New direct-acting antivirals for the treatment of hepatitis C virus (HCV) have moved a step closer to becoming available in the European Union and the United States in the past month.

On November 22, the European Medicines Agency recommended sofosbuvir for approval in the European Union. Sofosbuvir is a nucleotide polymerase inhibitor. Full recommendations on how the drug should be used will be issued when full marketing approval is granted during the first three months of 2014. The licence is likely to recommend its use in combination with pegylated interferon and ribavirin in genotype 1 infection, and in combination with ribavirin in genotype 2 and 3 infections. Sofosbuvir will be known by the brand name Sovaldi.

In the United States, both sofosbuvir and the second-generation HCV protease inhibitor simeprevir have received marketing approval in the past month.

Simeprevir will be marketed in the United States as Olysio, for use in combination with pegylated interferon and ribavirin by people with genotype 1 infection. The US Food and Drug Administration has strongly recommended that people with genotype 1a infection should be tested for a naturally occurring resistance mutation, Q80K, which substantially reduces the effect of simeprevir. This mutation may be present in up to half of people with genotype 1a infection in the United States.

Sofosbuvir has been approved in the United States for use in combination with pegylated interferon and ribavirin in genotype 1 infection, and in combination with ribavirin in genotype 2 and 3 infections. Its use may also be considered in combination with ribavirin for people with genotype 1 infection who are ‘ineligible’ for pegylated interferon. According to a poll of US physicians undertaken last week, the majority would consider a patient ‘ineligible’ to take interferon if they were unwilling to do so.

There has been considerable comment regarding the price of both drugs, and the implications of pricing for access to treatment in the United States.

The cost of a 12-week course of Olysio has been set at $66,360, roughly comparable to the cost of first-generation protease inhibitors telaprevir (called Incivo in Europe and Incivek in the US) and boceprevir (Victrelis). Pegylated interferon and ribavirin for use alongside simeprevir will cost around $18,000. The Fair Pricing Coalition urged Janssen to set a lower price and expressed concern about the possibility of price increases in the future. In the United States, many health insurance plans require patients to make substantial co-payments towards the cost of medication; the Fair Pricing Coalition expressed concern that substantial co-payments may restrict access to the drug. Janssen has established several mechanisms to help patients pay for the cost of treatment with simeprevir.

The pricing of sofosbuvir has attracted criticism too. At approximately $84,000 for a 12-week course of treatment, the drug will cost about $1000 a day. A 24-week course of treatment for genotype 3 in combination with ribavirin will cost more than $168,000. In response to proposals from the Fair Pricing Coalition, the drug’s manufacturer Gilead has agreed to a patient assistance programme and to contribute towards co-payments for the drug up to a ceiling of $16,000.

A large US company which negotiates drug prices on behalf of pharmacies, insurance plans and managed care organisations has warned that if other interferon-free combinations are cheaper, it will not pay for the more expensive combinations, even if they are more convenient to take. More formal appraisals of cost-effectiveness are likely to take place in most countries before the new hepatitis C drugs are approved for reimbursement. This means that there could be a long delay between licensing and reimbursement approval for new hepatitis C drugs in some European countries.

In an interview, published this week in the newsletter of the Hepatitis B & C Public Policy Association, Professor Jean-Michel Pawlotsky, director of the French National Reference Center for Hepatitis B and C, expressed concern about the possible restrictions on the prescribing of new hepatitis C drugs in Europe. He said that pressure from professional groups and patient associations would be essential to ensure access, and that “Close collaboration between medical societies and patients’ associations is therefore key and no major move has taken place over the past years without such collaboration.”

 There have also been calls for sofosbuvir to be made accessible to low- and middle-income countries, either through tiered pricing or through generic production in India. The Open Society Foundation says that current pricing of sofosbuvir means it is unavailable to 90% of the world’s population of people with hepatitis C. Gilead has promised it will announce its plans for tiered pricing in early 2014. Meanwhile, activists in India have launched a bid to prevent a patent approval for sofosbuvir in India. If the patent application is turned down – on the grounds of insufficient novelty – Indian manufacturers will be free to make sofosbuvir. Some countries may also be able to import any generic versions of sofosbuvir produced in India if they do not have trade agreements that prohibit such imports.

AbbVie is developing an interferon-free combination of three drugs plus ribavirin to treat hepatitis C. Results from two phase III studies to support marketing approval have been announced by AbbVie in the past month. Both studies show impressive results.

