Guidelines panel at the International Liver Congress 2014. Photo by Liz Highleyman, hivandhepatitis.com.

The European Association for the Study of the Liver (EASL) has issued new guidelines for the treatment of hepatitis C which recommend that, wherever possible, patients should be treated with the newest direct-acting antivirals. The new guidelines were presented at the International Liver Congress, the 49th Annual Meeting of the European Association for the Study of the Liver, which took place in London, 9-13 April 2014.

EASL is also encouraging European physicians to combine products from different pharmaceutical companies to achieve the most potent interferon-free regimens, often in advance of full phase III trial data.

In particular, the guidelines recommend that physicians may prescribe sofosbuvir (marketed as Sovaldi) in combination with daclatasvir for the treatment of genotypes 1, 3 and 4, and sofosbuvir and simeprevir (marketed as Olysio) for treatment of genotypes 1 and 4.

Guidelines panel chair Professor Jean-Michel Pawlotsky, director of the French National Reference Centre for Viral Hepatitis B, C and Delta said that the EASL guidelines were designed to accommodate the diversity of European populations and reimbursement practices. The guidelines were also designed to empower physicians to obtain permission to use new agents under compassionate access arrangements, prior to licensing, said Dr Alessio Aghemo, a member of EASL’s Scientific Committee and a professor of medicine at the University of Milan.

The guidelines make recommendations for the use of simeprevir and of daclatasvir in advance of European marketing approval, and cover all new direct-acting antivirals likely to be approved in the European Union in 2014. EASL plans to update its new guidelines as soon as marketing approval dates for further products become known.

The World Health Organization (WHO) has issued global treatment guidelines for hepatitis C, strongly recommending the use of the new direct-acting antivirals sofosbuvir (Sovaldi) with ribavirin for genotypes 1, 2, 3 and 4 or simeprevir (Olysio) with pegylated interferon and ribavirin for genotype 1 infection.

The guidelines also make a strong recommendation that everyone in a population with a high prevalence of hepatitis C should be offered an antibody test for hepatitis C, as should people with a previous risk of exposure to hepatitis C.

Stefan Wiktor, head of the WHO hepatitis programme, told Reuters: “I hope these guidelines will help to promote a reduction in price and thereby an increase in access.”

Gilead Sciences is already negotiating prices or voluntary licensing agreements for its new direct-acting antiviral sofosbuvir in several lower middle-income countries with a high burden of hepatitis C. In Egypt, for example, Gilead has offered a price of $900 to $1200 for a course of sofosbuvir treatment in the public health system. However, this price offer has been criticised because it only applies to the public health system. Gilead will not offer Egyptian pharmaceutical companies voluntary licences that would permit local production and price competition.

Research on hepatitis C treatment presented at the International Liver Congress reported very encouraging results across a range of populations. The most important advances were the very high cure rates achieved by a number of interferon-free regimens across multiple HCV genotypes, and the very good results achieved in populations previously considered hard to treat. It is now clear that hepatitis C will be curable with 12 weeks of treatment for the vast majority of patients when new drug combinations become available in 2015. Studies of combinations still in earlier stages of development may allow hepatitis C to be cured after 8 weeks of treatment.

Previously untreated patients

Nezam Afdahl of Deaconess Medical Center, Boston, presents results of ION-2. Photo by Liz Highleyman, hivandhepatitis.com.

In people with hepatitis C genotype 1 infection, the new fixed-dose combination of sofosbuvir and ledipasvir cured 99% of previously untreated patients in the ION-1 study, without ribavirin, after 12 weeks of treatment. The SAPPHIRE-1 study of a three-drug combination developed by AbbVie, plus ribavirin, cured 95-98% of previously untreated patients with genotype 1 infection after 12 weeks of treatment. (Study results were published in the New England Journal of Medicine during the congress.)

A two-drug combination developed by Bristol-Myers Squibb cured 90% of people with genotype 1b infection after 24 weeks of treatment.

A combination of two drugs developed by AbbVie cured 100% of previously untreated patients with genotype 4 infection when used with ribavirin, after 12 weeks of treatment.

Previous non-responders and relapsers

Professor Stefan Zeuzem speaking at the International Liver Congress 2014. Photo by Liz Highleyman, hivandhepatitis.com.

Outcomes were equally impressive in previous non-responders and previous relapsers. (‘Non-responders’ is the term used to descibe people whose viral load did not decline sufficiently sharply when taking treatment previously and ‘previous relapsers’ for people whose virus was brought below the limit of detection by the previous therapy, but a relapse occurred after treatment ended and the virus can be detected again.) The AbbVie three-drug regimen cured 96% of treatment-experienced people with genotype 1 after 12 weeks of treatment, when used with ribavirin.

The co-formulation of sofosbuvir and ledipasvir successfully treated a variety of difficult-to-treat patient populations including people with genotype 3, people with decompensated cirrhosis and people who were not cured with previous sofosbuvir-containing therapy. In people with genotype 3 and in people with prior experience of sofosbuvir treatment, 100% cure rates were reported. In people who failed to respond to previous interferon-based treatment, between 94 and 99% of patients were cured after 12 or 24 weeks of sofosbuvir/ledipasvir treatment.

Simeprevir combined with pegylated interferon and ribavirin cured 88% of European patients with genotype 1 infection after a total of 24 weeks of treatment in the phase III PROMISE study. European people with genotype 1a infection are much less likely to have the Q80K variant of genotype 1a which reduces the efficacy of simeprevir.

