Viral Hepatitis


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This was presented at the Resident and New Practitioners Forum on February 23rd and offered as a Continuing Education credit for those who attended.

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  • ALT and AST are not specific, as they are also found in skeletal muscle. LDH is even less specific.PT is insensitive. Levels don’t become abnormal until more than 80% of liver synthetic capacity is lost
  • Serum sickness: fever, joint inflammation or pain, or urticarial rash
  • Viral Hepatitis

    1. 1. JOY A. AWONIYI, PHARMD.PGY1 PHARMACY PRACTICE RESIDENT MIAMI VA HEALTHCARE SYSTEM Annual Resident and New Practitioner Continuing Education Forum Saturday, February 23rd, 2013
    2. 2. Objectives 2 To provide a brief overview of hepatitis To describe the anatomy and physiology of the liver To define hepatitis A, B and C To discuss the anatomy, pathophysiology, and epidemiology of each viral hepatitis condition To provide an overview of drug therapy for Hepatitis A, B,C To discuss associated patient assessment parameters including monitoring for efficacy and side effects of antiviral medications To explain the importance of laboratory tests and interactions used in the diagnosis and management of hepatitis To discuss the healthcare practitioners role in managing viral hepatitis
    3. 3. WHAT IS HEPATITIS? 3 Hepatitis is inflammation of the liver Causes of hepatitis  Viruses  Hepatitis A, B, C  Heavy alcohol use  Illicit Drugs  Medications  Allergic Reactions  Obesity  Autoimmune
    4. 4. ANATOMY AND PHYSIOLOGY OF THE LIVER 4  Anatomy  3 lb located on the right side and protected by the rib cage  Composed of a right and left lobe  Functions  Filters blood from the digestive tract  Detoxifies chemicals and metabolizes drugs  Manufactures proteins important for blood clotting and other functions
    5. 5. Hepatic Function Tests 5 Indicators of liver injury  In the event of injury to the liver, enzymes leak into circulation Lab Test Reference Range  Aspartate Aminotransferase (AST)  Alanine Aminotransferase (ALT) AST 8 - 48 U/L  Lactate Dehydrogenase (LDH) ALT 7 – 55 U/L  Alkaline Phosphatase (ALP) LDH 105 – 333 U/L  Levels may be normal in cases of chronic inflammation ALP 45 – 115 U/L Tbili 0.2 – 1.2 mg/dL Indicators of liver function  Total Bilirubin (Tbili) Albumin 3.5 – 5.0 g/dL  Albumin PT 9.5 – 13.8 seconds  Prothrombin Time (PT)
    6. 6. Symptoms of Viral Hepatitis 6 Fever Gray- colored Fatigue stoolAbdominal Loss of pain appetite Vomiting Nausea
    7. 7. Hepatitis A 7
    8. 8. Etiology and Pathophysiology 8  Caused by Hepatitis A Virus; a positive-strand, non- enveloped virus that infects only primates  Resistant to freezing, acid and detergents  Survives extended periods in water and soil  Inactivated by formalin and chlorine  Transmitted through fecal-oral route  Infection by person-to-person contact or ingestion of contaminated food or water  Higher prevalence in regions with low sanitation standards  Not associated with chronic disease - The adaptive immune response is effective in eliminating the virusHepatitis A
    9. 9. Epidemiology 9 Incidence rate was last Reported cases of Hepatitis A reported as 0.5 per declined 88% between 2000 and 100,000 population 2010 (2010) Risk Factors  Men who have sex with men  Recent international travel  Injection drug use  Sexual or household contact with an infected person  Involvement in a food/waterborne outbreakHepatitis A
    10. 10. Clinical Presentation 10 Incubation period  Typical Symptoms (15-50 days)  Fever/ Malaise  Nausea/vomiting  Abdominal discomfort  Jaundice Symptom Development  70% of children younger than 6 years are asymptomatic Elevation of Liver Enzymes  Physical Signs  Tender hepatomegaly  Splenomegaly Symptoms and lab  Bradycardiaabnormalities resolve within 2 months  Chronic infection does not occurHepatitis A
