Molecular Biology, Treatment, and Ongoing Global Management of Hepatitis

The discovery of the origin of hepatitis dates back to Hippocrates. Defined in its name as inflammation in the liver, the first encounter with hepatitis was regarded as epidemic jaundice, first reported in the 17th and 18th centuries.

The different strains of hepatitis were discovered based on their distinct etiology, epidemiology, and manifestations on the patient. Although there are 5 discovered strains of hepatitis, the most common are hepatitis A, B, and C.

Hepatitis A virus (HAV), generally regarded as the infectious hepatitis, is generally considered to have been discovered first. Hepatitis B virus (HBV) was later discovered in differentiation due its longer incubation period, later confirmed after the development of serologic tests that allowed for the definitive diagnosis of HBV.

Before the development of vaccines, hepatitis infections were treated through methods of prevention. Such methodologies included hygienic measures of washing hands before and after meals, and ensuring that food is sterilized.

Furthermore, passive immunity was also practiced through the use of immune globulin (IG). However, one of the greatest downsides to acquiring passive immunity is that the antibodies do not stay in the body for long, giving the patient only short-term immunity. Hence, vaccinations were developed to provide long-term protection against HAV infection. In 1995, the first HAV vaccines were licensed for use in the United States.

It was reasoned that encouraging widespread vaccination in the community setting for patients of susceptible risk will substantially lower disease incidence and eliminate virus transmission overall. After the widespread administration of HAV vaccines, cases decreased by more than 95% through 2011, making it no longer the most frequently reported type of hepatitis reported in the United States.¹

However, HAV re-emerged in 2016, reportedly as a result of drug use and increased rates of homelessness. As of February 2019, the US Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices issued recommendations on HAV vaccination for people experiencing homelessness, as their congregate living conditions have been attributed to their increased risk for disease transmission.²

HAV

A 27 nanometer, unenveloped, symmetrical RNA virus, HAV is found to belong to the picorna group of viruses. HAV is first diagnosed through the detection of IgM antibodies, found in the blood and lymph, and regarded as the first antibodies the body generates upon acute infection.

HAV is an infection that is endemic to a variety of places around the world. The most common route of transmission of the virus is the fecal-oral route. Developing countries with high poverty rates and poor living conditions have generally been the most common places where the virus spreads. However, because of continuous technological development, infrastructure, and improved levels of education and public sanitation, IgG antibodies indicative of active HAV infection have decreased in rates.

Interestingly, neonates (from birth to 1 month) are susceptible to infection parenterally via blood transfusions from donors who are hepatitis-positive and experiencing the initial symptom onset. When a neonate is infected by the donor, the neonate has the potential to have the virus within its system reflected in the stool for up to 5 months.³

Although HAV is generally a recoverable virus, there is a rare 1% in whom the virus may progress to acute liver failure and impaired clotting. If the INR or prothrombin ratio is greater than 1, liver transplantation is considered and the patient should be closely monitored. If the INR rapidly increases to >4, the patient should immediately be referred for transplantation to avoid the irreversible cerebral edema that might follow.³

HAV Vaccination

Generally, the HAV vaccine has been found effective in protection over the long term. There are currently 2 vaccines licensed for administration in the United States.

The first is the single HAV vaccine, which is authorized to be given for the first dose in those 1 year of age or older. The second dose is authorized to be given between 6 months and 4 or 5 years of age, but is commonly administered within the 6- to 18-month age range.

The second vaccine approved for administration is the combined immunization against HAV and HBV, which is currently authorized for those above 18 years of age. This vaccine is for instances in which there is no documentation and no recollection of previously receiving the vaccine. The combined vaccine has a 3-dose schedule that takes place over a duration of 6 months.⁴

HBV

HBV is categorized as a hepaDNA virus, with 4 distinct genomic regions and a complex mode of replication that holds susceptibility to the development of mutant forms. Diagnosis is typically made through the detection of active infection, using the hepatitis B surface antigen (HBsAg) test.

Different types of antigens within the HBsAg indicates the degree of infectiousness. If a patient has hepatitis Be antigen (HBeAg), the patient carries a larger viral load. If a patient has an acute or ongoing chronic infection, it is associated with antihepatitis Bc IgM.

