News from the 2018 International Liver Congress, Paris

This edition of the infohep bulletin covers news from the annual meeting of the European Association for the Study of the Liver (EASL), The International Liver Congress. The meeting took place in Paris from 11 to 15 April 2018.

Next month’s infohep bulletin will contain further news from the conference on viral hepatitis elimination, hepatitis B treatment and non-alcoholic fatty liver disease (NAFLD) treatment.

Effectiveness of hepatitis C treatment

Chiara Mazzarelli, one of the liver transplant study researchers, at The International Liver Congress, 2018. Photo by Liz Highleyman.

Direct-acting antiviral (DAA) treatment for hepatitis C is highly effective in curing hepatitis C infection but the long-term objective of treatment is to prevent liver disease and death. The long-term effects of curing hepatitis C virus (HCV) infection with DAAs was called into question by a Cochrane Collaboration systematic review in 2017. The review concluded that there was not yet sufficient evidence to show that curing HCV infection reduced illness and death. This conclusion was strongly questioned by liver experts.

At The International Liver Congress in Paris, a large prospective study carried out in Italy provided clear evidence that curing hepatitis C infection results in a reduction in the risk of dying from a liver-related cause. People with Child-Pugh A cirrhosis (compensated cirrhosis) were 15 times more likely to die of a liver-related cause if they did not achieve a sustained virologic response to DAA treatment, the study found. They were also at higher risk of dying from cardiovascular disease.

A study which followed everyone treated for hepatitis C in Scotland found that liver decompensation due to cirrhosis in people previously diagnosed with chronic hepatitis C declined by 29% between 2013 and 2016. During the same period 94% of people treated for hepatitis C in Scotland achieved a sustained virologic response.

Similarly, a Europe-wide study of liver transplants found that while the number of transplants carried out in Europe remained stable between 2007 and 2017, the proportion that were carried out as a consequence of hepatitis C fell from 23% to 11%. The decline in HCV-related transplants became evident after 2014 and was especially evident in people with HCV-related decompensated cirrhosis. The survival of liver transplant recipients with HCV also improved.

EASL HCV treatment guidelines

The EASL hepatitis C treatment guidelines panel at The International Liver Congress, 2018. Photo by Liz Highleyman.

The European Association for the Study of the Liver (EASL) released its latest hepatitis C treatment recommendations at the conference. The guidelines are available online in the Journal of Hepatology.

The recommendations – which are intended to apply to all European countries – include the most recently approved hepatitis C virus (HCV) therapies, with the acknowledgement that older options may still be used where newer ones are unavailable. The guidelines simplify treatment by doing away with HCV genotype testing and even post-treatment assessment of long-term virological response in many cases.

As in the previous guidelines, EASL recommends treatment for everyone living with hepatitis C, including those who were not cured or who became reinfected after a first treatment attempt.

The panel now recommends only interferon-free, ribavirin-free direct-acting antiviral regimens for people with or without compensated cirrhosis; those who were not previously treated and those who were treated with interferon-based regimens or sofosbuvir (Sovaldi) plus ribavirin; and people with or without HIV co-infection.

The panel recommends sofosbuvir/velpatasvir or glecaprevir/pibrentasvir for people with HCV genotypes 1a, 1b, 2, 3, 4, 5 and 6. Sofosbuvir/velpatasvir/voxilaprevir is also included for those with genotype 3. The recommended treatment duration is 12 weeks of sofosbuvir/velpatasvir and 8 or 12 weeks of glecaprevir/pibrentasvir for people with and without cirrhosis, respectively.

The panel also included some older genotype-specific regimens, which may be more readily available and less expensive in some countries. They added that generic drugs may be used if quality control can be assured. Sofosbuvir/ledipasvir (Harvoni) is recommended for genotypes 1a, 1b, 4, 5 and 6, while grazoprevir/elbasvir is recommended for 1a, 1b and 4. AbbVie's old ombitasvir/paritaprevir/ritonavir/dasabuvir (Viekirax/Exviera) regimen is appropriate only for easy-to-treat genotype 1b.

The panel also made recommendations for re-treatment, for treatment in people with decompensated cirrhosis and on whether to defer treatment until after a liver transplant. For further details see the full report on the guidelines.

Liver cancer treatment guidelines

The EASL liver cancer guidelines panel answer questions at The International Liver Congress, 2018. Photo by Liz Highleyman.

EASL also issued new guidelines on the treatment of hepatocellular carcinoma (HCC) at the conference.

Liver cancer is the fifth most common cancer and the second leading cause of cancer-related death, with about 854,000 new cases and 810,000 deaths per year, according to the guidelines. About 85% of all cases occur in East Asia and sub-Saharan Africa. HCC accounts for around 90% of primary liver cancers, meaning they originate in the liver.