    11. 11. Treatment 11 No medications are available for the treatment of Hepatitis A infection Supportive Treatments  Appropriate rest  Balanced Nutrition  Avoidance of hepatotoxins  Acetaminophen  Alcohol Patients may require hospitalization to treat dehydration or evidence of hepatic decomposition Contact precautions should be observed during infectious periodHepatitis A
    12. 12. Vaccination 12 Recommended for the following patient populations: Travelers to regions Children at 24 Men who have sex Illegal drug users with intermittent or months with men (both IV and non-IV) high rates of Hep. A Persons who work Persons who work Persons with clotting Patients with chronic with HAV-infected with HAV in factor disorders liver disease primates laboratories Families or caregivers of recent adoptees Anyone else seeking from countries were long-term protection Hepatitis A is commonHepatitis A
    13. 13. Vaccination 13 Hepatitis A  DoseVaccine, Inactivate  12 months -18 years – 0.5mL IM d  19 years and older – 1mL IM  Post-exposure: Single dose ASAP Havrix®  Administration • 1440 Units/1mL  Deltoid is preferred for patients 2 or • Booster after more years 6-18 months  Anterolateral thigh may be used between 12 and 23 months  SHAKE WELL BEFORE USING! Vaqta® • 50 Units/1mL  Side effects • Booster after  Injection site erythema, swelling, or pain 6-12 months  Headache, irritability, somnolence  Fatigue, fever, malaiseHepatitis A
    14. 14. Hepatitis B 14
    15. 15. Etiology and Pathophysiology 15  Caused by Hepatitis B Virus, a small enveloped animal viruses that replicates in hepatocytes  Utilizes reverse transcription for replication  8 recognized genotypes  Transmitted through exposure to infectious blood or body fluids containing blood  Percutaneously  Sexually  Perinatally  Carriers are at increased risk of developing cirrhosis, hepatic decompensation, or hepatocellular carcinomaHepatitis B
    16. 16. Viral Replication 16 Virions bind to the host cell and are internalized by endocytosis Covalently closed circular DNA (cccDNA) is established in the hepatocyte nucleus DNA Becomes integrated into the host genome through reverse transcription Hepatitis B surface antigens are created within the cellHepatitis B
    17. 17. Disease State Terminology 17 • Hepatitis B surface antigen HBsAg • Marker of HBV infection • Hepatitis B e antigen HBeAg • Marker of active viral replication • Antibody to Hepatitis B e Anti-Hbe • Marker of recoveryHepatitis B
    18. 18. Disease State Terminology 18 Chronic Hepatitis B • Chronic necroinflammatory disease of the liver caused by persistent infection with the HBV Inactive HBsAg Carrier state • Persistent HBV infection without significant, ongoing necroinflammatory disease Resolved Hepatitis B • Previous HBV infection of the liver without further evidence of active infection or disease Acute Exacerbation of Flare of Hepatitis B • Intermittent elevations of aminotransferase activity to more than 10 times the ULN and more than twice the baseline valueHepatitis B
    19. 19. Disease State Terminology 19 Reactivation of Hepatitis B • Reappearance of active necroinflammatory disease in a person known to have the inactive HBsAg carrier state or resolved Hepatitis B HBeAg Clearance • Loss of HBeAg in a person who was previously positive HBeAg Seroconversion • Loss of HBeAg and detection of anti-HBe in a person who was previously HBeAg positive and anti-HBe negativeHepatitis B
    20. 20. Epidemiology 20 CDC Surveillance Report Risk Factors 350 - 400 million people Healthcare Hemodialysis worldwide with Chronic workers patients Hepatitis B Household 1.25 million HBV carriers in contacts or sex partners of Recipients of blood products the United States in 2010 infected persons Patients with a Accounts for 4-5.5 Recent history of sexually- multiple sex thousand deaths in the partners transmitted disease United States yearly Estimated 35,000 cases of Men who have sex with Men IV drug users new infectionsHepatitis B
