Antiviral activity and safety of aplaviroc with lamivudine/zidovudine in HIV-infected, therapy-naive patients: the ASCENT (CCR102881) study.
BACKGROUND
This Phase IIb study explored the antiviral activity and safety of the investigational CCR5 antagonist aplaviroc (APL) in antiretroviral-naive patients harbouring R5-tropic virus.


METHODS
One hundred and forty-seven patients were randomized 2:2:1 to one of two APL dosing regimens or efavirenz (EFV). All dosage arms were administered twice daily and in combination with lamivudine/zidovudine (3TC/ZDV; Combivir, COM). Efficacy, safety, and pharmacokinetic parameters were assessed.


RESULTS
This study was prematurely terminated due to APL-associated idiosyncratic hepatotoxicity. The primary endpoint of the study was the proportion of patients with plasma HIV-1 RNA <400 copies/ml who remained on randomized treatment through week 12. Of the 147 patients enrolled, 145 patients received one dose of treatment and were included in the intention-to-treat population. The proportion of patients with HIV-1 RNA <400 copies/ml at week 12 was 53%, 50% and 66% in the APL 600 mg twice daily, APL 800 mg twice daily, and EFV arms, respectively. Common clinical adverse events (AEs) were diarrhoea, nausea, fatigue and headache. APL demonstrated non-linear pharmacokinetics with high interpatient variability. In addition to the hepatic findings, there was an apparent dose-response relationship in the incidence of diarrhoea.


CONCLUSIONS
Whereas target plasma concentrations of APL were achieved, the antiviral activity of APL as the third agent in a triple drug regimen did not appear to be comparable to EFV in this treatment-naive patient population.
Currier
Judith
J
UCLA Center for Care, Los Angeles, CA, United States. JSCurrier@mednet.ucla.edu
Lazzarin
Adriano
A
Sloan
Louis
L
Clumeck
Nathan
N
Slims
Jihad
J
McCarty
Deb
D
Steel
Helen
H
Kleim
Jörg-Peter
JP
Bonny
Tab
T
Millard
Judith
J
D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001565:Benzoates / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D054659:Diketopiperazines; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D023581:HIV Fusion Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D013141:Spiro Compounds / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome; D015215:Zidovudine / Q000008:administration & dosage / Q000627:therapeutic use
D019380:Anti-HIV Agents; D001565:Benzoates; D054659:Diketopiperazines; D023581:HIV Fusion Inhibitors; D010879:Piperazines; D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; D019259:Lamivudine; D015215:Zidovudine; C499671:aplaviroc