The 51st Meeting of the European Association for the Study of the Liver (EASL), also known as the International Liver Congress, took place in Barcelona from 13-17 April.

You can find comprehensive reporting on the meeting at infohep.org – here are some of the highlights below.

On 25th April, we held a webinar with updates from the 2016 International Liver Congress.

You can listen to the webinar again on infohep.org and view slides below.

Featuring:

• Dr Sanjay Bhagani, Consultant in Infectious Diseases, Royal Free Foundation NHS Trust, London – download slides
• Professor Jeffrey Lazarus, University of Copenhagen, Editor in Chief, Hepatology, Medicine and Policy – download slides
• Raquel Peck, Chief Executive Officer, World Hepatitis Alliance – download slides

Dr James Freeman presenting at ILC 2016. Photo by Liz Highleyman, hivandhepatitis.com

Generic versions of direct-acting antivirals (DAAs) purchased from China and India by people unable to obtain treatment in their own countries were just as effective and safe as the branded products, a study of 139 patients monitored by Australian doctor James Freeman has shown. The findings were presented in a late-breaking research session at the International Liver Congress in Barcelona earlier this month.

The high cost of branded DAAs has led to rationing of treatment, slow drug approvals and refusal of insurance coverage in many countries. People unable to obtain hepatitis C treatment through existing health care have turned in desperation to the FixHepC buyer’s club for help in obtaining generic versions of sofosbuvir, sofosbuvir/ledipasvir and daclatasvir.

Importation of medicines for personal use is permitted under customs regulations in Australia and the United Kingdom, and many other countries have regulations permitting the importation of small amounts of medicines for personal use or their carriage through customs in personal luggage. The FixHepC buyer’s club provided advice and information on how to do this safely and legally, starting in Australia, but soon responding to enquiries from people in Europe, North America, New Zealand and South East Asia.

FixHepC recommends that people who use its buyer’s club to obtain generic versions of hepatitis C drugs order products from companies in India, which have undergone manufacturing inspection by the World Health Organization (WHO) and that have a track record of manufacturing high-quality antiretroviral drugs for HIV treatment in large volumes. FixHepC is able to provide information about which companies have this experience. Nevertheless, it is important to note that, to date, no companies manufacturing DAAs have applied for or received WHO prequalification for hepatitis C products. WHO prequalification is the gold standard for generic products, and WHO has called on manufacturers to submit hepatitis C products for prequalification in order to build confidence in the quality of generic DAAs.

The FixHepC project used a test employed in pharmaceutical manufacturing to test medication ordered by people who used its service, in order to check that products contained the stated quantity of active ingredient.

Interim results from the study (four weeks after the completion of treatment) show that overall, 94.4% of people who received generic versions of DAAs had a sustained virologic response at this time point, similar to the performance of branded versions in large real-world cohorts (see below for more details).

The findings received prolonged applause from the large audience of liver specialists. Many leading liver specialists expressed frustration during the conference at the high prices of DAAs and the rationing of these drugs on the grounds of cost by governments and insurers.

But the study presented by Dr Freeman represents the tip of the iceberg in terms of the impact of generic drugs on hepatitis C treatment. Although obtaining generic drugs may help many individuals currently denied treatment on the grounds of cost, mail-order treatment is not a sustainable solution to a major public health problem. Only a combination of affordable pricing by companies and a commitment to hepatitis C treatment by governments will make a hepatitis C cure widely accessible.

Activists demanding access to hepatitis C treatment at ILC 2016. Photo by Liz Highleyman, hivandhepatitis.com

For lower-income and lower middle-income countries, generic versions of DAAs offer the prospect of affordable treatment – if governments and manufacturers can navigate a maze of voluntary licensing restrictions and exploit flexibilities in the TRIPS trade agreement which permit use of generics in some circumstances even when drugs are patented.

Several sessions at the conference highlighted the progress already being made in some countries as a result of the availability of generic DAAs. Manufacturers in India are able to make a course of DAA treatment for less than $300. As the volume of orders and the number of tenders increases, prices are likely to fall further as a result of competition. Uptake of hepatitis C is growing in India and Pakistan. In Egypt the government aims to treat 400,000 people by 2017, largely through the use of generic products. However, for Egypt to achieve the goal of elimination of hepatitis C – a 95% reduction in new infections – a large increase in screening for hepatitis C and in diagnosis and referral will be needed.

Activists at the Barcelona meeting called for access to generic DAAs, not just in lower- and middle-income countries, but in higher-income countries too. They called for an end to the rationing of treatment on the grounds of cost, pointing out that Gilead has already earnt more than $32 billion from hepatitis C drugs. Whereas Gilead charges up to $84,000 for a course of Sovaldi (sofosbuvir) in the United States, generic versions can be produced in India for less than $300 for a course of treatment.

