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

Woojin Lew, MD, MSc; Madhukar Pai, MD, PhD; Olivia Oxlade, MSc; Daniel Martin, BSc; and Dick Menzies, MD, MSc
[+] Article and Author 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@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.


Ann Intern Med. 2008;149(2):123-134. doi:10.7326/0003-4819-149-2-200807150-00008
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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.

Figures

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Figure 1.
Summary of literature search and study selection.

MDR TB = multidrug-resistant tuberculosis.

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Figure 2.
Forest plots of acquired drug resistance during treatment among cohorts with initially pan-sensitive strains.

BMRC = British Medical Research Council; E Africa = East Africa; E&C Africa = East and Central Africa; HK = Hong Kong; TBRC = Tuberculosis Research Centre; TBTC/CDC = Tuberculosis Trials Consortium/Centers for Disease Control and Prevention. * Pooled event rate (95% CI).

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Figure 3.
Forest plot of acquired drug resistance during treatment among cohorts with initially single drug–resistant strains.

BMRC = British Medical Research Council; E Africa = East Africa; E&C Africa = East and Central Africa; HK = Hong Kong; TBRC = Tuberculosis Research Centre. * Pooled event rate (95% CI).

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Grahic Jump Location
Figure 4.
Forest plots of acquired drug resistance during treatment among cohorts with initially polydrug-resistant strains.

BMRC = British Medical Research Council; E Africa = East Africa; E&C Africa = East and Central Africa; HK = Hong Kong. *Pooled event rate (95% CI).

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Figure 5.
Association of duration of rifampin therapy and initial drug resistance with failure, relapse, and acquired drug resistance.

Mean cumulative incidences and standard errors are shown for each estimate in which there were ≥2 studies. Single drug resistance is resistance to any 1 drug other than rifampin. Polydrug resistance is resistance to ≥2 drugs.

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