In the SAPPHIRE 1 study, 96% of previously untreated patients with genotype 1 infection achieved sustained virological response at 12 weeks – SVR12 (cure). This group of patients had mild-to-moderate fibrosis, and so would be considered easier to treat.

In the SAPPHIRE 2 study, 96% of patients who had previously experienced treatment failure with pegylated interferon and ribavirin, achieved SVR12 on the interferon-free combination. Approximately half the study participants had been previous null responders (they had not reached a sufficient viral response after 12 weeks of interferon treatment), and so would be considered a more difficult-to-treat patient population.

There was no difference in response between genotype 1a and 1b in either study.

Results from further studies will report on the efficacy of the combination in treatment-experienced patients, and also determine whether there are differences between genotypes 1a and 1b and between treatment-naïve and treatment-experienced patients in their need for ribavirin. The Turquoise study is comparing 12- and 24-week ribavirin-containing regimens in people with genotype 1, including those with cirrhosis.

AbbVie expects to submit licensing applications for the combination in the United States and European Union in the spring of 2014 and hopes to achieve marketing approval by early 2015.

Another new HCV protease inhibitor for treatment of genotype 1 infection is likely to receive marketing approval in 2014. Faldaprevir is being developed by Boehringer-Ingelheim, first of all for use in combination with pegylated interferon and ribavirin. The company hopes to develop an interferon-free combination including faldaprevir subsequently. The company announced this week that analysis of phase III studies also shows that the Q80K mutation, which limits response to simeprevir, does not have any impact on response to faldeprevir in people with genotype 1a infection.

An analysis of phase II studies of faldaprevir, presented at The Liver Meeting in early November, showed that people with genotype 1b infection were more likely than genotype 1a patients to achieve SVR when treated with an interferon-free triple therapy containing faldaprevir, deleobuvir and ribavirin, as were people with the IL28B ‘CC’ genotype, white and Asian patients and patients without cirrhosis.

A study of faldaprevir plus pegylated interferon and ribavirin in people with HIV and HCV co-infection was also presented at The Liver Meeting. The study presented results four weeks after treatment, which are not final results. Depending on the dose of faldaprevir they received, between 72 and 84% of participants in the study achieved a sustained virologic response at week 4 (SVR4). In this study, there was no difference in response between genotype 1a and 1b.

Faldaprevir is also being tested as part of an interferon-free combination. Early results suggest that the combination is very effective in harder-to-treat patients with genotype 1a infection.

Over years or decades, chronic hepatitis C virus (HCV) infection can lead to serious liver disease including cirrhosis, hepatocellular carcinoma (HCC) and end-stage liver failure. Up to 20% of people with chronic hepatitis C develop cirrhosis within 20 years, and among these patients, the risk of HCC may reach 4%. Successful treatment of hepatitis C has the potential to slow or halt liver disease progression and reduce the risk of long-term consequences including liver cancer and liver-related death.

A study of US patients found that a successful response to treatment reduced the risk of subsequent liver-related ill health by 27% and the risk of death by 45%. It is possible that the relatively low reduction in ill health was a consequence of very late treatment. If people were treated before the onset of liver cirrhosis, for example, they might have fewer subsequent liver-related problems. HCV is curable but it is much less likely that severe liver damage can be completely reversed by hepatitis C treatment. People who develop cirrhosis as a consequence of HCV infection remain at higher risk of liver cancer even if they are cured of HCV infection, for example.

Another study presented at The Liver Meeting in early November showed that only half of people in the United States with hepatitis C have been diagnosed, 32 to 38% get referred to care, 7 to 11% start treatment and only 5 to 6% are successfully treated.

Hepatitis C can live for six weeks outside the body

American researchers have discovered that when blood containing HCV is sprayed onto surfaces like metal, glass or plastic, the virus can live for up to six weeks at room temperature. Used at the right concentration, bleach removed all traces of HCV, but other medical disinfectants sometimes failed to remove the virus, especially if not used at the recommended levels. The findings explain why so many HCV infections occur in healthcare settings where rigorous infection control fails to be practised, say the researchers. Previously published research has shown even longer survival periods for HCV outside the body at stable temperatures, although that study indicated that the highest risk existed in the 24-hour period after blood samples were taken.

Hepatitis B vaccine protects for 30 years

Follow up of people in Canada who were among the first to receive a hepatitis B vaccine, in 1981, shows that after 30 years the majority of vaccinated people are still protected against hepatitis B.

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