The panel recommended enhanced screening programmes to identify people at risk for HCC. Regular surveillance is strongly advised for people with liver cirrhosis, with a weaker recommendation for those with advanced (stage F3) liver fibrosis. Abdominal ultrasound every six months is recommended.

Liver resection and liver transplantation are the first options for people with early tumours, according to the guidelines.

Radiofrequency thermal ablation is the standard of care for people with early HCC not suitable for surgery, and it can replace surgery as first-line treatment for those with very early cancer. Ethanol injection is another option, and microwave ablation shows some promise, but there is little evidence to support external beam radiation therapy.

Recurrence is common after surgery and follow-up is recommended every 3 to 4 months for the first year.

Systemic therapies, or drugs that affect the whole body, have seen the most evolution since the previous guidelines in 2012.

Sorafenib (Nexavar) is the standard-of-care first-line systemic therapy for people with advanced HCC or those with early tumours who are either considered unsuitable for or who experience disease progression on loco-regional therapies.

The guidelines also recommend lenvatinib (Lenvima), which has been found to be non-inferior to sorafenib, as an alternative first-line therapy for people with advanced HCC and good liver function.

Regorafenib (Stivarga) is recommended as a second-line treatment for people who experience disease progression on sorafenib. Studies have also shown that cabozantinib (Cabometyx tablet formulation and Cometriq capsule formulation) improved survival in this patient group.

EASL does not yet recommend immunotherapy for liver cancer. Last September the US Food and Drug Administration approved nivolumab (Opdivo) as second-line therapy for people with HCC who were previously treated with sorafenib, but it is not yet approved for this indication in Europe.

Liver cancer treatment

Jens Ricke at The International Liver Congress, 2018. Photo by Liz Highleyman.

Two studies reported on liver cancer treatment using combinations of systemic therapy with sorafenib and either selective internal radiation therapy (SIRT) or transarterial chemoembolization (TACE) in people with advanced liver cancer.

The SORAMIC study of sorafenib versus sorafenib and SIRT recruited people in Europe with locally advanced liver cancer considered unsuitable for potentially curative treatment. The aim of treatment was improved symptoms.

Sorafenib plus SIRT did not improve survival compared to sorafenib alone in the overall study population but analysis by sub-group showed that the combination treatment did improve survival in people without cirrhosis, in people without alcoholic liver disease and in people aged under 65.

The STAH trial recruited people with advanced hepatocellular carcinoma in South Korea and randomised study participants to receive either sorafenib alone or sorafenib plus TACE (injection of chemotherapy drugs into the blood vessels that supply tumours). This trial also found no overall survival difference but people who received two or more TACE sessions did have longer survival. Progression-free survival, median time to progression and tumour response rate were modestly, but significantly, greater in the combination arm. Serious adverse events occurred more frequently in the combination arm. The researchers concluded that the combination treatment improved survival in people able to undergo more than one TACE session but did not report predictors of which people would be able to undergo more than one session.

Liver cancer risk after DAA treatment

Recurrence of hepatocellular carcinoma (HCC) has been observed in previous studies of people with hepatitis C treated with direct-acting antivirals (DAAs). In 2016 Italian researchers reported an unexpectedly high rate of liver cancer recurrence in people treated with DAAs and warned of the need for close monitoring for HCC after DAA treatment. Subsequent research concluded that there was no increase in the risk of HCC after DAA treatment.

Three studies, two multicentre prospective cohort studies and one retrospective study, all conducted in Italy, reported on the potential risk of recurrence at the conference. The studies found that:

  • The risk of liver cancer recurrence was strongly associated with a lack of cure after DAA treatment and with a shorter duration between achieving a complete response to liver cancer treatment and starting DAA therapy.
  • The majority of new and recurrent cases occurred within a year of starting DAA treatment.

Access to treatment

Interim results from the STORM-C-1 study. Image credit: @DNDi

The combination of sofosbuvir and the new NS5A inhibitor ravidasvir cured 97% of people with hepatitis C in a study carried out in Malaysia, and could provide a safe and effective cure for hepatitis C in low- and middle-income countries for $300 or less, researchers of the Drugs for Neglected Diseases Initiative (DNDi) reported on the opening day of the conference.

Approximately 70 million people live with hepatitis C worldwide but access to curative treatment is restricted by price and by the lack of investments in health systems and viral hepatitis diagnosis and treatment.

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.

Ravidasvir is an NS5A inhibitor. It was developed by Presidio Pharmaceuticals and licensed to the Egyptian drug manufacturer Pharco Pharmaceuticals for development and marketing in low- and middle-income countries. The combination has already been studied in people with genotype 4 hepatitis C virus infection in Egypt. The combination of ravidasvir and sofosbuvir has the potential to be used to treat all genotypes of hepatitis C.

