News from The International Liver Congress, Vienna

The International Liver Congress, organised by the European Association for the Study of the Liver (EASL), took place earlier this month in Vienna, Austria. This month’s bulletin highlights the key news from the conference on viral hepatitis and liver disease.

Hepatitis C elimination by 2030 in doubt as countries fail to scale up diagnosis and treatment

Margaret Hellard of the Burnet Institute presenting their modelling study at The International Liver Congress. Image: @AnnetteGaudino and @TAGTeam_Tweets

Most countries will struggle to eliminate hepatitis C by 2030 due to lack of investment and political will, missing an internationally agreed target set by the World Health Organization, The International Liver Congress in Vienna heard earlier this month.

“Despite the progress we’ve seen, we’re clearly not going to make it,” said Gottfried Hirnschall, Director of HIV and Hepatitis at the World Health Organization (WHO), speaking at a symposium on elimination of viral hepatitis organised by WHO.

The World Health Assembly agreed ambitious targets for elimination of viral hepatitis in 2016. Countries pledged to scale up prevention, diagnosis and treatment so that deaths caused by viral hepatitis would be cut by 65% and new infections cut by 90%

Although 124 countries now have national plans for viral hepatitis elimination, 42% of plans have no domestic funding, Mark Bulterys, head of WHO’s hepatitis team told the symposium.

Furthermore, although 5 million people had been treated with direct-acting antivirals by the end of 2017, most of these treatments occurred in ten 'champion countries' which have scaled up treatment quickly, including Egypt, Brazil and Australia.

Even in higher-income countries, hepatitis C elimination may only be achieved by a handful of countries by 2030, the Center for Disease Analysis estimates. Nine countries – Australia, France, Iceland, Italy, Japan, South Korea, Spain, Switzerland and the United Kingdom – will achieve elimination by 2030 at current rates of diagnosis and treatment.

Modelling by Stanford University for WHO estimates it will cost $58.8 billion to achieve elimination of viral hepatitis by 2030, slightly higher than the $51 billion estimate presented by Professor Margaret Hellard of the Burnet Institute, Melbourne, on the opening day of the conference.

To speed up progress towards elimination, WHO emphasised the need for:

  • Lower-income countries to take advantage of voluntary licensing agreements that permit the importation of low-cost quality-assured direct-acting antivirals.
  • Countries to develop national plans for viral hepatitis elimination and to commit domestic funding to elimination.
  • Adoption of simplified treatment and monitoring protocols – including task shifting to general practitioners, nurses and community health workers – that will enable larger volumes of people to be diagnosed and treated.

30 million screened for hepatitis C in four months in Egypt

Egypt screened almost 30 million people for hepatitis C in the first four months of a national screening programme that kicked off in October 2018, Egyptian researchers announced at the conference.

A national screening programme was launched in 2018 that aims to screen 62 million adults and 15 million adolescents by 2020.

The free hepatitis C screening programme is integrated with screening for diabetes, high blood pressure and obesity. People diagnosed with hepatitis C receive a free 12-week course of treatment with generic versions of direct-acting antivirals. The drugs cost the Egyptian government US$45 per treatment course and the overall cost per cure including diagnostics is $75.

Rather than going door-to-door, the screening programme is offering testing at a combination of screening centres and mobile screening units at mosques, subway stations, sports grounds and factories. The country has been divided into three regions, each covered by up to 7000 screening sites that operate 12 hours a day, seven days a week.

The Egyptian screening programme reached 78% of the eligible population in areas where screening has already taken place. Screening identified 1.2 million people who were hepatitis C virus antibody positive, of whom 900,000 are chronically infected and in need of treatment.

Same-day diagnosis and treatment initiation for viral hepatitis

ELPA board member Gamal Shiha presenting the Egyptian pilot study at The International Liver Congress. Image: ELPA @HepatitisEurope

Egyptian doctors from the Egyptian charitable foundation ELRIAH (Egyptian Liver Research Initiative and Hospital) and Mansoura Hospital presented a pilot study of same-day diagnosis and treatment initiation.

