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OUTLOOK 30 March 2022

Research round-up: hepatitis B

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Genomic jigsaws, timely vaccinations and other highlights from studies about hepatitis
Related Articles
B.
Hepatitis B

Jyoti Madhusoodanan

Closing in on a cure for hepatitis B

Developing a cure for chronic

hepatitis B requires a fresh approach

How to stop mother-to-child

transmission of hepatitis B

Simplify access to hepatitis B care

Destigmatizing hepatitis B

Facing the challenge of eliminating

hepatitis B
Transmission electron microscope image of hepatitis B virus particles (orange). Credit: CDC/Erskine
Palmer

The global fight against hepatitis B is

benefitting some parts of the world
Virus creates genomic jigsaws more than others

Hepatitis B infections are a major cause of hepatocellular carcinoma (HCC), which kills more
than 700,000 people globally every year. The virus drives cancer by rearranging human
Africa’s struggle with hepatitis B
chromosomes — but exactly how and when it does so was uncertain. Last November, a study
by José Tubío at Spain’s University of Santiago de Compostela and his colleagues changed
that.
Why hepatitis B hits Aboriginal
The researchers sequenced 296 HCC samples along with Australians especially hard
RELATED
matched, cancer-free blood samples from the Pan-Cancer
Analysis of Whole Genomes project using long-read
technologies. They found that hepatitis B virus (HBV) had Hepatitis B and the liver cancer
integrated into the human genome nearly 150 times in 51 endgame
samples. A subset of 23 samples showed that viral integration
had triggered unique, dramatic changes, with megabase-sized
chunks chopped off the ends of chromosomes. Those changes Sponsor feature: Charting a new frontier in chronic
led to giant interchromosomal rearrangements, including hepatitis B research to improve lives worldwide

fusions resulting in chromosomes with two centromeres. The

integrations also resulted in the loss of tumour suppressor
Part of Nature Outlook: Sponsor feature: Addressing the unmet need for a
genes such as TP53. The work is “the first to show that HBV functional cure for chronic hepatitis B
Hepatitis B
integration results in the deletion of tumour suppressor genes”,
says virologist Peter Revill at the Peter Doherty Institute for
Infection and Immunity in Melbourne, Australia. Using techniques based on mutational rates
Subjects
to estimate the timing of the viral integration, the team discovered that in some cases, the
virus was probably present more than 20 years before the cancer was diagnosed. Therapeutics Diseases Medical research

Health care
The findings underscore the importance of studying how HBV integrates into the genome of
liver cells, Tubío says, and suggest that early antiviral therapy might help to prevent cancer-
causing mutations. Currently, people with chronic HBV infection can carry high levels of
virus, but aren’t eligible for treatment because they show no signs of liver disease. “This study
shows that the precursors to HCC are present very early, suggesting early initiation of therapy
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could be beneficial,” Revill says.
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Nature Commun. 12, 6910 (2021) every weekday.

Timely vaccinations could end epidemic Email address

Since 2009, the World Health Organization has recommended that babies be vaccinated as e.g. jo.smith@university.ac.uk

soon as possible after birth — ideally within 24 hours — to prevent infections transmitted by
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mothers who carry HBV. But these vaccinations have been slow and difficult to implement, email. I agree my information will be processed in
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particularly in rural areas where home births are common and cold storage is inaccessible. Limited Privacy Policy.

To estimate the importance of this first dose, Margaret de Villiers at Imperial College London Sign up
and her colleagues modelled the course of the HBV epidemic in 110 low- and middle-income
countries, tracking current rates of infection, treatment and vaccination, as well as deaths
caused by HBV-related cancer and cirrhosis. Last October, they reported that continuing to
vaccinate newborns at the same rate as in 2019 would not achieve the WHO goal of
eliminating new HBV infections by 2030. Delays caused by the COVID-19 pandemic would
probably boost the number of deaths by 15,000 deaths — mostly after 2050. “Because it’s
often many decades between vaccination and death from HBV-related cancer or liver disease,
people don’t recognize the connection between the vaccine and preventable deaths,” de
Villiers says.

The study is “well done and realistic”, says hepatologist Jordan Feld at Toronto General
Hospital Research Institute in Canada. Other strategies are important, too, he adds.

For instance, in a trial conducted in the Democratic Republic of the Congo, results of which
were published last August, paediatric infectious-disease specialist Peyton Thompson at the
University of North Carolina, Chapel Hill, and his colleagues found that screening pregnant
women for HBV and treating those who test positive with a daily pill to reduce their viral load
prevented mother-to-child transmission, even when infants were not vaccinated within their
first few months. This “may be an important strategy when birth-dose vaccination is not
reliably available”, Feld says. “Expanding HBV vaccination, whether by increasing infant
vaccination or by implementing high-coverage birth-dose vaccination, is a hugely effective
cancer prevention strategy.”

