Hepatitis B and C Virus characteristics

• Antivirals targeting HCV function by blocking viral protein synthesis.
• Nucleoside reverse transcriptase inhibitors (NRTIs) treat both Hepatitis B and HIV, but HBV requires lower doses.
• HIV screening is crucial before NRTI treatment for HBV to prevent resistance development if HIV is present.
• Hepatitis B is diagnosed by detecting HBsAg in the serum.
• HBV screening includes both HBsAg and anti-HBV tests.
• Laboratory serologies differentiate acute from chronic HBV infections.
• Acute HBV includes positive IgM anti-HBc, while chronic HBV is negative for IgM anti-HBc but can have low HBV DNA.
• The HBV vaccine is a subunit HBsAg vaccine and is recommended for high-risk individuals, like healthcare workers.

Acute HCV Infection Diagnostic Tests

• Antibody to HCV is positive after 6-24 weeks.
• HCV RNA is detectable in serum within 1-2 weeks.
• Alanine aminotransferase (ALT) is elevated.
• Viral RNA detection is done via PCR test.
• Liver biopsy assesses liver damage with lymphocyte clusters.

Chronic HCV Infection Diagnostic Tests

• Antibody to HCV is positive.
• HCV RNA is detectable in serum.
• ALT is typically elevated but fluctuates.

Recovered HCV Infection Diagnostic Tests

• Antibody to HCV is positive.
• HCV RNA is undetectable in serum.
• ALT may be normal or fluctuate.

Pharmacological Management of HCV

• Treatments can be curative using direct-acting antiviral agents (DAAs).
• DAAs inhibit specific viral proteins, blocking viral replication.
• DAAs include protease inhibitors, NS3B inhibitors, and NS5A inhibitors (e.g., ombitasvir, daclastavir, elbasvir, ledipasvir, pibrentasvir, velpastasvir).
• Nucleoside/nucleotide reverse transcriptase inhibitors incorporate into viral DNA, causing chain termination.
• Examples of nucleoside/nucleotide reverse transcriptase inhibitors include entecavir, lamivudine, tenofovir, and adefovir.
• Side effects of these inhibitors are lactic acidosis and hepatomegaly with steatosis (fat accumulation in liver cells).
• Monitored factors for patients on these medications should include HIV status, HBV DNA levels, HBVAg and anti-HBV levels, and bone mineral density (for Tenofovir).

Interferons

• Interferons are proteins that stimulate the immune system against viruses.
• Peginterferon alpha-2a is a modified form with a longer half-life, mainly used for hepatitis B and it induces the innate antiviral immune response.
• Side effects include suicidal ideation, neutropenia, thrombocytopenia, anemia, depression, hallucinations, aggression, and insomnia.
• Interferons are second- or third-line treatments for HBV due to resistance or inappropriate first-line prescriptions.
• Alpha interferon can treat HBV, HCV, and some cancers, while beta interferon is used for multiple sclerosis.

Direct Acting Antivirals (DAAs)

• Ombitasvir inhibits non-structural protein 5A (NS5A), limiting viral replication.
• Paritaprevir binds to the active site of HCV protease.
• Ritonavir inhibits CYP3A, increasing paritaprevir levels.
• Dasabuvir inhibits nonstructural protein 5B, RNA-dependent RNA polymerase (NS5B RdRp), halting viral replication.

Viekira Pak

• Viekira Pak contains NS5B polymerase inhibitors ("Buvir" drugs), NS5A inhibitors ("Asvir" drugs), and protease inhibitors ("Previr" drugs).

Ribavirin

• Ribavirin inhibits viral RNA polymerase, inhibiting protein synthesis and increases blood levels of other medications.
• Treatments once involved interferon-alpha and pegylated interferon, the recommendation now is protease inhibitors boceprevir and telaprevir.
• Contraindications include pregnancy, male patients with pregnant sexual partners, and significant cardiac disease.
• Side effects include teratogenicity, hemolytic anemia, worsening cardiac disease, and hypothyroidism.
• Ribavirin is not effective as monotherapy for HCV because no drugs are effective for that use.
• Ribavirin is so teratogenic that it cannot be prescribed to males with pregnant sexual partners as even a small amount in semen can cause fetal harm.
• Acute HCV infection is managed with supportive therapy only.
• Chronic HCV infection treatment with interferon alpha includes NRTIs (nucleoside analogs)
• NRTIs are lamivudine, adefovir, entecavir, and tenofovir.
• Interferons have harsh side effects.
• RNA polymerase lacks proofreading ability, leading to frequent mutations in the virus, resulting in high viral variability and difficulty in vaccine development.
• Liver transplant is a nonpharmacological intervention for advanced infection.
• Hepatitis B virus (HBV) is an enveloped, double-stranded DNA virus belonging to the hepadnavirus family.
• Hepatitis D virus (HDV) is an enveloped, single-stranded RNA virus that contains Hepatitis B surface antigen (HBsAg) in its membrane and Hepatitis D antigen (HDAg) in its capsid.

Modes of Transmission for HBV and HDV

• Sexual contact through semen or vaginal secretions
• Contaminated blood (transfusions, shared needles)
• Mother-to-child transmission during childbirth (rarely during pregnancy), not milk or amniotic fluid
• HDV spreads the same way but only causes disease in individuals with an active Hepatitis B infection.

HBV Life Cycle & Pathophysiology

• Entry into hepatocytes (liver cells)
• Fusion with the cell membrane and release of the capsid
• DNA elongation and transcription in the nucleus
• Translation of viral mRNAs into viral proteins
• Assembly of new viral particles
• Viral release without damaging hepatocytes

Hepatitis D Virus (HDV)

• Enters the hepatocyte the same way as HBV
• Uses the host cell’s RNA polymerase for replication
• Synthesizes delta antigens
• HDV RNA is packaged into a capsid
• Requires HBsAg for complete viral formation and exit
• HDV requires HBV for replication and cannot cause disease on its own.
• Superinfection is when HDV infects an individual with chronic HBV, more severe than co-infection (simultaneous HBV & HDV infection)
• Superinfection increases risk of fulminant hepatitis, massive liver necrosis, and hepatic encephalopathy.
• HDV directly damages hepatocytes, leading to more severe liver injury, unlike HBV which causes liver damage indirectly via immune system activation.
• Symptoms of acute hepatitis include jaundice, pale-colored stools, dark urine, and unexplained weight loss.
• 2–10% of adults and over 25% of young children remain chronically infected with HBV and it can lead to cirrhosis and hepatocellular carcinoma.

Clinical Manifestations

• (incubation Period: 1–6 months, usually 2–3 months)
• Acute Hepatitis B manifests as asymptomatic or mild symptoms (in two-thirds of cases) or symptomatic hepatitis (one-third of cases).
• Symptoms of a Pre-icteric phase: Fever, fatigue, body aches, nausea (few days to a week)
• Symptoms of a Icteric phase: Jaundice, dark urine, pale stools (1–2 weeks)
• Recovery phase
• Rare cases of fulminant hepatitis: Severe liver failure with fever, abdominal pain, vomiting, jaundice, confusion, and even coma

Chronic Hepatitis B

• Occurs in 5–10% of cases
• Symptoms are usually milder but can lead to cirrhosis and hepatocellular carcinoma (liver cancer)

HDV Diagnosis

• HDV RNA, delta antigen (HDAg), or anti-HDV antibodies confirm the infection
• No specific treatment—HBV treatment also helps control HDV
• Prevention: Avoid high-risk behaviors (unprotected sex, IV drug use)
• HBV vaccination protects against both HBV & HDV
• Post-exposure prophylaxis: Hepatitis B immune globulin (HBIG) within 1 week of exposure
• High-Risk Groups for Vaccination: Babies born to mothers with chronic HBV, IV drug users, People with multiple sex partners, Dialysis patients, Healthcare workers

Hepatitis C Virus (HCV)

• Hepatitis C virus is a lipoprotein enveloped, single-stranded RNA virus transmitted through contaminated blood or sexual contact.
• The virus uses its lipoprotein envelope which resembles LDL and VLDL, to attach to LDL receptors on the cell surface.
• The virus is wrapped by the cell membrane and brought inside in a bubble called an endosome.
• The viral membrane fuses with the endosome, releasing the capsid, which then dissolves, leaving only viral RNA in the cytoplasm.
• Viral RNA binds to host ribosomes, producing structural and non-structural proteins.
• RNA Replication occurs when the RNA-dependent RNA polymerase enzyme creates a negative-sense RNA template from the positive-sense viral RNA.
• The replication complex then uses this template to synthesize more copies of the positive-sense RNA, which will be packaged into new viral particles within the host cell’s endoplasmic reticulum.
• New viral particles exit the cell through exocytosis (reverse endocytosis).
• 70-80% of infected individuals show no symptoms
• Symptoms appear 2 weeks to 6 months after exposure and are usually mild and may include fatigue, nausea, loss of appetite, joint and muscle pain.
• Jaundice is uncommon in hepatitis C, unlike in other viral hepatitis infections.
• Untreated hepatitis C can lead to liver damage, liver cancer (hepatocellular carcinoma), and end-stage liver disease.
• About two-thirds of affected individuals may develop complications.
• Cryoglobulinemia – Presence of temperature-sensitive antibodies in the blood
• Autoimmune hemolytic anemia – Immune destruction of red blood cells
• Glomerulonephritis – Inflammation of kidney glomeruli
• Leukocytoclastic vasculitis – Inflammation of small blood vessels
• Other common complications: Diabetes, Hypothyroidism, Skin conditions (e.g., porphyria cutanea tarda, lichen planus)
• Since hepatitis C virus infects B lymphocytes, it may disrupt antibody production and function, contributing to these complications.
• CYP3A