SNAPSHOTS —Alan Franciscus, Editor-in-Chief

This month’s (October 2015) column features a variety of studies, including treatment of people with advanced liver disease, treating people who have not achieved a cure with direct acting antiviral therapy, including people who had developed RAVs.

Article:  Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease—M Charlton et al. 

Source:  Gastroenterology. 2015 Sep;149(3):649-59. doi: 10.1053/j.gastro.2015.05.010. Epub 2015 May 15.

Results and Conclusions

This was a phase 2 study of 337 patients with decompensated cirrhosis with genotype 1 (332 patients) and genotype 4 (5 patients) who received 12 or 24 weeks of Harvoni plus ribavirin twice daily.  None of the patients previously treated developed resistance to sofosbuvir.  People who had been previously treated with an NS5A inhibitor were excluded from the study. 

There were two groups in the study:

•  Group A, who had NOT had a liver transplant: 59 patients with Child-Pugh class B cirrhosis and 49 patients with Child-Pugh class C  cirrhosis*
•  Group B who HAD undergone liver transplantation:  111 patients without cirrhosis, 51 patients with Child-Pugh class A cirrhosis, 52 with Child-Pugh class B cirrhosis, 9 with Child-Pugh class C cirrhosis, and 6 with fibrosing cholestatic hepatitis*

 *Child-Pugh cirrhosis scoring is a system that uses various types of blood markers and liver disease progression such as ascites to evaluate a patient to establish the severity of cirrhosis and long-term patient survival.  The classes are A, B and C with A as the less severe and C as the most severe.  Cholestatic hepatitis is bile duct blockage with fibrosis.

Group A and B had 12- and 24-week treatment arms, but cure rates were similar regardless of treatment duration.

     

 The Bottom Line

In group A (those who had not received a liver transplant), the cure rate was 86% to 89%.  In group B (transplant group) the people who did not have cirrhosis or Class A cirrhosis—the cure rate was 96% to 98%.  Furthermore, in group B with class B cirrhosis (compensated) the cure rate was 85% to 88%, and those with class C cirrhosis (moderate impairment) achieved 60% to 75% cure rates. The people who had fibrosing cholestatic hepatitis achieved 100% cure rates.  There were 13 patients (4%) who discontinued treatment.  Ten patients died in the trial.  The deaths were mainly attributed to complications from hepatic decompensation or end-stage liver disease.

Editorial Comment

In the past, people with these types of severe disease progression have been very difficult to cure or even treat, but now with these ‘miracle’ drugs many people now have a second chance at life.  Now if we could just get these drugs to everyone with hepatitis C before this stage, we would eliminate the need to treat at these stages of disease severity. 

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Article:  Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent—X Forns et al.

Source:  J Hepatol. 2015 Sep;63(3):564-72. doi: 10.1016/j.jhep.2015.04.009. Epub 2015 Apr 18.

Results and Conclusions

There were 79 HCV genotype 1 patients in the study. 

• Sixty-six patients who had been previously treated patients with an NS3/4A protease inhibitor but had not been cured. 
• Of the 13 remaining patients, 12 had discontinued treatment due to side-effect(s). 
• Thirty-four patients had NS3 resistance-associated variants (RAVs), and eight patients had NS5A RAVs. 
• Eight patients treated with the combination of grazoprevir and elbasvir plus ribavirin twice daily.

 The Bottom Line

The overall cure rates were 96% (76 of 79 patients)—this included 93% (63 of 66 patients) of the genotype 1a, one hundred percent of the patients (43 of 43 patients) who DID NOT have RAVs achieved a cure.  Ninety-one percent of those who DID have NS3 RAV’s were cured and 75% (6 of 8 patients) of those who had NS5A RAVs were cured.  Of those with cirrhosis 94% were cured with this combination. 

Editorial Comment

The addition of ribavirin to grazoprevir and elbasvir works to help cure resistance-associated variants in people who have been previously treated but who have not been cured.  It is also good strategy to treat other negative predictors to current  medications.

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Article:  Ledipasvir-sofosbuvir plus ribavirin for patients with genotype 1 hepatitis C virus previously treated in clinical trials of sofosbuvir regimens—D Wyles et al.  

Source:  Hepatology. 2015 Jun;61(6):1793-7. doi: 10.1002/hep.27814. Epub 2015 Apr 27.

Results and Conclusions

There were 51 genotype 1 patients enrolled in the study (Note: one patient was incorrectly typed as genotype 1, but was subsequently correctly genotyped as genotype 3).  All of the patients in this trial were previously treated with a sofosbuvir containing regimes in Gilead’s phase 1 or phase 2 studies.  The treatment duration in this study was 12 weeks. 

