News from the International Liver Congress 2015

This edition of the bulletin is devoted to news from the International Liver Congress 2015, the 50th annual meeting of the European Association for the Study of the Liver (EASL), which took place 22-26 April in Vienna, Austria.

At this year’s Congress, much of the most important new research on direct-acting antiviral treatment for hepatitis C concerned the efficacy and safety of interferon-free combinations in special populations. Previously, these special populations were considered hard to cure using interferon-based treatment. Research presented at the International Liver Congress 2015 showed that interferon-free treatment has the potential to cure hepatitis C in a wide range of populations, many of which have an urgent need for treatment.

In the next edition of this bulletin we will report on studies of hepatitis B, screening for hepatitis C, access to treatment and further studies of direct-acting antiviral treatment for hepatitis C.

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Hepatitis C special population: Chronic kidney disease

Hepatitis C increases the risk of chronic kidney disease, although the mechanisms by which the virus causes kidney damage are still unclear. People with hepatitis C face more rapid progression of kidney disease once kidney function begins to decline, and as a consequence they are likely to reach a point where they need dialysis and kidney transplantation sooner than other people with kidney disease. People with hepatitis C also have an increased risk of developing new onset diabetes after developing kidney disease.

If a kidney transplant is necessary, people with hepatitis C have a higher risk of transplant rejection (also known as graft failure) and poorer survival after transplantation. But for many people with hepatitis C who have severe kidney disease, a transplant will remain out of reach; poorer survival among transplant recipients with hepatitis C means that people with hepatitis C are a low priority for transplant organs.

For all these reasons, curing hepatitis C is an essential part of effective management of chronic kidney disease for people who have the virus. However, available treatments have been unsuitable for people with kidney disease.

Two studies presented at the International Liver Congress showed that treatment with direct-acting antivirals can cure a high proportion of people with advanced kidney disease, including in people who require dialysis treatment.

The once-daily combination of grazoprevir and elbasvir cured hepatitis C in 99% of people with advanced chronic kidney disease in the C-SURFER study. This study recruited 122 people with stages 3 and 4 chronic kidney disease who received immediate treatment and 113 people who received deferred treatment. Three-quarters were dependent on dialysis. Grazoprevir (an NS3/4 protease inhibitor) and elbasvir (an NS5A inhibitor) are being developed by Merck. The combination is being studied as a once-daily, single-tablet regimen, with or without ribavirin. The two drugs are active against multiple genotypes of hepatitis C. This study is the largest to date in people with advanced kidney disease.

A cohort study of patients in the United States and Europe showed that sofosbuvir-based direct-acting antiviral therapy for hepatitis C can be used safely and effectively in people with very advanced kidney disease, including people on dialysis. The HCV-TARGET international cohort study documented responses to sofosbuvir-based regimens in people with various degrees of kidney disease, including 19 people with stages 4 or 5 chronic kidney disease. The study found that between 80% and 100% of people with advanced kidney disease were cured of hepatitis C, depending on the regimen used.

Treatment-experienced people

People with hepatitis C which failed to respond to previous regimens containing direct-acting antivirals may be more difficult to cure, either due to the presence of drug resistance or because of host factors such as liver damage (see Decompensated cirrhosis, advanced cirrhosis and transplant patients below). Several studies of interferon-free combinations presented at the International Liver Congress showed that new regimens can be highly effective in this group of patients. The studies also provided some insight into which patients may need ribavirin in order to achieve a cure.

The C-EDGE study of Merck’s combination of grazoprevir and elbasvir in people with hepatitis C genotypes 1, 4 or 6 showed that:

  • In people who previously failed to achieve a cure on pegylated interferon and ribavirin, 92-97% of all patients were cured after 12 or 16 weeks of grazoprevir and elbasvir, with or without ribavirin.
  • People with a previous null or partial response to treatment had a higher cure rate when they received ribavirin and were treated for 16 weeks.
  • The same was true for people with cirrhosis.