The Drugs for Neglected Diseases initiative (DNDi) is launching clinical trials in Thailand and Malaysia to test a combination of sofosbuvir and ravidasvir, an NS5A inhibitor, in at least 800 people with all genotypes of hepatitis C virus. The combination, manufactured by Egyptian company Pharco, could be made available for US$300 for a course of treatment if it proves safe and effective, DNDi executive director Bernard Pécoul announced ahead of the 2016 International Liver Congress in Barcelona earlier this month.

The studies aim to test an affordable pangenotypic combination and to provide data for regulatory submission.

Affordable pangenotypic treatment for hepatitis C would allow many lower- and middle-income countries to treat a wide range of people with hepatitis C, without the need for genotyping, reducing the cost of treating each patient.

Signing of the Joint Society Statement on Elimination of Viral Hepatitis. Photo by Liz Highleyman, hivandhepatitis.com

The adoption of elimination of viral hepatitis as an achievable goal was a major theme at the International Liver Congress. Leaders of liver disease associations from Europe, the US, Latin America and Asia released a Joint Society Statement on Elimination of Viral Hepatitis at the opening session, calling for enhanced efforts to diagnose and treat hepatitis B and C, with the goal of eliminating viral hepatitis as a public health threat.

The World Hepatitis Alliance announced that an international campaign, NOhep, will be launched on World Hepatitis Day, as an interactive web platform which can be used to connect people, lobby governments and international organisations and mobilise supporters. Organisations and individuals will be able to sign up as supporters and download campaign materials from 29 April on the World Hepatitis Day website.

Numerous studies presented at the International Liver Congress showed that direct-acting antivirals are achieving cure rates in everyday clinical practice similar to those seen in clinical trials, above 90% in almost all groups of patients.

In one of the largest studies, investigators from the United States Department of Veteran Affairs (VA) analysed outcomes in over 9000 patients treated with DAA combinations. Outcomes were excellent, with two combinations achieving cure rates of 93%, similar to those seen in randomised studies with strict eligibility criteria and close follow-up.

A report on outcomes in Portugal, where treatment for hepatitis C with sofosbuvir/ledipasvir (Harvoni) or sofosbuvir (Sovaldi) was made widely available in 2015 following price negotiations, found that the overall cure rate in 1069 patients who had completed treatment by January 2016 was 96%. Treatment also worked well for people with cirrhosis, achieving SVR rates of between 84 and 94%. The study found that outcomes were poorer in people with genotype 3 infection, underlining the importance of identifying highly potent regimens for treatment of genotype 3.

Dr Carlos Fernández Carrillo presenting at ILC 2016. Photo by Liz Highleyman, hivandhepatitis.com

Doctors need to have “full and frank” discussions with patients about the potential risks and benefits of using direct-acting antivirals (DAAs) to treat hepatitis C in late-stage liver disease, especially among those waiting for a liver transplant, liver specialists said at the International Liver Congress.

Another study found that although DAA treatment improved liver function sufficiently to allow 20% of patients to be taken off the waiting list for a liver transplant, the other 80% still needed a liver transplant after hepatitis C treatment, underlining the importance of expanding the supply of livers available for transplant by increasing the number of donors with hepatitis C. A review of liver transplants from donors with hepatitis C in the United States between 1995 and 2013 also presented at the International Liver Congress showed that people with hepatitis C who received a liver transplanted from an HCV-positive donor were no more likely to die or experience graft rejection than people with hepatitis C who received livers from HCV-negative donors.

The conference also featured research showing that people with cirrhosis who had received previous treatment for hepatocellular carcinoma (HCC – liver cancer), and who were treated with DAAs, had twice the expected risk of developing HCC again, either during treatment or in the six months following completion of hepatitis C treatment. The researchers say that all people with cirrhosis who receive hepatitis C treatment should continue to be closely monitored for liver cancer after completing treatment.

Eric Lawitz of the Texas Liver Institute presenting at ILC 2016. Photo by Liz Highleyman, hivandhepatitis.com

Hepatitis C treatment with new drug combinations can be highly effective in people who did not respond to a first course of direct-acting antiviral (DAA) treatment, studies presented at the International Liver Congress showed.

There has been concern that the failure of a course of DAA treatment might lead to drug resistance, which in turn might reduce the effectiveness of future attempts to cure hepatitis C virus (HCV) with a new regimen.

However, a study of resistance-associated variants (RAVs) of HCV in European patients found that most treatment-experienced patients with RAVs had a high probability of responding to a subsequent regimen.

New regimens in development by Gilead Sciences and AbbVie are highly effective in people who have failed to respond to the first generation of DAAs.

