Tuberculosis (TB) is the leading cause of morbidity and mortality in people living with the human immunodeficiency virus (HIV) [1]–[1]. Patients infected with HIV are at increased risk, up to 10% per year, of reactivating latent Mycobacterium tuberculosis infection, and of accelerated progression to TB disease soon after infection [5]–[8]. In addition, HIV appears to increase the rate of TB re-infection and recurrent disease [9], [10]. During the last decade, TB case notification rates have risen sharply in areas of high HIV prevalence, such as sub-Saharan Africa, largely attributable to the HIV epidemic [8], [11]–[13]. The World Health Organization (WHO) recommends that affected countries implement collaborative programmatic TB/HIV activities, including antiretroviral therapy (ART), as part of the health sector response to this syndemic [14], [15].

Before 1996, ART consisted of an antiretroviral (ARV) agent (primarily a nucleoside reverse transcriptase inhibitor, or NRTI) given alone or in combination with another ARV agent. Thereafter, the introduction of highly active ART (HAART), consisting of three ARV agents [including NRTI, non-nucleoside transcriptase inhibitors (NNRTI) and protease inhibitors (PI)], has had a significant impact on reducing the incidence of opportunistic infections (OI) in HIV-infected patients [16]–[19]. In prospective clinical studies, HAART has been shown to reduce the incidence of TB by as much as 80% [20]–[23]. Further, epidemiological models of TB in a theoretical setting of ART accessibility have demonstrated considerable impact of HAART on TB incidence, but these estimates have relied on assumptions such as ART being initiated early in the course of HIV infection and very high levels of treatment adherence being attained [24]. The true impact of ART on TB among people living with the human immunodeficiency virus under normal program conditions, however, has not been previously reported.

In 1996, Brazilian federal law established a mandate granting universal access to ART for all eligible HIV-infected individuals [25]. In a nation where the high national TB burden [estimated (2005) all case TB incidence and prevalence of 60/100,00 population (pop)/yr and 76/100,000 pop, respectively] points to significant community transmission, where the adult (15–49 yrs) HIV prevalence (2005) among TB patients is 14%, and where the vast majority of TB and HIV patients are managed in the public sector, Brazil's public policy guaranteeing universal ART access has important implications for TB control [25]. According to the WHO, in 2005, 9529 new TB cases and 2281 TB deaths (all forms) were attributable to HIV, despite the fact that 86% of known HIV-infected adults eligible for ART in Brazil were receiving this therapy [26], [27]. However, up to 64% of prevalent HIV infections remain undiagnosed in the country, according to estimates (2002) by Brazil's Ministry of Health (MoH), Programa Nacional de DST e AIDS (national program for STI and AIDS—unpublished data). This estimate suggests that, in addition to the need for improved HIV counseling and testing access, the total burden of HIV infection in Brazil represents a large reservoir of people at increased risk of TB [20]–[23].

This population-based study sought to evaluate the impact of universal access to ART on TB disease incidence in HIV-infected patients managed in the public health sector in Brazil.

Of 1002 records reviewed in 29 facilities in 11 Brazilian states, 307 (31%) were not included because 203/307 (66%), 63/307 (21%), and 41/307 (13%) individuals were not HIV-infected, lacked an HIV confirmatory test, and their initial facility visit occurred outside of the date parameters for inclusion, respectively. Of the remaining 695 (69%) records, 174 (25%) met exclusion criteria [73/174 (42%), 57/174 (33%), 12/174 (7%), and 32/174 (18%) represented individuals who attended clinic only once, were pregnant, were <18 years of age, or met more than one exclusion criteria, respectively]. An additional 58/695 (8%) records were excluded due to a recorded TB diagnosis occurring within 30 days of the recorded initial facility visit. Thus, 463/695 (66%) records comprised the study population, the median age of which was 34 years (range 18–71), and 70% were male (Table 3).