Nature Commun. 12, 6223 (2021); Lancet Glob. Health 9, E1600–E1609 (2021)

Epigenetic repression promotes persistence

Chronic HBV infections persist, in part, because the viral genome remains in cells in
structures known as covalently closed circular DNA (cccDNA), which are resistant to
treatment with drugs that target replicating viral DNA. These structures, also known as
episomes, continue to synthesize viral RNA and thereby cause relapses. But how they
withstand treatment is not entirely clear.

In a study published last November, Jieliang Chen and Zhenghong Yuan at Fudan University in
Shanghai, China, and their colleagues examined whether epigenetic changes might play a
part. In cultured liver cells, the team found that episomal DNA remained stable in non-
dividing cells, but was quickly lost from replicating ones. When transcription was repressed,
DNA was also more resistant to antiviral enzymes. When treated with a molecule that
reactivated transcription, cccDNA was once again susceptible to antiviral enzymes such as
APOBEC3A.

“It’s the first time we’re showing that epigenetically repressed cccDNA is resistant to enzymes
and antiviral treatments,” Chen says. The results could lead to new treatment regimens that
combine transcriptional activators with other HBV drugs to reduce the persistence of
episomal DNA.

Hepatology https://doi.org/hjdg (2021)

Gaps in chronic HBV care

In the United States, a large proportion of people with chronic HBV infection do not receive
adequate evaluation or treatment, according to an analysis of medical and pharmaceutical
insurance claims. Between 2003 and 2019, only half of patients with chronic HBV received
comprehensive laboratory testing to determine viral load. And only 60% of those who
qualified for treatment received it in the first 12 months after becoming eligible.

In a study published in last December, Mindie Nguyen of Stanford University in California and
her colleagues turned to a national database to determine how chronic HBV is assessed and
treated in US clinics. All of the 12,608 individuals included in their analysis had private health
insurance, and nearly 70% had annual household incomes of more than $60,000 (median
household income in the United States is about $67,000). Still, the team found substantial
gaps in care. “A large part of this gap is sociocultural,” Nguyen says. “It’s not just about having
money, education or access to care.”

Lack of knowledge of the risks of chronic HBV, stigma and patient denial are all contributing
to the gaps in care, she says. Black, white and Hispanic patients were all 50–60% less likely to
be receive full laboratory screening than were Asian patients. Nguyen suggests that targeted
campaigns and community awareness programmes in Asian communities might help. In
follow-up studies, the team aims to analyse patient communities for differences in disease
based on demographics or geographic location. “This will hopefully give us the data we need
to prioritize states or counties for community efforts,” she says.

J. Hepatol. 76, 63–74 (2022)

Drug delivers dual punch

Current treatments for hepatitis B involve long-term administration of antiviral drugs. These
compounds suppress viral replication, but do not eliminate the pathogen entirely. According
to a study published last May, one option for ridding the body of HBV is to target an enzyme
involved in cholesterol metabolization.

HBV replicates only in liver cells, and can suppress immune

RELATED
responses — such as those by T cells — to promote persistence in
chronic infections. Mala Maini at University College London and
her team wondered whether blocking the action of an enzyme
involved in T-cell responses to liver-cancer growth — known as
acyl-CoA:cholesterol acyltransferase, or ACAT) — might also
boost immune responses in HBV infections. “We see a lot of
More from Nature Outlooks
parallels between the exhausted T-cell response in tumours and
in chronic HBV,” Maini says.

The researchers found that ACAT-blocking drugs helped T cells primed to respond to HBV
infection to proliferate, and enhanced their activity in cultured liver and blood cells. The drug
probably acts by stopping cholesterol from accumulating in T cells, and redirecting it to the
cell membrane to enhance cellular function. This raises a potential problem: HBV requires
cholesterol to enter cells, so the drug might worsen infections. But instead, ACAT inhibitors
blocked HBV replication. “The really surprising thing was that this drug also has this direct
antiviral effect,” Maini says.

The researchers plan to continue studies in animal models and human liver cells to
understand the mechanisms at work. If they hold up, Maini says, ACAT inhibitors combined
with antiviral and other immune-modulating drugs could offer a “relatively cheap, simple and
safe approach to add to the efforts for a functional cure”.

Nature Commun. 12, 2814 (2021)

Nature 603, S66-S67 (2022)

doi: https://doi.org/10.1038/d41586-022-00822-z

This article is part of Nature Outlook: Hepatitis B, an editorially independent supplement

produced with the financial support of third parties. About this content.

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