Hepatitis Viruses: Types and Characteristics

Hepatitis

• Hepatitis is liver inflammation or injury marked by inflammatory cells in liver tissue.
• Toxins, certain drugs, heavy alcohol use, and bacterial/viral infections can cause it.

Hepatitis Viruses

• Viral hepatitis is a systemic illness affecting the liver
• Acute viral hepatitis in adults/children stems from five primary agents: HAV, HBV, HCV, HDV, and HEV.
• Hepatitis viruses result in acute liver inflammation, causing clinical illness, which includes fever, gastrointestinal issues like nausea and vomiting, and jaundice.

Hepatitis A

• HAV belongs to the picornavirus family, with a size range of 27-32 nm.
• HAV contains a linear, single-stranded RNA genome.
• There is only one identified serotype of HAV.
• HAV transmits through the fecal-oral route, shedding the virus via feces.
• Heating food to over 85°C for 1 minute and disinfecting surfaces with sodium hypochlorite (1:100 dilution of chlorine bleach) can inactivate HAV
• Due to HAV's resistance to disinfection, extra caution is needed when dealing with affected patients and their products.
• HAV is widespread globally.
• Hepatitis A outbreaks often occur in families, institutions, summer camps, day care centers, neonatal intensive care units and military troops.
• Hepatocytes are the primary site for HAV replication.
• Viral replication impairs severe cytopathology and liver function.
• Persistent infection and chronic hepatitis are uncommon with HAV.
• Infection is prevalent in developing countries with inadequate sanitation.
• HAV is seldom spread through contaminated needles/syringes or blood transfusions.

Hepatitis A Diagnosis

• Liver transaminases and bilirubin show a marked elevation.
• Anti-HAV IgM antibodies appear in the immunoglobulin M (IgM) fraction during the acute phase, peaking about 2 weeks after liver enzyme elevation.
• Anti-HAV IgM typically declines to undetectable levels within 3-6 months.
• Anti-HAV IgG surfaces shortly after the onset and lasts for decades; detecting IgM-specific anti-HAV in an acutely infected patient confirms the diagnosis.
• HAV can be detected in the liver, stool, bile, and blood through assays like RIA, PCR, and immune electron microscopy; the virus appears early and vanishes within 2 weeks after jaundice.

Hepatitis A Prevention and Treatment

• Prevention includes hand hygiene, chlorination and boiling of drinking water.
• Fecal contamination of food and water must be avoided.
• The inactivated Havrix vaccine is recommended for children over 1 year living in endemic areas, administering 2 doses at a 6-month interval protecting more than 95% of cases for over 20 years.
• Groups at high risk of acquiring hepatitis A should be vaccinated, including: injection drug users, persons with clotting factor disorders, persons in contact with nonhuman primates and individuals with chronic liver disease.
• Immune globulin (IG) from normal adult plasma offers passive protection in approximately 90% of exposed individuals when administered within 1-2 weeks of exposure.
• Its prophylactic benefit declines over time, with administration more than 2 weeks after exposure or after the onset of clinical symptoms not indicated
• Prescribed doses of IG do not prevent infection but make it mild/subclinical and allow active immunity to develop.
• There's no specific antiviral treatment for hepatitis A; care is supportive, aiming to resolve hepatocellular damage, recommending rest, avoiding fatty foods, consuming a balanced diet, and staying hydrated.

Hepatitis B

• Hepatitis B is the only human hepatitis virus using a DNA genome.
• It is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma.
• HBV has a worldwide distribution.
• HBV is found in all bodily fluids such as blood, semen, saliva, and breast milk and is a source of infection
• The viral load is very high at 1010 virus particles/ml.
• Hepatitis B is primarily a disease affecting infants in developing nations.
• There are over 350 million HBV carriers globally.
• About 600,000 deaths annually are linked to HBV-related liver conditions and hepatocellular carcinoma.
• HBV prevalence in Egypt among adults aged 15-59 is 1.4%.
• During infancy, the primary HBV transmission modes involve contact with an infected mother during delivery and infected household contact.
• There is no seasonal trend and no high age predilection for HBV infection.
• High-risk groups include parenteral drug abusers, healthcare personnel, multiply transfused/organ transplant/hemodialysis patients, and infants born to mothers with hepatitis B.
• Mandatory screening of blood donors for HBV markers has greatly lowered transfusion-associated hepatitis cases.
• Other transmission modes exist; HBsAg can be found in saliva, nasopharyngeal washings, semen, menstrual fluid, vaginal secretions, and blood.
• Transmission occurs from carriers to close contacts via oral/sexual routes or other exposures.
• Fecal-oral transmission has not been documented
• Any bodily fluid from HBV-infected patients may be infectious.
• Subclinical infections are common, a primary hazard to hospital personnel.
• Health care workers like surgeons, pathologists, physicians, nurses, lab technicians, and blood bank personnel have a higher hepatitis incidence.
• The incubation period is 50 to 180 days (60 to 90 days).
• The incubation appears linked to the HBV dosage and exposure route, prolonged with low viral doses, or non-percutaneous infection

