New US guidelines recommend screening of all adults for hepatitis C

All adults in the United States should be screened for hepatitis C by healthcare providers as part of routine medical care, updated guidelines from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America recommend. The testing is recommended as a one-time, opt-out routine test.

In addition, the new guidelines recommend repeat testing for people with behaviours, exposures or conditions associated with an increased risk of hepatitis C, and annual testing for people who inject drugs and for men who have condomless sex with men.

The new US guidelines also follow guidance issued in France earlier this year, recommending a simplified treatment protocol for people with hepatitis C who do not have cirrhosis. The new recommendation is designed to encourage primary care physicians to initiate treatment in previously untreated non-complicated patients.

People with cirrhosis, chronic kidney disease, HIV or hepatitis B co-infection and pregnant women should be treated by a liver specialist, as should people with a previous history of hepatitis C treatment.

The guidelines recommend two regimens, either glecaprevir/pibrentasvir (Maviret) or sofosbuvir/velpatasvir (Epclusa), as suitable for all people.

For people with compensated cirrhosis (Child-Pugh A, FIB-4 score > 3.25) and no complicating factors (such as HIV, pregnancy, chronic kidney disease or a previous history of hepatitis C treatment), an eight-week course of treatment with glecaprevir/pibrentasvir (Maviret) can be initiated by any physician. No genotyping is needed before starting treatment with glecaprevir/pibrentasvir.

For people who have recently acquired hepatitis C – acute infection – the guidelines have been updated to recommend immediate treatment. Previous guidance counselled physicians to wait and see whether patients cleared the virus spontaneously. The new guidance recommends immediate treatment to avoid further hepatitis C transmission.

A healthy lifestyle could prevent most liver cancer and liver-related deaths

Tracey Simon of Massachusetts General Hospital. Photo by Liz Highleyman.

A healthy lifestyle, including smoking cessation, moderate drinking, a balanced diet, exercise and weight loss could dramatically reduce the growing burden of liver cancer and deaths due to liver disease, according to a study presented last month at the AASLD Liver Meeting.

The study looked at data from two prospective cohorts of US adults. The Nurses’ Health Study (NHS) enrolled more than 121,000 women in 1976. The Health Professionals Follow-up Study (HPFS) enrolled over 51,000 men in 1986. Members of both cohorts provided detailed clinical, lifestyle and dietary information every two to four years.

The researchers looked at five healthy lifestyle factors:

  • Body mass index: normal weight, or a BMI of 24.9 or lower
  • Physical activity: at least 150 minutes of moderate to vigorous exercise each week
  • Smoking: current non-smoker, including both never-smokers and those who had quit
  • Diet: a score in the upper 40% on the Alternate Healthy Eating Index 2010, which assesses diet quality.
  • Alcohol: one or fewer drinks per day for women or two or fewer drinks for men.

For both liver cancer and liver-related death, body mass index and exercise were the two most important factors. Maintaining a healthy weight or exercising regularly could have prevented 22 to 25% of new liver cancer cases and 35 to 37% of liver-related deaths.

Compared with individuals with no healthy lifestyle factors, hepatocellular carcinoma (HCC) risk decreased by 27% among those with one factor, by 58% among those with two factors, by 81% among those with three factors and by 92% among those with four or more factors.

The findings were similar for liver-related death. Compared with those with no healthy lifestyle factors, mortality decreased by 33% among those with one factor, by 66% among those with two factors, by 74% among those with three factors and by 97% among those with four or more factors.

"These findings underscore the enormous potential of primary prevention to reduce the growing burden of HCC and liver-related mortality," the study authors concluded.

Global burden of deaths and liver cancer due to non-alcoholic fatty liver disease growing

Non-alcoholic fatty liver disease (NAFLD) is a growing cause of liver cancer and death in some regions of the world, an analysis of global reporting on liver disease shows. The findings were presented last month at the AASLD Liver Meeting in Boston.

The study investigators estimated that 2.2 million people died of liver-related causes in 2017 worldwide, 1.3 million of those from complications of cirrhosis and around 800,000 from liver cancer. Half of all deaths from liver-related causes occurred in east Asia and one in five in south Asia (India, Pakistan, Nepal and Bangladesh). The Middle East, north Africa and western sub-Saharan Africa showed the next highest burdens.

One million new cases of liver cancer and 5.2 million cases of cirrhosis were estimated to have been diagnosed in 2017. Once again, the highest burden of cases was concentrated in east Asia and south Asia.

Hepatitis B was the largest cause of liver cancer death worldwide in 2017, accounting for 39% of deaths. Hepatitis C caused 29% of deaths from liver cancer. Alcoholic liver disease accounted for 19% of deaths and NAFLD for 9% of deaths. Hepatitis B and C and alcoholic liver disease each caused around 30% of deaths from complications of cirrhosis.

Hepatitis B caused more than half of liver cancer-related deaths in east Asia (53%).

Alcoholic liver disease caused a higher proportion of liver-related deaths in western and central Europe (around 44%) than any other region of the world and alcoholic liver disease caused 35 to 40% of liver-related deaths in eastern Europe, Central America, the Caribbean and Andean Latin America.

The study showed that NAFLD is emerging as an important cause of liver disease and deaths in many regions of the world, not just in high-income countries. At least 10% of liver cancer and cirrhosis deaths were attributable to NAFLD in 10 of 21 global regions.

Thirteen per cent of liver cancer deaths in south Asia in 2017 were attributed to NAFLD and 7% in east Asia. In Andean Latin America (Bolivia, Ecuador and Peru), NAFLD was linked to 17% of liver cancer deaths and 23% of cirrhosis deaths.

