When they help the virus evade the effects of medication, we call these changes “drug resistance mutations” (DRMs), and they can make it much harder to cure infections. When a drug-resistant version of a virus becomes the dominant one, it can make a previously useful drug completely ineffective.
While multiple DRMs have been observed for all currently used antivirals, up until now it has not been known how this process actually allows the hepatitis C virus to overcome the effects of the medications. New research, published in Nature Communications in November, has started to dismantle this ignorance.
Many DAAs work by targeting a part of the hepatitis C virus called the nonstructural 3 (NS3) protein. The NS3 protein is created by hepatitis C to do a number of things, including allowing the virus to replicate in the human body. The research study, by Hang Zhang, Ahmed Abdul Quadeer (both based in Hong Kong) and Matthew R. McKay (based in Melbourne) looked specifically at the DAAs which target the NS3 protein, and found that a process call epistasis was significantly involved in growing drug resistance.
In simple terms, “epistasis” is like teamwork between different genes or mutations. Imagine you have a team of players in a game. The performance of one player might depend on how well another player is doing. If they work together well, the team performs better, but if there’s a problem between them, it might affect the whole team’s success. In genetics, it’s a similar process. Epistasis is when certain genetic changes or mutations work together in a way that influences how they function or how they affect a trait. So, it’s like the genes are cooperating or interfering with each other, and this teamwork can have a big impact on how things turn out, like in the case of drug resistance mutations in the hepatitis C virus.
The study showed that hepatitis C is extremely good at mutating under the selective pressure of antiviral drugs, and that the easiest way for it to do this in a way that makes the drugs work less well is by modifying genes that, by epistasis, affect the NS3 protein. This means that future antiviral research and development needs to focus on ways to overcome that. This might mean creating antivirals that affect other parts of hepatitis C than the NS3 protein, or perhaps ones which attack NS3 in a different way that mutations in other parts of the virus can’t overcome.
]]>
The project is especially useful because it divides the country up into small areas (sometimes called statistical areas or SAs), meaning that it can be used to pinpoint exactly where and how easily people are being diagnosed and treated across the country. Localised health care and access to treatment for hepatitis B and C is a key objective of recent healthcare reform in Australia and enhancing access to treatment and care is a priority action in both the National Hepatitis B Strategy 2018-22 and the National Hepatitis C Strategy 2018-22.
The Project’s national report on hepatitis B for 2021 has just been published, and it shows some interesting and concerning trends (the report on hepatitis C is forthcoming).
An estimated 200,385 people were living with chronic hepatitis B (CHB) in Australia in 2021, representing 0.78% of the total population.
The highest rates, by a significant margin, were found in the Northern Territory (1.73%, more than twice the national average), while Adelaide and Country SA were below the average (with 0.66% and 0.32% respectively).
Some people living with hepatitis B require antiviral therapy to prevent disease progression. Nationally, treatment uptake for chronic hepatitis B in 2021 was 12.7%, which is significantly short of the target of 20% set by the National Hepatitis B Strategy 2018–2022. Worryingly, although the number of people receiving treatment has increased over time, the rate of increase has reduced in recent years.
Treatment uptake was highest in Public Health Networks (PHNs) in Sydney, Melbourne, and Brisbane, as well as in the Australian Capital Territory.
Only 13 of the statistical areas (4.4% of those reported) had already reached the 2022 treatment uptake target of 20%.
General practitioner (GP) prescribing for hepatitis B treatment was stable in 2021, and 22.2% of people treated for it in 2020 had a GP prescribe at least one of their prescriptions.
All people living with hepatitis B should be engaged in care. Nationally, engagement in care (either undergoing treatment or regular monitoring of disease progression) in 2021 was 26.0%, which is sadly only just over half the National Strategy 2018–2022 target of 50% by 2022.
As with treatment uptake, care uptake was highest in PHNs in Sydney, Melbourne, Brisbane and Australian Capital Territory. Only three statistical areas had already reached the National Strategy 2018–2022 care uptake target of 50% by 2022. These were in the Northern Territory (East Arnhem), Northern Queensland (Far North) and Brisbane South.
Overall, the number of people engaged in monitoring (those who received a viral load test while not receiving antiviral treatment) reduced in 2020 and in 2021, impeding progress toward the care uptake target. GPs provided almost half of all monitoring tests in 2021.