Hepatitis B Pathogenesis

• Outcomes after HBV infection range from full recovery to chronic hepatitis and, rarely, death from fulminant disease.
• In adults, 65-80% of infections are inapparent, with 90-95% of patients recovering completely, but 80-95% of infants and young children with HBV become chronic carriers who test positive for HBsAg.
• Most individuals with chronic HBV are asymptomatic for many years, which may or may not have detectable liver disease.
• Chronic carriers have a high risk of developing Hepatocellular Carcinoma (HCC)
• Hepatocellular carcinoma (HCC) is a major cause of death.
• 80% of primary HCCs occur in HBV-infected individuals.
• As a DNA virus, HBV integrates its viral genome into the host's chromosome, which can lead to mutation, with concomitant changes in cell growth control

Hepatitis B Diagnosis & Treatment

• Diagnosis includes liver function tests with liver biopsy, PCR for viral DNA, and ELISA for viral antigens/antibodies.
• HBV DNA and HBeAg indicate the viremic stage during incubation, with high concentrations in the blood and high communicability.
• HBsAg is detectable for 2-6 weeks and persists with the disease's active course.
• Recovery from infection leads to the disappearance of HBsAg.
• High levels of IgM-specific anti-HBc signal the onset of clinical illness; its presence indicates viral replication.
• Chronic HBV carriers have persistent HBsAg for over 6 months, with/without HBeAg or anti-HBe.
• HBsAg may persist for years after the loss of HBeAg.
• Low titers of IgM anti-HBc are found in most chronic HBsAg carriers.
• Acute HBV needs no treatment 95% of the time (self-limited).
• Chronic HBV treatment aims to reduce the risk of liver disease and complications like cirrhosis or HCC.
• Pegylated interferon alfa-2a, entecavir, and tenofovir are first-line therapies.
• Telbivudine is a second-line cytosine nucleoside analog that inhibits HBV DNA polymerase.
• Lamivudine, 3TC, and adefovir are third-line nucleoside analog viral polymerase inhibitors.

Hepatitis B Prevention

• General measures include screening blood before transfusion and infection control practices (hand hygiene, gloves, disposable syringes).
• Active immunization involves recombinant HBsAg synthesized by yeast.
• Egypt's HBV vaccination program since 1992 schedules doses at 2, 4, and 6 months.
• Unvaccinated adults/others can receive 3 IM doses over 6 months.
• Immunocompromised groups respond less effectively to vaccination.
• Passive immunization with hepatitis B immunoglobulin, HBIG, is effective post-exposure, not pre-exposure.
• Immediate administration of HBIG and the HBsAg vaccine at different sites provides immediate and long-term protection for those exposed to HBV percutaneously or via mucosal surfaces.
• Recommended to give to infants of HBV-positive mothers (+ HBV vaccine) and those accidentally exposed to contaminated blood via needle-stick.

Hepatitis C

• Hepatitis C, a cause of NANB transfusion-associated hepatitis, was discovered in 1988.
• Around 1% of people are infected globally, per the WHO, which equates to 70 million chronic carriers susceptible to cirrhosis or liver cancer.
• Per the Egyptian Health Issues Survey (EIHS), 7% of those aged 15-59 had active hepatitis in 2015, exceeding global averages.
• The transmission occurs through direct percutaneous exposure to blood.
• 80% of Hepatitis C transmissions are from injecting drug users.
• Other possible exposures include hemophiliacs treated with blood-clotting products treated prior to 1987, recipients of HCV-positive transfusions, chronic hemodialysis patients (10%), and health workers (1%).
• The virus can transmit mother to infant, though less often than Hepatitis B.
• About 3-10% of these newborns vertically transmit the virus.
• Higher loads of HCV or coinfection with HIV more frequently yields transmission.
• Breastfeeding poses no risk of Hepatitis C transmission.
• HCV is found in saliva in more than a third of patients coinfected with HCV and HIV.
• The average incubation period for HCV is 6 to 7 weeks, and around 90% of patients test anti-HCV-positive within 5 months.
• Viral replication is in hepatocytes.
• Liver cell destruction may result from viral gene product or host immune response, including cytotoxic T cells.
• A majority of infections are subclinical but around 25% have acute hepatitis with jaundice.
• A significant proportion progress to chronic hepatitis and cirrhosis. Some develop hepatocellular carcinoma (5-25%) many years (15-60) after initial infection.
• Around 40% of chronic liver diseases are associated with HCV.
• End-stage liver disease due to HCV frequently indicates an adult liver transplant.
• HCV genotypes 1-4 are the primary types.
• Genotype 4 has the highest frequency of leading to chronic infection after an acute case.

