Hepatitis C Virus

Hepatitis C is the most common blood-borne pathogen and a leading cause of morbidity and mortality (Basit 2021). Hepatitis C is caused by the hepatitis C virus (HCV) belonging to the family Flaviviridae and genus hepacivirus.

Epidemiology (CDC 2020)

• 50,300 new U.S. HCV infections in 2018
• 2.4 million U.S. people living with HCV infection in 2016
• Approximately 45% of persons with HCV infection are unaware of their HCV status.

Transmission

HCV is transmitted primarily through parenteral exposures to infectious blood or body fluids that contain blood. Common exposures include

• Injection-drug use (currently the most common mode of HCV transmission in the United States)
• Birth to an HCV-infected mother

Less frequently, HCV can also be spread through:

• Sex with an HCV-infected person (an inefficient means of transmission, although HIV-infected men who have sex with men [MSM] have increased risk of sexual transmission)
• Sharing personal items contaminated with infectious blood, such as razors or toothbrushes
• Other health-care procedures that involve invasive procedures, such as injections (usually recognized in the context of outbreaks)
• Unregulated tattooing
• Receipt of donated blood, blood products, and organs (rare in the United States since blood screening became available in 1992)
• Needlestick injuries in health-care settings

Virus

HCV is a lipoviroparticle. HCV particle contains a single strand of viral RNA embedded within core proteins and enveloped by a membrane studded with E1 and E2 glycoproteins. The membrane is tightly associated with an aggregation of lipids and apolipoproteins (Alazard-Dany 2019).

HCV exhibits extensive genetic variability which has hindered vaccine development.  HCV has been classified into seven genotypes and at least eighty sub-types that vary in prevalence geographically:

• Genotype 1: the most widely dispersed worldwide, 60% to 70% of isolates from the United States are subtype 1a or 1b.  Genotype 1, is associated with more severe liver disease and a much greater risk of developing liver cancer.
• Genotype 2: widely dispersed but most diverse in central and west Africa
• Genotype 3: widely distributed but most diverse in Asia, linked to illicit drug use
• Genotype 4: Northern Africa and the Middle East. 
• Genotype 5: South Africa
• Genotype 6: Southeast Asia. 
• Genotype 7: Central Africa (Congo) (Basit 2021)

HCV lifecyle:

1. HCV enters the blood stream and travels to the the liver
2. HCV envelope glycoproteins binds to receptors on a hepatocyte cell membrane. 
3. HCV and host hepatocyte membranes fuse and endocytosis brings the virus into the hepatocyte.
4. The viral core is dismantled, releasing the HCV RNA strand into the cytosol for replication.
5. The HCV RNA travels to a membrane bound ribosome on the endoplasmic reticulum (ER).
6. The ribosome translates a single, long, viral polyprotein into the lumen of the ER.
7. Host enzymes in the host ER cleave the polyprotein into structural proteins (core and E proteins)

• Core - protects the viral RNA
• E1 & E2 work together to bind to and fuse with external and internal hepatocyte membranes, cell membrane and endosome membrane, respectively.
• NS2 - acts as a protease to separate NS2 from NS3
• NS3 - is a protease that cleaves the non-structural proteins and inhibits cellular defenses
• NS4a - facilitates NS3, Ns4b, NS5a, and assist with viral assembly
• NS4b - is essential forming the replication complex on the ER
• NS5a - interacts with NS4b, NS5b and RNA and host proteins to regulate viral replication, assembly and pathogenisis
• NS5b - is critical to RNA replication

Visit the amazing website Hepatitis C Online for a thorough explanation of the HCV Life Cycle
  https://www.hepatitisc.uw.edu/biology/lifecycle

Incubation period

An incubation period is the time from exposure to an agent until the onset of symptoms. The incubation period of HCV is 14-182 days with an average range of 14-84 days.

Screening for HCV exposure

CDC recommends hepatitis C screening of all adults aged ≥18 years once in their lifetimes, and screening of all pregnant women (regardless of age) during each pregnancy.  Testing of persons with risk factors and those with ongoing risk factors should be tested regardless of age or setting prevalence, including continued periodic testing as long as risks persists.  Any person who requests hepatitis C testing should receive it, regardless of disclosure of risk, because many persons might be reluctant to disclose stigmatizing risks.

