The Liver Meeting, the annual meeting of the American Association for the Study of Liver Diseases (AASLD), is one of the two major hepatitis meetings of the year. This year’s conference saw new data on interferon-free treatment for hepatitis C virus (HCV) and the effects of treatment on the progression of liver disease in hepatitis C. These studies are reviewed in this edition of the infohep news bulletin.

Next month’s infohep news bulletin will review further studies on diagnosis and treatment of hepatitis B, hepatitis C treatment and the costs of hepatitis C treatment presented at The Liver Meeting.

Sofosbuvir/ledipasvir is a fixed-dose once-daily combination of two drugs developed by Gilead Sciences, with the brand name Harvoni. The fixed-dose pill combines a highly potent nucleotide NS5B polymerase inhibitor (sofosbuvir), with a drug that inhibits the hepatitis C NS5A protein (ledipasvir).

Harvoni has received marketing approval in the United States and is already being prescribed. Harvoni received marketing approval in the European Union in November 2014, but individual EU countries will make their own decisions about whether to grant reimbursement for this combination. (It is worth noting that nine months after European approval for sofosbuvir (Sovaldi) was granted, the drug has cleared reimbursement approval processes in only a handful of European countries. It is unlikely that Harvoni will become available more quickly.)

Data on the use of sofosbuvir/ledipasvir in the following groups of patients were presented at The Liver Meeting:

• People with decompensated cirrhosis.
• People with genotype 4 infection (see the genotype 4 section of this bulletin below).
• People with HIV and HCV co-infection.

Steven Flamm, speaking at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Photo by Liz Highleyman, hivandhepatitis.com.

Before direct-acting antiviral agents became available, people with hepatitis C who had decompensated cirrhosis were considered too ill to treat with interferon-based therapy. Those who were treated on an experimental basis did not tolerate drugs well and had a low likelihood of sustained response. There is currently no approved treatment for this population.

With the advent of new direct-acting antivirals that are highly effective and well-tolerated, treating this sickest group of patients has become a priority. Ideally, effective treatment would eradicate HCV and allow the liver to heal, restoring some function and perhaps making liver transplants unnecessary.

A study of 108 patients with genotype 1 or 4 hepatitis C and decompensated cirrhosis randomly assigned participants to receive sofosbuvir/ledipasvir for 12 or 24 weeks. All participants received weight-based ribavirin. 87% of those treated for 12 weeks and 89% of those treated for 24 weeks achieved a sustained virologic response at week 12 after completing treatment (SVR12) and treatment was well tolerated. Treatment was also associated with improvements in liver disease as measured by MELD scores.

Shyam Kottilil speaking at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Photo by Liz Highleyman, hivandhepatitis.com.

A US study of a 12-week course of treatment with sofosbuvir/ledipasvir in people with HIV and hepatitis C co-infection found that 98% (49 patients out of 50) achieved SVR12. Thirty-seven out of 50 were taking antiretroviral therapy at the same time but no harmful effects as a result of a potential drug-drug interaction were observed.

The researchers concluded that sofosbuvir/ledipasvir can be used in exactly the same way in people living with HIV as in those without HIV.

Daclatasvir-based treatment

Andrew Muir speaking at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Photo by Liz Highleyman, hivandhepatitis.com.

Daclatasvir is another NS5A inhibitor. It works in the same way as ledipasvir and is highly potent. Daclatasvir is already approved in Europe but in the United States, developer Bristol-Myers Squibb has decided to wait for approval until it has completed studies of daclatasvir as part of a three-drug, once-daily combination that also includes the protease inhibitor asunaprevir and the non-nucleoside polymerase inhibitor beclabuvir.

Bristol-Myers Squibb presented results of two phase III studies of this combination at The Liver Meeting.

The first study looked at the combination in 202 people with cirrhosis and genotype 1 infection. One group received ribavirin to see whether it made a substantial difference to cure rates in this difficult-to-cure group of patients.

In the group of previously untreated people with cirrhosis, 93% achieved a cure after 12 weeks of treatment and 98% achieved a cure if the regimen also contained ribavirin. In the group of treatment-experienced patients, 87% achieved a cure after 12 weeks of treatment and 93% achieved a cure if the regimen also included ribavirin.

The second study tested the combination in 312 previously untreated and 103 treatment-experienced patients with HCV genotype 1. Ribavirin was not used in this trial. The overall SVR12 rate in this study was 91%, with similar response rates in the treatment-naive (92%) and treatment-experienced (89%) groups.

Cure rates were slightly better in this study for patients with genotype 1b.

These results will enable Bristol-Myers Squibb to obtain approval for the combination in the United States in 2015 and afterwards in Europe.

The Merck interferon-free combination

Mark Sulkowski, of Johns Hopkins University, speaking at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Photo by Liz Highleyman, hivandhepatitis.com.

Merck is a little way behind other companies in testing its interferon-free combination, but had hoped that its combination would prove so potent that the duration of treatment could be reduced to six or even four weeks if combined with sofosbuvir. That would make the combination highly attractive, but a proof-of-concept study in 102 patients with genotype 1 infection found that those treated for less than eight weeks already showed higher rates of viral relapse after four to eight weeks of post-treatment follow-up than people treated for eight weeks.

What these results mean for shortening the duration of treatment is unclear, but looking on the positive side, the study found that an eight-week course of treatment was sufficient to achieve a post-treatment virological response at weeks 4 or 8 in 19 out of 20 people with cirrhosis who started treatment.

