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MEDICAL SCIENCES / <«g©LL©(MUM~J©U®MaL» #8(167), 2023
Melenko Svitlana Romanivna.
PhD, Associate Professor of the Department of Infectious Diseases and Epidemiology
Bukovinian State Medical University Voitiuk Anastasia Andriivna.
student
Bukovinian State Medical University Rudoy Andriana Ivanivna
student
Bukovinian State Medical University DOI: 10.24412/2520-6990-2023-8167-24-26 HEPATITIS B MODERN TREATMENT
Abstract.
Hepatitis B is the most common serious liver infection in the world. It is caused by the hepatitis B virus that attacks and injures the liver. Two billion people (or 1 in 3) have been infected and about 300 million people are living with a chronic hepatitis B infection.Hepatitis B is transmitted through direct contact with infected blood or certain bodily fluids. The virus is most commonly transmitted from an infected pregnant person to their baby during childbirth, due to the blood exchange that happens between mother and baby. It is also transmitted through unsterile medical or dental equipment, unprotected sex, or unsterile needles, or by sharing personal items such as razors, toothbrushes, nail clippers, body jewelry.
Keywords: Hepatitis B, virus infection, chronic liver disease, cytokines, jaundice, vaccination, therapeutic goals.
Pathogenesis of the hepatitis B.
HBV is not directly cytopathic by itself and the hepatocellular injuries are considered to be the results of a complex interplay among HBV, hepatocytes and immune cells of the host. It has been documented by weekly to monthly assays that there is an upsurge of serum HBV DNA prior to the abrupt elevation of ALT. There is also a parallel elevation of the serum HBsAg level along with the upsurge of serum HBV DNA. Using a hybridization assay for HBV DNA and a conventional enzyme immunoassay to measure the HBeAg level, an earlier study showed significant parallel increases in serum HBeAg and HBV DNA levels and accumulation of intracellular viral proteins several weeks before the hepatitis flare. In addition, there was a subsequent increase in anti-HBe production and HBeAg/anti-HBe immune complex formation, implicating the important role of the immune response to HBV in initiating the hepatitis flare. Immunohistologic studies during the hepatitis flares have shown CD8+ T cells in the mononuclear cell infiltrates, strong membranous expression of human leukocyte antigen class I (HLA-I), and cytoplasmic or membranous/submembra-nous hepatitis B core antigen (HBcAg) expression. Earlier immunologic studies showed a 2-4 fold elevation of HBcAg/HBeAg-specific precursor T cell frequencies, with an increase of HBcAg/HBeAg-specific T cell proliferation before and during the hepatitis flares, an increased production of interferon gamma (IFN-y) at the time of hepatitis flares and Th1 phenotypic cytokines (IL-2 and IFN-y) were upregulated during high ALT levels. It was demonstrated that an increase in circulating and intrahepatic IL-17-producing CD4+ T cells correlated well with ALT level and liver injury. Longitudinal immunologic studies showed a decline of HBcAg-specific regulatory T cell (Treg) frequencies, associated with an increase in HBcAg-specific cyto-toxic T lymphocyte (CTL) frequencies prior to the peak of the hepatitis flare, IL-10-producing regulatory B cell
frequencies and serum IL-10 level peaked with the increase in viral load and decreased at the same time or shortly after the peak of ALT, large fluctuations in serum IFN-a and IL-8 concentrations with peak levels coinciding with a sharp increase in viral load preceding the onset of the hepatitis flare, and the increases in serum IFN-a and IL-8 promoted a pathway for the natural killer (NK)-cell mediated liver damage. It was also shown that hepatitis flares were temporarily associated with high serum levels of INF-y inducible chemokines CXCL-9 and CXCL-10, and that increase, peak and decline in the levels of the programmed cell death protein 1 (PD-1) and its ligand PD-L1 went parallel with the ascend, peak and decline of HBV-specific T cells and serum ALT levels. Integrated together, these findings suggest that hepatitis B flares are the results of dynamic changes of the innate and adaptive immune responses with HLA-I restricted, CTL mediated immune cytoly-sis of HBV antigen(s) expressing hepatocytes and its downstream apoptotic mechanisms. Accordingly, a higher ALT level represents a more vigorous endogenous immune response against HBV. It is still not clear, however, what triggers the initiation of the immune cascade.
