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The push is on to cure hepatitis B, a long-overlooked scourge of millions / Emerging Therapies Toward a Functional Cure for Hepatitis B Virus Infection
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The latest statistics from the World Health Organization state that 250 to 300 million people in the world are infected with HBV, making this disease a significant public health problem worldwide. There are many classes of targets currently under investigation. The data to date seem to indicate that 2 components are needed. One is to fundamentally disrupt the viral life cycle, and the other is to encourage the host immune system to try to break through the tolerance that is preventing cure of the infection. My interpretation of the emerging data is that both of these components have to work together. Therefore, some element of immunomodulators is likely necessary, at least in the beginning stages of the cure effort, as well as direct-acting antiviral agents with viral or intracellular targets. Identifying what may be the ideal combination seems to be what most researchers are trying to figure out because none of the compounds previously mentioned appear to completely eliminate the virus by themselves. The data are promising for curing the virus, as compared to merely suppressing it, but we are not there yet. We would like to be able to achieve what we have come to expect with HCV. I have been telling my patients that a functional cure may come within 5 years for the past 5 years, so I have stopped trying to predict the future. However, I suspect that patients whose disease activity is controlled on their own or by long-term antiviral medications will likely be the easiest to lead to functional cure.
......Population surveys have suggested that there are between 700,000 and 800,000 people living with hepatitis B virus (HBV) infection in the United States. However, those population surveys tend to miss people with a high prevalence of HBV infection, including recent immigrants and institutionalized people. Altogether, it has been suggested that up to 1.5 to 2 million people in the United States may actually have HBV infection.
.........Eugene Schiff, an 81-year-old liver specialist at the University of Miami in Florida whose father was also a prominent liver clinician, has worked in the field since its birth, and he's bullish about a cure. "A couple of years ago, they said it was impossible to clear cccDNA," says Schiff, who is the co-editor of Schiff's Diseases of the Liver, a standard textbook now in its 12th edition. "You never say that with science, and I knew it was BS. Now, people in the field are estimating it will take 5, maybe 10 years to clear cccDNA. And if we can cure the ones who have hepatitis B and continue to vaccinate the ones who don't, we can eradicate the disease."
The push is on to cure hepatitis B, a long-overlooked scourge of millions
Science Mag - Jon cohen Jan 2019 - see below full text
In a push to cure hepatitis B, drug developers are targeting nearly every step in the virus's complex life cycle. They are also trying to boost the immune response. But some say it won't be enough to block the virus's entry into the cell (left) or the transcription, assembly, and release of new viruses (right). They believe a curative drug will have to eliminate covalently closed circular DNA (cccDNA), a minichromosome that the virus creates inside an infected cell. The cccDNA can remain latent for years or can adopt a highly active "open" form (inset) that churns out new viruses. (DNA integrated into the host genome produces viral proteins but not new virus.)
Like nearly 2 billion other people, Koo had somehow been infected with HBV and never knew it. HBV is at least 100 times as infectious as HIV, but it moves between people in similar ways: from mother to child (primarily at the time of birth), through sex, and among drug users sharing syringes. Odd clusters of cases have also been linked to day care centers, football teams, butcher shops, a sumo wrestling club, and an acupuncturist-settings where the virus could have spread through seemingly innocuous open wounds. The Western Pacific region, including China and Taiwan, where Koo grew up, accounts for nearly half of the chronically infected population.
Eugene Schiff, an 81-year-old liver specialist at the University of Miami in Florida whose father was also a prominent liver clinician, has worked in the field since its birth, and he's bullish about a cure. "A couple of years ago, they said it was impossible to clear cccDNA," says Schiff, who is the co-editor of Schiff's Diseases of the Liver, a standard textbook now in its 12th edition. "You never say that with science, and I knew it was BS. Now, people in the field are estimating it will take 5, maybe 10 years to clear cccDNA. And if we can cure the ones who have hepatitis B and continue to vaccinate the ones who don't, we can eradicate the disease."
n September, Gilead signed a $445 million deal with Precision BioSciences of Durham, North Carolina, to codevelop what are known as homing endonucleases-DNA cutting enzymes-designed to snip cccDNA. Gilead scientists have also helped clarify how a particular HBV protein known as X turns on cccDNA to produce more virus, providing a new drug target. "We're in early days," McHutchison says. "The field feels like it's really starting to gain traction and momentum." Other companies hope to use CRISPR, the genome editor, to cripple cccDNA in patients, as it has done in some test tube experiments.
