Date Published: July 13, 2013
Publisher: BioMed Central
Author(s): Rong Chu, Edward J Mills, Joseph Beyene, Eleanor Pullenayegum, Celestin Bakanda, Jean B Nachega, P J Devereaux, Lehana Thabane.
Tuberculosis (TB) disease affects survival among HIV co-infected patients on antiretroviral therapy (ART). Yet, the magnitude of TB disease on mortality is poorly understood.
Using a prospective cohort of 22,477 adult patients who initiated ART between August 2000 and June 2009 in Uganda, we assessed the effect of active pulmonary TB disease at the initiation of ART on all-cause mortality using a Cox proportional hazards model. Propensity score (PS) matching was used to control for potential confounding. Stratification and covariate adjustment for PS and not PS-based multivariable Cox models were also performed.
A total of 1,609 (7.52%) patients had active pulmonary TB at the start of ART. TB patients had higher proportions of being male, suffering from AIDS-defining illnesses, having World Health Organization (WHO) disease stage III or IV, and having lower CD4 cell counts at baseline (p < 0.001). The percentages of death during follow-up were 10.47% and 6.38% for patients with and without TB, respectively. The hazard ratio (HR) for mortality comparing TB to non-TB patients using 1,686 PS-matched pairs was 1.37 (95% confidence interval [CI]: 1.08 – 1.75), less marked than the crude estimate (HR = 1.74, 95% CI: 1.49 – 2.04). The other PS-based methods and not PS-based multivariable Cox model produced similar results. After controlling for important confounding variables, HIV patients who had TB at the initiation of ART in Uganda had an approximate 37% increased hazard of overall mortality relative to non-TB patients.
The total number of people living with human immunodeficiency virus (HIV) reached 34.0 million (31.6 – 35.2 million) worldwide by the end of 2010,  with the majority in Sub-Saharan Africa. One-third of HIV-infected people are estimated to be co-infected with Mycobacterium tuberculosis (TB) which can activate or reactivate during the initiation of antiretroviral therapy (ART) due to immune reconstitution inflammatory syndrome (IRIS). However, TB incidence rates vary according to geography and patients’ degrees of immunosuppression. The incidence proportion of active TB in HIV-infected patients with latent TB infection is about 10% per year compared to 10% per lifetime for an HIV-uninfected individual . TB is a leading cause of HIV-related death . Recent trial data have shown that early initiation of ART (within two weeks) during TB therapy can improve survival for patients with co-infection [4-6]. Guidelines and policies on joint HIV/TB interventions have been developed to promote synergies between TB and HIV/AIDS prevention and care activities, [7-9] aimed at reducing morbidity and mortality in co-infected patients. On the other hand, joint treatment containing ART and anti-TB drugs may be complicated by overlapping toxicity profiles, complex drug-drug interactions, and IRIS [10-13].
This is, to our knowledge, the largest cohort of HIV-infected patients receiving ART in a single African country that has evaluated mortality outcomes in co-infected patients. Descriptive analysis showed that TB patients, compared to non-TB patients, were more likely to be immunosuppressed, have a history of opportunistic infections, and live in particular geographical regions of Uganda. The results of Cox PH analysis using PS matching for confounding control showed that having pulmonary TB disease at the initiation of ART led to a 37% increase in the hazard of all-cause mortality during the follow-up period between 2000 and 2009. Additional analyses using two other PS methods and the conventional (not PS-based) multivariable Cox regression model showed similar results. These analyses may be viewed as sensitivity analyses because different methods use different assumptions and the results seem to remain robust to different ways of adjusting for baseline confounding.
In summary, our current study suggests a moderate increase in the hazard of death associated with having active TB disease at the initiation of ART in HIV-infected patients receiving ART in Uganda. Our finding is complementary to results of the recent SAPIT,  CAMELIA,  and STRIDE trials  that demonstrate improved survival when ART is initiated during TB therapy. The results also validate the WHO guidelines that urge a more aggressive approach to management of both TB and HIV .
TB: Tuberculosis; ART: Antiretroviral therapy; HIV: Human immunodeficiency virus; AIDS: Acquired immune deficiency syndromes; WHO: World Health Organization; TASO: AIDS Support Organization; IRIS: Immune reconstitution inflammatory syndrome; PCP: Pneumocystis pneumonia; PS: Propensity score; HR: Hazard ratio; MI: Multiple imputation; MAR: Missing at random; SD: Standard deviation; CI: Confidence interval; ENT: Entebbe; JIN: Jinja; MAS: Masaka; MBL: Mbale; MBR: Mbarara; MUL: Mulago; TOR: Tororo; GUL: Gulu; SOR: Soroti; MSD: Masindi; IQR: Interquantile range.
The authors declare that they have no competing interest.
RC participated in the conception and design of the study, data cleaning and analysis, results interpretation, and drafting and revision of the manuscript. EM participated in the conception and design of the study, data collection, results interpretation, and revision of the manuscript. JB and EP participated in review of statistical methods, results interpretation, and revision of the manuscript. CN participated in data collection from TASO clinics and review of drafts. JBN and PJD participated in results interpretation and revision of the manuscript. LT participated in the conception and design of the study, results interpretation, and revision of the manuscript. All authors read and approved the final manuscript.