The Liver Meeting (also known as AASLD) is the annual meeting of the American Association for the Study of Liver Diseases. It took place 1-5 November in Washington DC. Once again, it was the venue for the presentation of many highly encouraging studies regarding treatment of hepatitis C.

You can view full coverage of the meeting at the infohep web page dedicated to the The Liver Meeting 2013.

Before we start looking at the news of new drugs in development, here is a quick guide to help distinguish what type of drug we are talking about.

All drugs of the same class are given a name with a common ending. The first part of the name is specific to the drug. Some are easier to pronounce than others! In the case of hepatitis C drugs, the 'family' names have the following endings:

• HCV protease inhibitors – ending in 'previr' – include the approved drugs boceprevir and telaprevir as well as simeprevir (submitted for European and US approval), asunaprevir, danoprevir, faldaprevir, sovaprevir, ABT-450 and MK-5172.
• HCV polymerase inhibitors – ending in 'buvir' – may be nucleoside/nucleotide analogues such as sofosbuvir (also submitted for approval), mericitabine and ALS-2200 (VX-135), or non-nucleoside such as deleobuvir, setrobuvir, ABT-072, ABT-333, BMS-791325 and VX-222.
• NS5A inhibitors – ending in 'asvir' – include daclatasvir, ledipasvir and ABT-267.

If these drugs are given marketing approval they will be given a brand name too. Sometimes these brand names may differ between North America and Europe, or even within Europe.

Interferon-free combinations for the treatment of hepatitis C combine several agents, often from different classes.

The United States Food and Drug Administration (FDA) is expected to grant marketing approval to two new drugs for the treatment of hepatitis C in December, following unanimous recommendations by a scientific advisory committee. The final decisions on which patient populations will be able to use each drug will be made by the FDA after considering the recommendations of the advisory committee and announced at the time of marketing approval.

Sofosbuvir, a nucleotide polymerase inhibitor, has been recommended for use in two different treatment regimens.

For people with genotype 1 or 4 hepatitis C infection, sofosbuvir has been recommended for use in combination with pegylated interferon and ribavirin for 12 weeks.

For people with genotype 2 or 3 hepatitis C infection, sofosbuvir has been recommended for use in combination with ribavirin alone.

Simeprevir, a protease inhibitor, has been recommended for US approval for treatment of genotype 1 hepatitis C infection, for use in combination with pegylated interferon and ribavirin for 12 weeks (followed by 12 or 36 weeks of therapy with pegylated interferon and ribavirin, according to virologic response to therapy at weeks 4 and 12).

Simeprevir has been recommended for approval for people who have not previously taken treatment, and for people who have experienced treatment failure on a previous course of interferon-based therapy.

Simeprevir is less effective in treating hepatitis C with a naturally occurring mutation called Q80K. Up to 40% of people with genotype 1a hepatitis C in the United States are estimated to have this form of hepatitis C, so resistance testing prior to treatment is necessary. This mutation is rare in the form of genotype 1a that is found in Europe.

Speakers at The Liver Meeting in Washington DC agreed that both drugs represent an improvement in hepatitis C treatment when used in combination with pegylated interferon and ribavirin in genotype 1 infection. Both drugs are better tolerated than telaprevir (Incivo) and boceprevir (Victrelis), the protease inhibitor already licensed for hepatitis C treatment.

Both sofosbuvir and simeprevir are likely to receive approval in the European Union in the first quarter of 2014. Availability will vary between European countries according to the speed of reimbursement approval.

The Liver Meeting also heard results of new studies of interferon-free regimens for the treatment of hepatitis C virus (HCV). It is possible that the first interferon-free drug combinations for the treatment of hepatitis C genotypes 2 and 3 could be approved by the end of 2013 in the United States, and shortly afterwards in the European Union. Interferon-free drug combinations for genotype 1 could be approved by the end of 2014 or in early 2015.

Several companies are competing to develop interferon-free regimens. Each has different strengths and weaknesses, based on the data presented so far. Larger phase III licensing studies will further illuminate the differences, but it may take a number of years before any studies take place which compare interferon-free regimens directly, if at all.

These combinations are briefly described below, in alphabetical order by name of the company developing each combination.

AbbVie

Eric Lawitz of the Texas Liver Institute, presents results of the AbbVie interferon-free phase II study at The Liver Meeting 2013. Photo by Liz Highleyman, hivandhepatitis.com.

AbbVie is testing ABT-450, an HCV protease inhibitor boosted by ritonavir, and ABT-267, an NS5A inhibitor, in several phase III studies in combination with a third drug, the non-nucleoside polymerase inhibitor ABT-333. These trials will begin to report results by the end of 2013, and it is likely that AbbVie will submit a licensing application in early 2014 for this three-drug, interferon-free combination in order to achieve marketing approval in the second half of 2014.

