A number of new HCV combination therapies show promise: A study on grazoprevir and elbasvir, the focus too of a study of the once-daily single tablet regimen of grazoprevir and elbasvir without ribavirin in people with genotypes 1, 4 or 6 hepatitis C infection. Also, an oral regimen of sofosbuvir/ledipasvir (Harvoni) and ribavirin in advanced liver disease patients.
New data shows that grazoprevir and elbasvir combination therapy produced high sustained virologic response rates among patients with hepatitis C virus infection, reports Healio.
Dr Stefan Zeuzem, department of medicine, Goethe University Hospital, Frankfurt, Germany, and colleagues randomly assigned 421 treatment-naive patients with and without cirrhosis to receive either a combinations fixed-dose of 100 mg of grazoprevir and 50 mg of elbasvir (MK-5172, MK-8742; Merck; n=316) or placebo (n=105) once daily for 12 weeks. The patients included had either HCV genotype 1, 4 or 6 infection, according to the presentation.
"The results of this study are consistent with those from the grazoprevir and elbasvir clinical study program, in which SVR12 rates of 94% to 100% were achieved in diverse patient populations," Zeuzem said during his presentation.
Overall, 95% of patients in the combination therapy group achieved a sustained virologic response at 12 weeks (SVR12). At 4 weeks, 97% of patients in the combination group had achieved SVR.
The found that 92% of patients with HCV genotype 1a reached SVR12, as well as 99% of patients with HCV genotype 1b, 100% of patients with HCV genotype 4 and 80% of patients with HCV genotype 6. Virologic failure occurred in 1.6% of patients. One patient with HCV genotype 1 experienced virologic breakthrough at 8 weeks and 4 patients relapsed (two with genotype 1a, two with genotype 6) by 4 weeks.
Less than 5% of patients in the combination therapy group experienced adverse events. The most common adverse events were headache, fatigue, nausea and arthralgia. No serious drug-related adverse events were observed. Two patients died for reasons unrelated to the drug combination.
"Grazoprevir and elbasvir were generally well-tolerated, with a similar safety profile in cirrhotic and non-cirrhotic patients," Zeuzem said.
Also, a 12-week course of treatment with two direct-acting antivirals in development by Merck cured hepatitis C infection in 90% of people with very advanced cirrhosis and at imminent risk of liver failure, Dr Ira Jacobson of Weill Cornell Medical College, New York, has reported. The preliminary phase 2 study looked at the use of the combination of the HCV protease inhibitor grazoprevir and the NS5A inhibitor elbasvir in people with Child-Pugh B cirrhosis.
People with a Child-Pugh B score have significantly impaired liver function and are at high risk for progression to decompensated cirrhosis. They also have a poor prognosis: on average, only 60% of people with Child-Pugh B cirrhosis survive for more than two years once they reach this stage of liver damage. Effective treatment for patients at this stage of liver disease is especially urgent, but until the introduction of interferon-free combinations treatment responses were very poor in this group of patients.
The C-SALT study was designed to evaluate the safety and efficacy of the once-daily single tablet regimen of grazoprevir and elbasvir without ribavirin in people with genotypes 1, 4 or 6 hepatitis C infection. The study population was restricted to people with Child-Pugh B cirrhosis.
The study was divided into two phases: a phase 2 study in which the pharmacokinetics of grazoprevir and elbasvir were assessed in cirrhotic patients in comparison to a non-cirrhotic control group of people with hepatitis C, alongside safety and efficacy assessments, and a phase 3 study in which a larger number of cirrhotic patients will be treated. Participants received grazoprevir and elbasvir for 12 weeks, without ribavirin. Grazoprevir was dosed at 50mg for cirrhotic patients rather than the usual dose of 100mg owing to the potential for higher drug levels in people with seriously impaired liver function. Elbasvir was dosed at 50mg once daily as normal, but the drugs were administered separately rather than in a single fixed-dose pill.
The study enrolled 30 participants with Child-Pugh B cirrhosis and a control group of 10 patients without cirrhosis. All participants had genotype 1 infection (90% of cirrhotics had genotype 1a, compared to 60% of non-cirrhotics). 57% of those with cirrhosis were male, and all were white. Patients had Child-Pugh B cirrhosis, and the median MELD score was 9.5 (standard deviation 2-46), indicating a moderate-to-high mortality risk in the study population.
The 12-week post-treatment (SVR12) results showed that the interferon- and ribavirin-free regimen was highly effective in this small pilot study. 95% of people with Child-Pugh B cirrhosis and 100% of non-cirrhotic controls achieved SVR12. Two post-treatment viral relapses occurred, by weeks 4 and 8 respectively, and one patient died due to liver failure after achieving end-of-treatment viral suppression.
Analysis of outcomes according to Child-Pugh score showed that a Child Pugh B score of 7 or less was associated with an SVR12 rate of 95%, whereas a score of 9 or above was associated with an SVR12 rate of 50%. Adverse events were no more frequent in the cirrhosis arm, with the exception of a higher frequency of grade 3 or 4 bilirubin elevations (13.3% vs 0%), which resolved after the completion of treatment.
And, an oral regimen of sofosbuvir/ledipasvir (Harvoni) and ribavirin taken for 12 or 24 weeks produced sustained virological response rates of 85-88% for genotype 1 or 4 hepatitis C patients with decompensated cirrhosis and 95-98% for liver transplant recipients with less advanced liver damage, according to results from the SOLAR-2 study.
