Minimal Diversity of Drug-Resistant Mycobacterium tuberculosis Strains, South Africa1

Neel R. Gandhi

, James C.M. Brust, Prashini Moodley, Darren Weissman, Moonseong Heo, Yuming Ning, Anthony P. Moll, Gerald H. Friedland, A. Willem Sturm, and N. Sarita Shah

Author affiliations: Albert Einstein College of Medicine, Bronx, New York, USA (N.R. Gandhi, J.C.M. Brust, D. Weissman, M. Heo, Y. Ning, N.S. Shah); Rollins School of Public Health, Emory University, Atlanta, Georgia, USA (N.R. Gandhi); Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa (P. Moodley, A.W. Sturm); Philanjalo, Tugela Ferry, South Africa (A.P. Moll); Church of Scotland Hospital, Tugela Ferry (A.P. Moll); Yale University School of Medicine, New Haven, Connecticut, USA (G.H. Friedland)

Abstract

Multidrug- (MDR) and extensively drug-resistant tuberculosis (XDR TB) are commonly associated with Beijing strains. However, in KwaZulu-Natal, South Africa, which has among the highest incidence and mortality for MDR and XDR TB, data suggest that non-Beijing strains are driving the epidemic. We conducted a retrospective study to characterize the strain prevalence among drug-susceptible, MDR, and XDR TB cases and determine associations between strain type and survival. Among 297 isolates from 2005–2006, 49 spoligotype patterns were found. Predominant strains were Beijing (ST1) among drug-susceptible isolates (27%), S/Quebec (ST34) in MDR TB (34%) and LAM4/KZN (ST60) in XDR TB (89%). More than 90% of patients were HIV co-infected. MDR TB and XDR TB were independently associated with mortality, but TB strain type was not. We conclude that, although Beijing strain was common among drug-susceptible TB, other strains predominated among MDR TB and XDR TB cases. Drug-resistance was a stronger predictor of survival than strain type.

Drug-resistant tuberculosis (TB) has emerged as a substantial threat to advances in global TB control over the past several decades (1). Worldwide, an estimated 630,000 cases of multidrug-resistant (MDR) TB occurred in 2011, and extensively drug-resistant (XDR) TB has now been reported in 84 countries (2). MDR TB and XDR TB are each associated with very high mortality rates (3), and their transmission—both in community and health care settings—remains an ongoing challenge in resource-limited settings and in countries with high rates of HIV co-infection.

In South Africa, the incidence of MDR TB has increased 5-fold since 2002 (2,4). MDR TB treatment is now estimated to consume more than half of the budget allocated for TB control in South Africa (5). The emergence of XDR TB, and its associated high mortality rates, have further underscored the need for clarifying the factors driving the drug-resistant TB epidemic to better focus control efforts (3,6,7).

Drug-resistant TB is generally considered a human-made phenomenon that occurs when inadequate TB treatment creates selection pressure for the emergence of drug-resistant Mycobacterium tuberculosis subpopulations (acquired resistance) (1). Researchers initially believed that the mutations causing drug resistance would exert a “fitness cost,” rendering those strains too weak to be transmitted (8,9). Nonetheless, transmission of drug-resistant TB strains has now been well-documented (10–13), and laboratory studies have shown that clinical strains may have minimal fitness costs or even none (14). Emerging data suggest that most MDR TB and XDR TB cases in South Africa and worldwide are likely caused by primary transmission of drug-resistant strains (2,15–19).

Although the M. tuberculosis W/Beijing strain family has been described among cases of drug-susceptible, MDR TB, and XDR TB in South Africa, numerous other strain types have also been identified (20,21). Little is known about the transmissibility and virulence of M. tuberculosisstrains aside from the W/Beijing strain family (22,23). In the Eastern Cape and Western Cape Provinces of South Africa, strains from the W/Beijing family have most often been associated with transmission of drug-resistant TB (24–27). At our study site in KwaZulu-Natal Province, however, the LAM4/KZN strain type has predominated among MDR TB and XDR TB cases and has been linked to nosocomial transmission and high mortality rates (3,16,17,28,29). This strain is a member of the Euro-American strain family and was first described in this region in 1994, evolving into an increasingly resistant phenotype over time (29).

The reasons for why the LAM4/KZN strain is prominent in KwaZulu-Natal Province, rather than the Beijing strain, which is seen globally and in other parts of South Africa, is unclear. Moreover, it is unknown whether the higher mortality among patients with MDR TB and XDR TB in KwaZulu-Natal can be explained, in part, by a difference in genotypic prevalence and associated differences in strain virulence (3,6,7,28). In this study, we sought to characterize the genotypic diversity of M. tuberculosis strains among isolates causing drug-susceptible TB, MDR TB, and XDR TB in KwaZulu-Natal Province, South Africa. We also examined the relationship between M. tuberculosis strain, drug resistance, and patient survival.