Reporting

Cases of hepatitis C should be reported to the appropriate state or local health jurisdiction in accordance with requirements for reporting acute, perinatal, and chronic HCV infection. 

Severity of disease

• Acute Infection Symptoms
  • Jaundice might occur in 20%–30% of people
  • Nonspecific symptoms (e.g., anorexia, malaise, or abdominal pain) might be present in 10%–20% of people
• Chronic infection symptoms occurs in over 50% of newly infected people.
  • Approximately 5%–25% of persons with chronic hepatitis C will develop cirrhosis over 10–20 years
  • People with hepatitis C and cirrhosis have a 1%–4% annual risk for hepatocellular carcinoma.

Diagnosis

• Acute HCV infection is rarely diagnosed by the non-specific symptoms alone e.g., fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain. History and risk factors may indicate the need to initiate HCV screening.
  • Clinical criteria include one or more of the following:
    • Jaundice, OR
    • Peak elevated total bilirubin levels ≥ 3.0 mg/dL, OR
    • Peak elevated serum alanine aminotransferase (ALT) levels >200 IU/L,

    AND

    The absence of a more likely diagnosis (which may include evidence of acute liver disease due to other causes or advanced liver disease due to pre-existing chronic Hepatitis C virus (HCV) infection or other causes, such as alcohol exposure, other viral hepatitis, hemochromatosis, etc.).

• Chronic HCV infection may present no visible evidence of liver disease or may have a spectrum of disease ranging from chronic hepatitis to cirrhosis or liver cancer.
  • Confirmatory laboratory evidence:
    • Positive hepatitis C virus detection test: Nucleic acid test (NAT) for HCV RNA positive (including qualitative, quantitative, or genotype testing), OR
    • A positive test indicating presence of hepatitis C viral antigen(s) (HCV antigen)

    Presumptive laboratory evidence:

    • A positive test for antibodies to hepatitis C virus (anti-HCV)

Testing

CDC Recommended Testing for Identifying Current Hepatitis C Virus Infection

• Screening tests for antibody to HCV (anti-HCV)
  • enzyme immunoassay (EIA)
  • enhanced chemiluminescence immunoassay (CLIA)
  • Chemiluminescence microparticle immunoassay (CMIA)
  • Microparticle immunoassay (MEIA)
  • Electrochemiluminescence immunoassay (ECLIA)
  • Immunochromatographic assay (rapid test)
• Qualitative nucleic acid tests to detect presence HCV RNA
• Quantitative nucleic acid tests to detect levels of HCV RNA

Treatment

Significant advancement in the treatment of HCV has occurred since the introduction of Direct Acting Antiviral (DAA) medication in 2011 (Geddawy 2017). The goal of treatment is to reach a sustained virologic response (SVR), that is the hepatitis C virus RNA is not detected in the blood 12 weeks or more after completing treatment. About 99% of people are considered cured of their infection when the virus is not detected 12 weeks or more after completing treatment. 

Chances are very low for the virus to be detected again after SVR is achieved. Studies have shown this type of relapse occurs in less than 1% of patients who complete treatment. The virus is more likely to return as a result of re-infection (new infection from exposure to someone else who is infected with hepatitis C)

Direct Acting Antivirals

There are 3 non-structural protein targets on the hepatitis C virus (HCV) that currently recommended direct-acting antiviral (DAA) medications attack to destroy the virus. Each DAA medication attacks one of these targets; combination DAA tablets attack more than one target. DAA medications are classified based on which mechanism they use against HCV. Recognizing the DAA medication class(es) becomes particularly important when retreating a patient for HCV who has been previously treated with a DAA-based therapy. There are 3 classes of currently recommended DAA medications:

• NS3/4A protease inhibitors
• NS5A polymerase inhibitors
• NS5B polymerase inhibitors (Va.gov 2018)

