Pathophysiology and Evidence-Based Analysis=- Hepatitis C

Pathophysiology and Evidence-Based Analysis- Hepatitis C

Pathophysiology and Evidence-Based Analysis: Hepatitis C

This practice guideline summarizes and evaluates the available evidence on the pathophysiology and analysis of Hepatitis C. It develops evidence-based knowledge to improve current practices in managing Hepatitis C and related health complications. This guideline utilizes the American Association for the Study of Liver Diseases (AASLD) guidance on developing practice guidelines. It applies AASLD’s GRADE (Grading of Recommendations Assessment, Development, and Evaluation system) approach to acquire and utilize the evidence to develop practice recommendations. It refers to current evidence to present the pathophysiological mechanisms of Hepatitis C and its clinical manifestations. It presents the therapeutic considerations in managing Hepatitis C and related complications and summarizes the key messages outlined in this practice guideline.

Hepatitis C is a liver disease resulting from an infection with the hepatitis C virus (HCV). Hepatitis C virus (HCV) infection is a blood-borne and transfusion-transmitted infection (TTI), meaning that most HCV human-human transmissions occur as a result of direct percutaneous exposure to infected blood. Percutaneous exposures may occur due to blood transfusions, illegal drug injections, hospital- and healthcare-related injections, organ transplants, and accidental exposure to contaminated blood via piercing objects. Other populations with a high risk of exposure to HCV are people living with HIV, men who have sex with men (MSM), people who use drugs (PWUD), and those born between 1945 and 1965. The virus is related to hepatitis G, dengue, and yellow fever viruses (Geitona et al., 2017).

HCV infections lead to acute, chronic inflammation and lifelong infections. Despite the therapeutical advancements made so far, HCV infections remain a major healthcare problem of global concern (Kumar et al., 2018). According to Kapadia and Marks (2018), quality HCV treatment and management within the primary care settings can be achieved by having an accurate diagnosis of the disease, evaluating and identifying comorbidities before treatment to stratify risks associated with the disease, developing genotype-targeted HCV treatment regimens, on-treatment, and post-treatment monitoring, and quality care for existing comorbidities such as cirrhosis and for PWUD.

The diagnostic landscape for HCV screening, testing, and treatment is substantially evolving. New screening methods and treatment regimens with high efficacy and effectiveness have been developed and introduced to manage HCV. As HCV remains a public health issue of concern, the first step toward improving the management of HCV and reducing and preventing future infections is developing optimal knowledge of the pathophysiology and analysis of HCV. This step is based on reviewing available research evidence and developing evidence-based recommendations to guide future practice.

Significance of this Guideline

HCV Epidemiology and Diagnosis Rate

An estimated 71.1 million people, accounting for 1% of the global population in 2015, were chronically infected with HCV (Hannula et al., 2021). The World Health Organization (WHO) estimates that 58 million people have chronic HCV infection, while over 1.5 million new HCV incidents occur yearly (World Health Organization, 2022). The WHO further estimates that over 290,000 people died in 2019 due to HCV infection-related complications, majorly cirrhosis and hepatocellular carcinoma (World Health Organization, 2022). The Centers for Disease Control and Prevention (CDC) noted that HCV infections have risen in the United States from 2013 to 2019, with varying infection rates among men and women and based on age (Centers for Disease Control and Prevention, 2021). The CDC reported 137,713 newly diagnosed cases with chronic HCV in the U.S alone.

This guideline will improve the number of people diagnosed with HCV infection to aid with the prevention of HCV spread and elimination as per the WHO’s objectives of eliminating HCV by 2030. The WHO issued ambitious guidelines to eliminate HCV by 2939, reduce liver-related deaths by 65%, and reduce new HCV incidents by 90% by improving the number of diagnosed infections by over 90% by 2030 (World Health Organization, 2021). The U.S. Preventive Services Task Force (USPSTF) has also issued recommendations requiring screening all U.S. adults aged between 18 to 79 years without symptoms or preexisting liver issues (United States Preventive Services Taskforce, 2020). The USPSTF, in its directive, sought to improve the identification of HCV infections in asymptomatic cases.