Hepatitis C Diagnosis & Treatment

• Diagnosis involves serologic assays, which may take 3-6 months to detect.
• Enzyme immunoassays (EIA) detects antibodies but cannot distinguish acute, chronic or resolved infection.
• Nucleic acid-based assays such as real-time PCR (RT-PCR) detect circulating HCV RNA in blood or serum.
• Nucleic acid-based assays may be used to diagnose early cases, detect active viral replication (serum), follow up the response to treatment (viral load measurement), or to perform genotyping to predict the response to treatment.
• Classic treatment of Hepatitis C includes interferon plus ribavirin.
• Treatment response depends on several factors, such as patient age, viral load, liver fibrosis, and HCV genotype.
• Higher response rates typically occur for genotypes 2 and 3 (75-80%), as opposed to type 1 (30-35%).
• Subtype 4a has a poor response to therapy.
• Treatment generally lasts for 24–48 weeks based on the viral genotype.
• Second-generation treatments are direct-acting antiviral drugs. DAADs include: Sofosbuvir, a nucleotide analog HCV viral RNA polymerase inhibitor, Simepravir, an HCV protease inhibitor, and Daclatasvir, which prevents RNA replication and virion assembly.
• Second-generation treatments have less toxicity with greater efficacy, provide a higher cure rate, fewer side effects, and reduced duration of therapy compared to first line treatments.

Hepatitis C Treatment Timeline

• From 2006 to 2014, Interferon plus Ribavirin achieved less than 60% Sustained Virologic Response (SVR).
• In October 2014, Sofosbuvir/Ribavirin (82.7% SVR) and Sofosbuvir/PegIFN/Ribavirin (93.9% SVR) regimens were introduced, with a prioritization of patients with advanced fibrosis and cirrhosis.
• By May 2015, Simeprevir/Sofosbuvir regimens achieved a 94-98.5% SVR, with all fibrosis patients eligible for treatment, ending prioritization.
• In December 2015, the main line of treatment was Sofosbuvir/Daclatasvir + Ribavirin yielding a 94.7% / 95.4% SVR.
• The nationwide screening program launched in October 2018.

Hepatitis C Prevention

• A hepatitis C vaccine is not available.
• Screening of HCV in blood, plasma, organ and tissue is important.
• Inactivation of the virus is needed in plasma-derived products is vital.
• Avoid exposure to blood/body fluids through standard precautions.
• Implementation of infection control in healthcare settings is essential.
• Post-exposure, wash the exposed area with soap and water or saline for blood splashes to the eyes. Follow-up post exposure is recommended.

Hepatitis D

• Hepatitis D is caused by the Delta agent.
• HDV always occurs as a coinfection with hepatitis B (HBV) and is more common in Mediterranean countries.
• HDV is transmitted through the same routes as HBV but does not appear to transmit sexually.
• Liver damage is similar to other forms of viral hepatitis but may be more extensive/severe in HDV
• Diagnosis includes detection of anti-HDV antibodies via ELISA and/or PCR.
• There is no specific treatment for Hepatitis D.
• HBV vaccination can prevent hepatitis B and D, but does not prevent hepatitis B carriers from getting a superinfection from Hepatitis D.

Hepatitis E

• HEV is a non-enveloped, single-stranded RNA virus that causes enterically transmitted, waterborne hepatitis resembling HAV.
• HEV occurs primarily in developing countries through the fecal oral route.
• The ELISA test detects viral RNA via RT-PCR, along with anti-HEV IgM and IgG in the feces of infected individuals.
• Symptoms are similar to acute viral hepatitis, but progression to chronic hepatitis is not seen; therefore, it's similar in Hepatitis A.
• No antiviral therapy or vaccines exist.

Types of viral Hepatitis Summary

• Important information of the different types of hepatitis virus is provided
• The type of virus, prevalence, chronic infection, oncogenicity & HCC, source of virus and mode of transmission are all listed

Retroviruses

• Retroviruses have reverse transcriptase enzyme, which converts ssRNA into dsDNA.
• Retroviruses reverse the order of information transfer like RNA.
• Retro = backwards
• Two genera of human interest are: Lentivirus, which includes HIV-1 and HIV-2 and Human T-cell lymphotrophic virus-bovine leukemia virus group (HTLV-BLV group), which contains human T-cell leukemia viruses 1 and 2 (HTLV-1 and -2).

