Bepirovirsen Shows Positive Results In The Treatment Of Chronic Hepatitis B
Bepirovirsen produced sustained clearance of hepatitis B virus and hepatitis B surface antigens.
Bepirovirsen , an investigational antisense oligonucleotide, produced sustained clearance of hepatitis B virus and hepatitis B surface antigens in patients on concurrent nucleoside/nucleotide analogues and in patients not-on-NA therapy, according to results from the B-Clear phase 2B trial.
The trial found potential in bepirovirsen as a potential monotherapy or in combination with NAs, which could result in functional cure, according to GSK. Additionally, the trial identified a potential patient subgroup who are more likely to benefit from treatment with bepirovirsen.
results from the B-Clear study are a promising step forward for the approximately 300 million people living with chronic hepatitis B, said Chris Corsico, SVP, Development, GSK, in a press release. We look forward to confirming these findings for bepirovirsen in our phase 3 study starting next year, as well as exploring potential sequential therapy options with the aim of helping more people living with achieve functional cure.
Patients with low baseline HBV surface antigen levels had the best response to treatment with bepirovirsen in treatment arm 1, with 16% of patients on NA and 25% of patients not on NA achieving the primary endpoint.
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Is There A Cure For Hepatitis B
The long and short answer is that there is not yet a cure for hepatitis B. Understanding why requires insight into the virus itself and the challenges cure researchers face.
Hepatitis B is an infectious disease caused by the hepatitis B virus . While most people exposed to hepatitis B will spontaneously clear the virus soon after infection, a proportion will go on to develop a chronic infection.
Of these, around one in four will develop severe liver complications, including cirrhosis and liver cancer, typically years after the initial infection.
Efforts to find a cure for hepatitis B have been underway since the virus was first identified by scientists at the National Institutes of Health in 1966. It soon became clear, however, that numerous hurdles would need to be overcome before an actual cure could be achieved. Chief among these are:
Combination Of Na Plus Peg
Although the current monotherapy of anti-HBV drugs can suppress viral replication, prevent the progression of CHB to cirrhosis, and decrease the rates of HBV-related HCC in most CHB patients, long-term anti-HBV monotherapy rarely achieves the higher rate of HBsAg loss. Hence, to accomplish the goal of a functional cure in more CHB patients, the combination of NA with Peg-IFN- has been evaluated. The reason for this is that the two classes of anti-HBV drugs have different mechanisms of action. Thus, their combination would result in a synergistic anti-HBV effect. Several studies have demonstrated that the combination of NA with Peg-IFN- can substantially enhance the rates of HBsAg loss, but the benefits are mainly limited to a small proportion of patients and depend on HBV genotype and patient geographical distributions. Moreover, NAs and Peg-IFN- treatment have no direct impact on viral transcription or cccDNA. Thus, there is a very high risk of reactivation of HBV and the emergence of downstream disease symptoms after stopping treatment. Therefore, new therapeutic drugs that target different HBV life cycle steps or modulate the host immune system are needed.
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Its Great Weve Got But Its Not Where We Need To Be He Says One Class Is Hard To Take The Other You Need To Take Forever
HBVs assault on the liver causes a disease called Hepatitis B . Most adults with hepB recover within one to three months after symptoms start, but when the infection persists longer than six months its considered chronic. As the virus attacks the liver cells, it leaves behind nasty scars called fibrosis. In up to one-third of the patients the scars become severe , eventually resulting in liver failure or liver cancer. While hepB can be fatal, it is treatable, but it is also easily prevented to a degree of 95% through routine, safe, immunisation.
Upscaling vaccination, screening and treatment is the best way to keep this viral criminal at bay. New developments or scientific breakthroughs in any of these three areas is bad news for HBV, but good news for us. So, when scientists on the frontline say this deadly disease is about to meet its match, its great news.
Is Hepatitis B Curable
Theres no cure for hepatitis B. The good news is it usually goes away by itself in 4 to 8 weeks. More than 9 out of 10 adults who get hepatitis B totally recover.
However, about 1 in 20 people who get hepatitis B as adults become carriers, which means they have a chronic hepatitis B infection. Carriers are more likely to pass hepatitis B to other people. Most carriers are contagious meaning they can spread hepatitis B for the rest of their lives.
