Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis.

BACKGROUND: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Multidrug-resistant tuberculosis treatment failure detection depends on monitoring interval and microbiological method.

Debate persists about monitoring method (culture or smear) and interval (monthly or less frequently) during treatment for multidrug-resistant tuberculosis (MDR-TB). We analysed existing data and estimated the effect of monitoring strategies on timing of failure detection.We identified studies reporting microbiological response to MDR-TB treatment and solicited individual patient data from authors. Frailty survival models were used to estimate pooled relative risk of failure detection in the last 12 months of treatment; hazard of failure using monthly culture was the reference.Data were obtained for 5410 patients across 12 observational studies. During the last 12 months of treatment, failure detection occurred in a median of 3 months by monthly culture; failure detection was delayed by 2, 7, and 9 months relying on bimonthly culture, monthly smear and bimonthly smear, respectively. Risk (95% CI) of failure detection delay resulting from monthly smear relative to culture is 0.38 (0.34-0.42) for all patients and 0.33 (0.25-0.42) for HIV-co-infected patients.Failure detection is delayed by reducing the sensitivity and frequency of the monitoring method. Monthly monitoring of sputum cultures from patients receiving MDR-TB treatment is recommended. Expanded laboratory capacity is needed for high-quality culture, and for smear microscopy and rapid molecular tests.

Patient- and provider-level risk factors associated with default from tuberculosis treatment, South Africa, 2002: a case-control study.

BACKGROUND: Persons who default from tuberculosis treatment are at risk for clinical deterioration and complications including worsening drug resistance and death. Our objective was to identify risk factors associated with tuberculosis (TB) treatment default in South Africa. METHODS: We conducted a national retrospective case control study to identify factors associated with treatment default using program data from 2002 and a standardized patient questionnaire. We defined default as interrupting TB treatment for two or more consecutive months during treatment. Cases were a sample of registered TB patients receiving treatment under DOTS that defaulted from treatment. Controls were those who began therapy and were cured, completed or failed treatment. Two respective multivariable models were constructed, stratified by history of TB treatment (new and re-treatment patients), to identify independent risk factors associated with default. RESULTS: The sample included 3165 TB patients from 8 provinces; 1164 were traceable and interviewed (232 cases and 932 controls). Significant risk factors associated with default among both groups included poor health care worker attitude (new: AOR 2.1, 95% CI 1.1-4.4; re-treatment: AOR 12, 95% CI 2.2-66.0) and changing residence during TB treatment (new: AOR 2.0, 95% CI 1.1-3.7; re-treatment: AOR 3.4, 95% CI 1.1-9.9). Among new patients, cases were more likely than controls to report having no formal education (AOR 2.3, 95% CI 1.2-4.2), feeling ashamed to have TB (AOR 2.0, 95% CI 1.3-3.0), not receiving adequate counseling about their treatment (AOR 1.9, 95% CI 1.2-2.8), drinking any alcohol during TB treatment (AOR 1.9, 95% CI 1.2-3.0), and seeing a traditional healer during TB treatment (AOR 1.9, 95% CI 1.1-3.4). Among re-treatment patients, risk factors included stopping TB treatment because they felt better (AOR 21, 95% CI 5.2-84), having a previous history of TB treatment default (AOR 6.4, 95% CI 2.9-14), and feeling that food provisions might have helped them finish treatment (AOR 5.0, 95% CI 1.3-19). CONCLUSIONS: Risk factors for default differ between new and re-treatment TB patients in South Africa. Addressing default in both populations with targeted interventions is critical to overall program success.

Time to sputum culture conversion in multidrug-resistant tuberculosis: predictors and relationship to treatment outcome.

BACKGROUND: Conversion of sputum mycobacterial cultures from positive growth to negative growth of Mycobacterium tuberculosis in patients with pulmonary tuberculosis (TB) is considered the most important interim indicator of the efficacy of anti-TB pharmacologic treatment for multidrug-resistant disease. OBJECTIVE: To evaluate and compare time to and predictors of initial sputum culture conversion with predictors of treatment outcome for patients with multidrug-resistant TB. DESIGN: Retrospective cohort study. SETTING: Latvia. PATIENTS: All civilian patients with multidrug-resistant TB treated with the DOTS-Plus strategy between 1 January and 31 December 2000. INTERVENTION: Individualized treatment for confirmed sputum culture-positive pulmonary multidrug-resistant TB. MEASUREMENTS: Time to initial sputum culture conversion and treatment outcome. RESULTS: Among 167 patients who were sputum culture-positive at initiation of second-line therapy, 129 (77%) converted in a median time of 60 days (range, 4 to 462 days) and 38 (23%) did not convert. Independent predictors of a longer sputum culture conversion time, using an accelerated failure time regression model, included previous treatment for multidrug-resistant TB, high initial sputum culture colony count, bilateral cavitations on chest radiography, and the number of drugs the initial isolate was resistant to at treatment initiation. Treatment outcomes were statistically significantly worse for patients who did not convert their sputum culture within 2 months. LIMITATIONS: Twenty-five percent of patients missed 5 or more monthly sputum collections. CONCLUSIONS: Under program conditions in Latvia, most patients with multidrug-resistant TB achieved sputum culture conversion within 12 weeks of starting treatment. Chest radiography and sputum culture drug susceptibility testing can assist physicians in predicting which patients will convert more slowly. Sputum culture conversion is a useful and appropriate interim indicator of treatment outcome in patients with multidrug-resistant TB.

Clinical outcome of individualised treatment of multidrug-resistant tuberculosis in Latvia: a retrospective cohort study.

BACKGROUND: Latvia has one of the highest rates of multidrug-resistant tuberculosis (MDRTB). Our aim was to assess treatment outcomes for the first full cohort of MDRTB patients treated under Latvia's DOTS-Plus strategy following WHO guidelines. METHODS: We retrospectively reviewed all civilian patients who began treatment with individualised treatment regimens for pulmonary MDRTB in Latvia between Jan 1, and Dec 31, 2000. We applied treatment outcome definitions for MDRTB, developed by an international expert consensus group, and assessed treatment effectiveness and risk factors associated with poor outcome. FINDINGS: Of the 204 patients assessed, 55 (27%) had been newly diagnosed with MDRTB, and 149 (73%) had earlier been treated with first-line or second-line drugs for this disease. Assessment of treatment outcomes showed that 135 (66%) patients were cured or completed therapy, 14 (7%) died, 26 (13%) defaulted, and treatment failed in 29 (14%). Of the 178 adherent patients, 135 (76%) achieved cure or treatment completion. In a multivariate Cox proportional-hazards model of these patients, independent predictors of poor outcome (death and treatment failure) included having previously received treatment for MDRTB (hazard ratio 5.7, 95% CI 1.9-16.6), the use of five or fewer drugs for 3 months or more (3.2, 1.1-9.6), resistance to ofloxacin (2.6, 1.2-5.4), and body-mass index less than 18.5 at start of treatment (2.3, 1.1-4.9). INTERPRETATION: The DOTS-Plus strategy of identifying and treating patients with MDRTB can be effectively implemented on a nationwide scale in a setting of limited resources.