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Viral hepatitis-a-b-c-d.pp
The document discusses the five main types of viral hepatitis: A, B, C, D, and E. It provides information on the source of the virus, route of transmission, potential for chronic infection, and methods of prevention for each type. It also discusses epidemiology, clinical features, testing approaches, and public health responses related to hepatitis A and E.
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Viral hepatitis-a-b-c-d.pp
- 1. Hepatitis Viral :A, B, C, D, E Dr. Hugo Abel Pinto Ramírez Especialidad en Medicina familiar y Especialista en Urgencias, Maestría en Farmacología (2011) 1
- 2. Viral Hepatitis -Historical Perspective “Infectious” A Enterically E transmitted Viral hepatitis NANB Parenterally “Serum” B D C transmitted F, G, ? other Dr. Hugo Abel Pinto Ramírez 2
- 3. Viral Hepatitis A B C D E Source of feces blood/ blood/ blood/ feces virus blood-derived blood-derived blood-derived body fluids body fluids body fluids Route of fecal-oral percutaneous percutaneous percutaneous fecal-oral transmission permucosal permucosal permucosal Chronic no yes yes yes no infection Prevention pre/post- pre/post- blood donor pre/post- ensure safe exposure exposure screening; exposure drinking immunization immunization risk behavior immunization; water modification risk behavior modification Dr. Hugo Abel Pinto Ramírez 3
- 4. Viral Hepatitis 1982-1993 34% 42% 16% 3% Source: CDC Sentinel Counties Study on Viral Hepatitis Dr. Hugo Abel Pinto Ramírez 4
- 5. Estimates of Acuteand Chronic Disease Burden for Viral Hepatitis, United States HAV HBV HCV HDV Acute infections (x 1000)/year* 125-200 140-320 35-180 6-13 Fulminant deaths/year 100 150 ? 35 Chronic 0 1-1.25 3.5 infections million million 70,000 Chronic liver disease deaths/year 0 5,000 8-10,000 1,000 * Source: CDC -Range based on estimated annual incidence, 1984-1994. Dr. Hugo Abel Pinto Ramírez 5
- 6. Hepatitis A Virus(HAV) Dr. Hugo Abel Pinto Ramírez 6
- 7. HAV Transmission xClose personal contact household contact, sex contact, child day care centers xContaminated food, water infected food handlers, raw shellfish xBlood exposure (rare) injecting drug use, transfusion Dr. Hugo Abel Pinto Ramírez 7
- 8. Hepatitis A -Clinical Features Incubation period: Mean 30 days Range 15-50 days Jaundice by <6 yrs, <10% age group: 6-14 yrs 40%-50% >14 yrs 70%-80% Complications: Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis Chronic sequelae: None Dr. Hugo Abel Pinto Ramírez 8
- 9. HAV - TypicalSerologic Course Symptoms Total anti-HAV ALT Titer Fecal HAV IgM anti-HAV 0 1 2 3 4 5 6 12 24 MonthsHugo Abel Pinto Ramírez Dr. after Exposure 9
- 10. Serological Testing HAV total Ab appears 4-5 weeks after infection and remains positive for the patient’s lifetime HAV IgM is present at the onset of symptoms and usually disappears after 4-6 months. The presence of total Ig without IgM indicates past infection Dr. Hugo Abel Pinto Ramírez 10
- 11. HAV Immune Globulin IM administration within 2 weeks after HAV exposure is >85% effective in preventing symptomatic infection. HAV IG and vaccine does not alter seroconversion rates but lower serum antibody concentrations may be obtained. HAV IG administration will alter normal serological profiles for 6-12 months. Dr. Hugo Abel Pinto Ramírez 11
- 12. Hepatitis A Virus Highest virus concentrations occur in stool 1-2 weeks before the onset of illness. Transmission is most likely at this time. Minimal virus present in stool 1 week after the onset of jaundice. In neonates and young children, virus may be detected in stool for months. Dr. Hugo Abel Pinto Ramírez 12
- 13. Virus Detection Culture is worthless except for research purposes. PCR detection is available but cannot distinguish recent from past infection. Nucleic acid sequencing is useful for tracking HAV outbreaks. Dr. Hugo Abel Pinto Ramírez 13
- 14. Mitch, a 43year old salesman, has increasing fatigue x 5 days and vague abdominal pain x 3 days. He ate at the Stage Deli (site of a recent HAV outbreak) 10 days previously. His liver enzymes are within normal limits. HAV AB (total) Positive HAV IgM Negative Does he have HAV infection?
