Hepatitis B, C, and HIV Treatment

• Antivirals for Hepatitis C Virus (HCV) function by impeding viral protein synthesis.
• Nucleoside reverse transcriptase inhibitors (NRTIs) treat both Hepatitis B and HIV, with lower doses used for Hepatitis B.
• HIV screening is essential before NRTI treatment because using lower Hepatitis B doses in HIV patients can lead to resistance.
• Hepatitis B is diagnosed via detectable Hepatitis B surface antigen (HBsAg) in serum.
• Screening for Hepatitis B Virus (HBV) employs both HBsAg and anti-HBV.
• Acute Hepatitis B includes positive IgM anti-HBc, while chronic Hepatitis B includes negative IgM anti-HBc, though it can have low HBV DNA.
• Hepatitis B vaccination uses a subunit HBsAg vaccine, recommended for high-risk groups like healthcare workers.

Acute HCV Infection Diagnostic Tests:

• Antibody to HCV is positive in 6–24 weeks, negative early in the infection.
• Viral load (HCV RNA in serum) is detectable within 1–2 weeks.
• Alanine aminotransferase (ALT) levels are elevated.
• Confirmed by viral RNA detection (PCR test).
• Liver biopsy can assess liver damage with clusters of lymphocytes.

Chronic HCV Infection Diagnostic Tests:

• Antibody to HCV is positive.
• Viral load (HCV RNA in serum) is detectable.
• ALT is typically elevated but fluctuates to near normal.

Recovered from HCV Infection Diagnostic Tests:

• Antibody to HCV is positive.
• Viral load (HCV RNA in serum) is undetectable.
• ALT may be normal but can fluctuate.

HCV Pharmacological Management:

• Treatments can now be curative, using direct-acting antiviral agents (DAAs).
• DAAs block viral replication by inhibiting specific viral proteins.
• DAAs include protease inhibitors (interferon A), NS3B inhibitors, and NS5A inhibitors like ombitasvir, daclastavir, elbasvir, ledipasvir, pibrentasvir, and velpastasvir.
• Nucleoside/nucleotide reverse transcriptase inhibitors inhibit reverse transcriptase, integrate into viral DNA, and terminate DNA chain.
• Examples of Nucleoside/nucleotide reverse transcriptase inhibitors include entecavir, lamivudine, tenofovir, and adefovir.
• Side effects includes lactic acidosis, hepatomegaly with steatosis.
• Essential monitoring includes HIV status, HBV DNA levels, HBVAg and anti-HBV, and bone mineral density (tenofovir).
• Interferons stimulate the immune system against viruses, inducing the innate antiviral immune response.
• Peginterferon alpha-2a, a modified form of interferon-alpha, has a longer half-life and is used mainly for hepatitis B.

Interferon Side Effects:

• Side effects include suicidal ideation, neutropenia, thrombocytopenia, anemia and psychiatric issues.
• Serious psychiatric side effects include depression, hallucinations, aggression, and insomnia.
• Interferons are second- or third-line treatment for Hepatitis B Virus (HBV) due to resistance or inappropriate first-line therapy. Alpha interferon can be used for HBV, HCV, and some cancers. Beta interferon is used for multiple sclerosis.
• Ombitasvir inhibits non-structural protein 5A (NS5A), which limits viral replication.
• Paritaprevir binds to the active site of HCV protease.
• Ritonavir inhibits CYP3A, boosting paritaprevir levels.
• Dasabuvir inhibits nonstructural protein 5B, RNA-dependent RNA polymerase (NS5B RdRp), terminating viral replication.
• Viekira Pak illustrates four main drug classes:: NS5B polymerase inhibitors ("Buvir" drugs), NS5A inhibitors ("Asvir" drugs), and protease inhibitors ("Previr" drugs).

