Hepatitis C virus- An Overview

Hepatitis C virus (HCV) is a member of the Flaviviridae family, which includes other viruses such as yellow fever virus, dengue fever virus, and West Nile virus. HCV is classified in the Hepacivirus genus, which also includes tamarin virus and GB virus B. HCV is the causative agent of hepatitis C, a chronic liver disease that affects more than 170 million people worldwide.

HCV is an enveloped virus, meaning that it has a lipid membrane derived from the host cell that surrounds its nucleocapsid, which is the protein shell that protects its RNA genome. The lipid membrane contains two envelope glycoproteins, E1 and E2, that are responsible for binding to host cell receptors, mediating membrane fusion, and facilitating viral entry . The envelope glycoproteins form heterodimers (E1/E2) that can further assemble into trimers and pentamers on the surface of the virion.

The HCV genome is a positive-sense single-stranded RNA molecule that is about 9.6 kilobases long . It has a single open reading frame (ORF) that encodes a large polyprotein of about 3000 amino acids, which is then cleaved by host and viral proteases into at least 10 different proteins . The ORF is flanked by untranslated regions (UTRs) at both ends, which are involved in translation initiation and replication of the viral RNA .

The HCV proteins can be divided into structural and nonstructural proteins. The structural proteins are located at the N-terminal part of the polyprotein and include the core protein (C), which forms the nucleocapsid, and the envelope glycoproteins (E1 and E2) . The nonstructural proteins are located at the C-terminal part of the polyprotein and include NS2, NS3, NS4A, NS4B, NS5A, and NS5B . NS2 is a zinc-dependent metalloprotease that cleaves between NS2 and NS3. NS3 is a multifunctional protein that has serine protease and helicase activities. NS4A is a cofactor for NS3 protease. NS4B is a membrane-associated protein that induces the formation of membranous webs where HCV replication occurs. NS5A is a phosphoprotein that regulates viral replication and assembly. NS5B is the RNA-dependent RNA polymerase (RdRp) that synthesizes new viral RNA strands .

The HCV genome has a high degree of genetic diversity due to its error-prone RdRp and high replication rate. There are at least 6 major genotypes and more than 80 subtypes of HCV recognized based on phylogenetic analysis of nucleotide sequences. The genotypes differ by about 30% in their nucleotide sequences, while the subtypes differ by about 15%. The genotypes have different geographic distributions, clinical outcomes, and responses to antiviral therapy.

Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) worldwide. According to the World Health Organization (WHO), about 71.1 million people are chronically infected with HCV, accounting for 1% of the global population. The prevalence of HCV infection varies widely among different regions and countries, depending on the modes and history of transmission, the availability of screening and treatment, and the implementation of prevention measures.

The main routes of HCV transmission are parenteral exposure to blood or blood products, such as injection drug use (IDU), blood transfusion, unsafe medical injections, and occupational exposure . Other modes of transmission include vertical transmission from mother to child during pregnancy or delivery, sexual transmission among high-risk groups or partners of HCV-infected individuals, and tattooing or piercing with unsterile equipment . The risk of HCV transmission varies according to the viral load, the type and frequency of exposure, and the presence of co-infections such as human immunodeficiency virus (HIV) or hepatitis B virus (HBV).

The global incidence of HCV infection was estimated at 23.7 cases per 100,000 population in 2015, with 1.75 million new infections occurring that year. However, the incidence may be underestimated due to underreporting and asymptomatic nature of most acute infections. The incidence of HCV infection has increased in some countries in recent years, mainly due to the rise of IDU and the opioid epidemic . Moreover, the incidence of HCV infection among pregnant women has also increased, posing a threat to the perinatal transmission and the future burden of chronic HCV infection.