For any country, the number of steps that a person must go through to be diagnosed and treated for hepatitis C pose one of the biggest challenges to achieving elimination. At each stage in the diagnostic pathway there is a risk that people will be lost from care. Speeding up the process and trying to offer diagnosis and treatment on the same day could increase cure rates. This is especially important in lower-income countries where treatment centres for viral hepatitis may be few and far between.

Portable diagnostic equipment is now making it easier to carry out point-of-care diagnostic testing for many diseases. The Egyptian pilot study used the Gene Xpert test platform to test for chronic hepatitis C infection (HCV RNA) within two hours and used portable Fibroscan equipment to evaluate liver fibrosis.

The pilot study screened 473 people in one village in one day. Forty-three were RNA positive and 40 started treatment on the same day. Testing of the first group of patients began at 9 am and the first patients to test positive were offered treatment by 12.30 pm.

Hepatitis B cure strategy launched

The Global Scientific Strategy to Cure Hepatitis B (The ICE-HBV Strategy) by the International Coalition to Eliminate HBV (ICE-HBV), a global group of researchers, patient representatives and health organisations, was released on the opening day of the conference.

Over 257 million people worldwide are living with chronic hepatitis B infection and over 887,000 die due to the infection each year. Chronic hepatitis B causes almost 40% of hepatocellular carcinoma, which is the second leading cause of cancer-related mortality worldwide.

Hepatitis B infection cannot usually be cured with current treatments. Scientists are pursuing two approaches to curing hepatitis B infection.

One approach is to aim for a sterilising cure, defined as complete elimination of hepatitis B cccDNA (covalently closed circular DNA) and integrated DNA from liver cells and undetectable hepatitis B surface antigen (HBsAg) in the blood.

The other approach is to achieve a functional cure, defined broadly as undetectable HBsAg or HBV DNA in blood after discontinuation of antiviral treatment.

Experimental hepatitis B drug produces deep and rapid decline in HBV DNA

An experimental drug designed to inhibit multiple steps in the hepatitis B virus (HBV) lifecycle produced rapid and deep declines in HBV DNA in two phase 2a studies presented at the conference.

ABI-H0731 is being developed by Assembly Biosciences. It is a core protein allosteric modifier (CpAM) that targets the HBV core protein and interferes with multiple steps of the viral lifecycle, including cccDNA formation. Preventing cccDNA formation may be a key step in eliminating hepatitis B infection or achieving remission, as cccDNA forms the reservoir of hepatitis B in the body that allows the infection to persist despite treatment. Currently available antiviral drugs do not prevent cccDNA formation.

In two small studies, ABI-H0731 plus entecavir was compared to placebo (study 201) or to entecavir alone (study 202).

In both studies, the combination regimen led to faster, steeper and larger declines in HBV viral load starting at week 2. In study 201, 5 out of 6 people who received ABI-H0731 had undetectable HBV using the most sensitive measures, indicating that residual virus had been eliminated.

"The accelerated decline and significant loss of baseline RNA and DNA viraemia suggest that combination therapy with a core inhibitor plus [nucleoside/nucleotide analogues] may enhance loss of cccDNA and viral antigen once residual viraemia has been fully cleared," said Jay Lalezari of Assembly Biosciences in a conference press release.

Another laboratory study, in mice, showed that a compound called ccc_R08 eliminated HBV cccDNA from human liver cells in the laboratory and from the livers of mice treated for two weeks with the compound.

Non-alcoholic fatty liver disease and NASH

New research on non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) was a major theme of the 2019 International Liver Congress.

Research carried out in the south-west of England showed the scale of NAFLD among young people. A longitudinal study, Children of the 90s, has been monitoring children and young people in Bristol since 1991. At the age of 18 2.5% had NAFLD. By the age of 24, Fibroscan testing revealed that 20% had some liver fat accumulation and half of that group had severe NAFLD. The presence of liver fat was strongly associated with obesity.