AASLD: Hepatitis Debrief: The Liver Meeting 2018 - (11/19/18)
HBV Therapies in Development - (11/15/17)
Drugs in Development for Hepatitis B 2017 -
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529495/
Compounds in Development for Chronic Hepatitis B - Updated January 2019
http://www.hepb.org/treatment-and-management/drug-watch/
AASLD: Safety, Pharmacokinetics and Antiviral Activity of Novel HBV Capsid Assembly Modulator, JNJ-56136379, in Patients with Chronic Hepatitis B - (02/13/19)
AASLD: FINAL RESULTS OF A PHASE 1B 28-DAY STUDY OF ABI-H0731, A NOVEL CORE INHIBITOR, IN NON-CIRRHOTIC VIREMIC SUBJECTS WITH CHRONIC HBV - (02/13/19)
AASLD: First results with RNA interference (RNAi) in chronic hepatitis B (CHB) using ARO-HBV - (02/13/19)
AASLD: TLR7 agonist RO7020531 triggers immune activation after multiple doses in chronic hepatitis B patients - (02/13/19)
AASLD: Limited sustained response and lack of HBsAg decline after stopping long-term nucleos(t)ide analogue therapy in HBeAg negative patients with chronic hepatitis B: Results of the prospective, randomized, open-label phase IV STOP study - (02/13/19)
AASLD: Interim results of a multicenter, open-label phase 2 clinical trial (MYR203) to assess safety and efficacy of Myrcludex B in combination with PEG-IFNαin patientswithchronicHBV/HDV co-infection - (02/13/19)
AASLD: PREDICTABILITY OF SERUM HBcrAg, HBsAg AND INTERFERON INDUCIBLE PROTEIN 10 (IP10) LEVELS IN NON-CIRRHOTIC HBeAg-NEGATIVE CHRONIC HEPATITIS B PATIENTS WHO DISCONTINUE ENTECAVIR (ETV) OR TENOFOVIR (TDF) THERAPY: RESULTS FROM THE PROSPECTIVE DARING-B STUDY - (01/02/19)
AASLD: KINETICS OF SERUM HEPATITIS B CORE RELATED ANTIGEN (HBcrAg) IN NON-CIRRHOTIC HBeAg-NEGATIVE CHRONIC HEPATITIS B (CHBe-) PATIENTS WHO DISCONTINUE EFFECTIVE LONG-TERM THERAPY WITH ENTECAVIR (ETV) OR TENOFOVIR DISOPROXIL FUMARATE (TDF) - (01/02/19)
AASLD: Safety, Pharmacokinetics, and Pharmacodynamics of Oral TLR8 Agonist GS-9688 in Patients With Chronic Hepatitis B: a Randomized, Placebo-Controlled, Double-blind Phase 1b Study - (12/31/18)
AASLD: No Resistance to Tenofovir Alafenamide Detected Through 144 Weeks of Treatment in Patients With Chronic Hepatitis B - (12/31/18)
AASLD: 3-Year Efficacy and Safety of Tenofovir Alafenamide Compared With Tenofovir Disoproxil Fumarate in HBeAg-Negative and -Positive Patients With Chronic Hepatitis B - (12/31/18)
AASLD: Bone and Renal Safety Are Improved in Chronic HBV Patients 1 Year After Switching to Tenofovir Alafenamide From Tenofovir Disoproxil Fumarate - (12/31/18)
AASLD: Prediction and need for surveillance of hepatocellular carcinoma (HCC) development after the first 5 years of entecavir (ETV) or tenofovir disoproxil fumarate (TDF) therapy in Caucasian chronic hepatitis B (CHB) patients of the PAGE-B cohort - (12/17/18)
AASLD: Single-Dose Pharmacokinetics (PK), Safety and Tolerability of JNJ-64530440 (JNJ-0440), a Novel Hepatitis B Virus (HBV) Capsid Assembly Modulator (CAM), in Healthy Volunteers (HV) - (12/17/18)
AASLD: In Vitro Antiviral Activity and Mode of Action of JNJ-64530440, a Novel Potent Hepatitis B Virus Capsid Assembly Modulator in Clinical Development - (12/17/18)
AASLD: ALT levels and risk of hepatocellular carcinoma in Caucasian chronic hepatitis B (CHB) patients under long-term therapy with entecavir or tenofovir disoproxil fumarate - (12/17/18)
AASLD: Early adoption of tenofovir alafenamide (TAF) for Hepatitis B in US clinical practice; real-world evidence from the TRIO network - (12/11/18)
AASLD: Treatment of hepatitis B in the US; real-world evidence from the TRIO network- (12/11/18)
More Hep B Articles... EASL Reports, hundreds of recent reports & new drug data reported at hepatitis conferences
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Gastroenterology & Hepatology
July 2018 - Volume 14, Issue 7
Emerging Therapies Toward a Functional Cure for Hepatitis B Virus Infection
W. Ray Kim, MD
Professor of Medicine (Gastroenterology and Hepatology)
Stanford University Medical Center
Stanford, California
G&H Currently, what is the burden of hepatitis B virus infection in the United States?