Developed immunity against HBV is denoted by anti-hepatitis B (anti-HBe), and later anti-hepatitis B surface (anti-HBs) antibodies. Hepatitis B surface antibodies have viral DNA inblood/liver tissue that can be further tested using polymerase chain techniques. Transmission techniques include parenteral, percutaneous, or transmucosal, through either blood or contaminated body fluids from acutely infected patients/carriers.³

Clinical Features

Generally, children younger than 5 years of age tend to present with no symptoms. However, older children, adolescents, and adults experience a wide range of symptoms that include, but are not limited to, fever, fatigue, loss of appetite, and nausea and vomiting.⁵

Prevention and Treatment

One of the primary shared goals of health care professionals in the management of hepatitis is practicing and taking preventive measures to minimize the active infection rates as much as possible. Vaccination in the early parts of life is the most effective strategy to achieve this goal. For instances in which HBV infection is acquired through the mother of the infant, administration of hepatitis B immunoglobulin and the HBV vaccine to infants within 24 hours of birth has been found effective.

In areas such as Africa and Italy where most infections occur after 5 months of life, combining HBV vaccination into the routine childhood immunization schedule is effective if unable to afford hepatitis B immunoglobulin. In areas of low risk and transmission rates, clinicians screen pregnant women via HBsAg testing for active infection and immunize newborns of all HbsAG-positive mothers—regardless of whether antibodies are present in the mother—with specific immunoglobulins, if available, and vaccination. Booster doses are available and administered to children 3 to 5 years of age to maintain antibody titers greater than 100 mIU/ml to maintain immunity.³

Although vaccination is a great tool as a preventative measure, it is quite important that antibody levels are maintained. For those with active HBV infection, one of the only treatments available are the interferon alfa (IFN-a), which works by directly inactivating viral DNA through the inhibition of protein synthesis.⁶

Hepatitis C Virus (HCV)

Not verified yet in its exact molecular features, it is predicted that the hepatic C virus is a 30 to 60 nm enveloped, single stranded heterogeneous RNA virus, composed of 10,000 nucleotides, bound to a nucleocapsid and covered by a glycoprotein coat. There have been at least 6 genetic types identified, but this remains an area of research to explore for its therapeutic potential.³

Diagnosis of HCV

Polymerase chain reaction techniques are one of the primary methods for detection of antibodies to components of HCV, evident of an infection that has/is taking place. Special patient populations in whom comorbidities may affect the accuracy of the diagnostic tests include patients with rheumatoid factor, hypergammaglobulinemia, and paraproteinemia due to the detectable IgM kappa monoclonal gammopathy.⁷

Transmission

HCV is most commonly transmitted through parental exposure and via contact with blood from an infected person, typically through the practice of sharing needles, syringes, or any other equipment used for recreational drug administration.⁸

Clinical Features

In children and adults, hepatic C can cause acute hepatitis that can be linked to HCV. Typically, mild alanine aminotransferase (ALT) elevations of 30-100 IU are associated with viral hepatitis.⁹ Symptoms include, but are not limited to fever, pain in the right upper abdomen, abdominal swelling due to fluid (ascites), and clay colored or pale stool.¹⁰

Prevention and Treatment

Preventative measures for HCV include the screening of blood donors to minimize cross contamination and disinfection. The development of direct acting antivirals with sofosbuvir in the 2010s revolutionized the treatment of HCV, with a success rate of greater than 90%, even including patients with comorbidities such as liver cirrhosis, mechanistically inhibiting the NS5B polymerase.¹¹

Global Initiatives

In 2016, the International Viral Hepatitis Meeting, a part of the World Health Assembly, unanimously adopted a resolution and global campaign to eliminate HBV and HCV infection by 2030. The International Task Force for Disease Eradication adapted and endorsed the goals of the World Health Organization (WHO).¹²

The WHO established a framework to guide implementation of the key interventions at a national level to achieve the global elimination goals. By 2017, only 9 of 45 countries were on track to achieve the WHO goals for elimination of HBV and HCV. The disparity and lack of collective effort was attributed to a lack of appropriate resources, commitment, and allocation.¹²

In other parts of the world, countries such as Egypt have taken part in an ambitious strategy to eliminate HCV, as the country’s infection prevalence rate was among the highest in the world. In 2014, Egypt embarked on an aggressive screening and treatment program that evolved into a national strategy, as encouraged by the WHO, to eliminate HCV as a public health threat by 2021.

