In this study, we have shown that HIV-infected patients with tuberculosis are significantly more likely to relapse after completion of a rifamycin-based regimen than HIV-uninfected/unknown patients. Of five prior publications in which recurrence data were compared and reported, none showed a statistically significant difference between HIV-infected and HIV-uninfected/unknown patients (8
). The recurrence rate in HIV-infected individuals treated for tuberculosis was around 5% in all of these studies except one, which was located in an area of endemic tuberculosis and reported a high recurrence rate of 9% (11
). Because this latter study did not have access to molecular genotyping, no distinction could be made between recurrence from relapse or reinfection (21
). A recent follow-up (22
) of an observational cohort study originally published in 1999 (12
) that included molecular genotyping showed findings similar to ours: HIV-infected patients were five times more likely to recur. In studies reporting tuberculosis outcomes in HIV-infected individuals only (23
), designed primarily to compare various treatment regimens, relapse rates ranged from 0% in one study in which the continuation phase was extended to 7 months (26
) to 10% in a study using twice-weekly isoniazid and rifampin during the continuation phase (27
). Thus, our finding that 6.6% of our HIV-infected cohort experienced a second episode of tuberculosis, representing a relapse rate of 9.3 per 100 person-years, is at the higher end of the range reported for rifamycin-based regimens. Moreover, it is significantly greater than the relapse rate of 1.0 per 100 person-years in our HIV-uninfected/unknown cohort. Whether this is a result of extraordinary successes in the HIV uninfected/unknown or of the inherent complexities of treating HIV and tuberculosis coinfected patients cannot be readily determined from a retrospective study.
In this study, we have also shown that duration of tuberculosis treatment and intermittent dosing were strong independent predictors of relapse in HIV-infected patients. Patients who received 6 months of a rifamycin-based tuberculosis regimen were four times more likely to relapse than those treated longer than 6 months, and patients who received intermittent dosing were four times more likely to relapse than those who had daily dosing (). Although the association of relapse with intermittent therapy is in line with recent publications (20
), the importance of the duration of treatment in our study is not. A recent meta-analysis of prospective clinical trials reported no significant difference in risk of recurrence between HIV-infected patients who received 5 to 6 months of rifampin-based therapy and those who received 7 months or longer (29
). This finding may reflect the fact that our study was a review of tuberculosis management outside the controlled context of a clinical trial. Indeed, a study of tuberculosis outcomes in HIV-uninfected patients also under program settings showed that extension of intensive phase and overall treatment protected against relapse (19
). Being hospitalized for tuberculosis, which is possibly a marker of severity of disease and immunosuppression, was the only other predictor of relapse in our HIV-infected cohort, with a p value close to statistical significance. Several characteristics were exclusively associated with HIV-infected individuals whose tuberculosis relapsed and thus could not be entered into multivariate regression models: All 13 HIV-infected–associated relapses presented with noncavitary disease on plain radiograph, and none received HAART during the study period. To our knowledge, a potential link between receiving HAART and lower risk for tuberculosis relapse has not been noted in the literature. Although prior publications have reported that the risk of progression to tuberculosis is significantly reduced among HIV-infected individuals receiving HAART (30
), none have reported a beneficial effect of HAART on tuberculosis outcomes (33
). Initial CD4+
T-lymphocyte count did not predict relapse in our HIV-infected cohort, in contrast to a prior publication in which a low median initial CD4+
T-lymphocyte count was reported as being the sole predictor of relapse (22
). However, mortality during follow-up was associated with having a low initial CD4+
T-lymphocyte count, and this relationship may have masked the presence of a possible association between CD4+
T-lymphocyte count and relapse.
We have shown that the use of HAART during treatment for tuberculosis significantly protected against mortality when compared with HIV-infected patients who received no antiretroviral medication or antiretroviral regimens other than HAART (RR, 0.36; 95% CI, 0.14–0.91; p = 0.01). Furthermore, HIV-infected patients who received HAART during their tuberculosis treatment converted their sputum smears and cultures to negative significantly faster than those not treated with HAART (mean of 3.5 vs. 5.9 wk [p = 0.01] and mean of 5.1 vs. 8.7 wk [p = 0.003], respectively). However, the administration of HAART was associated with a significant prolongation of tuberculosis treatment for unclear reasons. Despite the apparent benefits associated with HAART, only 32 (44%) of the 73 HIV-infected patients treated for tuberculosis during or after 1996 received HAART. This was likely due to the lack of an expert consensus about whether and when HAART should be initiated during the treatment of HIV-related tuberculosis—an issue that remains controversial (34
). Even though delaying HAART until the end of tuberculosis treatment simplifies the management of the two diseases, our results are in line with recent literature (35
) and provide compelling evidence to warrant the initiation of HAART during tuberculosis treatment in select patients. Until there is further information from prospective clinical trials about the optimal time to initiate HAART, the current World Health Organization recommendations remain our best guide (36
Our study was limited by potential biases. The effect of physician preference for prolonging treatment in HIV-infected patients proved to be difficult to control. Throughout chart reviews, it was evident that certain cases had treatment prolonged by their physician due to profound HIV-mediated immunosuppression rather than due to the standard reasons for prolonging therapy. Determining cause of death also proved difficult. We reviewed all available charts, computer records, death certificates, and autopsy information to determine cause of death; however, only a minority of cases had post mortem
analyses. The retrospective cohort design of this study precluded analysis of the effects of the timing of initiating HAART on tuberculosis outcomes and time-matched comparisons of CD4+
T-lymphocyte count and viral load in those receiving various antiretroviral regimens versus those receiving none. To determine the optimum duration of therapy for tuberculosis in an era of HAART and to determine the optimum time to initiate HAART would require a large randomized clinical trial. The database for this cohort was initiated in the early 1990s when the immune reconstitution syndrome in HIV-infected patients was starting to be described (37
); therefore, our data on this syndrome are limited. There was differential attrition in the two groups. However, most of the attrition in the HIV-infected patients was due to HIV-related death. Had these patients lived longer, the relapse rate would have likely been even higher.
In summary, we have shown in this study that HIV-infected patients who successfully completed a rifamycin-based course of therapy, regardless of its duration, were more likely to relapse in follow-up when compared with HIV-uninfected patients. We have also shown that HIV-infected patients who received a 6-month, rifamycin-based course of tuberculosis treatment or who were treated intermittently had a relapse rate that was significantly higher than HIV-infected individuals who received a longer duration of therapy or were treated with daily dosing, respectively. Despite the varying recurrence rates noted in the literature, the generally recommended treatment for HIV-infected patients with tuberculosis is 6 months of a rifamycin-based regimen (2
). Based on our findings, we recommend that further research is warranted to identify the most efficacious duration of therapy and the optimum timing for HAART in the treatment of HIV-related tuberculosis.