Tuesday, May 17, 2022

New Treatment For Hepatitis B

The Future Therapeutic Target For Chronic Hbv Infection

Treatment of Hepatitis Part 3 – Hepatitis B (HBV) Treatment

The first step in the development of a new treatment is to set targets such as reversal or prevention of fibrosis/cirrhosis progression, improvement or maintenance of liver homeostasis, or prevention of transplantation or death. Many different antiviral drugs are used in the treatment of chronic HBV infection, for various reasons, and it seems likely that chronic HBV infection will evolve into liver cirrhosis, liver failure, or liver cancer. Currently, a new therapeutic target has been established by studies on gut microbiota.11

Fecal microbiota transplantation refers to the process of infusing fecal suspension from a healthy donor to the intestinal tract of a recipient to normalize the intestinal microbiotas composition and functionality. FMT can be applied to normalize the composition of the gut microbiota and increase the proportion and diversity of beneficial bacteria. FMT also provides the necessary signals for epithelial regeneration, induces mucins and antimicrobial peptide production, and reduces intestinal permeability to preserve the integrity of the epithelial barrier.53

Is Hep C Curable

The latest drugs available for hepatitis C have high success rates when it comes to curing the condition.

In conversations with your doctor, you can discuss the full range of treatment options. Some of these are combination drugs.

But its important to note that not every medication may be effective for you, even if its for the right genotype.

Immune Function Of Gut Microbiota In The Development Of Chronic Hbv Infection

In recent years, different studies indicated that the gut microbiota composition influences the host immune response to HBV, and when the intestinal flora is changed, the infection can easily turn into a chronic infection.25 Immune injuries triggered by structural changes in the gut microbiota are often caused by inflammatory pathways between the gut microbiota, the immune system, and the liver initiated by crosstalk.32

Kupffer cells, hepatic stellate cells, plasmacytoid dendritic cells , and hepatocyte cells are capable of expressing TLRs that recognize pathogen-associated molecular patterns and initiating the innate immune response.44 Intestinal PAMPs associated with chronic infection with HBV are now considered to consist predominantly of lipopolysaccharide , bacterial DNA/RNA, teichoic acid , peptidoglycan and non-methylated CpG DNA, flagellin, and metabolic by-products.40

Other translocated bacterial products can also activate an inflammatory response by activating TLRs. TLR-2 recognize peptidoglycan and lipoteichoic teichoic acid , which are components of the cell wall of gram-positive bacteria, and TLR5 are mainly activated by bacterial flagellin, whereas TLR-9 is recognized as unmethylated CpG DNA, and TLR3 can combine with dsRNA in bacteria, and ssRNA can activate TLR7 and TLR8 receptors.50,51

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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 M√ľnchen 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.

Who Can I Talk With During Treatment

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Since hepatitis C treatment plans last several weeks, you should regularly attend medical appointments. Your doctor may have a list of local groups where you can find emotional support.

There may also be other resources like community nurses and walk-in clinics. With this information, youll know where to go for help between appointments.

Another option is to explore the online hepatitis C community, where people share their experiences with hepatitis C.

For example, the Inspire hepatitis C group allows people to connect, share stories, discuss treatment, and more.

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Stimulating The Adaptive Immune Response

An interesting observation has shown that patients with CHB who received a bone marrow transplant from donors with resolved HBV infection may become HBsAg negative. This highlights the efficacy of HBV-specific immunity via the action of memory B and T cells. A similar situation is observed in patients with controlled HBV infection, showing coordinated activation of humoral and cellular immunity against HBV. However, this is not observed in most patients, as T cells progressively become dysfunctional and lose their proliferative and cytotoxic activity owing to continued exposure to HBV antigens . Thus, activating HBV-specific responses could be another option in antiviral regimens, which could be achieved with checkpoint inhibitors or therapeutic vaccines.

