Timing of antiretroviral therapy for HIV-1 infection and tuberculosis.

University of California, San Francisco, 995 Potrero Ave., Bldg. 80, Ward 84, San Francisco, CA 94110-2897, USA.
New England Journal of Medicine (Impact Factor: 54.42). 10/2011; 365(16):1482-91. DOI: 10.1056/NEJMoa1013607
Source: PubMed

ABSTRACT Antiretroviral therapy (ART) is indicated during tuberculosis treatment in patients infected with human immunodeficiency virus type 1 (HIV-1), but the timing for the initiation of ART when tuberculosis is diagnosed in patients with various levels of immune compromise is not known.
We conducted an open-label, randomized study comparing earlier ART (within 2 weeks after the initiation of treatment for tuberculosis) with later ART (between 8 and 12 weeks after the initiation of treatment for tuberculosis) in HIV-1 infected patients with CD4+ T-cell counts of less than 250 per cubic millimeter and suspected tuberculosis. The primary end point was the proportion of patients who survived and did not have a new (previously undiagnosed) acquired immunodeficiency syndrome (AIDS)-defining illness at 48 weeks.
A total of 809 patients with a median baseline CD4+ T-cell count of 77 per cubic millimeter and an HIV-1 RNA level of 5.43 log(10) copies per milliliter were enrolled. In the earlier-ART group, 12.9% of patients had a new AIDS-defining illness or died by 48 weeks, as compared with 16.1% in the later-ART group (95% confidence interval [CI], -1.8 to 8.1; P=0.45). Among patients with screening CD4+ T-cell counts of less than 50 per cubic millimeter, 15.5% of patients in the earlier-ART group versus 26.6% in the later-ART group had a new AIDS-defining illness or died (95% CI, 1.5 to 20.5; P=0.02). Tuberculosis-associated immune reconstitution inflammatory syndrome was more common with earlier ART than with later ART (11% vs. 5%, P=0.002). The rate of viral suppression at 48 weeks was 74% and did not differ between the groups (P=0.38).
Overall, earlier ART did not reduce the rate of new AIDS-defining illness and death, as compared with later ART. In persons with CD4+ T-cell counts of less than 50 per cubic millimeter, earlier ART was associated with a lower rate of new AIDS-defining illnesses and death. (Funded by the National Institutes of Health and others; ACTG A5221 number, NCT00108862.).

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    ABSTRACT: Background To evaluate predictors and outcomes of Mycobacterium tuberculosis bacteremia among participants undergoing baseline mycobacterial blood culture in the ACTG A5221 STRIDE study, a randomized clinical trial comparing earlier with later ART among HIV-infected patients suspected of having tuberculosis with CD4-positive T-lymphocyte counts (CD4 counts) <250 cells/mm3. We conducted a secondary analysis comparing participants with respect to presence or absence of M. tuberculosis bacteremia.Methods Participants with a baseline mycobacterial blood culture were compared with respect to the presence or absence of M. tuberculosis bacteremia. Baseline predictors of M. tuberculosis bacteremia were identified and participant outcomes were compared by mycobacteremia status.ResultsOf 90 participants with baseline mycobacterial blood cultures, 29 (32.2%) were female, the median (IQR) age was 37 (31¿45) years, CD4 count was 81 (33¿131) cells/mm3, HIV-1 RNA level was 5.39 (4.96¿5.83) log10 copies/mL, and 18 (20.0%) were positive for M. tuberculosis. In multivariable analysis, lower CD4 count (OR 0.85 per 10-cell increase, p¿=¿0.012), hemoglobin ¿8.5 g/dL (OR 5.8, p¿=¿0.049), and confirmed tuberculosis (OR 17.4, p¿=¿0.001) were associated with M. tuberculosis bacteremia. There were no significant differences in survival and AIDS-free survival, occurrence of tuberculosis IRIS, or treatment interruption or discontinuation by M. tuberculosis bacteremia status. IRIS did not differ significantly between groups despite trends toward more virologic suppression and greater CD4 count increases at week 48 in the bacteremic group.Conclusions Among HIV-infected tuberculosis suspects, lower CD4 count, hemoglobin ¿8.5 g/dL, and the presence of microbiologically confirmed pulmonary tuberculosis were associated with increased adjusted odds of mycobacteremia. No evidence of an association between M. tuberculosis bacteremia and the increased risk of IRIS was detected.Trial NCT00108862.
    BMC Infectious Diseases 01/2015; 15(1):12. DOI:10.1186/s12879-014-0735-5 · 2.56 Impact Factor
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    ABSTRACT: Access to antiretroviral therapy (ART) is improving worldwide. Immune reconstitution inflammatory syndrome (IRIS) is a common complication of ART initiation. In this review, we provide an overview of clinical and epidemiological features of HIV-associated IRIS, current understanding of pathophysiological mechanisms, available therapy, and preventive strategies. The spectrum of HIV-associated IRIS is described, with a particular focus on three important pathogen-associated forms: tuberculosis-associated IRIS, cryptococcal IRIS, and Kaposi's sarcoma IRIS. While the clinical features and epidemiology are well described, there are major gaps in our understanding of pathophysiology and as a result therapeutic and preventative strategies are suboptimal. Timing of ART initiation is critical to reduce IRIS-associated morbidity. Improved understanding of the pathophysiology of IRIS will hopefully enable improved diagnostic modalities and better targeted treatments to be developed.
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    ABSTRACT: Antiretroviral therapy (ART) initiation during treatment for tuberculosis (TB) improves survival in human immunodeficiency virus (HIV)/TB-coinfected patients. We compared virological suppression (VS) rates, mortality, and retention in care in HIV-positive adults receiving care in 5 Ethiopian health centers with regard to TB coinfection. Human immunodeficiency virus-positive ART-naive adults eligible for ART initiation were prospectively recruited. At inclusion, all patients underwent microbiological investigations for TB (sputum smear, liquid culture, and polymerase chain reaction). Virological suppression rates after 6 months of ART (VS; viral load <40 and <400 copies/mL) with regard to TB status was the primary outcome. The impact of HIV/TB coinfection on VS rates was determined by multivariate regression analysis. Mortality and retention in care were analyzed by proportional hazard models. Among 812 participants (TB, 158; non-TB, 654), 678 started ART during the follow-up period (TB, 135; non-TB, 543). No difference in retention in care between TB and non-TB patients was observed during follow-up; 25 (3.7%) patients died, and 17 (2.5%) were lost to follow-up (P = .30 and P = .83, respectively). Overall rates of VS at 6 months were 72.1% (<40 copies/mL) and 88.7% (<400 copies/mL), with similar results for subjects with and without TB coinfection (<40 copies/mL: 65 of 92 [70.7%] vs 304 of 420 [72.4%], P = .74; <400 copies/mL: 77 of 92 [83.7%] vs 377 of 420 [89.8%], P = .10, respectively). High rates of VS can be achieved in adults receiving ART at health centers, with no significant difference with regard to TB coinfection. These findings demonstrate the feasibility of combined ART and anti-TB treatment in primary healthcare in low-income countries. NCT01433796.

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