Elsevier

The Lancet

Volume 368, Issue 9553, 16–22 December 2006, Pages 2142-2154
The Lancet

Articles
Epidemiology of antituberculosis drug resistance (the Global Project on Anti-tuberculosis Drug Resistance Surveillance): an updated analysis

https://doi.org/10.1016/S0140-6736(06)69863-2Get rights and content

Summary

Background

The burden of tuberculosis is compounded by drug-resistant forms of the disease. This study aimed to analyse data on antituberculosis drug resistance gathered by the WHO and International Union Against Tuberculosis and Lung Disease Global Project on Anti-tuberculosis Drug Resistance Surveillance.

Methods

Data on drug susceptibility testing for four antituberculosis drugs—isoniazid, rifampicin, ethambutol, and streptomycin—were gathered in the third round of the Global Project (1999–2002) from surveys or ongoing surveillance in 79 countries or geographical settings. These data were combined with those from the first two rounds of the project and analyses were done. Countries that participated followed a standardised set of guidelines to ensure comparability both between and within countries.

Findings

The median prevalence of resistance to any of the four antituberculosis drugs in new cases of tuberculosis identified in 76 countries or geographical settings was 10·2% (range 0·0–57·1). The median prevalence of multidrug resistance in new cases was 1·0% (range 0·0–14·2). Kazakhstan, Tomsk Oblast (Russia), Karakalpakstan (Uzbekistan), Estonia, Israel, the Chinese provinces Liaoning and Henan, Lithuania, and Latvia reported prevalence of multidrug resistance above 6·5%. Trend analysis showed a significant increase in the prevalence of multidrug resistance in new cases in Tomsk Oblast (p<0·0001). Hong Kong (p=0·01) and the USA (p=0·0002) reported significant decreasing trends in multidrug resistance in new cases of tuberculosis.

Interpretation

Multidrug resistance represents a serious challenge for tuberculosis control in countries of the former Soviet Union and in some provinces of China. Gaps in coverage of the Global Project are substantial, and baseline information is urgently required from several countries with high tuberculosis burden to develop appropriate control interventions.

Introduction

Despite the recent progress of global control efforts, tuberculosis remains a major public-health burden in most developing countries. Current global estimates indicate that about a third of the world's population is infected with Mycobacterium tuberculosis, 8·7 million individuals develop the disease annually, and, in 2003, almost 2 million deaths occurred.1 Tuberculosis control in some regions is jeopardised by the HIV epidemic.2, 3, 4 A third of the 40 million people living with HIV/AIDS are infected with M tuberculosis. In 2003, about 674 000 HIV-positive individuals developed tuberculosis,1 which represents the main cause of death in such individuals.5

The emergence of drug-resistant strains occurs with the wide use and misuse of antimicrobials.6 Wild isolates of M tuberculosis that have never been exposed to antituberculosis drugs almost never show any resistance.7, 8, 9, 10, 11, 12, 13, 14 Multidrug-resistant (MDR) tuberculosis—defined as resistance to at least isoniazid and rifampicin—represents a substantial challenge to tuberculosis control programmes, since the treatment of such cases is complex, more costly, and frequently less successful than treatment of non-resistant strains. Cure rates in cases harbouring MDR strains range from 6% to 59%.15

In 1994, WHO, the International Union Against Tuberculosis and Lung Disease, and other partners launched the Global Project on Anti-tuberculosis Drug Resistance Surveillance.16 The aim of this project is to determine the prevalence, patterns, and trends of antituberculosis drug resistance around the world, ultimately to improve the performance of national tuberculosis control programmes through policy recommendations on patient management. The project measures in-vitro drug susceptibility to four of the six first-line antituberculosis drugs—ie, isoniazid, rifampicin, streptomycin, and ethambutol.17

Through its first two reports18, 19 the project has provided a better understanding of the magnitude and distribution of antituberculosis drug resistance20, 21 and has led to policy development for the treatment of MDR tuberculosis. The DOTS-Plus strategy for the use of second-line drugs in the management of patients who harbour drug-resistant strains, including MDR tuberculosis,22, 23, 24 was developed in 1999, followed by the establishment of the Green Light Committee in 2000 to provide access to preferentially priced second-line drugs while ensuring rational use through mandatory programme review and monitoring. The culmination of these efforts has led to the development of WHO guidelines for the programmatic management of drug-resistant tuberculosis.25

One of the most important contributions of the Global Project to tuberculosis control has been the strengthening of national tuberculosis reference laboratories through the guidance of supranational reference laboratories. A network of these laboratories was developed in 1994 to provide an international external laboratory quality assurance system for countries taking part in this project. Today there are 25 of these laboratories in six regions that assist over 100 national reference laboratories in culture and drug susceptibility testing for drug-resistance programmes. This network has resulted in more reliable epidemiological and laboratory data and, ultimately, better diagnostics for patients. However, poorly functioning laboratory networks have proven to be a formidable obstacle in the control of tuberculosis, especially in the expansion of surveillance and treatment of MDR tuberculosis, and must be placed high on the agenda over the next decade.

Periodic assessment of trends in antituberculosis drug resistance will help inform best control practices and assess the performance of national tuberculosis control programmes over time, thus informing necessary adjustments in the approach to control. The Global Project completed a third round of surveys and surveillance in 2002. The data gathered, combined with those from the previous two rounds, provide information on 109 countries or geographical settings worldwide—areas that represent almost 40% of notified smear-positive pulmonary cases of tuberculosis. The aim of this paper is to analyse the data gathered.

Section snippets

Data collection

Details of the methods of the Global Project have been described elsewhere.18, 19, 20, 21 Briefly, surveys are done on the basis of three principles—the sample must be representative of the tuberculosis population in the area surveyed, the results of drug susceptibility testing must be quality controlled by a supranational reference laboratory, and data collection must differentiate between new and previously treated cases. Resistance in new and previously treated cases are proxy measures for

Results

The third round of the Global Project included data from 79 countries and geographical settings (table 1).26 66 of these countries or settings provided information on drug resistance in new, previously treated, and combined cases. 10 countries or settings reported drug susceptibility results from new cases only, and Kinshasa (Democratic Republic of the Congo), Scotland, and Australia reported data without differentiating treatment history. The median number of new cases tested per survey

Discussion

Data from the third round of the Global Project, gathered between 1999 to 2002, show that antituberculosis drug resistance has been identified in virtually all countries surveyed, reaching especially high levels in areas of the former Soviet Union and some provinces in China. The high prevalence of multidrug resistance reported from the expanding number of provinces surveyed in China and Russia is indicative of a larger epidemic than previously suspected. Also of note is that geographical areas

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