Effectiveness and Safety of a Shorter Treatment Regimen in a Setting with a High Burden of Multidrug-Resistant Tuberculosis.
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ABSTRACT:
SUBMITTER: Trubnikov A
PROVIDER: S-EPMC8069801 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundIn 2016, World Health Organization guidelines conditionally recommended standardised shorter 9-12-month regimens for multidrug-resistant (MDR) tuberculosis (TB) treatment. We conducted a prospective study of a shorter standardised MDR-TB regimen in Karakalpakstan, Uzbekistan.MethodsConsecutive adults and children with confirmed rifampicin-resistant pulmonary TB were enrolled between September 1, 2013 and March 31, 2015; exclusions included prior treatment with second-line anti-TB drugs, and documented resistance to ofloxacin or to two second-line injectable agents. The primary outcome was recurrence-free cure at 1?year following treatment completion.ResultsOf 146 enrolled patients, 128 were included: 67 female (52.3%), median age 30.1 (interquartile range 23.8-44.4) years. At the end of treatment, 71.9% (92 out of 128) of patients achieved treatment success, with 68% (87 out of 128) achieving recurrence-free cure at 1?year following completion. Unsuccessful outcomes during treatment included 22 (17.2%) treatment failures with fluoroquinolone-resistance amplification in 8 patients (8 out of 22, 36.4%); 12 (9.4%) lost to follow-up; and 2 (1.5%) deaths. Recurrence occurred in one patient. Fourteen patients (10.9%) experienced serious adverse events. Baseline resistance to both pyrazinamide and ethambutol (adjusted OR 6.13, 95% CI 2.01; 18.63) and adherence <95% (adjusted OR 5.33, 95% CI 1.73; 16.36) were associated with unsuccessful outcome in multivariable logistic regression.ConclusionsOverall success with a standardised shorter MDR-TB regimen was moderate with considerable treatment failure and amplification of fluoroquinolone resistance. When introducing standardised shorter regimens, baseline drug susceptibility testing and minimising missed doses are critical. High rates globally of pyrazinamide, ethambutol and ethionamide resistance raise questions of continued inclusion of these drugs in shorter regimens in the absence of drug susceptibility testing-confirmed susceptibility.
| S-EPMC7869592 | biostudies-literature
Project description:BACKGROUND:In 2016, the World Health Organization (WHO) recommended a shorter (9-12 month) multidrug-resistant tuberculosis (MDR-TB) treatment regimen (as compared to the conventional 18-24 month regimen) for patients without extrapulmonary TB, pregnancy, a previous second-line TB medication exposure, or drug resistance to pyrazinamide, ethambutol, kanamycin, moxifloxacin, ethionamide, or clofazimine. The recommendation was based on successful clinical trials conducted in Asia and Africa, but studies, using mainly European data, have shown few patients in higher-resource settings would meet WHO eligibility criteria. METHODS:We assessed eligibility for the shorter regimen among US MDR-TB cases that had full drug susceptibility testing (DST) results and were reported during 2011-2016 to the US National TB Surveillance System. We estimated costs by applying the eligibility criteria for the shorter regimen, and proportional inpatient/outpatient costs from a previous, population-based study, to all MDR-TB patients reported to the National TB Surveillance System. RESULTS:Of 586 reported MDR-TB cases, 10% (59) were eligible for the shorter regimen. Of 527 ineligible patients, 386 had full DST, of which 246 were resistant to ethambutol and 217 were resistant to pyrazinamide. Compared with conventional MDR-TB treatment, implementing the shorter regimen would have reduced the US annual societal MDR-TB cost burden by 4%, but the cost burden for eligible individuals would have been reduced by 37-46%. CONCLUSIONS:Relying on full DST use, our analysis found a minority of US MDR-TB patients would have been eligible for the shorter regimen. Cost reductions would have been minimal for society, but large for eligible individuals.
| S-EPMC6788947 | biostudies-literature
Project description:BackgroundAt the end of 2018, South Africa updated its all-oral regimen, to include bedaquiline (BDQ) and two months of linezolid (LZD) for all patients initiating the shorter 9 to 12 months regimen for rifampicin-resistant tuberculosis (RR-TB). We assessed a group of patients in rural KwaZulu-Natal for safety and effectiveness of this treatment regimen under programmatic conditions.MethodsWe conducted a retrospective cohort analysis on RR-TB patients treated with a standardized all-oral short regimen between July 1, 2018 and April 30, 2019 in three facilities in King Cetshwayo District. An electronic register (EDR Web) and facility-based clinical charts were used to collect variables which were entered into an Epi-Info database.ResultsOur cohort included 117 patients; 68.4%(95%CI:59.3-76.3) were HIV positive. The median time to culture conversion was 56 days(95%CI:50-57). Treatment success was achieved in 75.2%(95%CI:66.5-82.3) of patients. Mortality within the cohort was 12.8%(95%CI:7.8-20.3). Anaemia was the most frequent severe adverse event. The median time to develop severe anaemia was 7.1 weeks(IQR 4.0-12.9) after treatment initiation. LZD was interrupted in 25.2%(95%CI:17.8-34.5) of participants.ConclusionsAn all-oral shorter regimen, including BDQ and LZD as core drugs for the treatment of RR-TB, shows good outcomes, in a high HIV burden rural setting. Adverse events (AEs) are common, especially for LZD, but could be managed in the program setting. Support is needed when introducing new regimens to upskill staff in the monitoring, management and reporting of AEs.
