HCV Treatment: What Can I Do Now? What's Coming Next?

Rowen K. Zetterman, MD


August 24, 2015

In This Article

Emerging Drugs


An investigational NS5A inhibitor, daclatasvir[18,19] has a high potency for suppression of new viral replication and inhibition of virus release from infected cells.[20] Activity is present against all genotypes, especially genotypes 1, 2, and 3, with greater activity against genotype 1a than 1b. Lesser activity of daclatasvir is noted against genotypes 4 and 5.

Approximately 10% of this drug is excreted in the urine, and the remainder in the feces. When added to sofosbuvir, daclatasvir provides an antiviral effect, including a genetic barrier to the development of resistance associated variants.[21]

An open-label Japanese trial of daclatasvir plus asunaprevir for 24 weeks in patients with genotype 1b infection produced an SVR in 87% of interferon-ineligible or -intolerant patients and 81% of treatment-experienced patients.[22] When stratified by the presence or absence of cirrhosis, 91% of patients with cirrhosis and 84% of those without cirrhosis developed an SVR.

Similar results were also noted with this drug combination in a multicohort study (HALLMARK-DUAL),[23] with an SVR of 90% in treatment-naive patients, 82% in treatment-experienced patients, and 82% in interferon-ineligible or -intolerant patients.

Two recent studies of daclatasvir, asunaprevir, and beclabuvir have been reported in genotype 1-infected patients without cirrhosis and patients with compensated cirrhosis. The study of genotype 1-infected patients who lacked cirrhosis (73% with genotype 1a) resulted in an SVR at 12 weeks of 92% in treatment-naive patients and 89% in treatment-experienced patients.[24]

The trial (UNITY-2) of genotype 1-infected patients with compensated cirrhosis (74% with genotype 1a) produced an SVR of 93% in treatment-naive patients and 87% in treatment-experienced patients.[25] When ribavirin was added to daclatasvir, asunaprevir, and beclabuvir, SVR occurred in 98% of treatment-naive patients and in 93% of treatment-experienced patients.

In the ALLY-3 trial, the combination of daclatasvir and sofosbuvir produced an SVR of 90% in treatment-naive patients and 86% in treatment-experienced patients.[26] Gender, age, and HCV-RNA levels did not affect treatment outcome.

Daclatasvir is currently approved for use in Europe in combination with other antiviral agents for genotypes 1, 2, 3, and 4, and is available in Japan with asunaprevir for genotype 1b. The combination of daclatasvir and sofosbuvir was approved by the FDA in July 2015 for the treatment of genotype 3 HCV disease. Consideration for approval by the FDA of the combination of daclatasvir and asunaprevir has been withdrawn by the manufacturer.

Additional Agents

Grazoprevir/elbasvir is an investigational combination using the NS3/4A protease inhibitor grazoprevir and the NS5A inhibitor elbasvir, which have activity against multiple HCV genotypes coupled with the reduced risk for development of viral resistance variants.[27] The C-EDGE trial[28] evaluated patients with (22%) or without cirrhosis who had genotype 1 (328 patients), genotype 4 (26 patients), or genotype 6 (13 patients) infection. Genotype 1-infected patients were essentially equally divided between genotype 1a and 1b.

In the immediate-treatment group, SVR at 12 weeks occurred in 92% of patients with genotype 1a, 99% with genotype 1b, 100% with genotype 4, and 98% with genotype 6. An SVR of 100% was observed when baseline HCV RNA levels were 800,000 IU/mL or less, compared with 92% when levels were more than 800,000 IU/mL. The most common side effects of this combination included headache, fatigue, and nausea.

The PEARL-1 trial used ombitasvir and paritaprevir/ritonavir with or without weight-based ribavirin to treat genotype 4-infected patients without cirrhosis who were treatment-naive or treatment-experienced.[29] A 100% SVR was observed in both treatment-naive and treatment-experienced patients when ribavirin was added. When the drug combination was used without ribavirin, the SVR was 91% in treatment-naive and 100% in treatment-experienced patients. Anemia occurred in the patients receiving ribavirin, and headache was a common side effect (occurring in 29%) but did not require discontinuation of the drug.

The combination of ombitasvir, paritaprevir, and ritonavir with the use of ribavirin was approved by the FDA in July 2015 for the treatment of genotype 4 HCV infection.


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