Published: Nov 16, 2014
By Ed Susman, Contributing Writer, MedPage Today
Reviewed by F. Perry Wilson, MD, MSCE;
Assistant Professor, Section of Nephrology, Yale School of Medicine
Action Points
In the 4-week duration part of a multi-arm clinical trial, all 31 non-cirrhotic genotype 1 HCV-infected patients achieved undetectable virus at follow-up week 2. according to Eric Lawitz, MD, of the Texas Liver Institute in San Antonio.
But by week 8, 19 of those patients had relapsed, giving an SVR rate of 38.7%, Lawitz reported in his poster presentation and at a press briefing at the annual meeting of the American Association for the Study of Liver Diseases.
Among the 30 patients treated for 6 weeks, all reached undetectable virus by follow-up week two, but four of those patients later relapsed, giving an 86.7% SVR at week 8.
"This is a phase II study. This is a proof of principle that we can accomplish SVR at 8 weeks," Lawitz told MedPage Today. "This was the first time there was a planned 4-week duration trial. Even though there were a number of relapses, it is biologically plausible to cure a very select subset of patients at 4 weeks."
The researchers conducting the so-called C-SWIFT trial also looked at 6-week and 8-week courses of treatment for harder-to-cure cirrhotic genotype 1 HCV patients.
"Cirrhotics had SVR of about 95% at 8 weeks," Lawitz said. He noted that all 102 patients in the study -- cirrhotics and non-cirrhotics -- achieved undetectable virus by follow-up week two. Among the cirrhotic patients, four patients out of 20 who were treated for 6 weeks relapsed. There was one relapse among the 21 cirrhotic patients treated for 8 weeks.
"There are some valuable lessons learned from this," Lawitz said. "It is encouraging to see a three-drug regimen achieve a 95% SVR at 8 weeks in the setting of cirrhosis. It shows we may be able to get to an 8-week regimen for all patient types.
"Our study looks at short duration therapy," Lawitz said. The registration trial for the two investigative agents will show SVR12 results. "In the C-SWIFT trial, which is ongoing, we used a three-drug regimen of grazoprevir and elbasvir -- the investigative drugs -- and sofosbuvir, which is already on the market."
"What we saw at the end of 4 weeks was that all but six patients had achieved undetectable virus, but by follow-up week two those six patients went on to be undetectable, so at follow-up week two there was 100% of patients that were undetectable." he said.
"In the 6-week arm, all but one patient was negative at the end of the treatment and that patient also went on to become negative by follow-up week two. In the cirrhotic arms all patients were undetectable at either 6 or 8 weeks," he said.
Lawitz said the three-drug regimen was well-tolerated with few serious adverse events occurring in any treatment regimen, possibly a factor of the short treatment duration.
In commenting on the research, press conference moderator Michael Fried, MD, director of the University of North Carolina Liver Center, Chapel Hill, told MedPage Today, "I agree that this is a very important study because it does sort of set the limits of where we might be able to go with these drugs in terms of duration of therapy.
"Everyone is sort of focused on shorter duration of therapy, and perhaps we can identify certain subgroups that may be able to get treated for 4 weeks, but it certainly will require a lot more research in that area."
The patients in the C-SWIFT study were in their 50s and more than 60% of each arm of the trial were men. More than 75% of the patients were diagnosed with genotype 1a. Lawitz said the overall study also includes patients diagnosed with genotype 3 hepatitis C virus infection, but the results from that group will be reported at a later meeting.
Meanwhile, the same drugs, but without sofosbuvir, appeared to allow difficult to treat HCV patients to attain a sustained virologic response with or without the addition of ribavirin, Lawitz reported in a separate presentation.
The C-WORTHY was a randomized, dose response, parallel-group, multiple-site, double-blind clinical trial comparing diverse patient populations exposed to different durations of treatment of grazoprevir/elbasvir with or without ribavirin in patients with chronic hepatitis C virus infection.
In C-WORTHY Parts A and B which were presented at AASLD, 471 patients with chronic hepatitis C virus genotype 1 infection were enrolled and randomized. The research was published online in The Lancet simultaneously with presentation at the meeting.
At the meeting, Lawitz reported:
"High efficacy was observed regardless of the presence or absence of ribavirin or extended treatment duration from 12 weeks to 18 weeks," Lawitz said in his oral presentation during a special hepatitis plenary session at the annual meeting of the American Association for the Study of Liver Diseases..