Hepatitis B immunisation is recommended for all infants born in Australia. Further, there are also publicly funded immunisation programs to ensure certain higher risk groups are also able to access hepatitis B vaccine.
Even though in previous years the National Strategy 2018–2022 target of infant immunisation against hepatitis B, a rate of 95%, has been met, in 2021 the national rate declined to 94.6%.
Coverage was even lower among Aboriginal and Torres Strait Islander children (91.8%), and this also declined between 2020 and 2021.
The 95% coverage target was met in 16 of Australia’s 31 PHNs for all children, and in eight PHNs for Aboriginal and Torres Strait Islander children.
Maintaining high testing rates among all populations at risk is critical to ensure people living with hepatitis B are quickly diagnosed and linked to care. Nationally, the number of hepatitis serology tests occurring through Medicare reduced in 2020, and this decline has continued through the end of 2022, resulting in an estimated 1.3 million fewer serology tests over this time period.
Although the rate of decline varied, between 2019 and 2022 it took place in all states and territories.
Treatment uptake for hepatitis B in SA during 2021 was measured at 10.9%, notably lower than the national average of 12.7%. SA ranked in fourth place for treatment uptake out of the eight states and territories.
As you might expect, given ease of access, treatment uptake was highest in Adelaide and lower in more remote regions. In the Adelaide PHN it was 12%, and an impressive 18.9% in the Port Adelaide – West statistical area. Though this was still below the 20% target from the national strategy, if the trends in the number of people receiving treatment in this area continue, it is projected to have reached the 20% National Strategy treatment uptake target in 2022.
Treatment uptake was also above the national average in the Salisbury (15.6%), Charles Sturt (14.2%) and Norwood – Payneham – St Peters (13.6%) statistical areas. However, there was a decline in the rate of people receiving treatment in the Mitcham, Playford and Unley statistical areas.
Assessing variation in treatment uptake within Country SA is difficult, as most statistical areas in the region have a small population, leading to high uncertainty within the data. However, the available data does not suggest substantial variation in uptake within the PHN. The number of people receiving treatment in this PHN increased at a similar rate to the national trend during 2019–2021.
]]>
Hepatitis C was discovered in 1989 and is one of the most studied viruses on the planet, but its ability to evade the human immune system has never been successfully explored before.
A new method for examining virus samples has led researchers at the University of Copenhagen and Hvidovre Hospital to the answer, which is: the virus just puts on a ‘mask’. By donning this mask, the virus can remain hidden while making copies of itself to infect new cells. The mask cloaks the virus in the form of a molecule already in our cells. Disguised by the molecule, our immune systems confuse the virus with something harmless that needn’t be reacted to.
Most RNA viruses (like hepatitis C, COVID-19, the flu, and others) have something called a five-prime cap (often written as a 5′ cap) on their ends, which acts to protect the virus and maintain its stability during replication. Until now, nobody had been able to find hepatitis C’s five-prime cap.
Now, thanks to this research, we know that the five-prime cap used by HCV is flavin adenine dinucleotide (FAD), a common chemical already present in the biological machinery of our cells. FAD is a molecule composed of Vitamin B2 and the vital energy-carrying molecule ATP. FAD is vital for our cells to convert energy. The FAD molecule’s importance and familiarity to our cells makes it ideal camouflage for a malicious virus.
“How the Hepatitis C virus manages to hide in our liver cells without being detected by the immune system has always been a bit of a mystery. Our revelation of the virus’ masking strategy is important, as it could pave the way for new ways of treating viral infections. And it is likely that other types of viruses use the same trick,” explained Associate Professor Jeppe Vinther of the University of Copenhagen’s Department of Biology, who together with associate professor Troels Scheel and professor Jens Bukh, from Copenhagen Hepatitis C Program, headed the research.
For several years, the research team had a good idea that FAD was helping the virus hide in infected cells, but they lacked a clear way to prove it. To solve the challenge, they turned to Arabidopsis, a well-known experimental plant among researchers. It was, for example, the first plant to have its full genome sequenced.
“We were getting desperate to find a way to prove our hypothesis, which is when we purified an enzyme from the Arabidopsis plant that can split the FAD molecule in two,” explains Anna Sherwood from Department of Biology, who together with Lizandro Rene Rivera Rangel are first authors of the study.
Using the enzyme, the researchers were able to split the FAD and prove that the hepatitis C virus used it as a mask.