RK Population surveys have suggested that there are between 700,000 and 800,000 people living with hepatitis B virus (HBV) infection in the United States. However, those population surveys tend to miss people with a high prevalence of HBV infection, including recent immigrants and institutionalized people. Altogether, it has been suggested that up to 1.5 to 2 million people in the United States may actually have HBV infection.
G&H What should be the goal of HBV treatment?
RK The current goal is limited by the tools that are available to treat the disease. These tools, namely oral HBV polymerase inhibitors, are very effective at suppressing the virus from replicating and preventing damages to the liver, but they are not curative (unlike hepatitis C virus [HCV] treatment). Thus, the current treatment goal is remission of liver disease by effective suppression of HBV. It is important to keep in mind that this treatment goal can only be achieved in patients who are diagnosed with HBV infection and are being followed, and that there are many people living with HBV infection who have not even been diagnosed or connected to the health care system. Therefore, a larger health care system–wide goal is to provide treatment to all people at risk of future complications so that they can be prevented.
It should also be pointed out that, ideally, the treatment goal would be to cure HBV infection. Although achieving that goal is not currently possible, there are many compounds being tested at the present time. Hopefully in the next decade, there will be a cure for this disease.
G&H How can functional cure of HBV infection be defined?
RK The prevailing definition of functional cure at the present time is loss of hepatitis B surface antigen (HBsAg) in the blood. However, what this means biologically is not completely understood. There are several barriers to cure, one of which involves covalently closed circular DNA, a sort of viral chromosome in the liver cells of an infected person. This replication template is not affected by the current polymerase inhibitors. Another barrier is that some of the viral genome is inserted into host chromosomes, which can generate viral proteins. The extent to which this contributes to the maintenance of chronic infection is unknown, as is whether it is possible to achieve functional cure by interrupting the viral cycle at different points. Functional cure may not translate to complete cure because of the viral genome fragments that persist in the host cells.
G&H What treatment approaches or targets are currently being used for HBV infection, and what are their functional cure rates to date?
RK Currently, only 2 classes of HBV treatment agents are available. One is interferon, which is an immunomodulatory drug as well as an antiviral agent. Interferon has a low functional cure rate, but the rate varies according to the host phase of infection. People who are younger and have more active underlying liver inflammation tend to respond better, whereas older people with less inflammatory activity have a lower cure rate. After interferon therapy, the functional cure rate is, at most, 20%. In functional cure with interferon, a certain percentage of HBsAg loss can occur after treatment is completed. The other class of medicine for current HBV treatment consists of HBV polymerase inhibitors, often called nucleoside or nucleotide analogues. These agents are very effective at suppressing the virus by blocking the viral enzyme needed for the virus to replicate itself. However, they do nothing directly to the host immune system, and their functional cure rate is lower than that of interferon (<10% over many years of follow-up).
G&H What treatment approaches or targets are currently being investigated for HBV infection?
RK There are many classes of targets currently under investigation, some of which are listed in the Table. One class blocks the entry of HBV into hepatocytes, as the virus usually takes advantage of a receptor to insert itself into the cytoplasm of a hepatocyte. One agent in this class (Myrcludex B, Hepatera/MYR) is being tested in a phase 2 clinical trial.
Another class undergoing fairly active investigation involves small interfering RNAs. This class targets the viral genome in different areas to disrupt viral protein production and interrupt its life cycle. Within this class, there are several compounds being tested, and the difference between them relates to the region of the RNA that each is targeting and how the RNAs are introduced into hepatocytes.
