News from The Liver Meeting

This month’s infohep bulletin highlights the key news from The Liver Meeting 2019, organised by the American Association for the Study of Liver Diseases (AASLD), which took place in Boston, USA from 8 to 12 November 2019.

Coalition of liver associations calls for simplification of hepatitis C care

Liver association representatives signing the statement at The Liver Meeting 2019. Photo by Liz Highleyman.

Leaders of liver disease associations from Europe, the United States, Latin America and Asia issued a global call to action at The Liver Meeting in Boston, aiming to advance toward the goal of eliminating hepatitis C as a public health threat.

The new statement, signed by representatives of the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), the Latin American Association for the Study of the Liver (ALEH) and the Asian Pacific Association for the Study of the Liver (APASL), calls for efforts to simplify hepatitis C testing and treatment in order to make them more widely available, especially in resource-limited settings.

The four associations, which are undertaking this initiative in partnership with the Clinton Health Access Initiative (CHAI), outlined four strategies to achieve this goal:

  • Simplifying diagnosis and treatment algorithms
  • Integrating hepatitis C treatment into primary care and other disease programmes
  • Decentralising hepatitis C services to the local level
  • Task-sharing with primary care clinicians and other healthcare practitioners.

These strategies are made possible by recent advances in the field, including rapid hepatitis C antibody screening and confirmatory viral load testing that can be done at a single clinical visit, direct-acting antivirals (DAAs) that are highly effective and well tolerated and, most recently, new pangenotypic DAAs that make genotypic testing unnecessary.

Liver cancer survival after DAA treatment

Prof Mindie Nguyen of Stanford University and team members at The Liver Meeting. Photo by Liz Highleyman.

People with liver cancer who achieved a sustained virological response (SVR) to direct-acting antiviral (DAA) therapy for hepatitis C saw a reduction in both liver-related and all-cause mortality over five years, according to research presented at the conference.

"Patients with HCC [hepatocellular carcinoma] have such dismal prognosis, especially those who are not candidates for curative treatment, and unfortunately, these are the majority of the HCC population," Prof Mindie Nguyen of Stanford University in California said in an AASLD press release. "[Patients with SVR] following treatment with very safe and well-tolerated DAAs could increase their survival rates by a median of 18 months, [which is] considerable progress compared to other currently available systemic therapies for HCC."

The study looked at 642 people in the United States, Japan, South Korea and Taiwan followed between 2005 and 2017, half who were not treated for hepatitis C and half who were successfully treated with interferon-free DAA regimens.

After adjusting for other factors, achieving SVR with DAAs was associated with a 76% lower risk of five-year liver-related mortality and a 63% reduction in five-year all-cause mortality, both of which were statistically significant.

Organ transplants from donors with hepatitis C

The demand for donor organs continues to grow in North America, and the supply of potential organs from donors who die from opioid overdose has also grown substantially over the past decade. Organs from donors who died of opioid overdose now make up around 15% of potential donors in the United States, compared to 1% in 2000.

But up to 30% of potential organ donors who died from overdose were infected with hepatitis C in 2016, which led many organs from otherwise young and healthy donors to be rejected.

At The Liver Meeting researchers from the Toronto Centre for Liver Disease reported that hepatitis C transmission was prevented in all cases when people receiving organs from donors with hepatitis C were treated with a preventative regimen of direct-acting antivirals to prevent hepatitis C replication and a cholesterol-lowering drug that has been shown to prevent hepatitis C entry into liver cells.

The study recruited 25 people awaiting lung, liver, kidney, heart or pancreas transplants, under the age of 65 with no evidence of liver disease.

Organ recipients received glecaprevir/pibrentasvir (300/120 mg) combined with 10mg of ezetimibe six to 12 hours before transplantation, then the same therapy daily for seven days.

Transient viraemia was detected in 18 of 25 recipients during treatment.

Three recipients had transient detectable HCV RNA after completion of treatment, but 18 recipients achieved a sustained virological response at week 12 (SVR12) and seven recipients had an undetectable HCV RNA at week 6 post-transplant but have not yet completed 12 weeks of post-transplant follow-up.