People with cirrhosis

Professor Fred Poordad, of the Texas Liver Institute at the University of Texas, speaking at the International Liver Congress 2014. Photo by Liz Highleyman, hivandhepatitis.com.

Treatment responses were also highly encouraging for people with cirrhosis of the liver. Sofosbuvir and ribavirin achieved end-of-treatment virological response rates in 93% and 100% of patients with class B (advanced) and class A (well-compensated) cirrhosis respectively (using the Child-Pugh system of assessing the severity of liver cirrhosis).

AbbVie reported that the largest study of new direct-acting antivirals yet conducted in people with hepatitis C genotype 1 who have compensated cirrhosis showed that it is possible to cure between 92 and 96% of people with cirrhosis, regardless of previous treatment history, within 12 to 24 weeks.

Liver transplant patients  

Xavier Forns speaking at the International Liver Congress 2014. Photo by Liz Highleyman, hivandhepatitis.com.

New direct-acting antiviral combinations also protect against the recurrence of hepatitis C in a high proportion of liver transplant patients. When combined with ribavirin, AbbVie’s three-drug combination cured 96% of liver transplant patients with genotype 1 infection. A study of patients with more advanced post-transplant liver damage due to HCV recurrence found that 64% were cured after 24 to 48 weeks of treatment with sofosbuvir and ribavirin. This study reported on patients who received sofosbuvir on compassionate release in Spain.

HIV co-infection

Anu Osinusi, from the US National Institute of Allergy and Infectious Diseases, speaking at the International Liver Congress 2014. Photo by Liz Highleyman, hivandhepatitis.com.

New EASL guidelines state there is no reason to treat people with HIV and HCV co-infection for longer, or with different drugs, than the rest of the population with HCV. Results of a pilot study of sofosbuvir/ledipasvir in people with HIV and HCV genotype 1 co-infection pointed to the possibility of universal cure of hepatitis C in this population. An interim analysis of the ERADICATE study showed that all patients with co-infection with 12 weeks of post-treatment follow-up were cured of hepatitis C.

Reduction of hepatitis C prevalence and transmission through expanded treatment – known as ‘treatment as prevention’ – was widely discussed at the International Liver Congress. By providing treatment to people who are most likely to pass on HCV to others, regardless of liver disease stage, the long-term burden of liver disease could be greatly reduced, in theory.

A mathematical model of hepatitis C prevalence and transmission among people who inject drugs in France provided one projection of how expanded treatment might cut new infections. If testing for hepatitis C, linkage to care, and treatment of hepatitis C could each be increased to very high levels in people who inject drugs in France over the next ten years, the incidence and prevalence of hepatitis C might be reduced by two-thirds by 2024. These are very ambitious targets, and would require much more aggressive efforts to find and treat people with hepatitis C.

Cihan Yurdaydin, of the University of Ankara, speaking at the International Liver Congress 2014. Photo by Liz Highleyman, hivandhepatitis.com.

Long-term nucleoside or nucleotide treatment for hepatitis B is the recommended treatment for hepatitis B patients with more advanced liver disease and/or higher viral load, but this treatment may not be affordable in middle-income and lower-income countries where the vast majority of people with hepatitis B virus (HBV) live. A number of studies have been designed to investigate whether addition of pegylated interferon to nucleoside treatment can allow treatment to be stopped after several years. These studies looked at the effect of adding pegylated interferon after a period of nucleos(t)ide therapy. Three studies were presented at the International Liver Congress.

These studies found that adding pegylated interferon to nucleos(t)ide antiviral treatment for hepatitis B led to greater HBV viral load decline and higher likelihood of serological response in people with HBeAg-positive chronic hepatitis B, as did added interferon after long-term nucleos(t)ide therapy.

Heiner Wedermeyer speaking at the International Liver Congress 2014. Photo by Liz Highleyman, hivandhepatitis.com.

Hepatitis delta virus (HDV) is the most severe form of chronic viral hepatitis. HDV is a defective virus that can only complete its lifecycle in the presence of hepatitis B virus (HBV). HDV and HBV are transmitted in similar ways and an estimated 15 million people are co-infected with both, with the highest prevalence in regions where hepatitis B epidemics are primarily related to injection drug use including Russia, Romania and the Mediterranean countries. Antiviral drugs such as tenofovir (Viread) or entecavir (Baraclude) that suppress HBV viral load do not stop HDV replication, so people with this co-infection remain at risk for complications such as liver cirrhosis.

The current treatment option for hepatitis delta is one to one and a half years of treatment with pegylated interferon. An international study presented at the International Liver Congress  found that a 96-week course of treatment with tenofovir and pegylated interferon did not result in a significantly higher rate of undetectable hepatitis delta RNA compared to pegylated interferon treatment alone. It was also poorly tolerated.

At the International Liver Congress, we launched three new hepatitis C treatment factsheets.

Each factsheet focuses on one direct-acting antiviral drug and gives an overview of how it works, who can use it, how it is taken, what trial results tell us about how effective it is, known side-effects and drug interactions.

The factsheets are available to read online, and are also designed to be printed and shared.

We have also recently developed a simple tool to customise the hepatitis treatment information on infohep.org.

For example, you can choose to search for information according to the genotype it is relevant to, or information relevant for people who have taken treatment before.

Answer a few simple questions, and the information presented will be our news reporting on the studies relevant to your search.

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