Symptoms of hepatitis B infection.
Not everyone has symptoms. If you do, they can range from mild to severe. You may have symptoms (or not) during the acute phase of infection, and you may also have them (or not) with chronic infection. You're still contagious with or without symptoms.
Typical symptoms of infection include:
• Fever
• Loss of appetite.
• Nausea and vomiting.
• Abdominal pain.
• Weakness and fatigue.
• Joint pain.
You may also have symptoms of liver disease, including:
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• Jaundice.
• Dark-colored urine.
• Light or clay-colored poop.
• Swelling with fluid in your belly or arms and
legs.
With acute infection, symptoms of liver disease may indicate a more severe reaction than usual. Although many people clear the HBV virus without treatment, you should see a healthcare provider if you have symptoms of liver disease.
With chronic infection, you may have mild or vague symptoms on an ongoing basis, or you may not have symptoms at all for decades. When symptoms appear later, especially symptoms of liver disease, it may indicate your liver is beginning to fail.
Vaccination
Hepatitis B virus (HBV) is a partly double-stranded DNA virus that cause acute and chronic liver infection. Screening for Hepatitis B is recommended in pregnant women at their first prenatal visit and in adolescents and adults at high risk of chronic infection. Hepatitis B vaccination is recommended for medically stable infants weighing 2,000g or more within 24 hours of birth, unvaccinated infants and children, and unvac-cinated adults requesting protection from Hepatitis B or who are at increased risk of infection.
HBV infection is preventable through vaccination—a major focus toward reaching 2030 goals. Hepli-sav-B was approved by the FDA in November 2017 for use in adults 18 years and older. The ACIP included Heplisav-B in its list of recommended adult HBV vaccines in February 2018. The dosing schedule includes fewer intramuscular injections than are required for 3-dose aluminum-adjuvanted HBV vaccines. Use of Heplisav-B led to faster and higher rates of seroprotec-tion than were seen with the use of Engerix-B in pivotal trials. Heplisav-B is playing an important role in helping to reach 2030 public health goals through its demonstrated immunogenicity among both the general public and high-risk special populations. Additionally, Heplisav-B provides a flexible and efficient option in prevention of HBV, as well as cost savings that benefit the health care system and, ultimately, patients.
Therapeutic goals
A treatment for acute HBV infection has to be studied in terms of interest, efficacy and tolerance. In adults, in contrast to acute HCV infection, less than 5% of acute HBV hepatitis infections will progress to chronic carriage. The distinction between acute HBV hepatitis and chronic hepatitis B with an acute flare has recently been reevaluated; of several diagnostic combinations, IgM anti-HBc jointing HBV-DNA is most effective.
Antiviral therapy should be changed as soon as possible in case of confirmed genotypic resistance. Adding a second antiviral agent seems beneficial over switching to another agent. With the availability of multiple new antiviral drugs for the treatment of chronic hepatitis B, effective treatment is now possible for more patients and for longer periods. However, the complexity of HBV therapy has also increased. Nowadays, virtually all chronic HBV-infected patients can be effectively managed, either by inducing sustained off-
treatment response or by maintaining an on-treatment response.
As a key element during HBV replication, a nucle-ocapsid is considered a promising target for the treatment of chronic hepatitis B. The present study aimed to identify small molecules as novel capsid assembly modulators with antiviral activity. Structure-based virtual screening of an integrated compound library led to the identification of several types of HBV inhibitors. Among these inhibitors, N-sulfonylpiperidine-3-car-boxamides (SPCs) potently reduced the amount of secreted HBV DNA. Mechanism studies showed that C-39 dose-dependently inhibited the formation of HBV capsid, synthesis of cccDNA, e antigen (HBeAg), viral pregenomic RNA (pgRNA), and HBV DNA levels, thereby restraining HBV replication. In Abstract, SPCs represent a new class of capsid assembly modulators. Further optimization of SPCs is expected to obtain new antiviral drugs against HBV infection.
