imageBoston—Enthusiasm is growing for the various interferon (IFN)-free therapies on the horizon for patients with hepatitis C virus (HCV) infection. At the recent annual meeting of the American Association for the Study of Liver Diseases (AASLD), The Liver Meeting 2012, four of the six late-breaking abstracts and a slew of other studies discussed new oral regimens that can be used to achieve high rates of sustained virologic response (SVR) in a variety of HCV patient cohorts, including null responders.
“We can see a light at the end of the tunnel,” said Guadalupe Garcia-Tsao, MD, professor of medicine at Yale University, New Haven, Conn., and chief of the section of digestive diseases at the Connecticut Veterans Affairs Healthcare System, West Haven, referring to a future that includes IFN-free regimens for the treatment of HCV infection. “It is going to come to a point where we are going to have a lot of options.”

Dr. Garcia-Tsao, who also is president of the AASLD, thinks that some doctors may choose to “warehouse” or delay treating some patients with HCV infection in anticipation of an IFN-free regimen soon becoming available.

“It depends on where the patient stands in the natural history of the disease,” she explained. “If you are very early in the fibrotic process, and we think we are going to get more effective oral drugs in the next two or three years, would you wait or would you want to go ahead with current therapies?” It requires a big discussion, she said, and ... doctors need to find out what each patient’s priorities are.
Following are highlights from some of the trials of IFN-free therapies presented at the AASLD meeting.

Kris Kowdley, MD, director of research and director of the Liver Center of Excellence at the Digestive Disease Institute, Virginia Mason Medical Center, Seattle, discussed the AVIATOR trial.
The trial tested eight-, 12- and 24-week regimens of a combination of ribavirin plus three direct-acting antiviral agents (DAAs) being developed by Abbott Laboratories: ABT-450, ABT-267 and ABT-333. ABT-450, an NS3/4A protease inhibitor, is coadministered with ritonavir (ABT-450/r) in a once-daily dose. ABT-267, an NS5A inhibitor, also is a once-daily therapy. ABT-333, a non-nucleoside polymerase inhibitor, is used twice daily.

In exploratory studies, combinations containing ABT-450/r have achieved SVR rates greater than 90% in HCV genotype (GT) 1–infected patients. In the current study, researchers set out to identify the optimal drug combination for HCV GT1–infected patients who were either treatment-naive or null responders to previous treatment with peginterferon and ribavirin. To be eligible, participants could not have cirrhosis or HIV infection. Seven arms of the study, which included 571 patients, were evaluated for different drug combinations and regimen durations, up to 24 weeks. Dr. Kowdley presented results of the eight- and 12-week regimens, which included 448 patients.

“Regardless of treatment assignment, very high rates of SVR at week 12 were reached across all categories, both in the treatment-naive and null responders, but in particular, the group receiving three DAAs and ribavirin showed the highest SVR rates,” said Dr. Kowdley, who is clinical professor of medicine at the University of Washington in Seattle. SVR rates at week 12 were 97.5% in the treatment-naive group and 93.3% in null responders. Relapses primarily occurred in patients who received eight weeks of therapy compared with those who received 12 weeks.

Ninety-six percent of HCV GT1a–infected treatment-naive patients and 89% of HCV GT1a–infected null responders achieved SVR at week 12.

“High SVR12 rates were observed across all interleukin-28B [IL28B] genotypes,” Dr. Kowdley noted.

No serious adverse events (AEs) were observed, and only two of the 448 patients discontinued treatment due to an AE attributed to the study drug.

“The most commonly reported AEs were fatigue, headache, insomnia and nausea, which were reported infrequently,” Dr. Kowdley said. An 8% rate of fatigue was identified in one group, but all other AEs were observed at rates of 4% or lower. “The only laboratory irregularity that occurred with any frequency was an elevation of total bilirubin, occurring in 6.7% of treatment-naive patients and in 12.2% of null responders.”

The researchers said they will be moving the combination of ABT-450/r, ABT-267 and ABT-333 forward in Phase III trials, but ABT-450/r and ABT-267 will be coformulated into one tablet. The regimen will be tested with and without ribavirin.

The ELECTRON trial evaluated sofosbuvir (Gilead Sciences), an NS5B inhibitor, as a backbone of antiviral therapy in patients with HCV GT1-3 infection, for treatment-naive patients and patients who previously had been treated (abstract 229). Various drug combinations have been used in the trial, which has 11 arms so far.

