Impact and cost-effectiveness of the 6-month BPaLM regimen for rifampicin-resistant tuberculosis in Moldova: A mathematical modeling analysis.

BACKGROUND: Emerging evidence suggests that shortened, simplified treatment regimens for rifampicin-resistant tuberculosis (RR-TB) can achieve comparable end-of-treatment (EOT) outcomes to longer regimens. We compared a 6-month regimen containing bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) to a standard of care strategy using a 9- or 18-month regimen depending on whether fluoroquinolone resistance (FQ-R) was detected on drug susceptibility testing (DST). METHODS AND FINDINGS: The primary objective was to determine whether 6 months of BPaLM is a cost-effective treatment strategy for RR-TB. We used genomic and demographic data to parameterize a mathematical model estimating long-term health outcomes measured in quality-adjusted life years (QALYs) and lifetime costs in 2022 USD ($) for each treatment strategy for patients 15 years and older diagnosed with pulmonary RR-TB in Moldova, a country with a high burden of TB drug resistance. For each individual, we simulated the natural history of TB and associated treatment outcomes, as well as the process of acquiring resistance to each of 12 anti-TB drugs. Compared to the standard of care, 6 months of BPaLM was cost-effective. This strategy was estimated to reduce lifetime costs by $3,366 (95% UI: [1,465, 5,742] p < 0.001) per individual, with a nonsignificant change in QALYs (-0.06; 95% UI: [-0.49, 0.03] p = 0.790). For those stopping moxifloxacin under the BPaLM regimen, continuing with BPaL plus clofazimine (BPaLC) provided more QALYs at lower cost than continuing with BPaL alone. Strategies based on 6 months of BPaLM had at least a 93% chance of being cost-effective, so long as BPaLC was continued in the event of stopping moxifloxacin. BPaLM for 6 months also reduced the average time spent with TB resistant to amikacin, bedaquiline, clofazimine, cycloserine, moxifloxacin, and pyrazinamide, while it increased the average time spent with TB resistant to delamanid and pretomanid. Sensitivity analyses showed 6 months of BPaLM to be cost-effective across a broad range of values for the relative effectiveness of BPaLM, and the proportion of the cohort with FQ-R. Compared to the standard of care, 6 months of BPaLM would be expected to save Moldova's national TB program budget $7.1 million (95% UI: [1.3 million, 15.4 million] p = 0.002) over the 5-year period from implementation. Our analysis did not account for all possible interactions between specific drugs with regard to treatment outcomes, resistance acquisition, or the consequences of specific types of severe adverse events, nor did we model how the intervention may affect TB transmission dynamics. CONCLUSIONS: Compared to standard of care, longer regimens, the implementation of the 6-month BPaLM regimen could improve the cost-effectiveness of care for individuals diagnosed with RR-TB, particularly in settings with a high burden of drug-resistant TB. Further research may be warranted to explore the impact and cost-effectiveness of shorter RR-TB regimens across settings with varied drug-resistant TB burdens and national income levels.

Distributional Cost-Effectiveness of Equity-Enhancing Gene Therapy in Sickle Cell Disease in the United States.