Capsid inhibitors comprise another class of agents currently undergoing investigation for HBV treatment. Capsid, the protein surrounding the viral genome, plays multiple roles, allowing capsid inhibitors to have multiple modes of inhibiting HBV. Currently, several of these agents are being tested.
Another class in clinical development consists of HBsAg inhibitors. The last step of the HBV life cycle is for the virus (or surface protein) to be exocytosed, and this particular class of chemical inhibits HBsAg from being processed and released outside of the cell. Interestingly, this seems to trigger an immune reaction from the host, as the viral proteins circulating in the body may play a role in paralyzing the immune response. Preliminary studies indicate that, when combined with other antiviral agents, a HBsAg inhibitor may help patients restore their immune function, leading to HBsAg loss and sometimes hepatitis B surface antibody production.
In addition, there are a number of agents purported to improve host immune response against HBV. Some of them are innate immune enhancers, including Toll-like receptor agonists. Also in early development is a RIG-I activator that triggers interferon response, as well as directly interrupts HBV replication. Finally, there are a number of agents targeting the adaptive immune system. For example, programmed cell death protein 1 and
programmed death-ligand 1 inhibitors are checkpoint inhibitors that have led some patients to lose HBsAg by breaking the immune tolerance that perpetuates the infection. A number of therapeutic vaccines are under development as well.
G&H What clinical trial data are available on these agents?
RK The clinical trial data are either phase 1 or 2 at most, so they are not very mature, but they are promising. However, there have not yet been large-enough trials to conclusively tell us that any of these molecules will consistently provide high rates of functional cure that are clinically meaningful.
G&H Overall, what appears to be critical for achieving functional cure?
RK The data to date seem to indicate that 2 components are needed. One is to fundamentally disrupt the viral life cycle, and the other is to encourage the host immune system to try to break through the tolerance that is preventing cure of the infection. My interpretation of the emerging data is that both of these components have to work together. Therefore, some element of immunomodulators is likely necessary, at least in the beginning stages of the cure effort, as well as direct-acting antiviral agents with viral or intracellular targets. Identifying what may be the ideal combination seems to be what most researchers are trying to figure out because none of the compounds previously mentioned appear to completely eliminate the virus by themselves. The data are promising for curing the virus, as compared to merely suppressing it, but we are not there yet. We would like to be able to achieve what we have come to expect with HCV.
A major unknown factor in functional cure of HBV is the integration of HBV DNA into the host. Once HBV is incorporated into the host genes, it is a challenge to remove it. This is thought to be an important barrier to achieving functional cure, but it remains to be seen whether this will continue to be the case as better treatments are developed. Another issue is at what cost we should try to achieve functional cure. Currently, there are very effective viral suppressive medicines that drive the hepatitis B viral load to zero (ie, undetectable levels) as well as cause the patient's liver inflammation to disappear and the progression of liver disease to halt (and sometimes even reverse). Those agents achieve very good outcomes without too many long-term safety concerns, so the bar is set fairly high that (1) functional cure should actually provide more advantage to the patient and (2) functional cure could be achieved safely. It is unknown what it means to have HBsAg disappear if all that it accomplishes is status quo plus cosmetic disappearance of the antigen. Does that simply mean patients would be able to stop taking suppressive medicine long term? Or does functional cure really mean fundamental alteration of the natural history of the infection (ie, eliminating the risk of liver cancer, which would be groundbreaking)? This issue remains to be sorted out.
G&H Are there any data showing that the elimination of HBsAg is actually meaningful?
RK Proponents of functional cure as the next endpoint point to data obtained from people who experience HBsAg loss, untreated or treated with the currently available medications. They observe that patients who lose HBsAg have much better outcomes over time than patients who fail to lose HBsAg. However, these 2 groups of people are often too different to compare. People who lose HBsAg on their own, or even those who are taking the currently available antiviral agents (particularly nucleoside/nucleotide analogues), may have something in their body, perhaps in their immune system, that lets them achieve functional cure. Their underlying ability (ie, a host factor) may be what is driving the apparent benefit of HBsAg loss rather than the fact that the HBsAg has become undetectable in their blood.
G&H Is it possible that a single drug may be able to achieve functional cure of HBV?