As an RNA virus, hepatitis C’s genetic material consists of RNA that must be copied once the virus enters its host organism. New RNA copies are used to take over new cells, and one end of the RNA’s genetic material is masked by the FAD.
According to Jeppe Vinther, it is very realistic that other RNA viruses use similar masking techniques to spread without being detected by cellular control systems. In fact, researchers have already found another virus that uses the same strategy. And there are likely more.
“All RNA viruses have the same need to hide from the immune system and there is a good chance that this is just the beginning. Now that we’re attuned to this trick, it opens up the possibility of developing new and perhaps improved methods of tracking and treating viral infections in the future,” concludes Jeppe Vinther.
]]>
It also aimed to map legal, policy and practice frameworks affecting people with hepatitis C, and devise practical strategies and reforms for reducing post-cure discrimination.
The final report (which can be read here) contains a lot of detail, so here we’ll look at some of the key findings and recommendations.
The following recommendations seek to reduce experiences of hepatitis C-related stigma and discrimination, including among those who have been treated for the virus. To that end, they propose the development of new policies, legal mechanisms and systems, alongside reforms to or improvements of existing ones. While each of these recommendations are targeted to a specific government or non-government organisation or to a specific sector, other relevant organisations or stakeholders may be engaged in these actions. All these recommendations are prefaced by the guiding principles that:
The project’s work dovetailed with several relevant national and state inquiries, legislative debates, law reforms and community consultations, including the development of the Sixth National Hepatitis C Strategy 2023-2030. The Draft Strategy took up recommendations from the project, including recommendations to establish baseline measures for legal and human rights issues and a strengthened emphasis on addressing post-cure life. The research team also contributed to the development of the inaugural National Stigma and Discrimination Reduction Strategy through its public consultation process; and gave written and oral evidence to the Inquiry into the New South Wales Mandatory Testing Bill 2020, expressing opposition to the Bill on the grounds that it undermined efforts to reduce the stigma and discrimination associated with blood-borne viruses and was in tension with public health and disease prevention efforts.
]]>
However, since 2016, the entire landscape of hepatitis C has been transformed. That was the year new treatments called direct-acting antivirals, or DAAs, became available. In Australia they were introduced under the Pharmaceutical Benefits Scheme (PBS), at an estimated initial cost to the federal government of $3 billion. DAAs can cure chronic hepatitis C infection in more than 95% of cases. And so, since 2016, over 95,000 people have been treated with them in Australia, and at least 94% of these people were cured. That’s more than half of the estimated number of people in the country with hepatitis C, which is a lot of lives transformed and many potentially saved.
Because of its prevalence among people who have injected illicit drugs, chronic hepatitis C is a heavily stigmatised condition. This is certainly the case in Australia, where this group are the key population affected by the virus, and where illicit drug injecting is criminalised in most jurisdictions. People who contract the virus often go on to experience discrimination and stigma, often in extreme and damaging forms.
Such stigma and discrimination can happen at work, and in intimate and family relationships, but has been most documented in healthcare settings, where it can disturb or even block access to some of the most basic and vital forms of care. This means that stigma can injure or kill.
Stigma and discrimination is also a legal issue, and can rear its head in contexts where people apply for insurance, citizenship, and more. Among some people with, or treated for, hepatitis C, it has been such a common experience in their life with the disease that it starts to seem ordinary.
So what about the DAA treatments for hepatitis C, far simpler and more effective to administer than previous treatments, and been hailed as ‘ground-breaking’ and ‘game-changing’ for hepatitis C and people affected by the virus. What changes have these revolutionary curative treatments caused in the stigma and discrimination associated with hepatitis C? Does their advent herald a transition to a truly ‘post-cure world’? What does life look like for people after treatment, and does the stigma and discrimination that often accompanies it go away when they clear the virus? Or do people with a history of hepatitis C still experience stigma and discrimination? If so, where does it occur and in what ways?
Also, given there are forms of structural discrimination, inequity and stigma baked into laws, policies, and service practices, are there systems and mechanisms from before the advent of DAAs that need updating? Which laws, policies and practices are in need of reform so that people with or treated for hepatitis C can live better, less burdensome lives?
Researchers at the Gender, Law and Drugs (GLaD) program at La Trobe University, Melbourne, wanted to know the answers to these questions, and for three years have been running the Post-Cure Lives Project. This Australian Research Council-funded project, led by Associate Professor Kate Seear, with a team of five chief and associate investigators, and three project staff, has been investigating these questions through a number of different methods of data collection and analysis. This included interviews with people who have experienced these treatments across three states in Australia, and interviews with people who work with affected communities across law, policy and service provision, including in drug user organisations, legal services, and government departments developing and implementing new policy on hepatitis C.
