Anita Kohli, presenting at CROI 2014. Photo by Liz Highleyman, hivandhepatitis.com.

Interferon- and ribavirin-free treatment using sofosbuvir, ledipasvir and a third direct-acting drug for as little as six weeks can cure most previously untreated people with genotype 1 hepatitis C virus (HCV), including those with traditional predictors of poor response, according to results from the SYNERGY trial presented at the 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014) in early March.

SYNERGY enrolled 60 mostly low-income people with chronic hepatitis C in Washington, DC. Most had factors traditionally associated with poor treatment response: about 70% were men, around 90% were African-American, about 85% had unfavourable non-CC IL28B gene variants and 70% had hard-to-treat HCV subtype 1a. About one-quarter had advanced liver fibrosis or cirrhosis, but people with cirrhosis were excluded from the six-week arms.

Simeprevir, the HCV protease inhibitor developed by Janssen and Medivir, received a positive scientific opinion from the European Medicines Agency Committee on Human Medicinal Products (CHMP) in March and is likely to receive marketing approval in June 2014.

Simeprevir will be marketed as Olysio in Europe. It is taken once daily. Approval was based on the results of trials in which simeprevir was taken in combination with pegylated interferon and ribavirin. The licensing indication states that simeprevir should be used in combination with other medicinal products. This license will allow simeprevir to be combined with sofosbuvir or daclatasvir in an interferon-free combination.

Janssen released new analyses from phase III studies showing that in genotype 1b infection simeprevir combined with pegylated interferon and ribavirin cured 85% of previously untreated patients and 86% of previous non-responders. Janssen also released data showing that simeprevir was non-inferior to telaprevir when combined with pegylated interferon and ribavirin. The ATTAIN study, conducted in treatment-experienced patients, found that patients who received simeprevir were significantly less likely than patients who received telaprevir to experience any adverse events, serious adverse events or to discontinue treatment because of adverse events.

Prof. Rajendar Reddy, of the University of Pennsylvania Hospital, presenting at CROI 2014. Photo by Liz Highleyman, hivandhepatitis.com.

Genotype 1b is the most common genotype of hepatitis C globally, and comprises the largest proportion of infections in the European region, Latin America, Russia, Turkey, China and Japan.

While genotype 1b was traditionally considered difficult to treat in the era of dual interferon and ribavirin therapy, it has been found to respond well to many new antiviral HCV regimens with and without interferon.

AbbVie’s '3D' combination of direct-acting antivirals cured 99% of previously untreated patients with genotype 1b infection after a 12-week course of treatment in the PEARL III study. The study evaluated treatment with a combination of the HCV protease inhibitor ABT-450 boosted with ritonavir co-formulated with the HCV NS5A inhibitor ABT-267, plus the HCV non-nucleoside polymerase inhibitor ABT-333. These were tested with or without ribavirin, in people who had not taken treatment before.

PEARL III is one of six phase III studies of the ‘3D’ combination in various populations. These studies will support marketing applications for the combination. AbbVie hopes to obtain US marketing approval before the end of 2014 and European approval shortly afterwards.

Prof. Douglas Dieterich of Mount Sinai School of Medicine discusses recent advances in treatment of hepatitis C and HIV co-infection at CROI 2014. Photo by Liz Highleyman / hivandhepatitis.com

HIV infection speeds the progression of liver disease in people living with HIV and hepatitis C co-infection. Interferon-based hepatitis C treatment has been less effective in people with co-infection. Access to new therapies for people with co-infection may close the gap, according to results of three major trials released this month. Cure rates for hepatitis C in people with HIV co-infection are now just as good as those in people with hepatitis C mono-infection, the studies show.

Almost 80% of people with HIV and hepatitis C co-infection treated with simeprevir plus pegylated interferon and ribavirin were cured after 24 or 48 weeks of treatment. The study recruited previously untreated and treatment-experienced patients with genotype 1 infection. All participants apart from previous null responders were eligible for response-guided therapy. Of the participants who achieved a cure in this study, 89% were treated for 24 weeks.

An interferon-free regimen of sofosbuvir plus ribavirin for 24 weeks led to sustained response in three-quarters of previously untreated people with genotype 1 hepatitis C and HIV co-infection in the PHOTON-1 study. The study recruited people with genotype 1 infection. The current US licence for sofosbuvir recommends a 12-week course of sofosbuvir with pegylated interferon and ribavirin.

Approximately 70% of people with HIV and HCV co-infection who received faldaprevir, pegylated interferon and ribavirin were cured after 24 or 48 weeks of treatment. The study recruited patients with genotype 1 infection. IL28B genotype influenced treatment response in this study: people with a favourable IL28B cc genotype, indicating a better response to interferon, were significantly more likely to achieve SVR12. People with cirrhosis (15% of study participants) were just as likely to achieve SVR 12 as people without cirrhosis. This finding has led some experts to speculate that faldaprevir may have a particular role in treating people with cirrhosis.

Trevor Hawkins, from the Southwest CARE Center in New Mexico, presenting at CROI 2014. Photo by Liz Highleyman, hivandhepatitis.com.

An interferon-free combination being developed by Bristol-Myers Squibb cured 92% of previously untreated patients with genotype 1 infection. The combination comprises the NS5A inhibitor daclatasvir, the protease inhibitor asunaprevir and the non-nucleoside BMS-791325, dosed for 12 weeks. The combination is now being studied in larger phase III trials in preparation for a marketing application.

