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Vicriviroc: An OverviewVicriviroc is an oral CCR5 receptor antagonist in development by Schering-Plough. Vicriviroc is a novel entry and fusion inhibitor that has shown promise in the treatment of HIV patients who are resistant to enfuvirtide (Fuzeon) and other antiretrovirals. The US Food and Drug administration has granted fast-track approval status to vicriviroc.

Entry and fusion inhibitors act differently than other classes of anti-HIV drugs (e.g., protease inhibitors, nucleoside reverse transcriptase inhibitors) by preventing HIV from infecting and entering cells, rather than trying to eradicate HIV after the virus has infected a cell.

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.

The CCR5 receptor acts with the CD4 receptor on the surface of T cells to facilitate entry of HIV into cells. Because previous research has suggested that individuals who lack a functional CCR5 receptor are largely resistant to HIV infection, the CCR5 receptor has been a target of investigation in development of anti-HIV therapy.

 
 

A Phase II trial of vicriviroc in treatment-naive patients was discontinued in October 2005 because detectable viral levels returned in some patients taking the drug with lamivudine/zidovudine compared to the control group taking efavirenz and lamivudine/zidovudine. No significant adverse events contributed to the discontinuation. Patients in this study will remain on vicriviroc until alternate regimens are chosen with their physicians.

A second Phase II trial in treatment-experienced patients will continue. The manufacturer also plans to continue evaluating SCH-D in combination with other treatment regimens in treatment-naive and -experienced patients.

Phase I studies of SCH-D have evaluated 10 mg, 25 mg, and 50 mg tablets.

Researchers have evaluated the immunologic profiles of HIV-infected subjects following VCV treatment to assess its effect on peripheral lymphocyte populations. Complete differential blood counts, including absolute CD4 and %CD4 were measured in 282 HIV-infected subjects enrolled in 4 independent trials. Subjects received a range of VCV doses for 2-48 weeks, either as monotherapy or in combination with an optimized background or Combivir®.

Results:

BL differential blood counts and absolute and %CD4 were similar across studies. Change from BL in absolute CD4, %CD4, and WBC counts at 24 and 48 weeks are shown in the Table. There was no clinically significant impact on WBC,

lymphocytes, or neutrophils during follow-up. As expected in ARV-treated patients, there was a substantial and sustained improvement in CD4 with VCV; this was greater than was seen with control. There was no apparent increase in infections with VCV relative to control.

 

Mean change from BL at 24 and 48 weeks

VCV 5 mg*
VCV 10 mg*
VCV 15 mg*
Control
Week 24 Abs CD4
n=43 +98.4
n=47 +130.2
n=48 +143.9
n=46 +43.4
% CD4
+4.9
+5.8
+5.7
+3.8
WBC
+1.2
+0.25
+0.75
-0.1
Week 48
Abs CD4
n=25
+138.9
n=28
+191.5
n=32
+158.9
n=32
+36.6
% CD4
+3.2
+6.3
+5.2
+2.7
WBC
+1.8
+0.8
+1.2
+0.2
*or equivalent of 25, 50, 75 mg in a non-ritonavir-containing regimen

VCV was associated with a durable improvement in CD4. In this group of studies, VCV had no adverse effect on WBC counts in HIV-1 infected patients, and was not associated with an increased risk of infections.

Two-year Follow up of Treatment-experienced Patients on Vicriviroc

VCV demonstrated durable antiretroviral activity and CD4 response in treatment-experienced (TE) subjects at 48 weeks (Gulick, IAS 2007 abstract 1623). Researchers presented 2-year data for TE patients who received VCV and participated in a roll-over study.

HIV-1 infected subjects successfully completing the 48-week phase of ACTG 5211 could enter this open-label multicenter study and receive VCV 15 mg in addition to previously optimized background therapy (OBT) that included a ritonavir-boosted protease inhibitor.

Additionally, subjects with a tropism shift to R5/X4 virus with HIV RNA ?1 log10 below baseline and no decrease in CD4 count could enroll. We assessed change from baseline in HIV RNA and CD4 in subjects who had ?12 months follow-up, as well as new opportunistic infections (OIs); malignancies; seizures; and hepatotoxicity.

Results

Of 79 subjects entering the study, 54 had at least 12 months exposure to VCV. Data were available for 39 subjects (data pending for 15 ongoing subjects): mean treatment duration (from first dose in ACTG 5211 to last dose in the rollover protocol) was 103 weeks (range 49-145).

Median change in HIV RNA from baseline (ACTG 5211) was -2.2 log10; median change in CD4 count was +84 cells/mm3; 23/39 subjects (60%) had HIV-RNA <50 copies/mL and 28/39 (72%) had <400 copies/mL.

12 subjects discontinued: 2 due to adverse events, 6 for patient choice, 2 for administrative reasons, and 2 for virologic failure. 6 tropism shifts occurred during the study: 2 to X4 and 4 to R5/X4.

Other than pulmonary TB (n=1), no OIs, VCV-related hepatotoxicity, cardiovascular events, seizures, or new lymphomas (since February 2006) were reported.

The authors concluded that VCV, 15 mg qd, plus OBT was generally well tolerated and provided potent and durable antiretroviral activity.

These results represent the longest follow-up data available for a CCR5-containing regimen to date.