Thursday, June 1, 2017

Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection

New England Journal of Medicine

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Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection
Marc Bourlière, M.D., Stuart C. Gordon, M.D., Steven L. Flamm, M.D., Curtis L. Cooper, M.D., Alnoor Ramji, M.D., Myron Tong, M.D., Natarajan Ravendhran, M.D., John M. Vierling, M.D., Tram T. Tran, M.D., Stephen Pianko, M.D., Meena B. Bansal, M.D., Victor de Lédinghen, M.D., Robert H. Hyland, D.Phil., Luisa M. Stamm, M.D., Ph.D., Hadas Dvory-Sobol, Ph.D., Evguenia Svarovskaia, Ph.D., Jie Zhang, Ph.D., K.C. Huang, Ph.D., G. Mani Subramanian, M.D., Diana M. Brainard, M.D., John G. McHutchison, M.D., Elizabeth C. Verna, M.D., Peter Buggisch, M.D., Charles S. Landis, M.D., Ph.D., Ziad H. Younes, M.D, Michael P. Curry, M.D., Simone I. Strasser, M.D., Eugene R. Schiff, M.D., K. Rajender Reddy, M.D., Michael P. Manns, M.D., Kris V. Kowdley, M.D., and Stefan Zeuzem, M.D., for the POLARIS-1 and POLARIS-4 Investigators*

N Engl J Med 2017; 376:2134-2146
June 1, 2017 DOI: 10.1056/NEJMoa1613512

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.

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.

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.

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 numbers, NCT02607735 and NCT02639247.)

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NEJM Journal Watch - Commentary On The Article
When DAA Treatment for Hepatitis C Fails, 3-Drug Regimen "Highly Effective"
By Kelly Young
Edited by Susan Sadoughi, MD, and Richard Saitz, MD, MPH, FACP, DFASAM
The combination of sofosbuvir, velpatasvir, and voxilaprevir is effective for hepatitis C in patients with virologic failure after direct-acting antiviral agent (DAA) treatment, according to two phase 3, industry-funded trials in the New England Journal of Medicine.

For POLARIS-1, roughly 300 patients with genotype-1 hepatitis C infection whose prior NS5A-inhibitor treatment had failed were randomized to either daily sofosbuvir-velpatasvir-voxilaprevir or placebo for 12 weeks. An additional 100 patients with non-genotype 1 infection were enrolled in the treatment group.

For POLARIS-4, over 300 patients with hepatitis C who had taken a direct-acting antiviral other than an NS5A inhibitor were randomized to receive sofosbuvir-velpatasvir with or without voxilaprevir.

Sustained virologic response 12 weeks after treatment ended was 96% for the POLARIS-1 treatment group (vs. 0% with placebo).

In POLARIS-4, the three-drug regimen had a 98% response rate, compared with 90% for sofosbuvir-velpatasvir. Sustained response rates were high for all genotypes.

Infectious disease expert Dr. Paul Sax comments: "This triple-therapy treatment strategy provides a highly effective option for that small proportion of patients who failed prior treatment for hepatitis C with non-interferon-based regimens. Although few in number, candidates for this treatment (and their clinicians) will welcome this treatment when it is FDA approved."

Triple-DAA Pill Offers HCV Retreatment Option
Most patients, all unsuccessful on previous DAA regimens, cleared the virus
combination of three drugs that act directly to block hepatitis C (HCV) replication successfully cured most patients who had previously failed therapy with such agents, researchers reported.

In two phase III trials, the investigational combination of sofosbuvir, velpatasvir, and voxilaprevir cleared the virus in 96% and 98% of patients, regardless of whether they had compensated cirrhosis or not, according to Marc Bourlière, MD, of Hôpital Saint-Joseph in Marseille, France, and colleagues.
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Media Coverage Of This Article

New Combo Pill Offers Hope to Hepatitis C Patients Who Fail Other Treatment
Updated: May 31, 2017 — 7:00 PM EDT

WEDNESDAY, May 31, 2017 (HealthDay News) -- A pill that contains three powerful antiviral drugs might offer a cure for many hepatitis C patients who have failed other treatments, researchers report.

The pill -- which contains the antiviral drugs sofosbuvir (Sovaldi), velpatasvir and voxilaprevir -- was nearly 100 percent effective in curing hepatitis C in patients whose disease returned after treatment with other antiviral drugs, the researchers said.

"Currently, we have very good treatments for hepatitis C, and we are able to achieve a cure in over 90 percent of patients. So globally, although only a few patients relapse, it still is a significant number," said lead researcher Dr. Marc Bourliere, from the Hospital Saint Joseph in Marseilles, France.

This new pill is being developed as a rescue treatment for patients who have failed other therapy, he said. When it was used as an initial treatment in another study, the combination pill fared no better than the usual treatment, he added.

The data from these and other trials, funded by Gilead Sciences, the maker of the combination pill, is in the hands of the U.S. Food and Drug Administration, where it is undergoing the approval process, Bourliere said.

The bottom line, according to Bourliere, is: "We have other options even if you fail the first treatments."

The new combination pill is likely to be expensive. In 2014, Gilead introduced a combination drug for hepatitis C called Harvoni, which was priced at more than $1,000 a dose with a 12-week course of treatment running $94,500, the Associated Press reported.

Hepatitis is an inflammation of the liver that can be caused by several viruses, including hepatitis C. Hepatitis C is usually spread when blood from an infected person enters the body of someone not infected. Most people become infected with hepatitis C by sharing needles or other equipment to inject drugs, the U.S. Centers for Disease Control and Prevention says.

Approximately 75 percent to 85 percent of people who have hepatitis C will develop chronic infection. In the United States, as many as 4 million people have chronic hepatitis C, according to the CDC.

Many people infected with hepatitis C don't know they have it because they don't look or feel sick.
Chronic hepatitis C is serious and can result in long-term health problems, including liver damage, liver failure, liver cancer or death. Hepatitis C is the leading cause of cirrhosis and liver cancer, and the most common reason for liver transplantation in the United States.
In two, phase 3 trials, Bourliere and his colleagues treated patients with the combination pill or a placebo or other antiviral drugs.

In the first trial, 300 patients were randomly assigned to the combination pill or a placebo. These patients all had hepatitis C genotype 1. In addition, 114 patients with other genotypes of hepatitis C were given the combination pill. Patients took the pill daily for 12 weeks.

Among patients taking the combination pill, 96 percent responded to treatment. None on the placebo showed a response, the researchers found.

The second trial included 314 patients with hepatitis C genotypes 1, 2 or 3. All had failed other treatments, but hadn't been given a NS5A inhibitor, such as velpatasvir or daclatasvir. This group received either the combination pill (163 patients) or sofosbuvir-velpatasvir (151 patients).
In addition, 19 patients with genotype 4 hepatitis C were given the combination pill.

In this trial, 98 percent of the patients taking the combination pill responded to 12 weeks of treatment. And 90 percent of those who received sofosbuvir-velpatasvir responded to treatment, the findings showed.

The most common side effects were headache, fatigue, diarrhea and nausea, Bourliere said. Only 1 percent or fewer patients stopped treatment because of the side effects, he said.

Dr. David Bernstein is chief of hepatology at Northwell Health in Manhasset, N.Y. He called the new drug "a very important advance. This is really for salvage therapy. I don't think this is first-line therapy, but it gives hope to the people who fail the current therapies we have."
The report was published June 1 in the New England Journal of Medicine.

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