Breaking it down by type of prior type of non-response:

• 25 pts (49%) had previously received sofosbuvir plus pegylated interferon plus ribavirin
• 20 pts (39%) had previously received sofosbuvir plus ribavirin
• 5 pts (10%) received sofosbuvir (sugar pill/placebo) plus pegylated interferon and ribavirin
• 1 pt (2%) received GS-0938 only fourteen patients (27%) had compensated cirrhosis.

 The Bottom Line

The total number of patients who achieved a cure was 98% (50 of 51 patients).  Among those who had received a prior course of sofosbuvir 98% (44 of 45) were cured.  The only patient who did not achieve a cure was the patient who was originally misdiagnosed as a genotype 1. 

The most common side effects were fatigue, headache and diarrhea.  The patients in this trial are considered some the most difficult to treat—those who have not achieved a cure with a previous course of a direct acting antiviral medication, those with cirrhosis, and people with resistant antiviral variants (RAVs). 

Editorial Comment

The addition of ledipasvir and ribavirin to sofosbuvir increased the cure rates to 100% for genotype 1.  Excellent results!  This is a good strategy with another type of direct acting antiviral to stop the virus from replicating and escaping.

Gilead, Merck, AbbVie, Janssen, and Achillion are working on other HCV drugs that have a higher barrier to resistance to avoid the development of resistance and to work for people who are not responding to the current medications.

FDA approves new treatment for chronic hepatitis C genotype 3 infections

The Food and Drug Administration today approved Daklinza (daclatasvir) for use with sofosbuvir to treat hepatitis C virus (HCV) genotype 3 infections. Daklinza is the first drug that has demonstrated safety and efficacy to treat genotype 3 HCV infections without the need for co-administration of interferon or ribavirin, two FDA-approved drugs also used to treat HCV infection.

Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. Most people infected with HCV have no symptoms of the disease until liver damage becomes apparent, which may take several years. Some people with chronic HCV infection develop scarring and poor liver function (cirrhosis) over many years, which can lead to complications such as bleeding, jaundice (yellowish eyes or skin), fluid accumulation in the abdomen, infections or liver cancer. According to the Centers for Disease Control and Prevention, approximately 2.7 million Americans are infected with HCV of which, approximately 10 percent are genotype 3.

“Today’s approval provides a new option for patients with genotype 3 HCV, including those patients who cannot tolerate ribavirin,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

The safety and efficacy of Daklinza in combination with sofosbuvir were evaluated in a clinical trial of 152 treatment-naive and treatment-experienced participants with chronic HCV genotype 3 infection. Participants received Daklinza 60 mg plus sofosbuvir 400 mg once daily for 12 weeks and were monitored for 24 weeks post treatment. The studies were designed to measure whether a participant’s hepatitis C virus was no longer detected in the blood 12 weeks after finishing treatment (sustained virologic response), suggesting a participant’s infection had been cured.

Results showed that 98 percent of the treatment-naive participants with no cirrhosis of the liver and 58 percent of the treatment-naive participants with cirrhosis achieved sustained virologic response. Of the participants who were treatment-experienced, 92 percent with no cirrhosis of the liver and 69 percent with cirrhosis achieved sustained virologic response. Daklinza labeling carries a Limitations of Use statement to inform prescribers that sustained virologic response rates are reduced in HCV genotype 3 infected patients with cirrhosis.

Safety information was available for approximately 1,900 patients with HCV treated with the recommended dose of Daklinza in combination with other anti-HCV drugs in clinical trials. The most common side effects of Daklinza with sofosbuvir were fatigue and headache.

Daklinza carries a warning for patients and health care providers that serious slowing of the heart rate (symptomatic bradycardia) and cases requiring pacemaker intervention have been reported when amiodarone is co-administered with sofosbuvir in combination with another HCV direct-acting antiviral, including Daklinza. Co-administration of amiodarone with Daklinza in combination with sofosbuvir is not recommended.

Daklinza was reviewed under the FDA’s priority review program, which provides for an expedited review of drugs that treat serious conditions and, if approved, would provide significant improvement in safety or effectiveness.

Daklinza is marketed by Bristol-Myers Squibb, based in Princeton, New Jersey.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Press Release Source:  http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455888.htm

Genotype 3: An Unmet Treatment Need for Some, by Alan Franciscus, Editor-in-Chief

 Originally Published June 15, 2015

 

While conducting a workshop in New England, I was asked a question about genotype 3 treatment for people who are treatment experienced and had cirrhosis—a question I am frequently asked.  At this time, we do not have an interferon-free treatment with high cure rates for this particular group of people with hepatitis C.  This is an unmet medical need for a large group of people in the United States and Worldwide.  I am asked this question at almost every workshop, which surprises me. 

