Abstract & Commentary

Timing of Initiation of ART in Patients with TB Meningitis

By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.

Dr. Winslow is a speaker for Cubist Pharmaceuticals and GSK, and is a consultant for Siemens Diagnostics.

Synopsis: Two hundred fifty-three patients with HIV-associated tuberculous meningitis (TBM) were randomized to immediate vs. deferred ART. Immediate ART initiation did not improve outcome and was associated with more grade 4 adverse events.

Sources: Torok ME, Yen NT, Chau TT, et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)-associated tuberculous meningitis. Clin Infect Dis 2011;52:1374-1383.

A randomized, double-blind, placebo-controlled trial of immediate vs. deferred ART in 253 patients with HIV-associated TB meningitis was conducted to determine whether immediate ART reduced the risk of death. ARV drugs (AZT, 3TC, and efavirenz) were started either at study entry (n = 127) or 2 months after randomization (n = 126). All patients received standard antituberculosis treatment, adjunctive dexamethasone, and prophylactic trimethoprim-sulfamethoxazole, and were followed for 12 months. Seventy-six patients in the immediate arm and 70 patients in the deferred arm died within 9 months. There was no relationship between timing of ART and the time to a new AIDS event or death. Percentage of patients with serious adverse events (grade 3 or 4) was high in both arms (90% in the immediate and 89% in the deferred arm), but there were significantly more grade 4 adverse events in the immediate vs. deferred arm (102 vs. 87; P = 0.04)

Commentary

This study was conducted in Vietnam in collaboration with research teams from the United Kingdom and the Netherlands. The patients were young (median age, 28-29 years), were quite ill (many with focal neurologic findings), had low baseline CD4+ counts (median 39-44), and 35-37% had positive CSF AFB smears. The study conclusively demonstrated no association between immediate ART and improved survival of patients with HIV-associated TBM. However immediate ART was associated with a higher frequency of grade 4 adverse reactions, although an increase in neurologic events in the immediate ART group was not observed, possibly related to the use of adjunctive corticosteroids. The most common laboratory adverse event was hepatitis (grade 4, defined as serum transaminase > 5× upper limit of normal). HBV and HCV infection were both common in this population, but were equally prevalent in the immediate and deferred groups.

This study is important in that two studies presented recently as abstracts suggested a benefit of early ARV initiation in patients with pulmonary TB (not TBM) and CD4+ < 50.1,2 A study of patients with HIV-associated cryptococcal meningitis showed that early ART initiation was detrimental,3 but this latter study was conducted in Africa and there was little attempt to manage increased intracranial pressure. Bottom line from my perspective is that briefly deferring ART (for 2 months) in patients with HIV-associated TBM seems to be prudent and simplifies management of these very ill and complicated patients.

References

  1. Havlir D, et al. International randomized trial of immediate vs. early ART in HIV positive patients treated for TB. ACTG 5221 STRIDE study. Program and Abstracts 18th CROI 2011; abstract #38.
  2. Abdool-Karim S, et al. Optimal timing of ART during TB therapy: Findings of the SAPIT trial. Programs and Abstracts 18th CROI 2011; abstract #39LB.
  3. Makadzange AT, et al. Early versus delayed initiation of antiretroviral therapy in concurrent HIV infection and crypto-coccal meningitis in sub-saharan Africa. Clin Infect Dis 2010;50:1532-1538.