RK Thus far, the data seem to suggest that none of the compounds being tested may be sufficient individually to achieve functional cure. At the present time, I think it is likely that some type of combination will be needed, perhaps one that works on intracellular targets and another on host immune cells.
G&H Is achieving functional cure a feasible goal for all HBV patients in the near future?
RK It depends on how the near future is defined. I have been telling my patients that a functional cure may come within 5 years for the past 5 years, so I have stopped trying to predict the future. However, I suspect that patients whose disease activity is controlled on their own or by long-term antiviral medications will likely be the easiest to lead to functional cure.
Nevertheless, it is important to keep in mind that HBV is a difficult disease to cure. People may have unrealistic expectations due to the recent success of HCV drugs for completely eliminating the disease in the vast majority of patients. However, these 2 diseases are quite different. Even if functional cure of HBV is achieved, the viral genetic material is likely to remain in the host; therefore, the extent of risk reduction associated with functional cure is likely to be smaller. The biggest concern for HBV patients is liver cancer. There is a real risk of liver cancer, even when the virus is suppressed.
G&H What are the most important next steps in research in this area?
RK One of the most important next steps is to determine what combination of drugs may be most effective for HBV treatment. As previously discussed, there are many compounds being developed, but a combination will likely be needed. Then, I think the next challenge will be to take the tools that are developed and apply them to people living with HBV infection throughout the world. The latest statistics from the World Health Organization state that 250 to 300 million people in the world are infected with HBV, making this disease a significant public health problem worldwide.
Dr Kim has served on advisory boards of Gilead, Roche, and Inovio.
Suggested Reading
Alonso S, Guerra AR, Carreira L, et al. Upcoming pharmacological developments in chronic hepatitis B: can we glimpse a cure on the horizon? BMC Gastroenterol. 2017;17(1):168.
Dawood A, Abdul Basit S, Jayaraj M, Gish RG. Drugs in development for hepatitis B. Drugs. 2017;77(12):1263-1280.
Gehring AJ. New treatments to reach functional cure: rationale and challenges for emerging immune-based therapies. Best Pract Res Clin Gastroenterol. 2017;31(3):337-345.
Lok AS, Zoulim F, Dusheiko G, Ghany MG. Hepatitis B cure: from discovery to regulatory approval. J Hepatol. 2017;67(4):847-861.
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The push is on to cure hepatitis B, a long-overlooked scourge of millions
By Jon CohenNov. 29, 2018
In the quest to cure hepatitis B, an infectious disease that afflicts as many as one in four people worldwide, a small laboratory in a lonely nook of the Rocky Mountains of Idaho plays an outsize role. The lab, two nondescript buildings that abut a forest off a dirt road, houses 600 woodchucks, also known as groundhogs. These large rodents are a natural host for a cousin of the hepatitis B virus (HBV), making them a favorite research model for studying the disease. The owner, James Whipple, both traps pregnant females in the wild and breeds woodchucks in the colony. These days, he says, "It's a job keeping up with the demand."
In woodchucks, as in people, the virus is a shape-shifter. It can lie low, tucking itself away in liver cells and giving few signs of its presence. It can establish a chronic infection, churning out new viruses but doing little harm. Or it can rage, triggering liver damage that can develop into HBV-related cirrhosis or cancer, which kills nearly 900,000 people around the world each year. Whipple's woodchucks, which his lab infects with the virus to study its life cycle and assess experimental medicines, are also afflicted. On this October morning, a veterinarian is doing an ultrasound on the belly of an animal with a tumor-ridden liver. "That's gnarly," Whipple says as the bulky mass appears on the screen.
HBV can be controlled with drugs and prevented with a vaccine, but the drugs have to be taken for a lifetime and vaccine coverage is spotty, even in many wealthy countries. Now, there's a drive underway to find drugs that can permanently cure the infection, suppressing the virus thoroughly enough to free patients from the burden and expense of daily pills. In all, nearly 50 potential treatments are under development, which either directly attack different steps of the viral life cycle or boost host immunity. It has been a boon for Whipple's business. "There's been a flurry of activity with lots of companies," he says. This year alone, Whipple's lab, Northeastern Wildlife in Harrison, Idaho, has evaluated seven novel treatments.
