Miriam E. Tucker

November 11, 2013

WASHINGTON, DC — Hepatitis C treatment options on the horizon that hold promise for better viral clearance with less toxicity than current regimens enthused many hepatologists here at The Liver Meeting 2013.

"This is a very exciting time in liver diseases," Greg Fitz, MD, president of the American Association for the Study of Liver Diseases (AASLD), told reporters attending a news conference. "In the past 10 years, a revolution has taken place. Suddenly, it's realistic to think we can cure most patients with hepatitis C."

In October, a US Food and Drug Administration advisory committee voted unanimously to recommend approving the NS5B polymerase inhibitor sofosbuvir (Gilead) and the protease inhibitor simeprevir (Medivir and Janssen) for use in combination with pegylated interferon alfa and ribavirin in select patients infected with hepatitis C.

It is anticipated that both direct-acting antiviral agents will receive approval on December 8.

This is a very exciting time in liver diseases.

New data were presented at the meeting for both direct-acting antivirals and for some investigational agents used in combination regimens for patients with genotypes 1 to 4 hepatitis C. Several trials suggest the potential for interferon- and ribavirin-free all-oral regimens for genotypes 2 and 3 hepatitis C, and there is a variety of new combinations for the hard-to-treat genotype 1.

To date, research has shown better sustained viral clearance rates for the new direct-acting antivirals than for current regimens containing interferon and ribavirin (80% vs 50%), and with greater tolerability.

"I think the move away from interferon and toward a high probability of success is remarkably encouraging for all of us," Dr. Fitz told reporters.

The new data "are giving us a peek at what the next incremental steps are likely to be, and those are coming soon," he told Medscape Medical News in an interview before the meeting.

Fast-Paced Change

At the news conference, Dr. Fitz reporters that the AASLD is collaborating with the Infectious Disease Society of America and will launch a Web site in January 2014 to keep clinicians who treat patients with hepatitis C apprised of the rapidly moving field.

Practice guidelines can "take 2 years to develop. In this field at this time, that's too long. If something happens, we want it out there in a couple weeks. It's not going to be guidelines, but it's intended to be current info you can trust," Dr. Fitz explained.

Some key industry-sponsored trials were presented in late-breaking oral abstract sessions or were highlighted by other speakers during state-of-the-art symposia.

An open-label phase 3 study conducted in Japan evaluated Bristol Myers-Squibb's all-oral interferon- and ribavirin-free triple combination of the investigational NS5A replication inhibitor daclatasvir, the NS3 protease inhibitor asunaprevir, and the non-nucleoside NS5B polymerase inhibitor BMS-791325.

The regimen was compared in 135 interferon-ineligible or -intolerant patients with genotype 1b hepatitis C and 87 nonresponders to interferon and ribavirin. Sustained viral response at 24 weeks was better in the ineligible or intolerant group than in the nonresponders (87.4% vs 80.5%). Serious adverse events occurred in 5.9% of patients, and 5.0% discontinued treatment because of adverse events — 90% of which were related to liver enzyme elevation. Bristol Myers-Squibb has filed for regulatory review of the triple therapy in Japan.

A 12-week phase 2b study evaluated the same triple combination in 166 treatment-naïve patients with genotype 1 hepatitis C. Sustained viral response at 12 weeks, considered to be a cure, was achieved in more than 90% of the 15 patients with genotype 1a or 1b and in the 151 with or without cirrhosis.

Studies Abound

In a phase 3 study of another all-oral regimen, sustained viral response at 12 weeks was achieved in 85% of 250 patients with genotype 3 hepatitis C who were treated with Gilead's combination of sofosbuvir plus ribavirin for 24 weeks. The majority of the patients had failed previous therapy.

A Gilead-sponsored 12-week open-label study evaluated the triple combination of sofosbuvir, interferon, and ribavirin. Of the 47 patients with genotype 2 or 3 hepatitis C who had previously failed treatment with interferon and ribavirin, 26 had cirrhosis. Sustained viral response at 12 weeks was achieved by 96% of those with genotype 2 and 83% of those with genotype 3 disease. Adverse events were consistent with the safety profile of interferon and ribavirin without sofosbuvir.

A 2-part open-label phase 2a study involved the interferon-free combination of sofosbuvir plus simeprevir with or without ribavirin in patients with genotype 1 hepatitis C. One study cohort consisted of 80 previous null responders to interferon and ribavirin who had a METAVIR score of F0 to F2; the second cohort consisted of 87 patients who were both treatment-naïve and previous null responders with more severe liver fibrosis (METAVIR score, F3 or F4). Sustained viral response at 12 weeks in the first cohort was 93% without ribavirin and 96% with it.

In the second cohort, rates were 100% for the treatment-naïve patients with or without ribavirin and for the nonresponders without ribavirin. For nonresponders who received ribavirin, the response was 93%.

This is high cost, high-gain therapy for those who respond. Patients can be cured.

A phase 3 study looked at the investigational combination of faldaprevir, interferon, and ribavirin (Boehringer Ingelheim). In 1045 patients with genotype 1 hepatitis C, sustained viral response at 12 weeks was 72% to 73%, depending on dosage. Response was 70% in the 99 patients who had relapsed on previous treatment and 58% in the 57 who had partially responded to previous treatment. Sustained viral response at 12 weeks was 33% in the 145 patients who had not responded at all to previous treatment.

An open-label phase 3 all-oral study of sofosbuvir plus ribavirin evaluated 68 treatment-naïve patients who were coinfected with HIV. Sustained viral response at 12 week rates was 88% for the 26 patients with genotype 2 hepatitis C and 67% for the 42 patients with genotype 3. Most were also on antiretroviral therapy.

In a phase 2 trial of 61 patients infected with hepatitis C who were awaiting liver transplantation, 37 had an undetectable viral load (<25 IU/mL) after 48 weeks of treatment with sofosbuvir and ribavirin. Of those, 62% had an undetectable viral load 12 weeks after transplantation. In a second phase 2 study of 35 patients with established recurrent hepatitis C infection after liver transplantation, 77% responded after 24 weeks of sofosbuvir and ribavirin.

"I think this field is going to have multiple agents and multiple combinations," Dr. Fitz said. "There's absolutely a requirement for an individual doctor and an individual patient to come together. If something fails, you might opt for off-label use, but that's not the same as knowing what works best. Doing the studies is going to be necessary for using these new tools wisely."

He noted that screening is merited to identify more patients and get them into treatment, even though the new treatments are likely to be expensive. "This is high cost, high-gain therapy for those who respond. Patients can be cured. That is a powerful positive that really demands treatment."

These studies are industry funded and many of the investigators have financial relationships with the companies. Dr. Fitz has disclosed no relevant financial relationships.

The Liver Meeting 2013: American Association for the Study of Liver Diseases (AASLD). Presented November 3 and 4, 2013.


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