Hepatitis C incidence in Canadian men who have sex with men on PrEP

Jordan Feld from the Toronto Centre for Liver Disease, who presented the study findings, at The Liver Meeting. Photo by Liz Highleyman.

Canadian researchers found low incidence of hepatitis C infection among men who have sex with men (MSM) who were taking antiretroviral drugs to prevent HIV infection (pre-exposure prophylaxis, or PrEP).

"HCV [hepatitis C virus] infection has emerged as an STI among HIV-positive men who have sex with men over the past decade," lead researcher Dr Sahar Tabatabavakili, of the Toronto Centre for Liver Disease, said in an AASLD press release. "Generally, HIV-positive MSM are disproportionally affected by HCV compared with HIV-negative MSM, mainly due to the fact that HIV itself might facilitate sexual transmission of HCV in addition to different sexual activities and networks of these groups."

Hepatitis C transmission in HIV-negative MSM using PrEP has been observed in several European countries in recent years.

European AIDS Clinical Society and US Centers for Disease Control and Prevention guidelines recommend that people should be tested for HCV, as well as bacterial STIs, before they start PrEP. However, they do not include HCV testing as part of the monitoring that PrEP users are advised to undergo every three months. AASLD HCV guidelines recommend HCV testing at least annually at follow-up PrEP visits, with more frequent testing warranted depending on sexual activity or drug use.

Canadian researchers identified two acute HIV infections in 199 PrEP users. 1.8% of people who were evaluated for PrEP had undiagnosed chronic HCV infection. Based on these findings, the study authors concluded that baseline HCV testing for those starting PrEP "is clearly required". But they say that further cost-effectiveness analyses are required to determine the optimal frequency of HCV testing after HIV-negative people start using PrEP.

Treatments for NASH

Stephen Harrison presenting the selonsertib trial results at The Liver Meeting. Photo by Liz Highleyman.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), its more severe form, are responsible for a growing proportion of advanced liver disease. The build-up of fat in the liver triggers inflammation, which over time can lead to fibrosis, cirrhosis and liver cancer. Fatty liver disease is increasingly recognised as a manifestation of the metabolic syndrome, a cluster of conditions that include abdominal obesity, elevated blood glucose and abnormal blood lipids.

There are currently no effective medical therapies for NASH, and management relies on lifestyle changes such as weight loss. In recent years, several NAFLD/NASH drug candidates that appeared promising based on animal research and biomarkers in early human studies were found not to significantly improve fibrosis when tested alone in later-stage clinical trials. Results for two of these, the pan-caspase inhibitor emricasan and the ASK1 inhibitor selonsertib, were reported at The Liver Meeting.

Studies of four newer candidates – MSDC-0602K, tropifexor, licogliflozin and saroglitazar magnesium – were presented as late-breakers at the conference.

MSDC-0602K, from Cirius Therapeutics, is a second-generation insulin-sensitising drug. The drug had a positive impact on metabolic markers and liver enzymes in the phase 2b study reported at The Liver Meeting but did not produce significant improvement in NASH score compared to a placebo.

Tropifexor, a farnesoid X receptor (FXR) agonist, is being developed by Novartis. FXR regulates bile acid synthesis and plays a role in lipid metabolism. Phase 2 study results showed that tropifexor produced significant reductions in liver enzymes and liver fat levels compared to a placebo. Itching (pruritus) was a common side effect and approximately 5% of study participants reported severe itching. Analysis of liver biopsies to determine the impact of the drug on liver fibrosis will be reported at a future conference.

Licogliflozin, also from Novartis, is an inhibitor of sodium-glucose co-transporters 1 and 2 (SGLT1/2) that blocks glucose absorption from the gut and reabsorption by the kidneys. Findings of a phase 2a dose-ranging study showed significant reductions in liver enzymes and liver fat at the highest dose tested. People who received the drug lost weight at all doses, but mild diarrhoea was a common side effect.

Saroglitazar, a novel non-thiazolidinedione dual PPAR-alpha-gamma agonist, developed by Zydus, induces fatty acid oxidation and reduces triglyceride production in the liver, thereby improving insulin sensitivity and glucose metabolism. A phase 2 study showed that all doses reduced liver enzymes but only the highest dose was associated with liver fat reduction. Biochemical markers of liver fibrosis fell significantly in those receiving the highest dose but there were no significant reductions in liver stiffness.

