Issue: August 2015
August 14, 2015
4 min read

Recent Approval Holds Promise for Genotype 3, but Hurdles Anticipated

Issue: August 2015
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Genotype 3 accounts for 10% to 15% of patients with hepatitis C in the United States, but has been estimated to be the second most prevalent genotype around the world. We’ve learned more recently that genotype 3 is the most pathogenic genotype. There’s been much speculation about what gives genotype 3 this propensity to cause more rapidly progressive liver disease, with a focus on the tendency for patients with genotype 3 to have substantial amounts of fat deposition in the liver. This has been called viral steatosis by some authors, as opposed to metabolic steatosis often present in the population at large and in genotype 1. The steatosis in genotype 3-infected livers clears when you eradicate the virus. In patients with other genotypes, the fat does not clear because it’s not part of the viral infection.

In light of its recently acquired reputation for being the most difficult genotype to treat with direct-acting antiviral agents (DAAs), it is ironic that genotype 3 was always relatively responsive to interferon-based therapy, perhaps not quite as responsive as genotype 2 but certainly much more so than genotype 1. At the onset of the DAA era, early results suggested parity between genotypes 2 and 3 in terms of responsiveness to sofosbuvir (Sovaldi, Gilead Sciences) -based therapy, but this was dispelled by the phase 3 trials, which showed lower rates of sustained virologic response in genotype 3 patients than genotype 2 patients with sofosbuvir and ribavirin, especially when given for 12 weeks.

Patients with genotype 3 at the greatest disadvantage were those with cirrhosis, particularly those who had failed interferon therapy. These patients needed longer treatment durations and the standard approach to genotype 3 has become 24 weeks of sofosbuvir and ribavirin, which dramatically improved cure rates in those without cirrhosis to the 90% or higher level and close to that in treatment-naive patients with cirrhosis. Unfortunately, treatment-experienced cirrhotics were still at a major disadvantage with SVR rates around 60%.

It’s been clear that sofosbuvir and ribavirin alone, although a wonderful advance for genotype 3 patients, is not the end of the story. Just as we do for other genotypes, we want to have combinations of potent antivirals to treat this seemingly most refractory genotype, especially in cirrhotic patients.

The challenge has been that the inhibitors of other viral proteins, namely protease and NS5A inhibitors, have been developed to target genotype 1 and there are specific molecular differences between genotypes 1 and 3 that render these drugs variably less effective against genotype 3 than they are against genotype 1. Simeprevir (Olysio, Janssen), a protease inhibitor, and ledipasvir (Gilead Sciences), an NS5A inhibitor, do not have a high level of antiviral activity, and do not confer adequate response rates, in genotype 3.

Ira M. Jacobson

Daclatasvir (Daklinza, Bristol-Myers Squibb), which was the first-in-class NS5A inhibitor developed, was approved in Europe in 2014, and has finally been approved in the United States as of July 2015, specifically for use in genotype 3.

Studies showed 12 weeks of daclatasvir and sofosbuvir for genotype 3 results in SVR12 of well over 90% in non-cirrhotics, both treatment-naive and -experienced. But ALLY-3 showed SVR rates ranging between 58% and 69% in cirrhotics, which is no better than sofosbuvir/ribavirin for 24 weeks.

The registration trials for daclatasvir in genotype 3 have not included 24-week arms, but at the International Liver Congress 2015, very important insights into the potential efficacy for prolonging treatment duration were presented from real-world European studies. Hezode et al showed extension of daclatasvir and sofosbuvir to 24 weeks dramatically improved the response rates in genotype 3 cirrhotics to 88% SVR4.

For this reason, the EASL treatment guidelines recommend a 24-week course of daclatasvir/sofosbuvir, with ribavirin, for genotype 3 cirrhotic patients. The demonstrated SVR rates in the range of 90% have established this, for now, as the preferred interferon-free regimen in genotype 3 patients.


The recent approval of daclatasvir is an important advance in the U.S. for genotype 3 patients. The problem lies in the 24 week duration not having been studied in the registration trials. The FDA only approved 12 weeks in the package insert. It was apparently not feasible to incorporate real-world, non-randomized trial data from Europe into a package insert in the United States.

We eagerly await AASLD Guidance Panel recommendations. With EASL’s precedence, it’s widely hoped that this panel, too, will recommend a 24-week duration for cirrhotics, and that this will facilitate access to this regimen even though 12 weeks was recently identified as the stipulated dose in the U.S. package insert for the newly approved daclatasvir. For completeness, we should mention The BOSON study presented at EASL which showed that 12 weeks of peginteferon, ribavirin and sofosbuvir was superior to 24 weeks of sofosbuvir and ribavirin for genotype 3. Were it not for the approval of daclatasvir, clinicians would need to give serious consideration to this regimen for genotype 3 patients while we await the advent of pangenotypic NS5A inhibitors such as GS-5816, now in phase 3 trials, which will represent another step forward in the treatment of genotype 3. Even now, it would not be wrong to mention the option of interferon for the sake of complete disclosure to patients about their options, especially in cirrhotics if we have difficulties accessing 24 weeks of treatment.

With the major triumphs that were registered for genotype 1 in 2013 and 2014, the approvals of daclatasvir and the ombitasvir/paritaprevir/ritonavir regimen (Technivie, AbbVie) with ribavirin for genotype 4 are gratifying developments. The revolution in our ability to effectively treat an increasingly broad spectrum of patient characteristics as well as viral genotypes continues to evolve.

– Ira M. Jacobson, MD
Co-Chief Medical Editor
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