Improved HCV Virological Testing

Continuous hepatology-focused research has improved the knowledge of HCV and impacted the diagnosis of HCV infections. New HCV viral screening methods, such as the use of serum or plasma taken from venous punctures, including point-of-care (POC) tests and dried blood spot (DBS) such as HCV Serologic Testing (HCV Ab) tests, have been developed. Further, research has improved the genotype mapping for HCV, improving knowledge of the virus genotypes and subtypes and the related infections. HCV infections are genotype-specific, and generalized tests do not capture the HCV genotype and subtype. Therefore, newer tests focused on HCV tests, such as HCV Serologic Testing (HCV Ab), HCV Genotype Testing, and HCV Resistance Testing (RAV testing) for drug resistance to HCV infections due to mutations, have been developed. These improved screening methods offer alternatives to classical HCV virological tests. The accuracy of HCV testing, as in all other diseases, determines the effectiveness and efficacy of the care plan adopted. The development of advanced screening methods for HCV prompts updated practice guidelines for HCV screening, diagnosis, and management to manage the disease effectively and achieve the desired WHO 2030 outcomes.

Contents of the Hepatitis C Pathophysiology and Evidence-Based Analysis Guideline

This practice guidance will highlight the pathophysiological mechanisms of HCV to help improve the diagnostic accuracy of existing methods. It will support the efforts to improve the diagnosis rate and reduce HCV incidents and deaths. The guideline develops the following recommendations:

Implementing programs to improve knowledge of the Hepatitis C virus among healthcare workers and promote research focused on developing the efficiency of testing and therapies options for HCV

Testing of individuals aged above 18 years, regardless of their risk of exposure or activities that increase the risk of exposure

Implementation of policies that support and guide routine HCV screening for people at a heightened risk of HCV exposure, such as MSM, PWUD, and people living with HIV

Implementation of comprehensive community-wide initiatives to promote awareness among the population on HCV, HCV infections, and the need to get tested

Pathophysiological Mechanism of Hepatitis C

A better understanding of the pathophysiological mechanisms of hepatitis C can best be developed by creating knowledge of the HCV viral structure, genotypes, and the taxonomy of HCV.

HCV Viral Structure

Viruses lack an organized cellular structure. The HCV consists of an acid core, a genome of RNA (Ribonucleic acid), or DNA within a protein coat. HCV virions have a spherical lipid membrane envelope enclosing two glycoproteins: the HCV E1 and E2 glycoproteins. The HVC E1 and E2 glycoproteins form the outer layer of the HCV virion. The HCV E2 contains HVR1 and 2 hypervariable regions and structures that bindings sites for CD81. Within this envelope is the HCV nucleocapsid that holds the HCV RNA. Like other RNA viruses, the HCV genomes have a multifunctional role as they control the translation, replication, and encapsidation during conduct with the host cell (Romero-López & Berzal-Herranz, 2020).

HCV structure: (Labpedia.net, n.d.)

Genotypes and Taxonomy of HCV

The HCV is a member of the Hepacivirus genus of the Flaviviridae family. HCV virus has expressed extreme viral genotypic diversity based on various virological tests indicating eight genotypes and 90 subtypes (Shah et al., 2021). This genomic diversity is linked to HCV’s high replication rate and errors in the HCV RNA polymerase. With continued error-prone RNA polymerase, it is expected that newer and quasi-HCV subtypes will be identified as research develops. The diversification of HCV genotypes contributes to the diversity of HCV in individual patients and the chronicity of the infection. The genotypic differences also account for the varied efficacy and effectiveness of medication regimens across patients.

