Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection.

Abstract

BACKGROUND:

Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options.

METHODS:

We conducted two phase 3 trials involving patients who had been previously treated with a DAA-containing regimen. In POLARIS-1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks. Patients who were infected with HCV of other genotypes (114 patients) were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group. In POLARIS-4, patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir-voxilaprevir (163 patients) or sofosbuvir-velpatasvir (151 patients) for 12 weeks. An additional 19 patients with HCV genotype 4 infection were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group.

RESULTS:

In the three active-treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS-1, the rate of sustained virologic response was 96% with sofosbuvir-velpatasvir-voxilaprevir, as compared with 0% with placebo. In POLARIS-4, the rate of response was 98% with sofosbuvir-velpatasvir-voxilaprevir and 90% with sofosbuvir-velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active-treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower.

CONCLUSIONS:

Sofosbuvir-velpatasvir-voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV genotypes in whom treatment with a DAA regimen had previously failed. (Funded by Gilead Sciences; POLARIS-1 and POLARIS-4 ClinicalTrials.gov numbers, NCT02607735 and NCT02639247 .).

• Authors: Marc Bourlière, Stuart C Gordon, Steven L Flamm, Curtis L Cooper, Alnoor Ramji, Myron Tong, Natarajan Ravendhran, John M Vierling, Tram T Tran, Stephen Pianko, Meena B Bansal, Victor de Lédinghen, Robert H Hyland, Luisa M Stamm, Hadas Dvory-Sobol, Evguenia Svarovskaia, Jie Zhang, K C Huang, G Mani Subramanian, Diana M Brainard, John G McHutchison, Elizabeth C Verna, Peter Buggisch, Charles S Landis, Ziad H Younes, Michael P Curry, Simone I Strasser, Eugene R Schiff, K Rajender Reddy, Michael P Manns, Kris V Kowdley, Stefan Zeuzem, POLARIS-1 and POLARIS-4 Investigators
• Journal: The New England journal of medicine (N Engl J Med) Vol. 376 Issue 22 Pg. 2134-2146 (06 01 2017) ISSN: 1533-4406 [Electronic] United States
• PMID: 28564569 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Aminoisobutyric Acids
• Antiviral Agents
• Carbamates
• Cyclopropanes
• Drug Combinations
• Heterocyclic Compounds, 4 or More Rings
• Lactams, Macrocyclic
• Macrocyclic Compounds
• Protease Inhibitors
• Quinoxalines
• Sulfonamides
• Viral Nonstructural Proteins
• voxilaprevir
• Proline
• NS-5 protein, hepatitis C virus
• Leucine
• velpatasvir
• Sofosbuvir

Topics

• Adult
• Aged
• Aged, 80 and over
• Aminoisobutyric Acids
• Antiviral Agents (adverse effects, therapeutic use)
• Carbamates (adverse effects, therapeutic use)
• Cyclopropanes
• Drug Combinations
• Drug Resistance, Viral
• Female
• Genotype
• Hepacivirus (drug effects, genetics)
• Hepatitis C (complications, drug therapy, virology)
• Heterocyclic Compounds, 4 or More Rings (adverse effects, therapeutic use)
• Humans
• Lactams, Macrocyclic
• Leucine (analogs & derivatives)
• Liver Cirrhosis (etiology)
• Macrocyclic Compounds (adverse effects, therapeutic use)
• Male
• Middle Aged
• Proline (analogs & derivatives)
• Protease Inhibitors (therapeutic use)
• Quinoxalines
• Sofosbuvir (adverse effects, therapeutic use)
• Sulfonamides (adverse effects, therapeutic use)
• Viral Nonstructural Proteins (antagonists & inhibitors)