Sofosbuvir plus pegylated interferon/ribavirin is highly effective for people with hard-to-treat genotype 3 hepatitis C

Graham Foster of Queen Mary's University of London presenting results of the BOSON study. Photo by Liz Highleyman,
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A throwback regimen of sofosbuvir (Sovaldi), ribavirin and pegylated interferon taken for 12 weeks cured 93% of people with hepatitis C virus (HCV) genotype 3 – substantially more than sofosbuvir plus ribavirin alone taken for 16 or 24 weeks, according to results from the BOSON study presented on Saturday at the European Association for the Study of the Liver (EASL) 50th International Liver Congress in Vienna, Austria. Interferon-containing therapy for three months was described as "surprisingly well-tolerated".

The advent of direct-acting antiviral agents has brought about a revolution in treatment for chronic hepatitis C. As direct-acting antivirals were developed they were first tested in combination with pegylated interferon and ribavirin, the old standard of care. But researchers soon discovered that most people could be cured of hepatitis C using all-oral regimens without interferon, which must be injected and often causes difficult side-effects.

However, people with HCV genotype 3 do not respond as well to available interferon-free regimens, and those with liver cirrhosis and non-responders to prior therapy are particularly in need of more effective treatment options.



Severe fibrosis, or scarring of organs. The structure of the organs is altered, and their function diminished. The term cirrhosis is often used in relation to the liver. 

sustained virological response (SVR)

The continued, long-term suppression of a virus as a result of treatment. In hepatitis C, refers to undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 12 or 24 weeks after ending treatment and is considered to be a cure (SVR12 or SVR24).

pegylated interferon

Pegylated interferon, also known as peginterferon, is a chemically modified form of the standard interferon, sometimes used to treat hepatitis B and C. The difference between interferon and peginterferon is the PEG, which stands for a molecule called polyethylene glycol. The PEG does nothing to fight the virus. But by attaching it to the interferon (which does fight the virus), the interferon will stay in the blood much longer. 


A drug that acts against a virus or viruses.


To eliminate a disease or a condition in an individual, or to fully restore health. A cure for HIV infection is one of the ultimate long-term goals of research today. It refers to a strategy or strategies that would eliminate HIV from a person’s body, or permanently control the virus and render it unable to cause disease. A ‘sterilising’ cure would completely eliminate the virus. A ‘functional’ cure would suppress HIV viral load, keeping it below the level of detection without the use of ART. The virus would not be eliminated from the body but would be effectively controlled and prevented from causing any illness. 

Graham Foster of Queen Mary's University of London and fellow investigators conducted the BOSON study to explore whether returning to an interferon-containing regimen could raise cure rates for people with hard-to-treat genotype 2 and 3 HCV.

Prior clinical trials showed that sofosbuvir plus ribavirin taken for 12 weeks cured 82% of people with HCV genotype 2 who had cirrhosis, Foster noted as background. Among people with genotype 3, this dual combination taken for 24 weeks cured only 68% of people with cirrhosis. These rates fall well below the 95% or greater sustained response rates that are now expected for people with easier-to-treat HCV.

The phase 3 BOSON trial (GS-US-334-0153) included 592 people – 48 with genotype 2 and 544 with genotype 3 – enrolled in the UK, North America, Australia and New Zealand. All participants with genotype 2 were both treatment-experienced and had compensated cirrhosis. Among the participants with genotype 3, about half were prior non-responders and about a third had cirrhosis.

Overall, 67% of participants were men, the mean age was 50 years, most were white and 13% were Asian. More than two-thirds had unfavourable IL28B gene variants associated with poor interferon response and the mean baseline HCV viral load was 6.3 log10.

Participants were randomly assigned to receive extended-duration therapy with 400mg once-daily sofosbuvir plus 1000-1200mg weight-based ribavirin for either 16 or 24 weeks, or else sofosbuvir and ribavirin with 180mcg once-weekly pegylated interferon for 12 weeks. The primary endpoint was sustained virological response, or HCV RNA below the lower limit of quantification (<15 IU/ml) at 12 weeks after the end of treatment (SVR12).