Hepatitis B infections that last a long time may lead to serious liver diseases like cirrhosis and liver cancer. About 1 in 5 people with chronic hepatitis B die from it. There are medicines that can help treat chronic hepatitis B infections.
Most babies who get hepatitis B during birth develop chronic infection, unless they get treated right away. But treatments are almost always effective if your baby gets them quickly. Thats why its important for pregnant people to get tested for hepatitis B.
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Hbv Genome And Life Cycle
HBV is a small virus of the Hepadnaviridae family which infects hepatocytes, replicates, and persists in the nucleus. HBV particles include the HBV genome, nucleocapsid, and envelope proteins. The HBV genome is partially double-stranded DNA, with approximately 3200 base pairs that form a relaxed circular DNA genome. The minus strand is the longer-strand DNA which complements pre-genomic RNA . The plus strand is the shorter-strand DNA. The minus strand has four overlapping open reading frames , consisting of PreC/C, P, PreS/S, and X. The PreC/C ORF encodes the hepatitis B e antigen and hepatitis B core antigen . The P ORF encodes the HBV DNA polymerase. The PreS/S ORF encodes the large , the middle , and the small envelope proteins. The X ORF encodes the X protein .
The large envelope protein contains the receptor-binding domain and is involved in viral entry into the cytoplasm by receptor-mediated endocytosis. This process involves the sodium taurocholate co-transporting polypeptide receptor in the hepatocyte membrane. After attachment, two pathways for cell entry include endocytosis and fusion of the HBV envelope with the plasma membrane. Then, individual rcDNAs are modified into cccDNAs, packaged into chromatin by histone and non-histone proteins. The cccDNAs are responsible for viral persistence in the nuclei of infected cells. These cccDNAs also use pre-C mRNA and all other sub-genomic mRNAs that code for the main viral proteins.
Whats The Prognosis For Hepatitis B
Your doctor will know youâve recovered when you no longer have symptoms and blood tests show:
- Your liver is working normally.
- You have hepatitis B surface antibody.
But some people dont get rid of the infection. If you have it for more than 6 months, youâre whatâs called a carrier, even if you donât have symptoms. This means you can give the disease to someone else through:
- Unprotected sex
- Contact with your blood or an open sore
- Sharing needles or syringes
Doctors donât know why, but the disease does go away in a small number of carriers. For others, it becomes whatâs known as chronic. That means you have an ongoing liver infection. It can lead to cirrhosis, or hardening of the organ. It scars over and stops working. Some people also get liver cancer.
If youâre a carrier or are infected with hepatitis B, donât donate blood, plasma, body organs, tissue, or sperm. Tell anyone you could infect whether itâs a sex partner, your doctor, or your dentist that you have it.
Show Sources
CDC: âHepatitis B Questions and Answers for Health Professionals,â âHepatitis B Questions and Answers for the Public.â
Mayo Clinic: âHepatitis B.â
UpToDate: âHepatitis B virus: Screening and diagnosis.â
CDC.
HealthyPeople.gov: âHepatitis B in Pregnant Women: Screening.â
Annals of Internal Medicine: âScreening for Hepatitis B Virus Infection in Nonpregnant Adolescents and Adults: U.S. Preventive Services Task Force Recommendation Statement.â
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Recommended Reading: Testing For Hepatitis B Immunity
Low Response Rates And Nonresponders
Low vaccination response rates have been associated with obesity, smoking, immunosuppression , and advanced age. Approximately 25-50% of persons who initially do not have a vaccine response will show a response to one additional vaccine dose, and 50-75% of individuals will have a response to a fourth higher dose of Engerix B or Recombivax HB, or a second 3-dose series.
Postvaccine antibody titers do not need to be obtained in routine vaccinations of children or adults. It is recommended that testing for anti-HBs be obtained 4-12 weeks after vaccination in the following groups :
- Immunocompromised patients, including those on hemodialysis, HIV patients, and others
- Infants born to HBsAg-positive mothers
- Healthcare professionals
- Sexual partners of HBsAg-positive patients
Nonresponders, should be revaccinated with another series of 3-dose hepatitis B vaccine. Consider delaying revaccination for several months after initiation of antiretroviral therapy in patients with CD4 counts below 200 cells/mm3 or those with symptomatic HIV disease. The delay in these individuals is an attempt to maximize the antibody response to the vaccine.