Direct-acting antiviral agents in interferon-free regimens have revolutionised hepatitis C treatment, curing most patients including those traditionally considered difficult to treat. But challenges remain for people with advanced liver disease, including those with decompensated cirrhosis (when the liver can no longer carry out its vital functions) and patients who are awaiting or have received liver transplants.
Michael Manns of Hannover Medical School in Germany and fellow investigators with the SOLAR-2 trial evaluated the safety and efficacy of the nucleotide HCV polymerase inhibitor sofosbuvir and NS5A inhibitor ledipasvir, taken as a once-daily fixed-dose coformulation, plus daily ribavirin for people with advanced liver disease.
This phase 2 study enrolled more than 300 chronic hepatitis C patients in Europe, Canada, Australia and New Zealand. Three-quarters were men, more than 90% were white and the median age was nearly 60 years. Most had HCV genotype 1 (about half with 1a and 40% with 1b) while about 10% had genotype 4. About 80% had received prior treatment without being cured.
SOLAR-2 included 160 people with decompensated cirrhosis who were either awaiting or had received liver transplants. They were classified as Child-Pugh-Turcotte (CPT) class B or C, an index of liver disease severity based on bilirubin and albumin levels, blood clotting capacity and presence of ascites or hepatic encephalopathy. About one-quarter of the CPT B/C patients had a MELD score greater than 15 (another measure of liver disease severity). The study also included 168 liver transplant recipients with recurrent HCV who had less severe liver disease – CPT Class A and absent to advanced liver fibrosis (stage F0-F3).
Participants were randomly assigned to receive sofosbuvir/ledipasvir plus ribavirin for either 12 or 24 weeks. Manns explained that when the study was designed it was not yet known how well sofosbuvir/ledipasvir without ribavirin would work for patients with advanced disease, so there was no ribavirin-free arm.
Preliminary results showed that after 12 weeks of post-treatment follow-up, the CPT B/C patients had sustained virological response (SVR12) rates of 85% with 12 weeks of treatment and 88% with 24 weeks. In the CPT A group SVR12 rates were 95% and 98%, respectively. A single genotype 1 CPT A patient, six genotype 1 CPT B/C patients and three genotype 4 CPT B/C patients relapsed after finishing treatment.
Overall cure rates were similar for 12 and 24 weeks of therapy. Participants with CPT B responded somewhat better than those with CPT C, and within the CPT C group pre-transplant patients did better than post-transplant patients. Looking only at the genotype 1 patients, the SVR12 rates were similar to the overall rates. Among genotype 4 CPT B/C patients, however, only 57% were cured with 12 weeks of therapy, rising to 86% with 24 weeks; the corresponding rates were 91% and 100% for genotype 4 CPT A patients. Mann cautioned that the genotype 4 numbers were too small to make meaningful comparisons, though he suggested that 24 weeks is probably preferable for genotype 4.
Sustained viral suppression was associated with improved liver function. Almost all CPT class A participants remained the same, 35% of those initially classified as class B reverted to class A, while 48% of those classified as class C reverted to class B and 5% to class A. CPT and MELD scores fell largely due to decreased bilirubin and improved ability to synthesize proteins such as albumin.
Given that this was a population with advanced disease, almost all participants experienced some adverse events. About 15% of CPT A patients and 28% of CPT B/C patients had serious adverse events, but only a few cases were deemed related to the study drugs. Twelve participants died during the study – mostly due to liver-related complications – but no deaths were considered treatment-related. Six patients discontinued treatment due to adverse events, all but one of whom had decompensated cirrhosis. The most common adverse events were fatigue, anaemia, nausea and headache.
Sofosbuvir/ledipasvir plus ribavirin "resulted in high SVR2 rates in HCV patients with advanced liver disease, irrespective of transplantation status," the researchers concluded. They added that this regimen "was generally safe and well-tolerated in patients with advanced liver disease, pre- and post-liver transplantation."
Looking at another group of patients with advanced liver disease, Xavier Forns and colleagues describe 11 participants in SOLAR-1 and SOLAR-2 who developed fibrosing cholestatic hepatitis, a rare severe form of recurrent hepatitis that can occur after liver transplantation. All of these patients achieved SVR12 after 12 or 24 weeks of treatment with sofosbuvir/ledipasvir plus ribavirin, according to a press release issued by manufacturer Gilead Sciences.
"The patients included in these analyses are among the most difficult to both treat and cure and, until now, have had limited or no treatment options," Mann stated in the release, commenting on both studies. "These data demonstrate that, even among these difficult-to-treat patient groups, sofosbuvir-based oral therapy offers the potential of high cure rates, improves outcomes and is generally well tolerated with a favourable safety profile."
[link url="http://www.healio.com/hepatology/hepatitis-c/news/online/%7Be46d7447-13c4-4574-ace5-95d5806f05ea%7D/c-edge-grazoprevirelbasvir-regimen-yielded-high-svr-rates-in-patients-with-hcv"]Full Healio report[/link]
[link url="http://annals.org/article.aspx?articleid=2279766&resultClick=3"]Annals of Internal Medicine abstract[/link]
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[link url="https://ilc-congress.eu/abstract_25_04/ILC2015-abstract-book-25-04-Saturday.pdf"]EASL Congress 2015 G02 abstract[/link]
[link url="https://ilc-congress.eu/abstract_25_04/ILC2015-abstract-book-25-04-Saturday.pdf"]EASL Congress 2015 P0779 abstract[/link]
[link url="http://www.gilead.com/news/press-releases/2015/4/gileads-harvoni-and-sovaldi-demonstrate-efficacy-and-safety-among-chronic-hepatitis-c-patients-with-advanced-liver-disease"]Gilead Sciences material[/link]