The investigators say that although trends in liver cancer and cirrhosis related to viral hepatitis in some regions of the world – notably sub-Saharan Africa and western Europe – are promising, trends in disease and death related to NAFLD point to the need for national and global policies and programmes to address the underlying causes and clinical diagnosis and management of NAFLD.

Immunotherapy combination improves liver cancer survival

Bruno Sangro at The Liver Meeting. Photo by Liz Highleyman.

A combination of nivolumab (Opdivo) and ipilimumab (Yervoy), two different types of checkpoint inhibitor immunotherapy, led to higher response rates and longer survival than nivolumab alone in people with advanced liver cancer, according to a study presented at the AASLD Liver Meeting last month in Boston.

Nivolumab is a PD-1 checkpoint inhibitor that helps the immune system fight cancer. PD-1 is a receptor on T-cells that helps regulate immune function. Drugs that block the interaction between PD-1 and its binding partner, PD-L1, can restore T-cell activity against tumours. Ipilimumab is a different type of checkpoint inhibitor that blocks the CTLA-4 receptor, which dampens immune responses by suppressing T-cell replication.

A third of people treated with the most effective combination regimen experienced tumour regression, the median overall survival was nearly two years and side effects were generally manageable, reported Dr Bruno Sangro of Clinica Universidad de Navarra in Spain.

Dr Sangro said that a new phase III clinical trial, CheckMate 9DW, will evaluate nivolumab plus ipilimumab versus the targeted therapies sorafenib or lenvatinib (Lenvima) as first-line treatment for advanced hepatocellular carcinoma (HCC).

Nivolumab alone and in combination with ipilimumab is also being evaluated as neoadjuvant therapy for people with less advanced HCC. This type of treatment aims to shrink tumours enough to enable them to be surgically removed. An analysis of eight people presented earlier this year showed that three people – two taking nivolumab alone and one taking the combination – experienced pathological complete response, meaning no evidence of cancer remaining in the liver tissue removed during surgery.

Nivolumab is approved both in the EU and in the US for the treatment of certain cancers affecting the skin, kidney, lung, head and neck and other organs. In the USA, nivolumab has also been approved for HCC treatment since September 2017. It is currently not approved for HCC treatment in Europe.

Combination therapies show promise against hepatitis D

Heiner Wedemeyer presenting results of a phase 2b study of bulevertide at the AASLD LIver Meeting, 2019. Photo by Liz Highleyman.

Two different combination regimens using lonafarnib or bulevirtide reduced levels of hepatitis delta virus (HDV) in a majority of people with HDV and hepatitis B virus (HBV) co-infection, researchers reported at the AASLD Liver Meeting last month in Boston.

HDV is a small, defective virus that can only replicate in the presence of HBV. Worldwide, as many as 20 million people are thought to carry HDV, according to Dr Christopher Koh of the US National Institute of Diabetes and Digestive and Kidney Diseases.

Koh presented findings from a phase II study of the prenylation inhibitor lonafarnib (brand name Sarasar) in combination with pegylated interferon lambda. The LIFT-HDV trial included 26 participants.

Among participants treated for 24 weeks, HDV viral load fell by a mean of 3.18 log10 IU/ml, a significant decline from the baseline level. Among the 19 people who completed treatment, all but one (95%) had more than a 2 log10 IU/ml decline in HDV RNA and 10 (53%) achieved an undetectable level. Lower HDV viral load at baseline appeared to be a predictor of response, Koh said.

Prof Heiner Wedemeyer of Essen University Hospital in Germany presented the latest results from a phase IIb study of another combination therapy for people with HBV/HDV co-infection, bulevirtide with either pegylated interferon alfa or tenofovir disoproxil fumarate (TDF).

Bulevirtide, formerly known as Myrcludex B, is an experimental entry inhibitor that binds to the receptor HBV uses to enter liver cells, interfering with the lifecycle of HBV and thereby also preventing HDV replication.

The main MYR203 trial enrolled 60 people who were randomly assigned to receive 2mg or 5mg bulevirtide by subcutaneous injection once daily plus 180mcg pegylated interferon alfa injected once weekly, 2mg bulevirtide alone or pegylated interferon alone for 48 weeks.

As Wedemeyer reported at this year's EASL International Liver Congress, 50% of participants in the two combination arms had undetectable HDV RNA at week 48, compared with 13% in the two monotherapy groups. At week 72 – six months after completing treatment – 40% still had an undetectable level of HDV RNA. Forty per cent also experienced ALT normalisation, which suggests an improvement of liver inflammation. In addition, 27% achieved hepatitis B surface antigen (HBsAg) loss and 20% experienced HBs antibody seroconversion; this is considered a functional cure of hepatitis B. As HDV depends on the HBsAg of hepatitis B, this is expected also to have permanently resolved the HDV infection. On the other hand, no one in the monotherapy arms experienced a sustained response.

At the AASLD meeting, Wedemeyer presented interim findings from an extension phase of the study that evaluated 10mg daily bulevirtide plus weekly pegylated interferon alfa or 5mg twice-daily bulevirtide plus daily TDF for 48 weeks.

At the end of treatment, 87% of those taking 10mg daily bulevirtide plus pegylated interferon had undetectable HDV viral load. The 48-week response rate in the 5mg twice-daily bulevirtide plus TDF group was 40%. ALT normalisation rates at week 48 were 27% and 40%, respectively.

However, only one person taking the 10mg daily bulevirtide plus pegylated interferon regimen and no one taking the TDF combination achieved HBsAg loss, failing to replicate the promising functional cure rate seen in the main study. Seventy-two week follow-up results are pending.

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