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Studies Show High Cure Rates for Interferon-free Hepatitis C Treatment

An all-oral combination of daclatasvir (Daklinza) plus asunaprevir led to sustained virological response (SVR) in 82%-90% of treatment-naive and previously treated people with hepatitis C virus genotype 1b, while a regimen of sofosbuvir (Sovaldi) plus simeprevir (Olysio) cured 92%-94% of hepatitis C patients with or without cirrhosis, according to findings from a pair of clinical trials reported in the July 28 advance online edition of The Lancet.

Daclatasvir + Asunaprevir

Michael Manns from Hanover Medical School and fellow investigators with the HALLMARK-DUAL trial evaluated a 2-drug regimen of the HCV NS5A replication complex inhibitor daclatasvir and the NS3 protease inhibitor asunaprevir for people with HCV subtype 1b, the easier-to-treat variant of genotype 1.

As previously reported at the EASL International Liver Congress in April, this Phase 3 study included 747 participants in 18 countries. Previously untreated patients were randomly assigned to receive 60 mg once-daily daclatasvir plus 100 mg twice-daily asunaprevir or placebo for 24 weeks. Prior non-responders and patients who were ineligible for or intolerant of interferon received open-label daclatasvir plus asunaprevir for 24 weeks.

At 12 weeks post-treatment, SVR12 rates were 90% for the treatment-naive group, 82% for prior non-responders, and 82% for the ineligible/intolerant group. Treatment was generally safe and well-tolerated with 5%-7% experiencing serious adverse events and 1%-3% stopping therapy early for this reason.

"These results support the use of daclatasvir plus asunaprevir as an all-oral, interferon-free and ribavirin-free treatment option for patients with HCV genotype 1b infection, including those with cirrhosis," the researchers concluded.

Daclatasvir and asunaprevir drugs are under FDA review in the U.S., have been approved in Japan, and daclatasvir has received a favorable opinion in Europe.

Sofosbuvir + Simeprevir

As also previously reported at the EASL meeting, Eric Lawitz from the Texas Liver Institute and fellow investigators with the COSMOS trial evaluated a dual combination of the HCV polymerase inhibitor sofosbuvir and the protease inhibitor simeprevir, both of which were approved in late 2013.

COSMOS included 167 participants with HCV genotype 1, both treatment-naive and prior non-responders, divided into 2 cohorts with absent to moderate fibrosis (stage F0-F2) or advanced fibrosis or cirrhosis (stage F3-F4). Particpants were randomly assigned to receive 400 mg sofosbuvir plus 150 mg simeprevir, both once-daily, for 12 or 24 weeks, with or without ribavirin.

SVR12 rates were 92% in the non-cirrhotic cohort and 94% for patients with advanced fibrosis or cirrhosis. Again, treatment was generally safe and well-tolerated, with 2% overall experiencing serious adverse events and 2% stopping treatment early due to adverse events.

While the FDA-sanctioned label indications for sofosbuvir and simeprevir do not include their combined use, this off-label approach is recommended in recent AASLD/IDSA/IAS-USA and EASL guidelines for people who cannot tolerate or will not use interferon.

Below is an edited excerpt from a press release issue by The Lancet describing the 2 studies and their findings.

The Lancet: New Oral Drug Regimens Cure Hardest-to-treat Hepatitis C Infected Patients and Could Improve Treatment Uptake

July 27, 2014 -- Two new pill-only antiviral drug regimens could provide shorter, more effective treatment options with fewer side effects for the majority of patients infected with hepatitis C, even those most difficult to treat, according to the results of two studies published in The Lancet. Both studies focused on hepatitis C genotype 1, which is the most common genotype in the USA, Europe, North Asia, Australia, and South America, and one of the most difficult to treat.

Around 150 million people worldwide have chronic hepatitis C virus (HCV) infection, a condition that is a major cause of liver cirrhosis and liver cancer. In the USA, numbers of people with HCV-related liver failure and liver cancer are expected to treble by 2030 because of low treatment rates.

