icon-    folder.gif   Conference Reports for NATAP  
 
  15th CROI
Conference on Retroviruses and Opportunistic Infections Boston, MA
Feb 3-6, 2008
Back grey_arrow_rt.gif
 
 
 
Vicriviroc in Combination Therapy With an Optimized Antiretroviral Regimen for Treatment-Experienced Subjects: The VICTOR-E1 Trial
 
 
  Reported by Jules Levin
CROI 2008, Boston
 
Barry Zingman1, Jamal Suleiman2, Edwin DeJesus3, Jihad Slim4, Carmen Mak5, Michael McCarthy5, Natalie Case5, and Lisa Dunkle5
1Montefiore Medical Center and the Einstein/Montefiore Center for AIDS Research, Bronx, NY, USA; 2Brazilmed Assistencia Medica e Pesquisa, Sao Paolo, Brazil; 3Orlando Immunology Center, Orlando, FL, USA;
4St. Michael`s Medical Center-Infectious Diseases, Newark, NJ, USA; and 5Schering-Plough Research Institute, Kenilworth, NJ, USA
 
AUTHOR CONCLUSIONS
· Vicriviroc (30 and 20 mg, QD) + OBT demonstrated superior virologic and immunologic efficacy compared with OBT alone in a ART-experienced population.
 
· This efficacy benefit was apparent regardless of number of active drugs in OBT.
 
· The vicriviroc 30 mg dose resulted in greater median Cmin when compared with the 20 mg dose.
 
· A vicriviroc Cmin >100 ng/mL had a noticeable association with improvement in virologic efficacy.
 
· Vicriviroc 30 mg showed superior results in advanced HIV-infected patients (baseline HIV RNA >100,000 copies/mL or 0-1 active drug in the OBT). - This superiority may have been due to the increased VCV exposure observed with the 30 mg dose.
 
· Emergence of detectable dual/mixed or X4-tropic HIV tended to occurring early and was not assoicated with virologic failure. - Early detection of X4 was likely due to pretreatment existence of undetectable minority strains.
 
· Greater increases in CD4 cell counts were observed with vicriviroc 30 mg and 20 mg.
 
· Vicriviroc's mechanism of action had no noticeable negative impact on immune restoration, as indicated by the lack of occurrence of AIDS-defining events.
 
· There were no clinically relevant safety differences between vicriviroc and the placebo groups.
 
· Vicriviroc (30 mg, QD) as part of a ritonavircontaining, PI-based regimen is now in Phase 3 clinical trials enrolling HIV monoinfected and HIV/HCV coinfected treatment-experienced patients.
 
Abstract Results
Background:
Vicriviroc (VCV) is a next-generation small molecule CCR5 antagonist, administered orally QD, now in worldwide Phase 3 development for treatment of HIV. This Phase 2 study determined the optimal dose for Phase 3 in combination with an optimized background antiretroviral regimen (OBT) containing a ritonavir (RTV)-boosted protease inhibitor (PI), based on efficacy, safety and durability of antiretroviral effect.
 
Methods: This was a multinational, randomized, doubleblind, placebo (PBO)-controlled trial comparing VCV 20 or 30 mg QD plus optimized background therapy (OBT) to placebo (PBO) plus OBT for 48 weeks. Eligible subjects were CCR5-tropic HIV-1-infected adults who had received 3 prior classes of antiretroviral therapy (ART) and had >/=1000 copies/mL plasma HIV RNA despite a current 3-drug ART regimen. Subjects with HBV or HCV coinfection were allowed; prior seizure disorder or malignancy was excluded. OBT could include any available ART except efavirenz, including those on EAPs.
 
Results: 116 subjects were randomized 1:1:1 to VCV 20 mg, 30 mg or PBO QD, administered with a new OBT. Mean age was 45 years: 77% were male; 68% white, 17% black, 72% Latino. Mean plasma HIV RNA was 4.5 log10 copies/mL and CD4 count was 210 cells/mL. 51% had an AIDS-defining event prior to study; 6 (5%) were HCV coinfected. OBT included 2 active drugs in 43% of subjects; 27 (23%) received darunavir. Two never received study drug, 21 (18%) discontinued prematurely due to virologic failure (14 on PBO), and 2 discontinued due to adverse events, neither attributable to study drug.
 
