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There is a growing need to identify appropriate standardised treatment strategies that will adequately treat various forms of drug-resistant tuberculosis (TB) and prevent multidrug-resistant (MDR)-TB. A Markov model estimated treatment-related acquired MDR-TB, mortality, disability-adjusted life years and costs in settings with different prevalence of isoniazid monoresistant TB and MDR-TB. We compared four treatment strategies: 1) the standard World Health Organization recommended treatment strategy; 2) adding ethambutol throughout the 6-month treatment of new cases; 3) using a strengthened standardised retreatment regimen; and 4) using standardised MDR treatment for failures of initial treatment. Treatment-related outcomes were derived from the published literature, and costs from direct surveys. A strengthened retreatment regimen, which could achieve lower failure, relapse and acquired MDR rates in isoniazid monoresistant cases, was predicted to be the most cost-effective strategy in all modelled settings. Empirical MDR treatment of failures of initial treatment was the most costly strategy but resulted in the fewest deaths. Adding ethambutol throughout initial treatment would be most effective in preventing acquired MDR, but would lead to excess cases of blindness. A high priority should be given to improving the standardised retreatment regimen, as this is predicted to produce greater benefits than other recently recommended strategies. Introduction The World Health Organization (WHO) estimated that in 2017 there were 8.7 million new tuberculosis (TB) cases and 1.4 million TB deaths [1]. As a consequence of inadequate TB treatment and management, drug-resistant TB has emerged in all parts of the world and now accounts for ∼17% of all new cases [2]. The most common form of drug-resistant TB is isoniazid (INH) resistance, which is seen in 10% of new cases [2]. INH resistance is of concern as INH is one of the two most effective and potent first-line anti-TB drugs, and approximately one-third of new cases with INH resistance, or 3% of all new cases, has multidrug-resistant (MDR)-TB, which is a strain resistant to both INH and rifampicin (RMP) [2]. Patients with MDR-TB have substantially worse treatment outcomes [3, 4], despite a course of treatment that is much longer [5], and is more toxic and expensive [1], than for drug-sensitive TB. The proportions of MDR-TB have been increasing in many parts of the world; the highest proportions recorded in the history of the WHO Global Project on Anti-tuberculosis Drug Resistance Surveillance reached 35.3% among new and 76.5% of previously treated TB cases in 2017 in Minsk, Belarus [6]. Globally, <4% of all new cases of TB are estimated to receive drug susceptibility testing [1]. Thus, the vast majority of drug-resistant TB patients are unrecognised and do not receive adequate treatment [2]. In order to prevent MDR-TB where proper diagnostic testing is unavailable, the WHO recommends empirically adding ethambutol (EMB) throughout the initial treatment of new cases in settings with high levels of INH resistance [7]. However, the ability of EMB to protect against MDR-TB is uncertain [8, 9], and should be weighed against the risk of ocular toxicity [10–14]. The WHO also recommends using an 8-month regimen for previously treated patients who relapsed or defaulted [7]. This standardised retreatment regimen is comprised entirely of first-line drugs, was designed for populations with low levels of INH resistance and has never been tested in randomised clinical trials [4]. Published s point towards unacceptably high rates of treatment failure, relapse and acquired drug resistance with this regimen in the presence of (non-MDR) INH resistance [3, 4]. Given that ∼28% of all retreatment TB cases are resistant to INH globally [2], this regimen will probably be frequently unsuccessful [3]. A third related WHO recommendation is to use an empirical MDR regimen for patients who have failed initial treatment [15]. Methods Overview We estimated the treatment outcomes and costs of four different treatment strategies over a 10-year analytical horizon, using a Markov decision analysis model. We adhered to published recommendations for conducting and ing a cost-effectiveness analysis [16, 17]. We assumed a societal perspective to evaluate costs and discounted both costs and health effects at a 3% annual rate. Our model assumed that drug susceptibility testing was not available and did not influence the treatment given, thus all treatment regimens modelled were standardised. There is insufficient published literature for estimating input parameters specific to HIV-TB co-infected patients; thus, we assumed that patients with HIV co-infection would have similar treatment outcomes [18]. Each cohort represented a different setting with varying prevalence of primary INH monoresistance and MDR-TB in