HCV Pathogenesis and Hepatitis C Pathophysiological Mechanisms

Hepatitis C is a disease that results from an HCV infection. Most HCV infections, amounting to 60% of all diagnosed cases, result in chronic hepatitis C. Subsequently, HVC is a hepatotropic virus that leads to liver inflammation and various related complications, or even death. The HCV genome is a positive, single-stranded RNA molecule with numerous conserved structural elements that play numerous roles in the HCV lifecycle (Romero-López & Berzal-Herranz, 2020). The HCV, being an RNA virus, cannot integrate itself into the host genome and, therefore, utilizes an interaction mechanism with host cell proteins that induce specific cell responses (Mahmmudi & Gorzin, 2018). The interaction mechanism involves dynamic interactions for both viral and cell components. The HCV, being a non-cytopathic virus, follows a complex long-range RNA-RNA interaction during the infection process, including immune-mediated cytolysis of the host cell. Therefore, the primary target cells for HCV upon entry into the body are the hepatocytes and B lymphocytes. As the virus exploits bacterial components within the cell environment, the resulting viral infections increase bacterial pathogenesis and initiation of the innate immune system response, which may further aid in the lifecycle of HCV.

The E2 proteins on the HCV envelope bind to the viral receptor complex sites of the host cell, majorly the CD81 molecule. The CD81 molecule is present in all nucleated cells, which binds with the HCV particles and plays a central role in the entry process of HCV into the liver cells (Rodríguez-Salazar & Recalde-Reyes, 2021). The HCV infection process after cell surface receptor bindings proceed to cytoplasmic unpacking of the HCV RNA genome. The HCV, like all other RNA viruses, infects the host cells by stimulating the rearrangement of intracellular membranes of the host cell to actively replicate the HCV RNA. The RNA-RNA interactions between the HCV RNA and the host cell’s RNA initiate the HCV replication process through endoplasmic reticulum (ER) site-mediated translation of HCV RNA and replication (Romero-López & Berzal-Herranz, 2020). The next stages in the HCV pathogenesis include the repacking and maturation of the HCV and release, leading to acute HCV infection. The release of the fully repackaged and developed HCV results in the infection of more cells and the recurrence of the HCV life cycle, weakening the host’s immunity and resulting in acute Hepatitis C.

T cells are crucial in developing and suppressing HCV infection during the acute stages. Cytotoxic T lymphocytes (CTL), such as CD4+ and CD8+ T cells, control and suppress HCV infections by eliminating the infected by releasing cytotoxic granules that kill the infected cells or inhibit HCV RNA replication (Rios et al., 2021). The inhibition of the development of HCV infection can be achieved through innate immunity and adaptive. However, several factors may influence the efficient functioning of the CTL. Besides the immune mediation in the HCV pathogenesis, these factors further influence the development of hepatitis C and further suppress innate and adaptive immunity. They include HCV-induced insulin resistance, oxidative stress, and hepatic steatosis. These conditions occur due to the influence of HCV on metabolism. In addition, another issue of concern is the activation of innate immune antiviral response during acute HCV infection, which can have an inflammatory effect on the liver, contributing to the progression of the disease (Njiomegnie et al., 2020).

Other factors that influence the progression of HCV infection include age, gender, lifestyle, and the presence of other viral infections such as hepatitis B or HIV. Therefore, the persistence of HCV infection and the progression result from weakened CD4+ and CD8+ T-cells, and the double effect of the natural killer immune cells inhibit normal liver function. Persistent infection appears to be due to weak CD4+ and CD8+ T-cell responses during acute infection, which slowly progresses to chronic infections. Two out of every three acute infections progress to chronic HCV (Njiomegnie et al., 2020).

Clinical Manifestations of Hepatitis C

The failure of CTL to control viral replication leads to the development of acute hepatitis C. However, the HCV infection process is slow. The viral incubation period may range between two weeks to six months. During this period, the infection is mostly asymptomatic, accounting for the progression of the infection to chronic hepatitis C. However, acute symptoms may be notable within three months of infection: infected persons experience fevers, continued fatigue, loss of appetite, nausea, and vomiting, changes in urine and stool color with urine becoming dark and stool pale, and increased arthritis-like joint pains and jaundice (World Health Organization, 2022). These acute symptoms occur due to the continued inflammation of the liver as an effect of innate immunity function (Njiomegnie et al., 2020).

The immune response during acute infection activates the natural killer (NK) cell, causing inflammation, which further leads to the activation of the adaptive system, influencing the progression of HCV infection, as discussed earlier. Chronic HCV infection impairs the liver’s functions and innate and adaptative immune systems, leading to hepatic injury and cirrhosis. Chronic manifestations may include increased weight loss and adverse effects, myalgia, and arthralgia.

Health Complications Related to Hepatitis C

Hepatic Complications

The two most serious complications include cirrhosis and liver cancer (hepatocellular carcinoma). According to a study by Roudot-Thoraval (2021), it is estimated that about 10-20% of individuals who are chronically infected with HCV eventually develop complications, such as cirrhosis and hepatocellular carcinoma (HCC) within 20-30 years of HCV infection. Cirrhosis is a serious healthcare issue. The complication results from the scaring of the liver due to the viral infection and immune responses. The scarring may cover the whole liver, causing it to shrink and harden. Prolonged hepatic injuries due to chronic HCV infection may slow the rate of fibrogenesis. However, the rate of fibrosis is influenced by other factors besides the HCV progression, such as genetics, the duration of the HCV infection, comorbid conditions, and lifestyle choices such as continued alcohol use. HCC is related to cases of cirrhosis to the oncogenic effects of HCV infection (Mahmmudi & Gorzin, 2018)

Extrahepatic Complications

Metabolic complications include HCV-associated oxidative stress, HCV-induced steatosis, and HCV-induced insulin resistance. These HCV-metabolic complications are related to extrahepatic complications such as mixed cryoglobulinemia, lymphoma, membranoproliferative glomerulonephritis, and various dermatological diseases. The induction of HCV-related insulin resistance in susceptible populations is related to an increased risk of diabetes mellitus (Wang et al., 2020).

Basis of this Guideline and Gaps in Hepatitis C Pathophysiology and Analysis Evidence

Many people living with HCV today have not been screened and are unaware of their HCV status. This increases the risk of newer infections and a higher community viral load (CVL) of HCV. The lack of screening also leads to chronic HCV infections, which have adverse population health outcomes and complications. The burden of HCV infections increases due to a lack of screening and early identification of cases, leading to an increased HCV health-related economic burden. Early diagnosis and identification of cases have improved the success of recently developed antiviral therapies such as direct-acting antiviral (DAA) tablets. The development of undiagnosed HCV to chronic phases challenges existing therapies and reduces their efficacy and effectiveness. This creates a need to develop better approaches to managing HCV, including improved screening and diagnosis.

The current testing methods detect the HCV antigens in cells. Although this suggests that the patient may have or currently has an HCV infection, it does not indicate the viral load within each cell. Further exploration of the pathophysiology of hepatitis C and the replication process of HCV is required for better diagnosis. A clinical study by (Rios et al., 2021) noted that most studies focused on hepatitis C pathogenesis have used animal models in studies, and therefore, there lack an actual study. The available human-related studies have used peripheral blood samples; however, such samples cannot capture crucial aspects of the diseases within the context of the human body. Therefore, there is a need to explore the human liver microenvironment to better understand HCV infection and pathogenesis and the role of the immune system. This can further improve screening and treatment to reach WHO 2030 goals.

Another study by (Sangiovanni et al., 2020) noted that hepatitis C patients with related cirrhosis showed recurrent HCC after the use of DAA treatment in patients. This study related DAA to the high HCC incidence in patients with undefined or non-malignant nodules. The authors question the efficacy of current screening and treatment methods in diagnosing and treating hepatitis C and related complications. For that reason, there is a need to further explore the pathophysiology of hepatitis C to help further understand the disease and develop improved screening and treatment options.

References

Centers for Disease Control and Prevention. (2021). National Progress Report 2025: Goal Reduce estimated* new hepatitis C virus infections by ≥20%. Centers for Disease Control and Prevention. Retrieved June 9 2022, from https://www.cdc.gov/hepatitis/policy/NPR/2021/NationalProgressReport-HepC-ReduceInfections.htm.

Geitona, M., Kousoulakou, H., Goulis, I., Manolakopoulos, S., Vasiliadis, T., Christodoulou, D., Gogos, C., Dourakis, S., George Koskinas, I., Papadokostopoulou, A., Lathouris, A., & Papatheodoridis, G. (2017). Managing Hepatitis C Patients in Greece: A Budget Impact Analysis of Simeprevir plus Pegylated Interferon/Ribavirin Regimen at Early Stages of the Disease. Health, 09(11). https://doi.org/10.4236/health.2017.911109

Hannula, R., Söderholm, J., Svendsen, T., Skaland, M., Nordbø, S. A., Steinum, H., & Damås, J. K. (2021). Hepatitis C outreach project and cross-sectional epidemiology in high-risk populations in Trondheim, Norway. Therapeutic Advances in Infectious Disease, 8. https://doi.org/10.1177/20499361211053929

Kapadia, S. N., & Marks, K. M. (2018). Hepatitis C Management Simplification From Test to Cure: A Framework for Primary Care Providers. Clinical Therapeutics, 40(8), 1234–1245. https://doi.org/10.1016/J.CLINTHERA.2018.05.010

Kumar, A., Rajput, M. K., Paliwal, D., Yadav, A., Chhabra, R., & Singh, S. (2018). Genotyping & diagnostic methods for hepatitis C virus: A need of low-resource countries. In Indian Journal of Medical Research (Vol. 147, Issue May). https://doi.org/10.4103/ijmr.IJMR_1850_16

Labpedia.net. (n.d.). Hepatitis C Virus, HCV Profile, Diagnosis and Treatment. Retrieved June 13, 2022, from https://labpedia.net/hepatitis-c-virus-hcv-profile-diagnosis-and-treatment/

Mahmmudi, Z., & Gorzin, A. A. (2018). Hepatitis C virus. Annals of Tropical Medicine and Public Health, 1.2 Special Issue, SP37. https://doi.org/10.29309/tpmj/2017.24.11.646

Njiomegnie, G. F., Read, S. A., Fewings, N., George, J., McKay, F., & Ahlenstiel, G. (2020). Immunomodulation of the natural killer cell phenotype and response during HCV infection. In Journal of Clinical Medicine (Vol. 9, Issue 4). MDPI. https://doi.org/10.3390/jcm9041030

Rios, D. A., Casciato, P. C., Caldirola, M. S., Gaillard, M. I., Giadans, C., Ameigeiras, B., de Matteo, E. N., Preciado, M. V., & Valva, P. (2021). Chronic Hepatitis C Pathogenesis: Immune Response in the Liver Microenvironment and Peripheral Compartment. Frontiers in Cellular and Infection Microbiology, 11. https://doi.org/10.3389/fcimb.2021.712105

Rodríguez-Salazar, C. A., & Recalde-Reyes, D. P. (2021). Design of inhibitory peptides of the interaction between the E2 protein of the Hepatitis C Virus and the CD81 and CD209 receptors. Infectio, 25(4). https://doi.org/10.22354/in.v25i4.955

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Shah, R., Ahovegbe, L., Niebel, M., Shepherd, J., & Thomson, E. C. (2021). Non-epidemic HCV genotypes in low- and middle-income countries and the risk of resistance to current direct-acting antiviral regimens. In Journal of Hepatology (Vol. 75, Issue 2). https://doi.org/10.1016/j.jhep.2021.04.045

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World Health Organization. (2022). Hepatitis C. Who. int. Retrieved June 9, 2022, from https://www.who.int/news-room/fact-sheets/detail/hepatitis-c.

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