News from the International Liver Congress 2015 This edition of the infohep.org 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. The monthly hepatitis news bulletin from infohep.org is
usually only available in English. We would like to offer it in other
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news special in French, Portuguese, Russian and Spanish next week. If you would
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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,
hivandhepatitis.com
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,
hivandhepatitis.com.
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, hivandhepatitis.com.
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, hivandhepatitis.com.
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, hivandhepatitis.com.
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.
EASL guidelines on treatment of hepatitis C Jean-Michel Pawlotsky presenting at the International Liver Congress. Photo by Liz Highleyman, hivandhepatitis.com.
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).
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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