Multidrug-Resistant Tuberculosis, People’s Republic of China, 2007–2009

Guang Xue He¹ , Hai Ying Wang¹, Martien W. Borgdorff, Dick van Soolingen, Marieke J. van der Werf, Zhi Min Liu, Xue Zheng Li, Hui Guo, Yan Lin Zhao, Jay K. Varma, Christopher P. Tostado, and Susan van den Hof

Author affiliations: Chinese Center for Disease Control and Prevention, Beijing, People’s Republic of China (G.X. He, H. Guo, Y.L. Zhao); University of Amsterdam, Amsterdam, the Netherlands (G.X. He, M.W. Borgdorff, M.J. van der Werf, S. van den Hof); Shandong Provincial Tuberculosis Control Center, Jinan, People’s Republic of China (H.Y. Wang, Z.M. Liu, X.Z. Li); National Institute for Public Health and the Environment, Bilthoven, the Netherlands (D. van Soolingen); KNCV Tuberculosis Foundation, The Hague, the Netherlands (M.J. van der Werf, S. van den Hof); Centers for Disease Control and Prevention, Atlanta, Georgia, USA (J.K. Varma); Tsinghua University, Beijing (C.P. Tostado)

Abstract

We conducted a case–control study to investigate risk factors for multidrug-resistant tuberculosis (MDR TB) in the People’s Republic of China. Genotyping analysis was used to estimate the percentage of cases from recent transmission among 100 MDR TB case-patients hospitalized during April 2007–July 2009. Molecular subtyping of isolates showed that 41% of MDR TB strains clustered. Beijing genotype was found in 94% of the MDR TB isolates and 79% of the pan-susceptible isolates. In multivariate analysis, MDR TB was independently associated with Beijing genotype, retreatment for TB, symptoms lasting >3 months before first evaluation at the hospital, lack of health insurance, and being a farmer (vs. being a student). MDR TB was associated with Beijing genotype and lower socioeconomic status. A large percentage of MDR TB cases seemed to result from recent transmission. Early detection, effective treatment, and infection control measures for MDR TB are needed to reduce transmission.

Multidrug-resistant tuberculosis (MDR TB), defined as resistance to at least isoniazid and rifampin, has emerged as a global public health problem (1). The People’s Republic of China has the second greatest number of MDR TB cases in the world (2). According to the National Anti-Tuberculosis Drug Resistance Survey in 2007, an estimated 120,000 new MDR TB cases emerge annually in China, accounting for ≈24% of MDR TB worldwide (3). Although MDR TB represents only 8% of incident TB cases in China, controlling MDR TB is challenging because it is difficult to diagnose and treat (4). Thus, MDR TB is increasingly becoming a serious threat to TB control (3,5), and the recognition of extensively drug-resistant TB has furthered highlighted this threat (6,7).

The first pilot sites for the programmatic management of drug-resistant TB in China were established in October 2006. By the end of July 2010, similar management programs covered 41 prefectures/cities in 12 provinces in which ≈1,000 patients with MDR TB were treated with standardized treatment regimens recommended by the World Health Organization (8,9).

Mycobacterium tuberculosis acquires resistance to antimicrobial drugs through the selection of bacteria with mutations in resistance genes (10). Particular resistance genotypes, such as isoniazid-resistant strains from which the katG gene has been deleted, have been associated with decreased growth and persistence of M. tuberculosis in mice and guinea pigs (11). A recent molecular study suggests that drug-resistant strains of M. tuberculosis may be as transmissible as pan-sensitive strains (12). However, some isoniazid-resistant strains, such as those with a mutation at aa 315 of the katG gene, were as transmissible as drug-susceptible strains; these resistant, but equivalently transmissible, strains are typically associated with outbreaks (13–15).

In the past decade, many studies have evaluated the role of the Beijing genotype of M. tuberculosis in the worldwide TB epidemic (16,17). Beijing genotype strains are emerging in Southeast Asia, former Soviet republics, the Baltic states, and South Africa and are associated with multidrug resistance (17–22). In Europe, during 2003–2006, about half of MDR TB and extensively drug-resistant TB cases were caused by recent transmission, and 85% of those cases were caused by Beijing strains; during the same period, only 6%–7% of drug-susceptible TB cases in Europe were caused by Beijing strains (21,22). As the name suggests, Beijing genotype strains are particularly prevalent in China. In a survey of 10 provinces in China, the average percentage of Beijing genotype strains was 73%, but the percentage varied substantially by region, with the highest (93%) in the Beijing region (23).

Genotyping studies help elucidate transmission of TB by specific strains (17–20). Since 1993, IS6110 restriction fragment-length polymorphism typing has been considered the standard for studying the molecular epidemiology of TB (24). Although restriction fragment-length polymorphism typing has brought significant new insights into TB transmission, the method is technically demanding and time-consuming (23). Therefore, a new standard typing method using mycobacterial interspersed repetitive unit–variable-number of tandem repeats (MIRU-VNTR) in the genome was recently proposed for studying clustering and transmission (25). The analysis of regions of difference (RDs) in the genome of M. tuberculosis complex can be used to study the phylogeny of these bacteria; this approach can also be used as an alternative to the more complicated spoligotyping method for Beijing genotype strain identification (26,27).

We used the RD105 deletion detection method to identify Beijing genotype strains. We also used 24-locus VNTR typing to investigate MDR TB transmission in patients admitted to the largest TB hospital in Shandong Province during April 2007–July 2009. Our goal was to characterize the genotypes of different MDR TB strains and identify specific risk factors associated with MDR TB and MDR TB strain clustering. A study in TB patients in the same hospital during 2004–2007 showed a prevalence of MDR TB of 10.8% (28). Although the national guideline of the TB control program requests directly observed treatment, in which TB patients take all doses under supervision, another study in rural Shandong showed that most TB patients do not receive directly observed treatment (29), which poses a risk for drug resistance. In Shandong Province, the programmatic management of drug-resistant TB has been introduced only in 1 prefecture, starting in October 2008.

Methods

full-text:
Multidrug-Resistant Tuberculosis, People’s Republic of China, 2007–2009 - Vol. 17 No. 10 - October 2011 - Emerging Infectious Disease journal - CDC

Suggested citation for this article: He GX, Wang HY. Borgdorff MW, van Soolingen D, van der Werf MJ, Liu ZM, et al. Multidrug-resistant tuberculosis, People’s Republic of China, 2007–2009. Emerg Infect Dis [serial on the Internet]. 2011 Oct [date cited]. http://dx.doi.org/10.3201/eid1710.110546