Looking first at the hard-to-treat genotype 2 patients, SVR12 rates were 87% for sofosbuvir plus ribavirin for 16 weeks, 100% for the dual regimen for 24 weeks, and 94% for sofosbuvir plus ribavirin with pegylated interferon for 12 weeks.

Turning to the larger group of participants with genotype 3, sustained response rates were 71% for sofosbuvir plus ribavirin for 16 weeks and 84% for 24 weeks, but rose to 93% for sofosbuvir plus ribavirin with pegylated interferon – the highest cure rate observed to date for this challenging population in a phase 3 study.

Within the genotype 3 group, SVR12 rates were 80%, 87% and 95%, respectively, for people without cirrhosis. The most dramatic improvement in response was seen for people with cirrhosis: 51% with sofosbuvir and ribavirin for 16 weeks, 79% for 24 weeks and 88% with interferon. Among previously untreated patients, SVR12 rates were 77%, 88% and 95%, respectively. A big improvement was also seen when adding interferon for treatment-experienced patients: 64%, 80% and 91%, respectively.

Focusing on the patients Foster described as the "toughest of the tough" – genotype 3 prior non-responders with cirrhosis – the cure rate rose from just 47% for sofosbuvir plus ribavirin taken for 16 weeks to 86% for the interferon-containing regimen taken for 12 weeks. All other subgroups had SVR12 rates above 80% using the interferon-free dual regimen for 24 weeks, confirming that this is the preferred duration for difficult-to-treat patients.

Poor tolerability is a major reason for avoiding interferon, but the short interferon-containing regimen in this study was "by and large very well-tolerated," Foster said. The most frequently reported adverse events across all treatment arms were fatigue, headache, insomnia and nausea. Flu-like illness and fever were more common with the interferon-containing regimen.

While almost all participants in all treatment arms reported some adverse events, grade 3-4 (moderate to severe) events were uncommon: 6% with sofosbuvir plus ribavirin for 16 weeks, 4% with the dual regimen for 24 weeks and 8% with the interferon-containing regimen for 12 weeks. Serious adverse events (4%, 5% and 6%, respectively) and treatment discontinuations due to adverse events (2%, 1% and <1%) were rare and occurred with similar frequency across treatment arms. Grade 3-4 laboratory abnormalities, however, were more than twice as common in the interferon-containing arm (15%, 15% and 38%, respectively) owing to anaemia and reduced platelet counts.

The surprisingly good tolerability of pegylated interferon in this study may be attributable to its short duration, Foster suggested. Before the advent of direct-acting antivirals, the usual course of pegylated interferon/ribavirin was 24 weeks for HCV genotypes 2 and 3 or 48 weeks for genotypes 1 and 4.

Based on these results, treatment-experienced patients with genotype 2 who had cirrhosis had "high SVR12 rates with all regimens," while people with genotype 3 had "higher SVR12 rates with sofosbuvir plus pegylated interferon/ribavirin than with sofosbuvir plus ribavirin for 16 or 24 weeks," the researchers concluded. They added that all three regimens were "well-tolerated with a low rate of treatment discontinuation due to adverse events."

While most people with hepatitis C and health professionals seek to avoid interferon-containing therapy in the direct-acting antiviral era, Foster said that "interferon may still have a role to play" for niche patient populations.

"I don't think any of us are happy going back to interferon and ribavirin, but these are patients who can't wait for the next generation [of antivirals]," he said. "It is an interim solution – I don't think any of us are pretending this is a prefect long-term option."

Asked about using sofosbuvir/ledipasvir (Harvoni) for this patient population, Foster explained that ledipasvir "doesn't have much activity" against HCV genotype 3. Sofosbuvir plus Bristol-Myers Squibb's HCV NS5A inhibitor daclatasvir (Daklinza) is a potential interferon-free alternative. Gilead Sciences, which produces sofosbuvir and Harvoni, is also working on a pangenotypic NS5A inhibitor (GS-5816) with more potent activity against genotype 3.


Foster GR et al. Sofosbuvir + peginterferon/ribavirin for 12 weeks vs sofosbuvir + ribavirin for 16 or 24 weeks in genotype 3 HCV infected patients and treatment-experienced cirrhotic patients with genotype 2 HCV: the BOSON study. EASL 50th International Liver Congress, Vienna, abstract L05, 2015.