Session moderator Anna Lok, MD, of the University of Michigan in Ann Arbor, told MedPage Today, "The data are impressive."
The combination is "is going through Phase III clinical trials so we will have to see what those results look like. If the Phase II results are confirmed, the treatment will be approved," Lok said.
"I don't think we can say that one regimen will be superior to another, but it is comparable to other treatments we have seen. That means that we have more choices. If we have more choices then maybe the prices will come down a bit through competition. That's what we all hope."
Grazoprevir/elbasvir (formerly known as MK-5172/MK-8742 consists of grazoprevir, an oral, once-daily NS3/4A protease inhibitor, and elbasvir, an oral, once-daily NS5A inhibitor.
The treatment naïve patients in the study arms were about 58 years old; the treatment experienced null responders were about 54 years of age. There were more men than women in the study and more than 90% of the patients in the study arms were white. Almost all the patients in the treatment naïve population had cirrhosis (one patient did not). About 35% of patients who were null responders had cirrhosis.
Adverse events were infrequent. Lawitz said the treatment was well-tolerated. He noted that more adverse events were noted when ribavirin was added to the treatment regimen.
Merck plans to submit the New Drug Application to the FDA for grazoprevir/elbasvir in 2015.
- Note that a trial of a three-drug direct-acting drug regimen against HCV revealed that a short course was associated with some degree of sustained virologic response, but did not perform as well as longer courses.
- Another trial of combination direct acting therapy found that SVR rates were very high even without the addition of ribavirin.
BOSTON -- A new study suggests that some subgroups of patients with hepatitis C (HCV) infection can achieve sustained virologic responses (SVR) in as short as 4 weeks using an aggressive, investigational three-drug regimen, researchers reported here.
In the 4-week duration part of a multi-arm clinical trial, all 31 non-cirrhotic genotype 1 HCV-infected patients achieved undetectable virus at follow-up week 2. according to Eric Lawitz, MD, of the Texas Liver Institute in San Antonio.
But by week 8, 19 of those patients had relapsed, giving an SVR rate of 38.7%, Lawitz reported in his poster presentation and at a press briefing at the annual meeting of the American Association for the Study of Liver Diseases.
Among the 30 patients treated for 6 weeks, all reached undetectable virus by follow-up week two, but four of those patients later relapsed, giving an 86.7% SVR at week 8.
"This is a phase II study. This is a proof of principle that we can accomplish SVR at 8 weeks," Lawitz told MedPage Today. "This was the first time there was a planned 4-week duration trial. Even though there were a number of relapses, it is biologically plausible to cure a very select subset of patients at 4 weeks."
The researchers conducting the so-called C-SWIFT trial also looked at 6-week and 8-week courses of treatment for harder-to-cure cirrhotic genotype 1 HCV patients.
"Cirrhotics had SVR of about 95% at 8 weeks," Lawitz said. He noted that all 102 patients in the study -- cirrhotics and non-cirrhotics -- achieved undetectable virus by follow-up week two. Among the cirrhotic patients, four patients out of 20 who were treated for 6 weeks relapsed. There was one relapse among the 21 cirrhotic patients treated for 8 weeks.
"There are some valuable lessons learned from this," Lawitz said. "It is encouraging to see a three-drug regimen achieve a 95% SVR at 8 weeks in the setting of cirrhosis. It shows we may be able to get to an 8-week regimen for all patient types.
"Our study looks at short duration therapy," Lawitz said. The registration trial for the two investigative agents will show SVR12 results. "In the C-SWIFT trial, which is ongoing, we used a three-drug regimen of grazoprevir and elbasvir -- the investigative drugs -- and sofosbuvir, which is already on the market."
"What we saw at the end of 4 weeks was that all but six patients had achieved undetectable virus, but by follow-up week two those six patients went on to be undetectable, so at follow-up week two there was 100% of patients that were undetectable." he said.
"In the 6-week arm, all but one patient was negative at the end of the treatment and that patient also went on to become negative by follow-up week two. In the cirrhotic arms all patients were undetectable at either 6 or 8 weeks," he said.
Lawitz said the three-drug regimen was well-tolerated with few serious adverse events occurring in any treatment regimen, possibly a factor of the short treatment duration.
