Early versus delayed antiretroviral therapy and cerebrospinal fluid fungal clearance in adults with HIV and cryptococcal meningitis

Clin Infect Dis. 2013 Apr;56(8):1165-73. doi: 10.1093/cid/cit019. Epub 2013 Jan 29.


Background: The burden of Cryptococcus neoformans in cerebrospinal fluid (CSF) predicts clinical outcomes in human immunodeficiency virus (HIV)-associated cryptococcal meningitis (CM) and is lower in patients on antiretroviral therapy (ART). This study tested the hypothesis that initiation of ART during initial treatment of HIV/CM would improve CSF clearance of C. neoformans.

Methods: A randomized treatment-strategy trial was conducted in Botswana. HIV-infected, ART-naive adults aged≥21 years initiating amphotericin B treatment for CM were randomized to ART initiation within 7 (intervention) vs after 28 days (control) of randomization, and the primary outcome of the rate of CSF clearance of C. neoformans over the subsequent 4 weeks was compared. Adverse events, including CM immune reconstitution inflammatory syndrome (CM-IRIS), and immunologic and virologic responses were compared over 24 weeks.

Results: Among 27 subjects enrolled (13 intervention and 14 control), [corrected] the median times to ART initiation were 7 (interquartile range [IQR], 5–10) and 32days (IQR, 28–36), respectively. The estimated rate of CSF clearance did not differ significantly by treatment strategy (-0.32 log10 colony-forming units [CFU]/mL/day±0.20 intervention and -0.52 log10 CFUs/mL/day (±0.48) control, P=.4). Two of 13 (15%) and 5 of 14 (36%) subjects died in the intervention and control arms, respectively (P=0.39). Seven of 13 subjects (54%) in the intervention arm vs 0 of 14 in the control arm experienced CM-IRIS (P=.002).

Conclusions: Early ART was not associated with improved CSF fungal clearance, but resulted in a high risk of CM-IRIS. Further research on optimal incorporation of ART into CM care is needed.

Clinical trials registration: NCT00976040.

Publication types

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

MeSH terms

  • AIDS-Related Opportunistic Infections / cerebrospinal fluid
  • AIDS-Related Opportunistic Infections / drug therapy*
  • AIDS-Related Opportunistic Infections / mortality
  • Adenine / analogs & derivatives
  • Adenine / therapeutic use
  • Adult
  • Amphotericin B / therapeutic use*
  • Anti-HIV Agents / therapeutic use
  • Antifungal Agents / therapeutic use*
  • Antiretroviral Therapy, Highly Active / adverse effects
  • Benzoxazines / therapeutic use
  • Colony Count, Microbial
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / therapeutic use
  • Emtricitabine
  • Female
  • Humans
  • Immune Reconstitution Inflammatory Syndrome / chemically induced
  • Male
  • Meningitis, Cryptococcal / cerebrospinal fluid
  • Meningitis, Cryptococcal / drug therapy*
  • Meningitis, Cryptococcal / mortality
  • Organophosphonates / therapeutic use
  • Survival Analysis
  • Tenofovir
  • Treatment Outcome


  • Anti-HIV Agents
  • Antifungal Agents
  • Benzoxazines
  • Organophosphonates
  • Deoxycytidine
  • Amphotericin B
  • Tenofovir
  • Emtricitabine
  • Adenine
  • efavirenz

Associated data

  • ClinicalTrials.gov/NCT00976040