Except for patients with a history of injection drug use (IDU; Χ², p = 0.02), no statistically significant differences were observed between the patients who eventually developed TB and those who did not develop TB with respect to sex, age, mode of sexual transmission, or state where the patient was clinically managed (Table 3). For whom the information was available in the patient record (i.e., denominators vary), 229 and 116 of 379 patients presented with a baseline viral load of ≥10,000 and ≥100,000 copies/ml, respectively; and 263/429 (61%) presented with a baseline CD4+ T-lymphocyte <200 cells/mm³. Two-hundred and twenty-three of 271 (82%) patients presented or developed WHO stages 3 or 4 clinical disease. Recorded modes of HIV transmission (not mutually exclusive) included 136/232 men who had sex with men (MSM), 61/461 with history of IDU, 232/297 with multiple sexual partners (heterosexual and MSM), 151/244 with HIV-positive partner contact, and 12/331 with prior blood transfusion.

Except for the 76/463 (17%) patients who remained ART-naïve, all patients who initiated any ART (n = 387) did so at some point after their initial recorded facility visit. At the time of the primary endpoints, 245 [patients treated exclusively with ART non-HAART (n = 81)+those initially treated with ART non-HAART and later switched to HAART (n = 164)] and 306 [patients treated exclusively with HAART (n = 142)+those initially treated with ART non-HAART and later switched to HAART (n = 164)] patients had contributed survival time to ART non-HAART and HAART regimens, respectively (Fig. 1). One hundred-fifty seven patients received no HAART. The drug classes and specific agents that composed the most commonly prescribed ART regimens in this study are listed in Table 2. At least one dose of CTM was prescribed for 204/441 (46%) patients.

Nine (23%) confirmed, 8 (21%) probable, and 22 (56%) presumed TB diagnoses (n = 39) were made during the study period. Twenty-three (59%) patients had pulmonary TB, the remaining 16 (41%) had extrapulmonary disease. Eighteen (46%) TB cases occurred in ART-naïve patients. The median baseline absolute CD4+ T-lymphocyte count for patients who developed TB was not significantly different from patients who remained TB free (111 cells/mm³ vs. 253 cells/mm³, respectively. Χ², p>0.05). However, a higher proportion of patients with TB had median baseline CD4+ T-lymphocyte counts <200 cells/mm³ compared to patients without TB (57% vs. 37%, respectively. Χ², p = 0.01). The median pre-diagnostic (TB) CD4+ T-lymphocyte count was 134 cells/mm³ (range 6–821 cells/mm³). The median time elapsed between the pre-diagnostic CD4+ T-lymphocyte count and the diagnosis of TB was 73 days (range 0–572).

Mean duration of follow-up from the initial recorded facility visit to a primary endpoint was 330, 1059, and 1125 days for TB diagnosis , patient death, and last clinic visit, respectively. Of the 43 (9% of study population) patient deaths recorded during the study period, 3 had been diagnosed with TB disease (Χ²: p>0.05).

We analyzed potential risk factors for TB disease in the study population (Table 4). Patients with a baseline CD4+ T-lymphocyte count of <200 cells/mm³ had more than twice the incidence of TB disease than those with a baseline CD4+ T-lymphocyte count >200 cells/mm³ {hazards ratio (HR) 2.3; [95% confidence interval (CI)] 1.2, 4.4}. A history of IDU, incarceration, hospitalization, and prior TB were also associated with a statistically significantly higher incidence of TB disease (Table 4). No statistically significant difference was observed in the incidence of TB disease among patients with baseline (i.e., at initial visit to the facility) WHO clinical stages 3 and 4 vs. 1 and 2, [HR 1.4; (95% CI 0.5, 3.6)].

In univariate screening (Table 4), ART-naïve patients had a statistically significantly higher incidence of TB disease than those receiving any ART [HR 5.0; (95% CI 3.3, 10.0); p<0.01]. Statistically significant protective effects against incident TB disease was observed for both ART non-HAART (exclusively) [HR 0.4; (95% CI 0.2, 0.9), p = 0.03] and HAART [HR 0.1; (95% CI, 0.1, 0.2), p<0.001].

