Cobicistat-boosted darunavir in HIV-1-infected adults: week 48 results of a Phase IIIb, open-label single-arm trial.
BACKGROUND
Cobicistat is an alternative pharmacoenhancer to ritonavir. In healthy volunteers, darunavir exposure was comparable when darunavir 800 mg once daily was co-administered with cobicistat 150 mg once daily (as single agents or a fixed-dose combination) vs. with ritonavir 100 mg once daily.


METHODS
This 48-week, Phase IIIb, single-arm, US multicenter study (NCT01440569) evaluated safety, efficacy and pharmacokinetics of darunavir/cobicistat 800/150 mg once daily (as single agents) plus two investigator-selected nucleoside/tide reverse transcriptase inhibitors (N[t]RTIs) in HIV-1-infected adults. Patients had no darunavir resistance-associated mutations (RAMs), plasma viral load (VL) ≥1000 HIV-1 RNA copies/ml, eGFR ≥80 ml/min and genotypic sensitivity to the two N[t]RTIs. The primary endpoint was any treatment-emergent grade 3 or 4 adverse events (AEs) through Week 24.


RESULTS
The majority of the 313 intent-to-treat patients were treatment-naïve (295/313; 94%), male (89%), White (60%) and received a tenofovir-based regimen (99%). Median baseline VL and CD4(+) count overall were 4.8 log10 HIV-1 RNA copies/ml and 361 cells/mm(3), respectively. Overall, 86% of patients (268/313) completed the study. The majority of discontinuations were for AEs (15/313; 5%). The incidence of treatment-emergent grade 3 or 4 AEs regardless of causality was 6% through Week 24 and 8% through Week 48. Most common AEs through Week 48 were diarrhea (27%) and nausea (23%), which were grade 1 or 2 in severity. Week 48 virologic response rates (% with VL <50 HIV-1 RNA copies/ml; Snapshot analysis) were 81% overall and 83% in treatment-naïve patients; median increases in CD4(+) count at 48 weeks were 167 and 169 cells/mm(3), respectively. Of 15/313 patients who met the criteria for resistance analysis, one developed a darunavir RAM as a mixture with wild-type (I84I/V), without phenotypic resistance to darunavir. The mean population pharmacokinetic-derived darunavir areas under the plasma concentration-time curve were 102,000 overall and 100,620 ng•h/ml in treatment-naïve patients. No clinically relevant relationships were seen between darunavir exposure and virologic response, AEs or laboratory parameters.


CONCLUSIONS
Darunavir/cobicistat 800/150 mg once daily was generally well tolerated through Week 48, with no new safety concerns. Pharmacokinetics, virologic and immunologic responses for darunavir/cobicistat were similar to previous data for darunavir/ritonavir 800/100 mg once daily.
The Miriam Hospital, Alpert Medical School of Brown University, 164 Summit Avenue, Providence, RI 02906 USA.
Karen
K
Tashima
Gordon Crofoot Research, Houston, TX USA.
Gordon
G
Crofoot
Janssen Research & Development LLC, Titusville, NJ USA.
Frank L
FL
Tomaka
Janssen Research & Development LLC, Titusville, NJ USA.
Thomas N
TN
Kakuda
Janssen Research & Development, Beerse, Belgium.
Anne
A
Brochot
Janssen Infectious Diseases BVBA, Beerse, Belgium.
Tom
T
Van de Casteele
Janssen Infectious Diseases BVBA, Beerse, Belgium.
Magda
M
Opsomer
Gilead Sciences, Foster City, CA USA.
William
W
Garner
Gilead Sciences, Foster City, CA USA.
Nicolas
N
Margot
Gilead Sciences, Foster City, CA USA.
Joseph M
JM
Custodio
Gilead Sciences, Foster City, CA USA.
Marshall W
MW
Fordyce
Gilead Sciences, Foster City, CA USA.
Javier
J
Szwarcberg
Cobicistat; Darunavir; Efficacy; Pharmacokinetics; Safety; Virology