For the first time ever, the project mapped the laws and legal statutes, and the state and Commonwealth policies relevant to the virus to then analyse how they shape hepatitis C-related stigma—either in ways that reduce or amplify it—and whether they are in need to reform.
All of the work has been focused on the goals of better understanding the experience of hepatitis C in the era of cure, in what ways hepatitis C-related stigma and discrimination persists, and how to tackle it. Although the focus has been on the unique context of Australia, the project’s findings will have worldwide application and ramifications, particularly as other countries follow Australia’s lead in working to scale up the provision of DAA treatment and pursuing the World Health Organization’s global goal to eliminate hepatitis C.
In August 2023, the GLaD team released their summary report from the project. It includes an overview of findings, as well as a list of recommendations for reforms to law, policy and practice in Australia. These recommendations all aim to reduce the stigma and discrimination related to the virus, to make life better for people with (a history of) hepatitis C in various ways, and to support viral elimination.
The team were excited to launch the report at an event that included reflections on life after treatment, highlights from the project, and a robust discussion of its recommendations and how they might be implemented among a range of stakeholders in the sector. The report is now available to download and read here. We’ll have a look at the results in our next blog post.
]]>
Across the world, there is a clear disparity in HCV outcomes in Indigenous populations. A new study—believed to be the first published research incorporating a systematic review to explicitly examine the barriers and enablers to diagnosis and treatment amongst rural Indigenous peoples living with HCV in Australia—has looked at what specific problems Indigenous people living in rural South Australia are encountering.
The study, Barriers and Facilitators to Hepatitis C Virus (HCV) Treatment for Aboriginal and Torres Strait Islander Peoples in Rural South Australia: A Service Providers’ Perspective, was published in the International Journal of Environmental Research and Public Health in March.
The study found that key implications for public health policy include emphasising culturally appropriate HCV education for clients, the community, and health service providers. Continued efforts to facilitate the uptake of DAA medications for Aboriginal peoples in rural and remote areas should use a multifaceted approach to provide education to clinicians and the community, increasing HCV knowledge and cultural awareness, and aiding in reducing stigma and discrimination.
In Australia, HCV remains one of the most commonly notified diseases with Aboriginal and Torres Strait Islander peoples (particularly in rural and remote areas) recognized as a high-risk population group. These discrepancies can be exacerbated in rural and remote areas; for example, Aboriginal and Torres Strait Islander peoples living remotely in Australia are 4.3 times more likely to experience a potentially preventable hospitalization than those living in major cities. They are also significantly more likely to be diagnosed with HCV, but access to HCV treatment by Aboriginal peoples in remote communities is halved compared to others residing in urban areas.
…most recent data available demonstrate that the notification rate for new HCV diagnoses for Aboriginal and Torres Strait Islander peoples increased by 15% between 2013 and 2017, while the rate in the non-Indigenous population decreased by 12%…
Worryingly, the most recent data available demonstrate that the notification rate for new HCV diagnoses for Aboriginal and Torres Strait Islander peoples increased by 15% between 2013 and 2017, while the rate in the non-Indigenous population decreased by 12%, a concerning statistic in a time of planned global eradication. New HCV infections within the teenage Aboriginal and Torres Strait Islander male population (aged 15–19) were nine times higher than rates in the non-Indigenous population in the same age group.
Most health service providers interviewed as part of the study identified that both behavioural risk factors and limited knowledge regarding HCV transmission could mean that people are unaware they are at risk of HCV, while one indicated that people would be aware of HCV and some risk factors, such as intravenous drug use, but might not be aware of other modes of transmission. All agreed that there was limited knowledge of the new DAA medications for Aboriginal peoples at risk of HCV, and that therefore their clients might not know that HCV is curable. There was also hesitancy to adopt the new DAAs due to personal or community experience of the much more severe side effects and lower efficacy of previous interferon-based therapies.