Checkpoint inhibitors reinvigorate pre-existing antiviral immunity by preventing the action of signalling pathways that limit the duration and amplitude of immune responses. This type of negative regulatory mechanism is induced to reduce tissue damage. One strategy, for example, is to prevent the inhibitory signals generated from the interaction between programmed cell death 1 ligand 1 and its receptor programmed cell death 1 . This PD-L1/PD1 interaction regulates the activity of T cells in peripheral tissues, playing a key role during inflammatory responses directed to control infection. ASC22 is an anti-PD-L1 antibody currently in phase II clinical trial to evaluate its safety and efficacy in CHB patients .

What Do I Need To Know About Having Hepatitis B

If you have chronic hepatitis B, getting the right medical care can help you stay healthy. Taking good care of your liver is important. Talk with your doctor before you take any prescription medication, over-the-counter drugs, vitamins, or nutritional supplements to make sure they wont hurt your liver. You should also stay away from alcohol, because drinking can damage your liver.

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Hbsag Clearance After Na Treatment

There are few large or conclusive studies on the clearance of HBsAg after NA treatment, and some of these studies are single-centre retrospective studies. Kim et al. reported a clearance rate of 1% or less in 110 CHB patients who were treated with ETV/LAM for approximately 1 year. A retrospective study by Yip et al. reported an HBsAg clearance rate of 2.1% after an average follow-up of 4.8 years in 20,263 CHB patients treated with ETV/TDF for longer than 6 months. Wong et al. retrospectively evaluated 1072 CHB patients on antiviral therapy for approximately 6 years and found an HBsAg clearance rate of 4.58%. This study found no significant difference in the clearance rate between HBeAg-positive and HBeAg-negative patients, but the rate in patients with cirrhosis was significantly lower than patients without cirrhosis . These results suggested that the clearance rate of non-cirrhosis patients was higher after NA treatment, which is not consistent with the results of patients who experienced spontaneous clearance. Compared to patients with normal baseline ALT, patients with higher ALT levels had significantly higher rates of achieving HBsAg clearance. In general, the clearance rate may increase with the extension of treatment in CHB patients, but the overall rate with currently available NA treatment is low. The HBsAg clearance rates were 1.45.1% after an average follow-up of 27 years after NA treatment .

Gene Editing Strategies: Cccdna Formation Inhibitors

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Silencing or depleting the cccDNA pool in infected hepatocytes is the goal in new approaches to treatment. Targeted mutagenesis has attracted considerable interest in recent years. This was achieved through the use of sequence-specific RNA-guided nucleases and proteins as a means to cure HBV infection by permanently disabling cccDNA . The RGN family includes zinc finger nucleases , transcription activator-like effector nucleases , and clustered regularly interspaced short palindromic repeats with CRISPR-associated systems , all showing antiviral efficacy.

The cccDNA is a stable non-integrated minichromosome wrapped in transcriptionally active and inactive chromatin . Designer nucleases can cleave at pretargeted sequences in the HBV genome to result in predefined mutagenesis. Although mutated cccDNA can be transcribed, the resulting mutated viral proteins is not able to engage in viral replication. Hence, HBV cccDNA is an optimal target for nuclease gene editing, due to its episomal minichromosome configuration and sequence stability. More specifically, the efficacy of CRISPR/Cas9 for cleavage and inactivation of the cccDNA, as well as inhibition of hepatocarcinogenesis, has been reported .

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What Is Hepatitis B

Hepatitis B is a viral infection that causes liver inflammation and damage. Inflammation is swelling that occurs when tissues of the body become injured or infected. Inflammation can damage organs.

Viruses invade normal cells in your body. Many viruses cause infections that can spread from person to person. The hepatitis B virus spreads through contact with an infected persons blood, semen, or other body fluids.

You can take steps to protect yourself from hepatitis B, including getting the hepatitis B vaccine. If you have hepatitis B, you can take steps to prevent spreading hepatitis B to others.

The hepatitis B virus can cause an acute or chronic infection.