| S-EPMC8563184 | biostudies-literature
Project description:BackgroundSince a meta-analysis showed little or no effect of second-line injectables on treatment success, and using injectables may induce ototoxicity, injectable-free rifampicin-resistant tuberculosis (RR-TB) treatment regimens are recommended. However, acquired resistance preventing activity was overlooked. No previous study assessed the effect of shortening the duration of kanamycin administration to 2 months during the intensive phase of the RR-TB shorter treatment regimen (STR).MethodsRetrospective cohort study of the effect of using 2 months of kanamycin instead of the standard 4(+) months (extension if lack of smear conversion at 4 months) on recurrence (either treatment failure or relapse) and fluoroquinolone acquired drug resistance, in patients treated with a gatifloxacin-based STR in Damien Foundation supported clinics in Bangladesh. Logistic regression was used to estimate associations.ResultsFive of 52 (9.6%) treated with a STR containing two months of kanamycin had recurrence, compared to 21 of 738 (2.8%) patients treated with the standard STR containing 4(+) months of kanamycin (OR 3.7; 95%CI:1.5-10.3). In those with initially fluoroquinolone-susceptible TB, acquired resistance to fluoroquinolone was detected in none of 639 patients treated with 4(+) months of kanamycin and two (4.5%) of 44 treated with two months of kanamycin (OR 75.2; 95%CI:3.6-1592.1).ConclusionTwo months of kanamycin was insufficient to prevent recurrence with acquired resistance to gatifloxacin, the core drug of the most effective RR-TB STR. Injectable mediated resistance prevention is important to reach high effectiveness, to safeguard all treatment options after recurrence, and to prevent the spread of resistant TB. Studies on all-oral regimens should also assess the effect of regimen composition on resistance acquisition. Until evidence shows that other drugs can assure at least the same strong resistance preventing activity of the injectables, it seems wise to continue using this group of drugs, and adapt the regimen if any ototoxicity is detected.
| S-EPMC7458281 | biostudies-literature
Project description:OBJECTIVES:We investigated whether companion drug resistance was associated with adverse outcomes of the shorter multidrug-resistant tuberculosis (MDR-TB) treatment regimen in Bangladesh after adjustment for fluoroquinolone resistance. METHODS:MDR-TB/rifampicin-resistant tuberculosis patients registered for treatment with a standardized gatifloxacin-based shorter MDR-TB treatment regimen were selected for the study. Drug resistance was determined by the proportion method, gatifloxacin and isoniazid minimum inhibitory concentration testing for selected isolates, and whole-genome sequencing. RESULTS:Low-level fluoroquinolone resistance and high-level fluoroquinolone resistance were the most important predictors of adverse outcomes, with pyrazinamide resistance having a significant yet lower impact. In patients with fluoroquinolone-/second-line-injectable-susceptible tuberculosis, non-eligibility for the shorter MDR-TB treatment regimen (initial resistance to pyrazinamide, ethionamide, or ethambutol) was not associated with adverse outcome (adjusted odds ratio 1.01; 95% confidence interval 0.4-2.8). Kanamycin resistance was uncommon (1.3%). Increasing levels of resistance to isoniazid predicted treatment failure, also in a subgroup of patients with high-level fluoroquinolone-resistant tuberculosis. CONCLUSIONS:Our results suggest that resistance to companion drugs in the shorter MDR-TB treatment regimen, except kanamycin resistance, is of no clinical importance as long as fluoroquinolone susceptibility is preserved. Hence, contrary to current WHO guidelines, exclusions to the standard regimen are justified only in the case of fluoroquinolone resistance. and possibly kanamycin resistance.
