354m people worldwide live with hepatitis B or C

•4.5m premature deaths could be prevented in ‘poor’ countries by 2030 through vaccination, diagnostic tests, medicines, and education campaigns

• Two preliminary studies finding adeno-associated viruses in paediatric hepatitis cases suggest child’s genetic background, and other viruses all act in concert

As part of efforts to contain hepatitis as well as mark World Hepatitis Day (WHD) 2022, July 28, the World Health Organisation (WHO), yesterday, said an estimated 354 million people worldwide live with hepatitis B or C, and most, testing and treatment remain beyond reach.

The WHO, in a statement, said some types of hepatitis are preventable through vaccination. A WHO study found that

an estimated 4.5 million premature deaths could be prevented in low- and middle-income countries by 2030 through vaccination, diagnostic tests, medicines and education campaigns. WHO’s global hepatitis strategy, endorsed by all WHO the Member States, aims to reduce new hepatitis infections by 90 per cent and deaths by 65 per cent between 2016 and 2030.

Hepatitis is an inflammation of the liver that is caused by a variety of infectious viruses and noninfectious agents leading to a range of health problems, some of which can be fatal.

There are five main strains of the hepatitis virus, referred to as types A, B, C, D and E. While they all cause liver disease, they differ in important ways including modes of transmission, severity of the illness, geographical distribution and prevention methods.

In particular, types B and C lead to chronic disease in hundreds of millions of people and together are the most common cause of liver cirrhosis, liver cancer and viral hepatitis-related deaths.

World Hepatitis Day is observed each year on 28 July to raise awareness of viral hepatitis, which causes inflammation of the liver that leads to severe disease and liver cancer.

The world is currently facing a new outbreak of unexplained acute hepatitis infections affecting children. WHO, together with scientists and policymakers in affected countries, are working to understand the cause of this infection that does not appear to belong to any of the known five types of viral hepatitis viruses: A, B, C, D, and E.

This new outbreak brings focus on thousands of acute viral hepatitis infections that occur among children, adolescents and adults every year. Most acute hepatitis infections cause mild disease and even go undetected. But in some cases, they can lead to complications and be fatal. In 2019 alone, an estimated 78 000 deaths occurred worldwide due to complications of acute hepatitis A to E infections.

Meanwhile, starting in April in the United Kingdom and other countries, young children suffering from mysterious cases of acute liver inflammation began to attract scientific—and media—attention. Most would recover, some after liver transplants, but a few died.

Physicians could find no evidence in the children of the standard viruses that caused their hepatitis, but researchers homed in on an unexpected suspect: adenovirus, a family of cold-causing viruses common in kids. Now, a sweeping genetic search of these patients instead implicates another virus, one thought to be completely harmless.

In two independent, preliminary studies, United Kingdom (U.K.) researchers found high levels of adeno-associated virus 2 (AAV2) in the blood or liver cells of all but one of 25 children with unexplained hepatitis. In a group of children without this condition, almost none had AAV2, even those with adenovirus. In addition, the young hepatitis patients with AAV2 were much likelier to have a genetic mutation that may make their immune systems overreact to a viral infection.

The studies, one a preprint posted on July 19 and the other just submitted to medRxiv, offer new clues to the mystery of pediatric hepatitis, which now numbers more than 1000 probable cases in 35 countries and at least 22 deaths.

But outside researchers are cautious about the studies, especially because they haven’t yet been peer-reviewed. A paediatric gastroenterologist at Emory University School of Medicine, Saul Karpen, said: “It’s intriguing for sure, but it’s a very small number of cases and controls. It could be associations and not causation.”

Severe hepatitis in children is rare and often goes unexplained. But alarm bells went off in the spring after hospitals in the United Kingdom reported a rise in cases—now up to 272—that are not linked to the usual causes, such as hepatitis A, B, or C virus. Another 334 unexplained cases have been reported in the United States, but the Centers for Disease Control and Prevention said in June that these are not above usual levels.

Still, a spring spike in adenovirus infections in the United Kingdom lent credibility to a hepatitis surge there. And last week in two papers in The New England Journal of Medicine, teams in Birmingham, England, and Birmingham, Alabama, reported adenovirus 41, a specific type that causes gastrointestinal illness, in the majority of nine U.S. and 30 U.K. cases tested.

