Viral Hepatitis Therapeutics
Hepatitis- Description • Inflammation of the liver • Acute viral hepatitis • Most common cause • Viral infection accounts > 1/2 cases of acute hepatitis • Types of Infectious Viral Hepatitis: • A • B • C • D • E • G
Hepatitis- Description • Other possible causes • Drugs (alcohol) • Chemicals • Autoimmune liver disease • Metabolic diseases • Viruses
Epidemiology of Viral Hepatitis • HAV is the most common cause of acute hepatitis • HCV is the most common cause of chronic hepatitis. • See Table 1
Clinical Manifestations 1-Preicteric phase • Precedes jaundice • Lasts from 1 to 21 days • Period of maximal infectivity for hepatitis A • Anorexia • Nausea • Abdominal discomfort • Right upper quadrant
Clinical Manifestations -Preicteric phase • Vomiting • Constipation • Diarrhea • Malaise • Headache • Low-grade fever • Arthralgias • Skin rashes
Clinical Manifestations 2-Icteric phase • Lasts 2 to 4 weeks • Characterized by jaundice • Pruritus 3-Posticteric phase • Begins as jaundice is disappearing • Lasts weeks to months • Malaise • Easy fatigability
Complications • Most patients with acute viral hepatitis recover completely with no complications • Overall mortality rate < 1% • Fulminant hepatic failure FHF • Chronic hepatitis • Cirrhosis • Hepatocellular carcinoma HCC
Diagnostic Studies • Transaminases (ALT, AST) • Alkaline phosphatase • Serum proteins • Serum bilirubin • Urinary bilirubin • Prothrombin time • Biopsy • Physical assessment • Splenomegaly • Palpable liver • Serology
Treatment • No specific treatment or therapy for acute viral hepatitis • Most patients can be managed at home • Drug Therapy • No specific drug therapies • Supportive therapy • antiemetics • diphenhydramine (Benadryl) • chloral hydrate
Hepatitis A (HAV) • “Infectious Hepatitis” • Picornavirus family (RNA)-cytopathic • More common in developing countries • Travelers • Frequently occurs in small outbreaks
Clinical Features of HAV • Fecal-oral (food, water) route of transmission • Found in feces 2 or more weeks before the onset of symptoms and up to 1 week after the onset of jaundice • Present in the blood only briefly • 2-4 weeks incubation
Clinical Manifestations of HAV • Acute onset • Mild flu-like manifestations • More severe & higher mortality in adult > children • Typical cases→several weeks of malaise, anorexia, nausea, vomiting, and ↑ ALT/AST • Jaundice develops in more severe cases. • no carrier state • Fulminant hepatic failure rare (0.14% fatal) but almost exclusively in >50 y.o. age group
Diagnosis of hepatitis A • Anti-HAV immunoglobulin M (IgM) • Appears in the serum as the stool becomes negative for the virus • Detection of IgM anti-HAV indicates acute hepatitis • disappears several months after the initial infection • Anti-HAV immunoglobulin G (IgG) • IgG anti-HAV is an indicator of past infection • Presence of IgG antibody provides lifelong immunity
Treatment of acute of HAV Infection • Treatment is supportive • no antiviral therapy available. • Hospitalization for patients with nausea and vomiting →dehydration. • Patients with acute liver failure require close monitoring to ensure they do not develop FHF
Control of Hepatitis A-Vaccine Active Immunity • Two-dose vaccine (HAVRIX or VAQTA) -adults every 6-12 months -peds=3 doses (0,1,6-12mo.) Especially For • International travelers to endemic regions. • Where endemicity rates are high (high-risk sexual activity, IV drug abusers, developmentally challenged, daycare employees, lab workers, handlers of primates, any patient with chronic liver disease)
Hepatitis A Vaccine Combination vaccine-A+B (Twinex) • Typical administration involves 3 injections of 1 mL IM on a 0-, 1-, and 6-month schedule. • FDA approved for use in adults only
Control of Hepatitis A- IG Passive immunotherapy with IgG 1-Pre-exposure • 0.02 mL/kg IM for individuals who anticipate spending < 3 months in an endemic region. • 0.06 mL/kg IM every 4-6 months if they are planning to spend > 3 months in a region where HAV is endemic
Control of Hepatitis A- IG Passive immunotherapy with IgG 2-Post-exposure • 0.02 mL/kg, given IM as a single dose.