Until recently, the standard of care for chronic HCV genotype 1 involved a combination of three drugs: ribavirin (RBV), pegylated interferon (PEG), and a protease inhibitor [boceprevir or telaprevir], which together inhibit viral replication and enhance the body’s immune response to eradicate the virus. These drugs can place a substantial burden on the patient, with complicated injection and pill regimens, which can involve up to 18 tablets a day and last for up to a year, and can also cause severe side effects including anemia and depression. Direct-acting antiviral agents (DAAs) provide new opportunities for treatment whilst reducing the need for interferon and ribavirin and their potential side effects.

In the HALLMARK-DUAL phase 3 study, Professor Michael Manns from Hannover Medical School in Germany and colleagues randomly assigned 645 patients with HCV genotype 1b from 18 countries to receive a 6-month course of treatment with a pair of oral DAAs asunaprevir and daclatasvir. A further 102 treatment-naive patients were assigned to a placebo control group. The regimen was highly effective at clearing the virus and well tolerated even in patients who have traditionally been the hardest to treat. 90% of previously untreated patients and 82% who were intolerant of, or who had been treated unsuccessfully using standard regimens, were cured. No differences in response were seen in individuals who had characteristics such as being male, older, African American race, or having advanced liver disease -- that are recognized as predictors of poor response to treatment.

According to Professor Manns, "The efficacy and safety of 24 weeks of daclatasvir plus asunaprevir represents a huge improvement on the first generation of protease inhibitor based triple therapies for HCV genotype 1b infection (up to 48 weeks of boceprevir or telaprevir in combination with PEG/RBV). This new all-oral interferon and ribavirin-free combination could provide a more effective, safer, shorter, and simpler treatment option for those traditionally hard-to-cure patients with cirrhosis or those who have failed to respond to existing therapies."

In the COSMOS study, a team of US and European researchers led by Professor Eric Lawitz from the Texas Liver Institute, University of Texas Health Science Center in San Antonio randomly assigned 167 individuals with HCV genotype 1a and 1b to receive a 12-week or 24-week course of once-daily sofosbuvir plus simeprevir with or without ribavirin. After just 12 weeks of treatment without ribavirin, 93% of participants (including those with cirrhosis and previous non-responders to interferon-based treatment) were cured -- with no detectable virus in their blood 3 months after treatment had stopped. Neither extending treatment to 24 weeks nor adding ribavirin provided any clear benefit. The 12-week sofosbuvir plus simeprevir regimen was well tolerated with less than 2% of participants reporting serious adverse events or discontinuing treatment due to an adverse event.

According to Professor Lawitz, "We saw a cure rate of about 93% with only 12 weeks of treatment using an all-oral regimen that did not include interferon or ribavirin. This is especially encouraging given the high proportion of participants who had multiple characteristics traditionally associated with low cure rates including cirrhosis. This is the first trial combining two DAAs that are currently on the market and supports recent American Association for the Study of Liver Diseases/Infectious Disease Society of America (AASLD/IDSA) and the European Association for the Study of the Liver (EASL) treatment recommendations."

Writing in a linked Comment, Professor Ed Gane, Director of the New Zealand Liver Transplant Unit at Auckland City Hospital in New Zealand says, "In the future, very-short-duration, all-oral DAA regimens should improve treatment uptake and success, and reduce the health burden from liver-related complications. When combined with targeted testing and treatment of populations who transmit infection (i.e., treatment as prevention), these DAA regimens might eventually eliminate HCV infection."

"The only barrier to achieving this goal will be the ability to access these new therapies. In many developing countries where HCV is endemic, interferon-based therapy will remain the first choice because of the high cost of DAAs and lack of reimbursement. As almost 75% of all patients with HCV infection reside in economically deprived regions of eastern Europe, Asia, and the Middle East, consideration should be given to discounting prices in these regions. Eradication of HCV infection worldwide will only be achievable through universal access to HCV testing and new DAA regimens."

8/12/14

References

M Manns, S Pol, IM Jacobson, et al. All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. The Lancet. July 28, 2014 (Epub ahead of print).

E Lawitz, MS Sulkowski, R Ghalib, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. The Lancet. July 28, 2014 (Epub ahead of print).

E Gane. Hepatitis C beware -- the end is nigh. The Lancet. July 28, 2014 (Epub ahead of print).

Other Source

The Lancet. New oral drug regimens cure hardest-to-treat hepatitis C infected patients and could improve treatment uptake. Press release. July 27, 2014.