Efficacy and Safety of Antiretroviral Therapy Initiated One Week after Tuberculosis Therapy in Patients with CD4 Counts < 200 Cells/μL: TB-HAART Study, a Randomized Clinical Trial

PLoS One. 2015 May 12;10(5):e0122587. doi: 10.1371/journal.pone.0122587. eCollection 2015.

Abstract

Background: Given the high death rate the first two months of tuberculosis (TB) therapy in HIV patients, it is critical defining the optimal time to initiate combination antiretroviral therapy (cART).

Methods: A randomized, open-label, clinical trial comparing efficacy and safety of efavirenz-based cART initiated one week, four weeks, and eight weeks after TB therapy in patients with baseline CD4 count < 200 cells/μL was conducted. The primary endpoint was all-cause mortality rate at 48 weeks. The secondary endpoints were hepatotoxicity-requiring interruption of TB therapy, TB-associated immune reconstitution inflammatory syndrome, new AIDS defining illnesses, CD4 counts, HIV RNA levels, and AFB smear conversion rates. All analyses were intention-to-treat.

Results: We studied 478 patients with median CD4 count of 73 cells/μL and 5.2 logs HIV RNA randomized to week one (n = 163), week four (n = 160), and week eight (n = 155). Sixty-four deaths (13.4%) occurred in 339.2 person-years. All-cause mortality rates at 48 weeks were 25 per 100 person-years in week one, 18 per 100 person-years in week four and 15 per 100 person-years in week eight (P = 0.2 by the log-rank test). All-cause mortality incidence rate ratios in subgroups with CD4 count below 50 cells/μL versus above were 2.8 in week one (95% CI 1.2-6.7), 3.1 in week four (95% CI 1.2-8.6) and 5.1 in week eight (95% CI 1.8-16). Serum albumin < 3 gms/dL (adjusted HR, aHR = 2.3) and CD4 < 50 cells/μL (aHR = 2.7) were independent predictors of mortality. Compared with similar subgroups from weeks four and eight, first-line TB treatment interruption was high in week one deaths (P = 0.03) and in the CD4 subgroup <50 cells/μL (P = 0.02).

Conclusions: Antiretroviral therapy one week after TB therapy doesn't improve overall survival. Despite increased mortality with CD4 < 50 cells/μL, we recommend cART later than the first week of TB therapy to avoid serious hepatotoxicity and treatment interruption.

Trial registration: ClinicalTrials.gov NCT 01315301.

Trial registration: ClinicalTrials.gov NCT01315301.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AIDS-Related Opportunistic Infections / drug therapy*
  • AIDS-Related Opportunistic Infections / etiology
  • Adult
  • Anti-HIV Agents / administration & dosage
  • Anti-HIV Agents / adverse effects
  • Anti-HIV Agents / therapeutic use*
  • Antiretroviral Therapy, Highly Active / adverse effects
  • Antitubercular Agents / administration & dosage
  • Antitubercular Agents / adverse effects
  • Antitubercular Agents / therapeutic use*
  • CD4 Lymphocyte Count
  • Drug Administration Schedule
  • Female
  • HIV Infections / complications
  • HIV Infections / drug therapy*
  • Humans
  • Male
  • Middle Aged
  • Tuberculosis / drug therapy*
  • Tuberculosis / etiology

Substances

  • Anti-HIV Agents
  • Antitubercular Agents

Associated data

  • ClinicalTrials.gov/NCT01315301

Grants and funding

The study was supported by grants from SIDA/SAREC grant no. SWE 2004-098, HIV-2006-031, SWE 2007-270, and EDCTP grant no CT.2005.32030.001. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.