HCV is classified into seven major genotypes (1-7) and more than 80 subtypes (a, b, c, etc.) based on the genetic diversity of the viral genome. The distribution of HCV genotypes varies geographically and epidemiologically. Globally, the most common genotypes are 1 (44% of cases), 3 (25% of cases), and 4 (15% of cases). Genotype 1 is predominant in North America, Europe, Latin America, and Asia; genotype 3 is prevalent in South Asia, Australia, and some European countries; genotype 4 is mainly found in Africa and the Middle East; genotype 5 is restricted to South Africa; genotype 6 is common in Southeast Asia; and genotype 7 is rare and has been reported only in a few cases in Central Africa .

The natural history of HCV infection is variable and influenced by several host, viral, and environmental factors. About 15-45% of acutely infected individuals clear the virus spontaneously within six months, while the remaining 55-85% develop chronic infection. Among those with chronic infection, about 10-20% develop cirrhosis over a period of 20-30 years, and about 1-5% develop HCC over a period of 30-40 years. The progression to cirrhosis and HCC is faster in older age, male sex, alcohol consumption, co-infection with HIV or HBV, immunosuppression, diabetes mellitus, obesity, and steatosis.

The diagnosis of HCV infection is based on serological tests for anti-HCV antibodies and molecular tests for HCV RNA detection. Anti-HCV antibodies can be detected by enzyme-linked immunosorbent assay (ELISA) or chemiluminescence immunoassay (CLIA), but they do not distinguish between acute, chronic, or resolved infection. Therefore, anti-HCV positive individuals should be tested for HCV RNA by polymerase chain reaction (PCR) or nucleic acid amplification test (NAT) to confirm the presence or absence of active infection. HCV RNA can also be used to quantify the viral load and to determine the genotype and subtype of the virus.

The treatment of HCV infection has improved dramatically in recent years with the development of direct-acting antivirals (DAAs), which target specific viral proteins involved in replication. DAAs have shown high efficacy (>90%), short duration (8-12 weeks), good tolerability, and pangenotypic activity against most HCV genotypes . The WHO recommends that all individuals diagnosed with chronic HCV infection should be assessed for treatment eligibility and offered DAAs regardless of disease stage or comorbidities. However, access to DAAs remains limited in many resource-constrained settings due to high cost and lack of infrastructure.

The prevention of HCV infection relies on reducing the risk of exposure to blood or blood products through various measures such as screening blood donors and recipients; ensuring safe injection practices in health care settings; providing harm reduction services for people who inject drugs; promoting safe sex practices among high-risk groups; implementing infection control practices among health care workers; offering antenatal care and testing for pregnant women; and providing post-exposure prophylaxis for exposed individuals. Currently, there is no vaccine available for preventing HCV infection. However, several vaccine candidates are under development and undergoing clinical trials .

Hepatitis C virus (HCV) is a bloodborne virus that can cause both acute and chronic hepatitis, ranging in severity from a mild illness to a serious, lifelong illness including liver cirrhosis and cancer. The virus can be transmitted from one person to another through exposure to blood or body fluids that contain blood .

The major routes of transmission are :

• Injection drug use: Sharing needles, syringes, or other equipment used to inject drugs with an infected person is the most common way of getting HCV. This accounts for more than 60% of new HCV infections worldwide.
• Blood transfusion: Receiving blood or blood products that have not been screened for HCV can result in infection. This is now rare in most countries that have implemented routine screening of blood donors since the early 1990s.
• Unsafe medical procedures: Reusing or inadequately sterilizing medical equipment, especially syringes and needles, in health care settings can transmit HCV. This is a problem in some low- and middle-income countries where infection control practices are suboptimal.
• Occupational exposure: Health care workers can get HCV through accidental needle stick injuries or splashes of blood or body fluids from an infected patient.
• Tattooing and piercing: Getting tattoos or piercings at places that do not follow proper infection control measures, such as using sterile equipment and disposable gloves, can expose people to HCV-contaminated blood or instruments .