- 15. CDC Recommendations: Testing andVaccination Dr. Hugo Abel Pinto Ramírez 15
- 16. PRE-VACCINATION TESTING Considerations: Cost of vaccine Cost of serologic testing (including visit) Prevalence of infection Impact on compliance with vaccination Likely to be cost-effective for: Persons born in high endemic areas Older U.S. born adults Older adolescents and young adults in certain groups (e.g., Native Americans, Alaska Natives, Hispanics, IDUs) Dr. Hugo Abel Pinto Ramírez 16
- 17. POST-VACCINATION TESTING Not recommended: • High response rate among vaccinees • Commercially available assay not sensitive enough to detect lower (protective) levels of vaccine-induced antibody Dr. Hugo Abel Pinto Ramírez 17
- 18. ACIP RECOMMENDATIONS: PERSONS AT INCREASED RISK OF INFECTION • Men who have sex with men • Illegal drug users • International travelers • Persons who have clotting factor disorders • Persons with chronic liver disease Dr. Hugo Abel Pinto Ramírez 18
- 19. STD Treatment Guidelines MMWR August 4, 2006 55 (RR11) “Vaccination against hepatitis is the most effective means of preventing sexual transmission of hepatitis A and B.” Dr. Hugo Abel Pinto Ramírez 19
- 20. Indications for IGfor Post-Exposure Prophylaxis Household and sexual contacts if exposure is within 2 weeks. Childcare center employees and children when HAV infection is identified in a child or employee. Close school contacts if transmission within the school has occurred. Dr. Hugo Abel Pinto Ramírez 20
- 21. Indications for IGfor Post-Exposure Prophylaxis Person exposed to contaminated food/water. Persons who ate food prepared by HAV+ food handler. Dr. Hugo Abel Pinto Ramírez 21
- 22. Hepatitis A Surveillance andResponse Dr. Hugo Abel Pinto Ramírez 22
- 23. Hepatitis A Surveillance& Response Urgently reportable condition in S.C. – Acute HAV infection must be reported by phone to health department within 24 hours. Investigation of a case of hepatitis A must be initiated by health department and district epi staff within 24 hours of notification. All cases must be reported to CDC. Dr. Hugo Abel Pinto Ramírez 23
- 24. Important Information Date of onset of symptoms Occupation If child, whether child attends childcare Names of household/sexual contacts Restaurants attended 2-6 weeks prior to symptoms Dr. Hugo Abel Pinto Ramírez 24
- 25. Management of Outbreaks Initiate enteric precautions during the first 2 weeks of illness. Refer symptomatic contacts to physician. Exclude adults/children with HAV infection from work/school until 1 week after onset of illness or until IG PEP has been initiated. Provide education re transmission, prevention, and hygiene. Dr. Hugo Abel Pinto Ramírez 25
- 26. Hepatitis E Virus Dr. Hugo Abel Pinto Ramírez 26
- 27. Amita, a 23 year old student, returned from India one month ago where she spent 3 weeks visiting her future in-laws. She presented with fever, jaundice, malaise, and significantly elevated ALT levels. Antibody tests were positive for HEV IgG and IgM. How does she prevent the spread of HEV to family and friends?