Furthermore, study participants suggested that lower levels of education and poorer engagement with health services were barriers to HCV treatment within regional and remote Aboriginal communities. Health services were the locations where clients were most likely to notice information about DAAs, so poor engagement with these services could contribute to the lack of knowledge in the rural community.
a counter-intuitive delaying of treatment until social and emotional needs have been met could contribute to improved outcomes
In interviews with residents of regional and remote Aboriginal communities, many people pointed out that cultural obligations could delay treatment uptake and contribute to poor medication adherence and loss of follow-up. Healthcare workers confirmed these obligations might take precedence over a person’s health: responsibilities in looking after an extended family or the increased burden of dealing with the illnesses of loved ones, and being involved in a high number of funerals. “Sorry business” in Aboriginal communities was more important for clients to attend and a higher priority than health appointments. Study participants suggested that a counter-intuitive delaying of treatment until social and emotional needs have been met could contribute to improved outcomes.
The asymptomatic nature of early HCV infection may impact treatment uptake and completion in rural Aboriginal communities, as clients often do not feel acutely unwell for many years. However, study participants also highlighted that HCV could be considered less of a priority when other comorbidities and Aboriginal peoples’ social and emotional wellbeing are also affected. Over time, the accumulative nature of problems can become overwhelming. Therefore, an approach that focuses on holistic healthcare, which supports both emotional and spiritual health as well as physical, could result in better engagement in health services within regional and remote communities.
Interviews about barriers to accessing treatment emphasised the typically long wait times for referrals to specialists. A shorter wait time between diagnosis and specialist appointments could help reduce the distress associated with being diagnosed. Not linking clients to services or not having frequent and regular specialist access was also identified as a barrier to HCV treatment in a rural setting. Telehealth services within Indigenous communities can help overcome these barriers.
…point-of-care testing had been very beneficial within regional and remote Aboriginal communities, particularly with transient clients.
For some the transient nature of living was noted as a complicating factor that must be considered: frequent moving from place to place was mentioned by study participants as a primary reason for the disruption to the continuity of care and poor medication adherence. Study participants also felt that point-of-care (POC) testing had been very beneficial within regional and remote Aboriginal communities, particularly with transient clients. One focus group also spoke about their relationship with the local prison in providing health summaries after discharge, which enabled follow-up with their clients, further illustrating the benefit of cross-provider solid relationships where strong rapport is built.
‘Transient’ healthcare workers in regional and remote areas was also noted as a problem: some services indicated they relied on locum doctors, and felt this did not allow clients to build sufficient rapport with their clinicians. This jeopardized the aim of providing holistic care, as clients were less likely to discuss their HCV risks, diagnosis, or treatment without trust.
Finally, the related issues of confidentiality, stigma, discrimination, and shame were seen as key issues. Many clients reported concerns regarding how others would perceive them if they disclosed their HCV status, while many also reported previous general negative experiences as Indigenous people within mainstream health services encountering discriminatory attitudes and treatment. Cultural shame was also reported as an important problem: clients often believed they would bring shame to themselves and their friends and family through their HCV status and, consequently, be alienated by their communities. This greatly impacted clients’ cultural identity, with some describing it as the ‘broken spirit’ disease.
Overall, the study emphasises the importance of emphasising culturally appropriate HCV education for clients, the community, and health service providers. Continued efforts to facilitate the uptake of DAA medications for Aboriginal peoples in rural and remote areas should use a multifaceted approach to provide education to clinicians and the community, increasing HCV knowledge and cultural awareness, and aiding in reducing stigma and discrimination.
]]>The newly released 2022 annual report from the Burnet and Kirby institutes, Australia’s Progress Towards Hepatitis C Elimination, has a story of mixed success to tell.
Unrestricted access to direct-acting antivirals (DAAs) through public subsidy since March 2016 means there is a real opportunity to reach the official government target of eliminating hepatitis C as a public health threat in Australia by 2030.
However, at the end of 2020, an estimated 47% of people living with hepatitis C were yet to be treated, representing 117,800 people living with chronic hepatitis. It is clear from data collated in this year’s report that declines in testing and treatment are substantial and ongoing. Without a reinvigoration of efforts to increase diagnosis, Australia will definitely not achieve its elimination goals.
To understand progress towards hepatitis C elimination, monitoring trends in data to assess the impact of these components is required, from measurement of new infections, counts of people tested and treated, and people receiving hepatitis C‑related liver transplants, through to projections based on mathematical modelling. This is the fourth national report on progress towards hepatitis C elimination in Australia. It brings together national data from across the sector, to give an overview on progress towards eliminating hepatitis C in Australia. This report also highlights gaps in our knowledge and informs future directions in Australia’s hepatitis C elimination response.