| S-EPMC7670168 | biostudies-literature
Project description:Treatment for multidrug-resistant tuberculosis (MDR TB) is associated with adverse events (AE). Patients treated with an MDR TB regimen in Hospital Nossa Senhora da Paz, Cubal, Angola, were prospectively enrolled from May 2013 to July 2015. Baseline characteristics, AE, and clinical and microbiological outcomes were recorded. A total of 216 patients were treated with an MDR TB regimen and 179 (82.9%) patients developed at least one AE. The most common AE were elevation of liver enzymes (46.8% of patients), elevated creatinine (44.4% of patients), and ototoxicity (40.7% of patients). Previous TB treatment was associated with the occurrence of AE (OR 4.89, 95% CI: 2.09-11.46, P < 0.001) and months on treatment was associated to severe AE (OR 1.11 95% CI: 1.04-1.18, P = 0.001). Successful treatment was achieved in 117 (54.2%) patients. Incidence of AE was associated with an unsuccessful outcome (OR 1.23, 95% CI: 1.09-1.40, P = 0.001). Patients treated with MDR TB treatment frequently experience AE, and these are related with previous TB treatment and duration of treatment. Given the high percentage of patients experiencing AE and the low treatment success rates, more effective and less toxic drugs to treat MDR TB are urgently needed.
| S-EPMC6726936 | biostudies-literature
Project description:Sputum cultures are an important tool in monitoring the response to tuberculosis treatment, especially in multidrug-resistant tuberculosis. There has, however, been little study of the effect of treatment regimen composition on culture conversion. Well-designed clinical trials of new anti-tuberculosis drugs require this information to establish optimized background regimens for comparison. We conducted a retrospective cohort study to assess whether the use of an aggressive multidrug-resistant tuberculosis regimen was associated with more rapid sputum culture conversion. We conducted Cox proportional-hazards analyses to examine the relationship between receipt of an aggressive regimen for the 14 prior consecutive days and sputum culture conversion. Sputum culture conversion was achieved in 519 (87.7%) of the 592 patients studied. Among patients who had sputum culture conversion, the median time to conversion was 59 days (IQR: 31-92). In 480 patients (92.5% of those with conversion), conversion occurred within the first six months of treatment. Exposure to an aggressive regimen was independently associated with sputum culture conversion during the first six months of treatment (HR: 1.36; 95% CI: 1.10, 1.69). Infection with human immunodeficiency virus (HR 3.36; 95% CI: 1.47, 7.72) and receiving less exposure to tuberculosis treatment prior to the individualized multidrug-resistant tuberculosis regimen (HR: 1.58; 95% CI: 1.28, 1.95) were also independently positively associated with conversion. Tachycardia (HR: 0.77; 95% CI: 0.61, 0.98) and respiratory difficulty (HR: 0.78; 95% CI: 0.62, 0.97) were independently associated with a lower rate of conversion. This study is the first demonstrating that the composition of the multidrug-resistant tuberculosis treatment regimen influences the time to culture conversion. These results support the use of an aggressive regimen as the optimized background regimen in trials of new anti-TB drugs.
| S-EPMC4169600 | biostudies-other
Project description:SETTING:Since August 2016, after the Ebola outbreak, the Guinean National Tuberculosis Programme and Damien Foundation implemented the shorter treatment regimen (STR) for multidrug-resistant tuberculosis (MDR-TB) in the three MDR-TB sites of Conakry. Previously, the longer regimen was used to treat MDR-TB. OBJECTIVES:In a post-Ebola context, with a weakened health system, we describe the MDR-TB treatment uptake, patients characteristics, treatment outcomes and estimate the effect of using the longer versus STR on having a programmatically adverse outcome. DESIGN:This is a retrospective cohort study in RR-TB patients treated with either the longer regimen or STR. RESULTS:In Conakry, in 2016 and 2017, 131 and 219 patients were diagnosed with rifampicin-resistant tuberculosis (RR-TB); and 108 and 163 started treatment, respectively. Of 271 patients who started treatment, 75 were treated with the longer regimen and 196 with the STR. Patients characteristics were similar regardless of the regimen except that the median age was higher among those treated with a longer regimen (30 years (IQR:24-38) versus 26 years (IQR:21-39) for the STR. Patients treated with a STR were more likely to obtain a programmatically favorable outcome (74.0% vs 58.7%, p = 0.01) as lost to follow up was higher among those treated with a longer regimen (20.0% vs 8.2%, p = 0.006). Patients on a longer regimen were more than 2 times more likely (aOR: 2.5; 95%CI:1.3,4.7) to have a programmatically adverse outcome as well as being 45 years or older (aOR: 2.8; 95%CI:1.3,6.2), HIV positive (aOR:3.3; 95%CI:1.6,6.6) and attendance at a clinic without NGO support (aOR:3.0; 95%:1.6,5.7). CONCLUSION:In Guinea, patients treated with the STR were more likely to have a successful outcome than those treated with the longer MDR-TB treatment regimen. Lost to follow-up was higher in patients on the longer regimen. However, STR treatment outcomes were less good than those reported in the region.
