New European guidelines for treatment of hepatitis C

Laurent Castera and Jean-Michel Pawlotsky present the 2016 EASL treatment guidelines. Photo by Liz Highleyman,

The European Association for the Study of the Liver (EASL) released its latest recommendations on treatment of hepatitis C at a special meeting last Thursday in Paris. The updated guidelines now include highly effective interferon-free options for all hepatitis C virus (HCV) genotypes and for people who are the most challenging to treat.

EASL usually releases revised recommendations at its International Liver Congress in the spring, but this year the guidelines panel decided to hold off the release to wait for European approval of two newer direct-acting antiviral (DAA) regimens, grazoprevir/elbasvir (Zepatier) and sofosbuvir/velpatasvir (Epclusa).

The new 2016 guidelines call for universal access to hepatitis C treatment, stating that "All treatment-naive and treatment-experienced patients with compensated or decompensated chronic liver disease due to HCV must be considered for therapy."

Acknowledging that treatment may not be immediately available to all due to cost and other factors, the recommendations stress that some people should be treated without delay, including those with significant liver fibrosis or cirrhosis (Metavir stage F2 or higher), those with clinically significant extra-hepatic manifestations and those with HCV recurrence after a liver transplant. This is broader than the 2015 recommendations, which prioritised people at stage F3 or higher.

The new guidelines also call for prioritisation of individuals at risk for transmitting HCV, including people who inject drugs, gay and bisexual men with high-risk sexual practices, women who wish to get pregnant, kidney dialysis patients and people in prison.

All recommended regimens now include at least two DAAs. For the first time no interferon-containing regimens are listed among the recommended options, although the guidelines say these should still be considered if they are the only agents available in a given country.

Ribavirin still plays a role in helping prevent relapse in people who are difficult to treat such as those with genotype 3, prior treatment failure, cirrhosis or high viral load.

Presenting the guidelines, Prof. Jean-Michel Pawlotsky recommended ribavirin for people who are likely to experience treatment failure. "It's very important with DAAs that patients respond immediately," he said. "We can't just try the simplest regimen and retreat if needed."

Notable changes from the 2015 recommendations include the addition of grazoprevir/elbasvir (Zepatier) and sofosbuvir/velpatasvir (Epclusa), omission of sofosbuvir (Sovaldi) plus ribavirin alone for genotypes 2 and 3, removal of sofosbuvir (Sovaldi) plus simeprevir (Olysio) for genotype 1, and removal of sofosbuvir (Sovaldi) or simeprevir (Olysio) plus pegylated interferon and ribavirin for any genotype.

The approval of sofosbuvir/velpatasvir (Epclusa) now offers a single-tablet option for genotype 3, which remains a bit more difficult to treat. However, the panel decided that all treatment-experienced people with genotype 3 should use it with ribavirin (differing from US recommendations, which only recommend ribavirin for treatment-experienced people with cirrhosis).

The new guidelines also contain specific recommendations, summarised in the Infohep report on the guidelines, for the treatment of the following groups of people or situations:

  • People with HIV/HCV co-infection
  • People with HCV/hepatitis B virus co-infection
  • People who inject drugs
  • People previously treated with DAAs
  • Decompensated cirrhosis
  • Post-transplant recurrence of HCV
  • Acute HCV infection.

Viral monitoring is not necessary during treatment, as DAA therapy has high response rates and does not rely on response-guided treatment adjustments. Monitoring can be simplified by measuring HCV RNA or HCV core antigen only before starting treatment and at 12 or 24 weeks after completing therapy.

However, people who are at ongoing risk for hepatitis C – including people who inject drugs and men who have sex with men – should be tested at least annually for reinfection. Individuals who continue to inject drugs "should not be excluded from treatment on the basis of perceived risk of reinfection," the guidelines state.

HCV treatment for people who inject drugs

Holly Hagan of New York University presenting at INHSU 2016. Photo by Liz Highleyman,

Around 6 million people who inject drugs have hepatitis C worldwide, according to best estimates, and using contaminated injecting equipment is now the main route of transmission of hepatitis C in most regions of the world.

Earlier this month an international conference, the 5th International Symposium on Hepatitis Care in Substance Users (INHSU 2016), took place in Oslo, Norway, with the aim of examining how to improve diagnosis, treatment and prevention of hepatitis C in people who inject drugs.