Other routes of transmission are less common and include :

• Mother-to-child transmission: Infected mothers can pass HCV to their babies during pregnancy or delivery. The risk is higher if the mother is also infected with HIV or has a high viral load of HCV. Breastfeeding does not transmit HCV unless the nipples are cracked and bleeding.
• Sexual transmission: Having unprotected sex with an infected person can transmit HCV, but this is rare. The risk is higher for people who have multiple sexual partners, have sexually transmitted infections (STIs), engage in rough sex that causes bleeding, or are men who have sex with men (MSM) .
• Household contact: Sharing personal items that may have come into contact with blood, such as razors, toothbrushes, or nail clippers, with an infected person can transmit HCV. Casual contact, such as hugging, kissing, and sharing food or drinks, does not spread HCV .

Hepatitis C is not transmitted by air, water, food, insects, or animals.

Hepatitis C virus (HCV) is a positive-strand RNA virus that replicates its genome in the cytoplasm of infected hepatocytes. The replication cycle of HCV can be summarized as follows:

• After entry and uncoating, the viral RNA is translated into a single polyprotein that is cleaved by host and viral proteases into 10 different proteins: core, E1, E2, p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B.
• The core protein forms a nucleocapsid with the viral RNA and associates with lipid droplets in the cytoplasm. The envelope glycoproteins E1 and E2 are inserted into the endoplasmic reticulum (ER) membrane and mediate viral assembly and budding. The non-structural proteins are involved in RNA replication and modulation of host cell functions.
• HCV RNA replication takes place in a membrane-associated replication complex that consists of viral proteins (NS3, NS4A, NS4B, NS5A and NS5B), viral RNA and cellular factors. The replication complex is located in a specialized membrane structure called the membranous web, which is derived from the ER and other intracellular membranes.
• The viral RNA-dependent RNA polymerase NS5B initiates RNA synthesis by using the positive-strand genomic RNA as a template to produce a negative-strand intermediate. The negative-strand RNA then serves as a template for the synthesis of more positive-strand RNA molecules that can be used for translation, replication or packaging.
• The newly synthesized positive-strand RNA molecules are either released from the replication complex or remain associated with it. The released RNA molecules can interact with the core protein on lipid droplets and form new nucleocapsids. The associated RNA molecules can continue to replicate or be recruited for translation.
• The assembly of new virus particles occurs at the ER membrane, where the nucleocapsids interact with the envelope glycoproteins E1 and E2. The virus particles then bud into the ER lumen and are transported to the Golgi apparatus, where they undergo further maturation and acquire cellular lipoproteins. The mature virus particles are then released from the cell by exocytosis.

Hepatitis C virus (HCV) causes inflammation and damage to the liver by interacting with the host immune system and metabolic pathways. The pathogenesis of HCV infection is complex and multifactorial, involving both viral and host factors.

HCV is a non-cytopathic virus, meaning that it does not directly kill the infected cells. Instead, most of the liver injury is caused by the immune response of the host to the virus. HCV can trigger both innate and adaptive immune responses, which can either control or exacerbate the infection.

The innate immune response is the first line of defense against HCV infection. It involves the recognition of viral components by pattern recognition receptors (PRRs) on various cells, such as hepatocytes, dendritic cells, macrophages, and natural killer (NK) cells. The activation of PRRs leads to the production of interferons (IFNs) and other cytokines, which can inhibit viral replication and activate other immune cells. However, HCV has evolved several strategies to evade or suppress the innate immune response, such as interfering with IFN signaling, blocking PRR activation, or modulating NK cell function.

The adaptive immune response is the specific and long-lasting response to HCV infection. It involves the activation of B cells and T cells by antigen-presenting cells (APCs), such as dendritic cells and macrophages. B cells produce antibodies that can neutralize the virus or facilitate its clearance by complement or phagocytosis. T cells can either help B cells or directly kill infected cells by releasing cytotoxic molecules. However, HCV can also escape or impair the adaptive immune response, such as by mutating its antigens, inhibiting T cell activation, inducing T cell exhaustion or apoptosis, or suppressing B cell function.

