John Bartlett, MD

Disclosures

July 23, 2003

In This Article

Tuberculosis (TB)

Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med. 2003;163:1009-1021. Abstract This is a report from the London School of Tropical Medicine, WHO and the UN Program on AIDS that used multiple data sources to determine the global burden of TB, with particular attention to its interaction with the HIV epidemic. The results showed an estimated 8.3 million new TB cases in 2000 ( Table 13 ). The highest incidence was in Africa at 290/100,000 per year, and this area also had the highest rate of increase in the number of cases at 6%. Of all new cases in adults, 9% were attributed to HIV infection, but in Africa and the United States these figures were 31% and 26%, respectively. TB accounted for 11% of AIDS deaths. The total number of co-infected patients was estimated at 11 million, or 0.36%.

Table 14 summarizes the 2000 data for estimates by region of TB incidence, prevalence of HIV in new TB cases, percent of adult population with co-infection, and deaths due to TB (including AIDS deaths in persons with TB), and TB deaths ascribed to HIV infection. The second table provides similar data by country.

The authors conclude that the HIV pandemic is driving the TB epidemic. They emphasize the urgency of campaigns to prevent HIV and TB and a "focused effort to control HIV-related TB in areas of HIV prevalence."

Comment: This is an extraordinary collection and distillation of data from the most reliable sources available. The focus is on the impact of HIV and TB, the 2 most common microbial causes of death on earth. The greatest impact, not surprisingly, is in Africa. The highest annual incidence rates of TB were in sub-Saharan Africa and the largest number of cases (3 million) was in southeastern Asia. Of the 15 countries with the highest per capita incidence, 13 were in Africa, but half of the new cases (4.4 million) were in the top 5 countries in Asia. The number of new TB cases increased at 1.8%/year from 1997 to 2000, with the greatest increases in Russia (6%/year) and sub-Saharan Africa (6.4%/year). TB death rates varied from 9/100,000 in Brazil to 139/100,000 in South Africa; the difference was largely attributed to the differences in HIV infection rates. The impact of HIV was also highly variable, with prevalence rates in new TB cases ranging from < 1% in Afghanistan, Bangladesh, China, and Indonesia, to > 60% in South Africa and Zimbabwe. The highest numbers of co-infected persons were in South Africa (2 million), India (1.7 million) and Nigeria (0.9 million). The authors point out that HIV fuels the TB epidemic primarily by the high rate of active disease in the 1.8 billion persons with previously latent infection. Transmission of TB in these patients is less important because co-infected patients are less likely to be smear-positive, and the duration of active disease is reduced by rapid progression. This conclusion is supported by the relatively small increase in annual risk of TB in children, despite the substantial increase in TB incidence in adults. They estimate that the lifetime risk of active TB is 30% to 40% for co-infected persons in Africa. Brazil is cited as the only country with a large population of co-infected persons (100,000) that have the potential to reduce the risk of HIV-related TB due to the universal access to highly active antiretroviral therapy (HAART).

Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med. 2003;167:1472-1477. Abstract The authors report a retrospective analysis of 430 patients treated for active TB at the Montreal Chest Institute to determine the frequency and risks for serious adverse reactions. Serious adverse reactions were defined as reactions that require discontinuation of 1 or more drugs and/or reactions that resulted in hospitalization. Hepatitis was defined when the transaminase levels increased to ≥ 3 times the upper limit of normal (UNL) with symptoms or ≥ 5 times UNL without symptoms. A drug was defined as responsible if symptoms and signs resolved with drug withdrawal and recurred if there was rechallenge. The results showed a total of 46 events in 37 patients, the most common being rash with or without drug fever (21 cases), hepatitis (12), and severe GI intolerance (11). With regard to individual drugs, the highest risk was with PZA, with an incidence of 1.48/100 person-months of therapy. For isoniazid (INH) and for rifampin (RIF), the incidence was 0.49 and 0.43, respectively. There was only 1 adverse reaction, visual toxicity, attributed to ethambutol (ETH). These results are summarized in Table 15 .

With regard to patient risks, those that were significant by hazard ratio were increased age, female sex, HIV co-infection, and birth in Asia. These results are shown in Table 16 .

The authors conclude that serious adverse reactions are common with anti-TB drugs. PZA-induced liver disease and rash were significantly more common than with other first-line drugs, and other risk factors were female sex, HIV infection, increased age, and Asian-born.

Comment: This study showed that the frequency of serious adverse events was 9% and that 5% of all patients were hospitalized for a median of 16 days. The most important observation was the toxicity attributed to PZA. It is noted in the accompanying editorial by R. Chaisson[26] that this observation regarding PZA toxicity may overestimate frequency, since the results are reported by incidence/100 patient-months, INH and rifampin are given for longer courses, and all but 1 of the adverse events were noted within the first 60 days. Dr. Chaisson also noted that little is known about the mechanism of PZA toxicity and that the high frequency of serious adverse reactions is particularly disturbing considering the extensive use of these drugs in resource-limited areas where there is generally little or no clinical supervision. The conclusion is that anti-TB drugs are highly effective, with cure in the great majority of patients using regimens given for 6 months at a cost of $10 to $200. However, serious toxicity is also common, and this again argues for the great need for new drug development for multidrug-resistant TB as well as better-tolerated agents.

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