Elsevier

The Lancet

Volume 380, Issue 9851, 20–26 October 2012, Pages 1406-1417
The Lancet

Articles
Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study

https://doi.org/10.1016/S0140-6736(12)60734-XGet rights and content

Summary

Background

The prevalence of extensively drug-resistant (XDR) tuberculosis is increasing due to the expanded use of second-line drugs in people with multidrug-resistant (MDR) disease. We prospectively assessed resistance to second-line antituberculosis drugs in eight countries.

Methods

From Jan 1, 2005, to Dec 31, 2008, we enrolled consecutive adults with locally confirmed pulmonary MDR tuberculosis at the start of second-line treatment in Estonia, Latvia, Peru, Philippines, Russia, South Africa, South Korea, and Thailand. Drug-susceptibility testing for study purposes was done centrally at the Centers for Disease Control and Prevention for 11 first-line and second-line drugs. We compared the results with clinical and epidemiological data to identify risk factors for resistance to second-line drugs and XDR tuberculosis.

Findings

Among 1278 patients, 43·7% showed resistance to at least one second-line drug, 20·0% to at least one second-line injectable drug, and 12·9% to at least one fluoroquinolone. 6·7% of patients had XDR tuberculosis (range across study sites 0·8–15·2%). Previous treatment with second-line drugs was consistently the strongest risk factor for resistance to these drugs, which increased the risk of XDR tuberculosis by more than four times. Fluoroquinolone resistance and XDR tuberculosis were more frequent in women than in men. Unemployment, alcohol abuse, and smoking were associated with resistance to second-line injectable drugs across countries. Other risk factors differed between drugs and countries.

Interpretation

Previous treatment with second-line drugs is a strong, consistent risk factor for resistance to these drugs, including XDR tuberculosis. Representative drug-susceptibility results could guide in-country policies for laboratory capacity and diagnostic strategies.

Funding

US Agency for International Development, Centers for Disease Control and Prevention, National Institutes of Health/National Institute of Allergy and Infectious Diseases, and Korean Ministry of Health and Welfare.

Introduction

Multidrug-resistant (MDR) tuberculosis, defined as tuberculosis caused by Mycobacterium tuberculosis resistant to at least isoniazid and rifampicin, accounts for 3·6–4·8% of incident cases of tuberculosis worldwide—around 440 000 new cases in 2008.1, 2 In 2000, the Green Light Committee was formed within the Stop TB Partnership and WHO to increase access to high-quality, second-line antituberculosis drugs at low prices, to prevent additional drug resistance, and to contribute evidence for policy development. By 2011, 255 project applications to the Green Light Committee had been approved that covered more than 130 000 patients with MDR tuberculosis.3, 4

The global emergence of extensively drug-resistant (XDR) tuberculosis heralds the advent of widespread, virtually untreatable tuberculosis.2, 5 XDR tuberculosis is defined as disease caused by M tuberculosis strains resistant to at least isoniazid, rifamipicin, and one or more drugs within each of the two most important groups of second-line antituberculosis drugs (fluoroquinolones and injectable drugs).5, 6 XDR tuberculosis has been reported in 77 countries, but precise prevalence is unclear. Only two of 27 high-burden MDR tuberculosis countries routinely test for resistance to second-line drugs.2

After an epidemic of XDR tuberculosis in South Africa, the South Africa Medical Research Council convened an emergency consultation in August, 2006, that outlined a global strategy to combat this form of disease.7, 8 This strategy was refined in October, 2006, by the WHO Global Task Force on XDR-TB and disseminated widely.7, 8 The strategy underscored the urgent need to quantify the extent of XDR tuberculosis with population-based data.7, 8 Limited laboratory capacity and inconsistent procedures for testing have hindered understanding of resistance to second-line drugs.2, 9

Shortly before these events, we launched a multinational, epidemiological study of MDR tuberculosis, the Preserving Effective TB Treatment Study (PETTS). It focused on the risk factors for and frequency and consequences of acquired resistance to second-line drugs in people with MDR tuberculosis. In view of the emergence of XDR tuberculosis, we expanded PETTS in November, 2005, to include additional study sites and participants to provide poulation-based data on the prevalence of second-line-drug resistance in patients with MDR tuberculosis. Here we report the findings of the expanded study in eight countries.

Section snippets

Participants

The PETTS proposal was presented at an open meeting of the International Working Group on MDR tuberculosis in October, 2003, and included an open invitation to centres to participate. Clinical centres in nine countries (Estonia, Latvia, Peru, the Philippines, Russia, South Africa, South Korea, Taiwan, and Thailand) volunteered to participate. The drug-susceptibility data for Taiwan were not available at the time of data analysis and, therefore, were not included in this report (figure).

Results

Of 3034 eligible patients, 1782 (58·7%) were enrolled (figure). The most common reasons for patients not to be enrolled were no positive follow-up culture, no consent, previous treatment with second-line drugs for MDR tuberculosis, and staff turnover, although exact numbers for the different reasons are not available. Baseline isolates were not shipped to CDC for 242 (13·5%) patients. The centres in Estonia, Latvia, South Africa, and Masan, South Korea, maintained the original follow-up culture

Discussion

This large, prospective study of resistance to second-line drugs for MDR tuberculosis shows comprehensively that the prevalence of resistance is high (43·7%), and that the risk of XDR tuberculosis (6·7%) in the eight countries studied is worrying.

The prevalence of drug resistance correlates with the time that second-line drugs have been available in each country. They had been available for 10 years or less in Thailand (7 years), the Philippines (9 years), and Peru (10 years), and these

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