Studies of the Gilead regimen of sofosbuvir, velpatasvir and GS-9857 showed that 99% of people with genotypes 1-6 were cured, and the presence of cirrhosis or previous treatment history did not affect response. A second study of this regimen with or without additional ribavirin, looking only at patients with genotype 1, found a similarly high rate of response. Not adding ribavirin did not reduce the chance of cure, but did reduce the frequency of side-effects.

The AbbVie experimental regimen of ABT-493 (protease inhibitor) and ABT-530 (NS5A inhibitor) also proved highly effective in people who had not been cured after treatment with a DAA regimen. Between 77 and 86% had at least one major resistance-associated variant. In the phase II study, which recruited 50 patients, 95% of participants were cured.

Paul Kwo presenting at ILC 2016. Photo by Liz Highleyman, hivandhepatitis.com

Genotype 3 hepatitis C virus (HCV) is more difficult to cure than other genotypes of HCV, requiring a longer course of treatment with most regimens. The most effective available regimens for treatment of genotype 3 have cured between 78 and 88% of people treated. AbbVie is developing the combination of ABT-493 and ABT-530 as a pangenotypic regimen for hepatitis C treatment.

Results from the SURVEYOR-II phase II study showed that the regimen is highly effective in people with genotype 3 and compensated cirrhosis, a group of patients with an especially high need for an effective regimen. It is of utmost importance to prevent the progression of liver disease in people with compensated cirrhosis. The study found that a 12-week treatment course cured all participants in this 48-person study.

A second study of the regimen in people with genotype 3 found that in those without cirrhosis, an 8-week course of treatment was sufficient to cure previously untreated people, without the need for additional ribavirin.

Prof. Heiner Wedemeyer of Hannover Medical School presenting at ILC 2016. Photo by Liz Highleyman, hivandhepatitis.com

There are high rates of ongoing hepatitis C virus (HCV) transmission in two populations in the European region: people who inject drugs and HIV-positive men who have sex with men. In the latter group, HCV transmission is occurring due to both re-use of injecting equipment and sexual transmission.

A European collaborative study presented at the International Liver Congress showed that there is also a high incidence of HCV reinfection among HIV-positive MSM previously cured of hepatitis C. The study found that just under 25% of men were reinfected, after a median of 1.8 years, and in some cases men were reinfected multiple times. The researchers expressed concern that current prevention measures are failing to prevent reinfection, but the high rate of reinfection is hardly surprising given that there is also a high rate of HCV acquisition among HIV-positive MSM – and an estimated prevalence of around 7% among HIV-positive MSM in Western Europe. This study provides more evidence of the lack of preventive education and harm reduction measures targeted at all MSM living with HIV.

Research presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in March showed that a 6-week course of sofosbuvir/ledipasvir was sufficient to cure hepatitis C in acutely infected people with HIV/HCV co-infection with lower viral load.

At the International Liver Congress, results from the German HepNet Acute HCV IV Study were presented, showing that a 6-week course of sofosbuvir/ledipasvir cured all acutely infected people with hepatitis C alone, including those with high viral load. Study investigators advised against delaying treatment in the hope that spontaneous clearance might occur, pointing out that this treatment strategy could leave patients ill for months – and would not prevent onward transmission of HCV.

David Wyles presenting at ILC 2016. Photo by Liz Highleyman, hivandhepatitis.com

Studies have shown that HIV-positive people with hepatitis C virus (HCV) genotype 1 have a high likelihood of being cured of HCV with interferon-free direct-acting antiviral (DAA) therapy, which is particularly beneficial because they experience more rapid liver disease progression if left untreated.

Yet there is still room to optimise therapy for people with HCV genotypes other than 1. Genotype 3 is now considered the most difficult to treat, while there are fewer data for genotypes 4, 5 and 6. Ideally, combination DAA regimens will be pangenotypic – active against all genotypes – meaning they could be prescribed without the need for genotype testing.

The ASTRAL-5 trial evaluated a pangenotypic combination consisting of Gilead Sciences’ sofosbuvir and the second-generation NS5A inhibitor velpatasvir (formerly GS-5816) for people with HIV and HCV co-infection. The sofosbuvir/velpatasvir co-formulation is currently under review by the US Food and Drug Administration and European regulatory authorities and is likely to receive marketing approval by the end of 2016.

The ASTRAL-5 study enrolled HIV-positive participants in the United States with genotype 1-4 HCV infection, taking a broad range of antiretroviral regimens. About one-third had previous experience of hepatitis C treatment and 18% had compensated cirrhosis. The overall cure rate was 95%, with very little difference between genotypes (although the number of participants with genotype 4 was very low).

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