treatment-naïve patients, as follows: 1) low prevalence of both forms of drug resistance (5% INH monoresistant and 1% MDR-TB); 2) high prevalence of INH monoresistance (15%) and low prevalence of MDR-TB (1%); 3) low prevalence of INH monoresistance (5%) and high prevalence of MDR-TB (10%); and 4) high prevalence of both forms of drug resistance (15% INH monoresistant and 10% MDR-TB). The cycle length of the model was 1 year, which was chosen in order to accommodate the following different treatment lengths: 6 months for initial treatment regimens; 8 months for retreatment regimens; and 24 months for the MDR regimen, which took two cycles. After the first year in the model, patients all moved through a probability tree that determined the Markov state they would be in during the following year. Depending on transition probabilities, patients could fail, default or successfully complete treatment and be cured; become blind due to the ocular toxicity of ethambutol; or die from TB or non-TB causes. Those who failed or defaulted treatment could undergo treatment the following year; however, their underlying drug resistance could have changed and the new regimen they received depended on the treatment strategy being modelled. Those who successfully completed treatment would be in the “cured” state but could relapse and return to treatment; for simplicity, we assumed that all relapses would occur only in the year immediately following treatment completion. Estimates of transition probabilities and treatment outcomes were derived from published literature whenever possible and expert clinical judgement when not (table 1). Model outcomes Each health state had corresponding health outcomes (table 1) and costs (online supplementary table S1). At the end of each year, the costs and health outcomes were accrued for the patients. Patients who completed treatment accrued the total cost of treatment. There were no costs assigned to the states “dead”, “blind”, “cured” and “alive with untreated TB”. Our model results were expressed in terms of costs, INH monoresistant cases prevented, MDR-TB cases prevented, excess blindness, TB-related deaths averted and disability-adjusted life years (DALYs) gained. DALYs are an effectiveness measure introduced by the WHO to combine mortality and morbidity associated with diseases and injuries into one value. The DALY is calculated using disability weights estimated by the WHO, and for this study the weights used were 1 for cured TB (assumed perfect health), 0.729 for active TB (treated or untreated), 0.4 for blind and 0 for dead [36]. For example, if during the 10 years in the model, a patient lived with active TB for 2 years and then was cured and lived for another 8 years, then adjusting for disability, they would have lived for 2×0.729 (for active TB)/8×1 (for cured state)=9.46 DALYs. During each 1-year cycle, if a patient died, defaulted, relapsed or became blind, we assumed the transition between the two corresponding Markov states (e.g. from active TB undergoing treatment to blind) occurred halfway during the year. Reference treatment strategy (status quo): standard This consisted of initial treatment of new cases with the WHO-recommended 6-months standardised initial regimen (known as 2HRZE/4H3R3) consisting of 2 months of INH, RMP, pyrazinamide (PZA) and EMB taken daily (initial phase), followed by 4 months of INH and RMP taken three times per week (continuation phase). Patients who failed, relapsed after cure or defaulted received the WHO-recommended standardised retreatment regimen with first-line drugs only (known as 2HRZES/1HRZE/5H3R3E3): streptomycin is given daily in the first 2 months; INH, RMP, PZA and EMB are taken daily for the first 3 months; and then INH, RMP and EMB are taken three times per week in the last 5 months. Ethambutol added to initial treatment: EMB initial All new patients received the WHO-recommended 6-month standardised initial regimen in settings with a high prevalence of INH resistance (2HRZE/4H3R3E3), consisting of 2 months of INH, RMP, PZA and EMB taken daily (initial phase), followed by 4 months of INH, RMP and EMB taken three times per week (continuation phase). Patients who failed, relapsed after cure or defaulted received the standardised retreatment regimen as in the standard strategy. Compared with the standard strategy, the addition of EMB throughout the initial regimen was assumed to reduce by 50% the probability of acquired INH monoresistance and acquired MDR-TB after initial treatment, and to increase the probability of EMB-induced blindness from 0% to 0.23%, but did not change any other probabilities. Strengthened retreatment: Str retreat New patients received the same initial treatment as in the standard strategy, but those who failed or relapsed after cure or default received a retreatment regimen that included second-line drugs (2 months of daily levofloxacin, rifampicin, pyrazinamide, ethambutol and