Researchers announced that 100% of 25 patients with HCV GT1 infection who were treatment-naive achieved an SVR at week 4 using a combination of sofosbuvir, GS-5885 (Gilead) and ribavirin. HCV genotype or IL28B genotype did not affect sofosbuvir’s performance. AEs were generally mild: 48% of patients experienced at least two AEs, including anemia (20%), headache (4%) and depression (8%).

“In HCV genotype 1 infection, sofosbuvir plus GS-5885 plus ribavirin [taken] for 12 weeks appears to be a safe and effective regimen for treatment-naive patients,” said Edward Gane, MD, deputy director of the New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, who reported the results of the study.

Sound-C2 Trial
The SOUND-C2 trial tested a combination of two drugs developed by Boehringer Ingelheim, faldaprevir and BI 207127—with or without ribavirin, in treatment-naive patients with HCV GTI infection (abstract 84). Faldaprevir is a NS3/4A protease inhibitor, and BI207127 is a non-nucleoside NS5B inhibitor.

The study, which included 362 patients (33 with cirrhosis), had five arms, testing different dosing schemes and different treatment durations, from 16 to 40 weeks. The 28-week regimen, using a twice-daily dosing scheme performed the best, resulting in a 69% SVR overall at week 12 and an 85% SVR at week 12 in HCV GT1b patients. Patients with cirrhosis achieved an SVR of 67%.
The most common AEs were asthenia, pruritus, rash, photosensitivity, jaundice, nausea, vomiting, diarrhea and transient indirect hyperbilirubinemia. Overall, 36% of patients experienced AEs: 12% were considered severe, and 8% led to discontinuation of treatment. The company is launching a Phase III trial to further test this IFN-free drug regimen.

Ribavirin-Free Regimens
Mark Sulkowski, MD, medical director of the Viral Hepatitis Center in the Divisions of Infectious Diseases and Gastroenterology & Hepatology at Johns Hopkins School of Medicine, Baltimore, presented results of a study that tested an all-oral combination of daclatasvir (Bristol-Myers Squibb), an NS5A inhibitor, and sofosbuvir, with or without ribavirin (abstract LBA2). The combination—tested in treatment-naive patients—was given for 24 weeks to patients infected with HCV GT1a, GT1b, GT2 or GT3, and for 12 weeks to patients with HCV GT1a or GT1b. All patients were noncirrhotic

Researchers randomized 44 patients with HCV GT2/3 to one of three treatment groups: daclatasvir 60 mg daily plus sofosbuvir 400 mg daily with or without ribavirin for 24 weeks, or sofosbuvir daily for seven days and then daclatasvir daily plus sofosbuvir daily for a total treatment time of 24 weeks. Researchers also randomized 44 patients with HCV GT1a/1b to receive sofosbuvir every day for seven days and then daclatasvir and sofosbuvir daily for a total of 24 weeks, or daclatasvir plus sofosbuvir daily, with or without ribavirin, for 24 weeks. During a second stage of the study, 82 patients with HCV GT1a or GT1b were randomized to receive 12 weeks of daclatasvir plus sofosbuvir with or without ribavirin.

Overall, more than 93% of patients with HCV GT1, GT2 or GT3 achieved an SVR with the drug combinations. Among the 44 patients with HCV GT2 or GT3 infection, 93% achieved an SVR at week 24, with one patient having a confirmed relapse. Among the 126 patients with HCV GT1 infection, 96% of those who had reached the 12 weeks post-treatment stage had an SVR at week 12; this included three patients who did not have an SVR at week 4. The SVR rate at week 24 in this group was 98%. The drug combination was well tolerated.

“Virologic response did not vary according to IL28B genotype, viral subtype or with the administration of ribavirin,” Dr. Sulkowski said. “Up until very recently, ribavirin has played a critical role in hepatitis C treatment regimens. It was surprising and also encouraging that this combination—daclatasvir, an NS5A inhibitor, plus sofosbuvir, a nucleotide analog—may not require ribavirin.”

Gregory Everson, MD, director of the section of hepatology at the University of Colorado Denver, in Aurora, presented results from a Phase IIa open-label study of AI443-014 (abstract LBA3), which tested a 12-week regimen of three drugs developed by Bristol-Myer Squibb: daclatasvir, asunaprevir and BMS-791325. The four-armed study included treatment-naive, noncirrhotic patients with HCV GT1 infection. Results were presented only for the two arms of the study that included BMS-791325 75 mg plus daclatasvir and asunaprevir. One group of patients was treated for 12 weeks (n=16) and the other was treated for 24 weeks (n=16). Patients (mean age, 48 years) had a high viral load and 75% were infected with HCV GT1a. (The other two study arms received 150 mg of the investigational agent.)