What New Treatments Are On The Horizon For Hepatitis B/d Coinfected Patients

Although there are highly effective treatments available to manage hepatitis B, there are few available treatments for hepatitis D, and none are U.S. Food and Drug Administration approved. Hepatitis D is the most severe form of viral hepatitis, and coinfection can accelerate liver damage and cause cirrhosis or liver cancer in as little as 5 years for some patients. Currently there is no approved drug for acute or chronic hepatitis B/D coinfection, but in trials pegylated interferon alpha has shown to be somewhat effective. By stimulating the bodys immune system, around 25-30% of patients are able to suppress their hepatitis D viral load with weekly injections over 48 weeks. Emerging research is showing higher rates of effectiveness with prolonged interferon treatment beyond one year, but it can be difficult for patients to continue due to the physical and mental toll of interferon on the body. Antiviral medications that are proven effective against hepatitis B are sometimes prescribed along with interferon therapy for patients with a high hepatitis B viral load, but these have no effect on hepatitis D. It is urgent that more treatment options be developed for the millions of hepatitis B/D patients that are eagerly awaiting them.

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Click here for more information about the phases of the clinical trial process.

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Eating Diet And Nutrition For Hepatitis B

If you have hepatitis B, you should eat a balanced, healthy diet. Obesity can increase the chance of nonalcoholic fatty liver disease , and NAFLD can increase liver damage in people who have hepatitis B. Talk with your doctor about healthy eating and maintaining a healthy weight.

You should also avoid alcohol because it can cause more liver damage.

Nucleocapsid Assembly Inhibitors And Core Inhibitors

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The HBV core protein plays a central role in the viral replication cycle starting with uncoating and release of rcDNA, delivery to the nuclear pore basket, nucleocapsid formation and packaging of pgRNA, and finally interaction with HBsAg during the end stages of morphogenesis. There is indirect evidence that the protein binds to cellular promoters and regulates gene expression . In this respect it constitutes another attractive antiviral target.

The following two classes of core protein allosteric modulators have been discovered: the heteroaryldihydropyrimidines and the phenylpropenamides , sulfamoylbenzamides, and several other chemotypes .

HAP derivatives, misdirect core protein dimers to assemble aberrant non-capsid polymers, leading to the degradation of the core protein . GLS4 is a representative compound of the HAP family.

Type II CpAMs were found to accelerate formation of capsid assembly, possibly at an inappropriate time and place, thereby preventing pgRNA encapsidation and, instead, inducing the assembly of empty capsids .

In vitro, GLS4 inhibited virus accumulation in the supernatant of hepatic cell lines. This was tested in vivo in nude mice inoculated with HepAD38 cells, which then grew out as tumors, resulting in viremia. Treatment of mice with GLS4 and BAY 41-4109 caused a strong and sustained drop in HBV DNA to about the same extents both during and after treatment .

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Challenges Facing Future Treatment Efforts

Although more-potent and more-specific antiviral treatments promise to improve the frequency and durability of responses to therapy among a wider spectrum of patients with CHB, many significant challenges remain . The emergence of resistance and management of resistance have implications broader than those discussed for each of the agents described in the present article. One important consideration comes from the realization that both the envelope and the polymerase gene map to overlapping regions in the HBV genome . Because of this structure, mutations in the polymerase gene can result in changes to the envelope as well. When immunodominant epitopes are involved, such polymerase gene mutations have been documented to lead to immunologic escape from vaccination and treatment failures .

Treatment responses for approved therapies for hepatitis B virus infection. A, Results of trials involving hepatitis B e antigen positive subjects with chronic hepatitis B . B, Results of trials involving HBeAg-negative individuals with CHB . *, Necessary data not available lightly shaded bar, HBeAg seroconversion horizontally striped bar, loss of HBV DNA darkly shaded bar, histologic improvement.