The push for a cure reflects both need and opportunity. Nearly 300 million people worldwide have chronic infections, although only 10% have been diagnosed, and fewer still receive treatment. Meanwhile, recent insights into the virus's complex life cycle have offered new drug targets, and the advent of remarkable-and extremely profitable-drugs that can cure hepatitis C, caused by an unrelated virus, have raised hopes of a similar victory against HBV. The result was the formation in 2016 of the International Coalition to Eliminate HBV, which includes more than 50 scientists from 21 countries.
Although the coalition has "eliminate" in its name, it has a more modest initial goal. HBV's most insidious feature is a latent form of viral DNA called covalently closed circular DNA (cccDNA), which forms a stealthy minichromosome inside the nucleus of infected cells. Many researchers think HBV infection can't be completely cured without eliminating this stowaway. But no drugs specifically targeting cccDNA are yet in clinical trials, and for now the coalition is trying to catalyze development of "functional" cures. The idea is to knock back the virus, including its cccDNA form, to levels low enough for the immune system to keep the infection in check, allowing people to stop treatment.
Frank Chisari, a pioneering hepatitis immunologist who is a senior adviser to the group and an emeritus professor at Scripps Research in San Diego, California, says cccDNA demands far more attention. "Very little work was done on it until a couple of years ago," says Chisari, who adds, "we know virtually nothing" about how it's created, persists, or decays. That's because basic research on HBV has languished. Unlike, say, cancer and HIV/AIDS, HBV lacks a powerful advocacy group to push for more funding. "I don't understand why hepatitis B is such an orphan," Chisari says. "The magnitude of this disease is enormous."
Hitting a virus where it lives
In a push to cure hepatitis B, drug developers are targeting nearly every step in the virus's complex life cycle. They are also trying to boost the immune response. But some say it won't be enough to block the virus's entry into the cell (left) or the transcription, assembly, and release of new viruses (right). They believe a curative drug will have to eliminate covalently closed circular DNA (cccDNA), a minichromosome that the virus creates inside an infected cell. The cccDNA can remain latent for years or can adopt a highly active "open" form (inset) that churns out new viruses. (DNA integrated into the host genome produces viral proteins but not new virus.)
HBV ambushed Arthur Koo, a structural engineer in Atlanta. After developing double vision that led to a diagnosis of a rare lymphoma, Koo began chemotherapy in early 2015. Routine lab work showed he had no liver abnormalities and no evidence of an HBV infection. By April, scans indicated he was tumor free, his double vision had cleared, and his doctors decided to do a final round of chemo as insurance. "It was amazing," says his daughter, Joyce Dalrymple. "He was so much better that we were going to take a Disney cruise with all the grandchildren."
On 16 April, when Koo began the last chemo round, tests showed his liver enzymes had become abnormally high, a sign of damage to the organ. His blood also harbored HBV's surface antigen, HBsAg, a protein that signals an active infection. Koo's doctors thought they could treat the virus after he finished chemo. The next day, he felt faint and went to an emergency room. He had an astronomically high viral load and soon was vomiting and battling diarrhea, but it was too late to start HBV drugs. "He was mystified," Dalrymple says. "He had fought all the side effects from the chemo and was prepared for that, but this was shocking."
Koo died 6 days later of fulminant hepatic failure.
Like nearly 2 billion other people, Koo had somehow been infected with HBV and never knew it. HBV is at least 100 times as infectious as HIV, but it moves between people in similar ways: from mother to child (primarily at the time of birth), through sex, and among drug users sharing syringes. Odd clusters of cases have also been linked to day care centers, football teams, butcher shops, a sumo wrestling club, and an acupuncturist-settings where the virus could have spread through seemingly innocuous open wounds. The Western Pacific region, including China and Taiwan, where Koo grew up, accounts for nearly half of the chronically infected population.
Although the HBV vaccine has greatly reduced mother-to-child transmission since it was introduced in 1981, some countries-even wealthy ones such as Canada and several in northern Europe-have been slow to adopt it as a routine childhood immunization because their burden of disease is low. China, which aggressively promotes vaccination, still misses many people in rural areas, says Jake Liang, an HBV researcher at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland. "They haven't really reached out to the masses," he says, even though up to 15% of the population is infected. Often the vaccine is not used as recommended: The latest global figures show 84% of infants received their three shots, but only 39% of babies got the critical first dose within 24 hours of birth.
Hepatitis B is completely overlooked and the funding is totally out of proportion to the problem and the need.