In the group receiving treatment for 24 weeks, researchers only had complete data for SVR at week 4 (94%). Two patients assigned to this arm discontinued treatment before completing the 24-week phase: One patient, who withdrew consent at week 9 of treatment, was lost to follow-up (HCV RNA was undetectable at week 8), and the other patient, who stopped treatment at week 14 due to poor venous access, achieved SVR at week 4. In the group that received 12 weeks of treatment, SVR was 94% at weeks 4 and 12. Two patients assigned to this arm discontinued treatment before completing the full 12-week phase: One patient stopped treatment at week 11 but still achieved SVR at week 12, and the other completed the 12 weeks of treatment but failed to return for post-treatment follow-up (HCV RNA was undetectable at end of treatment). These high rates for SVR were achieved despite the more difficult-to-treat characteristics of HCV GT1a infection and non-CC IL28B genotypes of the patients. Although four patients in the study discontinued treatment prematurely, there were no discontinuations because of AEs.

“The regimen was generally well tolerated. There was no viral breakthrough and no post-treatment relapse to date,” Dr. Everson said. “Some of these patients have been followed now for 24 weeks, and with available data to date, we have not yet seen relapse. Further investigation of this regimen in the treatment of hepatitis C is warranted.”

The trial is being extended into other populations, including null responders, treatment-experienced patients and patients with more advanced fibrosis.

Dr. Everson cautioned, however, that the current results come from a small number of select patients.

Difficult-to-Treat Populations
Anu Osinusi, MD, MPH, of SAIC-Frederick Inc./National Institutes of Health (NIH), Bethesda, Md., presented the interim results of the NIH SPARE (Selective bladder Preservation Against Radical Excision) trial.

The two-part trial tested six months of treatment with sofosbuvir in combination with ribavirin in patients with treatment-naive HCV GT1. In the first phase, 10 patients with stage 0 to 2 fibrosis received sofosbuvir and a weight-based dose of ribavirin 1,000 to 1,200 mg per day. In the second phase, 50 patients with all stages of fibrosis, including Child Pugh Class A, were randomized to receive either weight-based or low-dose ribavirin (600 mg) daily.

Eighty-three percent of the study population was black, largely overweight, and had the less favorable IL28B CT/TT genotype. A majority of patients had a high HCV viral load and GT1a infection.

The investigators found that 77% of patients who received weight-based ribavirin had an SVR at week 4, and 56% of those who received low-dose ribavirin had an at week 4.
“There were no safety signals or drug-related discontinuations in this study,” Dr. Osinusi said.

Many More Cures
“It was not long ago that nearly all hepatologists felt that IFN would always be a mainstay of HCV therapy,” Dr. Everson observed. “The current experience is proving that bias to be wrong: Clearly IFN-free treatment is not only possible but highly effective. IFN-free treatment represents a real breakthrough for patients: a high likelihood for SVR; few, if any, side effects; shorter duration of treatment; and newer formulations combining two or more antivirals into a single tablet that will improve compliance to the treatment regimen. Simply speaking, these advances should translate into many more cures.”

Drs. Garcia-Tsao and Osinusi reported no conflicts of interest. Dr. Kowdley has received grants/research support from and serves on the advisory board of Abbott Laboratories. Dr. Gane has served on committees and review panels for Boehringer Ingelheim, Gilead Sciences, Jannsen Cilag, Novartis, Pharmasset, Roche and Vertex Pharmaceuticals. Dr. Sulkowski has served as a consultant for Abbott Laboratories, BIPI, Bristol Myers-Squibb, Gilead Sciences, Janssen, Merck & Co., Novartis, Roche/Genentech and Vertex Pharmaceuticals; he has received grants/research support from Abbott Laboratories, BIPI, Gilead Sciences, Janssen, Merck & Co., Roche/Genentech and Vertex Pharmaceuticals; and he has served on advisory committees and review panels for Pfizer. Dr. Everson has received grants/research support from Abbott Laboratories, Bristol-Myers Squibb, Conatus, GlobeImmune, GlaxoSmithKline, Pfizer, Pharmasset, PSC Partners, Roche/Genentech, Schering Plough, Tibotec, Vertex Pharmaceuticals and ZymoGenetics; he has served on advisory committees and review panels for Hep C Connection and Roche/Genentech Merck; he has served as a consultant for Abbott Laboratories and Roche/Genentech; and he has served as a board member for HepQuant LLC and PSC Partners.