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


BACKGROUND
NCT00976040.
Department of Medicine, Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, and The Children’s Hospital of Philadelphia, Philadelphia, PA 19104-6021, USA. bisson@mail.med.upenn.edu
Gregory P
GP
Bisson
Mooketsi
M
Molefi
Scarlett
S
Bellamy
Rameshwari
R
Thakur
Andrew
A
Steenhoff
Neo
N
Tamuhla
Tumelo
T
Rantleru
Irene
I
Tsimako
Stephen
S
Gluckman
Shruthi
S
Ravimohan
Drew
D
Weissman
Pablo
P
Tebas
D017088:AIDS-Related Opportunistic Infections / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000401:mortality; D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000328:Adult; D000480:Alkynes; D000666:Amphotericin B / Q000627:therapeutic use*; D019380:Anti-HIV Agents / Q000627:therapeutic use; D000935:Antifungal Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D048588:Benzoxazines / Q000627:therapeutic use; D015169:Colony Count, Microbial; D003521:Cyclopropanes; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000068679:Emtricitabine; D005260:Female; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000139:chemically induced; D008297:Male; D016919:Meningitis, Cryptococcal / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000401:mortality; D063065:Organophosphonates / Q000627:therapeutic use; D016019:Survival Analysis; D000068698:Tenofovir; D016896:Treatment Outcome
D000480:Alkynes; D019380:Anti-HIV Agents; D000935:Antifungal Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D063065:Organophosphonates; D003841:Deoxycytidine; D000666:Amphotericin B; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine; C098320:efavirenz