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ABSTRACT & COMMENTARY

Direct-acting antivirals for hepatitis C show promise

March 1, 2013
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By Dean L. Winslow, MD, FACP, FIDSA, Chairman, Department of Medicine, Santa Clara Valley, Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.

Dr. Winslow is a consultant for Siemens Diagnostic.

Synopsis: Gane et al found that sofosbuvir (nucleotide inhibitor of the NS5B HCV RNA-dependent RNA polymerase) plus ribavirin (RBV) showed efficacy in previously untreated patients with HCV genotype 1, 2, or 3 infection. Poordad et al found that ABT-450 (a HCV NS3 protease inhibitor) plus ABT-333 (a non-nucleoside NS5B polymerase inhibitor) showed efficacy in patients with HCV genotype 1 infection.

Sources: Gane EJ, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. New Eng Jrl Med 2013;368:34-44. Poordad F, et al. Exploratory study of oral combination antiviral therapy for hepatitis C. New Eng Jrl Med 2013;368:45-53.

Gane et al conducted a randomized open label trial of 40 patients with HCV genotype 2 or 3 infection which evaluated sofosbuvir 400 mg once daily plus ribavirin (RBV) for 12 weeks. Ten were treated without pegylated interferon (IFN) and 30 received sofusbuvir plus RBV for 12 weeks along with IFN for 4, 8, or 12 weeks. All of these patients had sustained virologic response (SVR) at 24 weeks. In addition, 35 patients with HCV genotype 1 infection were treated sofosbuvir plus RBV as well. There were 21/25 previously untreated patients (84%) and 1/10 (10%) of genotype 1 patients with no response to previous therapy with IFN plus RBV had SVR at 24 weeks. Adverse effects were mild in patients not treated with IFN and appeared to be largely attributable to RBV.

Poordad et al conducted a 12-week phase 2a open label study of HCV genotype 1 infected patients without cirrhosis. All patients received ABT-333 400 mg BID plus RBV 1000-1200 mg daily. Groups 1 and 2 included previously untreated patients with group 1 receiving ABT-450 250 mg plus ritonavir 100 mg. Group 2 received ABT-450 150 mg with ritonavir. Group 3 included patients who had demonstrated either a null or partial response to previous therapy with IFN+RBV and received ABT-450 150 mg plus ritonavir. Overall, 17/19 (89%) group 1 patients had an extended virologic response (undetectable HCV RNA at 12 weeks); 11/14 (79%) group 2 patients and 8/17 (47%) group 3 patients had SVR 12 weeks after completion of therapy. Adverse events included abnormal LFT’s, fatigue, nausea, headache, dizziness, insomnia, pruritus, rash, and vomiting. They were generally mild-moderate and did not appear to be dose-related.

Commentary

While the use of newer pegylated IFN’s plus weight-based RBV has modestly increased the efficacy of treatment for HCV infection, response rates remain low for HCV genotype 1 infection and patients co-infected with HIV. Also, treatment generally needs to be given for 48 weeks and side effects of IFN-based regimens are considerable with many patients unable to complete their planned courses of treatment.

In the past few years several pharmaceutical companies have made steady progress discovering and developing direct-acting antivirals (DAA’s) for HCV infection. HCV possesses a serine protease encoded by the NS3-4A region of the HCV genome, and a HCV RNA-dependent RNA polymerase encoded by NS5B. HCV protease has proven to be a somewhat difficult target for which to design inhibitors (compared to the HIV aspartyl protease) but persistence has paid off and now a number of potent, orally bioavailable small molecule HCV PI’s are entering late stage clinical trials. Similarly both nucleoside/nucleotide analogue competitive inhibitors and non-nucleoside allosteric inhibitors of the HCV polymerase have reached clinical development. Lastly, inhibitors of the NS5A replication complex have been identified and are in clinical trial (but are not discussed in this review).

The small open-label trials presented here demonstrate that these new DAA’s are potent and clinically effective. At least in treatment-naïve patients with HCV, treatment courses consisting of oral small molecule drugs administered for as little as 12 weeks without IFN appear to be close on the horizon. It should be noted that the design of the two trials reported here also used RBV, which likely caused many of the side effects seen. It is conceivable that some combinations of these newer DAA’s might someday make cure of HCV possible without IFN or RBV. Stay tuned!