Timothy Block, Hepatitis B Foundation
Koo was likely infected at birth or early in life. He was among the minority of those infected early who "resolve" the infection, suppressing the virus so well they have no signs of its existence. Other infected children produce huge amounts of virus for years, but they may suffer no apparent harm. That is one of the disease's odd features: HBV itself doesn't kill hepatocytes, the cells that make up the liver. The immune response to the virus does the damage, and many children have relatively tame reactions to it for a few decades, leading to the notion that they "tolerate" the infection.
Most people infected as adults, in contrast, appear to resolve the infection. "There's lots of hand-waving and speculation about why that happens," says Chisari, although it may reflect adults' more mature immune systems.
But most-if not all-of the people who have resolved the infection still harbor cccDNA, and in Koo's case the consequences were fatal. The chemotherapy suppressed his immune system, allowing the cccDNA to reawaken and generate a massive viral onslaught. "Every big cancer center has had at least one of these patients, and they learn from it," says Su Wang, a physician at Saint Barnabas Medical Center in Livingston, New Jersey, who is a friend of the Koo family-and is chronically infected with HBV herself.
Wang is on the executive board of the World Hepatitis Alliance, a London-based nonprofit run by people who are living with, or have cleared, hepatitis B or C infections. This year the alliance launched a program to "find the missing millions" unknowingly infected with these viruses, promoting a "massive scale up" in screening and, ultimately, treatment. One pillar of the campaign is to reduce stigma and discrimination: Wang says people who reveal their status sometimes are dumped by partners or booted from medical school and health care jobs. This is a main reason why she recently decided to start speaking publicly about her own infection.
Wang only learned her HBV status when she was a university undergraduate. Because she has normal liver enzymes and has consistently maintained low levels of HBsAg and viral DNA, guidelines do not recommend treatment with current HBV drugs. Nor do they recommend treatment for the tolerant group who, despite having high viral loads, have relatively controlled immune responses and no liver damage. But learning about her infection has protected her family. Wang's husband received the vaccine, as did her four children, who were also infused with hepatitis B immunoglobulin (an antibody preparation against the virus). None is infected.
For those who show signs of liver damage, doctors have been offering the same three first-line drugs for the past 2 decades. Two of them, tenofovir (borrowed from HIV treatment) and entecavir, target the production of viral DNA. Both cripple the reverse transcriptase (RT) enzyme that converts what's known as pregenomic viral RNA-a product of cccDNA-into the DNA of new viruses. The third drug, interferon, is an immune system messenger that by illdefined mechanisms attacks various parts of the viral life cycle and also boosts the immune response against it. Each of these drugs can reduce a person's viral load to undetectable levels and, in some cases, clear viral antigens from the blood. But none eliminates cccDNA.
A year ago, a small study of HBV patients treated with RT inhibitors for 6 years or longer briefly raised hopes. Three successive liver biopsies found the 43 participants had "profoundly" reduced cccDNA levels after treatment, a group led by hepatologist Ching-Lung Lai of the University of Hong Kong in China wrote last year in the Journal of Hepatology. In 21 of them, even the most sensitive tests could not find cccDNA. Yet a follow-up study presented at a liver meeting later in the year found that in 13 of the fully suppressed people who went off their drugs, the virus rebounded within 6 months in all but one of them, leading them to restart treatment.
There's growing hope for a more permanent victory. The Hepatitis B Foundation, a nonprofit based in Doylestown, Pennsylvania, tracks the drug development pipeline; it tallies more than 30 drugs now in human trials-a tripling over the past 10 years. "Hepatitis C was consuming all the hepatitis drug space, and with that cure, we've seen a stampede of interest in hepatitis B," says Timothy Block, a microbiologist who started the foundation after his wife, a nurse, learned she was infected (and promptly lost her job).
The potential treatments move beyond RT inhibition. Almost every known step in HBV's life cycle, from infection to the assembly of new viral particles, is a target for at least one new drug. Others are immune modulators designed to turn up specific beneficial responses or dampen harmful ones. Many researchers suspect that, as with HIV, combining treatments that attack the virus from different angles ultimately has the best chance of success.
Lots of pharmaceutical companies are throwing everything against the wall to see what sticks.