BACKGROUND: Gene therapy is a potential cure for sickle cell disease (SCD). Conventional cost-effectiveness analysis (CEA) does not capture the effects of treatments on disparities in SCD, but distributional CEA (DCEA) uses equity weights to incorporate these considerations. OBJECTIVE: To compare gene therapy versus standard of care (SOC) in patients with SCD by using conventional CEA and DCEA. DESIGN: Markov model. DATA SOURCES: Claims data and other published sources. TARGET POPULATION: Birth cohort of patients with SCD. TIME HORIZON: Lifetime. PERSPECTIVE: U.S. health system. INTERVENTION: Gene therapy at age 12 years versus SOC. OUTCOME MEASURES: Incremental cost-effectiveness ratio (ICER) (in dollars per quality-adjusted life-years [QALYs] gained) and threshold inequality aversion parameter (equity weight). RESULTS OF BASE-CASE ANALYSIS: Gene therapy versus SOC for females yielded 25.5 versus 15.7 (males: 24.4 vs. 15.5) discounted lifetime QALYs at costs of $2.8 million and $1.0 million (males: $2.8 million and $1.2 million), respectively, with an ICER of $176 000 per QALY (full SCD population). The inequality aversion parameter would need to be 0.90 for the full SCD population for gene therapy to be preferred per DCEA standards. RESULTS OF SENSITIVITY ANALYSIS: SOC was favored in 100.0% (females) and 87.1% (males) of 10 000 probabilistic iterations at a willingness-to-pay threshold of $100 000 per QALY. Gene therapy would need to cost less than $1.79 million to meet conventional CEA standards. LIMITATION: Benchmark equity weights (as opposed to SCD-specific weights) were used to interpret DCEA results. CONCLUSION: Gene therapy is cost-ineffective per conventional CEA standards but can be an equitable therapeutic strategy for persons living with SCD in the United States per DCEA standards. PRIMARY FUNDING SOURCE: Yale Bernard G. Forget Scholars Program and Bunker Endowment.

Reassessing the operative threshold for abdominal aortic aneurysm repair in the context of COVID-19.

OBJECTIVE: The worldwide pandemic involving the novel respiratory syndrome (COVID-19) has forced health care systems to delay elective operations, including abdominal aortic aneurysm (AAA) repair, to conserve resources. This study provides a structured analysis of the decision to delay AAA repair and quantify the potential for harm. METHODS: A decision tree was constructed modeling immediate repair of AAA relative to an initial nonoperative (delayed repair) approach. Risks of COVID-19 contraction and mortality, aneurysm rupture, and operative mortality were considered. A deterministic sensitivity analysis for a range of patient ages (50 to >80), probability of COVID-19 infection (0.01%-30%), aneurysm size (5.5 to >7 cm), and time horizons (3-9 months) was performed. Probabilistic sensitivity analyses were conducted for three representative ages (60, 70, and 80). Analyses were conducted for endovascular aortic aneurysm repair (EVAR) and open surgical repair (OSR). RESULTS: Patients with aneurysms 7 cm or greater demonstrated a higher probability of survival when treated with immediate EVAR or OSR, compared with delayed repair, for patients under 80 years of age. When considering EVAR for aneurysms 5.5 to 6.9 cm, immediate repair had a higher probability of survival except in settings with a high probability of COVID-19 infection (10%-30%) and advanced age (70-85+ years). A nonoperative strategy maximized the probability of survival as patient age or operative risk increased. Probabilistic sensitivity analyses demonstrated that patients with large aneurysms (>7 cm) faced a 5.4% to 7.7% absolute increase in the probability of mortality with a delay of repair of 3 months. Young patients (60-70 years) with aneurysms 6 to 6.9 cm demonstrated an elevated risk of mortality (1.5%-1.9%) with a delay of 3 months. Those with aneurysms 5 to 5.9 cm demonstrated an increased survival with immediate repair in young patients (60); however, this was small in magnitude (0.2%-0.8%). The potential for harm increased as the length of surgical delay increased. For elderly patients requiring OSR, in the context of endemic COVID-19, delay of repair improves the probability of survival. CONCLUSIONS: The decision to delay operative repair of AAA should consider both patient age and local COVID-19 prevalence in addition to aneurysm size. EVAR should be considered when possible due to a reduced risk of harm and lower resource utilization.

Public Health System Research in Public Health Emergency Preparedness in the United States (2009-2015): Actionable Knowledge Base.