Australia has made considerable progress towards elimination in recent years with 95,395 people initiating DAA treatment between March 2016 and the end of 2021. Where available, the data show that numbers/rates of current infections have declined, particularly among the priority population of people who inject drugs and among HIV‑positive men who have sex with men.
Of note, there has been a significant and increasing contribution of prison‑based hepatitis services in progressing Australia’s elimination goals. In 2021, DAA treatment initiations in prison‑based hepatitis services represented 41% of the total national DAA treatment initiations, an increase from 2019 (30%) and 2020 (37%). These data reflect the ongoing importance of supporting the justice sector to eliminate hepatitis C and underscore the crucial role prison hepatitis services play in reaching people at risk of hepatitis C and Australia achieving its elimination goals.
Despite these successes over the past six years, that still leaves us to face the uncomfortable figure of 117,800 people living with chronic hepatitis C, highlighting the considerable challenge that remains to eliminate hepatitis C in Australia.
Levels of hepatitis C testing, and therefore diagnosis and treatment have declined. While this decrease in the number of people living with hepatitis C who have been tested and was observed prior to the COVID‑19 pandemic, the pandemic definitely exacerbated the decline and continues to create additional challenges to accessing health care for people affected by hepatitis C.
To ensure elimination goals are met health promotion campaigns are needed to ensure key risk populations are aware that treatment and retreatment is available to them and to encourage them to engage in care.
Considerable effort and investment are also needed to support the provision of accessible, simplified, and convenient models of testing and treatment, to ensure people living with or at risk of hepatitis C access testing, are retained in care, and complete treatment in a timely fashion.
This may include novel models of care such as point‑of‑care testing, of the sort Hepatitis SA is heavily involved in, as well as peer‑led models of care, testing and treatment in non‑traditional settings such as pharmacies, and expanding drug treatment programs to include hepatitis C care.
Expanding models of care also requires supporting the relevant workforce through education and skill development.
There also needs to be ongoing investment in the prevention of new infections and reinfection through harm minimisation, including in prisons.
Importantly, this report highlights that stigma and discrimination towards people at risk of and living with hepatitis C remains prevalent. Interventions to reduce stigma in the community and health care settings will be necessary to increase engagement with hepatitis C testing and treatment services and continue progress towards hepatitis C elimination.
2030 is close, and more action is needed now.
To examine how COVID‑19 related restrictions changed uptake of HCV antibody and HCV RNA testing, data from 11 ACCESS clinics located in Victoria which specialise in the care of people who inject drugs were included in a careful analysis.
Data from all services during the 125 weeks between 1st January 2019 and 25th May 2021 were included, thus including a year of data from before the pandemic, as well as more than a year of data once the pandemic began.
Pre‑COVID, an average of 80.6 HCV antibody and 25.7 HCV RNA tests were performed each week (note that a declining trend was observed prior to COVID‑19‑related lockdowns). After the first lockdown in Victoria (April 2020), there was an immediate drop of 23.2 HCV antibody tests and 8.6 HCV RNA tests per week (equivalent to a 30.9% and 46.0% drop, respectively).
After the second Victorian lockdown (July 2020), there was an immediate drop of 17.2 HCV antibody tests and 4.6 HCV RNA tests per week (equivalent to a 26.2% and 33.3% drop, respectively).
Some recovery in HCV antibody testing in the months following the lockdowns was observed, but the average level of HCV antibody testing had not returned to pre–pandemic levels by the end of May 2021.
It is important to note that Victoria’s lockdowns were the most severe for an state in Australia.
Hepatitis A is a short-term liver disease caused by the hepatitis A virus. Worldwide, an estimated 1.4 million cases of hepatitis A occur each year. There were 145 notified cases in Australia in 2016. Hepatitis A infection does not cause chronic liver disease, but the symptoms can be debilitating. It is rarely fatal, but can sometimes lead to fulminant hepatitis (acute liver failure), which can lead to death. It is contracted through the faecal-oral route, ie usually by consuming food or water that has been contaminated with infected sewage.
Though there is a vaccine for hepatitis A, there is no current treatment for it if a person becomes infected. It is here that an understanding of how the virus reproduces would be extremely useful.
