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Tuberculosis has afflicted humans as far back as we have records, predating written history. Mycobacterium tuberculosis is exclusively a human pathogen, so it has had to adapt to its only host, and we in turn have adapted to it. It is estimated that one third of the world’s population is currently infected, but only ~% of infected people will develop active tuberculosis, a tribute to the effectiveness of our innate and acquired immune responses to this potentially deadly pathogen. Nevertheless, many asymptomatically infected people harbor viable tubercle bacilli, possibly for a lifetime, and those are the ones who can re-activate their infections later in life. Only those with active pulmonary tuberculosis can transmit the infection, so it is part of the organism’s strategy to remain viable until immunity begins to wane. HIV has completely changed that balance; patients who are HIV+ with positive tuberculin skin tests have a 30% risk of developing active tuberculosis.1 There are clearly genetic polymorphisms that make some individuals more susceptible to tuberculosis,2 but the effects of genetic polymorphisms do not approach the profound effect that loss of CD4 T cells has on the risk of developing active tuberculosis. The good news is that isoniazid (INH) for 6 months will reduce the risk of developing active tuberculosis by ~0%, even in patients who are HIV+.3 In addition, conventional four-drug therapy cures tuberculosis in patients who are HIV+ who adhere to therapy for 6–9 months, even those with low numbers of CD4 T cells or extra-pulmonary tuberculosis.4 This is in sharp contrast to M. arium complex infections, which are never cured in patients with AIDS unless T cells are restored, because we do not have effective bactericidal antibiotics for that organism.5
The paper from Kawai and others in this issue, reminds us of how important effective anti-tuberculous therapy is when patients lack immune defenses against M. tuberculosis. The authors prospectively followed two cohorts of patients with newly diagnosed tuberculosis in Lima, Peru.6 One group had HIV infection and the other did not (some HIV+ cases may have escaped detection because not everyone was tested, but that would not change the results of the study). Although CD4 T cell counts were not available, almost certainly all the patients who were HIV+ in the study had advanced immuno-suppression because they were recruited from a unit in a hospital that specializes in treating AIDS. The authors tested all isolates for rifampin and INH susceptibility and sub-divided the patients into those with resistant bacteria (MDR-TB) and those with susceptible isolates. Although the number of patients in the different cohorts was relatively small, the differences in outcome were so dramatic that they are worthy of attention. The shocking observation was that 50% of patients who were HIV+ infected with MDR-TB died within 2 months of diagnosis, despite receiving directly observed therapy (DOT) with INH, rifampin, pyrazinamide, and ethambutol. Thus, in the absence of effective antibiotics and an effective immune system, bacterial growth was unchecked and quickly led to death. The mortality of this group of patients was much higher than a cohort from the same hospital that did not have tuberculosis, implying that most of these patients died of tuberculosis rather than other complications of AIDS, although they do not have direct evidence for that.
Given the rapid progression of the tuberculosis infection, the current practice of initiating tuberculosis therapy using a standard four-drug regimen is clearly inadequate treatment of nearly one half of the patients who were HIV+ with tuberculosis in Lima. Because so many patients with AIDS with MDR-TB died in less time than it usually takes to complete susceptibility studies, the authorities will have to invest in new rapid methods for doing drug susceptibility testing, such as the one used by the authors of this paper.7 The government will also have to be ready to provide second-line drugs for the treatment of these patients. Although second-line treatment of tuberculosis is expensive and more toxic than treatment with first-line drugs, the alternative is to allow patients with smear positive pulmonary MDR-TB to essentially go untreated. That increases the risk of the spread of MDR-TB to others with AIDS, health care workers, and family members. Even the use of second-line drugs is no guarantee of success in this battle against tuberculosis, because resistance to second-line drugs is becoming a problem in countries that use them extensively. New, cheaper, more effective drugs are desperately needed to treat tuberculosis.8
Prevention is at least as important as treatment, so it is important to understand the epidemiology of MDR-TB in Peru to try to limit its spread. Tuberculosis is endemic in Peru, and 50% of Peruvians with AIDS will develop tuberculosis at some point in their illness.9 One striking feature of tuberculosis in Lima is that nearly 50% of tuberculosis in patients with AIDS in Lima are infected with MDR strains as documented in this and another recent study.9 In both studies, the patients with AIDS with tuberculosis were recruited from the same public hospital in Lima that treats the largest number of HIV-infected patients. In both studies, the authors found an association between receiving care at this hospital and having MDR-TB, suggesting nosocomial transmission of the resistant bacteria. The use of molecular typing could easily confirm this hypothesis. Because nosocomial acquisition of MDR-TB has been previously documented and confirmed by restriction fragment length polymorphism (RFLP) analysis in at least one South American country, this would have major implications for the practice of cohorting patients with AIDS in specialized treatment facilities that lack negative pressure rooms, especially if they also care for patients with tuberculosis.10 Even in the United States, which has hospital facilities for negative pressure isolation, this led to disastrous outbreaks of MDR-TB.11
* Address correspondence to Joshua Fierer, University of California, San Diego, CA. E-mail: jfierer{at}ucsd.edu 
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