Do not defer vaccination in pregnant patients or patients who are unlikely to achieve an increased CD4 count. Individuals at increased risk of severe complications due to HBV infection include those unlikely to achieve CD4 counts of 200 cells/mm3 or above after antiretroviral therapy and HIV-infected pregnant women.
Accessibility And Hbsag Clearance Rate
HBsAg clearance occurs spontaneously or via antiviral treatment in CHB patients. The most commonly used drugs are nucleoside analogue and pegylated interferon . NA drugs include entecavir , tenofovir disoproxil fumarate and tenofovir alafenamide fumarate . The 2018 AASLD guidelines recommend Peg-IFN, ETV, or TDF as the preferred initial therapy for adults with immune-active CHB. It also suggests that alanine transaminase levels be tested at least every 6 months for adults with immune-tolerant CHB to monitor for potential transition to immune-active or immune-inactive CHB . The 2017 EASL guideline recommends ETV, TDF and TAF as the preferred monotherapy regimens, and the extension of the duration of Peg-IFN therapy beyond week 48 may be beneficial in selected HBeAg-negative CHB patients . The potential side effects of NAs include lactic acidosis for ETV and nephropathy, osteomalacia, lactic acidosis for TDF. CHB patients should be clinically monitored. The most frequently reported side effects for Peg-IFN are flu-like syndrome, myalgia, fatigue, mood disturbances, weight loss, hair loss and local reactions at the site of injection, and these side effects may be partially managed with dose reduction . Currently, the clearance of HBsAg is based primarily on sequential or combined treatment with NA and Peg-IFN.
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What Treatments Are Available For Chronic Hepatitis B
Hepatitis B
Hepatitis B treatment is based on the results of blood tests, age, and the degree of scarring in the liver. Hepatitis B treatment is recommended for patients with very active virus and an inflamed liver. People with chronic hepatitis B and cirrhosis also may be candidates for treatment.
Treatment involves taking an oral antiviral medication. In some cases, injections may be used.
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Prognosis Improvement After Hbsag Clearance
These related studies provide clear recommendations that patients who achieve HBsAg clearance have favourable clinical outcomes compared to patients who achieve only HBV DNA suppression and HBeAg seroconversion. HBsAg clearance leads to biochemical, virological and liver histological improvements, and it significantly reduces the risk of HCC. However, HCC may occur after HBsAg seroclearance despite it being the ultimate treatment endpoint recommended by current guidelines. The risk factors associated with HCC include the presence of cirrhosis, male sex, and age50 years at the time of HBsAg clearance . Closer attention should be given to patients with one or more of these risk factors.
These high-risk patients should be re-examined in a timely manner even if HBsAg clearance is obtained. These results also suggest that achieving a functional cure early in the absence of cirrhosis results in a better prognosis .
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New Immunotherapy ‘highly Effective’ Against Hepatitis B
- Date:
- University College London
- Summary:
- Scientists have identified a new immunotherapy to combat the hepatitis B virus , the most common cause of liver cancer in the world.
Scientists at UCL have identified a new immunotherapy to combat the hepatitis B virus , the most common cause of liver cancer in the world.
Each year, globally, chronic HBV causes an estimated 880,000 deaths from liver cirrhosis and hepatocellular carcinoma/liver cancer .
The pioneering study used immune cells isolated directly from patient liver and tumour tissue, to show that targeting acyl-CoA:cholesterol acyltransferase , an enzyme that helps to manage cholesterol levels in cells*, was highly effective at boosting immune responses.
Published in Nature Communications, the findings show that blocking the activity of ACAT with ACAT inhibitors boosts the specific immune cells that can fight both the virus and associated cancerous tumours, demonstrating its effectiveness as an immunotherapy. Inhibiting ACAT was also found to impede HBV’s own replication, thereby also acting as a direct antiviral. ACAT inhibitors such as avasimibe, taken orally, have previously been shown to be well-tolerated as cholesterol-lowering drugs in humans.