Given the number of different biological processes that play a role in the development of fatty liver disease, optimal treatment may involve combining agents that work by different mechanisms.

These four new agents, along with emricasan and selonsertib, produced modest but generally positive effects on biomarkers of metabolism and liver health. Stephen Harrison of Pinnacle Clinical Research in Texas suggested that drugs that do not work well on their own but show positive effects may have potential as components of combination therapy.

Studies of such regimens are now underway. The ELIVATE study, for example, will evaluate licogliflozin plus tropifexor in people with NASH and liver fibrosis. The ATLAS trial is testing selonsertib plus Gilead Science's FXR agonist, cilofexor, and the acetyl-CoA carboxylase inhibitor firsocostat.

On 25 November, manufacturer CymaBay announced that they had terminated a NASH phase 2b trial with seladelpar, after planned biopsies at week 52 raised concerns of potential liver toxicity. Seladelpar is an experimental PPAR-agonist, which has been in clinical development for NASH as well as in PSC and PBC, two autoimmune biliary liver diseases. The recently initiated PSC trial with seladelpar was terminated at the same time. In PBC, where seladelpar has been most extensively studied so far, all ongoing trials were put on hold, pending further review and follow-up.

Hepatitis B: antivirals reduce liver cancer risk

Treating hepatitis B with nucleoside/nucleotide antiviral drugs was associated with a lower risk of developing hepatocellular carcinoma (HCC), the most common type of liver cancer, according to studies presented at the conference.

An analysis of two phase 3 clinical trials comparing tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) for hepatitis B found that antiviral treatment reduced the risk of developing HCC by 58% compared to a historical control group of untreated people.

An analysis of 2346 people who received antiviral treatment for hepatitis B in the French Hepather cohort found no difference in the incidence of HCC according to whether people received treatment with tenofovir or entecavir. This finding conflicts with the results of a recent study carried out in Hong Kong, which found that tenofovir treatment was associated with a lower risk of HCC than entecavir.

Therapeutic vaccine for hepatitis B

Osamu Yoshida Ehime of University School of Medicine in Japan presenting the NASVAC study at The Liver Meeting. Photo by Liz Highleyman.

An experimental therapeutic vaccine called NASVAC, which targets two different hepatitis B virus (HBV) antigens, led to a reduction in hepatitis B surface antigen (HBsAg) levels, according to study presented at The Liver Meeting. What's more, a small number of study participants experienced HBsAg loss, considered a functional cure.

Nucleoside/nucleotide antivirals such as tenofovir disoproxil fumarate (Viread), tenofovir alafenamide (Vemlidy) or entecavir (Baraclude) can suppress HBV replication indefinitely during treatment, but they seldom lead to a cure. Across studies, around 10% of people treated with pegylated interferon, about 5% of hepatitis B 'e' antigen (HBeAg) positive people treated with antivirals and as few as 0% of HBeAg negative people treated with antivirals achieve HBsAg loss.

NASVAC, initially developed by the Center for Genetic Engineering and Biotechnology in Cuba, contains both HBsAg and hepatitis B core antigen (HBcAg). The HBsAg component triggers production of anti-HBs antibodies, while the HBcAg component promotes T-cell activity that inhibits HBV replication. The nasally administered vaccine has been evaluated for both prevention and treatment.

The current study included 29 participants on antiviral therapy and 42 untreated people with inactive hepatitis B.

NASVAC administration had little effect on viral load. People on antiviral therapy maintained undetectable HBV DNA levels, while untreated participants saw a non-significant decrease of 10.5%.

However, the vaccine did reduce HBsAg levels in three-quarters of participants in both groups. HBsAg declined by an average of 16.7% from baseline in the antiviral group and by 18.3% in the untreated group; both declines were statistically significant.

Two people in each group experienced HBsAg loss – far higher than the rates typically seen in HBeAg negative people treated with antiviral therapy.

Based on these findings, the researchers concluded, "NASVAC could be a novel immune therapy for achieving functional cure in HBV-infected patients."

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