CCR5 antagonists are a newly approved class of
antiretroviral agents used to treat HIV. These drugs prevent the virus from using
one of the 2 co-receptors (CCR5 and CXCR4) it requires to enter host cells.
HIV-1
interacts with a cell-surface receptor, primarily CD4, and through conformational
changes becomes more closely associated with the cell through interactions with
other cell-surface molecules, such as the chemokine receptors CXCR4 and CCR5.
CCR5
is present on a variety of immune cells, including both CD4 and CD8 T-cells. The
normal functions of CCR5 and the potential effects of inhibiting its activity
are not fully understood. Prior research has shown that people who have reduced
or absent CCR5 expression due to a natural genetic mutation known as delta 32
do not have serious immune system impairment, but seem to have some degree of
immune dysfunction as indicated, for example, by a higher risk of symptomatic
West Nile virus infection and a lower likelihood of clearing hepatitis C virus
(HCV).
The
study originally intended to enroll 40 coinfected patients with suppressed HIV
viral load (< 400 copies/mL) taking a HAART
regimen containing a ritonavir-boosted
protease inhibitor (PI) at baseline. The trial was closed after enrollment
of 28 participants (18 men, 10 women). Most (86%) were Caucasian, the median age
was 42 years, and the median CD4 cell count was 436 cells/mm3.
In this
randomized, double-blind, placebo-controlled trial, participants received the
experimental
CCR5 inhibitor vicriviroc at doses of 5, 10, or 15 mg or placebo for 28 days
in addition to their stable existing regimen.
Safety was the primary objective
of this study, and pharmacokinetics was a secondary objective. Clinical examination
and laboratory tests were conducted throughout the study. An intention-to-treat
analysis was performed including all randomized subjects with HCV RNA at all time
points as the primary parameter.
Results
•
No substantive changes from baseline in HCV
RNA levels were noted over the course of the study in patients receiving vicriviroc
or placebo.
•
HCV infection did not adversely affect HIV
suppression or CD4 cell counts in patients taking vicriviroc.
•
Adverse events were equally distributed in
the vicriviroc and placebo arms and were generally mild (e.g., headache, diarrhea).
•
Transient elevations of alanine aminotransferase
(ALT), aspartate aminotransferase (AST), or gamma-glutamyl transferase (GGT) occurred
in 4 patients (3 in vicriviroc arms, 1 in placebo arm).
•
2 of these elevations (1 in 10 mg vicriviroc
arm, 1 in placebo arm) were considered clinically significant.
•
Pharmacokinetic parameters (Cmax, Cmin, AUC)
of vicriviroc were dose-dependent and were comparable to those previously observed
in healthy HIV and HCV negative volunteers.
•
No vicriviroc dose adjustment was indicated
in HIV-HCV coinfected patients when used as part of a ritonavir-containing regimen.
Conclusion
The
investigators noted that this was the first study of a CCR5 antagonist in patients
with HIV-HCV coinfection.
They concluded that, "No clinically meaningful
changes in HCV viral load were observed in stable coinfected patients receiving
vicriviroc in combination with a ritonavir-containing PI regimen. Vicriviroc in
combination with background therapy was safe and well tolerated when administered
for 28 days."
These findings support continuation of an ongoing Phase
3 study testing 30 mg vicriviroc in both HIV monoinfected and HIV-HCV coinfected
HAART-experienced patients.
Univ.
Cologne, Germany; Univ. Kiel, Germany; Charité-Universitätsmedizin,
Berlin, Germany; Centre-CAP, Montpelleir, France; Saint Michael's Medical Center,
Newark, NJ; Schering-Plough Research Institute, Kenilworth, NJ.
2/15/08
Reference Gerd
Fatkenheuer, C Hoffmann, J Slim, and others. The Effect of Vicriviroc upon HCV
Viral Load in HIV/HCV-co-infected Patients Receiving a Ritonavir-containing Protease
Inhibitor Regimen. 15th Conference on Retroviruses and Opportunistic Infections.
Boston, MA. February 3-6, 2008. Abstract 1068.
Vicriviroc
Is Safe in HIV-HCV Coinfected Patients, but Does Not Show Activity against HCV
Results
