Initial Drug Resistance and Tuberculosis Treatment Outcomes: Systematic Review and Meta-analysis

15 July 2008 | Volume 149 Issue 2 | Pages 123-134

Background: Despite the increasing prevalence of drug-resistant tuberculosis, most low- and middle-income countries use standardized regimens, without assessment of drug susceptibility.

Purpose: To perform a systematic review and meta-analysis of the effect of initial drug resistance and treatment regimen on tuberculosis treatment outcomes.

Data Sources: PubMed, the Cochrane Central Database of Clinical Trials, and EMBASE were searched for studies published in English from 1965 to June 2007. Additional studies were identified from cited references.

Study Selection: Randomized, controlled trials and cohort studies of standardized treatment of previously untreated patients with culture-confirmed pulmonary tuberculosis. Drug-susceptibility testing was done on pretreatment isolates from all patients and from patients with treatment failure or relapse.

Data Extraction: Two authors reviewed the studies for methods, initial drug resistance, treatment regimens, and outcomes.

Data Synthesis: Pooled cumulative incidences were computed with random-effects meta-analyses. Association between risk factors and outcomes were determined by using stratified analyses. The cumulative incidence of acquired drug resistance with initially pan-sensitive strains was 0.8% (95% CI, 0.5% to 1.0%) compared with 6% (CI, 4% to 8%) with initially single drug–resistant strains and 14% (CI, 9% to 20%) with initially polydrug-resistant strains. Failure and relapse were most strongly associated with initial drug resistance. Failure was also associated with shorter duration of rifampin therapy and nonuse of streptomycin, whereas the rate of relapse was higher with shorter duration of rifampin therapy and nonuse of pyrazinamide.

Limitations: Few studies included HIV-infected persons, and treatment outcomes were pooled despite considerable heterogeneity.

Conclusion: Treatment outcomes were substantially worse in the presence of initial drug resistance, which has important implications in resource-limited settings in which drug resistance is prevalent.

Editors' Notes Context Identifying strategies to optimize tuberculosis treatment outcomes is important in light of the increasing occurrence of drug-resistant tuberculosis. Contribution This systematic review of 22 trials and 7 cohort studies involved 14 333 new tuberculosis cases. Findings showed that poor outcomes were associated with initial drug resistance and that treatment was not based on susceptibility testing. Estimated rates of failure or relapse were 35% to 40% for patients who received rifampin for 2 months and 20% for those who received rifampin for 6 months. Implication These findings suggest that poor outcomes can be anticipated in settings that, because of limited resources, do not do susceptibility testing before initiation of tuberculosis treatment. —The Editors

 

Author and Article Information

From the Montreal Chest Institute, McGill University, Montreal, Quebec, Canada.

Acknowledgment: The authors thank Ria Choe for extensive assistance with preparation of the manuscript and Kevin Schwartzman, MD; Andrea Benedetti, MD; and Hans Rieder, MD, for helpful discussions and reviews of earlier versions of the manuscript. The authors also thank Robert Jasmer, MD, and Giovanni B. Migliori, MD, for providing additional data and Mahlon Wilkes, MD, for advice on production of forest plots.

Grant Support: Salary support from the Canadian Institutes of Health Research (PHI-77906 [Dr. Lew], New Investigator Award [Dr. Pai], and CGD-80429 [Ms. Oxlade]). Dr Menzies also received salary support from the Fonds de la recherche en santé du Québec.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Dick Menzies, MD, MSc, Montreal Chest Institute, Room K1.24, 3650 St. Urbain, Montreal, Quebec H2X 2P4, Canada; e-mail, dick.menzies{at}mcgill.ca.

Current Author Addresses: Dr. Lew: Korean Institute of Tuberculosis, 14 Woomyundong, Sochogu, Seoul, Korea 137-900.

Drs. Pai and Menzies, Ms. Oxlade, and Mr. Martin: Montreal Chest Institute, 3650 St. Urbain, Montreal, Quebec H2X 2P4, Canada.