The Era of Direct-acting Antivirals Has Begun

The Beginning of the End for HCV?

Marie-Louise Vachon, M.D., M.Sc.; Douglas T. Dieterich, M.D.


Semin Liver Dis. 2011;31(4):399-409. 

In This Article

Danoprevir (RG7227/ITMN-191)

Danoprevir is a potent macrocyclic inhibitor of the HCV NS3/4A serine protease. In phase 1b studies in treatment naïve patients with HCV genotype 1, administration of danoprevir for 14 days was associated with a maximal median reduction of HCV RNA of 3.8 log10 in monotherapy and 5.7 log10 IU/mL in combination therapy with pegIFN and RBV.[22] In subsequent studies, danoprevir was boosted by ritonavir, a strong inhibitor of the CYP3A4 enzyme. A phase 1b study evaluated multiple ascending doses of ritonavir-boosted danoprevir in combination with pegIFN/RBV in 30 patients with HCV genotype 1 naïve to treatment.[23] More patients using boosted danoprevir (72%, 18/25 and 100%, 8/8 in the group receiving danoprevir 200 mg/ritonavir 100 mg twice daily) achieved undetectable HCV RNA (<15 IU/mL) at day 15 compared with patients who had previously received high-dose unboosted danoprevir (14%, 1/7) or placebo (20%, 1/5). This boosting allowed the use of a significantly lower dose of danoprevir, resulting in lower area under the curve (AUC) and maximum concentration (Cmax) of danoprevir. This reduced systemic exposure can improve the safety profile and reduce the probability of grade 4 ALT elevations, which had been seen with unboosted danoprevir at a dose of 900 mg twice daily.[24] Danoprevir/ritonavir is now being evaluated in several phase II clinical trials. A randomized, open-label study is evaluating SVR of danoprevir/ritonavir in combination with pegIFN/RBV in treatment of naïve patients with HCV genotype 1. Week 12 results of a substudy of 24 prior null responders treated with open-label danoprevir/ritonavir 100 mg/100 mg twice daily with pegIFN and RBV were recently presented.[25] Patients received 12 weeks of triple therapy after which they continued on pegIFN/RBV for a total of 48 weeks. At week 12, results showed a significant disparity between patients with HCV genotype 1a versus 1b. Fifty percent (50%) of patients with HCV genotype 1a achieved EVR versus 88% of those with HCV genotype 1b. Four of the eight patients with HCV genotype 1a experienced viral breakthrough with selection of the R155K mutation compared with 6% of patients with HCV genotype 1b.

A randomized open-label phase II study is evaluating SVR with danoprevir/ritonavir and RBV in combination with mericitabine (RG7128), a polymerase inhibitor, and/or pegIFN in patients with HCV genotype 1 who failed previous standard therapies. In this study, the six study arms contain RBV, but two of the six study arms are pegIFN-free.

A second phase II study, INFORM-SVR, is recruiting patients to evaluate the combination of danoprevir/ritonavir plus mericitabine with and without RBV in patients with HCV genotype 1. This is a pegIFN-free trial. In two arms, interferon-naïve patients will receive danoprevir 100 mg/ritonavir 100 mg twice daily with mericitabine 1000 mg twice daily with or without RBV for 12 weeks or 24 weeks. The third arm will enroll interferon-unable/intolerant patients who will receive an open-label combination of danoprevir/ritonavir/mericitabine plus RBV for 24 weeks. The combination of danoprevir/ritonavir with mericitabine looks promising and results of these phase II trials are awaited.


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