streptomycin, followed by 1 month of daily levofloxacin, rifampicin, pyrazinamide and ethambutol, then by 6 months of thrice-weekly levofloxacin, rifampicin, and ethambutol; 2LfxRZES/1LfxRZE/5Lfx3R3E3): for costing purposes (but without data confirming the efficacy of this regimen), we assumed the regimen would be an 8-month standardised regimen in which INH was replaced with levofloxacin. Compared with the standard strategy the strengthened retreatment strategy was assumed to reduce by 50% the probability of failure, or relapse and associated acquired MDR-TB in retreated patients with initial INH resistance, but did not change any other probabilities. Standardised MDR treatment for failures of initial treatment: MDR failures New patients received the same initial treatment as in the standard strategy. Patients who defaulted or relapsed after cure from initial treatment received the same retreatment regimen as described for the standard strategy. But those who failed initial treatment received a 24-month standardised MDR regimen. All patients were hospitalised for only 1 month at the start of MDR treatment, given published studies of the effectiveness of community-based treatment [37–39]. Amikacin (Am) is injected daily for the first 6 months. PZA, EMB, levofloxacin and ethionamide are taken daily for 24 months (6AmZELfxEth/18ZELfxEth) [5, 27, 29]. Compared with the standard strategy, the MDR failures strategy (MDR failures) was assumed to improve treatment outcomes in failure cases who had MDR in order to achieve cure rates equivalent to published estimates using this regimen [3]. All other probabilities remained unchanged. For the first three strategies, patients who failed, relapsed or defaulted after retreatment received the WHO recommended standardised MDR regimen (6AmZELfxEth/18ZELfxEth) [5]. For all four strategies, patients who failed, relapsed or defaulted after receiving one course of the MDR regimen were assumed to receive no further treatment, and to enter a state of untreated TB from which they could continue to live, die or be spontaneously cured. The annual spontaneous cure rate was assumed at 25% [28, 33]. Costs Costs were estimated from the societal perspective, and included health systems costs, patients' and families' out-of-pocket expenditure, and lost wages (online supplementary table S1). All costs were expressed in 2017 international US dollars, which were adjusted using 2017 power purchasing parity estimates for Ecuador [41], and inflated to 2017 currency using the average consumer price index in the US for 2017 and 2017 [42]. We used cost estimates from Ecuador because direct and indirect patient costs had been estimated there recently [43]. Indirect patient costs were based on patient and family time lost during TB diagnosis and treatment, which was converted into monetary costs using the hourly wage based on the power purchasing parity-adjusted average per capita gross national income [44]. Ecuador has one of the highest levels of MDR-TB in Latin America [2], which makes it an appropriate setting for estimating MDR-TB treatment costs. The country achieved national implementation of directly observed therapy, short course (DOTS) in 2017, and provides TB treatment and diagnosis free of charge for patients [45, 46]. Thus, estimated treatment costs should be comparable with other countries that have national coverage for DOTS. Estimating health system costs An interviewer-administered health facility cost survey was used to collect health system data in Ecuador. The interviews were conducted in 19 urban health facilities that treated TB patients in two provinces (Guayas and Tungurahua) between September and October 2017: 16 Ministry of Health clinics, two Ministry of Health hospitals and one nongovernment hospital (Erika Leung, McGill University, Montreal, Canada; personal communication). Salary levels of Ministry of Health employees were retrieved from the Ministerio de Inclusión Económica y Social [47]. We assumed that the personnel costs made up 80% of the total facility budget [48, 49]. The average health system cost per outpatient visit was the quotient of dividing the estimated total facility budget of each Ministry of Health clinic by the ed number of annual outpatient visits. We assumed that the total inpatient budget of a hospital was the difference between the total health facility budget and the total outpatient budget. The per diem cost was the total inpatient budget divided by annual number of bed-days. Only data from one Ministry of Health hospital, Hospital Alfredo J. Valenzuela, was included because it was a respiratory/pulmonary-specific hospital and would be more applicable for estimating TB-related per diem costs. The cost of each directly observed therapy visit was estimated to be a third of the cost of an outpatient visit. This assumption was based on previously published surveys of health system costs [50, 51].()，英语论文，英语毕业论文 |