- 28. Hepatitis E Virus Most outbreaks associated with fecally contaminated drinking water Minimal person-to-person transmission U.S. cases usually have history of travel to HEV-endemic areas Dr. Hugo Abel Pinto Ramírez 28
- 29. Geographic Distribution ofHepatitis E Outbreaks or Confirmed Infection in >25% of Sporadic Non-ABC Hepatitis Source: CDC
- 30. Hepatitis E Virus Incubation period: Average 40 days Range 15-60 days Case-fatality rate: 1%-3% overall 15%-25% in pregnancy Illness severity: Increased with age Chronic sequelae: None identified Dr. Hugo Abel Pinto Ramírez 30
- 31. Typical Serological Course- HEV Symptoms anti-HEV ALT IgM anti-HEV Titer Virus in stool 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Weeks Hugo Abel Pinto Ramírez Dr. after Exposure 31
- 32. Serological Profile HEV IgM is usually present at the onset of symptoms and persists for 3-4 months HEV IgG is also present at the onset of symptoms and persists for the patient’s lifetime Dr. Hugo Abel Pinto Ramírez 32
- 33. CDC Criteria forTesting Acute Phase Sera Discrete onset of illness with jaundice or x Serum ALT >2.5 times the upper limit of normal and HAV IgM negative HBV Core IgM negative HCV Ab negative Dr. Hugo Abel Pinto Ramírez 33
- 34. HEV Detection Culture is worthless PCR can detect HEV RNA in serum and stool specimens from 2 weeks before, to 2 weeks after, the onset of symptoms Nucleic acid sequencing is useful for tracking HEV outbreaks Dr. Hugo Abel Pinto Ramírez 34
- 35. Steps to preventHEV transmission in home setting? 2. Safe sex practices 3. Do not share eating/grooming utensils. 4. Respiratory precautions 5. Vigorous hand washing 6. No special requirements needed Dr. Hugo Abel Pinto Ramírez 35
- 36. Hepatitis C Virus Dr. Hugo Abel Pinto Ramírez 36
- 37. Claudia is a46 year old divorced female. She has a new man in her life. She has had unprotected sex for the past 3 weeks. She just learned that her new friend is HCV positive. What is her HCV risk?
- 38. What is Claudia’sRisk of Infection? 1. High risk – HCV can be transmitted sexually. 2. Low risk – The efficiency of sexual transmission is low. Dr. Hugo Abel Pinto Ramírez 38
- 39. HCV - Sourcesof Infection Injecting drug use 60% Sexual 15% Transfusion 10% (before screening) Other* 5% Unknown 10% *Nosocomial; Health-care work; Perinatal Source: Centers for Disease Control and Prevention Dr. Hugo Abel Pinto Ramírez 39
- 40. Sexual Transmission Transmission efficiency is low Rare between long-term steady partners (1.5%) Factors that facilitate transmission between partners (e.g., viral load) are unknown Male to female transmission may be more efficient Dr. Hugo Abel Pinto Ramírez 40
- 41. Other Transmission Issues HCV is not spread by kissing, hugging, sneezing, coughing, food or water, sharing eating utensils or drinking glasses, or casual contact HCV infection status should not be used to exclude patients from work, school, play, child-care or other settings Dr. Hugo Abel Pinto Ramírez 41
- 42. Hepatitis C Genotypes Genotype: Countries Where Prevalent: 1a USA, England, Europe 1b USA, Japan, Europe 2a, 2b, 2c, 2d Japan, China 3a, 3b, 3c, 3d, 3e, 3f Scotland, England 4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4j Middle East, Africa 5a Canada, South Africa 6a Hong Kong, Macau Dr. Hugo Abel Pinto Ramírez 42
- 43.
- 44. Hepatitis C: AGlobal Health Problem 170 Million Carriers Worldwide, 3-4 MM new cases/year EAST WEST FAR EAST ASIA MEDITERRANEAN EUROPE 60 M 20M 9M U.S.A. 4M SOUTH EAST ASIA AFRICA 30 M 32 M SOUTH AMERICA 10 M AUSTRALIA 0.2 M SOURCE, WHO 1999 Dr. Hugo Abel Pinto Ramírez 44