The balance between the immune response and viral evasion determines the outcome of HCV infection. In some cases, the immune response can clear the virus within 6 months of infection, resulting in acute resolution. In other cases, the immune response fails to eliminate the virus, leading to chronic infection. Chronic HCV infection can persist for decades and cause progressive liver damage, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The risk of developing these complications depends on several factors, such as viral genotype, viral load, host genetics, age, gender, alcohol consumption, co-infection with other viruses (e.g., HBV or HIV), and metabolic disorders (e.g., insulin resistance or steatosis).

The pathogenesis of HCV infection is not fully understood and is an active area of research. A better understanding of the molecular mechanisms involved in HCV-host interactions may lead to improved diagnosis, prevention, and treatment of this global health problem.

Hepatitis C virus (HCV) infection can cause a wide range of clinical manifestations, from asymptomatic chronic infection to acute hepatitis, chronic liver disease, cirrhosis, and hepatocellular carcinoma. The severity and course of the disease depend on several factors, such as the viral genotype, viral load, host immune response, co-infections, and environmental factors.

Acute hepatitis C

Acute hepatitis C is defined as the first six months of infection with HCV. Most people with acute hepatitis C do not have any symptoms or have mild and nonspecific symptoms, such as fatigue, nausea, fever, and muscle aches. Only about 20% to 30% of people with acute hepatitis C develop jaundice, which is the yellowing of the skin and eyes due to elevated bilirubin levels in the blood. Acute hepatitis C is usually diagnosed by detecting HCV RNA or anti-HCV antibodies in the blood of a person with risk factors for exposure.

About 15% to 25% of people with acute hepatitis C clear the virus spontaneously without treatment, meaning that they do not have detectable HCV RNA in their blood after six months of infection. The factors that influence spontaneous clearance are not fully understood, but they may include the viral genotype, the host immune response, and the age, sex, and ethnicity of the person infected. People who clear the virus may still have anti-HCV antibodies in their blood for years, but they are not infectious and do not have liver damage.

Chronic hepatitis C

Chronic hepatitis C is defined as persistent infection with HCV for more than six months. About 75% to 85% of people with acute hepatitis C develop chronic infection. Chronic hepatitis C is often asymptomatic or mildly symptomatic for many years, until the virus causes significant liver damage. Some people with chronic hepatitis C may experience fatigue, poor appetite, abdominal pain, dark urine, itching, fluid accumulation in the abdomen (ascites), swelling in the legs, weight loss, confusion, drowsiness, and slurred speech (hepatic encephalopathy). These symptoms are usually signs of advanced liver disease or liver failure.

Chronic hepatitis C can cause inflammation and scarring (fibrosis) of the liver tissue, which can progress to cirrhosis over time. Cirrhosis is a condition where the normal liver structure is replaced by scar tissue and nodules, impairing the liver function and blood flow. Cirrhosis can lead to serious complications such as portal hypertension, bleeding varices, ascites, hepatic encephalopathy, and liver cancer. The risk of developing cirrhosis depends on several factors, such as the duration of infection, the viral genotype, the viral load, the host immune response, co-infections with other viruses (such as hepatitis B or HIV), alcohol consumption, obesity, diabetes, and age at infection. It is estimated that about 10% to 20% of people with chronic hepatitis C develop cirrhosis within 20 to 30 years of infection.

Hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a type of liver cancer that originates from the hepatocytes, the main cells of the liver. HCC is one of the most common cancers worldwide and one of the leading causes of cancer-related death. Chronic infection with HCV is a major risk factor for developing HCC. It is estimated that about 1% to 3% of people with chronic hepatitis C develop HCC within 20 to 30 years of infection. The risk of HCC increases with the severity of liver damage, especially cirrhosis. Other factors that increase the risk of HCC include co-infection with hepatitis B or HIV, male sex, older age, alcohol consumption, smoking, obesity, diabetes, aflatoxin exposure, and genetic factors.

