Several aspects of this observational study should be noted. First, it was large and included data from more than 37
000 HIV-infected persons who initiated antiretroviral therapy in 16 cohorts from across the United States and Canada. This enhances the generalizability of the results to this region. Second, tuberculosis risk was highest in the first 3 months of HAART. This finding is consistent with previous studies conducted in both the developed and developing world [1
]. However, the tuberculosis incidence rate during the first 3 months (215 per 100
000 person-years) was substantially lower than has previously been reported, even in developed world settings (1300–1700 per 100
000 person-years) [1
]. Although the reason is unclear, it may be due to differences in patient population, tuberculosis prevalence, or implementation of tuberculosis prevention strategies. In addition, we included persons who had previously received non-HAART antiretroviral therapy; tuberculosis risk could be higher among persons naive to antiretroviral therapy. Third, tuberculosis diagnosed in the first 3 months of antiretroviral therapy was not associated with a significantly higher mortality risk than tuberculosis diagnosed subsequently. This finding (from a low-incidence region) differs from findings reported from Haiti [12
] but is consistent with a study from Uganda (both high-incidence countries) [22
Tuberculosis diagnosed within the first 3 months of HAART may be due to incomplete immune reconstitution—insufficient to prevent disease—or unmasking of previously undiagnosed tuberculosis. The latter may be particularly important in a setting with low rates of M. tuberculosis transmission, such as the United States and Canada. Such disease was either not clinically apparent prior to the initiation of antiretroviral therapy, or the signs and symptoms were attributed to processes other than tuberculosis. This possibility highlights the importance of determining the risk factors associated with such tuberculosis cases, so that these patient groups can be targeted for tuberculosis screening just prior to antiretroviral therapy initiation or within the initial months of treatment initiation.
In this study, the risk factors independently associated with tuberculosis diagnosis after HAART initiation were black race, other nonwhite race, Hispanic ethnicity, a history of injection drug use, and baseline CD4+ lymphocyte count <200 cells/mm3
. Persons who were antiretroviral therapy-naive tended to have an increased tuberculosis risk, but it was not statistically significant in the multivariate models (). The piece-wise Weibull model identified an increased tuberculosis risk with HIV-1 RNA levels within the first 3 months of HAART that was ~2-fold increased risk for every 1 log increase in HIV-1 RNA (). The increased tuberculosis risk among men in the first 3 months of HAART was of borderline statistical significance. The findings were similar when the analysis was limited to persons with complete data (ie, no imputation; Supplementary Table 2
), although perhaps slightly weaker for HIV-1 RNA and slightly stronger for male sex.
The finding that lower CD4+ lymphocyte count was associated with early tuberculosis risk was consistent with several prior reports [1
]. Of note in the present study, tuberculosis risk was similarly increased in the 3 categories of baseline CD4+ lymphocytes ≤200 compared with CD4+ lymphocyte count >200 cells/mm3
A history of injection drug was also associated with accelerated tuberculosis risk in this study. This finding is consistent with previous studies of tuberculosis risk after antiretroviral therapy initiation [1
], as well as reports from the United States demonstrating an association between substance abuse (including injection drug use) and tuberculosis [23
Black race, other nonwhite race, and Hispanic ethnicity have not previously been associated with increased tuberculosis risk after HAART initiation to our knowledge. However, this finding is not unexpected in the United States and Canada, where such groups have a disproportionately high tuberculosis risk in the general population, irrespective of HIV status [24
]. It is unclear why persons of black race in Canada appeared to have a higher tuberculosis risk than blacks in the United States, but this may be due in part to differences in how black race was characterized in these 2 countries.
Although tuberculosis risk was lower than previously reported and decreased with time on HAART, it was still significantly higher than in the general population of the United States and Canada even after >5 years of HAART. The tuberculosis incidence rate in such persons in our study was 43 per 100
000 person years—more than 8-fold higher than the overall tuberculosis incidence rate in the United States and Canada during the study period—approximately 5 per 100
000 population [25
]. This finding highlights the importance of continued surveillance for tuberculosis, even after prolonged HAART use.
The rate of recurrent tuberculosis in this study population (1.5%; 390 per 100
000 person-years) was low compared with other studies in North America, even with a long median follow up of 43 months after completion of antituberculosis therapy. Recurrent tuberculosis risk among HIV-infected persons in the United States has been reported as high as 8.3% and 9300 per 100
000 person-years [27
]. This suggests a beneficial effect of HAART on recurrence risk, which would be expected given the decreased risk of recurrent tuberculosis with increasing CD4+ lymphocyte count [27
]. Of note, however, although the confidence intervals were wide, the tuberculosis recurrence rate in this study was higher than in the “high-risk” first 3 months after HAART initiation (215 per 100
000 person-years). This finding is consistent with studies from high tuberculosis incidence settings without widespread HAART use, in which recurrence rates exceed incidence rates [29
]. These findings provide additional impetus for prevention of tuberculosis in persons infected with HIV.
Of the tuberculosis cases that had received TST and had a positive test, only 39% received treatment of latent M. tuberculosis
infection prior to tuberculosis diagnosis. This observation is consistent with other studies that have identified potentially preventable tuberculosis cases among HIV-infected persons [9
]. A strategy of screening for and treating latent infection is effective in preventing tuberculosis among persons infected with and adds benefit compared with HAART alone [33
This study had some limitations. First, it was observational, and tuberculosis was diagnosed not through active screening of all study participants but as part of ongoing health care for individuals. Therefore, some tuberculosis cases could have been missed. However, because patients were in HIV care and tuberculosis is a reportable disease, all cases should have been captured by the individual cohorts. Second, the NA-ACCORD database included only persons with at least 1 follow-up visit within 12 months of entering observation in the current analysis. Tuberculosis cases in any persons without such a follow-up visit would therefore have not been included.
In summary, our study highlights the possible benefit of screening for tuberculosis prior to and shortly after antiretroviral therapy initiation, even in low tuberculosis incidence areas such as the United States and Canada. Screening should be focused on persons with baseline CD4+ <200 lymphocytes/mm3 or increased HIV-1 RNA, persons of nonwhite race or Hispanic ethnicity, history of injection drug use, and possibly male sex. The tuberculosis recurrence rate of 1.5% among persons receiving HAART illustrates an important paradox: HAART appeared to confer a benefit regarding recurrence risk, but the risk of recurrent tuberculosis was high relative to tuberculosis risk among all HIV-infected persons in this study.