development to improve treatment outcomes and reduce costs. We estimated potential savings from a societal perspective in Brazil following the introduction of a hypothetical four-month regimen for tuberculosis treatment. METHODS: Data were gathered in ten randomly selected health facilities in Rio de Janeiro. Health service costs were estimated using an ingredient approach. Patient costs were estimated from a questionnaire administered to 126 patients. Costs per visits and per case treated were analysed according to the type of therapy: self-administered treatment (SAT), community- and facility-directly observed treatment (community-DOT, facility-DOT). RESULTS: During the last 2 months of treatment, the largest savings could be expected for community-DOT; on average USD 17,351-18,203 and USD 43,660-45,856 (bottom-up and top-down estimates) per clinic. Savings to patients could also be expected as the median (interquartile range) patient-related costs during the two last months were USD 108 (13-291), USD 93 (36-239) and USD 11 (7-126), respectively for SAT, facility-DOT and community-DOT. CONCLUSION: Introducing a four-month regimen may result in significant cost savings for both the health service and patients, especially the poorest. In particular, a community-DOT strategy, including treatment at home, could maximise health services savings while limiting patient costs. Our cost estimates are likely to be conservative because a 4-month regimen could hypothetically increase the proportion of patients cured by reducing the number of patients defaulting and we did not include the possible cost benefits from the subsequent prevention of costs due to downstream transmission averted and rapid clinical improvement with less side effects in the last two months.

The Impact and Cost-Effectiveness of a Four-Month Regimen for First-Line Treatment of Active Tuberculosis in South Africa.

BACKGROUND: A 4-month first-line treatment regimen for tuberculosis disease (TB) is expected to have a direct impact on patient outcomes and societal costs, as well as an indirect impact on Mycobacterium tuberculosis transmission. We aimed to estimate this combined impact in a high TB-burden country: South Africa. METHOD: An individual based M. tb transmission model was fitted to the TB burden of South Africa using a standard TB natural history framework. We measured the impact on TB burden from 2015-2035 of introduction of a non-inferior 4-month regimen replacing the standard 6-month regimen as first-line therapy. Impact was measured with respect to three separate baselines (Guidelines, Policy and Current), reflecting differences in adherence to TB and HIV treatment guidelines. Further scenario analyses considered the variation in treatment-related parameters and resistance levels. Impact was measured in terms of differences in TB burden and Disability Adjusted Life Years (DALYs) averted. We also examined the highest cost at which the new regimen would be cost-effective for several willingness-to-pay thresholds. RESULTS: It was estimated that a 4-month regimen would avert less than 1% of the predicted 6 million person years with TB disease in South Africa between 2015 and 2035. A similarly small impact was seen on deaths and DALYs averted. Despite this small impact, with the health systems and patient cost savings from regimen shortening, the 4-month regimen could be cost-effective at $436 [NA, 5983] (mean [range]) per month at a willingness-to-pay threshold of one GDP per capita ($6,618). CONCLUSION: The introduction of a non-inferior 4-month first-line TB regimen into South Africa would have little impact on the TB burden. However, under several scenarios, it is likely that the averted societal costs would make such a regimen cost-effective in South Africa.

Alignment of new tuberculosis drug regimens and drug susceptibility testing: a framework for action.

New tuberculosis drug regimens are creating new priorities for drug susceptibility testing (DST) and surveillance. To minimise turnaround time, rapid DST will need to be prioritised, but developers of these assays will need better data about the molecular mechanisms of resistance. Efforts are underway to link mutations with drug resistance and to develop strain collections to enable assessment of new diagnostic assays. In resource-limited settings, DST might not be appropriate for all patients with tuberculosis. Surveillance data and modelling will help country stakeholders to design appropriate DST algorithms and to decide whether to change drug regimens. Finally, development of practical DST assays is needed so that, in countries where surveillance and modelling show that DST is advisable, these assays can be used to guide clinical decisions for individual patients. If combined judiciously during both development and implementation, new tuberculosis regimens and new DST assays have enormous potential to improve patient outcomes and reduce the burden of disease.

The multi-step process of building TB/HIV collaboration in Cambodia.