    21. 21. Clinical Presentation 21 Incubation period  Signs/Symptoms  Gradual onset of anorexia, malaise, (30-180 days) and fatigue  Right upper quadrant pain  Dark urine, light-colored stoolsSymptom Development and  Illness resembling serum sickness Elevation of liver enzymes  Jaundice  Yellowing of the skin, white of the eyes or other body fluids Jaundice  Variable Course  Rapid symptom improvement  Prolonged disease with slow resolution Variable Course  Relapsing hepatitis  Rapid progression to hepatic failureHepatitis B
    22. 22. Goals of Treatment 22 Reduce viral replication to achieve remission of liver disease Improve natural history of chronic infection Prevent cirrhosis, hepatic failure, and hepatocellular carcinomaHepatitis B
    23. 23. Interferons 23 Naturally produced proteins  Side Effects with antiviral, antitumor, and  Flu-like symptoms immunomodulatory actions  Cytopenia  Depression, anxiety, irritabilit Options y  Intron A (Interferon alpha-2b)  Autoimmune disorders  Pegasys (Pegylated interferon alpha-2a)  Contraindicated in  Pegintron (Pegylated decompensated cirrhosis interferon alpha-2b)  Advantage: Resistance Administration does not occur  Given as subcutaneous injections  Weekly for 48 weeksHepatitis B
    24. 24. Antiviral Agents 24 Interfere with viral replication and weaken or eliminate activity All are administered orally once everyday All should be dose adjusted for patients with reduced CrCl HBV DNA Polymerase Inhibitors NRTIs: Nucleoside Reverse Transcriptase InhibitorsHepatitis B
    25. 25. Antiviral Agents – Polymerase Inhibitors 25 Adefovir (Hespera®)  Modest potency  Moderate resistance  10mg/day  Side effects: hematuria, asthenia, hepati tis exacerbation Entecavir (Baraclude®)  Telbivudine (Tyseka®)  High potency  High potency  Low resistance  High resistance  0.5mg/day  600mg/day  Side effects:  Side effects: fatigue, headache, dizzines fatigue, creatinine kinase s elevation, headache, diar rheaHepatitis B
    26. 26. Antiviral Agents - NRTIs 26 Lamivudine (Epivir®)  Tenofovir (Viread®)  Moderate potency  Showed to be more effective than adefovir  High resistance  High potency  100mg/day  Low resistance  Side effects: Pancreatitis, fatigue, neuropathies,  300mg/day diarrhea  Side effects: asthenia, diarrhea, naus ea, pain, anorexiaHepatitis B
    27. 27. Antiviral Agents – Not FDA Approved 27 Emtricitabine (Emtriva®)  NRTI  No advantage over lamivudine Clevudine  Provides sustained suppression of HBV DNA for several months after the cessation of therapy  Less potent in inducing suppression and seroconversion  Approved and marketed in South KoreaHepatitis B
    28. 28. Treatment Indications 28HBeAg HBV DNA (IU/mL) ALT (x ULN) First Line TherapyPositive >20,000 ≤2 Do not treatPositive >20,000 >2 Interferon, adefovir, or entecavirNegative >20,000 >2 Interferon, adefovir, or entecavirNegative >2000 1 to >2 Liver biopsyNegative ≤2000 ≤1 ObserveEither with ≥10 to 100 ≤1 to >2 Compensated: Adefovir or Entecavircirrhosis Decompensated: add Lamivudine or Telbivudine; Liver transplantationEither with <10 to 100 < 1-2 Compensated: Observecirrhosis Decompensated: Liver TransplantationHepatitis B
    29. 29. Combination Therapy 29 Combination does not increase efficacy in patients who have not received treatment Adding a second antiviral agent after the emergence of resistance has been successful Current guidelines do not recommend combination  Exception is made when resistance may lead to or aggravate hepatic failure  Examples: Decompensated cirrhosis or after liver transplantation In the event of drug resistance, it is recommended to add an agent rather than switch to another antiviral agentHepatitis B
    30. 30. Vaccination 30 Recommended for the following patient populations: Older children Susceptible sex Persons with who have not Infants at birth partners of multiple sex been infected persons partners vaccinated Persons with Men who have Injection drug Persons with HIV chronic liver sex with men users infection disease Healthcare Adults aged 19- Anyone else workers exposed Persons with 59 with diabetes seeking long- to blood on the ESRD mellitus term protection jobHepatitis B