Bristol-Myers Squibb's NS5A inhibitor daclatasvir has shown promising outcomes in all-oral combinations with drugs including the HCV protease inhibitor asunaprevir and Gilead Sciences' recently approved HCV polymerase inhibitor sofosbuvir (Sovaldi). The daclatasvir/asunaprevir combination has been submitted for approval in Japan, and the US FDA has designated it as a 'breakthrough therapy' for expedited review. Daclatasvir is pending European Union approval for use with other direct-acting agents.

An all-oral regimen of daclatasvir plus simeprevir, without interferon or ribavirin, led to sustained response in 85 to 95% of people with hepatitis C genotype 1b, but this combination did not work as well against genotype 1a, researchers reported in March at the 21st Conference on Retroviruses and Opportunistic Infections (CROI) in Boston.

An all-oral combination of the hepatitis C virus (HCV) protease inhibitor MK-5172 and NS5A inhibitor MK-8742, with or without ribavirin, demonstrated promising end-of-treatment viral suppression in people with HIV and HCV co-infection and high cure rates for people with hepatitis C alone, according to findings from the C-WORTHY study presented at recent conferences.

Professor David Goldberg, who led the widely recognised and successful Scottish National Hepatitis C Action Plan, puts forward recommendations in a new report for raising the standards of HCV services and care across the European Union (EU).  

These include:

• Establishment of HCV case-finding standards for the EU.
• 5-10% annual increase in the proportion of estimated HCV-infected population who are diagnosed.
• Development of HCV clinical standards for delivery of services to people with HCV to ensure consistent standard of care across the EU.
• Establishment of an EU standard for the development and implementation of funded national action plans for HCV across all member states.

The European Liver Patients Association has issued a manifesto on liver disease in Europe in advance of the European Parliament elections in May 2014. It urges Members of the European Parliament (MEPs) to support policies to increase public awareness of liver diseases, and to moderate the harmful effects of alcohol. The manifesto also calls for liver enzyme tests to become a mandatory part of routine health checks for adults aged 20 to 60, and for all people with elevated liver enzymes to be tested for viral hepatitis. An alternative to external reference pricing for pharmaceutical products is also needed to ensure access to new hepatitis C treatment throughout the EU, the manifesto states.

An expert advisory board to US health insurers has concluded that sofosbuvir (Sovaldi) represents “low value” in comparison to previous regimens for treatment of hepatitis C, except for people with cirrhosis. They concluded that despite greater efficacy, the new drug would not result in a reduction in the cost of treating liver disease over a 20-year period. Sofosbuvir is priced at $84,000 for a 12-week treatment course in the United States. The advisory board reached the same conclusion regarding simeprevir (Olysio), which costs $66,000.

Médecins du Monde has published an analysis of how current patterns of voluntary licensing agreement for HIV drugs and for sofosbuvir might affect the future availability of interferon-free treatment for hepatitis C in low- and middle-income countries. The voluntary licence for sofosbuvir excludes many lower middle-income countries with a high burden of hepatitis C, such as Vietnam, Indonesia and countries in central Asia. Based on the voluntary licensing arrangements for HIV drugs between 43 and 65% of people with hepatitis C in low- and middle-income countries are likely to be excluded from access if the definitions of eligible countries are based on current GDP per capita, according to Médecins du Monde.

The first ever HCV World Community Advisory Board (CAB) met with six pharmaceutical companies in Bangkok, Thailand, in February to demand affordable prices for HCV treatment in low- and middle-income countries. 

The Egyptian government has negotiated a deal with Gilead to buy sofosbuvir at a cost of $900 for a 12-week treatment course. This represents a 99% discount on the price being charged in the United States. It also undercuts the price of the currently recommended treatment regimen in Egypt. The current cost of pegylated interferon and ribavirin in Egypt is approximately $2000 for a 48-week course of treatment.

Egypt’s government has committed to ambitious targets for treatment of hepatitis C. This commitment has allowed the government to negotiate low prices for pegylated interferon and now for sofosbuvir.

Egypt has the highest prevalence of hepatitis C in the world. Approximately 6 million Egyptians are estimated to be infected with hepatitis C – around 1 in 12 of the population. Around 90% of these infections are genotype 4.

Evidence regarding the efficacy of sofosbuvir plus ribavirin in genotype 4 is limited to data from a few small studies, which show varying degrees of efficacy. An analysis of 28 patients with genotype 4 infection in the phase III Neutrino study found that 96% were cured after 12 weeks of treatment, however these patients also received pegylated interferon and ribavirin. A second study conducted in 60 patients treated for either 12 or 24 weeks with only sofosbuvir and ribavirin found that cure rates of 93% and above were achieved in previously treated and untreated patients who received a 24-week course. Cure rates were lower in patients treated for 12 weeks.

A modelling study has found that treating all patients in Egypt who have F2 to F4 stage fibrosis with pegylated interferon and ribavirin would be cost effective at a price of $2000 per year. Treating patients with F1 fibrosis would be cost effective if therapy could achieve a higher cure rate. However, Médecins du Monde estimates that at a price of $2000, providing sofosbuvir to patients with F3 or F4 fibrosis would cost the Egyptian government 62 times the current annual budget of the HCV care and treatment programme.

The International Liver Congress takes place in London, April 9-13. Infohep will be reporting from the conference. Next month’s infohep bulletin will be devoted to news from the International Liver Congress.

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