Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis

Summary

Multidrug-resistant (MDR) tuberculosis is a growing clinical and public-health concern. To evaluate existing evidence regarding treatment regimens for MDR tuberculosis, we used a Bayesian random-effects meta-analysis of the available therapeutic studies to assess how the reported proportion of patients treated successfully is influenced by differences in treatment regimen design, study methodology, and patient population. Successful treatment outcome was defined as cure or treatment completion. 34 clinical reports with a mean of 250 patients per report met the inclusion criteria. Our analysis shows that the proportion of patients treated successfully improved when treatment duration was at least 18 months, and if patients received directly observed therapy throughout treatment. Studies that combined both factors had significantly higher pooled success proportions (69%, 95% credible interval [CI] 64–73%) than other studies of treatment outcomes (58%, 95% CI 52–64%). Individualised treatment regimens had higher treatment success (64%, 95% CI 59–68%) than standardised regimens (54%, 95% CI 43–68%), although the difference was not significant. Treatment approaches and study methodologies were heterogeneous across studies. Many important variables, including patients' HIV status, were inconsistently reported between studies. These results underscore the importance of strong patient support and treatment follow-up systems to develop successful MDR tuberculosis treatment programmes.

Introduction

Mycobacterium tuberculosis strains that are resistant to anti-tuberculosis medications have generated increasing international concern. An estimated 489 000 cases of multidrug-resistant (MDR) tuberculosis (defined as resistance to at least isoniazid and rifampin) occurred worldwide in 2006.¹ Treatment of drug-resistant tuberculosis is expensive and complex because it necessitates the use of second-line tuberculosis drugs, which are associated with a greater incidence of adverse reactions,2, 3 and require a longer treatment duration than first-line drugs. However, comprehensive treatment programmes have shown the efficacy of MDR tuberculosis treatment,⁴ and mathematical models have suggested that this therapy is cost-effective in resource-poor settings.⁵ Nevertheless, current guidelines for MDR tuberculosis management are largely based on expert opinion and case series, rather than on the results of clinical trials.⁶ Guidelines in different countries are based on variable health-system approaches to MDR tuberculosis treatment. Some programmes use second-line drug-susceptibility testing to design individualised treatment regimens for patients with MDR tuberculosis, minimising amplification of resistance and sparing patients from otherwise toxic drugs. Other programmes use standardised drug regimens based on population surveys of local drug-susceptibility patterns in the context of limited laboratory capacity or pharmaceutical access (such as lack of participation in the WHO Green Light Committee programme, which provides countries with access to quality-assured second-line drugs at substantially reduced prices).⁷

Programmes differ in their use of strategies to promote adherence such as directly observed therapy (DOT). Some treatment programmes use only self-administered therapy,⁸ some use DOT only for the intensive phase,⁹ and others incorporate DOT throughout treatment.¹⁰ MDR tuberculosis treatment programmes also vary in other characteristics, including the size of drug regimens, duration of treatment, definitions of cure, and follow-up protocols. The impact of these variations on the probability that patients will achieve treatment success is unknown.

Previous reviews of MDR tuberculosis therapy have not identified which factors are the most important contributors to treatment success. One review found that initial drug resistance and treatment composition could predict the development of acquired drug resistance and treatment failure for patients receiving first-line drug regimens, but did not present outcomes specifically from MDR tuberculosis patients or examine the impact of other treatment programme characteristics.¹¹ Other reviews have assessed treatment outcomes in patients with MDR tuberculosis, but included too few studies to statistically determine which factors specifically affect treatment success.12, 13

In this study, we did a systematic review and meta-analysis of available therapeutic studies to characterise factors associated with improved treatment outcomes among patients with MDR tuberculosis who were treated with second-line drugs. Our analysis assesses the role of individualised versus standardised treatment regimens, characteristics of patients and programmes, study settings, and outcome definitions on the reported efficacy of MDR tuberculosis treatment.