At 24 weeks (N=91), mean decline in HIV RNA was -2.04, -2.04 and -0.96 log10 in the 3 groups, respectively (p<0.001, active vs. PBO).
 
Percent with HIV RNA <400 copies were 75%, 72% and 34% (p<0.01) and <50 copies were 58%, 64% and 26% (p<0.01) in the 3 groups, respectively.
 
Mean CD4 counts rose 100, 94 and 56 cells/mL in the 3 groups, respectively (p=0.15). No toxicities or signals of safety issues were observed.
 
Conclusions:
VCV at 20 and 30 mg once daily demonstrated superior antiviral efficacy over optimized ART alone. Virologic benefit was achieved even when OBT contained >2-3 active drugs; there was no geographic difference in efficacy. The most stringent criteria of efficacy favored VCV 30 mg QD. No clinically significant differences in the safety profile between VCV and PBO groups emerged in this study, including hepatotoxicity, opportunistic infections, malignancies or other conditions. Efficacy and safety supported 30 mg once daily for Phase 3 studies. Forty-eight week results will be available.
 
Introduction

· Vicriviroc (VCV) is a next-generation extracellular inhibitor of HIV infection designed to block entry of infectious virions into uninfected CD4 cells via antagonism of the CCR5 co-receptor (CCR5 antagonist).1
 
· VCV plasma concentrations are increased 2-6 fold by CYP3A inhibitors, including ritonavir.2
 
· VCV plasma half-life of >24 hours allows for once-daily dosing.3
 
· VCV may be taken with or without food.4

 
· VCV has demonstrated potent and durable antiretroviral activity in CCR5-tropic ART-experienced patients.5
 
METHODS
VICTOR-E1 is a multicenter, multinational, randomized, Phase 2b study comparing VCV 20 and 30 mg QD plus optimized background therapy (OBT) to placebo plus OBT.
 

Figure1Design-1.gif

· Primary endpoint: log10 plasma HIV RNA change from baseline at Week 48
 
· Key secondary endpoints
- Proportion of subjects with >/=1.0 log10 change from baseline in HIV RNA at 48 weeks
- Proportion of subjects with HIV RNA <400 copies/mL and <50 copies/mL at 48 weeks
- Time to confirmed virologic failure, defined as either failure to experience HIV RNA decline of >/=0.5 log10 by Week 4 (time to failure = 0) or rebound of HIV RNA to within 0.5 log10 of baseline at any time after maximum suppression
- Interim analyses after 12 and 24 weeks of treatment · After 48 weeks, subjects were to continue on VCV 30 mg QD plus OBT
 
Entry Criteria
· CCR5-tropic virus only
· Triple-class experienced HIV+ patients
· 31 reverse transcriptase resistance mutation
· 31 primary protease inhibitor resistance mutation
· HIV RNA 31000 copies/mL
· On a stable antiretroviral regimen for 36 weeks prior to screening (38 weeks prior to randomization)
· Acceptable laboratory parameters
· Hepatitis B or C coinfection allowed with stable disease and acceptable liver enzymes. Liver enzymes within the range of inclusion criteria: AST (SGOT) and ALT (SGPT)  
Exclusion Criteria
· Recurrent seizures, or CNS condition that may predispose to seizure
· History of prior malignancy (except resolved Kaposi's sarcoma of the skin or fully resected basal cell carcinoma)
· Active untreated AIDS-defining opportunistic infections
 
Statistical Considerations
· Planned enrollment of approximately 120 subjects randomized in a 1:1:1 ratio (20 mg vicriviroc: 30 mg vicriviroc: placebo)
- 90% power to detect a difference of at least 0.7 log10 HIV RNA copies/mL, assuming a pooled standard deviation of 0.9 log10 HIV RNA copies/mL · Analysis of primary efficacy variable (change from baseline in log10 HIV RNA at Week 48) using an ANOVA model that adjusts for treatment and stratification factors
- Stratification: baseline HIV RNA · Time to virologic failure and time to AIDS-defining events were analyzed using the stratified log-rank test
 
RESULTS
 

Brazil-2.gif

Disposition-3.gif

HIV-4.gif

· Sharp initial decline in HIV RNA in each arm, with virologic nadir by Week 4 for PBO arm, Week 12 for the VCV-containing arms.
 