- 45. Acute Hepatitis CClinical Presentation and Natural History HCV RNA can be detected in blood within 1-3 weeks after exposure Average time from exposure to seroconversion is 8-9 weeks Average time from exposure to symptoms period 6-7 weeks Liver injury (elevations in ALT) with 4-12 weeks Symptoms develop in only of 20% of patients Nonspecific 10%-20% Jaundice in only 20%-30% CDC. MMWR. 1998; 47(No. RR-19):1-39. Hoofnagle JH Hepatology. 1997;26 (suppl 1): 15S-20S NIH Consensus Development Conference Panel Statement Management of Hepatitis C, 2002 45
- 46. Hepatitis C Infection Incubation period Average 6-7 weeks Range 2-26 weeks Case fatality rate Low Chronic infection 75%-85% Chronic hepatitis 70% (most asx) Cirrhosis 10%-20% Mortality from CLD 1%-5% Dr. Hugo Abel Pinto Ramírez 46
- 47. Natural History ofHepatitis C 10-20 years Acute Hepatitis C Chronic Hepatitis 75%-85 % Cirrhosis 20 % Hoofnagle JH Hepatology. 1997;26 (suppl 1): 15S-20S Di Bisceglie, Hepatology, 2000 Dr. Hugo Abel Pinto Ramírez 47
- 48. Natural History ofHepatitis C Annual rate Cirrhosis 20 % Decompensation HCC 6% 4% Death ≈ 4% Hoofnagle JH Hepatology. 1997;26 (suppl 1): 15S-20S Di Bisceglie, Hepatology, 2000 Dr. Hugo Abel Pinto Ramírez 48
- 49. Acute HCV Infectionwith Recovery HCV Ab Symptoms +/- HCV RNA Titer ALT Normal 0 1 2 3 4 5 6 1 2 3 4 Months Years Time after Exposure 49
- 50. Chronic Hepatitis C A leading cause of cirrhosis in the US 10,000-20,000 deaths/yr This number expected to triple in the next 10 to 20 years (without therapy) Associated with an increased risk of liver cancer Most common reason for liver transplantation in the United States CDC. MMWR. 1998; 47(No. RR-19):1-39. NIH Consensus Development Conference Panel Statement Management of Hepatitis C, 2002 Dr. Hugo Abel Pinto Ramírez 50
- 51. Acute HCV Infectionwith Progression to Chronic Infection HCV Ab Symptoms +/- HCV RNA Titer ALT Normal 0 1 2 3 4 5 6 1 2 3 4 Months Years Time after Exposure 51
- 52. Hepatitis C Complications Hepatitis encephalopathy – if untreated can lead to: Confusion Disorientation Hallucination Stupor/Coma Jaundice Pruritus Renal damage/failure Hypo/Hyperthyroidism Varices of Esophagus, Stomach, Rectum Muscle Wasting Dr. Hugo Abel Pinto Ramírez 52
- 53. Extrahepatic Manifestations of Hepatitis C Hematologic: Mixed cryoglobulinemia (10%–25% of HCV patients)* Renal: Glomerulonephritis Dermatologic: Porphyria cutanea tarda Cutaneous necrotizing vasculitis Lichen planus Management of Hepatitis C. NIH Consensus Statement, 2002. Dr. Hugo Abel Pinto Ramírez 53
- 54. Chronic Hepatitis C FactorsPromoting Progression or Severity Increased alcohol intake Age > 40 years at time of infection HIV co-infection Other Male gender Chronic HBV co-infection Dr. Hugo Abel Pinto Ramírez 54
- 55. Claudia needs tosee her family physician. She wants to be tested for HCV. What test do you recommend?
- 56. Diagnostic Tests forHCV Anti-HCV RIBA (supplemental assay) Qualitative PCR Quantitative PCR Genotyping assays Dr. Hugo Abel Pinto Ramírez 56
- 57. HCV Antibody Tests Screening tests - total antibody detected Sensitivity is about 95% Predictive value High Risk Population: 90-95% Low Risk Population: 50-60% (false positives) False Negatives due to “window period” and immunosuppression Dr. Hugo Abel Pinto Ramírez 57
- 58. Hepatitis C AntibodyTest: Signal to Cut Off (S/CO) Ratio S/CO ratio is a comparison of the pt’s positive EIA result with the lab’s positive EIA control. A positive EIA test with a s/co ratio of 3.8 or higher is indicative that the pt truly has HCV and that the RIBA test will be positive (95%-97% predictive value). Dr. Hugo Abel Pinto Ramírez 58