By focusing on the replication cycle of the hepatitis A virus — how the individual viruses invade human body cells and hijack their machinery to create more of themselves — the UNC team, led by Dr Stanley Lemon, discovered that replication requires specific interactions between a human protein (known as ZCCHC14) and a group of little-understood enzymes called the TENT4 poly(A) polymerases. The research also found that a particular medication known as oral compound RG7834, which is known to inhibit the hepatitis B virus, stopped hepatitis A replication at a key stage, making it impossible for the virus to infect liver cells.
These findings, published in the Proceedings of the National Academy of Sciences, are the first to demonstrate an effective drug treatment against hepatitis A .
Dr Lemon explained that “our research demonstrates that targeting this protein complex with an orally delivered, small-molecule therapeutic halts viral replication and reverses liver inflammation of hepatitis A [in mice], providing proof-of-principle for antiviral therapy and the means to stop the spread of hepatitis A in outbreak settings.”
Dr Lemon, who in the 1970s and 80s was part of the research team that developed the first vaccine made of inactive hepatitis A to be administered to humans, said that the amount of research on HAV had dramatically decreased after the vaccine became widely available in the mid-1990s. Cases of HAV plummeted in the 2000s as vaccination rates skyrocketed, especially in countries like Australia with strong public health systems. Researchers turned their attention to hepatitis B and C viruses, both of which are very different from HAV and cause chronic disease. “It’s like comparing apples to turnips,” Lemon said. “The only similarity is that they all cause inflammation of the liver.” HAV is not even part of the same virus family as hepatitis B and C viruses.
…discoveries about the way that the hepatitis A virus changes dramatically inside the human liver.
But hepatitis A outbreaks have been on the rise since 2016, despite the effectiveness of the HAV vaccine. For example, in the US there have been 44,000 cases, 27,000 hospitalisations and over 420 deaths in the last five years.
In 2013, Lemon and his colleagues made several discoveries about the way that the hepatitis A virus changes dramatically inside the human liver. The virus hijacks bits of cell membrane as it leaves liver cells, cloaking itself from antibodies that would have otherwise quarantined the virus before it spread widely through the blood stream. This work was published in Nature.
That work led into the new research, Lemon said. “We found [the human body protein] ZCCHC14 binds very specifically to a certain part of the hepatitis A virus’s RNA, the molecule that contains the virus’s genetic information. And as a result of that binding, the virus is able to recruit [the human cellular enzyme] TENT4.”
In normal human biology, TENT4 is involved in modifying the body’s RNA during the usual process of cell growth. In someone infected with hepatitis A, the virus basically hijacks the TENT4 enzyme to build more of itself instead. This means that stopping the virus from accessing TENT4 could stop the virus from replicating and spreading.
Lemon’s lab then tested whether the compound RG7834 could work to block this process, since it has already been shown to block hepatitis B from replicating in a similar way, and indeed were able to show that it does.
However, this is not the final hurdle to be cleared. Though the amounts of RG7834 used in the study were shown to be safe, it is not known if it non-toxic enough to be used for the longer time-frames required for treatment in the general public.
“This compound is a long way from human use,” Lemon said, “But it points the path to an effective way to treat a disease for which we have no treatment at all. The treatment for hepatitis A would be short-term, and, more importantly, our group and others are working on compounds that would hit the same target without toxic effects.”
]]>Unlike other blood-borne viruses such as HIV and hepatitis B, the risk of a baby being infected with hepatitis C during the mother’s pregnancy or during birth is very low. Only about 5% of babies born to mothers who have hepatitis C are themselves infected by the disease.
A possible reason for this low figure is that the baby’s immune system has already destroyed the virus
before birth. A new study from researchers at Sweden’s Karolinska Institutet, published in the journal Gut, reveals clear adaptations of the uninfected babies’ immune system that may now lead the way to new treatment methods.
“The immune system of the [exposed but non-infected] babies shows similar changes to that in babies infected with hepatitis C,” explained Niklas Björkström, a doctor and researcher at the Institutet. “This could suggest that the immune cells have encountered the virus in the womb and managed to eliminate it before birth.”
The study was conducted in collaboration with a maternity hospital in Saint Petersburg, Russia. Of the 55 pregnant women participating, 40 had an active hepatitis C infection, while the others had been cured, but still tested positive for hepatitis C antibodies.
The babies born to women with an active infection were all considered exposed to the virus; despite this, only three of these 40 babies developed hepatitis C.
All the infants were monitored up to the age of 18 months through regular testing, and to increase the volume of comparable data, samples were added from 18 infants who had been infected with hepatitis C at birth.