    31. 31. Vaccination 31 Hepatitis B Vaccine  Dosing schedule  0-19 years: 0.5mL at 0,1, and 6 months  20+ years: 1mL IM at 0,1, and 6 months Engerix B®  Hemodialysis: 2mL at 0,1,2, and 6 months • 20mcg/mL  Administration  Deltoid is preferred  Anterolateral thigh preferred for neonates/infants/small children  DO NOT GIVE IV! Recombivax HB®  Side effects • 10mcg/1mL  Injection site pain, pruritis, erythema, or burning  Headache, vertigo, flushing  Fatigue, fever, malaiseHepatitis B
    32. 32. Vaccination 32 Twinrix ®  For adults 19 and older  Dose  1mL IM at 0,1, and 6 months  Accelerated schedule  1mL IM on days 0,7, and 21-30  Booster at 12 months  Side effects:  Soreness  Headache  FatigueHepatitis A/B
    33. 33. Hepatitis C 33
    34. 34. Etiology and Pathophysiology 34  Caused by Hepatitis C Virus  Enveloped single-stranded RNA virus  Naturally targets hepatocytes  Transmitted of blood contaminated with HCV  Tattooing, sharing razors or needles  Nosocomial patient-to-patient transmission, or needle-stick injuries to health care workers  Organ transplantation before 1992  Complications  Leads to chronic hepatitis in 70 - 75% of patients  Cirrhosis develops in 20-50% of patientsHepatitis C
    35. 35. Viral Replication 35 Virions bind to hepatocyte receptors and are taken up by endocytosis Protein coat dissolves and the RNA code is released inside the cell The RNA takes over the cell to make viral proteins Infected enzymes cut the protein strand into various viral proteins, making hundreds of copies Protein shells form around the RNA to make a new virus and are released from the infected cellHepatitis C
    36. 36. Epidemiology 36 Affects an estimated 180 million globally  More common among minority 15-30% of patients with chronic HCV populations have progression to cirrhosis over the  Associated with lower economic ensuing 30 years status and lower education levels Leading cause of chronic hepatitis, cirrhosis and liver cancer Principle cause of death from liver disease and leading indication for liver transplantation in the United States  Approximately 8-10 thousand deaths occur as a result every yearHepatitis C
    37. 37. Clinical Presentation 37 Most patients are  Extrahepatic asymptomatic Manifestations  Arthralgias Symptoms associated  Paresthesias with complications  Myalgias  Hepatic Encephalopathy  Pruritis*  Altered metal status  Sicca (Sjogren) Syndrome  Ascites  Sensory Neuropathy  Ankle edema  Abdominal distension  Variceal bleeding  Hematemesis  MelenaHepatitis C
    38. 38. Treatment Goals 38 Treatment Goals Therapy Options To achieve sustained  Interferon-based eradication of HCV antiviral therapy To prevent  Protease Inhibitors complications and death from infection  Liver transplantationHepatitis C
    39. 39. Virological Response Terminology 39 RVR • Rapid Virological Response • HCV RNA negative at treatment week 4 EVR •Early Virological Response •Partial: >2 log reduction in HCV RNA level compared to baseline at week 12 •Complete: HCV RNA negative at treatment week 12 ETR • End-of-treatment response • HCV RNA Negative at the end of 24 or 48 weeks of treatment SVR • Sustained Virological Response • HCV negative 24 weeks after treatment cessation • Associated with permanent cure in the majority of patientsHepatitis C
    40. 40. Disease-State Terminology 40Breakthrough Relapse • Reappearance of HCV RNA in serum while still on therapyNon-responder • Individual with failure to clear HCV RNA from serum after 24 weeks of therapyNull Responder • Individual with failure to decrease HCV RNA by <2logs after 24 weeks of therapyPartial Responder • Two log decrease in HCV RNA but still HCV RNA positive at week 24Hepatitis C
    41. 41. Interferon-based Antiviral Therapy 41 Currently recommended therapy for chronic HCV infection Peginterferon Alpha 2a/b (PegIntron®, Pegasys® )  Administered subcutaneously every week  Dose adjusted for neutropenia and/or thrombocytopenia  Dose adjusted for renal impairment Ribavirin (Rebetol®, Ribasphere®, others)  Daily oral administration  Addition provides a significant decrease in relapse rate compared to interferon alone  Dose adjusted for renal impairmentHepatitis C