High coverage of needle and syringe programmes plus widely available opioid substitution therapy (OST) can reduce the risk of hepatitis C virus (HCV) transmission by about 70%; inadequate coverage, however, is much less effective. Major political barriers to these harm reduction interventions remain in many parts of the world, and coverage of these interventions remains inadequate in all but a few countries. Large-scale transmission of HCV is being permitted to continue because of widespread moral disapproval of drug use and outdated views of drug use as a criminal problem rather than a public health problem.

People who inject drugs and have hepatitis C are often denied treatment on the grounds that they will not adhere to medication, but there is now good evidence that people receiving OST can achieve high cure rates. Several studies have shown that people who received OST maintained good adherence and had high sustained response rates comparable to those of non-drug users in the trials.

Increasing the proportion of people who inject drugs who are cured of hepatitis C may also reduce transmission. Modelling studies suggest that the lower the prevalence – that is, the more drug injectors remain susceptible to HCV infection – the greater the benefit of treatment as prevention. Treating people with advanced liver disease, who tend to be older and in networks with people who already have the infection, could have a major effect on liver disease morbidity and mortality, but not so much on transmission. However, treating younger, healthier people with mild or moderate liver disease could eliminate the virus among those most likely to transmit it.

Experts at the conference debated whether treatment should be provided for all people who inject drugs with hepatitis C in order to reduce transmission, or whether health systems should prioritise those with more advanced liver disease and wait for drug prices to come down before extending treatment to all.

Prof. Graham Foster of Queen Mary’s University, London, concluded that if we wait a couple of years we could expand treatment to people who inject drugs for less money – but "this dilemma just goes away if we can get [HCV] drugs at more affordable prices."

Alcohol and liver damage in people with hepatitis C

Low-to-moderate alcohol consumption is associated with an increased risk of liver cancer for people who have hepatitis C virus (HCV) infection with compensated cirrhosis, investigators from Belgium report in the Journal of Hepatology. Five-year incidence of hepatocellular carcinoma (HCC) was twice as high among people who reported alcohol consumption compared to individuals who did not drink alcohol. Levels of daily alcohol consumption among people who developed liver cancer were low – an average of one drink a day – and the investigators stress, "drinking alcohol, not the amount of alcohol intake, was associated with an increased risk of HCC." They therefore caution, "there is no safe threshold for alcohol" for people with HCV infection who have cirrhosis.

The study also found that although successful hepatitis C treatment reduced the risk of developing HCC in those who drank alcohol, it did not eliminate the risk altogether. Among those cured of hepatitis C during the five-year follow-up period, 6% of those who drank alcohol developed HCC, compared to none of those who abstained from alcohol during the same period. This finding shows that although successful treatment of hepatitis C will allow the liver to begin to heal, people with cirrhosis still remain at serious risk of liver cancer if they drink alcohol after being cured of hepatitis C.

Reduced fatigue after hepatitis C cure

Rasmus Thornhøj of Odense University Hospital presents findings from the FAT-HEP study. Photo by Liz Highleyman,

Fatigue is frequently reported by people with chronic hepatitis C and reduces quality of life, though its causes are not yet fully understood.

Last year the European Association for the Study of the Liver (EASL) recommended that debilitating fatigue should be among the indications for prioritising hepatitis C treatment.

Research presented earlier this month at the 5th International Symposium on Hepatitis Care in Substance Users (INHSU 2016) showed that people were much more likely to report fatigue when they had more severe liver inflammation or more advanced fibrosis. The study questioned people with hepatitis C in Denmark using three different tools for measuring fatigue. The study found that people with stages F3 or F4 fibrosis were six times more likely to report fatigue compared to people with less advanced fibrosis. People who were cured of hepatitis C had an 80% reduced likelihood of reporting fatigue.

The findings underline the importance of the EASL recommendation, and of the need for national guidelines and reimbursement policies to take account of severe fatigue as a factor when considering who should receive hepatitis C treatment. More research into the effects of treatment on fatigue by pharmaceutical companies would strengthen the case for providing treatment to people with severe fatigue, even if they do not have cirrhosis.