HCC usually does not cause any symptoms until it reaches an advanced stage. Some symptoms of HCC include abdominal pain or swelling, weight loss, loss of appetite, jaundice, ascites, variceal bleeding, hepatic encephalopathy. HCC is usually diagnosed by imaging tests such as ultrasound or CT scan and by measuring a tumor marker called alpha-fetoprotein (AFP) in the blood. Sometimes a biopsy may be needed to confirm the diagnosis. Treatment options for HCC depend on the stage and size of the tumor, the liver function and general health of the person affected. They may include surgery, liver transplantation, radiofrequency ablation, chemoembolization, targeted therapy, immunotherapy, or palliative care.

The diagnosis of hepatitis C virus (HCV) infection involves the detection of specific antibodies and/or viral RNA in the blood of the patient. The following are the main types of laboratory tests used for HCV diagnosis:

• Antibody detection: This test detects the presence of anti-HCV antibodies in the serum or plasma of the patient using enzyme-linked immunosorbent assay (ELISA) or chemiluminescence immunoassay (CLIA). Anti-HCV antibodies are usually detectable 7 to 31 weeks after infection, but they do not indicate whether the infection is active or resolved. There are different generations of ELISA tests that use different antigens from the HCV core, envelope, and nonstructural proteins. The current fourth generation ELISA test has high sensitivity and specificity for anti-HCV detection . A positive antibody test should be confirmed by a recombinant immunoblot assay (RIBA) or a nucleic acid test (NAT) to rule out false-positive results .

• HCV core antigen detection: This test detects the presence of HCV core protein in the serum or plasma of the patient using ELISA or CLIA. HCV core antigen is a marker of active viral replication and can be detected earlier than anti-HCV antibodies, usually within 1 to 3 weeks after infection. However, this test has lower sensitivity and specificity than NAT and may not detect low levels of HCV core antigen.

• Detection of viral RNA: This test detects the presence of HCV RNA in the serum or plasma of the patient using polymerase chain reaction (PCR) or nucleic acid amplification tests (NAT), such as transcription-mediated amplification (TMA). HCV RNA is a direct marker of active viral infection and can be detected within 1 to 2 weeks after infection . This test can also measure the quantity of HCV RNA in the blood (viral load) and identify the genotype of the virus, which are important for prognosis and treatment decisions . There are different types of NAT, such as qualitative NAT, which indicates whether HCV RNA is present or absent; quantitative NAT, which measures the amount of HCV RNA in international units per milliliter (IU/mL); and genotyping NAT, which determines the genetic subtype of HCV .

The recommended testing sequence for identifying current HCV infection is as follows:

• Perform an antibody test using a fourth generation ELISA or CLIA. If negative, no further testing is needed. If positive or indeterminate, proceed to the next step.
• Perform a NAT using PCR or TMA. If negative, no current HCV infection is present. If positive, current HCV infection is confirmed.
• Perform a quantitative NAT to measure viral load and a genotyping NAT to determine viral subtype.

The interpretation of results of tests for HCV infection and further actions are summarized in the table below:

The treatment of hepatitis C aims to clear the virus from the body and prevent or reverse the liver damage caused by chronic infection. The choice of treatment depends on several factors, such as the genotype of the virus, the viral load, the extent of liver fibrosis or cirrhosis, and the previous treatment history. The treatment options include:

• Antiviral medications: These are drugs that directly target and inhibit the replication of the hepatitis C virus. They are usually taken orally for 8 to 24 weeks, depending on the regimen and the response. The most commonly used antiviral medications are:

  • Sofosbuvir: This is a nucleotide analog that inhibits the NS5B polymerase, which is essential for viral RNA synthesis. It is effective against all genotypes of hepatitis C and can be combined with other antivirals, such as ribavirin, simeprevir, daclatasvir, or velpatasvir.
  • Simeprevir: This is a protease inhibitor that blocks the NS3/4A protease, which is involved in viral polyprotein cleavage and replication. It is mainly used for genotype 1 infection and must be given with sofosbuvir or pegylated interferon and ribavirin.
  • Daclatasvir: This is a NS5A inhibitor that interferes with viral assembly and release. It can be used for genotypes 1 to 4 infection and must be given with sofosbuvir.
  • Velpatasvir: This is another NS5A inhibitor that has activity against all genotypes of hepatitis C. It is given as a fixed-dose combination with sofosbuvir.
  • Glecaprevir/pibrentasvir: This is a combination of two antivirals: glecaprevir, a protease inhibitor, and pibrentasvir, a NS5A inhibitor. It can be used for all genotypes of hepatitis C and has a high cure rate.

