Low Doses of CCR5 Antagonist Vicriviroc Do Not Suppress HIV as well as Efavirenz (Sustiva) in Treatment-naive Patients; New Study Underway

By Liz Highleyman

Schering-Plough's experimental CCR5 antagonist vicriviroc is the second drug in its class to reach advanced clinical trials; Pfizer's maraviroc (Selzentry) was approved by the U.S. Food ad Drug Administration in August 2007.

In the October 15, 2008 Journal of Infectious Diseases, Raphael Landovitz of the Schering-Plough Research Institute and colleagues presented findings from a Phase II dose-finding study of vicriviroc in treatment-naive HIV patients with CCR5-tropic HIV.

CCR5 inhibitors work by blocking one of the 2 cell surface co-receptors -- CCR5 and CXCR4 -- that HIV uses, along with the CD4 receptor, to enter cells. A majority of previously untreated people with early-stage HIV infection have predominantly CCR5-tropic virus, but others have CXCR4-tropic HIV, virus that can use either co-receptor (dual-tropic), or a mixed population of viral strains. CCR5 antagonists only work in people with CCR5-tropic HIV.

A total of 92 study participants were enrolled between July 2004 and May 2005. Most (80%) were men, 86% were white, the median baseline CD4 cell count was 290 cells/mm3, and the median viral load was 4.79 log10 copies/mL (36% had HIV RNA > 100,000 copies/mL).

The double-blind, placebo-controlled trial began with a 14-day comparison of 3 once-daily doses of vicriviroc (25 mg, 50 mg, and 75 mg) with placebo. After 14 days of vicriviroc monotherapy, 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), zidovudine (AZT; Retrovir) and lamivudine (3TC; Epivir) were added in the vicriviroc arms. Control subjects receiving placebo were treated with efavirenz (Sustiva) plus zidovudine/lamivudine. The planned treatment duration was 48 weeks.

Results

• After 14 days of once-daily vicriviroc monotherapy, mean HIV viral load decreased from baseline by:

• 0.07 log10 copies/mL in the placebo arm;

• 0.93 log10 copies/mL in the 25 mg vicriviroc arm;

• 1.18 log10 copies/mL in the 50 mg vicriviroc arm;

• 1.34 log10 copies/mL in the 75 mg vicriviroc arm (P< 0.001 for each vicriviroc arm vs placebo).

• The combination therapy portion of the study was halted due to increased rates of virological failure in the vicriviroc 25 mg/day arm (relative hazard 21.6) and the vicriviroc 50 mg/day arm (relative hazard 11.7) compared with the control arm.

• Vicriviroc was well tolerated overall.

• No treatment-limiting toxicities were observed.

• There was 1 discontinuation due to adverse events (altered mental status, nausea and vomiting) and 1 grade 4 event (anemia), both thought to be unrelated to vicriviroc.

• No significant differences in adverse events, laboratory findings, electrocardiogram findings, or other safety parameters were observed between study arms.

• Seizures, QTc prolongation (a type of heart rhythm abnormality), and grade 3/4 elevations in transaminase (liver enzyme) levels were not observed.

• No treatment-emergent malignancies were reported in vicriviroc-treated patients.

• Dual/mixed-tropic HIV was detected in 7 patients and CXC4-tropic virus in 1 person.

Based on these findings, the study authors wrote, "this study demonstrated that, at the doses studied, vicriviroc possesses potent antiviral activity and is associated with a dose-related increase in CD4 cell count. Vicriviroc was safe and well tolerated."

However, they added, "At once-daily doses of 25 mg and 50 mg, vicriviroc plus dual NRTI therapy was not as effective as efavirenz plus dual NRTI therapy for viral suppression."

"Despite initial robust decreases in the HIV-1 RNA loads and increases in CD4 cell counts in all vicriviroc arms during the 2-week monotherapy lead-in period, persistent or recurrent detectable viremia was found in the combination-therapy arms containing lower-dose vicriviroc and prompted early termination of the study," they elaborated in their discussion.

"Subjects with virological failure appeared to segregate into 2 subsets: those experiencing virological failure coincident with a shift in coreceptor tropism use and those with virological failure in the absence of a tropism shift. Antiretroviral adherence, as measured by pill count and patient self-report, did not account for the virological failures," they continued.

Lack of a plateau in the dose response and wide variability in the inhibitory concentration suggest that higher doses of vicriviroc may be required to maximize virological suppression, they said. However, researchers have been reluctant to study higher doses due to seizures at high plasma concentrations in animal studies. No neurotoxicity has been observed, however, in human clinical trials.

In conclusion, the authors wrote, "Optimization of the role of vicriviroc in combination antiretroviral therapy and characterization of resistance mechanisms require further study."

In April, Schering-Plough announced the initiation of a new Phase II trial of vicriviroc in treatment-naive HIV patients. In this study, vicriviroc will be administered as a single once-daily 30 mg tablet in combination with the ritonavir-boosted protease inhibitor atazanavir (Reyataz); a control group will receive tenofovir (Viread) plus emtricitabine (Emtriva) -- the 2 drugs in the Truvada combination pill -- with boosted atazanavir. Further information about the trial is available online.

Schering-Plough Research Institute, Kenilworth, NJ; Department of Medicine, University of Ottawa, Ottawa, Canada; Second Department of Medicine, University of Schleswig-Holstein, Campus Kiel, and Department of Internal Medicine, University of Cologne, Cologne, Germany; Division of Infectious Diseases, University Hospital Zurich, Zurich, Switzerland.

10/14/08

Reference
RJ Landovitz, JB Angel, C Hoffmann, and others. Phase II study of vicriviroc versus efavirenz (both with zidovudine/lamivudine) in treatment-naive subjects with HIV-1 infection. Journal of Infectious Diseases 198(8): October 15, 2008. (Abstract).