| S-EPMC7416929 | biostudies-literature
Project description:BackgroundTreatment of multidrug-resistant tuberculosis (MDR-TB) is complex, lengthy, and involves a minimum of four drugs termed a background regimen (BR), that have not previously been prescribed or that have proven susceptible to patient sputum culture isolates. In recent years, promising new treatment options have emerged as add-on therapies to a BR. The aim of this study was to evaluate the long-term costs and effectiveness of adding the novel or group 5 interventions bedaquiline, delamanid, and linezolid to a background regimen (BR) of drugs for the treatment of adult patients with pulmonary multidrug-resistant tuberculosis (MDR-TB), within their marketing authorisations, from a German healthcare cost-effectiveness perspective.MethodsA cohort-based Markov model was developed to simulate the incremental cost-effectiveness ratio of bedaquiline plus BR, delamanid plus BR, or linezolid plus BR versus BR alone in the treatment of MDR-TB, over a 10-year time horizon. Effectiveness of treatment was evaluated in Quality-Adjusted Life-Years (QALYs) and Life-Years Gained (LYG), using inputs from clinical trials for bedaquiline and delamanid and from a German observational study for linezolid. Cost data were obtained from German Drug Directory costs (€/2015), published literature, and expert opinion. A 3% yearly discount rate was applied. Probabilistic and deterministic sensitivity analyses were conducted.ResultsThe total discounted costs per-patient were €85,575 for bedaquiline plus BR, €81,079 for delamanid plus BR, and €80,460 for linezolid plus BR, compared with a cost of €60,962 for BR alone. The total discounted QALYs per-patient were 5.95 for bedaquiline plus BR, 5.36 for delamanid plus BR, and 3.91 for linezolid plus BR, compared with 3.68 for BR alone. All interventions were therefore associated with higher QALYs and higher costs than BR alone, with incremental costs per QALY gained of €22,238 for bedaquiline, €38,703 for delamanid, and €87,484 for linezolid, versus BR alone. In a fully incremental analysis, bedaquiline plus BR was the most cost-effective treatment option at thresholds greater than €22,000 per QALY gained. In probabilistic analyses, the probability that bedaquiline plus BR was the most cost-effective treatment strategy at a willingness-to-pay threshold of €30,000 was 54.5%, compared with 22.9% for BR alone, 18.2% for delamanid plus BR, and 4.4% for linezolid.ConclusionsIn Germany, the addition of bedaquiline, delamanid, or linezolid to a BR would result in QALY gains over BR alone. Based on this analysis, bedaquiline is likely to be the most cost-effective intervention for the treatment of MDR-TB, when added to a BR regimen at thresholds greater than €22,000 per QALY.
| S-EPMC5341441 | biostudies-literature
Project description:BackgroundDespite the existence of effective drug treatments, tuberculosis (TB) causes 2 million deaths annually worldwide. Effective treatment is complicated by multidrug-resistant TB (MDR TB) strains that respond only to second-line drugs. We projected the health benefits and cost-effectiveness of using drug susceptibility testing and second-line drugs in a lower-middle-income setting with high levels of MDR TB.Methods and findingsWe developed a dynamic state-transition model of TB. In a base case analysis, the model was calibrated to approximate the TB epidemic in Peru, a setting with a smear-positive TB incidence of 120 per 100,000 and 4.5% MDR TB among prevalent cases. Secondary analyses considered other settings. The following strategies were evaluated: first-line drugs administered under directly observed therapy (DOTS), locally standardized second-line drugs for previously treated cases (STR1), locally standardized second-line drugs for previously treated cases with test-confirmed MDR TB (STR2), comprehensive drug susceptibility testing and individualized treatment for previously treated cases (ITR1), and comprehensive drug susceptibility testing and individualized treatment for all cases (ITR2). Outcomes were costs per TB death averted and costs per quality-adjusted life year (QALY) gained. We found that strategies incorporating the use of second-line drug regimens following first-line treatment failure were highly cost-effective compared to strategies using first-line drugs only. In our base case, standardized second-line treatment for confirmed MDR TB cases (STR2) had an incremental cost-effectiveness ratio of 720 dollars per QALY (8,700 dollars per averted death) compared to DOTS. Individualized second-line drug treatment for MDR TB following first-line failure (ITR1) provided more benefit at an incremental cost of 990 dollars per QALY (12,000 dollars per averted death) compared to STR2. A more aggressive version of the individualized treatment strategy (ITR2), in which both new and previously treated cases are tested for MDR TB, had an incremental cost-effectiveness ratio of 11,000 dollars per QALY (160,000 dollars per averted death) compared to ITR1. The STR2 and ITR1 strategies remained cost-effective under a wide range of alternative assumptions about treatment costs, effectiveness, MDR TB prevalence, and transmission.ConclusionsTreatment of MDR TB using second-line drugs is highly cost-effective in Peru. In other settings, the attractiveness of strategies using second-line drugs will depend on TB incidence, MDR burden, and the available budget, but simulation results suggest that individualized regimens would be cost-effective in a wide range of situations.
| S-EPMC1483913 | biostudies-literature