HIV

• HIV involves a retrovirus, with acquired immune deficiency syndrome stemming from the virus.
• Two copies single stranded RNA viruses are enveloped
• HIV contains reverse transcriptase, integrase and protease.
• Retrovirus replication steps include: binding on host cells by receptors, reverse transcription forming DNA, DNA integration to form provirus, and provirus creating mRNA in a specific code for viral particles.
• HIV is unique in that its assembly and budding process leads to cell lysis.
• HIV may have originated in central Africa.

HIV Transmission

• HIV is transmitted sexually, parenterally, or from mother to fetus.
• High titers present in semen and blood.
• Transmission typically occurs by sexual, parenteral (contaminated needles or blood products), and perinatal routes.
• HIV is found in both semen and vaginal secretions, the presence of other sexually transmitted diseases increases the risk of transmission by 100-fold.
• 15 to 40% of untreated women transmit the infection to newborns
• Infants become infected during birth, in utero or through breastfeeding.
• The majority of infections in infants (30-70%) occur in utero during delivery and there is additional risk from the breastfeeding.
• Perinatal HIV transmission can occur from 1/3 to 1/2 of infections in Africa, and due to breastfeeding infections usually occur early by 6 months.
• The major risk factor of transmission is due to higher maternal loads of the virus.
• Health care workers risk infection via needlestick with contaminated blood, though with lower incidence compared to needlestick accidents.
• Contrastingly, risk of Hepatitis C infection post needlestick is about 1.8%, while Hep B occurs with approximately 6-30% of infections.
• Transmission does not occur through sneezing, coughing, insect bites, touching, sharing cups, public baths, handshakes, food-borne routes, or during work/school.

HIV Pathogenesis

• Primary Stage
  • Involves a flu-like illness occurring 1-6 weeks post-infection where the individual can infect other people.
• Asymptomatic Stage
  • Lasts for 10 years.
  • It may involve swollen lymph nodes which causes continuous replication.
  • There level of HIV cells drops with CD8+ destroying cells and CD4+ replacing killed cells.
• Symptomatic Stage
  • CD4+ can not replace in cells in this stage, which causes the virus to mutate.
  • The virus numbers increases and the CD4+ decreases.
• Stage 4
  • Characterized by severe illnesses, leading to an AIDS diagnosis due to general weakness.
• The virus attacks T4 helper cells with CD4 molecules as entry sites.
• After expression at high levels on viral glycoproteins, the surface causes cell fusion with T4 cells leading to lysis and suppressing immune response.

HIV Diagnosis, Treatment and Prevention

• Diagnosis may include PCR, which aids to detect early and confirm ELISA results.
• A window lasts 25 days between the virus presence in the blood with detection of HIV antibodies.
• Treatment involves a multidrug strategy to counter resistance because reverse transcriptase lacks proofread activity.
• A high recombination rate mixes 2 mutations in one virus.
• HAART, or highly active antiretroviral therapy. has no cure for HIV/AIDS but controls via different drug classes, blocking distinct viral processes.
• Drug treatment includes non-nucleoside inhibitors, for example efavirenz, etravirine and nevirapine.
• Another treatment are Nucleoside or nucleotide, examples include Abacavir, Truvada, Descovy and Combivir. Protease are also helpful, for example atazanavir, darunavir and indinavir.
• Entry or fusion, Integrase and It can often suppress viral replication
• Entry in the body can be helped from enfuvirtide and maraviroc.
• Integrase includes raltegravir and dolutegravir, suppression of replication is useful, as well.
• HAART benefits come with challenges; high costs, toxicity, resistance, and access problems in the global spectrum inhibit the effects.
• Preventative antiretroviral drugs have shown HIV transmission with pre-exposure prophylaxis to add a preventative new structure.
• There is no available vaccine due to high mutation.
• High mutation rates with incomplete clearance.
• It not completely cleared by the host immune response after primary exposure, the virus infects the immune system and there are unclear cellular animal responses.
• Prevention involves screening blood supplies, sterilizing needles, and maintaining precautions by health workers.
• HIV's transmission from mother to child has shown significant reduction through AZT therapy, reducing transmission.
• AZT is Zidovudine
• Treatment decreases in viral load with AZT short courses and has shown a 50% reduction, depending on breastfeeding patterns.