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.
___________
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.
____________________
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.