In commenting on the research, press conference moderator Michael Fried, MD, director of the University of North Carolina Liver Center, Chapel Hill, told MedPage Today, "I agree that this is a very important study because it does sort of set the limits of where we might be able to go with these drugs in terms of duration of therapy.
"Everyone is sort of focused on shorter duration of therapy, and perhaps we can identify certain subgroups that may be able to get treated for 4 weeks, but it certainly will require a lot more research in that area."
The patients in the C-SWIFT study were in their 50s and more than 60% of each arm of the trial were men. More than 75% of the patients were diagnosed with genotype 1a. Lawitz said the overall study also includes patients diagnosed with genotype 3 hepatitis C virus infection, but the results from that group will be reported at a later meeting.
Meanwhile, the same drugs, but without sofosbuvir, appeared to allow difficult to treat HCV patients to attain a sustained virologic response with or without the addition of ribavirin, Lawitz reported in a separate presentation.
The C-WORTHY was a randomized, dose response, parallel-group, multiple-site, double-blind clinical trial comparing diverse patient populations exposed to different durations of treatment of grazoprevir/elbasvir with or without ribavirin in patients with chronic hepatitis C virus infection.
In C-WORTHY Parts A and B which were presented at AASLD, 471 patients with chronic hepatitis C virus genotype 1 infection were enrolled and randomized. The research was published online in The Lancet simultaneously with presentation at the meeting.
At the meeting, Lawitz reported:
- 28 of 31 cirrhotic patients naïve to antiviral therapy – 90% -- treated for 12 weeks with the fixed dose combination of grazoprevir 100 mg plus elbasvir 50 mg once daily plus ribavirin achieved the goal of sustained virologic response at 12 weeks (SVR12). There were two late relapses in this group.
- 28 of 29 similar patients –97% -- treated for 12 weeks with the dual investigative drug without ribavirin achieved SVR12. There was one relapse.
- 31 of 32 similar patients – 97% -- treated for 18 weeks with all 3 drugs achieved SVR12. There were no relapses in this group.
- 29 of 31 similar patients – 94% -- treated for 18 weeks without ribavirin achieved SVR12. There were two relapses.
- 30 of 32 null responders with or without cirrhosis – 94% -- treated for 12 weeks with the three drugs achieved SVR12. There were no relapses.
- 30 of 33 similar patients –91% -- treated for 12 weeks with the two investigational drugs achieved SVR12. There were three relapses in this group.
- 33 or 33 null responders with or without cirrhosis –100% -- treated for 18 weeks with all three drugs achieved SVR12. There were no relapses.
- 31 of 32 similar patients – 97% -- treated with the two investigational drugs for 18 weeks achieved SVR12. There were no relapses.
"High efficacy was observed regardless of the presence or absence of ribavirin or extended treatment duration from 12 weeks to 18 weeks," Lawitz said in his oral presentation during a special hepatitis plenary session at the annual meeting of the American Association for the Study of Liver Diseases..
Session moderator Anna Lok, MD, of the University of Michigan in Ann Arbor, told MedPage Today, "The data are impressive."
The combination is "is going through Phase III clinical trials so we will have to see what those results look like. If the Phase II results are confirmed, the treatment will be approved," Lok said.
"I don't think we can say that one regimen will be superior to another, but it is comparable to other treatments we have seen. That means that we have more choices. If we have more choices then maybe the prices will come down a bit through competition. That's what we all hope."
Grazoprevir/elbasvir (formerly known as MK-5172/MK-8742 consists of grazoprevir, an oral, once-daily NS3/4A protease inhibitor, and elbasvir, an oral, once-daily NS5A inhibitor.
The treatment naïve patients in the study arms were about 58 years old; the treatment experienced null responders were about 54 years of age. There were more men than women in the study and more than 90% of the patients in the study arms were white. Almost all the patients in the treatment naïve population had cirrhosis (one patient did not). About 35% of patients who were null responders had cirrhosis.
Adverse events were infrequent. Lawitz said the treatment was well-tolerated. He noted that more adverse events were noted when ribavirin was added to the treatment regimen.
Merck plans to submit the New Drug Application to the FDA for grazoprevir/elbasvir in 2015.
Source - MedPage Today
I was one of the treatment naïve patients with cirrhosis. I was Und at 4 week (October 1,2013) of 18 week arm. Considered SVR at 24 weeks post treatment. I had just turned 79 at start of treatment--had Hep c for about 50 years. It works for us "old people". Thanks Merck
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