Dr Xavier Forns of Hospital Clinic, Barcelona, presents results of the C-SALVAGE study. Photo by Liz Highleyman,

The C-SURFER study of Merck’s combination of grazoprevir and elbasvir, plus ribavirin, in people with hepatitis C genotype 1, showed that:

  • In people who previously failed to achieve a cure after a previous course of antiviral treatment containing pegylated interferon and either telaprevir, boceprevir or simeprevir, 95% of all patients were cured after 12 weeks of treatment.
  • Baseline protease inhibitor resistance mutations did not affect response.

A re-treatment study of people who failed to achieve a cure with 8 or 12 weeks of sofosbuvir/ledipasvir (Harvoni) showed that:

  • A 24-week course of the same regimen cured 70% of patients.
  • Baseline NS5A resistance-associated mutations did affect response.
  • A greater duration of prior treatment reduced the likelihood of cure.

Decompensated cirrhosis, advanced cirrhosis and transplant patients

People with very advanced liver disease have had few treatment options for hepatitis C until now, and treatment responses have been very poor when treatment is attempted in decompensated cirrhosis.

People with a Child-Pugh B score have significantly impaired liver function and are at high risk for progression to decompensated cirrhosis.

Four large studies reported on the performance of direct-acting antiviral combinations in people with advanced liver disease, either Child-Pugh B or decompensated liver disease.

Dr Ira Jacobson of Weill-Cornell Medical College presents results of the C-SALT study. Photo by Liz Highleyman,

The C-SALT trial of grazoprevir and elbasvir showed that a 12-week course of treatment with the two direct-acting antivirals cured hepatitis C infection in 90% of people with genotypes 1, 4 or 6. Responses were better in people with lower Child-Pugh B scores (<7). Participants in this study did not receive ribavirin.

Fred Poordad of the University of Texas Health Science Center, presenting results of the ALLY-1 study. Photo by Liz Highleyman,

An interferon-free regimen of sofosbuvir, daclatasvir and ribavirin for 12 weeks produced sustained response rates of 83% for people with hepatitis C who had advanced liver cirrhosis and 94% for people who had received liver transplants, with similar cure rates for those with hard-to-treat HCV genotype 3, according to findings from the ALLY-1 trial. ALLY-1 enrolled people with advanced liver cirrhosis and transplant recipients with HCV genotypes 1-6. The advanced cirrhosis group included people with decompensated cirrhosis.

Professor Rajender Reddy of University of Pennsylvania presents the HCV-TARGET study at the International Liver Congress 2015. Photo by Liz Highleyman,

Two large cohort studies also showed that sofosbuvir-based interferon-free treatment has the potential to cure the majority of people with decompensated cirrhosis, although cure rates were lower than in the C-SALT study. This was probably due to the fact that these real-world cohort studies treated patients with more severe cirrhosis (three-quarters in the HCV TARGET study and 90% in the English expanded access cohort had decompensated cirrhosis). These studies showed that more severe liver damage did not affect the response to treatment, but older patients (>65 years) and those with lower albumin levels were more likely to experience serious adverse events such as worsening of liver disease. In both cohorts, response rates in people with genotype 3 were lower (39% in HCV TARGET, and between 43% and 71% according to regimen in the English cohort).

There was little information regarding the improvement or worsening of cirrhosis in the clinical trials, and it is still unclear to what extent tr

Genotype 3

Graham Foster of Queen Mary's University of London presenting results of the BOSON study. Photo by Liz Highleyman,

Hepatitis C genotype 3 remains harder to treat with direct-acting antivirals than other genotypes. The BOSON study compared either 16 or 24 weeks of sofosbuvir and ribavirin to a 12-week course of sofosbuvir and ribavirin plus pegylated interferon in genotypes 2 and 3. A large proportion of the study population were at high risk of poor response to treatment: about half were prior non-responders, about one third had cirrhosis and two thirds had unfavourable IL28B gene variants associated with poor interferon response. The study showed that the interferon-containing regimen was more effective in genotype 3, especially in people with cirrhosis (91% cured). In genotype 3, all regimens were similarly effective.