- 59. HCV RIBA Tests Used to resolve possible false positive anti-HCV, particularly in low- risk patients (blood donors) Use is analogous to HIV western blot Core E1 E2/NS1 NS2 NS3 NS4 NS5 5’ UTR Dr. Hugo Abel Pinto Ramírez 59
- 60. HCV Screening Algorithm Negative (non-reactive) EIA for Anti-HCV STOP Positive (repeat reactive) OR Negative RIBA for Anti-HCV RT-PCR for HCV RNA Negative Indeterminate Positive Positive Additional Laboratory Medical STOP Tests (e.g. PCR, ALT) Evaluation Negative PCR, Positive PCR, Normal ALT Abnormal ALT Source: MMWR 1998;47 (No. RR 19)
- 61. Diagnosis of ViralHepatitis in the Primary Care Setting: Patients Who Have Risk Factors A single normal ALT level does not rule out chronic viral hepatitis ALT levels may be intermittently normal in a significant number of patients who have chronic hepatitis C Dr. Hugo Abel Pinto Ramírez 61
- 62. Diagnosis of ChronicViral Hepatitis Serologic Testing Patients should be tested if they: Have known risk factors for viral hepatitis Indicate possible risk factors for hepatitis Have elevated liver enzymes Management of Hepatitis C. NIH Consensus Statement, 1997. Dr. Hugo Abel Pinto Ramírez 62
- 63. Liver Biopsy May be guided by CT or ultrasound Provides information regarding Degree of inflammation Disease severity Tissue damage Presence/absence of cirrhosis Helps determine Degree of disease progression Cause of liver disease Need for treatment Dr. Hugo Abel Pinto Ramírez 63
- 64. Histologic Staging Stage 0 Stage 1 Stage 2 No Fibrosis Portal Fibrosis Few septa Stage 3 Stage 4 Numerous septa Cirrhosis Dr. Hugo Abel Pinto Ramírez 64
- 65. Diagnostic Evaluation ofHCV Infection Dr. Hugo Abel Pinto Ramírez 65
- 66. Hepatitis C Screeningand Diagnosis Summary Suspect disease on the basis of risk factors, not symptoms Positive anti-HCV result indicates current infection until refuted Measurement of HCV RNA may be required to establish diagnosis in selected cases Dr. Hugo Abel Pinto Ramírez 66
- 67. Treatment Dr. Hugo Abel Pinto Ramírez 67
- 68. Treatment for HepatitisC Interferon + Ribavirin x 6-12 months – about 40% - 50% sustain viral clearance > 3 years. Predictive Factors for Treatment Response: Genotype 2 and 3 Low initial viral load levels Young age Low Fibrosis Score (Liver Biopsy) Female Dr. Hugo Abel Pinto Ramírez 68
- 69. Treatment Side Effects Depression Sleep Disturbances (Insomnia) Irritability Anger Psychosis Excessive Fatigue Nausea/Diarrhea/Decreased Appetite/Weight Loss Anemia/Neutropenia Autoimmune Disorders, especially Thyroiditis Decreased Libido Menstrual Irregularities Dr. Hugo Abel Pinto Ramírez 69
- 70. Rationale for thedevelopment of a once-weekly pegylated interferon α-2b Dr. Hugo Abel Pinto Ramírez 70
- 71. Rationale for Pegylationof Protein Pharmaceuticals Pegylation = binding of ethylene oxide polymers to drug molecule Decreases clearance Prolonged half-life Sustained blood levels Decreases proteolysis Decreases immunogenicity Youngster S, et al. Curr Pharm Des. 2002;8:99. Harris JM, et al. Clin Pharmacokinet. 2001;40:539. Dr. Hugo Abel Pinto Ramírez 71
- 72. Why PEG asa Protein-Modifying Agent? Inert Water soluble Can be made any size and shape O CH 3- (OCH 2CH 2) n- O - C- N (protein) H m Bailon et al., Bioconjugate Chemistry, 2001 Wyss et al., Current Pharmaceutical Design, 2002 Dr. Hugo Abel Pinto Ramírez 72
