A combination therapy including two investigational direct-acting antiviral agents (DAAs)—asunaprevir and daclatasvir—suppressed hepatitis C virus (HCV) genotype 1 infection in a majority of patients who had previously not responded to treatment, according to results from a small Phase II study published in the Jan. 19 issue of The New England Journal of Medicine (Lok AS et al. 2012;366:216-224).
Success rates were 100% in patients who received the drugs in combination with peginterferon alfa-2a (Peg-IFN) and ribavirin (RBV).
And, most notably, even in patients who received daclatasvir and asunaprevir without Peg-IFN and RBV, sustained virologic response (SVR) was achieved in 36% of patients, making this the first published study to show that SVR can be achieved with an IFN-free treatment in previous null responders.
“The response in some patients to the combination of daclatasvir and asunaprevir alone showed proof-of-concept that a sustained virologic response can be achieved without peginterferon and ribavirin therapy,” concluded the research team, led by Anna S. Lok, MD, professor of internal medicine in the Division of Gastroenterology, University of Michigan Medical School, Ann Arbor.
In an editorial accompanying the study, Raymond T. Chung, MD, director of hepatology and medical director of the liver transplant program at Massachusetts General Hospital, Boston, called the study a “watershed moment in the annals of HCV therapy.
“It shows that sustained virologic response can be achieved without interferon. Implicit in this finding is the concept that two potent agents with complementary resistance profiles, given for a sufficient duration, can impose a stranglehold on viral replication and result in clearance of the virus.”

In this Phase II study, 10 patients received the experimental drugs in combination with Peg-IFN and RBV for 24 weeks. All 10 patients had undetectable viral loads at the end of treatment and at 12 weeks after stopping treatment. Nine patients continued to exhibit SVR at 48 weeks after treatment, whereas one patient had HCV RNA of less than 25 IU/mL at post-treatment week 48 and undetectable HCV RNA 13 days later.

In a separate arm of the study, 11 patients received asunaprevir and daclatasvir alone, without the addition of Peg-IFN and RBV.

Of these, four patients (36%) achieved an SVR at 12 and 24 weeks after treatment. Six patients (55%) had viral breakthrough during treatment, with resistance mutations to both antiviral agents. Breakthroughs occurred as early as treatment week 3 and as late as treatment week 12.

Although only one-third of the patients given the two-drug combination without Peg-IFN and RBV achieved an SVR, investigators and other hepatologists say the finding is “very promising.”

“For years, the concept of IFN-free therapy was hotly debated. Now, we’re very quickly moving toward IFN-free therapy. It’s potentially just around the corner,” said Donald M. Jensen, MD, professor of medicine and director of the Center for Liver Diseases, University of Chicago Medical Center.

“For patients who can wait, they might just have to wait a few more years until IFN-free therapy is on the market,” he said.

Daclatasvir is a first-in-class, highly selective HCV NS5A replication complex inhibitor that has shown picomolar potency in vitro. Asunaprevir is a highly active HCV NS3 protease inhibitor. Both drugs produce robust declines in HCV RNA levels in patients with HCV genotype 1 infection and, taken in combination, there is no clinically meaningful pharmacokinetic interaction.

Hepatologists say that treatment of HCV infection is entering a new era, highlighted by combinations of second-generation DAAs. As more DAAs are developed with non-overlapping resistance profiles, they may reduce dependence on treatment with IFN.

“These data are very encouraging because peginterferon-alfa and ribavirin are associated with many side effects and many patients with hepatitis C choose not to receive treatment for fear that they cannot tolerate those drugs,” said Dr. Lok, in a statement.

The participants in Dr. Lok’s study had previously failed to respond to Peg-IFN and RBV treatment, meaning they represent a difficult-to-treat population with poor expected outcomes. Previous null responders typically do not respond to retreatment with Peg-IFN and RBV and also tend to have a poor response to triple-combination therapy with Peg-IFN and RBV plus a protease inhibitor.
This combination of new DAAs, if supported by larger studies, could help the large number of patients who have not responded to previous treatment.