Hepatitis B • “Serum Hepatitis” • DNA- Virus • Incubation period = 45-180 days • Higher risk of developing HCC
Transmission of HBV • Perinatal • Sexual • Parenteral
High Risk Groups For HBV • Adolescents. • Residents / staff of homes for devel. challenged • Hemodialysis patients • Factor conc. recipients • Household members/ sex partners of HBV carriers • Travelers (> 6 mo., endemic, close with locals) • Travelers (short-term if med. setting) • IVDA • Prisoners
Clinical Manifestations • Insidious onset • Symptoms more severe • Fewer GI symptoms • the clinical illness associated with acute HBV infection may range from mild to severe (<1% FHF). • After acute hepatitis resolves • 95% of adult & 5-10% of infants develop anti-HBV antibody, clear HBsAg and HBV virions, and fully recover. • 5% of adult and 90-95% of infants develop chronic infection.
Inactive Carrier State • 70-90% of HBsAg carriers → inactive carrier state • Have no symptoms, WNL LFTs, and normal or minimally abnormal liver biopsy results. • Evidence of HBV replication nonexistent or minimal,(serum HBV DNA of 0-30,000 copies/ml) • Remain infectious to others through parenteral or sexual transmission. • Ultimately develop HBsAb and clear the virus. • Some develop chronic hepatitis • Remain at low risk for HCC. • no effective antiviral therapies are available
Chronic Hepatitis • 10-30% of HBsAg carriers develop chronic hepatitis. • Often symptomatic. most commonly with Fatigue • May occasionally experience acute flare of disease, similar to acute hepatitis. • May have extrahepatic manifestations, including polyarteritis nodosa, cryoglobulinemia, and glomerulonephritis. • Have abnormal LFTs, evidence for active HBV replication, and inflammatory or fibrotic activity on liver biopsy. • May be considered either HBeAg-positive or HBeAg-negative. • Approximately 20% develop cirrhosis or HCC.
Diagnosis of acute HBV infection HBsAg • The 1st serum marker • Represents presence of HBV virions in the blood. • does not indicate whether the infection is acute or chronic. • may remain detectable for life • Individuals with + HBsAg → carriers of HBV • Inactive carriers • chronic hepatitis. • +HBeAg and HBV DNA →a state of active viral replication and a high level of infectivity.
Diagnosis of acute HBV infection Anti-HBc (HBcAb). • The 1st antibody to appear • Initially, IgM → diagnostic for acute infection. • later, IgM disappears → IgG anti-HBc appears and indicates a patient has been infected with HBV • Remain + in patients who recover and in persistent infection
Diagnosis of acute HBV infection Anti-HBs • believed to offer immunity to future exposures to HBV. • may persist for the life of the patient. HBeAg a marker of viral replication disappears when viral replication slows& anti-HBe is detected. Anti-HBe may persist for years
Control of HBV -Vaccine 1-Pre-exposure Vaccination • Infants/children, at anterolateral thighs • 2-3 doses • Form 11-20 y.o. at 2,4,6 months • from Birth, at 1-2, 6-18 months • Adults, at Deltoid (3 doses) • 0,1,6 months (or 0,2,12 months) • use high dose vaccine in immunosupp., dialysis, severe liver disease • boost when level < 10mIU/mL on annual testing
Markers after vaccination for HBV • > 90% of recipients develop protective anti-HBs. • Vaccine recipients are not positive for anti-HBc unless previously infected with HBV.