    42. 42. Interferon-based Antiviral Therapy 42Hepatitis C
    43. 43. Interferon-based Antiviral Therapy 43 Adverse Events Contraindications  Pregnancy Many patients discontinued trials due to side effects  Autoimmune conditions, may be exacerbated by Pegylated Influenza-like effects: interferon fatigue, headache, fever, rigo rs (>50%)  Major uncontrolled depression or suicidal ideation Psychiatric effects: Depression, irritability, insomnia  Age less than 2 years (22-31%)  Hypersensitivity Laboratory Abnormalities requiring dose reduction  Solid organ transplantation  Neutropenia (18-20%)  Anemia  Untreated Thyroid disease  Hemolytic anemia with ribavirinHepatitis C
    44. 44. Interferon-based Antiviral Therapy 44 DOSE REDUCTIONSHepatitis C
    45. 45. Interferon-based Antiviral Therapy 45 DOSE REDUCTIONSHepatitis C
    46. 46. Response Predictors 46  Likelihood of SVR is lower with patients with a high pretreatment HCV RNA level  >600,000 IU/mL  Likelihood of SVR is higher among patients with better adherence to therapy  >80% of total therapy doses  Black patients have lower rates of SVR compared to white (28% vs 52%)Hepatitis C
    47. 47. Direct Acting Antiviral Agents 47 Standard of care for patients with genotype 1 infection became combination of oral protease inhibitors with interferon-based therapy Direct-acting Antivirals – Protease Inhibitors  Boceprevir (VictrelisTM)  4-week lead in period with PegIFN and RBV is required before adding Boceprevir  Telaprevir (IncivekTM)  Telaprevir is given with PegIFN and RBV for 12 weeks, followed by interferon based therapy aloneHepatitis C
    48. 48. Direct Acting Antiviral Agents 48 General Principles  Do not use the protease inhibitors without Ribavirin  Dose should never be reduced  Failure to one protease inhibitor is not an indication to switch Monitoring  CBC  Liver function tests  Creatinine  Glucose  TSH  Pregnancy  DepressionHepatitis C
    49. 49. PI Adverse Events 49 Telaprevir Boceprevir Rash  Anemia  Stop if rash is severe,  Dysgeusia covering more than 50% of BSA  Depression Pruritis  Neutropenia Hemorrhoids  Diarrhea Anorectal discomfort  Insomnia Anemia  Fatigue Nausea/VomitingHepatitis C
    50. 50. 50 Screening for HCV is recommended for the following populations: Screening* No vaccination is Current or Recipients of Persons born previousavailable against 1945-1965 injection drug clotting factorsHepatitis C before 1987 users* Screening is Long-term Persons withperformed with Hemodialysis exposures to HIV infectedEnzyme persons patients HCVimmunoassay (EIA)or Counting Patients with Donors ofImmunoassay Children born to signs or blood, plasma, infected(CIA)for Hepatitis C symptoms of organs, tissues or mothers liver disease semenantibodiesHepatitis C
    51. 51. Questions? 51
    52. 52. References 52 Brundage, Stephanie C and Fitzpatrick, A. Nicole.“Hepatitis A. American Family Physician, 15 Jun 2006; 73(12): 2162-68. Centers for Disease Control and Prevention. Viral Hepatitis Statistics & Surveillance. Accessed January 2, 2013, at: Statistics/index.htm. Last Updated June 22, 2012. Ghany MG, Strader DB, et al. AASLD Practice Guidelines: Diagnosis, Management, and Treatment of Hepatitis C: An Update. Hepatology, April 2009;49(4):1335-64. Johnston, David E. “Special Considerations in Interpreting Liver Function Tests”. Am Fam Physician. 1999 Apr 15;59(8):2223-2230. Lok, Ana S and McMahon, Brian J. ASSLD Practice Guidelines: Chronic Hepatitis B: Update 2009. Hepatology, 2009.50(3): 1-34. Martin, Annette and Lemon, Stanley. Hepatitis A Virus: From Discovery to Vaccines. Hepatology, 2006; 43(2): S164-72. Yee HS, Chang MF, Pocha C. Update on the Management and Treatment of Hepatitis Virus Infection: Recommendations from the Department of Veterans Affairs Hepatitis. Am J Gastroenterol. 24 April 2012. Available online at: