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MEDICAL SCIENCES / <«g©LL©(MUM~J©U®MaL» #8(167), 2023
UDC: 616.36-002-02-092-07-08
Melenko Svitlana Romanivna,
PhD, Associate Professor of the Department of Infectious Diseases and Epidemiology
Bukovinian State Medical University Todoriko Valentyna Pavlivna,
student
Bukovinian State Medical University Sliusarchuk Anatolii Vasyliovych
student
Bukovinian State Medical University DOI: 10.24412/2520-6990-2023-8167-44-46 HEPATITIS C VIRUS: CHRONOLOGY OF TREATMENT DEVELOPMENT
Abstract.
Chronic hepatitis C virus (HCV) infection is one of the leading causes of liver disease worldwide, affecting approximately 71 million people.
Hepatitis C virus is a small, enveloped, single-stranded RNA virus. It is a member of the genus hepacivirus of the family Flaviviridae [2]. There are seven main HCV genotypes. The introduction of direct-acting antiviral drugs (DAAs) has changed the treatment of HCV infection, allowing for a significant increase in treatment effectiveness.
Despite the availability and approval of highly effective and well-tolerated oral medicines, many challenges remain, including affordability, equitable distribution and access to medicines. The World Health Organisation aims to eliminate hepatitis C virus by 2030, as it poses a serious threat to public health. There is an urgent need to ensure uniform and early access to diagnostic and therapeutic tools worldwide.
Keywords: hepatitis C virus, interferon treatment, antiviral drugs, direct-acting antivirals, HCV therapy.
Hepatitis C virus is a single-stranded RNA fla-vivirus with seven known subtypes, designated according to different genotypes, 1a, 1b, 2, 3, 4 and 6. These genotypes have different prevalence in different countries. Because of its propensity for chronic necroinflam-mation, HCV remains a major cause of chronic hepato-pathies, including cirrhosis and hepatocellular carcinoma. In addition, workers infected with HCV have lost significantly more working days, including sick leave, short-term and long-term disability [1,2].
The treatment of hepatitis C is unparalleled among viral therapeutics and is therefore considered a medical revolution, especially with the transition to oral treatment, which has shown few or no side effects, high efficacy and a relatively short time to cure [3,7].
Discovery of the hepatitis C virus
The story of the discovery of hepatitis C is unique in that it was identified using unconventional methods, i.e. molecular biology, rather than direct imaging and cell culture. It is appropriate to briefly revisit this history to better understand the progress made in HCV diagnosis and therapy [8].
It all started when a new type of hepatitis was discovered in patients receiving blood transfusions in the early 1970s. Since hepatitis A virus and hepatitis B virus (HBV) were not present in these patients, Alter and his colleagues coined the term "non-A, non-B (NANBH) hepatitis" for this type of hepatitis in 1975. They collected plasma/serum samples from a donor with chronic hepatitis and four people who had developed NANBH hepatitis after a blood transfusion, and injected these samples into five chimpanzees. All five chimpanzees developed hepatitis, as evidenced by elevated serum alanine aminotransferase levels and pathological changes in the liver, confirming the presence of
an as-yet-unknown transmission agent in the blood of patients with NANBH hepatitis [9,10].
At the same time, progression to liver cirrhosis and hepatocellular carcinoma was confirmed in patients with NANBH. Hoofnagle et al. started a pilot study where NANBH was treated with interferon (IFN)-a2b. These were the same regimens that have been shown to be effective in treating patients infected with hepatitis B [11].
The results showed that during IFN therapy, serum aminotransferase levels decreased rapidly. Despite these findings, it took more than a decade of intensive laboratory research to finally identify the causative agent. In 1989, Houghton cloned and sequenced the genome of the NANBH virus and named it HCV. This discovery made it possible to use sensitive tests to detect HCV and eliminate the virus from transfused blood [12].
Development of antiviral drugs
The development of successful antiviral chemo-therapeutic agents has lagged behind antibiotics and has mainly developed over the past 50 years. The reason for this delay in development is due to many obstacles, such as delays in the availability of culture systems, experimental animal models and a standard method for formulating antiviral drugs [6]. In addition, the challenges faced in developing targeted therapies for a specific viral agent included drug toxicity, genetic variability of the virus and resistance profile, all of which prolonged the development process [13].
After the first attempts to treat patients with HCV with IFN-a2b, 2 randomised controlled trials were launched. One trial used 2 million units of IFN-a2b versus placebo 3 times a week, and the other trial used 3 or 1 million units versus placebo 3 times a week. In both studies, the treatment course lasted 6 months. The
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results showed that IFN-a2b was effective in reducing disease activity; however, many patients relapsed after stopping treatment [10]. To evaluate the effect of IFN-a2b therapy, HCV RNA levels were detected in another study, which confirmed that HCV RNA was successfully reduced or eliminated in some patients after IFN-a2b therapy. Following these studies, IFN-a2b was officially approved for the treatment of chronic hepatitis C; however, frequent side effects, high relapse rates, and a median sustained viral response (SVR) suggested that another drug was needed [10, 11, 13].
Specific antiviral agents against HCV had a similar delay in development. The discovery of hepatitis C began in 1975 with the identification of a new blood transfusion-related hepatitis virus, NANBH, before the isolation of a single cDNA clone called HCV in 1989. The successful pilot study of NANBH conducted by Hoofnagle in 1986 was the basis for two randomised trials [7]. Both trials demonstrated the effectiveness of interferon (IFN) alpha-b during treatment in the eradication of HCV. Thus, in 1991, the US FDA approved IFN-alpha for the treatment of chronic HCV infection. Later, ribavirin (RBV), an oral nucleoside analogue, was used as monotherapy for HCV infection. Due to the transient antiviral effect of RBV, the focus of clinical trials shifted to combination therapy [5].
Following large-scale multicentre randomised trials, the combination of INF-a and ribavirin was approved as the standard of care for chronic hepatitis C in 1999. INF-a2b and ribavirin were administered 3 times a week, and for many patients this regimen was difficult and associated with rapid drug elimination. Pegylated INF-a2b (PegINF-a2b) was developed to maintain stable levels of active drug and reduce the frequency of administration [2]. Subsequent studies have shown that PegINF-a2b is superior to non-pegylated IFN, and the new combination of PegINF-a2b and ribavirin became the standard choice for hepatitis C treatment for the next 10 years. Over these years, treatment response and duration were determined by measuring HCV RNA levels at baseline, weeks 4, 12 and 24, at the end of treatment, and 24 weeks post-treatment. Genome-wide association studies have also led to the identification of a single nucleotide polymorphism located in interleu-kin-28B (rs12979860) that is strongly associated with positive response to INF-a treatment and spontaneous HCV clearance. However, a better understanding of HCV structure, enzymes, and life cycle has led to the introduction of new targeted drugs and the discovery of DAAs [2,9].
DAAS.
Later, with the development of HCV molecular virology and the disclosure of the HCV life cycle, the three-dimensional structure of HCV and its enzymes led to the development of the first generation of NS3-4A protease inhibitors. In 2011, the first DAAs (telaprevir and boceprevir), used in combination with PegINF-a and ribavirin, were officially approved for the treatment of HCV GT1. Although the results of clinical trials were promising, adverse events and serious complications showed that there was room for im-
provement [11]. After several years of intensive research, safer and more effective DAAs were developed [3].
In 2013, simeprevir was approved in combination with PegINF-a and ribavirin for HCV GT1 and showed fewer side effects with the same SVR rates. In the same year, sofosbuvir, an NS5B polymerase inhibitor, was developed and shown to be effective against all hepatitis C. It was approved as part of the treatment of hepatitis C, GT1 and GT4 with PegINF-a and for GT2 and GT3 with ribavirin [4]. After 3 clinical trials showed that DAAs could be used alone to treat GT1 HCV with 94-99% SVR rates and significantly fewer side effects, the FDA approved the first fully DAA regimen with sofosbuvir/ledipasvir and sofosbuvir/simeprevir in 2014. The discovery of SOF was not only a breakthrough in the development of all-oral DAAs, but also a beacon of light for the control of HCV infection in patients with cirrhosis [4].
Today, there are many available DAAs for the treatment of HCV approved by EMEA and FDA, which are classified according to their chemical structure: NS3 protease inhibitors (glecaprevir, grazoprevir, paritaprevir, simeprevir, voxilaprevir), NS5A serine protease inhibitors (daclatasvir, elbasvir, ledipasvir ombitasvir, prebrentasvir, velpatasvir), inhibitors of NS5B RNA-dependent RNA nucleoside polymerase (sofosbuvir) and non-nucleoside polymerase (da-sabuvir) [13]. These drugs have different mechanisms of action against different HCV GTs, and their combinations create a higher barrier to resistance. Due to their virological efficacy, ease of use, safety and tolerability, DAA-based regimens are used in HCV patients without cirrhosis and with compensated cirrhosis, patients who have not previously received treatment, and patients who have previously received INF and ribavirin treatment [7].
Success in treating hepatitis C has created a rare opportunity for localised disease elimination or even global eradication. To achieve this, more effective, well-tolerated and affordable therapies are still needed in the future [9].
Conclusion.