Through a strategy of screening, monitoring, and treating with the assistance of the WHO in funding for the health care sector, 4 million people were able to be treated and 50 million were screened.¹³

The government of India announced that it will offer free testing and treatment for both HBV and HCV, as part of its universal health coverage plan, facilitated through the reduction in prices of medicines.¹⁴

Conclusion

Hepatitis has been regarded as an infectious disease that has potential to be eradicated but needs the consensus and support of people from across the world. Although preventative treatment and global initiatives have shown promise in eradicating its prevalence, continued consistency and allocation of resources for those in need must be continuously practiced.

Education on the importance of vaccination where it is applicable will continue to prove to be pivotal in fulfilling the World Health Assembly’s proposition of global eradication of viral hepatitis by 2030.

References

1. Pinkbook: Hepatitis A. Centers for Disease Control and Prevention, 18 Aug. 2021, https://www.cdc.gov/vaccines/pubs/pinkbook/hepa.html.

2. People Experiencing Homelessness and Viral Hepatitis. Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 18 Aug. 2020, https://www.cdc.gov/hepatitis/populations/peh.htm.

3. Gregorio, Germana V, et al. Viral Hepatitis. National Center for Biotechnology Information, U.S. National Library of Medicine, 1995, https://www.ncbi.nlm.nih.gov/pmc/.

4. Bhandari P, Brett C, Batool A, et al. Hepatitis A Vaccine. [Updated 2022 Sep 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554604/

5. What Is Hepatitis B. Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 30 Mar. 2022, https://www.cdc.gov/hepatitis/hbv/bfaq.htm#bFAQe01.

6. Houglum J. E. (1983). Interferon: mechanisms of action and clinical value. Clinical pharmacy, 2(1), 20–28

7. Surasak Faisatjatham, Noppacharn Uaprasert, Kroonpong Iampenkhae, and Suwasin Udomkarnjananun. SAGE Open Medical Case Reports 2022 10.1177/2050313X221140648

8. What Is Hepatitis C. Centers for Disease Control and Prevention, 28 July 2020, https://www.cdc.gov/hepatitis/hcv/cfaq.htm#:~:text=The%20hepatitis%20C%20virus%20is,to%20prepare%20and%20inject%20drugs.

9. Helsper C, van Essen G, Frijling BD, de Wit NJ. Follow-up of mild alanine aminotransferase elevation identifies hidden hepatitis C in primary care. Br J Gen Pract. 2012 Mar;62(596):e212-6. doi: 10.3399/bjgp12X630115. PMID: 22429439; PMCID: PMC3289828

10. Hepatitis C. Pennmedicine.org, https://www.pennmedicine.org/for-patients-and-visitors/patient-information/conditions-treated-a-to-z/hepatitis-c.

11. Gentile, I., Maraolo, A. E., Buonomo, A. R., Zappulo, E., & Borgia, G. (2015). The discovery of sofosbuvir: a revolution for therapy of chronic hepatitis C. Expert opinion on drug discovery, 10(12), 1363–1377. https://doi.org/10.1517/17460441.2015.1094051

12. Bhatia HK, Singh H, Grewal N, Natt NK. Sofosbuvir: A novel treatment option for chronic hepatitis C infection. J Pharmacol Pharmacother. 2014 Oct;5(4):278-84. doi: 10.4103/0976-500X.142464. PMID: 25422576; PMCID: PMC4231565.

13. Wiegand J, Berg T. Hepatitis C-committing the world to an eradication of the infection. Hepatobiliary Surg Nutr. 2021 Jan;10(1):96-99. doi: 10.21037/hbsn.2020.03.26. PMID: 33575293; PMCID: PMC7867724.

14. Hassanin A, Kamel S, Waked I, Fort M. Egypt's Ambitious Strategy to Eliminate Hepatitis C Virus: A Case Study. Glob Health Sci Pract. 2021 Mar 31;9(1):187-200. doi: 10.9745/GHSP-D-20-00234. PMID: 33795369; PMCID: PMC8087425