- 73. Pegylation: Effects onHalf-life Longer Shorter PEG Molecular Weight (PEG size) The clinical relevance of this in vitro data has not been established. Adapted from Youngster et al., Current Pharmaceutical Design, 2002, 8:2139-215 73
- 74. Pegylation: Antiviral Activity More Less PEG Molecular Weight (PEG size) The clinical relevance of this in vitro data has not been established. Adapted from Grace M et al., AASLD 2003, Abstract #1928 74
- 75. Relationship between PEGsize and Renal Clearance PEG 5,000 100 Relative clearance (%) 80 60 PEG 12,000 (used in PEG-IFN α-2b ) 40 20 PEG 20,000 0 10 30 80 100 Stokes radius (Angstroms) Wyss et al., Current Pharmaceutical Design, 2002 Xian-Hui He et al., Life Sciences, 1999 Dr. Hugo Abel Pinto Ramírez 75
- 76. HCV-Positive Persons for Whom Treatment is Recommended Persistently elevated liver enzyme (ALT) levels Presence of ↑ HCV RNA (viral load) A liver biopsy indicating fibrosis or at least moderate inflammation and necrosis Cessation of continuing alcohol/substance use HCV + HIV coinfection: especially difficult … Goal: Clear HCV, restore LFT, reverse pathology Dr. Hugo Abel Pinto Ramírez 76
- 77. Predicting Response toTreatment Dr. Hugo Abel Pinto Ramírez 77
- 78. Response Rate toTreatment Based on Genotype Genotype: Response Rate: 1a/1b 41% of patients 2-6 75% of patients Overall Response 52% of patients Dr. Hugo Abel Pinto Ramírez 78
- 79. HCV Kinetics Dr. Hugo Abel Pinto Ramírez 79
- 80. Goals of HCVTherapy Primary: HCV RNA below limits of detection at end of treatment Secondary: Inhibition of disease progression Reduction of incidence of hepatocellular carcinoma Reduction in need for liver transplant Dr. Hugo Abel Pinto Ramírez 80
- 81. Treatment Definitions The First aim is to clear The Second aim is to HCV RNA from prevent relapse in peripheral blood, a patients who cleared necessary, but not HCV RNA during sufficient condition to induction, in order to achieve a sustained achieve a sustained virological response. virological response Adapted from Pawlotsky JM, Hepatology vol. 32, #5, 2000 Dr. Hugo Abel Pinto Ramírez 81
- 82. Patterns of Responseto Initial Antiviral Therapy 7 Nonresponder (χ < 0.2) 6 1st Phase Serum HCV RNA Flat-partial responder 5 (0.0 < δ < 0.2) Slow-partial responder 4 (0.1 ≤ δ < 0.4) 2nd Phase 3 detection limit 2 Rapid responder 1 (δ ≤ 0.4) 0 1 2 3 7 14 21 28 Days Dr. Hugo Abel Pinto Ramírez 82
- 83. Changing Paradigms Speed of response is an important predictor of sustained virologic response. 66% of patients with HCV genotypes 2 and 3 had undetectable HCV levels within 4 weeks of treatment Sustained virologic response. 90% for 24 week treatment arm 75% for 16 week treatment Relapse rates 18% for 24 week treatment 31% for 16 week treatment Shiffman, et al., N. Eng. J. Med 2007;357:124-134 Dr. Hugo Abel Pinto Ramírez 83
- 84. Resources S.C. Hepatitis C Coalition SC DHEC Hepatitis Nurse Consultant Elona Rhame, RN Pharmaceutical Companies Physician Referral List Dr. Hugo Abel Pinto Ramírez 84
- 85. * SC Hepatitis C Coalition 803-898-9562 Mick Carnett, CDP, CRPS, D.Div., Executive Director Informational & support services to providers & patients Brochures/literature Presentations Annual Statewide Hepatitis C Summit Statewide Physicians Referral List ETV program, HCC videos, PSAs Dr. Hugo Abel Pinto Ramírez 85
- 86. Surveillance/Reporting Hepatitis C is reportable to the health department within 7 days. Acute and chronic HCV cases are reported by health department to CDC via CHESS. Dr. Hugo Abel Pinto Ramírez 86
- 87. Hepatitis B Dr. Hugo Abel Pinto Ramírez 87