Explaining the study, lead author Professor Mala Maini , said: “Chronic hepatitis B virus infection is a major global health problem and the most common cause of liver cancer in the world.
Grant funding came from the Wellcome Trust and Cancer Research UK.
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Unlikely Sources Of Infection
Trace levels of HBV can also be found in saliva, tears, urine, and feces but in amounts that are highly unlikely to cause infection.
While vaccination remains the cornerstone of HBV prevention, there are ways to further reduce the risk of transmission, especially if you or someone in your household has hepatitis B:
- Wash your hands with soap and water if exposed to blood.
- Avoid sharing razors or toothbrushes.
- Use condoms during sex.
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National Institutes Of Health Recommendations
The National Institutes of Health recommends nucleoside therapy for the treatment of patients with acute liver failure, as well as cirrhotic patients who are HBV DNA positive and those with clinical complications, cirrhosis or advanced fibrosis with positive serum HBV DNA, or reactivation of chronic HBV during or after chemotherapy or immunosuppression. In addition, immunoglobulin and vaccination should be administered to newborns born to women positive for hepatitis B surface antigen .
In general, for hepatitis B e antigen -positive patients with evidence of chronic HBV disease, treatment is advised when the HBV DNA level is at or above 20,000 IU/mL and when serum ALT is elevated for 3-6 months.
For HBeAg-negative patients with chronic hepatitis B disease, treatment can be administered when the HBV DNA is at or above 2,000 IU/mL and the serum ALT is elevated for 3-6 months.
In patients coinfected with HBV and HIV, initiate therapy against HBV and administer antiretroviral therapy as well.
The NIH also indicates that immediate therapy is not routinely indicated for patients who have the following :
-
Chronic hepatitis B with high levels of serum HBV DNA but normal serum ALT levels or little activity on liver biopsy
-
Low levels of or no detectable serum HBV DNA and normal serum ALT levels
-
Positive serum HBV DNA but not HBsAg , unless the patient is undergoing immunosuppression
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The Best Way To Cure Any Disease Is The One
Instead of the cure being a singular treatment or a singular element, like the kryptonite that threatens to destroy Superman, Dr Tavis says the cure to HBV will likely be a collection of powerful tools that together will have the strength to take on the virus.
Scientists all over the world are making huge advancements in new treatments that can attack the virus from every angle, he explains.
Like a squadron of disease-demolishing superheroes, some of the therapies in development focus on blocking the virus entering the cell in the first place, whilst others deactivate the DNA. There is one therapy that will distort the shell of the virus so HBV becomes inactive and unable to survive. Another will lock itself to the genetic material of the virus and either cause it to fall apart or stop it from working.
Clinical trials are underway to investigate how these various treatments can be combined to work safely and effectively with one another, so healthcare professionals will be able to pick from a toolbox of therapies to deliver patient-specific treatment. One pharmaceutical company, Replicor, is already doing it. Using a three-part combination of drugs, Replicor is achieving a functional cure rate of 35% in early clinical trials.
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European Commission And Thervacb Join Forces
The role of viral hepatitis as a public health threat has long been underestimated. Only very recently, the United Nations in their 2030 Agenda for Sustainable Development called for international action to combat viral hepatitis and reduce the disease burden. The major killer is the hepatitis B virus causing liver cirrhosis and liver cancer. Worldwide 880,000 humans die each year from the consequences of an HBV infection.
A prophylactic vaccine is available to prevent HBV infection, but more than 3% of the worlds population are chronically infected and do not profit from that vaccine anymore. For those suffering from chronic hepatitis B, until today no curative treatment option exists.
The European Commission therefore selected the project TherVacB led by Helmholtz Zentrum München for a five-year funding within the Horizon 2020 program. A consortium of leading virologists, immunologists and physicians specialized in treating viral hepatitis, will use a newly designed therapeutic vaccine, TherVacB, as an immunotherapy to cure HBV. TherVacB will be evaluated in a three-year clinical trial starting in 2022 conducted in Europe and in Africa. Integration of a partner site in Tanzania shall help building local capacities for diagnosing and treating hepatitis B and support an important goal of the consortium to raise awareness for hepatitis B.