AbbVie presented results of a study testing two drugs – ABT-450 and ABT-267 – in people with genotype. In this study, 90% of previous null responders and 95% of previously untreated patients achieved sustained virologic response (SVR12). 

A potential drawback of these combinations is the use of ritonavir to boost blood levels of ABT-450. Ritonavir causes increases in the levels of a wide range of other medicines. Use of ritonavir 100mg alongside at least 18 drugs from 10 different classes is contraindicated; these include commonly prescribed medications such as anti-arrhthymics, ergot alkaloids used in migraine treatment, and the statins simvastatin and lovastatin. The extent to which these potential interactions might pose a problem may become clearer when results of phase III studies are reported in April 2014 at the International Liver Congress, the annual meeting of the European Association for the Study of the Liver (EASL).

Boehringer-Ingelheim

Boehringer-Ingelheim previously presented phase II results of its study of an interferon-free combination containing the protease inhibitor faldaprevir, the non-nucleoside NS5B polymerase inhibitor deleobuvir (BI-207127) and ribavirin at The Liver Meeting 2012. This combination was most potent in patients with genotype 1b infection, and is being tested in phase III studies in this patient group only. Results of these studies are expected in the second quarter of 2014.

At The Liver Meeting 2013, Boehringer Ingelheim presented early results from a small phase II study of faldaprevir and deleobuvir combined with an NS5A inhibitor PPI-668, developed by its partner Presidio. The combination was tested with or without ribavirin in harder-to-treat patients with genotype 1a infection. Seventeen patients had completed a 12-week course of treatment by the time of The Liver Meeting, all had undetectable HCV at this point, and no viral relapse had occurred in 13 patients who had reached the 4-week post-treatment stage. Further results reporting the development of this combination can be expected in 2014.  

Bristol-Myers Squibb

Gregory Everson of the University of Colorado presents results of the BMS interferon-free phase II study at The Liver Meeting 2013. Photo by Liz Highleyman, hivandhepatitis.com.

Bristol-Myers Squibb presented results of a 12-week study of a three-drug combination which does not include ribavirin. This combination of daclatasvir, asunaprevir and BMS-791325 achieved cure rates of over 90% in this study of previously untreated patients. There was no difference in response between genotype 1a and 1b patients and the combination was well tolerated.

Gilead

Edward Gane, of Auckland Clinical Studies, presenting new data on sofosbuvir at The Liver Meeting. Photo by Liz Highleyman, hivandhepatitis.com.

Gilead presented results from two studies of a three-drug combination of sofosbuvir, ledipasvir and either ribavirin or GS-9669. In people with genotype 1 hepatitis C, with advanced liver disease (F3 or F4) and no previous response to interferon-based treatment, both combinations cured 100% of patients. People taking ribavirin experienced declines in haemoglobin levels but people taking GS-9669 did not. Up to 40% of people who received ribavirin developed anaemia. When a six-week course of sofosbuvir, ledipasvir and ribavirin was tested in previously untreated people with less advanced liver disease, one quarter experienced viral relapse after completing treatment. 

Merck

Merck presented results of an early-stage study of its two-drug combination. The study compared a combination of two drugs with and without ribavirin in previously untreated patients with genotype 1a and 1b hepatitis C infection. Merck is slightly behind several other pharmaceutical companies in progress towards the development of interferon-free drug combinations for treatment of hepatitis C.

Ribavirin made little or no difference to the chances of cure in this study, unlike some of the other interferon-free combinations being tested. All 11 patients in the ribavirin-free arm of this study were cured.

A two-company combination

Ira Jacobson of Weill Cornell Medical College presents results of the COSMOS study at The Liver Meeting 2013. Photo by Liz Highleyman, hivandhepatitis.com.

The most potent, the best tolerated or the most affordable combinations of hepatitis C drugs might come from mixing the products of different companies. Some drugs will only be available as part of fixed-dose, single-company combinations, but other agents will be available for combination.

Janssen has tested the combination of its protease inhibitor simeprevir with Gilead’s nucleotide polymerase inhibitor sofosbuvir in the COSMOS study. Results of this study show that in previous null responders with mild or moderate liver fibrosis and genotype 1 infection this combination cured all patients. In people with advanced liver disease (F3/F4), early results (four weeks post-treatment) indicate that this combination is also highly effective. Further research will be needed in a larger number of patients to provide more information on efficacy and safety.

The majority of studies presented at The Liver Meeting on hepatitis C treatment focused on people with genotype 1, but there was also important information on treatment of genotypes 2 and 3.

Several recent studies have indicated that genotypes 2 and 3 respond differently to the same drug combinations. Genotype 2 is more easily cured with interferon-free combinations than genotype 3. For example, a study of sofosbuvir and ribavirin has shown that people with genotype 2 are more easily cured. In particular, there was a much higher cure rate in people with genotype 2 who had cirrhosis, when compared with people with genotype 3 who had cirrhosis.

