This edition of the infohep.org bulletin is again devoted to news from the International Liver Congress 2015, the 50th annual meeting of the European Association for the Study of the Liver (EASL), which took place 22-26 April in Vienna, Austria.

The previous edition of this bulletin focused on important new research on direct-acting antiviral treatment for hepatitis C presented to the Congress. You can read it on our website.

Hepatitis B prevention and treatment had a higher profile at this year’s International Liver Congress in Vienna, which took place in late April. Global gaps in immunisation coverage and treatment availability were highlighted by a mathematical model developed by researchers from Imperial College, London. Using available data on the epidemiology and natural history of hepatitis B, researchers projected that without further intervention, the number of people living with hepatitis B will remain at current high levels for the next 40-50 years and there will be 20 million HBV-related deaths by 2030.

Modelling showed that incidence of new cases of chronic HBV infection could be reduced by 90% and mortality could fall by 65% by 2030 if the following interventions are implemented:

• Infant vaccination scaled up to >95%.

• 80% receive the birth dose of the vaccine and hepatitis B immune globulin (HBIG) and antivirals to interrupt mother-to-child transmission.

• A 90/90/90 strategy for people already infected: 90% screened for HBV, 90% of those eligible being treated, and 90% of those treated achieving durable viral suppression from the year 2020 onward.

This translates to an estimated 13 million deaths averted worldwide, including 6 million due to cancer. The projected global cost for expanded prevention and treatment would peak at US$7.5 billion (£5 billion) annually, but then decline rapidly after 2030.

The cost of treatment could be reduced substantially by use of generic versions of antiviral drugs. Large scale generic production of entecavir, one of two antiviral drugs recommended as first-line treatment for hepatitis B, could reduce the annual cost of treatment per person to US$36 a year, according to another study published by researchers from Imperial College, London. The patent on entecavir has already expired in the United States and will expire in many other countries over the next few years.

A large European cohort study presented at the International Liver Congress showed that five-year survival without liver transplantation among people receiving tenofovir or entecavir treatment for hepatitis B was very high, at 95%. Transplant-free survival was marginally lower in people who had cirrhosis at the time they started treatment (92% at 5 years). However, 4.6% of all patients developed hepatocellular carcinoma (liver cancer), of which only 56% survived for at least three years after diagnosis.

Another European study looked at the discontinuation of tenofovir treatment in people with hepatitis B after a prolonged period of suppression of HBV DNA. Preliminary results of the study showed that participants experienced modest increases in HBV DNA and liver enzymes after one year off treatment, and HBV DNA and ALT levels tended to improve as time off treatment continued.

Treating chronic hepatitis B with tenofovir plus pegylated interferon for 48 weeks resulted in a higher rate of hepatitis B surface antigen (HBsAg) clearance than either drug taken alone, though the response rate was still just 9%, according to another study presented at the International Liver Congress. Other researchers reported that adding interferon to nucleoside/nucleotide therapy increased the rate of HBsAg loss to about the same level, and switching to interferon may be effective for selected patients.

Hepatitis delta is a small virus that can only replicate in the presence of hepatitis B virus (HBV). Over years or decades, chronic hepatitis B can lead to advanced liver disease including cirrhosis and liver cancer. Disease progression is more rapid and more severe in people with HBV and hepatitis delta virus (HDV) co-infection.

There is currently no standard treatment for hepatitis D. Interferon can stimulate the immune response against both HBV and HDV, but hepatitis B treatment using nucleoside/nucleotide analogues such as entecavir (Baraclude) or tenofovir (Viread) only minimally suppresses HDV.

An estimated 15 million people have hepatitis delta worldwide – or about 5% of all people with hepatitis B. While Europe and the US have designated hepatitis delta as an orphan disease due to the small overall numbers of people infected, prevalence is much higher in certain regions including Turkey, Russia, and parts of Central Asia, China, Africa and South America.

Cihan Yurdaydin of Ankara University School of Medicine. Photo by Liz Highleyman, hivandhepatitis.com

Two studies reported promising early-stage results for drugs that target hepatitis delta. Lonafarnib, an inhibitor of viral assembly, reduced hepatitis delta viral load substantially when combined with pegylated interferon or with ritonavir (an agent already used for boosting other drugs). Hepatitis delta viral load began to increase after treatment stopped. Further studies will investigate longer durations of treatment. REP 2139-Ca, a nucleic acid polymer, lowered hepatitis B surface antigen (HBsAg) levels and significantly reduced hepatitis B and hepatitis delta viral loads when combined with pegylated interferon 2a. Montreal-based Replicor is developing nucleic acid polymers for the treatment of both hepatitis B and hepatitis delta.

Statins are used to lower blood cholesterol levels. They have been shown to prevent cardiovascular disease and reduce the risk of heart attack, stroke and death. Statins also have anti-inflammatory effects and some research has found them to be associated with reduced liver fibrosis progression and lower risk of liver cancer.

Studies have also shown that statins can decrease portal pressure – blood pressure in the veins that carry blood from the stomach and intestines through the liver – in people with cirrhosis and to improve survival in people with bleeding varices.

