Short-Term Administration of the CCR5 Antagonist Vicriviroc to Patients With HIV and HCV Coinfection Is Safe and Tolerable

Department I of Internal Medicine, University of Cologne, Cologne, Germany.
JAIDS Journal of Acquired Immune Deficiency Syndromes (Impact Factor: 4.56). 10/2009; 53(1):78-85. DOI: 10.1097/QAI.0b013e3181bb28dc
Source: PubMed


CCR5 antagonists block HIV cell entry through competitive binding to the CCR5 receptor present on the surface of CD4(+) cells. The CCR5 receptor is also present on CD8(+) cells involved in clearing hepatitis C virus (HCV). The goal of the present study was to examine the short-term safety of a CCR5 antagonist, vicriviroc, in patients with HIV/HCV coinfection.
A randomized, double-blind trial was conducted in 28 HIV/HCV-coinfected subjects with compensated liver disease and plasma HIV RNA below 400 copies/mL. All subjects were receiving a ritonavir-enhanced protease inhibitor regimen, to which vicriviroc (5, 10, or 15 mg/day) or placebo was added for 28 days. Clinical and laboratory evaluations were performed 21 days beyond the treatment period.
Treatment with vicriviroc resulted in no clinically meaningful changes in HCV or HIV viral load or any immune parameters. Adverse events were equally distributed among placebo and vicriviroc groups. Transaminase elevations of grade 1 or more were reported as AEs in 1 subject receiving 10-mg vicriviroc and 1 placebo subject. Vicriviroc plasma concentrations were similar to those observed in healthy subjects.
Short-term treatment with vicriviroc as part of a ritonavir-containing protease inhibitor-based regimen was safe and well tolerated in HIV/HCV-coinfected subjects. HIV/HCV coinfection also did not affect vicriviroc pharmacokinetics.

6 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although HIV has become a treatable disease with near to normal life expectancy, the quest for the development of better tolerated drugs with simple dosing schedules and a high barrier to the emergence of drug resistance remains. Vicriviroc is a small-molecule chemokine receptor antagonist that inhibits the binding of R5-tropic HIV-1 to host cells at the CC-chemokine receptor 5 (CCR5) co-receptor, thus, preventing viral entry. CCR5 inhibitors are believed to possibly decrease inflammation from the immune system and thereby offer additional properties further to their antiretroviral efficacy. This review is based on a PubMed search covering the years 2005 - 2010 for pharmacokinetic, pharmacological and clinical data of vicriviroc. In this review, the pharmacokinetic, pharmacological and clinical data of vicriviroc are presented. Moreover, the potential role of vicriviroc in the growing HIV armamentarium is discussed. Vicriviroc is being developed to be administered in combination with a ritonavir-boosted protease inhibitor for patients with R5-tropic virus. Early clinical trials have established the safety of vicriviroc in both treatment-naive and -experienced R5-tropic HIV-1 infected individuals. Recently, two Phase III clinical trials in treatment-experienced patients failed to prove its superiority over available HIV medications. Phase III trials for treatment-naive patients are still under planning. Clearly, more favorable study results are needed to move vicriviroc into drug registration and approval.
    Expert Opinion on Drug Metabolism &amp Toxicology 09/2010; 6(9):1139-50. DOI:10.1517/17425255.2010.510833 · 2.83 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: To address the ability of a 24-week Maraviroc (MVC) intensification of a stable antiretroviral therapy (cART) to significantly increase the CD4 cell count slope. Methods: Patients were eligible if they had CD4 <350 cells/mm, a CD4 slope <50 cells/mm per year, and sustained plasma HIV-RNA <50 copies/mL over the last 2 years, while receiving a stable cART. Patients harboring pure X4-using viruses by a phenotypic tropism assay were excluded. MVC was added to cART for 24 weeks, at the recommended dosage per drug-drug interactions. The primary endpoint was a significant positive difference in CD4 slopes (with MVC- pre-MVC, paired t test). Results: Sixty patients (55 men), with median age 51 years, baseline CD4 238 cells/mm, and slope before intensification +14.1 cells/mm per year were included. CD4 nadir was <50/mm in 47% of the population. The full set of patients (N = 57) completed week 24, and the on-treatment patients (N = 48) did not discontinue MVC. The median CD4 slope difference from baseline was +22.6 cells/mm per year (P = 0.08) in full set and +22.6 cells/mm per year (P = 0.04) in on-treatment. Slope evolution was not different according to baseline tropism, CD4 nadir, or ongoing cART regimen. No drug-related severe adverse events were recorded during intensification. MVC plasma concentrations were significantly different depending on drug-drug interaction with ongoing cART regimen and tended to be correlated with CD4 cells increase. Conclusion: In this study, MVC intensification of stable cART over 24 weeks was able to enhance CD4 cell slopes in patients with prior insufficient immune restoration despite long-term virological control.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 09/2012; 61(5). DOI:10.1097/QAI.0b013e318273015f · 4.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: IL28B polymorphisms strongly predict spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection. A recent study proposed a 32-base pair deletion in the CC-chemokine receptor 5 (CCR5) gene (CCR5-Δ32) interacting with the IL28B polymorphisms to influence spontaneous HCV clearance. The aim of this study was to clarify the role of CCR5-Δ32 in treatment-induced clearance of chronic hepatitis C (CHC). A cross-sectional cohort of 813 Caucasian patients with CHC genotype 1 (365 responders and 448 non-responders) who had received standard of care dual therapy with interferon (IFN)-α and ribavirin (RBV) was genotyped for the CCR5-Δ32 and IL28B polymorphisms to examine their interaction with respect to treatment response. CCR5-Δ32 did not influence treatment-induced recovery to IFN-α/RBV in CHC, and did not improve prediction of sustained virological response in the context of the IL28B polymorphisms in a multivariate model. CCR5-Δ32 homozygotes were significantly more frequent in those with CHC than healthy controls in the European cohorts (2.9% vs 0.4%, P<0.0001), but not in Australians of European ancestry. In conclusion, CCR5-Δ32 does not influence treatment response in the context of IL28B polymorphisms. Although CCR5-Δ32 may affect viral clearance within closely controlled geographical and genetic environments, we found no effect in larger cohorts treated with dual therapy.
    Genes and Immunity 04/2013; 14(5):286-290. DOI:10.1038/gene.2013.15 · 2.91 Impact Factor
Show more