Sofosbuvir and ribavirin is recommended for approval for treatment of genotypes 2 and 3 in the United States. The VALENCE study showed that if treated for longer than genotype 2 patients, those with genotype 3 did almost as well on sofosbuvir and ribavirin as genotype 2 patients.

People with hepatitis C virus (HCV) awaiting liver transplants are in urgent need of hepatitis C treatment but often cannot tolerate interferon-based therapy. Left untreated, HCV almost always infects the new liver soon after transplantation, which can lead to cirrhosis, graft failure and death. A study presented at The Liver Meeting showed that treatment with an interferon-free combination of sofosbuvir plus ribavirin administered before liver transplantation prevented hepatitis C recurrence in nearly two-thirds of patients, while the same regimen led to early viral clearance in three-quarters of those treated after transplantation.

It is important to note that participants in both studies did not have decompensated cirrhosis. This population might be harder to treat. On the other hand, 63% of the post-transplant treatment study participants had stage F3 / F4 fibrosis, a harder-to-treat population, but they did just as well as people with less advanced liver damage. These results are encouraging for people awaiting a liver transplant as well as for those who have already undergone liver transplant.

The European Medicines Agency announced on 25 October that it plans to issue guidance on the use of sofosbuvir on a compassionate basis, prior to licensing, for patients before and after liver transplant.

Ensuring access to new hepatitis C drugs – and making sure that they are tested adequately and speedily in liver transplant populations – will be important objectives for advocates.

James Galbraith, speaking at The Liver Meeting 2013. Photo by Liz Highleyman, hivandhepatitis.com.

Several studies presented at The Liver Meeting showed that age-based screening recommendations in the United States have the potential to uncover a huge number of previously undiagnosed cases of hepatitis C.

The US Preventive Health Task Force and the US Centers for Disease Control have recommended that all adults born between 1945 and 1965 should be tested once for hepatitis C. The prevalence of hepatitis C in this age group is much higher than in younger people. As 'baby boomers' with hepatitis C age, the incidence of liver disease is rising rapidly. As a result, age-based screening has been shown to be cost-effective for the United States.

Recommendations only have an impact on public health if they are implemented. A number of demonstration studies have shown that implementing age cohort screening was practical and resulted in a large number of new diagnoses. It would be useful to see what proportion of the people diagnosed in these studies had advanced but undiagnosed liver disease.

One study also found that current US guidance to test pregnant women for HCV only if they had risk factors would miss three-quarters of HCV infections in this population. HCV was associated with a three-fold higher risk of obstetrical pulmonary embolism, which is one of the most common causes of death in pregnant women around the time of delivery.

Tung-Hung Su, of National Taiwan University Hospital, describes long-term outcomes of hepatitis B treatment at the Liver Meeting 2013. Photo by Liz Highleyman, hivandhepatitis.com.

Long-term treatment with entecavir can reduce the likelihood that people with chronic hepatitis B will develop hepatocellular carcinoma, according to findings presented at The Liver Meeting. Another study, however, found that while entecavir and tenofovir can reduce the risk, people with hepatitis B should continue to undergo regular monitoring for liver cancer and better predictive models may be needed for Caucasian patients.

Mark Sulkowski, of Johns Hopkins Medical Center, speaking at The Liver Meeting 2013. Photo by Liz Highleyman, hivandhepatitis.com.

New HCV drugs are also being tested in people with HIV and HCV co-infection. There may be interactions between HIV and HCV drugs, and previous studies have shown that people with HIV tend to do less well on dual treatment with pegylated interferon and ribavirin than other people with HCV.

A large phase III study of simeprevir combined with pegylated interferon and ribavirin showed cure rates of 57 to 89% depending on previous treatment history. The response rates were similar to those seen in people without HIV infection. People who were taking HIV treatment at the same time as simeprevir did better in this study.

An interferon-free regimen of sofosbuvir plus ribavirin taken for 24 weeks cured hepatitis C infection in three-quarters of previously untreated HIV-positive people co-infected with hepatitis C virus (HCV) genotype 1, while 12 weeks of treatment cured 88 and 67% of those with genotypes 2 or 3, according to findings from the phase 3 PHOTON-1 study.

The HCV protease inhibitor faldaprevir added to pegylated interferon and ribavirin increased the likelihood that people with HIV/HCV co-infection would achieve a sustained virological response at four weeks after completing treatment. Further follow-up is needed in this population, but levels of response were similar to those seen in studies of simeprevir and of sofosbuvir.

A cohort study in HIV-positive gay men with acute hepatitis C infection found that treatment with telaprevir plus pegylated interferon and ribavirin was associated with a high rate of virologic response.

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