Causes of death among people with tuberculosis and low CD4 counts

Causes and determinants of mortality in HIV-infected adults with tuberculosis: an analysis from the CAMELIA ANRS 1295-CIPRA KH001 randomized trial.

Marcy O, Laureillard D, Madec Y, Chan S, Mayaud C, Borand L, Prak N, Kim C, Lak KK, Hak C, Dim B, Sok T, Delfraissy JF, Goldfeld AE, Blanc FX, CAMELIA (ANRS 1295-CIPRA KH001) Study Team.  Clin Infect Dis. 2014 Aug;59(3):435-45. doi: 10.1093/cid/ciu283. Epub 2014 Apr 23.

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 1 366.1 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 group 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.

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Editor’s notes: Tuberculosis (TB) remains the most important cause of death among HIV-positive people worldwide, despite increasing access to antiretroviral therapy. There is a strong emphasis on reducing TB mortality as part of the post-2015 global TB strategy. This makes it even more important to define causes of death, so that appropriate programmes can be introduced.

This analysis in Cambodia, reports causes of death among HIV-positive people with sputum smear-positive TB, and CD4 counts below 200. The participants took part in a trial of antiretroviral therapy started early, i.e. two weeks after start of TB treatment, versus late, eight weeks after TB treatment start. Causes of death were assigned by site investigators and validated by review of medical records by investigators who had not been involved in the patient’s care. Tuberculosis was the most frequently assigned cause of death (42 of 149 deaths). HIV-associated conditions accounted for 28 deaths of which diarrhoea, non-tuberculous mycobacterial disease and immune reconstitution syndrome were the most frequent. For 23 deaths, TB and HIV-associated conditions were considered equally likely. This highlights the difficulty in distinguishing between these two causes of death among people with advanced HIV-related immunosuppression. Limited autopsies based on multiple biopsies are far more acceptable to families than traditional full autopsy, and could be used to identify causes of death with greater accuracy. Further it was notable that cotrimoxazole prophylaxis was associated with a lower risk of death after 50 weeks of follow-up, underlining the importance of this programme.  

Avoid TB deaths
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