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UDC: 616.036-092-002-08
Melenko Svitlana Romanivna,
PhD, Associate Professor of the Department of Infectious Diseases and Epidemiology
Bukovinian State Medical University Omelchuk Oksana Olehivna student
Bukovinian State Medical University DOI: 10.24412/2520-6990-2023-8167-38-40 DEVELOPMENT AND PROGRESSION OF HEPATITIS C, MAIN WAYS OF TRANSMISSION, EFFECTIVENESS OF ANTIVIRAL THERAPY
Abstract.
Hepatitis C virus is an important public health problem worldwide. Reducing HCV-related morbidity and mortality is associated with several viral and host factors. Viral evolution plays a role in HCV transmission, disease progression and treatment outcomes. HCV evolution is shaped by various mechanisms: mutation, genetic drift, recombination, temporal variation, and compartmentalization. These processes contribute to a stepwise change in the composition of the HCV population in the host. HCV entry promotes tissue tropism and species specificity. This is crucial not only for understanding the pathogenesis of HCV infection, but also for the development of effective antiviral drugs and vaccines. HCV-host interactions during HCV binding and entry, understanding the molecular mechanisms that influence HCV entry into target cells, and the importance of HCV entry for the pathogenesis of hepatitis C virus-induced liver disease. The progress in controlling HCV replication has led to the development of many direct-acting antiviral drugs. This made it possible to achieve excellent sustained viral responses.
Keywords: hepatitis C virus, epidemiology of hepatitis C virus, diagnosis of hepatitis C virus, hepatitis C virus vaccine, interferons, direct-acting antiviral drugs.
Hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide. The widespread endemicity of HCV infection is the result of a combination of factors, including those related to the genetic diversity of the virus and the host response, as well as those related to specific conditions and behaviors that facilitate transmission. The majority of people who contract HCV infection become persistently infected, a mechanism related to the lack of development of an effective neutralizing immune response. The extent of HCV infection is primarily related to specific risk factors for transmission. The most common mechanism of transmission is injecting drug use. Factors that influence disease outcome, including age, gender and alcohol use, are poorly understood, and other factors, such as immu-nologic and genetic factors, may play an important role. [3]
HCV is a single-stranded, positive-sense RNA virus belonging to the genus Hepacivirus in the family Flaviviridae. HCV is a blood-borne virus that enters the liver through the bloodstream. The liver is the target organ of HCV, and hepatocytes are its main target cell. Hepatitis C is the main cause of cirrhosis and hepato-
cellular carcinoma, and end-stage liver disease associated with HCV is the first cause of liver transplantation in many countries. The long incubation period makes it difficult to link related cases to a common source of infection. In addition, acute HCV infections are usually asymptomatic, making it difficult to identify cases. The lack of laboratory methods and appropriate molecular surveillance systems to distinguish acute from chronic infections further complicates case identification. Recognizing HCV transmission is crucial for implementing measures to prevent the spread of the virus. Transmission of rapidly evolving viruses such as HCV is difficult to trace because strains from epidemiological^ related cases are genetically related but rarely identical. The evolution of HCV is also influenced by other events, such as coinfection with other viruses or pregnancy. This may be due to an implicit change in the mother's immune response. During pregnancy, viral levels typically increase and CD8+ T cell cytotoxicity decreases along with the loss of HLA mutants, resulting in the emergence of susceptibility strains and subsequent reversion between pregnancies. Impaired maternal cellular immunity and the emergence of more suit-
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able viruses may contribute to perinatal HCV transmission. Viral attachment to the cell surface followed by viral entry is the first step in a cascade of interactions between the virus and the target cell, which is necessary for successful cell entry and initiation of infection. [4] HCV infection is characterized by a tendency to chronicity. Due to its high genetic variability, HCV has the ability to evade the host's immune response. Hepatitis C virus (HCV) exists in various forms in the bloodstream of infected people: lipoprotein-bound and lipo-protein-free, enveloped and non-enveloped. Viral particles with the highest infectivity are associated with lipoproteins, while lipoprotein-free virions are low-infectious. The pathogenesis of HCV is a very