Previously untreated people

A 12-week course of the combination of grazoprevir and elbasvir cured 95% of previously untreated people with genotypes 1, 4 or 6 hepatitis C infection, according to results of the C-EDGE trial. The grazoprevir/elbasvir combination pill is due to be submitted for regulatory approval in the United States, Europe and other countries shortly, and may be approved by the end of 2015. It will be the third all-oral, interferon-free combination to be marketed exclusively by one company.

EASL guidelines on treatment of hepatitis C

Jean-Michel Pawlotsky presenting at the International Liver Congress. Photo by Liz Highleyman,

The European Association for Study of the Liver (EASL) issued new treatment recommendations at the International Liver Congress. They emphasised the importance of prioritising some groups of people due to a higher risk of liver disease progression. Experts presenting the guidelines said that this would be a reality in many European countries until drug costs come down.

Treatment is a priority for people with advanced fibrosis or cirrhosis (Metavir stage F3-F4), including people with decompensated cirrhosis, who stand to benefit greatly from treatment.

Other high-priority groups include people with HIV or hepatitis B virus (HBV) co-infection, people who are awaiting or have received a liver transplant, people with clinically significant extra-hepatic manifestations and those with debilitating fatigue.

The guidelines recommend interferon-free treatment wherever possible.

The following regimens are included in the new guidelines, along with the genotypes for which they are indicated:

Interferon-free regimens:

  • Sofosbuvir + ribavirin: genotypes 2 and 3
  • Sofosbuvir/ledipasvir +/- ribavirin: genotypes 1, 4, 5, and 6
  • Paritaprevir/ritonavir/ombitasvir + dasabuvir +/- ribavirin: genotype 1
  • Sofosbuvir + simeprevir +/- ribavirin: genotypes 1 and 4
  • Sofosbuvir + daclatasvir +/- ribavirin: all genotypes
  • Paritaprevir/ritonavir/ombitasvir +/- ribavirin: genotype 4

Interferon-containing regimens:

  • Pegylated interferon alfa-2a + ribavirin + sofosbuvir: all genotypes
  • Pegylated interferon alfa-2a + ribavirin + simeprevir: genotypes 1 and 4

The standard duration of interferon-free therapy is generally 12 weeks. Some people with genotype 1 and without cirrhosis can take sofosbuvir/ledipasvir for just 8 weeks without ribavirin. People with genotype 1 who have cirrhosis should add ribavirin or extend treatment to 24 weeks. Although HCV subtype 1a is considered harder to treat than 1b, treatment recommendations are generally similar.

Across genotypes, only a few regimens are recommended for people with decompensated cirrhosis: sofosbuvir plus ribavirin (genotype 2 and 3), and sofosbuvir with either ledipasvir (genotypes 1, 4, 5, and 6) or daclatasvir (all genotypes).

When to treat and liver damage in undiagnosed people

Although European treatment guidelines give priority to people with advanced liver damage, an analysis of people receiving hepatitis C care through the US medical system for military veterans – approximately 187,000 veterans diagnosed with hepatitis C between 1999 and 2010 – found a very strong association between later treatment and an increased risk of clinical illness and death. This study looked at people treated with pegylated interferon and ribavirin, which is less effective in people with cirrhosis, so it is unsurprising to find that people with cirrhosis had poorer outcomes despite treatment. However, the study also found that people with cirrhosis who were cured still had a poorer long-term prognosis than people who started treatment with less serious liver damage.

Another US study found that approximately one in five people with hepatitis C in the United States who do not know of their infection may already have advanced liver damage and be in urgent need of treatment.

Alcohol and liver disease in people with hepatitis C

A French study of everyone admitted to hospital in France between 2008 and 2012 found that a high proportion of clinical events and liver-related deaths in people with hepatitis C may be attributable to alcohol or to the presence of other serious comorbid conditions such as kidney disease. Alcohol misuse was highly prevalent among people with hepatitis C admitted to hospital.

On the other hand, only 14% of liver-related events in hospital patients with hepatitis C occurred in people without an alcohol misuse disorder or a serious comorbid condition.

Hepatitis C treatment factsheets

We have recently published a new factsheet on Harvoni, an addition to the five other 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.

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