Go And Kegg Pathway Enrichment Analyses Of Degs

The Database for Annotation, Visualization and Integrated Discovery that provides a comprehensive set of functional annotation information of genes and proteins, was used to analyze the DEGs enrichment and functional annotation. GO annotation was performed to analyze the biological process of DEGs. Kyoto Encyclopedia of Genes and Genomes pathway analysis to understand high-level functions and biological systems from large-scale molecular datasets generated by high-throughput experiments. The P< .05 was considered statistically significant.

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Hepatitis B And Pregnancy

The American College of Obstetricians and Gynecologists , the US Preventive Services Task Force , and the World Health Organization recommend routine prenatal screening for hepatitis B surface antigen in all pregnant womenduring every pregnancyregardless of previous test results or vaccinations. Pregnant women at risk for hepatitis B infections should be specifically targeted for vaccination. The risk of transmission of hepatitis B associated with amniocentesis is low. WHO further recommends all pregnant women undergo testing at least once for HIV and syphilis in addition to that for HBsAg and as early as possible in the pregnancy.

It is recommended that all infants receive their first dose of hepatitis B vaccine as soon as possible after birth , followed by two or three doses to complete the primary series.

To prevent maternal-fetal HBV transmission, a conditional WHO recommendation is that HBsAg-positive gravida who have an HBV DNA 5.3 log10 IU/mL receive tenofovir prophylaxis beginning the 28th week of pregnancy until at least birth. This is in addition to the three-dose hepatitis B vaccination in all infants, including a timely birth dose. When antenatal HBV DNA testing is not available, HBeAg testing can be used as an alternative study to determine eligibility for tenofovir prophylaxis to prevent mother-to-child transmission of HBV.

Hbv Structure And Genomic Organization

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Three types of viral particles are present in the serum of an infected individual visible by electron microscopy, i.e., the complete infectious virion or Dane particle and two types of subviral particles known as spheres and filaments . The Dane particle is a spherical particle measuring 42 nm in diameter and consists of an outer envelope made of HBsAg in a lipid bilayer . This encloses the nucleocapsid core of the virus, which in turn contains a single copy of the viral genome covalently linked to the terminal protein of the virus . There is an abundance of subviral particles, which outnumber infectious virions by 100- to 10,000-fold and are exclusively composed of HBs proteins and host derived lipids, lacking any nucleic acid containing cores .

The 3.2 kilobases in length circular partially double-stranded HBV DNA genome contains the four open reading frames of the virus which are the surface , core , polymerase and X. These encode a total of seven proteins translated from six co-terminal, unspliced and capped mRNAs ending at a common polyadenylation signal, which is situated in the core ORF. Regulatory elements such as the two enhancers , the four promoters , the polyadenylation, encapsidation , and replication signals are situated within these ORFs and direct the synthesis of the mRNA transcripts through the recruitment of transcription factors which are particularly enriched in hepatocytes .

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Targeting Hbv Gene Expression

As previously mentioned, high antigen load is thought to play a role in maintaining chronic HBV, so preventing HBsAg production by both cccDNA and integrated DNA is of interest. Moreover, targeting viral expression is not limited to HBsAg because the characteristics of the HBV genome allow selection of target sequences in overlapping coding regions and thus simultaneous degradation or translation inhibition of multiple transcripts can be achieved. Most of the HBV antiviral strategies under clinical evaluation are small-interfering RNAs and antisense oligonucleotides . At the molecular level, ASOs are distinct from siRNAs as they are not incorporated into the RNA-induced silencing complex to silence its target, but they induce RNase H-mediated RNA cleavage by binding to target RNA. Some of the molecules under evaluation include the siRNAs JNJ-3989, VIR-2218 and RG6346, and the ASOs GSK3228836 and RO7062931.

Finally, it is worth mentioning a third category of small molecules targeting HBV antigen production via RNA destabilization . Although these compounds are not in clinical development, drugs such as RG7834 have been shown to reduce HBsAg levels and HBV viraemia in animal models.

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