complex phenomenon and requires further study to identify other factors. but also to solve the problem of the window period, as well as to distinguish current infection from past infection. HCV is a non-cytopathic virus, so its pathogenesis is regulated by the host's immunity and metabolic changes, including oxidative stress, insulin resistance, and liver steatosis. Both innate and adaptive immunity play an important role in HCV pathogenesis. The innate immune system is the first line of defense to control HCV infection, as it is for several other viral infections. Once inside the cell, innate immunity against HCV is triggered by the host's recognition of viral macromolecular motifs known as pathogen-associated molecular patterns (PAMPs) by cellular pathogen recognition receptors. These receptors include tolllike receptors (TLRs) and retinoic acid-inducible gene-I (RIG-I) receptors. HCV can effectively evade innate immunity, leading to persistent viral infection. This is because HCV has evolved to counteract the RIG-1 pathway and thus avoid immune challenge. NK cells, a major part of the innate immune system, play an important role in the elimination of HCV. The liver is enriched with NK cells, which are usually activated at an early stage of HCV infection. Activated NK cells recruit virus-specific T cells and induce antiviral immunity in the liver. They also eliminate virus-infected hepatocytes directly through cytolytic mechanisms and indirectly through the secretion of cytokines. After virus entry and replication within liver cells, viral molecules are transported to the endoplasmic reticulum and bind to major histocompatibility complex molecules, which are finally transported to the cell surface. These molecules on the cell surface are recognized by T cells for their immune effect. Another pathway of the disease mechanism is the destruction of HCV-infected hepato-cytes, the release of HCV fragments that are taken up by myeloid dendritic cells. These dendritic cells migrate to the draining lymph nodes and express HCV antigens on HLA class II molecules. Cytotoxic lymphocytes demonstrate crucial activity during viral eradication or viral persistence and are influenced by viral proteins, HCV quasispecies, and several metabolic factors that regulate liver metabolism. [2]
HCV infection affects the overall metabolism, which leads to increased steatosis, fibrosis, inflammation, apoptosis, and insulin resistance during the course of the disease. This, in turn, increases the activity of li-pogenic enzymes, including acetyl-CoA carboxylase and FA synthase. At the same time, the intermediates
of triglyceride biosynthesis also activate insulin signaling inhibitors. Oxidative stress has been reported to be an important part of HCV-induced liver damage.The HCV-core protein, present in the outer mitochondrial membrane, induces glutathione oxidation and promotes Ca 2+ uptake by mitochondria. The molecular mechanism characterizes the oxidation of glutathione, which results in an increase in the production of reactive oxygen species by the mitochondrial electron transport complex I and III. Increased production of reactive oxygen species results in oxidative stress. Several studies have shown a decrease in glutathione levels during HCV infection. [1]
A number of immunoassays have been developed for the diagnosis of hepatitis C by detecting anti-HCV IgG in serum or plasma samples. The RIBA assay is used to detect anti-HCV IgG in serum or plasma samples that are reactive in anti-HCV screening tests. The detection of anti-HCV by RIBA is based on the immobilization of recombinant HCV antigens and synthetic peptides from bovine proteins as separate bands on a membrane. Reactivity with >2 proteins indicates a positive result. The test result is considered indeterminate if only 1 protein is detected. Indeterminate results may be due to nonspecific cross-reactivity or may indicate a recent infection that has not yet elicited a broad humoral response. In HCV-infected individuals, the test results become completely positive in 1-6 months. The advantages of the RIBAs are that they are serologic tests and can be performed on the same specimen used in the screening test, and that they are highly specific. However, these assays are not routinely used because of their relative reduced sensitivity, high cost, practical difficulty and length of procedure. In addition, a true positive RIBA result only indicates the presence of anti-HCV and may reflect a past infection with spontaneous clearance. Confirmation of active infection still requires HCV RNA testing. HCV RNA is detectable in serum or plasma as early as 1 week after exposure and therefore remains the most reliable marker and gold standard for diagnosing active HCV infection. NATs, which are now routinely used to detect HCV RNA, are based on polymerase chain reaction, branching DNA signal amplification, and transcription-mediated amplification. Among the new technologies currently being evaluated for their diagnostic potential in HCV infections is the use of aptamers as capture molecules. [5]
