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When to initiate antiretroviral therapy in patients with newly diagnosed HIV infection and TB has been debated. In this study from Cambodia, giving antiretrovirals 2 weeks after the start of TB therapy was superior to therapy begun at 8 weeks, with a decrease in mortality. Tuberculosis is a major cause of death in persons infected with the human immunodeficiency virus (HIV), especially in resource-limited settings. 1 , 2 Despite effective tuberculosis therapy, mortality is particularly high among patients with severe immunosuppression. 3 , 4 Although mortality among HIV-infected patients has been reported to be approximately 30% within the first 2 months of tuberculosis treatment if antiretroviral therapy (ART) is withheld, 5 the timing for starting ART in patients with tuberculosis has remained unclear. Arguments that support delayed initiation of ART include concern about the combined toxic effects of drugs, an increased risk of the immune reconstitution inflammatory syndrome (IRIS), and . . .

To assess efavirenz plasma concentrations and their association with treatment efficacy and tolerance of efavirenz 600 mg daily in HIV-tuberculosis co-infected patients. HIV-infected adults with CD4+ T cell count ≤ 200/mm(3) received standard 6-month tuberculosis treatment and antiretroviral therapy including a daily-dose of 600 mg of efavirenz, irrespective of their body weight. Mid-dose blood samples were drawn both on tuberculosis treatment (week +2 and week +6 after antiretroviral therapy initiation, and week 22 of follow-up) and off tuberculosis treatment (week 50 of follow-up). Considered therapeutic range was 1,000 to 4,000 ng/mL. Multivariate analysis was performed to evaluate the association between efavirenz concentration below 1,000 ng/mL and virological failure. Linear regression was used to test the association between efavirenz exposure and CD4+ T cell gain. Severe side effects potentially related to efavirenz were described and their association with efavirenz exposure was tested by multivariate analysis. Efavirenz plasma concentrations were available in 540 patients. Median [interquartile range] efavirenz concentrations were 2,674 ng/mL [1,690-4,533], 2,667 ng/mL [1,753-4,494] and 2,799 ng/mL [1,804-4,744] at week +2, week +6, week 22, respectively, and 2,766 ng/mL [1,941-3,976] at week 50. Efavirenz concentrations were lower at week 50 (off rifampicin) compared to week 22 (on rifampicin) (p<0.001). Late attendance to study visit and low hemoglobinemia were the only factors associated with an increased risk of efavirenz concentration below 1,000 ng/mL. Efavirenz concentration below 1,000 ng/mL was not associated with treatment failure. Efavirenz concentration above 4,000 ng/mL was associated with higher risk of central nervous system side effects (p<0.001) and of hepatotoxicity (p<0.001). Body weight and tuberculosis treatment were not associated with low efavirenz concentrations or treatment failure, supporting the 600 mg daily-dose of efavirenz in HIV-tuberculosis co-infected patients. High efavirenz concentrations were related to a higher risk of central nervous system side effects and hepatotoxicity. ClinicalTrials.gov NCT01300481.

Background. Shortening the interval between antituberculosis treatment onset and initiation of antiretroviral therapy (ART) reduces mortality in severely immunocompromised human immunodeficiency virus (HIV)–infected patients with tuberculosis. A better understanding of causes and determinants of death may lead to new strategies to further enhance survival. Methods. We assessed mortality rates, causes of death, and factors of mortality in Cambodian HIV-infected adults with CD4 count ≤200 cells/μL and tuberculosis, randomized to initiate ART either 2 weeks (early ART) or 8 weeks (late ART) after tuberculosis treatment onset in the CAMELIA clinical trial. Results. Six hundred sixty-one patients enrolled contributed to 1366.1 person-years of follow-up; 149 (22.5%) died. There were 8.3 deaths per 100 person-years (95% confidence interval [CI], 6.4–10.7) in the early-ART ground and 13.8 deaths per 100 person-years (95% CI, 11.2–16.9) in the late-ART group (P = .002). Tuberculosis was the primary cause of death (28%), followed by other HIV-associated conditions (19%). Factors independently associated with mortality in the first 26 weeks were the age, body mass index, hemoglobin, interrupted or ineffective tuberculosis treatment before identification of drug resistance, disseminated tuberculosis, and nontuberculous mycobacterial disease. After 50 weeks in the trial, the most frequent causes of death were non-HIV related or tuberculosis related, including drug toxicity; factors associated with mortality were late ART, loss to follow-up, and absence of cotrimoxazole prophylaxis. Conclusions. Despite ART introduction, mortality remained high, with tuberculosis as the leading cause of death. Reducing tuberculosis-related mortality remains a challenge in resource-limited settings and requires innovative strategies. Clinical Trials Registration. NCT00226434.

Objective To assess efavirenz plasma concentrations and their association with treatment efficacy and tolerance of efavirenz 600 mg daily in HIV-tuberculosis co-infected patients. Methods HIV-infected adults with CD4+ T cell count less than or equal to 200/mm3 received standard 6-month tuberculosis treatment and antiretroviral therapy including a daily-dose of 600 mg of efavirenz, irrespective of their body weight. Mid-dose blood samples were drawn both on tuberculosis treatment (week +2 and week +6 after antiretroviral therapy initiation, and week 22 of follow-up) and off tuberculosis treatment (week 50 of follow-up). Considered therapeutic range was 1,000 to 4,000 ng/mL. Multivariate analysis was performed to evaluate the association between efavirenz concentration below 1,000 ng/mL and virological failure. Linear regression was used to test the association between efavirenz exposure and CD4+ T cell gain. Severe side effects potentially related to efavirenz were described and their association with efavirenz exposure was tested by multivariate analysis. Results Efavirenz plasma concentrations were available in 540 patients. Median [interquartilerange] efavirenz concentrations were 2,674 ng/mL [1,690-4,533], 2,667 ng/mL [1,753-4,494] and 2,799 ng/mL [1,804-4,744] at week +2, week +6, week 22, respectively, and 2,766 ng/mL [1,941-3,976] at week 50. Efavirenz concentrations were lower at week 50 (off rifampicin) compared to week 22 (on rifampicin) (p<0.001). Late attendance to study visit and low hemoglobinemia were the only factors associated with an increased risk of efavirenz concentration below 1,000 ng/mL. Efavirenz concentration below 1,000 ng/mL was not associated with treatment failure. Efavirenz concentration above 4,000 ng/mL was associated with higher risk of central nervous system side effects (p<0.001) and of hepatotoxicity (p<0.001). Conclusion Body weight and tuberculosis treatment were not associated with low efavirenz concentrations or treatment failure, supporting the 600 mg daily-dose of efavirenz in HIV-tuberculosis co-infected patients. High efavirenz concentrations were related to a higher risk of central nervous system side effects and hepatotoxicity. Trial Registration ClinicalTrials.gov NCT01300481

Case-fatality among co-infected patients occurs mainly in the first months after the TB treatment initiation. [...] robust data regarding optimal timing of HAART initiation within this early period is critically needed.