BACKGROUND: In 2008, the Institute of Medicine released a letter report identifying 4 research priority areas for public health emergency preparedness in public health system research: (1) enhancing the usefulness of training, (2) improving timely emergency communications, (3) creating and maintaining sustainable response systems, and (4) generating effectiveness criteria and metrics. OBJECTIVES: To (1) identify and characterize public health system research in public health emergency preparedness produced in the United States from 2009 to 2015, (2) synthesize research findings and assess the level of confidence in these findings, and (3) describe the evolution of knowledge production in public health emergency preparedness system research. Search Methods and Selection Criteria. We reviewed and included the titles and abstracts of 1584 articles derived from MEDLINE, EMBASE, and gray literature databases that focused on the organizational or financial aspects of public health emergency preparedness activities and were grounded on empirical studies. DATA COLLECTION AND ANALYSIS: We included 156 articles. We appraised the quality of the studies according to the study design. We identified themes during article analysis and summarized overall findings by theme. We determined level of confidence in the findings with the GRADE-CERQual tool. MAIN RESULTS: Thirty-one studies provided evidence on how to enhance the usefulness of training. Results demonstrated the utility of drills and exercises to enhance decision-making capabilities and coordination across organizations, the benefit of cross-sector partnerships for successfully implementing training activities, and the value of integrating evaluation methods to support training improvement efforts. Thirty-six studies provided evidence on how to improve timely communications. Results supported the use of communication strategies that address differences in access to information, knowledge, attitudes, and practices across segments of the population as well as evidence on specific communication barriers experienced by public health and health care personnel. Forty-eight studies provided evidence on how to create and sustain preparedness systems. Results included how to build social capital across organizations and citizens and how to develop sustainable and useful planning efforts that maintain flexibility and rely on available medical data. Twenty-six studies provided evidence on the usefulness of measurement efforts, such as community and organizational needs assessments, and new methods to learn from the response to critical incidents. CONCLUSIONS: In the United States, the field of public health emergency preparedness system research has been supported by the US Centers for Disease Control and Prevention since the release of the 2008 Institute of Medicine letter report. The first definition of public health emergency preparedness appeared in 2007, and before 2008 there was a lack of research and empirical evidence across all 4 research areas identified by the Institute of Medicine. This field can be considered relatively new compared with other research areas in public health; for example, tobacco control research can rely on more than 70 years of knowledge production. However, this review demonstrates that, during the past 7 years, public health emergency preparedness system research has evolved from generic inquiry to the analysis of specific interventions with more empirical studies. Public Health Implications: The results of this review provide an evidence base for public health practitioners responsible for enhancing key components of preparedness and response such as communication, training, and planning efforts.

Global burden of disease due to rifampicin-resistant tuberculosis: a mathematical modeling analysis.

In 2020, almost half a million individuals developed rifampicin-resistant tuberculosis (RR-TB). We estimated the global burden of RR-TB over the lifetime of affected individuals. We synthesized data on incidence, case detection, and treatment outcomes in 192 countries (99.99% of global tuberculosis). Using a mathematical model, we projected disability-adjusted life years (DALYs) over the lifetime for individuals developing tuberculosis in 2020 stratified by country, age, sex, HIV, and rifampicin resistance. Here we show that incident RR-TB in 2020 was responsible for an estimated 6.9 (95% uncertainty interval: 5.5, 8.5) million DALYs, 44% (31, 54) of which accrued among TB survivors. We estimated an average of 17 (14, 21) DALYs per person developing RR-TB, 34% (12, 56) greater than for rifampicin-susceptible tuberculosis. RR-TB burden per 100,000 was highest in former Soviet Union countries and southern African countries. While RR-TB causes substantial short-term morbidity and mortality, nearly half of the overall disease burden of RR-TB accrues among tuberculosis survivors. The substantial long-term health impacts among those surviving RR-TB disease suggest the need for improved post-treatment care and further justify increased health expenditures to prevent RR-TB transmission.

Transoral incisionless fundoplication is cost-effective for treatment of gastroesophageal reflux disease.