In multivariate analysis, controlling for type of ART intervention, a baseline CD4+ T-lymphocyte count <200 cells/mm³, IPT, and prior history of TB, hospitalization, incarceration and IDU (Table 5), only HAART (vs. ART naïve) was associated with a statistically significant reduction in TB disease incidence [HR 0.2 (95% CI 0.1, 0. 6); p<0.01]. The reduction in TB disease among patients receiving ART non-HAART (vs. ART naïve) did not reach statistical significance [HR 0.4; (95% CI 0.2, 1.1); p = 0.08]. A baseline CD4+ T-lymphocyte count <200 cells/mm³ [HR 2.5; (95% CI 1.2, 5.4); p<0.01], prior hospitalization [HR 4.2; (95% CI 2.0, 8.8); p<0.001] , prior incarceration [HR 4.1; 95% CI 1.6, 10.3); p<0.01], and a positive tuberculin skin test [HR 3.1; (95% 1.1, 9.0); p = 0.04] were independently and positively associated with incident TB. All two-way interaction terms were tested and none were found to be statistically significant (i.e., p>0.1).

Ninety-five percent, 86%, and 69% of patients who received HAART, ART non-HAART , and remaining ART naïve, respectively, remained free of TB disease at primary endpoints (p<0.001 for all three situations, when evaluated together; see Figure 2).

The mortality rate of the study population at study end was 0.24 per 100-person years of follow-up. The proportional mortality of severely immunocompromised TB patients (CD4+ T-lymphocyte<200 cells/mm³) at 6 and 12 months after starting TB treatment, was 0.8% and 1.1%, respectively.

In this population-based retrospective cohort analysis of adult HIV-infected patients managed under normal programmatic conditions in public HIV treatment facilities in Brazil, we observed a statistically significantly lower (80%, p<0.01) incidence of TB in patients prescribed HAART compared to patients who remained ART-naïve. This effect of HAART remained statistically significant even when controlling for the patients' baseline immunological status, and other important characteristics and interventions (Tables 4 and 5). Though treatment with ART non-HAART also resulted in a lower TB incidence rate, the reduction did not reach statistical significance (p = 0.08). The findings in this study serve to validate similar findings in previous, more controlled studies, and demonstrate that it is possible for national programs to provide access to HAART under “real world” conditions, and in doing so, reduce the risk of the most common OI of adults living with HIV—TB [19]–[22].

In Brazil, it is customary for HIV treatment facilities to take over the care of newly diagnosed HIV-infected patients in the public sector, and thereafter, provide longitudinal comprehensive clinical management and ART, as indicated [25]. According to the WHO, 86% of diagnosed and eligible HIV-infected patients in Brazil were receiving ART in 2004, a proportion superior to that of low and middle income countries (e.g., Peru, 18%); and similar to that of developed countries in South America such as Argentina and Chile (both 100%) [26]. However, while access to ART remains very important, a significant impact in the reduction TB incidence for people living with HIV is unlikely unless a large proportion of the subset who are unaware of their HIV serostatus are tested, and national programs are able to deliver high quality comprehensive clinical care, including effective provision of ART to this population.

