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The Potential Disaster of Extensively Drug Resistant Tuberculosis

By John G. Bartlett, M.D., November 10, 2006

At the recent meeting of the Infectious Diseases Society of America (IDSA) in Toronto (October 12-15, 2006), Dr. Henry Blumberg of the Emory University School of Medicine presented a comprehensive review of tuberculosis in the world. The picture is grim.

The Global Burden of TB, the Inadequacy of DOTS alone, and the “Stop TB” Campaign

The global toll of TB deaths is 2 million per year, with 98% occurring in the developing world. The World Health Organization (WHO) has emphasized the importance of ‘directly observed treatment, short-course’ (DOTS) in treating and containing the disease. This strategy has been notably successful in, for instance, Peru, where new pulmonary TB rates have decreased by ≥ 5.8% per year since 1993, resulting in 91,000 fewer TB deaths between 1991 and 2000 [1]. However, it is now clear that DOTS alone will not quell the TB carnage, in large part because between 1990 and 2005, the spread of AIDS has resulted in a doubling of TB rates.

The Stop TB Partnership’s (http://www.stoptb.org and http://www.who.int/tb/en) “Global Plan to Stop TB 2006-2015” places a high priority on DOTS, but adds much more to the effort in calling for the following:

  • Treatment of 50 million TB-infected people, including 800,000 with presumed multidrug-resistant tuberculosis (MDR-TB) and 3 million people with HIV co-infection, who should also receive treatment for HIV with antiretrovirals

  • Development and ready availability of rapid and inexpensive diagnostic tests at the point of care

  • Development of the first new TB drug in 40 years by 2010 (This would represent the first new antimycobacterial class in 40 years.)

  • Assessment of the quality of TB diagnosis and treatment for all

  • Decreased duration of treatment,  to just 1 to 2 months

  • Development of a vaccine by 2015

  • A TB-free world by 2050

Multidrug-resistant Tuberculosis (MDR-TB)

Blumberg then reviewed the worrisome issue of MDR-TB, which is defined as strains resistant to INH and rifampin. The rate of MDR-TB in the U.S. is 1.6%, but it appears to be much higher in developing countries and Eastern Europe. Developing countries must implement routine culture and sensitivity tests for all suspected and confirmed cases of tuberculosis. This is not routinely done, but is an absolute requirement for the recognition of MDR-TB.

The best data on the predictors of treatment outcome for patients with MDR-TB is based on a retrospective cohort study of 167 patients with MDR-TB in Latvia: After initiation of second-line therapy, 129 (77%) had conversion of sputum mycobacterial cultures from positive growth to negative in a median time of 60 days (range, 4 to 462 days). Sputum conversion is the most important interim indicator of the efficacy of anti-TB treatment in MDR-TB infected patients [2]. However, 38 (23%) patients did not convert. Thus, special priority is the development of treatment protocols for MDR-TB that address the number of drugs needed, the most effective drugs, the duration of therapy, and the role of surgery [3].

Two obstacles in treating MDR-TB are the problems of tolerance and cost. One review of 818 cases showed that 30% of patients stopped treatment because they could not tolerate the drugs. With regard to cost, first line treatment for drug sensitive strains is only $20 for a 6-month course, whereas the average cost to treat MDR-TB is $17,000. To address the issue of high cost, the Stop TB Partnership's Green Light Committee was created in 2000 to increase access to second line anti-TB drugs worldwide, while ensuring their proper use to prevent increased drug resistance, by special arrangements with members of the pharmaceutical industry. The Green Light Committee has been able to reduce the cost of treatment of MDR-TB to $3,500 for developing countries. The goal is to make treatment available for 1 million MDR-TB patients.

Extensively Drug Resistant Tuberculosis (XDR-TB)

The final part of Blumberg’s discussion addressed the really worrisome and relatively new problem of extensively resistant TB strains, called extensively drug resistant TB (XDR-TB). These strains are defined by resistance to INH, rifampin, and at least 3 of the second line classes of anti-TB drugs [4, 5]. A review of 3,418 MDR-TB strains from various parts of the world indicated that 10% were actually XDR-TB strains.

The most important recent outbreak occurred in the KwaZulu-Natal province, South Africa [6,7], where, in January 2005, there were 544 cases of TB, of which 41% (221) were MDR-TB and 10% (53) were XDR-TB. Of the 53 cases of XDR-TB, 44 of the patients were found to be HIV-infected. Pulse-field gel electrophoresis (PFGE) showed that 26/30 strains were the same clone, and most were acquired nosocomially. The prognosis is dismal: 52 of the 53 patients infected with XDR-TB died, and the median survival was only 16 days. There has been an emergency meeting by WHO and CDC to deal with the problem of XRTB in Africa.

Conclusion

The emergence of XDR-TB threatens to undo all of the progress that has been achieved with the broad use of HIV treatment in developing countries. In their emergency meeting, the WHO and CDC identified six key areas of high importance: 

  1. Countries must undertake surveys to determine the extent of the problem

  2. Laboratory capacity to identify tuberculosis must be increased

  3. Technical support for clinics treating infected patients must be provided

  4. Infection control practices to prevent the spread of disease must be enforced

  5.  Diagnostic tests must be improved

  6.  Access to anti-TB drugs must be expanded in developing countries

The WHO’s Global Task Force on XDR-TB has stated that it “will help mobilize teams that can respond to requests for technical assistance from countries, and be deployed at short notice to XDR-TB risk areas.” Given that XDR-TB has been identified in all regions of the world, robust efforts to combat it seem appropriate.

References

  1. Suarez PG, Watt CJ, Alarcon E, Portocarrero J, et al. The dynamics of tuberculosis in response to 10 years of intensive control effort in Peru. J Infect Dis 2001;184:473-8.

  2. Holtz TH, Sternberg M, Kammerer S, Laserson KF, et al. Time to sputum culture conversion in multidrug-resistant tuberculosis: predictors and relationship to treatment outcome. Ann Intern Med 2006;144:650-9.

  3. Caminero JA. Treatment of multidrug-resistant tuberculosis: evidence and controversies. Int J Tuberc Lung Dis. 2006;10:829-37.

  4. Wright A, Bai G, Barrera L, Boulahbal F, et al. Emergence of Mycobacterium tuberculosis with extensive Resistance to Second-Line Drugs --- Worldwide, 2000-2004. MMWR Weekly 2006;55:302-305.

  5. Lawn SD and Wilkinson R. Extensively drug resistant tuberculosis. BMJ 2006;333:559-60.

  6. Dahle UR. Extensively drug resistant tuberculosis. BMJ 2006;333:705.

  7. Gandhi NR, Moll A, Sturm AW, Pawinski R, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006;368:1575-80.