The STORM-C-1 study was carried out by DNDi in Malaysia to test the efficacy and safety of the combination of ravidasvir and sofosbuvir. The study recruited people with a range of genotypes and included people with compensated cirrhosis and people who had not been cured by previous interferon-based treatment.

The study recruited 300 people in Malaysia and Thailand between October 2016 and June 2017. Participants received 12 weeks of once-daily open-label treatment with ravidasvir and sofosbuvir (200mg/400mg) if they did not have cirrhosis and 24 weeks of ravidasvir and sofosbuvir if they had compensated cirrhosis (Child-Pugh class A).

The cure rate was very high; by intent-to-treat analysis, 97% of participants achieved a sustained virologic response (99% genotype 1a, 100% genotype 1b and 2 and 97% genotype 3). The cure rate was slightly lower in people with genotype 6 (81%).

“The results indicate that the sofosbuvir/ravidasvir combination is comparable to the very best hepatitis C therapies available today but it is priced affordably and could allow an alternative option in countries excluded from pharmaceutical company access programs,” said Bernard Pécoul, Executive Director of DNDi.

Cost-effectiveness of early treatment for hepatitis C

Scott Johnson presenting at The International Liver Congress, 2018. Photo by Liz Highleyman.

Early treatment for hepatitis C would be highly cost-effective in Scotland when compared to treatment initiated at the stages of advanced fibrosis or cirrhosis, according to a cost-effectiveness analysis presented at the conference.

Medicus Economics and AbbVie, the manufacturer of the direct-acting antivirals glecaprevir/pibrentasvir (Maviret) developed a model of disease progression based on published natural history studies and applied it to the known characteristics of the population of people with diagnosed hepatitis C infection in Scotland.

Assuming that treatment is started when liver disease is at stage F0 or F1, the lifetime risk of developing decompensated cirrhosis is just 4% but that lifetime risk rises to 11.6% for people who do not begin treatment until reaching F4 fibrosis. Even delaying treatment until F2 fibrosis is present increases the lifetime risk of decompensated cirrhosis to 8.9%.

The lifetime risks of hepatocellular carcinoma (HCC) and liver-related death rise spectacularly for people who start treatment with F4 fibrosis. The lifetime risk of HCC is 35.2% and the risk of dying from any liver-related cause is 41.1% in this group of people, the model showed.

The lifetime medical cost incurred by starting treatment at stages F0-F1 is £32,966. Waiting until stage F4 increases the cost to £60,963 owing to the cost of treating an individual with cirrhosis, especially in cases of decompensated cirrhosis. Early treatment would be highly cost-effective if initiated at either stages F0-F1 or at stages F2-F3.

Shorter treatment courses for genotype 3

Alison Boyle presenting at The International Liver Congress, 2018. Image credit: @katjc1

Treatment for hepatitis C genotype 3 infection can be completed in 8 weeks in people without cirrhosis, three real-world studies presented at the conference confirmed.

Genotype 3 is especially common in people who inject drugs and former drug users. It has been considered 'harder to cure' although recent studies of newer agents in people with genotype 3 have shown high cure rates.

A Scottish study in people receiving opioid substitution therapy through community pharmacies showed that an 8-week course of sofosbuvir/velpatasvir (Epclusa) cured 93% of those who started treatment. The study recruited people with F2 or F3 fibrosis and people who were still injecting drugs or in the early stages of recovery received directly observed therapy each day.

Markus Cornberg presenting at a press conference at The International Liver Congress, 2018. Photo by Liz Highleyman.

Preliminary results from the German Hepatitis C Registry showed that an 8-week course of glecaprevir/pibrentasvir (Maviret) cured 97% of people with compensated cirrhosis or no cirrhosis who started treatment. The predominant genotypes were 1a (34%) and 3 (35%) and the cohort was predominantly male and untreated.

“It’s a very healthy cohort and it’s our impression that most patients with advanced disease are already treated in Germany. This cohort are younger and more likely to be drug users,” said Dr Thomas Berg of Leipzig University.

Italian investigators reported on the outcomes of 639 people who received an 8-week course of treatment with glecaprevir/pibrentasvir and 84 who received a 12 or 16-week course of treatment due to cirrhosis or previous treatment history. Almost all the 8-week treatment cohort had mild fibrosis (90% had F0-F2 fibrosis, the remainder F3 or F4).

Interim results were available for 314 of the 8-week treatment cohort patients who had week 4 post-treatment (SVR4) virological results available and final data for 44 patients with SVR12 results were available. In each group, one person had experienced post-treatment viral relapse, giving SVR4 and SVR12 results of 99.7% and 97.7% respectively.

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