- 88. Clinical Features Incubation period: Mean: 60-90 days Range: 45-180 days Clinical illness (jaundice): <5 yrs, <10% ≥5 yrs, 30%-50% Acute case-fatality rate: 0.5%-1% Chronic infection: <5 yrs, 30%-90% ≥ 5 yrs, 2%-10% Premature mortality from chronic liver disease: 15%-25% Dr. Hugo Abel Pinto Ramírez 88
- 89. Geographic Distribution ofChronic HBV Infection HBsAg Prevalence ≥8% - High 2-7% - Intermediate <2% - Low Source: Centers for Disease Control and Prevention Dr. Hugo Abel Pinto Ramírez 89
- 90. Hepatitis B SurfaceAntigen HBsAg Detection of acutely or chronically infected individuals. Antigen components used in HBV vaccine Should undergo testing to assess the status of their liver disease Assess hepatic synthetic function: serum albumin, prothrombin time Assess for hypersplenism: CBC (plts, wbc decreased) Assess for viral replication status: HBeAg and HBV DNA Dr. Hugo Abel Pinto Ramírez 90
- 91. Antibody to HBsAg Anti-HBsAg Identification of individuals who have resolved HBV infections. Determination of immunity after immunization. Dr. Hugo Abel Pinto Ramírez 91
- 92. Hepatitis B EnvelopeAntigen HBeAg Identification of infected individuals at increased risk for transmitting HBV Dr. Hugo Abel Pinto Ramírez 92
- 93. Antibody to HBe HBeAb or anti-HBe Identification of infected individuals with lower risk for transmitting HBV Dr. Hugo Abel Pinto Ramírez 93
- 94. Antibody to HBVCore Antigens Anti-HBc or HBcAb Identification of persons with acute, resolved, or chronic HBV infection. Anti-HBc is not present after immunization. Dr. Hugo Abel Pinto Ramírez 94
- 95. IgM Antibody toHBcAg IgM anti-HBc or HBc IgM Identification of acute or recent HBV infections (including those in HBsAg-negative persons during the “window” phase of infection) Dr. Hugo Abel Pinto Ramírez 95
- 96. Acute HBV Infectionwith Recovery Symptoms HBeAg anti-HBe Total anti-HBc Titer HBsAg IgM anti-HBc anti-HBs 0 4 8 12 16 20 24 28 32 36 52 100 Weeks after Exposure 96
- 97. Progression to ChronicHBV Infection Acute Chronic (6 months) (Years) HBeAg anti-HBe HBsAg Total anti-HBc Titer IgM anti-HBc 0 4 8 12 16 20 24 28 32 36 52 Years Weeks after Exposure 97
- 98. Chronic Hepatitis BInfection Defined as testing positive for the HBsAg for more than 6 months Patients are at increased risk for progressive liver disease and hepatocellular carcinoma Dr. Hugo Abel Pinto Ramírez 98
- 99. 35 year oldMedical Technologist who cut her hand. She was removing the top from a Vacutainer tube when the tube broke. Test Result HBsAg Negative Anti-HBc Negative Anti-HBc-IgM Negative Anti-HBs Positive Anti-HBs Ratio 23.1
- 100. 29 year oldautomotive engineer who presented with fatigue x 2 weeks and mild jaundice. Liver enzyme levels were significantly elevated. Test Result HBsAg Positive Anti-HBc Positive Anti-HBc-IgM Positive Anti-HBs Negative Anti-HBs Ratio <2.1
- 101. James is a23 year old food service employee. He was tested as part of his pre-employment physical examination. He was diagnosed with HBV infection one year ago. HBsAg Positive What is his HBV Status? Anti-HBc Positive Anti-HBc-IgM Negative Anti-HBs Negative HBe Ag Positive Anti-Hbe Negative
- 102. Chronic Active Hepatitis High levels of HBV in blood Increased risk of cirrhosis Increased risk of liver cancer Dr. Hugo Abel Pinto Ramírez 102
- 103. James, a 23year old food service employee. He was tested as part of his pre-employment physical examination. He was diagnosed with HBV infection one year ago. • High viral load Can he work as a • Increased risk of virus food handler in transmission your hospital?