Tuberculosis and HIV/AIDS have synergistic health impacts in terms of disease development and progression. Therefore, collaborative TB and HIV/AIDS activities are a logical health systems response. However, the establishment of these activities presents a challenge for countries that have strong vertical disease programs that differ in their implementation philosophies. Here, we review the process by which TB/HIV collaboration was established in Cambodia. A cycle of overlapping and mutually reinforcing initiatives - local research; piloted implementation with multiple options; and several rounds of policy formulation guided by a cross-functional Technical Working Group - was used to drive nationwide introduction of a full set of TB/HIV collaborative activities. Senior Ministry of Health officials and partner organizations brought early attention to TB/HIV. Both national programs implemented initial screening and testing interventions, even in the absence of a detailed, overarching framework. The use of multiple options for HIV testing identified which programmatic options worked best, and early implementation and pilots determined what unanswered questions required further research. Local conduct of this research - on co-treatment timing and TB symptom screening - speeded adoption of the results into policy guidance, and clarified the relative roles of the two programs. Roll-out is continuing, and results for a variety of key indicators, including screening PLHIV for TB, and testing TB patients for HIV, are at 70-80% and climbing. This experience in Cambodia illustrates the influence of health research on policy, and demonstrates that clear policy guidance, the pursuit of incremental advances, and the use of different approaches to generate evidence can overcome structural barriers to change and bring direct benefits to patients.

Size and usage patterns of private TB drug markets in the high burden countries.

BACKGROUND: Tuberculosis (TB) control is considered primarily a public health concern, and private sector TB treatment has attracted less attention. Thus, the size and characteristics of private sector TB drug sales remain largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We used IMS Health data to analyze private TB drug consumption in 10 high burden countries (HBCs), after first mapping how well IMS data coverage overlapped with private markets. We defined private markets as any channels not used or influenced by national TB programs. Private markets in four countries--Pakistan, the Philippines, Indonesia and India--had the largest relative sales volumes; annually, they sold enough first line TB drugs to provide 65-117% of the respective countries' estimated annual incident cases with a standard 6-8 month regimen. First line drug volumes in five countries were predominantly fixed dose combinations (FDCs), but predominantly loose drugs in the other five. Across 10 countries, these drugs were available in 37 (loose drug) plus 74 (FDCs) distinct strengths. There were 54 distinct, significant first line manufacturers (range 2-11 per country), and most companies sold TB drugs in only a single study country. FDC markets were, however, more concentrated, with 4 companies capturing 69% of FDC volume across the ten countries. Among second line drugs, fluoroquinolones were widely available, with significant volumes used for TB in India, Pakistan and Indonesia. However, certain WHO-recommended drugs were not available and in general there were insufficient drug volumes to cover the majority of the expected burden of multidrug-resistant TB (MDR-TB). CONCLUSIONS/SIGNIFICANCE: Private TB drug markets in several HBCs are substantial, stable, and complicated. This calls for appropriate policy and market responses, including expansion of Public-Private Mix (PPM) programs, greater reach, flexibility and appeal of public programs, regulatory and quality enforcement, and expansion of public MDR-TB treatment programs.

Adoption of new health products in low and middle income settings: how product development partnerships can support country decision making.

When a new health product becomes available, countries have a choice to adopt the product into their national health systems or to pursue an alternate strategy to address the public health problem. Here, we describe the role for product development partnerships (PDPs) in supporting this decision-making process. PDPs are focused on developing new products to respond to health problems prevalent in low and middle income settings. The impact of these products within public sector health systems can only be realized after a country policy process. PDPs may be the organizations most familiar with the evidence which assists decision making, and this generally translates into involvement in international policy development, but PDPs have limited reach into endemic countries. In a few individual countries, there may be more extensive involvement in tracking adoption activities and generating local evidence. This local PDP involvement begins with geographical prioritization based on disease burden, relationships established during clinical trials, PDP in-country resources, and other factors. Strategies adopted by PDPs to establish a presence in endemic countries vary from the opening of country offices to engagement of part-time consultants or with long-term or ad hoc committees. Once a PDP commits to support country decision making, the approaches vary, but include country consultations, regional meetings, formation of regional, product-specific committees, support of in-country advocates, development of decision-making frameworks, provision of technical assistance to aid therapeutic or diagnostic guideline revision, and conduct of stakeholder and Phase 4 studies. To reach large numbers of countries, the formation of partnerships, particularly with WHO, are essential. At this early stage, impact data are limited. But available evidence suggests PDPs can and do play an important catalytic role in their support of country decision making in a number of target countries.

Michael Rape interviewed by William A. Wells about the biology of destruction.

Michael Rape says that ubiquitination's diversity and adaptability makes it an ideal entry point for understanding vast swaths of biology.

The returning tide: how China, the world's most populous country, is building a competitive research base.

When China turned its back on the Cultural Revolution, it aimed to build a thriving capitalist sector. It got one. Now, it wants a world-class research enterprise. How far has it progressed in the biosciences, how did it get there, and how far does it have to go?

The returning tide: how China, the world's most populous country, is building a competitive research base.

When China turned its back on the Cultural Revolution, it aimed to build a thriving capitalist sector. It got one. Now, it wants a world-class research enterprise. How far has it progressed in the biosciences, how did it get there, and how far does it have to go?