“Because of this high unmet medical need, there is a necessity for new combination regimens that can increase response rates in that population,” said Dr. Lok.

Study Details
In the current study, investigators screened 56 patients and ultimately enrolled 21 patients in an exploratory cohort to assess the safety and antiviral activity of the new DAAs. All patients were between the ages of 18 and 70 years, had a chronic HCV genotype 1 infection with an HCV RNA level of 105 IU/mL or higher, showed no evidence of cirrhosis and exhibited no response to previous HCV therapy. Of these patients, 90% had interleukin 28B (IL28B) genotype CT or TT, both of which are associated with poor response to Peg-IFN and RBV, and most patients had HCV genotype 1a infection.

Daclatasvir was administered orally at a dose of 60 mg once daily and asunaprevir at a dose of 600 mg twice daily, with no dose reductions permitted. Ten patients also received Peg-IFN 180 mcg per week, administered subcutaneously, and RBV, administered orally twice daily, with doses determined according to body weight.

Investigators believe that the combination of two DAAs increases the resistance barrier, particularly for patients with HCV genotype 1b infection. In this study, all viral breakthroughs occurred in patients with HCV genotype 1a infection.

This study appears to confirm the results of a recent Japanese study, which showed a high SVR rate among patients with HCV genotype 1b infection in a pilot study of 10 previous non-responders who received combination therapy with asunaprevir and daclatasvir (Chayama K et al. Hepatology 2011 Oct 10; 10.1002/hep.24724 [Epub ahead of print]).

The key benefit of treatment with Peg-IFN and RBV appears to be prevention of viral breakthrough. No patient who received the four-drug combination in the current study experienced a viral breakthrough, whereas six patients in the group that received the DAAs alone had viral breakthroughs. All patients who had a viral breakthrough received and initially responded to Peg-IFN and RBV as rescue therapy. Most ultimately had therapeutic failure.

The high frequency of resistance sends a strong cautionary note about these therapies, said investigators. Future studies of combinations of DAAs without Peg-IFN and RBV in patients with HCV genotype 1a infection should proceed carefully, said the investigators.

But, they added, further research on combinations of DAAs, with or without Peg-IFN and RBV, should be encouraged.

The most common adverse events in this study were diarrhea, fatigue, headache and nausea, which were mild or moderate in all cases. Grade 3 or 4 neutropenia occurred in six patients, all of whom were receiving Peg-IFN and RBV in addition to the two DAAs. No grade 3 or 4 events related to hemoglobin levels or platelet counts were observed.

“This is an exciting study that means care will be better for patients,” said Andrew J. Muir, MD, clinical director of hepatology, Duke University Health System, Durham, N.C., who was not involved with the study.

“For the first time, patients were cured of HCV without interferon-a. Interferon-a has always been the backbone of HCV therapy but has many side effects that make treatment too difficult for many patients.”

Bristol-Myers Squibb, manufacturer of asunaprevir and daclatasvir, funded this study. Dr. Lok has received consulting fees from Abbott Laboratories, Bristol-Myers Squibb and Gilead Sciences, and grant support from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck–Schering-Plough and Roche. Dr. Muir has received grant support from Bristol-Myers Squibb, Gilead Sciences, Merck–Schering-Plough, Roche and Vertex Pharmaceuticals. Dr. Jensen has served on advisory committees or review panels for Abbott Laboratories, Boehringer Ingelheim, Genentech/Roche, GlobeImmune, Human Genome Sciences, Merck, Pfizer, Pharmasset, Tibotec and Vertex Pharmaceuticals; he has received consulting fees from Abbott Laboratories, Bristol-Myers Squibb, Genentech/Roche and Vertex Pharmaceuticals; and he has received grant/research support from Boehringer Ingelheim, Genentech/Roche, Tibotec and Vertex Pharmaceuticals.