This is particularly important research in the quest for a vaccine for hepatitis C.
The study showed that both the babies born with an infection and the babies who had been exposed to the virus by an infected mother had similar changes in their adaptive immune system, with clear adaptations of the body’s B lymphocytes, the role of which is to produce antibodies able to discover and identify alien microbes, such as viruses, bacteria and parasites.
“A possible explanation is that most babies exposed to the virus in utero manage to deal with it, which we can later see by the B lymphocytes,” said Dr Björkström. “One interesting hypothesis is that these cells can contain novel information that we can use to protect ourselves against hepatises C in the future.”
This is particularly important in the quest for a vaccine for hepatitis C. “This is why we need to continue researching,” Dr Björkström said. “We need to understand what it’ll take to obtain lasting protection against the virus. Only then can we attain the WHO goal of elimination.”
The researchers will now be investigating whether other immune cells in the infants have changed in a similar way. You can see the study here.
This article first appeared in issue 86 of the Hepatitis SA Community News.
]]>The hepatitis C virus (HCV) infects around 1per cent of the human population and is a devastating pathogen. In most people, it silently infects the liver for decades, and can cause life-threatening inflammation, scarring and even cancer. How the virus achieves this feat has long puzzled scientists.
In our latest study, published in the journal PLOS Pathogens, we found that a molecule that defends against HCV and other pathogens is weaker in humans than in our closest relative, the chimpanzee. This weakened molecule might have made it easier for some viruses, such as HCV, to infect humans and cause disease.
As humans, we are not completely defenceless against HCV. Our liver responds to infection by producing antiviral molecules called interferons. You can think of these molecules as the antiviral alarm system. Interferons are made rapidly once an invader has been spotted inside a cell. They are then released by the infected cell and begin to float across the nearby cells, sending chemical signals that warn them that a virus is near, and forcing them to defend themselves by making hundreds more antiviral molecules.
In particular, we produce what are known as lambda interferons against HCV that work well in liver cells. Strangely, one particular kind of interferon lambda, called IFNL4, is associated with a reduced chance of clearing HCV, making it easier for the virus to silently infect the liver for decades. How an antiviral molecule appears to help a virus to sustain infection over such a long time, and how this may have evolved, remains a mystery.
The long evolution of humans in Africa and our later global spread has resulted in genetically diverse populations of humans, each adapted to suit local environments and diseases. In our recent study, we searched through all the known genetic diversity of the IFNL4 gene, including that of chimpanzees, to identify whether people who carried different versions had different abilities to block viral replication. We hoped this would shine a light on the paradoxical role of IFNL4 during HCV infection.
What we found surprised us. A very rare version of IFNL4, which is only found in pygmies (hunter-gatherers from central Africa), was far better able to inhibit HCV infection in the lab. Even more surprisingly, this version had similar properties to the chimpanzee IFNL4. Nearly all humans, except this group of hunter-gatherers, produce a weaker version of IFNL4.
This more antiviral version of IFNL4, found in chimpanzees and a small pocket of Central African hunter-gatherers, was better able to turn on hundreds of antiviral molecules when it was added to cells in the lab. This heightened antiviral response was similar to what was found when we compared the genes produced in the liver in response to HCV in people and in chimpanzees. That is, chimpanzees appeared to mount a greater antiviral response to HCV than humans, turning on anti-HCV molecules and enhancing the immune response.
Chimpanzees are the only animal—other than humans—that can be infected by HCV, which is the reason they were used to study the virus and find effective antiviral drugs and vaccines. However, testing in chimpanzees is now banned.
Correlating with this stronger antiviral response is the fact that HCV infection in chimpanzees is less pronounced than in humans. Chimpanzees don’t develop serious hepatitis C. The virus appears to replicate more slowly, and it might be more difficult for HCV to gain a foothold in chimpanzees. Also, despite searching, scientists have been unable to find natural HCV infection in chimpanzees in the wild.
Our finding that very early in human evolution we evolved an antiviral molecule with a reduced ability to block viral infections, might help explain the insidious nature of HCV—and possibly other viral infections—in humans.
One remaining mystery is what evolutionary pressures drove early humans to reduce the antiviral activity of IFNL4, and why do a handful of people retain it? We may not have the answers yet, but studying the immune responses in our chimpanzee cousins in the wild, or in people who still carry the more antiviral version of IFNL4, may unlock some of the mysteries behind the role of IFNL4 in virus infection.
]]>