CCR5
antagonists are one of 2 new antiretroviral drug classes to come on the market
recently, with the approval of Pfizer's maraviroc
(Selzentry) in August 2007. These agents work by blocking the CCR5 co-receptor,
one of 2 "doorways" HIV uses to enter host cells.
This
double-blind trial conducted in 12 countries (most outside North America and Europe)
included 116 treatment-experienced participants with CCR5-tropic HIV who had used
at least 3 classes of antiretroviral drugs and had HIV RNA >1000 copies/mL
despite stable HAART. The mean age was about 45 years, about three-quarters were
men, 68% were Caucasian, and 71% were Latino; 5% were coinfected with hepatitis
C virus (HCV). The mean baseline HIV viral load was about 4.5 log10 copies/mL,
and the mean baseline CD4 cell counts were 202 cells/mm3 in the 2 vicriviroc arms
and 226 cells/mm3 in the placebo arm.
Patients were randomly assigned to
receive 20 or 30 mg once-daily vicriviroc or placebo, in combination with a new
> 3-drug optimized background therapy (OBT) regimen that included a
ritonavir-boosted protease inhibitor. A prior Phase
II trial (ACTG5211) suggested that the 10 and 15 mg doses previously tested
were suboptimal. About 25% in the vicriviroc arms and 14% in the placebo arm started
enfuvirtide (Fuzeon; T-20) for
the first time, while 23-31% in the vicriviroc arms and 16% in the placebo arm
started darunavir (Prezista).
After 48 weeks, patients had the option to remain on open-label vicriviroc.
The
primary study endpoint in VICTOR-E1 was change in HIV RNA at week 48. Secondary
endpoints included proportions achieving viral load < 400 and < 50 copies/mL.
Results
•
85% and 88% of patients, respectively, in
the 20 and 30 mg vicriviroc arms completed the study, compared with 49% in the
placebo arm (which had a higher rate of discontinuation due to virological failure).
•
Mean HIV RNA declines at week 48 were 1.77
log10 in the vicriviroc 20 mg arm, 1.75 log10 in the vicriviroc 30 mg arm, and
0.79 log10 in the placebo arm.
•
In an intent-to-treat analysis, 56% of patients
in the 30 mg vicriviroc arm and 53% in the 20 mg arm achieved HIV RNA < 50
copies/mL, compared with 14% in the placebo arm (67%, 60%, and 26%, respectively,
< 400 copies/mL).
•
In a stratification by baseline viral load
? 100,000 copies/mL, the 30 mg dose was superior to the 20 mg dose or placebo,
with 33%, 17%, and 10%, respectively, achieving HIV RNA < 50 copies/mL.
•
There was no difference between the vicriviroc
dose arms in patients with baseline HIV RNA < 100,000 copies/mL (67%, 68%,
and 16%, respectively, achieving < 50 copies/mL)
•
Among participants who included boosted darunavir
(Prezista) in their background regimen, the rates of viral suppression < 50
copies/mL were 75%, 67%, and 33%, respectively.
•
Patients with more active drugs in their OBT
regimens were more likely to achieve HIV RNA < 50 copies/mL:
•
> 3 active agents: 71%, 83%, and
0%, respectively; •
1-2 active agents: 64%, 58%, and 23%, respectively; •
0 active agents: 29%, 12%, and 0%, respectively.
•
Rates of virological failure were13% in the
20 mg vicriviroc arm, 8% in the 20 mg arm, and 38% in the placebo arm.
•
Mean CD4 cell count increases at week 48 were
102, 134, and 65 cells/mm3, respectively.
•
There were no apparent dose-related or drug-related
toxicities.
•
Rates of serious adverse events were 12%,
14%, and 22%, respectively.
•
Most treatment-emergent adverse events - including
ALT and total bilirubin elevation -- were evenly distributed across the treatment
arms.
•
No new cases of cancer occurred while on vicriviroc,
but 1 person developed Hodgkin's lymphoma during the open-label continuation period.
•
Emergence of detectable dual/mixed or CXCR4-tropic
HIV occurred before week 8 in 83%, 50%, and 60% of participants, respectively
(more often dual/mixed than exclusively CXCR4-tropic).
•
However, emergence of dual/mixed/CXCR4-tropic
virus did not necessarily coincide with virologic failure.
Conclusion
Based
on these findings, the investigators stated, "Vicriviroc 30 or 20 mg once
daily plus ritonavir-containing OBT provided sustained viral suppression in treatment-experienced
subjects and increased CD4 cell counts regardless of the number of active drugs
in OBT."
They added that the 30 mg dose showed superior efficacy based
on the percentage of patients with full HIV RNA suppression and was well tolerated,
with "no clinically relevant safety differences noted between vicriviroc
and placebo." This dose is being used in ongoing Phase 3 trials.
"Vicriviroc,
a potent CCR5 antagonist, has strong potential as a new treatment option for HIV-infected
subjects," they concluded."
Montefiore
Med Ctr, Bronx, NY; Brazilmed Assistencia Medica e Pesquisa, Sao Paolo, Brazil;
Orlando Immunology Ctr, FL; St Michael's Med Ctr, Newark, NJ; Schering-Plough
Res Inst, Kenilworth, NJ.
2/5/08
Reference B
Zingman, J Suleiman, E DeJesus, and others. Vicriviroc, a Next Generation CCR5
Antagonist, Exhibits Potent, Sustained Suppression of Viral Replication in Treatment-experienced
Adults: VICTOR-E1 48-week Results. CROI 2008. Boston, MA. February 3-6, 2008.
Abstract 39LB.
CCR5
Antagonist Vicriviroc Shows Continued Benefits and Good Tolerability at 48 Weeks:
VICTOR-E1 Trial
