Data from a new clinical trial have shown a 30 mg/day dosage of vicriviroc to be safe and effective after 48 weeks of use in treatment-experienced patients. These results, presented on Monday to the Fifteenth Conference on Retroviruses and Opportunistic Infections in Boston, corroborate the 48-week data on lower-dose vicriviroc from ACTG 5211 (http://www.aidsmap.com/en/news/EC706770-B3EF-4B02-81BD-8A3784614CD3.asp) reported at last year's IAS.
Earlier reports – the ACTG 5211 trial
Vicriviroc is a CCR5 inhibitor being developed by Schering Plough. Results reported to date have been drawn from ACTG 5211, an ongoing phase II clinical trial in treatment-experienced patients. This trial is planned to run for five years; 48-week data has demonstrated significant virologic efficacy and safety at vicriviroc dosages of 10 mg and 15 mg daily. (A 5 mg arm was discontinued early due to poor response.) The main concern to date has been eight reported cases of malignancies (cancers) in the vicriviroc study arms, as compared to two patients on placebo. However, the relationship between vicriviroc and the incidents of cancer is still uncertain due to the relatively small number of cases.
New data from CROI – the VICTOR-E1 trial
VICTOR-E1 is a randomised, double-blind clinical trial of vicriviroc being conducted across twelve countries. All VICTOR-E1 participants were treatment-experienced with three or more classes of antiretrovirals, with at least one confirmed resistance mutation to both the protease inhibitor (PI) and nucleoside analogue drug classes. At baseline, all 116 participants had HIV viral loads of at least 1000 copies/ml despite having been on a stable ART regimen for at least six months. All also showed purely R5-tropic HIV by the Trofile assay.
Participants received a new, PI-based, ritonavir-boosted optimised background therapy (OBT) combination consisting of at least three drugs. They were randomised to one of three treatment arms: OBT plus placebo, OBT plus 20 mg vicriviroc (VCV) once daily, or 30 mg VCV once daily. Participant characteristics were similar across the study arms: most were male (78%) and white (68%). Thirty-two percent were from North America and Europe, and 68% from Latin America and elsewhere. Five percent were co-infected with hepatitis C (HCV).
By intent-to-treat analysis, results at 48 weeks were as follows:
| VCV 30 mg daily | VCV 20 mg daily plus OBT (n=40) | OBT plus placebo (n=37 randomised, n = 35 treated) | |
| Baseline HIV RNA | 4.5 log10 | 4.5 log10 | 4.6 log10 |
| Baseline CD4 cell count | 202 cells/mm3 | 202 cells/mm3 | 226 cells/mm3 |
| Completed 48 weeks | 33 (85%) | 35 (88%) | 18 (49%) |
| HIV RNA | 22 (56%) (p=.0002) | 21 (52%) (p=.0004) | 4 (14%) |
| Mean HIV RNA decline | -1.77 log10 (p=.0017) | -1.75 log10 (p=.0026) | -0.79 log10 |
| Mean CD4 cell increase | +102 cells/mm3 (95% CI: -28.1, +103; p=0.26) | +134 cells/mm3 (95% CI: +3.6, +135; p=.04) | +65 cells/mm3 |
| Virologic failure | 5 (18%) | 3 (8%) | 14 (40%) |
| Emergent detectable dual/mixed/X4 virus | 10/12 (83%) | 4/8 (50%) | 3/5 (60%) |
| Grade 3 or 4 adverse events | 8/39 (21%) | 8/40 (20%) | 7/35 (20%) |
Emergence of detectable X4-tropic virus occurred mostly in the first eight weeks of treatment and did not necessarily coincide with virologic failure.
Vicriviroc appeared to have an additional virologic benefit even in participants with a higher number of active drugs in their background combination. (The number of "active drugs" was estimated using an overall susceptibility score (OSS), a scoring system based on an algorithm from Monogram Biosciences. Each drug in the OBT was counted as "active" only if it displayed no evidence of reduced efficacy based on phenotypic and genotypic information.) Virologic success (HIV RNA
| HIV RNA | VCV 30 mg daily | VCV 20 mg daily plus OBT | OBT plus placebo |
| Baseline viral load ≥ 100,000 copies/mL | 4/12 (33%) | 2/12 (17%) | 1/10 (10%) |
| Baseline viral load | 18/27 (67%) | 19/28 (68%) | 4/25 (33%) |
| Darunavir-containing OBT | 9/12 (75%) | 6/9 (67%) | 2/6 (33%) |
| 0 active drugs in OBT | 2/7 (29%) | 1/8 (12%) | 0/7 (0%) |
| 1-2 active drug in OBT | 14/22 (64%) | 15/26 (58%) | 5/22 (23%) |
| ≥3 active drugs in OBT | 5/7 (71%) | 5/6 (83%) | 0/6 (0%) |
The likelihood of suppression was related to minimum vicriviroc concentration: those with minimum concentrations less than 100 ng/ml were significantly more likely to be suppressed.
Conclusions and ongoing trials
The presenter concluded that vicriviroc in combination with optimised background therapy was significantly superior to OBT alone in this ART-experienced population, that added benefits were seen regardless of the number of active drugs in the OBT, and that there were "no clinically relevant safety differences observed" between vicriviroc and placebo.
Schering will continue to study vicriviroc at a 30 mg, once daily dose in phase III trials, several of which are already enrolling. These trials will investigate a variety of patient populations, including treatment-experienced patients with R5-tropic virus (studies P04405 and P04889), dual/mixed tropic (R5/X4) virus (study P05057). Another phase II/III trial (study P04875) will examine vicriviroc in combination with ritonavir-boosted atazanavir in a nucleoside-sparing regimen in treatment-naive patients.
References:
Zingman B et al. Vicriviroc, a next generation CCR5 antagonist, exhibits potent, sustained suppression of viral replication in treatment-experienced adults: VICTOR-E1 48-week results. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 39LB, 2008.
Zingman B et al. Vicriviroc in combination therapy with an optimized ART regimen for treatment-experienced subjects: VICTOR-E1. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, poster abstract 795, 2008.