The patients who developed TB disease in our study had similar risk factors for TB as HIV-infected patients in other settings, and 66% eventually received HAART [1], [8], [11], [22], [34], [35]. Nevertheless, 11 (4%) patients developed TB disease despite receiving HAART. A higher proportion of patients with TB had median baseline CD4+ T-lymphocyte counts <200 cells/mm³ compared to patients without TB (57% vs. 37%, respectively. Χ², p = 0.01). This suggests that those who developed TB may have been more immunocompromised at baseline than patients remaining TB free; however, the median baseline absolute CD4+ T-lymphocyte count and baseline WHO clinical staging characteristics were not significantly different between the two groups. We cannot exclude the possibility, however, that the study lacked the power to detect subtle but clinically important immunological differences among groups. In areas of high TB prevalence, TB can occur at all levels of CD4+ T-lymphocyte count, though ART-naïve patients who develop TB frequently present with low CD4+ T-lymphocyte counts prior to TB diagnosis [36], [37]. Both HAART and non-HAART regimens have been shown to raise CD4+ T-lymphocyte counts and improve the clinical status of HIV-infected patients with and without concomitant OI [20], [38], [39]. This suggests that other factors may be affecting TB disease risk after initiating ART. Indeed, evidence exists to suggest that HAART is unable to fully restore the immune response to Mycobacterium tuberculosis in HIV-infected patients, leading to a chronically heightened TB risk over an increased lifespan [39]–[41]. Addressing this heightened risk poses a challenge for the future control of TB; however, growing evidence also suggests that this risk may be mitigated by early initiation of HAART with corresponding high levels of treatment adherence [24], [41], [42]. Fortunately, currently and widely recommended clinical guidelines for the treatment of HIV infection and TB disease are helping to eliminate an important negative factor from the TB/HIV equation—suboptimal ART. Because of the timeframe selected for this study, 1995–2001, it was not uncommon, early within this time interval, to document ART regimens consisting of single and dual ARV agents. Nevertheless, we saw a corresponding shift toward HAART (data not shown) in this study as scientific thought about ART gradually evolved after 1995 [41]. Attention to other factors such as facility infection-control, active case finding, and wider use of appropriately administered IPT could be instrumental in further reducing TB disease risk in HIV-infected individuals (Golub JE, et al. Tuberculosis incidence by HAART and isoniazid prophylactic therapy in HIV-infected patients in Rio de Janeiro, Brazil. XVI International AIDS Conference, 2006 Abstract no. MoPE0395) [5], [9], [23], [42]–[45]. On-going studies with regard to the use of IPT in HIV infection should elucidate the optimal use of this intervention (Samandari T, et al. Characteristics of people living with HIV-1 screened for isoniazid preventive therapy-Botswana, 2004–2005. AIDS 2006-XVI International AIDS Conference, 2006 Abstract no. MoAB010).

Finally, there is now reliable information showing that HIV-related morbidity and mortality in adults and children, including that due to TB disease co-morbidity, can be significantly reduced with the adjunctive use of CTM prophylaxis [46]–[48]. We found that the mortality rate and overall mortality of the cohort and of severely immunocompromised TB patients was comparable, if not lower, than that observed for HIV infected patients managed and reported in high income countries after 1995 [16], [17], [49]. And, while many factors clearly confound any mortality considerations in this study, the fact that 46% and 33% of the cohort and of TB patients, respectively, in the study received at least one dose of CTM probably contributed to favorable outcomes in these patients. As is probably the case in many other clinical settings globally, the use of CTM prophylaxis among HIV-infected populations with TB can clearly be improved and, in doing so, independently reduce patient morbidity and mortality.

Our study population specifically excludes children (age<18 years) and pregnant women. Due to the retrospective and observational design of this study, we were also unable to control for factors specific to (a) patients (e.g., adverse nutritional and psycho-social issues); (b) facilities (e.g., infection control measures); and, (c) programs [e.g., erratic pharmacy drug stocks and diagnostic rigor (e.g., low sensitivity and specificity of X-ray imaging)]. In addition, patients with only one clinic visit were explicitly excluded from the study, and we were unable to consistently determine the degree of patient adherence to therapeutic regimens from patient records. With regards to treatment adherence, however, WHO and others estimate adherence to be approximately 75% among patients on ART in Brazil [27], [50].

An additional limitation of our study was that the majority of the TB diagnoses recorded were made, primarily, on clinical grounds (i.e., presumed); and therefore, an alternative diagnosis to TB cannot be excluded. As the most common opportunistic disease of HIV-infected patients, however, the clinical experience of health care staff in facilities with large HIV patient populations probably lessens this possibility. In addition, TB misdiagnosis would only tend to underestimate the degree of TB incidence reduction by HAART.

Despite the limitations of the study and the fact that a proportion of study patients received sub-optimal ART before being switched to HAART, the significant reduction in TB disease observed is all the more remarkable. Our findings, however, are not applicable to pediatric patients, and should be interpreted in light of the study limitations.

We conclude that, in settings of unrestricted access to ART, HAART can have a significant impact on the TB incidence of HIV-infected patients developing. We found that, even under programmatic conditions, a statistically significant reduction in TB incidence of 80% was observed among HIV-infected patients receiving HAART in the public sector in Brazil compared to patients who remained ART-naïve. We demonstrate that, although broad access to ART remains an elusive goal of low and middle income countries, a national policy that drives the effective implementation of a program that manages HIV-infected patients using HAART is an initiative that is not only beneficial in reducing TB disease in HIV-infected patients, but also a feasible one.