The treatment of hepatitis C is primarily determined by its etiology, the activity of the pathological process and concomitant diseases. The treatment regimen for viral hepatitis is an important factor in maintaining a state of compensation for liver function. It involves: exclusion of alcohol, exclusion of contact with hepatotoxic substances, limitation of physical and psycho-emotional stress, exclusion of hepatotropic drugs that damage the liver (tranquilizers, sedatives, analge-sics).A significant outcome of HCV treatment is a sustained virologic response, which is determined within six months after treatment completion. Until recently, the only treatment option for HCV was a combination of pegylated interferon-a and ribavirin. The efficacy of this regimen varies from 20% to 80%, depending on
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race, stage of disease, genotype of infection, and distinct single nucleotide polymorphisms located in the promoter gene. Chemically, HCV protease inhibitors can be divided into three main categories: 1. Linear peptidomimetics with an alpha-ketoamide group that binds the active site, covalently blocking enzymatic ac-tivity.2. Linear non-covalent peptidomimetic inhibitors. 3. Macrocyclic non-covalent peptidomimetic inhibitors. Telaprevir and boceprevir, both of which belong to the first class of protease inhibitors, were approved for the treatment of patients chronically infected with HCV genotype 1. Telaprevir and boceprevir have a limited spectrum of action on HCV genotypes. While telaprevir has some clinical effect against genotype 2 and boceprevir appears to be effective against genotype 3, their use is off-label for these genotypes. Drug resistance to protease inhibitors demonstrates a low genetic barrier (i.e., the number of nucleotide changes required to generate RAV), which is a particular problem in HCV subgenotype 1a infection, as the genetic barrier is lower than in subgenotype 1b. The second and third classes of NS3 protease inhibitors, which do not form covalent bonds with their targets, have several advantages over the first class of compounds. These NS3 protease inhibitors include linear non-covalent molecules such as faldaprevir, asuna-previr, and saunaprevir, and macrocyclic inhibitors such as simeprevir and danoprevir. [6]
Another strategy to inhibit viral replication is to develop polymerase inhibitors that prevent viral replication by binding to NS5B RdRp. NS5B inhibitors can be divided into two different categories: nucleoside inhibitors and non-nucleoside inhibitors. Nucleoside analog inhibitors mimic the natural substrates of the pol-ymerase, causing direct chain termination. The active site of NS5B is well conserved in all HCV genotypes, as amino acid substitutions at this site are usually poorly tolerated and lead to significant disability. Among the nucleoside analogs, mericitabine has been shown to be effective. In general, nucleoside polymer-ase inhibitors generally show good activity against a wide range of genotypes and have a high genetic barrier to resistance, making them a promising class of HCV drugs. Non-nucleoside inhibitors are chemically and functionally much more diverse than nucleoside inhibitors. Non-nucleoside inhibitors typically bind to several distinct sites on the HCV polymerase, leading to
conformational changes in the protein, to form an elon-gase complex.
Developing an effective vaccine remains the most challenging and urgent task. Because of the high protein variability of HCV, protective vaccines can be extremely difficult to produce, and therapeutic vaccines seem more realistic. Significant progress has been made in the field of HCV since its discovery, but significant efforts are needed to control HCV-related liver disease. [6]
Conclusion: Thus, the importance of HCV entry is explained by its role in initiating infection, being the main target of the immune response, and determining tissue and species tropism. Significant progress has been made in the study of HCV entry. Advances in diagnostics and therapeutics have been made to optimally treat HCV infection. But the disease still remains a serious problem for most developing countries. Therefore, there is a need to strengthen and develop a plan to combat hepatitis in low-, middle- and even high-income countries. In addition, support from civil society, pharmaceutical and medical companies is needed to fight this deadly disease.
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2. European Association for the Study of the Liver; Clinical Practice Guidelines Panel: Chair:; EASL Governing Board representative:; Panel members: EASL recommendations on treatment of hepatitis C: Final update of the series, J Hepatol. 2020.
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