WHO response
In May 2016, the World Health Assembly adopted the first Global health sector strategy on viral hepatitis, 2016-2020. The strategy highlighted the critical role of universal health coverage and sets targets that align with those of the Sustainable Development Goals. The strategy proposed the elimination of viral hepatitis as a public health threat by 2030 (defined as a 90% reduction in new chronic infections and a 65% reduction in mortality, compared with the 2015 baseline), and included a roadmap towards elimination by implementing key prevention, diagnosis, treatment and community interventions strategies. In May 2022 the 75th World Health Assembly noted a new set of integrated global health sector strategies on HIV, viral hepatitis and sexually transmitted infections for the period of 2022-2030. Based on these previous and now new strategies, a broad range of Member States have developed comprehensive national hepatitis programmes and elimination strategies guided by the global health sector strategy.
To support countries in achieving the global hepatitis elimination targets under the Sustainable Development Agenda 2030, WHO is working to:
• raise awareness, promote partnerships and mobilize resources
• formulate evidence-based policy and data for action
• increase health equities within the hepatitis response
• prevent transmission
• scale up screening, care and treatment services.
WHO organizes the annual World Hepatitis Day
campaign (as 1 of its 9 flagship annual health campaigns) to increase awareness and understanding of viral hepatitis. For World Hepatitis Day 2022, WHO focuses on the theme "Bringing hepatitis care closer to you" and calls for simplified service delivery of viral hepatitis services, bringing care closer to communities.
Implications and perspectives
Episodic hepatitis B flares with ALT >5 x ULN are not uncommon in patients with chronic HBV infection. ALT/hepatitis flares are the results of HLA-I restricted, CTL-mediated immune responses against HBV. Thus,
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higher ALT reflects more vigorous immune-mediated hepatocytolysis and is associated with stronger clearance of HBV and a higher chance of HBeAg loss and/or HBV DNA seroclearance, both in the setting of the natural course of infection and related to drug therapy. While flares in cirrhotic patients always require immediate antiviral therapy, flares with decreasing serum HBV DNA levels represent effective immune clearance of HBV that is likely to be followed by spontaneous HBeAg/HBV DNA seroconversion or seroclearance; thus, such patients may wait for 3-6 months to see whether drug therapy is needed. In contrast, hepatitis B flares with stable or increasing serum HBV DNA levels reflect ineffective immune clearance of HBV so that the patients are at risk of further hepatocytolysis or recurrent hepatitis B flare(s) and even hepatic decompensation, which requires timely treatment. In addition to the immediate risk of hepatic decompensation, more than one severe hepatitis flare is a factor for future development of liver cirrhosis. Therefore, patients with ALT levels of 2-5 x ULN who have a low chance of spontaneous HBV clearance should be considered for anti-HBV therapy to stop further liver injuries and to prevent hepatitis B flares and their adverse sequelae. These management decisions are summarised in a decision tree. Proper monitoring is required in patients who stopped antiviral therapy. In the setting of anti-HBV therapy, hepatitis B flares before, during and even after therapy are beneficial in terms of better response to therapy. Along this line, inducing a hepatitis flare by
priming with a short course of corticosteroid or Nuc therapy before planned anti-HBV therapy was reported in small studies. However, the benefit should be weighed against the risk of an adverse hepatitis B flare. Screening, monitoring and prophylaxis or pre-emptive anti-HBV therapy is mandatory in hepatitis B patients who are going to receive immunosuppression or cancer chemotherapy. In addition, HCC surveillance is also mandatory in all hepatitis B patients at risk.
List of references:
1.Hepatitis B: Screening, Prevention, Diagnosis, and Treatment
Thad Wilkins et al. Am Fam Physician. 2019.
2.Evolving considerations for choice of hepatitis B vaccine Dalga D Surofchy et al. Am J Manag Care. 2023 Feb.
3.Hepatitis B virus: From diagnosis to treatment. P Dény et al. Pathol Biol (Paris). 2010 Aug.
4.Treatment of chronic hepatitis B virus infection - Dutch national guidelines E H C J Buster et al. Neth J Med. 2008 Jul-Aug.
5. Structure-Based Discovery of N-Sulfonylpiper-idine-3-Carboxamides as Novel Capsid Assembly Modulators for Potent Inhibition of HBV Replication Yang Yang et al. Viruses. 2022
6. Hepatitis B Virus Infection: From Diagnostics to Treatments Thomas Tu et al. Viruses. 2020.
7. Hepatitis B flares in chronic hepatitis B: Patho-genesis, natural course, and management. Ming-Ling Chang Yun-Fan Liaw., August, 2014.