This literature review of optimal therapy for hepatitis C virus has reviewed many reports of significant success. However, the disease still remains a major challenge for all stakeholders, especially in developing countries. Many obstacles still need to be overcome before the disease is eliminated, as envisaged by the WHO's goal of eradicating hepatitis by 2030. A concerted and focused global effort is needed to effectively combat and eliminate this silent killer.
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2. Jefferies M, Rauff B, Rashid H, Lam T, Rafiq S. Update on global epidemiology of viral hepatitis and preventive strategies. World J Clin Cases. 2018;6:589-599.
3. World Health Organization. Global Health Sector Strategy on Viral Hepatitis 2016-2021. [cited 31
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4. Blumberg BS, Alter HJ, Visnich S. A "new" antigen in Leukemia Sera. JAMA. 1965 Feb;191(7):541-6.
5. Warkad SD, Song KS, Pal D, Nimse SB. Developments in the HCV Screening Technologies Based on the Detection of Antigens and Antibodies. Sensors (Basel) 2019.
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9. Petruzziello A, Marigliano S, Loquercio G, Cozzolino A, Cacciapuoti C. Global epidemiology of
hepatitis C virus infection: An up-date of the distribution and circulation of hepatitis C virus genotypes. World J Gastroenterol. 2016;22:7824-7840.
10. Prince AM. An antigen detected in the blood during the incubation period of serum hepatitis. Proc Natl Acad Sci USA. 1968 Jul;60(3):814-21.
11. El Kassas M, Elbaz T, Elsharkawy A, Omar H, Esmat G. HCV in Egypt, prevention, treatment and key barriers to elimination. Expert Rev Anti Infect Ther. 2018;16:345-350.
12. Petruzziello A, Loquercio G, Sabatino R, Balaban DV, Ullah Khan N, Piccirillo M, Rodrigo L, di Capua L, Guzzo A, Labonia F, Botti G. Prevalence of Hepatitis C virus genotypes in nine selected European countries: A systematic review. J Clin Lab Anal. 2019;33:e22876.;
13. Gocke DJ. A prospective study of posttransfusion hepatitis. The role of Australia Antigen. JAMA. 1972 Feb;219(9):1165-70.
Melenko Svitlana Romanivna,
PhD, Associate Professor of the Department of Infectious Diseases and Epidemiology
Bukovinian State Medical University Cherniievych Bohdan Oleksandrovych,
student
Bukovinian State Medical University
Nykoliuk Mariia Volodymirivna
student
Bukovinian State Medical University DOI: 10.24412/2520-6990-2023-8167-46-48 HEPATITIS A VACCINATION IN THE WORLD.
Abstract.
Hepatitis A is one of the most important healthcare issues. The first licensed vaccine against hepatitis A (HepA) was in 1992. Both live attenuatedHepA (HepA-L) and inactivatedHepA (HepA-I) are highly immunogenic and well tolerated, and immune protection post-vaccination can last for more than 18 years. HepA is effective for both postexposure and preexposure prophylaxis, especially among young adults and children. During the last 25 years, many countries have witnessed a significant reduction in the incidence of hepatitis A. However, outbreaks of hepatitis A continue to occur frequently among high-risk populations and individuals who have not been included in universal child vaccination programs in recent years. To better understand the changes in the epidemiology of hepatitis A, it is recommended to conduct disease surveillance and serosurveys. Additionally, further research should be carried out to examine the long-term effectiveness of a single dose of HepA in providing immune protection, and to evaluate the cost-effectiveness of different strategies for HepA vaccination. Taking into account this evidence, the recommendation for HepA vaccination should be scientifically based and updated in a timely and well-implemented manner.
Keywords: Immune protection post-vaccination , vaccine against hepatitis A, vaccination strategy, Hepatitis
A.
Introduction: Hepatitis A is a viral infection that spreads primarily through the fecal-oral route. The first reported case of hepatitis A in the United States was in 1973. In 1988, the world's largest outbreak of hepatitis A occurred in Shanghai, China, with over 310,000 cases and 8,000 hospitalizations. Since the first introduction of the hepatitis A vaccine (HepA) in 1992, its effectiveness in controlling the spread of the disease has been demonstrated in numerous countries. However, despite these efforts, over 7,000 people worldwide died from hepatitis A in 2016. In 2016, the World Health Organization (WHO) set a goal of eliminating
viral hepatitis by 2030, and continued efforts are necessary to achieve this objective. This review provides an overview of the global use of HepA vaccination, with the aim of identifying strategies to achieve this goal as scheduled.
Development of HepA : During the 20th century, the development of HepA was made possible due to the success of HAV cultivation in cell lines that are suitable for vaccine production. Nowadays, both inactivated HepA (HepA-I) and attenuated live HepA (HepA-L)
