Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)--associated tuberculous meningitis

Clin Infect Dis. 2011 Jun;52(11):1374-83. doi: 10.1093/cid/cir230.

Abstract

Background: The optimal time to initiate antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-associated tuberculous meningitis is unknown.

Methods: We conducted a randomized, double-blind, placebo-controlled trial of immediate versus deferred ART in patients with HIV-associated tuberculous meningitis to determine whether immediate ART reduced the risk of death. Antiretroviral drugs (zidovudine, lamivudine, and efavirenz) were started either at study entry or 2 months after randomization. All patients were treated with standard antituberculosis treatment, adjunctive dexamethasone, and prophylactic co-trimoxazole and were followed up for 12 months. We conducted intention-to-treat, per-protocol, and prespecified subgroup analyses.

Results: A total of 253 patients were randomized, 127 in the immediate ART group and 126 in the deferred ART group; 76 and 70 patients died within 9 months in the immediate and deferred ART groups, respectively. Immediate ART was not significantly associated with 9-month mortality (hazard ratio [HR], 1.12; 95% confidence interval [CI], .81-1.55; P = .50) or the time to new AIDS events or death (HR, 1.16; 95% CI, .87-1.55; P = .31). The percentage of patients with severe (grade 3 or 4) adverse events was high in both arms (90% in the immediate ART group and 89% in the deferred ART group; P = .84), but there were significantly more grade 4 adverse events in the immediate ART arm (102 in the immediate ART group vs 87 in the deferred ART group; P = .04).

Conclusions: Immediate ART initiation does not improve outcome in patients presenting with HIV-associated tuberculous meningitis. There were significantly more grade 4 adverse events in the immediate ART arm, supporting delayed initiation of ART in HIV-associated tuberculous meningitis. Clinical Trials Registration. ISRCTN63659091.

Publication types

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

MeSH terms

  • Adult
  • Alkynes
  • Anti-HIV Agents / administration & dosage*
  • Anti-HIV Agents / adverse effects
  • Anti-Inflammatory Agents / administration & dosage
  • Antiretroviral Therapy, Highly Active / adverse effects
  • Antiretroviral Therapy, Highly Active / methods*
  • Antitubercular Agents / administration & dosage
  • Benzoxazines / administration & dosage
  • Cyclopropanes
  • Dexamethasone / administration & dosage
  • Double-Blind Method
  • Female
  • HIV Infections / complications*
  • HIV Infections / drug therapy*
  • HIV Infections / mortality
  • Humans
  • Lamivudine / administration & dosage
  • Male
  • Placebos / administration & dosage
  • Time Factors
  • Treatment Outcome
  • Trimethoprim, Sulfamethoxazole Drug Combination / administration & dosage
  • Tuberculosis, Meningeal / complications*
  • Tuberculosis, Meningeal / drug therapy
  • Tuberculosis, Meningeal / mortality
  • Zidovudine / administration & dosage

Substances

  • Alkynes
  • Anti-HIV Agents
  • Anti-Inflammatory Agents
  • Antitubercular Agents
  • Benzoxazines
  • Cyclopropanes
  • Placebos
  • Lamivudine
  • Zidovudine
  • Dexamethasone
  • Trimethoprim, Sulfamethoxazole Drug Combination
  • efavirenz

Associated data

  • ISRCTN/ISRCTN63659091