These findings are early-phase research and larger trials may not reproduce this success rate. A new trial called C-CREST is planned to test 8-week and 6-week treatment regimens with a three-drug combination.

Several other phase II studies of the Merck protease inhibitor grazoprevir combined with its NS5A inhibitor elbasvir showed that this combination was highly effective in genotype 1a or 1b infection, curing 98% of people without cirrhosis after a 12-week course of treatment. An 8-week treatment course was slightly less effective even when ribavirin was included in the regimen. This study included a sub-set of patients with HIV and hepatitis C co-infection. In this group of patients, those who also received ribavirin were more likely to be cured (97%, versus 87% without).

In people with cirrhosis and those who had a null response to previous treatment – a hard-to-cure patient population – 12- and 18-week regimens were tested. Very high cure rates (above 90%) were achieved with or without ribavirin.

The regimen was well-tolerated in all patient groups.

Merck is conducting phase III studies in order to achieve licensing of a grazoprevir and elbasvir once-daily pill. These studies will show whether it is possible to achieve very high cure rates for patients who take treatment for 12 weeks. Merck hopes to obtain US marketing approval for its hepatitis C combination in the second half of 2015.

Most drugs in development for the treatment of hepatitis C are only effective against one or two genotypes of the virus. This means that patients must undergo genotype testing in order to select a treatment regimen. In settings where resources for health care are limited, a treatment regimen that is effective against all genotypes or the most common genotypes would be easier and cheaper to manage. Regimens or drugs of this sort are called pan-genotypic.

Gilead Sciences is developing a fixed-dose combination designed to treat multiple genotypes. The regimen combines sofosbuvir with the experimental NS5A inhibitor GS-5816. Several studies of this regimen were presented at The Liver Meeting.

A study in treatment-experienced patients with genotype 1 or 3 hepatitis C, with or without cirrhosis, found the combination to be highly effective at a dose of 100mg a day for 12 weeks, although in patients with genotype 3 and cirrhosis, a cure rate above 90% was achieved only in those who received ribavirin too.

In previously untreated patients with genotypes 1 and 2, an eight-week course of treatment was sufficient to cure 90% of genotype 1 patients and 88% of genotype 2 patients. The addition of ribavirin did not improve response rates in either group. None of these patients had cirrhosis.

A second study in previously untreated patients, ELECTRON-2, tested an eight-week treatment course of sofosbuvir and different doses of GS-5816 in genotype 3 patients without cirrhosis. This study found cure rates for a 100mg dose of 96 to 100%, with or without ribavirin. The only patient in the 100mg dose groups who did not achieve a cure had withdrawn consent. This dose is now being taken forward in phase III licensing studies, where it is being studied as a 12-week treatment course.

Anita Kohli, from the US National Institute of Allergy and Infectious Diseases (NIAID), speaking at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Photo by Liz Highleyman, hivandhepatitis.com.

Genotype 4 hepatitis C infection is most frequently found in the Middle East and parts of Africa, including Cameroon. The world’s largest hepatitis C epidemic, in Egypt, is predominantly genotype 4 hepatitis C.

Two studies presented at The Liver Meeting showed that interferon-free regimens are highly effective at curing genotype 4 infection. Sofosbuvir/ledipasvir without ribavirin and AbbVie’s 3D regimen (paritaprevir/ombitasvir plus dasabuvir) both produced high sustained virological response rates of 91 to 100% for people with hepatitis C virus (HCV) genotype 4.

Andrew Hill speaking at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Photo by Liz Highleyman, hivandhepatitis.com.

Achieving a cure of hepatitis C infection stops further liver damage, but does it reduce the long-term risk of death or liver cancer? This is a critical question not just for patients but also for health service payers faced with high costs of treatment.

Previous studies have shown that sustained virological response (SVR) – or continued undetectable HCV viral load after completion of treatment – reduces the risk of hepatocellular carcinoma (HCC), liver transplantation, liver-related death and all-cause mortality, but results have been inconsistent and many of these studies have been small.

A meta-analysis of more than 34,000 patients presented at The Liver Meeting showed that people who achieve sustained virological response (SVR) when treated with interferon-based therapy for hepatitis C have a lower risk of death, are less likely to develop liver cancer and need fewer liver transplants than those who were treated but not cured.

The meta-analysis found that the risk of death from any cause fell by 62% five years after being cured of hepatitis C, by 84% in people with cirrhosis cured of hepatitis C and by 73% in people with HIV and hepatitis C co-infection. The risk of liver cancer and liver transplant fell by a similar extent.

AbbVie has received scientific approval from the Committee for Medicinal Products for Human Use of the European Medicines Agency for both components of its interferon-free combination for hepatitis C treatment.

The combination consists of a once-daily fixed-dose tablet called Viekirax, combining the protease inhibitor paritaprevir, the boosting agent ritonavir and the NS5A inhibitor ombitasvir, and the twice-daily non-nucleoside polymerase inhibitor dasabuvir, which will be marketed as Exviera. AbbVie expects to receive European Union marketing approval in the first quarter of 2015 and will then begin reimbursement negotiations with European authorities. At this time the price of these agents has not been announced.

We have recently published a new factsheet on daclatasvir (Daklinza), an addition to the four other hepatitis C treatment factsheets published earlier this year.

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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