TB Notes Newsletter

No. 1, 2012

INTERNATIONAL RESEARCH AND PROGRAMS BRANCH UPDATE

The Preserving Effective TB Treatment Study

Antibacterial drugs are a two-edged sword. While they destroy pathogenic bacteria, they also select for drug-resistant bacteria against which those drugs are ineffective. In public health, one of the gravest examples is the worldwide emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB). Global surveillance has revealed drug-resistant TB to be widespread and a threat to TB control in many countries. Treating MDR TB is imperative to prevent further spread; however, the high cost of second-line drugs (SLDs) severely limits their use. On the other hand, increasing access to costly SLDs has the potential to hasten the development of resistance to these same drugs. To address this issue, in 2000 the World Health Organization (WHO) and the Stop TB Partnership formed the Green Light Committee (GLC), a subgroup of the International Working Group on MDR TB. By carefully evaluating and assisting proposed MDR TB programs to ensure they would use the second-line drugs optimally, the GLC aims to increase access to these TB drugs while at the same time preventing the emergence of resistance.

The Preserving Effective TB Treatment Study (PETTS) is a prospective cohort study that is being conducted to evaluate the extent to which the GLC mechanism prevents acquired resistance to second-line drugs. It is the largest prospective study of MDR TB ever carried out. The study was designed to compare the frequency and consequences of acquired resistance to second-line drugs in MDR TB patients between projects approved by Green Light Committee and other MDR TB treatment programs (non-GLC). PETTS was conducted in 9 countries (Peru, Russia, Latvia, Estonia, South Africa, Thailand, Philippines, South Korea, and Taiwan) from 2005 to 2010. The amplification of drug resistance was determined by examining the drug-susceptibility testing (DST) results and genotypes of each patient’s last positive culture compared with the same patient’s pretreatment isolate. Enrollment of patients in PETTS ended in December 2008, and follow-up ended in June 2010. Patients’ isolates of M. tuberculosis were shipped to CDC, where the laboratory carried out DST for all baseline and final isolates. Genotyping and data analysis are ongoing. The first round of DNA fingerprinting is being completed in March 2012.

Preliminary results indicate that baseline prevalence of drug resistance was similar in GLC-approved and non-GLC projects except for the GLC site in the Philippines, which had a low prevalence of baseline drug resistance. However, acquired resistance to fluoroquinolones and second-line injectable drugs was lower in the GLC sites among the first 550 patients with testing completed. These preliminary results need to be extended with the rest of the patients and confirmed with genotyping. Finally, cure rates were higher, while mortality and treatment failure were lower, in GLC-approved projects compared with non-GLC projects; mortality remained lower in GLC projects after exclusion of HIV-infected patients, the majority of those being from South Africa, a non-GLC site.

—Reported by Peter Cegielski, MD, MPH,
Ekaterina Kurbatova, MD, MPH, PhD,
Tracy Dalton, PhD, and Julia Ershova, PhD
Div of TB Elimination

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Tuberculosis Genetic Lineage and Clinical Site of Disease

Dr. Robert Koch’s discovery of the tubercle bacillus over 100 years ago opened the door to laboratory investigation of the bacterium that causes TB. Despite this long history of investigation, an understanding of the genetics of the bacterium that causes most TB in humans, Mycobacterium tuberculosis, largely remained elusive until recently. Over the past several years, genetic features of M. tuberculosis isolated from patients in many different places in the world have been compared. This work has resulted in the surprising finding that there are four principal genetic sub-groups of M. tuberculosis, and that these sub-groups are primarily found in different regions of the globe.¹ These four principal sub-groups, or lineages, of M. tuberculosis are each named for the region of the world in which they predominate: Euro-American, Indo-Oceanic, East African Indian, and East Asian.

Individual strains of M. tuberculosis bacteria vary genetically. Variation between individual bacterial strains allows genotyping such as is performed by the National Tuberculosis Genotyping Service in the United States.^2,3 It is this variation between strains which makes it possible to determine whether cases of TB in a local jurisdiction, for example, are likely to be part of the same chain of transmission. However, despite this variation between strains of M. tuberculosis, strains isolated from individual patients can be categorized as belonging to one of the four primary lineages according to genotyping information that is characteristic for each of the four lineages.

The finding that there are four principal genetic subgroups of M. tuberculosis raises the question: is the clinical disease caused by these sub-groups different? This question is important, because clinical differences could affect control and treatment strategies, including development of novel approaches to therapy and TB vaccines.¹

The January 15, 2012, issue of Clinical Infectious Diseases contains an article describing an analysis aimed at understanding whether cases of TB caused by the four principal lineages of M. tuberculosis differ by clinical site of disease.4 Although TB is primarily a disease of the lungs, virtually any organ system can be involved; however, factors that determine where disease occurs in the body are not well understood. Using data from the National Tuberculosis Genotyping Service linked to National Tuberculosis Surveillance System data, the authors analyzed 32,000 cases of TB reported during 2004–2008. Because of the diversity of patients with TB in the United States, with more than half born in other countries, these data provide a rich source of information on diverse strains from all four of the principal lineages. This study found that compared with the other lineages (East African Indian, Indo-Oceanic, and Euro-American), the East Asian lineage of M. tuberculosis (also known as the Beijing family) was associated with pulmonary disease more than with extrapulmonary disease.

This study contributes to a growing body of literature suggesting that there are differences in associated clinical disease between lineages.^5,6 Recently, the East Asian lineage has elicited particular interest as some investigators have suggested it is spreading globally.⁷ Because pulmonary TB is the infectious form of the disease, the finding that patients infected with this lineage more commonly develop pulmonary disease would be consistent with increased transmissibility of this lineage. This area of study, increasing our understanding of TB biology, is needed to improve diagnostic tests and prevention and treatment strategies, including drugs and vaccines.⁸

—Reported by Eleanor Click, MD
Div of TB Elimination

References

1. Gagneux S, Small PM. Global phylogeography of Mycobacterium tuberculosis and implications for tuberculosis product development. Lancet Infect Dis 2007; 7:328-37.
2. Ghosh S, Moonan PK, Cowan L, Grant J, Kammerer S, Navin TR. Tuberculosis Genotyping Information Management System: Enhancing Tuberculosis Surveillance in the United States. Infect Genet Evol 2011.
3. CDC. New CDC program for rapid genotyping of Mycobacterium tuberculosis isolates. MMWR 2005; (54):47.
4. Click ES, Moonan PK, Winston CA, Cowan LS, Oeltmann JE. Relationship between Mycobacterium tuberculosis phylogenetic lineage and clinical site of tuberculosis. Clin Infect Dis 2012; 54:211-9.
5. Coscolla M, Gagneux S. Does M. tuberculosis genomic diversity explain disease diversity? Drug Discov Today Dis Mech 2011; 7:e43-e59.
6. Kato-Maeda M, Nahid P. Mycobacterium tuberculosis lineage--what's in your lungs? Clin Infect Dis 2012; 54:220-4.
7. Parwati I, van Crevel R, van Soolingen D. Possible underlying mechanisms for successful emergence of the Mycobacterium tuberculosis Beijing genotype strains. Lancet Infect Dis 2010; 10:103-11.
8. Comas I, Gagneux S. A role for systems epidemiology in tuberculosis research. Trends Microbiol 2011; 19:492-500.

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