There are many drugs in development that hold the promise to solve this problem.  In the meantime, there is a solution—the combination of Sovaldi, pegylated interferon and ribavirin.   When I bring up interferon, I get the cringe reaction.  It is a very understandable reaction. However, there are a couple of serious points to consider:

• Cirrhosis can be a life-threatening event.  You do not want to wait—If you have genotype 3 and cirrhosis you should consider taking action now
• Genotype 3 leads to the formation of steatosis (fatty liver)—successful treatment reduces or eliminates steatosis
• Steatosis can accelerate HCV disease progression—by itself steatosis can lead to cirrhosis
• People with genotype 3 are at increased the risk for liver disease progression and liver cancer
• Pegylated interferon and ribavirin can be difficult to tolerate, but the majority of side effects occur after 12 weeks
• The side effects of pegylated interferon and ribavirin can be managed successfully especially if the medical provider and patient are proactive

Interferon-Free Therapy
The current standard of care for genotype 3 is the combination of Sovaldi (sofosbuvir) plus ribavirin for 24 weeks.  The cure rates for treatment experienced patients without cirrhosis are 85%, but for treatment experienced patients with cirrhosis the cure rates are 60%.  Clearly, genotype 3 patients who are treatment experienced with cirrhosis are in need of better treatment options.  I have listed below two studies that include treatment of Sovaldi, pegylated interferon plus ribavirin.  Note:  I only included the information about the cure rates of the genotype 3 treatment experience patients with cirrhosis treated for 12 weeks.

Sovaldi/Peg/RBV
A recently published study in Hepatology “Sofosbuvir with Peginterferon-Ribavirin for 12 Weeks in Previously Treated Patients with Hepatitis C Genotype 2 or 3 and Cirrhosis,” –E Lawitz et al. showed very high cure rates. 

Note:  There were 47 genotype 2 and 3 patients included in the study.  Only genotype 3 results are listed below. 

There were a total of 24 genotype 3 patients with and without cirrhosis.  All were treated for 12 weeks with Sovaldi (sofosbuvir), pegylated interferon plus ribavirin. 

The cure rates were the same for those with cirrhosis 83% (10 of 12 pts) and without 83% (10 of 12 pts) in the genotype 3 patients. 

The second study was presented at EASL 2015 “Sofosbuvir Plus Peg-IFN/RBV for 12 Weeks vs Sofosbuvir/RBV for 16 or 24 Week in Genotype 3 HCV Infected Patients and Treatment-Experienced Cirrhotic Patients with Genotype 2 HCV:  The BOSON Study,” –R Graham et al. 

Note:  This study was a large study of 592 genotype 3 treatment naïve/experienced patients without and without cirrhosis.  I will only list the treatment experienced patients with cirrhosis who were treated for 12 weeks with Sovaldi (sofosbuvir), pegylated interferon plus ribavirin and the comparator arm of the treatment experienced patients with cirrhosis who received Sovaldi plus ribavirin without pegylated interferon. 

After 12 weeks of treatment the group of patients who were treated with Sovaldi, pegylated interferon plus ribavirin achieved a cure rate of 86% (30 of 35 pts) compared to a cure rate of 47% (17 of 36 pts) for those who received Sovaldi plus ribavirin but without pegylated interferon. 

The most common side effects were flu-like symptoms, fatigue, and anemia. 

 
Comments: The addition of pegylated interferon to Sovaldi and ribavirin almost doubled the cure rates for people with genotype 3 in both studies who had cirrhosis and who were treatment experience.  The best strategy is to talk with your medical provider and come up with a plan to get treated as soon as possible, seek a possible cure and stop hepatitis C in its tracks.

http://hcvadvocate.org/news/newsLetter/2015/advocate0615_mid.html#2

Nursing Times-NHS-NICE gives backing to hepatitis C drug in latest draft guidance

“The marketing authorisation for ledipasvir-sofosbuvir recommends treatment for hepatitis C genotypes 1, 3 – in combination with ribavirin – and 4”.

“Genotypes 1 and 3 hepatitis C account for the majority of chronic hepatitis C cases in England (46% and 43%, respectively). Genotype 4 hepatitis C accounts for around 4% of cases”.

“Ledipasvir-sofosbuvir, manufactured by Gilead, is administered orally as a single tablet – with or without ribavirin – and works by inhibiting the replication of the hepatitis C virus. It prevents hepatitis C virus replication by inhibiting the NS5A and NS5B proteins”.

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