But the London and Glasgow, Scotland, teams behind the two preprints wanted to make sure some new virus or viral variant wasn’t emerging. They used Deoxyribonucleic Acid (DNA)/genetic material sequencing of tissue samples from U.K. cases to look for about 200 different virus families. AAV2 jumped out. It was in liver or blood samples in all nine Scottish cases examined and 15 of 16 separate cases from all over the United Kingdom, according to the studies. In contrast, almost none of the 158 controls had AAV2.

This family of viruses was initially discovered in samples that contained adenoviruses—AAVs need a protein from a distant viral relative, usually adenovirus or herpes virus, to replicate. Almost everyone is infected by AAV2 by age 10, but the virus can lie dormant in cells until that helper virus comes along and activates it.

Some of the hepatitis patients also had adenovirus, usually the 41 type. But this virus also turned up in the controls, which included healthy children and children with hepatitis for other reasons.

The authors of the preprints also ruled out SARS-CoV-2, an early suspect, partly because its infection rates weren’t higher than average in the Scottish cases.

The pandemic could, however, indirectly explain the rise of pediatric hepatitis in the United Kingdom. Relaxed COVID-19 restrictions meant children might have been exposed to a “cocktail of viruses” all at once versus gradually, according to Emma Thomson, an infectious diseases specialist at the MRC-University of Glasgow Centre for Virus Research and leader of the Scottish study.

Both studies also found that all but two of 14 sick children tested carried a specific mutation in a type of gene called HLA that helps shape the body’s response to pathogens. The mutation is particularly common in northern Europeans—11 per cent of British people carry it, and it is known to be linked to some autoimmune disorders, Thomson noted.

The researchers found no AAV2 proteins or actual copies of the virus in patients’ liver cells. That suggests instead of directly damaging liver cells, AAV2 may provoke an immune response that harms the organ. That theory is supported by the link with HLA type and that some kids had gastrointestinal illnesses many weeks before they developed hepatitis, said a leader of the London team, virologist Judy Breuer of Great Ormond Street Hospital and the University College London Great Ormond Street Institute of Child Health at a press briefing Monday.

A pathogenic role for AAV2 “goes against everything we know” about the virus, says virologist Eric Kremer of the Institute of Molecular Genetics of Montpellier. Looking at the children’s antibodies to AAV2, he notes, could support its guilt by distinguishing between a long-ago infection, or a more recent one timed with the onset of hepatitis. Those studies are planned, Thomson says.

The good news for U.K. parents in all this: Pediatric hepatitis cases have dropped in recent weeks “almost to the background,” said Meera Chand of the UK Health Security Agency, which expects to release its own study of adenoviruses in these cases this week.

At the same time, the studies raise questions about delivering therapeutic genes with AAVs, as many groups are trying to, Kremer notes. Although the viruses are further modified so they can’t replicate even if a helper virus is around, they have sometimes caused liver inflammation—which in rare cases may have contributed to deaths. Stanford University gene therapy researcher Mark Kay says the field may want to explore whether HLA type can predict whether an AAV gene therapy patient will experience liver toxicity.

Global efforts prioritise the elimination of hepatitis infections B, C and D infections. Unlike acute viral hepatitis, these three infections cause chronic hepatitis that lasts for several decades and culminates in over one million deaths per year from cirrhosis and liver cancer. These three types of chronic hepatitis infections are responsible for over 95 per cent of hepatitis deaths. While there are guidelines and tools to diagnose, treat, and prevent chronic viral hepatitis, these services are often out of reach of communities and are sometimes only available at centralised/specialised hospitals.

On World Hepatitis Day 2022, WHO is highlighting the need for bringing hepatitis care closer to the primary health facilities and communities so that people have better access to treatment and care, no matter what type of hepatitis they may have.

WHO aims to achieve hepatitis elimination by 2030. To get there, WHO calls on countries to achieve specific interim targets by 2025: To reduce new infections of hepatitis B and C by 50 per cent, and; reduce deaths from liver cancer by 40 per cent; to ensure that 60% of people with hepatitis B and C virus are diagnosed, and 50 per cent of those eligible receive appropriate treatment.