Jake Liang, National Institute of Diabetes and Digestive and Kidney Diseases
The 2012 discovery of the polypeptide receptor that HBV latches onto when it infects a cell was a key advance. It allowed researchers at long last to replicate the entire viral life cycle-including the formation of cccDNA-in laboratory cell cultures. The receptor also gives drug developers a new target. And by engineering the receptor into mice and monkeys, researchers are developing new animal models for HBV that, unlike the woodchuck, are vulnerable to the exact virus that infects humans.
Gilead Sciences of Foster City, California, which makes tenofovir and one of the bestselling hepatitis C cure drugs, has more than 60 scientists aiming to develop a similar weapon against HBV. "It's our largest program in virology by far," says John McHutchison, a gastroenterologist who is the company's chief scientific officer-and keeps a stuffed woodchuck in his office. "If anyone is going to cure hep B, Gilead would like to claim that."
Currently, the firm's lead experimental HBV drug turns on toll-like receptor 8, a protein on certain immune cells that reacts to viral genetic material by boosting production of interferon and other chemical messengers that crank up natural defenses against the virus. As Gilead reported last year at a liver conference, the drug worked well in woodchucks, driving cccDNA down to undetectable levels, and now is in phase II clinical trials. "This may be the next drug that will be licensed for HBV," says Stephan Menne, an immunologist at Georgetown University Medical Center in Washington, D.C., who contributed to the woodchuck study. Other drug developers are pinning their hopes on short interfering RNAs, meant to block the production of RNA from cccDNA, and on compounds designed to inhibit formation of the capsid protein that protects the virus's genetic cargo.
"Lots of pharmaceutical companies are throwing everything against the wall to see what sticks," says Liang, a coalition board member. Chisari worries that immune modulators, a popular strategy, could backfire. If a person has a high percentage of HBV-infected hepatocytes, bolstering the immune response to infected cells could lead to liver failure. "There are a lot of false starts underway, and some might inadvertently do harm," Chisari warns.
Like Chisari, the International Coalition to Eliminate HBV contends that more effort needs to go into targeting the belly of the beast, cccDNA. In September, Gilead signed a $445 million deal with Precision BioSciences of Durham, North Carolina, to codevelop what are known as homing endonucleases-DNA cutting enzymes-designed to snip cccDNA. Gilead scientists have also helped clarify how a particular HBV protein known as X turns on cccDNA to produce more virus, providing a new drug target. "We're in early days," McHutchison says. "The field feels like it's really starting to gain traction and momentum." Other companies hope to use CRISPR, the genome editor, to cripple cccDNA in patients, as it has done in some test tube experiments.
Proving that any treatment significantly depletes cccDNA reservoirs is a tall order. Current clinical trials evaluate how well a drug works by measuring its impact on HBsAg levels and viral load in blood, not on cccDNA. "That is nuts," Chisari says. "They're crossing their fingers and using wishful thinking." Yet monitoring cccDNA directly means subjecting patients to multiple, painful liver biopsies. That could change, if relatively painless and simple fine needle aspirates of the liver can capture enough tissue. Immunologist Mala Maini of University College London has used fine needle aspirates to assess a wide range of immune responses to HBV in the liver, and she's now collaborating with hepatologist Fabien Zoulim of the University of Lyon in France to see whether the technique can work for cccDNA studies.
In contrast to the growing interest in HBV from drug developers, the National Institutes of Health (NIH) spent a mere $44 million on HBV this year-and little of that went to "discovery research," Block says. "Hepatitis B is completely overlooked and the funding is totally out of proportion to the problem and the need," he says. Anthony Fauci, who heads NIH's National Institute of Allergy and Infectious Diseases in Bethesda, agrees and says if the stepped up push for a cure can show some progress, it will drive more funding to research. "All we need is a little bit of success to put more into it," Fauci says.
Eugene Schiff, an 81-year-old liver specialist at the University of Miami in Florida whose father was also a prominent liver clinician, has worked in the field since its birth, and he's bullish about a cure. "A couple of years ago, they said it was impossible to clear cccDNA," says Schiff, who is the co-editor of Schiff's Diseases of the Liver, a standard textbook now in its 12th edition. "You never say that with science, and I knew it was BS. Now, people in the field are estimating it will take 5, maybe 10 years to clear cccDNA. And if we can cure the ones who have hepatitis B and continue to vaccinate the ones who don't, we can eradicate the disease."
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