Background and study aims Given the sizable number of patients with symptomatic gastroesophageal reflux disease (GERD) despite proton pump inhibitor (PPI) therapy, non-pharmacologic treatment has become increasingly utilized. The aim of this study was to analyze the cost-effectiveness of medical, endoscopic, and surgical treatment of GERD. Patients and methods A deterministic Markov cohort model was constructed from the US healthcare payer's perspective to evaluate the cost-effectiveness of three competing strategies: 1) omeprazole 20 mg twice daily; 2) transoral incisionless fundoplication (TIF 2.0); and 3) laparoscopic Nissen fundoplication [LNF]. Cost was reported in US dollars with health outcomes recorded in quality-adjusted life years (QALYs). Ten-year and lifetime time horizons were utilized with 3 % discount rate and half-cycle corrections applied. The main outcome was incremental cost-effectiveness ratio (ICER) with a willingness-to-pay threshold of $ 100,000 per QALY. Probabilistic sensitivity analyses were also performed. Results In our base-case analysis, the average cost of TIF 2.0 was $ 13,978.63 versus $ 17,658.47 for LNF and $ 10,931.49 for PPI. Compared to the PPI strategy, TIF 2.0 was cost-effective with an incremental cost of $ 3,047 and incremental effectiveness of 0.29 QALYs, resulting in an ICER of $ 10,423.17 /QALY gained. LNF was strongly dominated by TIF 2.0. Over a lifetime horizon, TIF 2.0 remained the cost-effective strategy for patients with symptoms despite twice-daily 20-mg omeprazole. TIF 2.0 remained cost-effective after varying parameter inputs in deterministic and probabilistic sensitivity analyses and for scenario analyses in multiple age groups. Conclusions Based upon this study, TIF 2.0 was cost-effective for patients with symptomatic GERD despite low-dose, twice-daily PPI.

PET-Based Staging Is Cost-Effective in Early-Stage Follicular Lymphoma.

The objective was to assess the cost-effectiveness of staging PET/CT in early-stage follicular lymphoma (FL) from the Canadian health-care system perspective. Methods: The study population was FL patients staged as early-stage using conventional CT imaging and planned for curative-intent radiation therapy (RT). A decision analytic model simulated the management after adding staging PET/CT versus using staging CT alone. In the no-PET/CT strategy, all patients proceeded to curative-intent RT as planned. In the PET/CT strategy, PET/CT information could result in an increased RT volume, switching to a noncurative approach, or no change in RT treatment as planned. The subsequent disease course was described using a state-transition cohort model over a 30-y time horizon. Diagnostic characteristics, probabilities, utilities, and costs were derived from the literature. Baseline analysis was performed using quality-adjusted life years (QALYs), costs (2019 Canadian dollars), and the incremental cost-effectiveness ratio. Deterministic sensitivity analyses were conducted, evaluating net monetary benefit at a willingness-to-pay threshold of $100,000/QALY. Probabilistic sensitivity analysis using 10,000 simulations was performed. Costs and QALYs were discounted at a rate of 1.5%. Results: In the reference case scenario, staging PET/CT was the dominant strategy, resulting in an average lifetime cost saving of $3,165 and a gain of 0.32 QALYs. In deterministic sensitivity analyses, the PET/CT strategy remained the preferred strategy for all scenarios supported by available data. In probabilistic sensitivity analysis, the PET/CT strategy was strongly dominant in 77% of simulations (i.e., reduced cost and increased QALYs) and was cost-effective in 89% of simulations (i.e., either saved costs or had an incremental cost-effectiveness ratio below $100,000/QALY). Conclusion: Our analysis showed that the use of PET/CT to stage early-stage FL patients reduces cost and improves QALYs. Patients with early-stage FL should undergo PET/CT before curative-intent RT.

The Use and Misuse of Mathematical Modeling for Infectious Disease Policymaking: Lessons for the COVID-19 Pandemic.