Control of HBV -Vaccine 2-Post-Exposure HBV Prophylaxis • Risk of acquisition • 20-66% from needle-stick injury • 90% mother → child • HBV vaccine series + HBIG 0.06 ml/kg • May not need HBIG to prevent perinatal transmission (only vaccine) if mother is HBeAg –ve.
Control of HBV -IG Hepatitis B Immune Globulin • Hepatitis B immune globulin (HBIG) derived from plasma. • Provides passive immunization for individuals with recent exposure to a patient infected with HBV. • Also administered following liver transplantation to persons infected with HBV to prevent HBV-induced damage to the liver allograft.
Treatment of Chronic HBV • When to Treat? Candidates for antiviral therapy must have evidence of active HBV infection • HBV DNA > 105 copies/mL in patients who are positive for HBeAg • HBV DNA > 104 copies/mL in patients who are negative for HBeAg • Seropositive for HBsAg > 6mo • Increased AST/ALT
Treatment of Chronic HBV • Goal of antiviral treatment inhibition of viral replication→ loss of HBeAg and HBV DNA • Secondary goals • reduce symptoms • prevent or delay the progression of chronic hepatitis to cirrhosis or HCC. • Antiviral therapy infrequently leads to viral eradication • No antiviral therapy is available for inactive carriers who do not have actively replicating virus.
Treatment of Chronic HBV Interferon alfa • INF have antiviral and immunomodulatory effects. • ↑ ALT is common 8-12 weeks after starting therapy → INF-induced activation of the cell-mediated immune system. • Loss of HBeAg and HBV DNA occurs in 37% of patients. • INF is most effective when • administered shortly after exposure • when it is used in patients with an ALT > 100 U/L who do not have a markedly elevated level of HBV DNA.
Treatment of Chronic HBV Interferon is less effective in patients with (1) lifelong HBV infection, (2) a low ALT level (ie, <100 U/L), (3) a high HBV DNA level, (4) end-stage renal disease, (5) HIV infection, (6) a need for immunosuppressive therapy
Treatment of Chronic HBV Adverse Effects of INF • Common but lead to discontinuation of the drug in only 5-10% of patients. • Flu like symptoms (fatigue, fever, headache, myalgia, arthralgia), • Neuropsychiatric symptoms (depression, irritability, somnolence), • Hematological effects (granulocytopenia, thrombocytopenia), • Miscellaneous effects (pain at injection site, dyspepsia, alopecia, thyroid function abnormalities).
Treatment of Chronic HBV 1-INF Alpha- (2b) Monotherapy • Adults: 5mU qd or 10 mU 3/w x 4-8 months • Children: 6mU/sq.m. BSA 3/w x 4-8 months • Pegylated INF alfa may also be used once per week by S/c. • Don’t use if decompensated liver dis. • If doesn’t respond to course of IFN alone : • retreat,? IFN+ riba , IFN+ lami, IFN +adef, lami alone , adef alone
2-Lamivudine for Chronic HB • Lamivudine is a synthetic nucleoside analogue inhibits DNA polymerase–associated reverse transcriptase and can suppress HBV replication. • Treatment with 100 mg/d po for 1 year → loss of HBsAg in 32% of patients. • Histological improvement and a statistically significant ↓ in the rate of development of hepatic fibrosis.
Treatment of Chronic HBV Advantages of Lamivudine for Chronic HB • Ease of use and low risk of ADR • Effective in non-responders to INF (high HBV DNA levels). • Successful in decompensated cirrhosis and recurrent hepatitis B after liver transplantation. Disadvantages • 24% of patients who initially responded develop resistance within 1st year of therapy. • Incidence ↑ to 69% after 5 years of therapy. • Due to development of a mutation in the HBV DNA polymerase gene. • Resistance may also lead to a reversion of improvements seen on liver biopsy specimens