HCV vaccine

Professor Andrea Cox of Johns Hopkins University presenting at INHSU 2016. Photo by Liz Highleyman,

A vaccine against hepatitis C may still be needed to achieve elimination of the disease, delegates at the 5th International Symposium on Hepatitis Care in Substance Users (INHSU 2016) heard earlier this month. A vaccine is likely to be especially important in the population with the highest ongoing incidence, people who inject drugs.

Researchers have explored both preventive vaccines for hepatitis C virus (HCV) – for example, attempting to establish antibodies that can prevent the virus from taking hold in the body – and therapeutic vaccines that marshal immune responses to control the virus once infection occurs.

It is considered unsafe to use live attenuated (weakened) or killed or inactivated whole HCV for vaccines due to the risk that it could revert back to being virulent. Researchers have instead tested vaccines containing HCV proteins, HCV DNA (genetic material), virus-like particles and viral vectors in non-human primates, and a few of the best candidates have advanced into human trials.

A major difficulty in HCV vaccine development lies in the very fast mutation rate of the virus. Studies in people who spontaneously clear HCV have shown that immune responses to infection do not fully protect against subsequent reinfection, either because immune responses are not sufficiently broad to recognise all strains of HCV, or because they are not intense enough.

HIV also mutates very fast and researchers have been attempting to develop a vaccine for over 25 years, with only limited success. Vaccine development in the HIV field has attempted to get round the problem of mutation by using regions of the virus which are not involved in making new virus, and which do not vary substantially from person to person or from one subtype to another, as the core elements in the vaccine. In hepatitis C vaccine development, scientists need to find out which HCV proteins generate the most intense immune responses, as well as identifying which proteins stimulate the production of antibodies that bind to a wide range of hepatitis C subtypes.

Researchers are beginning to have success in stimulating stronger and broader immune responses to HIV, and it is hoped that a similar strategy may pave the way for a vaccine against HCV one day.

A large trial of a vaccine against hepatitis C is now underway, and could provide evidence by 2017 on the extent to which a vaccine against HCV which follows the approach outlined above can provide protection against infection – or reinfection. If that vaccine is successful in preventing HCV infection, it would need to go forward into larger trials before it could be approved for widespread use.

Another lesson from the field of HIV vaccine research is that vaccine research proceeds in incremental steps. It is possible that an early vaccine may prove to be no more than 30 to 40% efficacious – that is to say, it will reduce the number of new infections in vaccinated people by 30 to 40% compared to unvaccinated people. Although this level of efficacy may not be enough to warrant its use as a general preventive vaccine, it might have an impact on HCV incidence in people who inject drugs, where HCV incidence among new injectors may be as high as 60% in the first year if harm reduction measures such as needle and syringe programmes are not available.

Access to sofosbuvir in Ukraine

Médecins Sans Frontières (MSF) has called on Gilead Sciences not to challenge the marketing authorisation for a generic form of sofosbuvir in Ukraine. Sofosbuvir is not yet patented in Ukraine, and its previous patent applications have been successfully blocked by Ukrainian activists. Access to hepatitis C treatment is limited in Ukraine and generic manufacturers in India are excluded from exporting low-cost generic versions of sofosbuvir to Ukraine under the terms of voluntary licenses granted by Gilead. Instead, a generic version of sofosbuvir is being purchased from Egypt, where manufacturer Pharco is not prevented from selling its product in Ukraine. MSF says that stopping supply of the only approved generic version of sofosbuvir could limit its ability to begin providing hepatitis C treatment in Ukraine.

Gilead says that it is negotiating with the Ukrainian government to launch a national hepatitis C virus treatment programme, supplying sofosbuvir at a substantially lower cost than Pharco, at around $250 per bottle of pills. Research by Dr Andrew Hill of the University of Liverpool has shown that by December 2015, based on the cost of raw materials and manufacturing, it was already possible to manufacture a 12-week course of sofosbuvir for $178, with the potential for prices to fall further.

International Viral Hepatitis Elimination Meeting 2016

The International Viral Hepatitis Elimination Meeting 2016 is being held from 2-3 December in Amsterdam, The Netherlands.

This independent meeting aims to enhance elimination of viral hepatitis worldwide from the perspective of the medical community.

Following the framework of the recent World Health Organization goals, the meeting will provide an ideal forum for presenting plans to address the elimination of hepatitis B and C.

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