DAA Treatment Regimen	NS3/4A Protease Inhibitor	NS5B Nucleotide Polymerase Inhibitor	NS5A Polymerase Inhibitor	How Many DAA Tablets Taken Per Day?
edipasvir/sofosbuvir ± ribavirin		✔	✔	1
elbasvir/grazoprevir ± ribavirin	✔		✔	1
sofosbuvir/velpatasvir ± ribavirin		✔	✔	1
sofosbuvir/velpatasvir/voxilaprevir	✔	✔	✔	1
glecaprevir/pibrentasvir	✔		✔	3
Treatment section source: Va.gov: Veterans Affairs. HCV DAA Classes. (2018). Retrieved November 2, 2021, from https://www.hepatitis.va.gov/hcv/treatment/hcv-daa-class.asp.

Prevention counseling

There is no vaccine for hepatitis C. The best way to prevent hepatitis C is by avoiding behaviors that can spread the disease. To reduce your risk of getting hepatitis C:

• Injection drug use is the most common way people get hepatitis C. Avoid injecting drugs to reduce your risk. If you do inject drugs, use sterile injection equipment. Avoid reusing or sharing.
• Avoid sharing personal care items that might have blood on them (razors, toothbrushes, nail clippers)
• If you are a health care or public safety worker, follow universal blood/body fluid precautions and safely handle needles and other sharps
• Consider the risks if you are thinking about tattooing, body piercing, or acupuncture – are the instruments properly sterilized?
• If you’re having sex with more than one partner, use latex condoms correctly and every time to prevent the spread of sexually transmitted diseases, including hepatitis C.
• Get tested for hepatitis C is important, because treatments can cure most people with hepatitis C in 8 to 12 weeks.
• Prevent healthcare provider exposure to HCV by adhering to Standard Precautions which include:
  • Universal precautions
    • Treat all blood/body fluids as potentially infectious and use barrier precautions such as gloves, and appropriate clothing;
    • Wash hands thoroughly;
    • Prevent cutting or needle stick injuries by use of puncture resistant containers for disposal;
    • Use of mouthpieces and resuscitation bags to minimize exposure to saliva during resuscitation procedure; and
    • Clean surfaces as soon as possible when they become contaminated.
  • Engineering Controls
    • Hand washing facilities (or antiseptic hand cleansers and towels, or antiseptic towelettes), which are readily accessible to all who have a potential for exposure;
    • Self-sheathing needles;
    • Containers for contaminated re-useable sharps having the following characteristics:
      • puncture-resistant;
      • color-coded or labeled with a biohazard warning label;
      • specimen containers;
      • Containers for specimens of blood or other materials are required to be placed in designated leak-proof containers and appropriately labeled, for handling and storage
      • Containers for Special Medical Waste;
      • Disposable gloves, disposable containers.
  • Personal Protective Equipment (PPE)
    • PPE is an employee’s last line of defense against bloodborne pathogens.
    • PPE is selected based on anticipated exposure to blood.

Reference

Alazard-Dany, N., Denolly, S., Boson, B., & Cosset, F. L. (2019). Overview of HCV Life Cycle with a Special Focus on Current and Possible Future Antiviral Targets. Viruses, 11(1), 30. https://doi.org/10.3390/v11010030

Basit, H. (2021). Hepatitis C. StatPearls [Internet]. Retrieved October 30, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK430897/.

Geddawy, A., Ibrahim, Y. F., Elbahie, N. M., & Ibrahim, M. A. (2017). Direct Acting Anti-hepatitis C Virus Drugs: Clinical Pharmacology and Future Direction. Journal of translational internal medicine, 5(1), 8–17. https://doi.org/10.1515/jtim-2017-0007

The abcs of hepatitis – for health professionals - cdc.gov. (2020). Retrieved November 1, 2021, from https://www.cdc.gov/hepatitis/Resources/Professionals/PDFs/ABCTable.pdf

Va.gov: Veterans Affairs. HCV DAA Classes. (2018). Retrieved November 2, 2021, from https://www.hepatitis.va.gov/hcv/treatment/hcv-daa-class.asp.

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