Mathematical modeling has played a prominent and necessary role in the current coronavirus disease 2019 (COVID-19) pandemic, with an increasing number of models being developed to track and project the spread of the disease, as well as major decisions being made based on the results of these studies. A proliferation of models, often diverging widely in their projections, has been accompanied by criticism of the validity of modeled analyses and uncertainty as to when and to what extent results can be trusted. Drawing on examples from COVID-19 and other infectious diseases of global importance, we review key limitations of mathematical modeling as a tool for interpreting empirical data and informing individual and public decision making. We present several approaches that have been used to strengthen the validity of inferences drawn from these analyses, approaches that will enable better decision making in the current COVID-19 crisis and beyond.

Spillover Effects on Caregivers' and Family Members' Utility: A Systematic Review of the Literature.

BACKGROUND: A growing body of research has identified health-related quality-of-life effects for caregivers and family members of ill patients (i.e. 'spillover effects'), yet these are rarely considered in cost-effectiveness analyses (CEAs). OBJECTIVE: The objective of this study was to catalog spillover-related health utilities to facilitate their consideration in CEAs. METHODS: We systematically reviewed the medical and economic literatures (MEDLINE, EMBASE, and EconLit, from inception through 3 April 2018) to identify articles that reported preference-based measures of spillover effects. We used keywords for utility measures combined with caregivers, family members, and burden. RESULTS: Of 3695 articles identified, 80 remained after screening: 8 (10%) reported spillover utility per se, as utility or disutility (i.e. utility loss); 25 (30%) reported a comparison group, either population values (n = 9) or matched, non-caregiver/family member or unaffected individuals' utilities (n = 16; 3 reported both spillover and a comparison group); and 50 (63%) reported caregiver/family member utilities only. Alzheimer's disease/dementia was the most commonly studied disease/condition, and the EQ-5D was the most commonly used measurement instrument. CONCLUSIONS: This comprehensive catalog of utilities showcases the spectrum of diseases and conditions for which caregiver and family members' spillover effects have been measured, and the variation in measurement methods used. In general, utilities indicated a loss in quality of life associated with being a caregiver or family member of an ill relative. Most studies reported caregiver/family member utility without any comparator, limiting the ability to infer spillover effects. Nevertheless, these values provide a starting point for considering spillover effects in the context of CEA, opening the door for more comprehensive analyses.

Cost-effectiveness of public automated external defibrillators.

BACKGROUND: Despite a consistent association with improved outcomes, public automated external defibrillators (AEDs) are rarely used in out-of-hospital cardiac arrest. One of the barriers towards increased use might be cost-effectiveness. METHODS: We compared the cost-effectiveness of public AEDs to no AEDs for out-of-hospital cardiac arrest in the United States over a life-time horizon. The analysis assumed a societal perspective and results are presented as costs per quality-adjusted life year (QALY). Model inputs were based on reviews of the literature. For the base case, we modelled an annual cardiac arrest incidence per AED of 20%. A probabilistic sensitivity analysis was conducted to account for joint parameter uncertainty. RESULTS: The no AED strategy resulted in 1.63 QALYs at a cost of $28,964. The AED strategy yielded an additional 0.26 QALYs for an incremental increase in cost of $13,793 per individual. The AED strategy yielded an incremental cost-effectiveness ratio of $53,797 per QALY gained. The yearly incidence of cardiac arrests occurring in the presence of an AED had minimal effect on the incremental cost-effectiveness ratio except at very low incidences. In several sensitivity analyses across a plausible range of health care and societal estimates, the AED strategy remained cost-effective. In the probabilistic sensitivity analysis, the AED strategy was cost-effective in 43%, 85%, and 91% of the scenarios at a willingness-to-pay threshold of $50,000, $100,000, and $150,000 per QALY gained, respectively. CONCLUSION: Public AEDs are a cost-effective public health intervention in the United States. These findings support widespread dissemination of public AEDs.