· Loss in mean virologic suppression after Week 24 in the VCV and PBO arms (+0.29 log10 for VCV 30 mg, +0.31 log10 for VCV 20 mg, and +0.16 log10 for PBO) suggests that the decline in virologic suppression is primarily due to a gradual failure of the OBT.

ITT-5.gif

Copie-6.gif

TimeTLOVR-7.gif

· Most patients experiencing virologic failure with VCV had an initial response.
- The number failing to exhibit a 0.5 log10 reduction in HIV RNA at Week 4 was 1 (3%), 2 (5%) and 3 (9%) in the VCV 30 mg, VCV 20 mg and placebo arms, respectively.
- Rebounds tended to occur in patients who exhibited HIV RNA <400 copies/mL by Week 12 but did had no further virologic suppression.

Darunavir-8.gif

· For the entire population and in each subgroup, the VCV-containing arms demonstrated a superior virologic response compared with placebo. - Vicriviroc showed a trend to superiority even when the OBT contained 3 active drugs.
 
· The 30 mg VCV arm showed a trend to superiority compared with the 20 mg VCV arm in more advanced HIV-infected population.
- Patients with HIV RNA 3100,000 copies/mL.
- Patients with 0-1 active drugs in their OBT.

VrioiLogic-9.gif

· VCV plasma concentrations >100 ng/mL are more frequently achieved with the 30 mg dose.
- The vicriviroc 30 mg median Cmin was 202 ng/mL, compared with 141 mg/nL for the 20 mg dose.
 
· These consistent minimum concentrations >100 ng/mL are closely associated with virologic suppression, particularly by the most stringent <50 copies/mL criteria.
- Cmin highly correlates with total vicriviroc exposure (area under the curve).
 
· The pharmacokinetic-pharmacodynamic results may underlie the superior performance of the vicriviroc 30 mg dose in this trial's more advanced HIV-infected population.

DMX-10.gif

· This graph includes patients with detectable DM/X4 virus.
- The occurrence of DM/X4 variants at <8 weeks was 30 mg 10/12 (83%), 20 mg 4/8 (50%), PBO 3/5 (60%).
- Early detection of changes in coreceptor use are most likely due to the existence of undetectable minor CXCR4-using HIV strains (exclusively X4 or dual/mixed tropic) in patients' prescreening viral population.6
 
· Detection of DM/X4 variants was not linked to virologic failure.
 
SAFETY - Adverse Events

Tabl5-11.gif

TeimStudy-12.gif

LiverOBT-13.gif

REFERENCES
 
1. Strizki JM, Tremblay C, Xu S, et al. Discovery and characterization of vicriviroc (SCH 417690), a CCR5 antagonist with potent activity against human immunodeficiency virus type 1. Antimicro Agents Chemother. 2005;49:4911-4919.
2. Sansone A, Keung A, Tetteh E, et al. Pharmacokinetics of vicriviroc are not affected in combination with five different protease inhibitors boosted by ritonavir. In: Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections. Denver, CO, Feb. 5-8, 2006. Abstract 582.
3. Seiberling M, Kraan M, Keung A, et al. Similar increase in SCH 417690 plasma exposure with coadministration of varying doses of ritonavir in healthy volunteers. In: Program and abstracts of the 6th International Workshop on Clinical Pharmacology of HIV Therapy, Quebec City, Que., Canada, Apr. 28-30, 2005. Amsterdam: Virology Education, 2005. Abstract 6.4.
4. Sansone A, Keung A, Caceres M, et al. Effect of food on bioavailability of SCH 417690 in healthy volunteers. In: Programs and abstracts of the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, December 16-19, 2005, Washington, DC. Abstract A-1200.
5. Gulick RM, Su Z, Flexner C, et al. Phase 2 study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-infected, treatment-experienced patients: AIDS clinical trials group 5211. J Infect Dis. 2007;196:304-312.
6. Westby M, Lewis M, Whitcomb J, et al. Emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1- infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir. J Virol. 2006;80:4909-4920.