Ribavirin:

• Ribavirin inhibits viral RNA polymerase, inhibiting protein synthesis and boosts blood levels of other medications.
• Past treatments involved interferon-alpha and pegylated interferon, but now protease inhibitors like boceprevir and telaprevir are favored due to interferon's side effects.
• Contraindications include pregnancy, male patients with pregnant sexual partners, and significant cardiac disease.
• Side effects include teratogenicity, hemolytic anemia, worsening of cardiac disease, and hypothyroidism.
• Not effective as monotherapy for HCV.
• Many drug interactions.
• Pharmacologic management for acute HCV infection includes supportive therapy only.
• Chronic HCV infection treatment with interferon alpha includes nucleoside analogs like lamivudine, adefovir, entecavir, and tenofovir, though interferons have harsh side effects.
• RNA polymerase lacks proofreading ability, leading to frequent mutations, high viral variability and difficulty in vaccine development.
• Nonpharmacological management includes liver transplant for advanced infection.
• Hepatitis B virus (HBV) is an enveloped, double-stranded DNA virus and a member of the hepadnavirus family.
• Hepatitis D virus (HDV), also known as delta virus, is an enveloped, single-stranded RNA virus.
• HDV membrane contains Hepatitis B surface antigen (HBsAg).
• Hepatitis D antigen (HDAg) is found in the capsid of HDV.

Modes of Transmission:

• HBV and HDV:

  • Sexual contact through semen or vaginal secretions
  • Contaminated blood (e.g., transfusions, shared needles in IV drug use)
  • Mother-to-child transmission during childbirth (rarely during pregnancy) through milk, 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 cannot cause disease on its own; it requires HBV for replication.

Hepatitis D Superinfection:

• Co-infection (simultaneous HBV & HDV infection)
• Superinfection (HDV infects an individual with chronic HBV):
  • More severe than co-infection
  • Increases risk of fulminant hepatitis, massive liver necrosis, and hepatic encephalopathy.
• HDV directly damages hepatocytes, leading to more severe liver injury.

Symptoms of Acute Hepatitis:

• Jaundice (yellow skin & eyes)
• Pale-colored stools
• Dark urine
• Unexplained weight loss
• 2–10% of adults and over 25% of young children remain chronically infected with HBV, which can lead to cirrhosis and hepatocellular carcinoma. Clinical Manifestations (incubation Period: 1–6 months, usually 2–3 months)

Acute Hepatitis B:

• Asymptomatic or mild symptoms (in two-thirds of cases)
• Symptomatic hepatitis (one-third of cases)
  • Pre-icteric phase: Fever, fatigue, body aches, nausea (few days to a week)
  • 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.
• Treatment: 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 is a lipoprotein-enveloped, single-stranded RNA virus transmitted through contaminated blood or sexual contact.

Entry and Replication:

• Binding to Cells
  • The virus uses its lipoprotein envelope, which resembles LDL and VLDL, to attach to LDL receptors on the cell surface.
• Endocytosis
  • The virus is wrapped by the cell membrane and brought inside in a bubble called an endosome.
• Capsid Release
  • The viral membrane fuses with the endosome, releasing the capsid, which then dissolves, leaving only viral RNA in the cytoplasm.
• Protein Synthesis
  • Viral RNA binds to host ribosomes, producing:
    • Structural proteins (used to build new viral particles)
    • Non-structural proteins (used for replication)
• RNA Replication
  • 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.
• Viral Release
  • New viral particles exit the cell through exocytosis (reverse endocytosis).
• Lipoprotein enveloped, single-stranded RNA virus Hepatitis C virus is transmitted through contaminated blood or sexual contact.

Symptoms:

• 70-80% of infected individuals show no symptoms.
• If symptoms occur, they appear 2 weeks to 6 months after exposure.
• Symptoms 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.
• Without treatment, hepatitis C can lead to:
  • Liver damage
  • Liver cancer (hepatocellular carcinoma)
  • End-stage liver disease

Complications of Hepatitis C Infection:

• About two-thirds of affected individuals may develop complications, including:
  • 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
  • Diabetes
  • Hypothyroidism
  • Skin conditions (e.g., porphyria cutanea tarda, lichen planus)
• Hepatitis C virus infects B lymphocytes, it may disrupt antibody production and function, contributing to these complications.
• CYP3A