Arpan Mohanty of Yale University School of Medicine. Photo by Liz Highleyman, hivandhepatitis.com

A review of US military veterans with hepatitis C found that users of statins were significantly less likely to progress to decompensated disease and less likely to die if they used statins to control blood cholesterol.

The study matched each statin user with hepatitis C and cirrhosis to five non-users of statins with hepatitis C and cirrhosis. Over a two-year follow-up period, statins reduced the risk of decompensation and death by approximately 45%.

Another study of US military veterans, published in April, found that statins improved the likelihood of cure in people treated for hepatitis C, as well as reducing the risk of progression of cirrhosis and the incidence of hepatocellular carcinoma (liver cancer).

Over years or decades, chronic hepatitis C virus (HCV) infection can lead to advanced liver disease including cirrhosis and hepatocellular carcinoma (HCC), a type of liver cancer. But the effects of HCV infection elsewhere in the body are not fully understood. Chronic hepatitis C has been linked to cardiovascular disease, diabetes and several other conditions including non-Hodgkin's lymphoma; its association with other kinds of cancer is unknown.

Anders Nyberg of Kaiser Permanente San Diego. Photo by Liz Highleyman, hivandhepatitis.com

A study of a large population in southern California has found that people with hepatitis C had two-to-fourfold higher rates of several types of cancer when compared to people without hepatitis C, including colorectal cancer and cancers of the prostate, stomach, pancreas, kidney, lung and oesophagus, as well as head and neck cancer. After taking into account the cancer risks associated with smoking, heavy alcohol use and diabetes, the risk of liver cancer and non-Hodgkin’s lymphoma remained significantly higher in people with hepatitis C.

Numerous studies are underway to investigate whether the duration of hepatitis C treatment can be shortened. A shorter treatment course might be cheaper, and so allow more people to be cured. It would also make treatment easier for people who have difficulty in taking medication.

The current thinking among pharmaceutical companies and researchers is that in order to shorten treatment substantially, a successful regimen will need to combine drugs that act at several different points in the virus life cycle, in order to shut down virus replication as quickly as possible. Studies are looking at three-drug combinations.

Two studies presented at the International Liver Congress reported on shortening treatment courses, showing that if currently available drugs are used, it is unlikely that the duration of treatment can be pushed below 6 weeks. One study also showed that for genotype 3 hepatitis C, shorter treatment courses may be feasible.

The C-SWIFT study looked at the combination of the Merck HCV protease inhibitor grazoprevir, the NS5A inhibitor elbasvir and Gilead’s NS5B polymerase inhibitor sofosbuvir. The study found that shortening hepatitis C treatment to 6 weeks for easier-to-treat patients without cirrhosis did not greatly reduce the efficacy of hepatitis C treatment for people with genotype 1 infection. On the other hand, a 4-week course of treatment performed poorly in people without cirrhosis. The study found that people with cirrhosis and genotype 1 infection needed an 8-week course of treatment, as did people with genotype 3 infection without cirrhosis.

A 6-week regimen of sofosbuvir (Sovaldi) plus two experimental direct-acting antivirals being developed by Gilead Sciences cured more than 90% of previously untreated people with genotype 1 hepatitis C virus and no liver cirrhosis in a smaller study. A 4-week regimen was not effective for any group, however, and 6 weeks appears inadequate for harder-to-treat patients. The regimen consisted of sofosbuvir, the pan-genotypic NS5A inhibitor GS-5816 (veltapasvir) and the pan-genotypic HCV protease inhibitor GS-9857.

Gilead has faced continuing pressure over the past few months to ease restrictions on generic production of its hepatitis C drugs, in order to make them more accessible in middle-income countries. Activists have called on the company to relax the restrictions that prevent generic versions produced under licence in India from being sold in 51 middle-income countries. The Hep Coalition has criticised plans to extend the mandate of the Medicines Patent Pool to hepatitis C direct-acting antivirals. They say that the Medicines Patent Pool risks reinforcing the restrictions imposed by Gilead on access in middle-income countries, and voluntary licensing allows pharmaceutical companies, not governments and their people, to decide where affordable generic drugs are available.

In Latin America, where 2.6 million people have hepatitis C, governments are considering whether they can set up a pooled procurement mechanism, in order to negotiate lower prices for sofosbuvir (Sovaldi) and simeprevir (Olysio). In the United States, the US government is being urged to use compulsory licensing to allow generic versions of hepatitis C drugs to be used in US Veterans Affairs hospitals for former military personnel. These hospitals are funded directly by the US government, unlike the rest of the health care system, and treat an estimated 220,000 people who might eventually need hepatitis C treatment.

However, Gilead takes the view that its drugs are fairly priced, and justifies this view by arguing that the cost of a treatment course is lower than the cost of a liver transplant and hospitalisation for advanced liver disease if hepatitis C is left untreated.

We have recently published a new factsheet on Harvoni, an addition to the five other hepatitis C treatment factsheets.

Each factsheet focuses on one direct-acting antiviral drug and gives an overview of how it works, who can use it, how it is taken, what trial results tell us about how effective it is, known side-effects and drug interactions.

The factsheets are available to read online, and are also designed to be printed and shared.

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