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Initial evidence has come from observations among patients coinfected with the human immunodeficiency virus (HIV) in South Africa, where extensively drug-resistant tuberculosis has been fatal in virtually all cases.4 But evidence has also come from studies of mostly HIV-seronegative patients in Europe, the United States, and Korea,5,6,7 where extensively drug-resistant tuberculosis was associated with much higher failure and mortality rates than multidrug-resistant tuberculosis (see the letter "Treatment Outcomes in Extensively Resistant Tuberculosis" in this issue of the Journal). The report from metropolitan Lima, Peru, published in this issue of the Journal, however, reveals a new and brighter perspective: even in developing countries, extensively drug-resistant tuberculosis may be cured in the majority of cases when management is aggressive and appropriate.8 In this study, 60% of the patients with extensively drug-resistant tuberculosis completed treatment successfully, a percentage similar to that of patients in the same study with multidrug-resistant tuberculosis. This encouraging result constitutes a true change in the current perception of the disease as a virtual death sentence.
Because of this unexpected success, it is tempting to try to identify systematic biases in the study. For instance, the retrospective study design is such that the denominator is unknown and the patients referred to the treatment centers in metropolitan Lima could be the less sick, the most likely to survive, and the more likely to adhere to treatment. In fact, this study was not a large-scale, prospective, controlled intervention. Furthermore, one could speculate that drug-susceptibility testing for some of the second-line drugs was hampered by standardization problems9; thus, the results could be not entirely correct.
These points notwithstanding, one should focus on the factors that might have contributed to such a high level of treatment success among patients with extensively drug-resistant tuberculosis in a low-income country. These patients, whose previous treatment had failed or who had relapsed, were all at high risk for drug resistance. Thus, all patients underwent systematic drug-susceptibility testing, and while they awaited results and potential adjustments of treatment regimens, therapy with at least five (presumably effective) drugs was begun. In all cases, the regimens contained the most powerful second-line agents: a fluoroquinolone and an injectable drug. When regimens seemed to fail, and once drug-susceptibility testing results became available, the regimens were reinforced with the addition of known effective drugs and other secondary agents. The use of the injectable drug was prolonged for up to 15 months, the overall treatment lasted the required 2 years, and a few seriously ill patients were referred for surgery. This is an aggressive approach, and it would be interesting to know the frequency and seriousness of the side effects. Yet the results suggest that side effects were probably well managed; defaulting was minimal, and definitive suspension of treatment was not reported.
Furthermore, strict treatment supervision was enforced. This is essential in managing tuberculosis, particularly when second-line drugs are used; creating additional drug resistance will exacerbate an already catastrophic situation in the individual patient while creating the basis for dissemination in the community. However, supervision did not consist of merely watching people follow regimens; it had all the elements of support for successful long-term treatment: it was community-based in the majority of patients, thus avoiding the additional stress of prolonged hospitalizations; it included psychological support for people taking potentially toxic drugs; and it included nutritional support and financial incentives, when needed. Finally, bacteriologic and clinical monitoring was intense, allowing readjustments and optimization of the case-management approach.
All these elements are crucial to success in tuberculosis control in general and in the management of severely drug-resistant cases in particular. They are all part of the Stop TB Strategy promoted by the WHO10 and have been incorporated in recent international programmatic and care guidelines for drug-resistant cases.11,12 If every national program put this strategy in place with equal vigor and assertiveness, as in the metropolitan Lima project, drug resistance would be minimized and, when already present, effectively managed.
Why is it that such high rates of cure and low rates of fatality have not been achieved by tuberculosis programs elsewhere, including programs in the United States and Europe that specialize in the management of drug-resistant tuberculosis?5,6 The series reported so far from resource-rich countries may have included more severely, even terminally, ill patients. Possibly, the strains causing their disease were resistant to more drugs than the strains in Peru. For instance, the series reported from Italy included some patients affected by a form of extensively drug-resistant tuberculosis that was resistant to all available drugs.5 Or perhaps the individual care was not as rigorous as that provided in metropolitan Lima. In particular, supervision of treatment and patient support may not have been of the same quality, especially for the patients in the European study.5 Also, one cannot exclude the point that the Lima project enjoys a certain "exceptionality" bias. The project setting partly coincides with that of an exceptional site in northern Lima that has shown remarkable results among multidrug-resistant tuberculosis patients, with cure rates above 70%.13 The recipe for that project included a strong partnership shared by a local nongovernmental organization (NGO) that implemented care, a U.S.-based NGO providing expertise and financial resources, and the Ministry of Health of Peru. Such partnership has established local capacity and a level of expertise that is rarely found elsewhere. These new observations8 suggest that the model also works when used to address the most difficult challenge of tuberculosis control today, although further increases in cure rates could be achieved by perfecting the use of current tools and rapidly implementing new ones as they become available.
Can this model be scaled up to cover the entire country, and can it be replicated in other countries with different economic and social conditions? How can a rigorous approach to a high standard of individual care be expanded to a programmatic scale and become routine public health practice? In 2008, scaling up is indeed the major challenge faced by most complex health interventions worldwide, especially when health systems and services are not optimal.14 What is required is action that is borne out of clear planning, financial commitment and adequate resources, technical capacity, and partnership. Ultimately, the effectiveness of a complex intervention depends on coordinated work among all forces. The Peru experience is a clear example that, in this spirit, even the most difficult objectives can be reached. The challenge is to make this approach a sustainable reality worldwide.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Stop TB Department, World Health Organization, Geneva.
References
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Related Letters:
Extensively Drug-Resistant Tuberculosis
Dheda K., Shean K., Badri M., Cheruvu M., Bhadriraju S., Mitnick C. D., Bayona J., Becerra M. C.
Extract |
Full Text |
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N Engl J Med 2008;
359:2390-2391, Nov 27, 2008.
Correspondence
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