• Interferon and ribavirin: These are older drugs that are less commonly used nowadays due to their lower efficacy and higher side effects compared to the newer antivirals. Interferon is a protein that stimulates the immune system to fight the virus, while ribavirin is a nucleoside analog that enhances the antiviral effect of interferon. They are usually given by injection for 24 to 48 weeks.

• Liver transplantation: This is a surgical procedure that replaces the damaged liver with a healthy one from a donor. It may be considered for patients with advanced liver cirrhosis or liver failure who do not respond to antiviral therapy or have contraindications to it. However, liver transplantation does not cure hepatitis C, as the virus can infect the new liver as well. Therefore, antiviral therapy is usually given before or after the transplantation to prevent recurrence.

The treatment of hepatitis C has improved significantly in recent years with the development of new antiviral medications that have higher cure rates and fewer side effects than previous therapies. However, not everyone who has hepatitis C needs treatment, as some people may clear the virus spontaneously or have mild disease that does not progress to serious complications. Therefore, it is important to consult a doctor who can assess your condition and recommend the best treatment option for you.

Hepatitis C is a viral infection that causes inflammation and damage to the liver. It can lead to serious complications such as cirrhosis, liver cancer, and liver failure. Hepatitis C is spread through contact with blood from an infected person, mainly through injection drug use, blood transfusion, unsafe medical procedures, and sexual transmission.

Currently, there is no vaccine to prevent hepatitis C infection. However, researchers are working on developing effective and safe vaccines that can protect against different strains of the virus. Several vaccine candidates are in various stages of clinical trials, but none have been approved for public use yet.

The main challenges in developing a hepatitis C vaccine are:

• The high genetic diversity of the virus, which has at least six major genotypes and more than 80 subtypes that vary in their geographic distribution and response to treatment.
• The lack of a suitable animal model that can mimic the natural course of human infection and immunity.
• The poor understanding of the immune correlates of protection, which are the specific immune responses that can prevent or clear the infection.
• The ethical and logistical difficulties in conducting vaccine trials among high-risk populations, such as people who inject drugs or people with chronic liver disease.

Despite these challenges, there are some promising approaches to developing a hepatitis C vaccine, such as:

• Using recombinant proteins or peptides derived from the viral envelope glycoproteins E1 and E2, which are involved in viral entry into host cells and are targets of neutralizing antibodies.
• Using viral vectors or DNA plasmids that can deliver genes encoding viral antigens or immunomodulators into host cells and induce cellular and humoral immune responses.
• Using whole inactivated or attenuated viruses that can elicit broad and durable immune responses without causing disease.
• Using multivalent vaccines that can cover multiple genotypes or subtypes of the virus and provide cross-protection.

Until a vaccine becomes available, the best way to prevent hepatitis C infection is to avoid exposure to the virus by:

• Not sharing needles or other drug injection equipment
• Practicing safe sex by using condoms
• Avoiding tattooing, piercing, or acupuncture with unsterilized equipment
• Getting tested for hepatitis C if you have risk factors or symptoms
• Getting treated for hepatitis C if you are infected

Treatment for hepatitis C has improved significantly in recent years, with new direct-acting antiviral drugs that can cure most cases of chronic infection in 8 to 12 weeks. However, treatment is expensive and may not be accessible to everyone who needs it. Moreover, treatment does not provide immunity against reinfection. Therefore, a vaccine for hepatitis C is still urgently needed to prevent new infections and reduce the burden of disease worldwide.

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