Several drugs are in development to treat NASH, which develops when liver fat accumulation begins to cause damage to liver cells through inflammation. NASH may lead to fibrosis and eventually to liver cirrhosis or liver cancer, and also increases the risk of cardiovascular disease. NASH can be reversed by weight loss and the risk of developing NASH can be reduced by avoiding processed foods high in fat and sugar, as well as processed meat. The combination of fat and sugar is especially harmful. Shira Zelba-Sagi of Haifa University, Israel, told a symposium on NAFLD organised by the European Liver Patients Association that the contribution of sugar in soft drinks to the development of NAFLD justifies controlling added sugar in the same way as alcohol from a public health and regulatory standpoint.

Image from the EASL livestream of Zobair Younossi presenting the obeticholic acid study at The International Liver Congress.

A phase 3 study of obeticholic acid in people with F2 or F3 fibrosis caused by NASH showed that after 18 months, fibrosis improved by at least one stage in 23% of people who received the higher dose of the drug compared to 11% in the placebo group. Pruritus (itching) was reported by just over half of people who received the drug and 9% stopped treatment due to itching.

Although the improvement in fibrosis observed in this study was only modest, EASL vice-secretary Prof. Philip Newsome described the result as ‘very exciting’, as it shows that a medical treatment can improve fibrosis in NASH.

A study of emricasan, a drug to improve another complication of NASH – portal hypertension – failed to reduce portal blood pressure in the overall study group. Emricasan has been shown to reduce inflammation and improve liver function as measured by MELD score in a previous study in people with cirrhosis due to various causes. In this study, emricasan was tested in people with compensated cirrhosis due to NASH. The drug failed to reduce portal blood pressure in the overall study population but did reduce blood pressure in those patients with the highest blood pressure at baseline.

NAFLD in people living with HIV

Slide from the study presented by Zobair Younossi at The International Liver Congress. Image from the EASL livestream.

Now that hepatitis C can be successfully treated in people living with HIV, non-alcoholic fatty liver disease (NAFLD) is becoming an increasingly important cause of serious liver problems and liver-related death in this population in the US.

A new study found that the prevalence of NAFLD increased by 7% a year among people with HIV between 2006 and 2016. Deaths due to NAFLD increased by 8% a year.

Simplified monitoring and highly effective treatment for hepatitis C

Markus Cornberg presenting the real-world Maviret study at The International Liver Congress. Image: EASL Education @EASLedu

Two studies presented at The International Liver Congress show the potential for simplified monitoring and treatment to permit the scale-up of treatment, allowing many more people to be cured of hepatitis C.

The SMART-C study showed that people without potential adherence problems who had tests for hepatitis C viral load (HCV RNA) at the start of treatment and 12 weeks after completing treatment were just as likely to be cured as people who also underwent viral load tests during treatment and at the end of treatment. Reducing the number of clinic visits makes it easier for people to accept the idea of starting treatment and frees up healthcare workers to provide support to people who have adherence problems.

Two large real-world studies showed that the pangenotypic combination pills Epclusa (sofosbuvir/velpatasvir) and Maviret (glecaprevir/pibrentasvir) achieve very high cure rates and few patients are lost to follow-up when treated. Both simplified regimens can be dosed without ribavirin, have few adverse effects and do not require genotyping to determine treatment duration, making them ideal for use where monitoring resources are limited or where large numbers of people must be treated by a limited number of healthcare workers.

Tenofovir and liver cancer in HBV

People with hepatitis B who were treated with tenofovir disoproxil fumarate (TDF; Viread) were less likely to develop hepatocellular carcinoma than those treated with entecavir (Baraclude) in a large observational study, according to results presented at the conference.

The study of people with hepatitis B in Hong Kong found that people treated with tenofovir had approximately 60% lower risk of developing liver cancer compared to people treated with entecavir, after controlling for risk factors.

Although the analysis included nearly 30,000 people, only a small proportion of them used TDF. While the researchers attempted to control for other factors that might influence outcomes, it may be too early to conclude that TDF is a superior option for hepatitis B treatment.

Previous observational research has shown different courses of chronic hepatitis B in various ethnic cohorts. The observations made in Asian patients should be confirmed in trials including cohorts from other ethnic groups such as Caucasian and African patients. Also, the data were generated with TDF and it is not clear if the results would be the same for the newer tenofovir alefenamide (TAF).

If further data confirm these findings, it could have public health implications because entecavir is off patent and less expensive than TDF and TAF (Vemlidy).

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