- 104. HBV Transmission Parenteral Sexual Perinatal Risk of transmission increases with the level of HBV DNA in serum and HBeAg positive Dr. Hugo Abel Pinto Ramírez 104
- 105. HBV Concentrations inVarious Body Fluids Low/Not High Moderate Detectable blood semen urine serum vaginal fluid feces wound exudates saliva sweat tears breast milk Dr. Hugo Abel Pinto Ramírez 105
- 106. Outcome of HBVInfection Infection Symptomatic Asymptomatic acute hepatitis B Resolved Resolved Chronic Chronic infection Immune Immune infection Cirrhosis Cirrhosis Asymptomatic Asymptomatic Liver cancer Liver cancer Dr. Hugo Abel Pinto Ramírez 106
- 107. Chronic HBV Infection Immune tolerant patient HBeAg positive and HBeAb negative Viral load 100,000 to 1 billion copies/mL Normal ALT No necroinflammation in the liver Chronic Active Hepatitis B (Viral Load > 100,000 cy/mL) HBeAg positive (wild type virus) HBeAg negative (pre core or core promoter mutants) Elevated ALT and/or active liver biopsy Increased risk for progression to cirrhosis and ESL disease and candidates for therapy
- 108. Chronic HBV Infection Inactive HBsAg Carrier HBeAg negative and HBeAb positive Viral load 100 to 10,000 copies/mL Normal ALT Resolution of necroinflammation in the liver Reduced risk of progressive liver disease Resolution HBsAg negative, HBsAb positive Viral load <<< 20,000 copies/mL HBeAg negative and HBeAb positive Normal ALT Dr. Hugo Abel Pinto Ramírez 108
- 109. HBV DNA Testing Assess of viral replication in chronic HBsAg carriers. Assess the risk of progression toward cirrhosis and hepatocellular carcinoma. Decision to treat. Assess treatment efficacy and failure Dr. Hugo Abel Pinto Ramírez 109
- 110. Hepatitis B Vaccine •Licensed in 1982; currently recombinant (in US) • 3 dose series, typical schedule 0, 1-2, 4-6 months - no maximum time between doses (no need to repeat missed doses or restart) • 2 dose series (adult dose) licensed by FDA for 11-15 year olds (Merck) • Protection ~30-50% dose 1; 75% - 2; 96% - 3; lower in older, immunosuppressive illnesses (e.g., HIV, chronic liver diseases, diabetes), obese, smokers Dr. Hugo Abel Pinto Ramírez 110
- 111. Indications for Pre-ExposureVaccination Children < 19 yrs of age Persons at risk for sexual transmission. MSM Current/past IDU Family member of HBsAg + adoptees Persons at occupational risk Hemodialysis patients Dr. Hugo Abel Pinto Ramírez 111
- 112. Indications for Pre-ExposureVaccination Clients/staff of institutions for developmentally disabled Persons receiving clotting factors International travelers in high/intermediate areas Inmates Adults 19 years of age & older desiring protection Dr. Hugo Abel Pinto Ramírez 112
- 113. Indications for Post-ExposureProphylaxis Infants born to HBsAg + mothers Persons who have percutaneous or permucosal exposure to blood Sex partners of persons with acute HBV Household contacts of persons with acute HBV if blood exposure or if unimmunized infant Sex partners of persons with chronic HBV Household contacts of persons with chronic HBV Victims of sexual assault Dr. Hugo Abel Pinto Ramírez 113
- 114. Indications for Pre-Vaccination Serologic Testing: • Unimmunized sexual contacts of persons with acute and chronic Hepatitis. • Unimmunized household contacts of persons with acute HBV if there has been a blood exposure. • Unimmunized household contacts of person with chronic HBV. • Unimmunized persons in populations with high rates of HBV (IDU, inmates) Dr. Hugo Abel Pinto Ramírez 114
- 115. Indications for Post-Vaccination Serologic Testing Persons at occupational risk Infants born to HBsAg+ mothers Immunocompromised persons Dr. Hugo Abel Pinto Ramírez 115
- 116. Sexual Contacts toAcute HBV Sexual contacts of persons with acute HBV regardless of age: Test if unimmunized Administer HBIG and first hep B dose at time test is obtained. If negative, continue hepatitis vaccination series. Dr. Hugo Abel Pinto Ramírez 116
- 117. Household Contacts toAcute Cases Children (>12 months of age), Adolescents, and Adult Household Contacts to Acute Cases: Not at increased risk unless blood exposure. Only if blood exposure has occurred in past 14 days, test and give HBIG and first dose of hepatitis B vaccine. If negative, continue vaccination series. Dr. Hugo Abel Pinto Ramírez 117
- 118. Sexual and HouseholdContacts to Chronic Cases Sexual Contacts (regardless of age): If unimmunized, test and give first dose of vaccine. If test is negative, continue series. Household Contacts (regardless of age): If unimmunized, test and give first dose of vaccine. If test is negative, continue series. Dr. Hugo Abel Pinto Ramírez 118
- 119. Victims of SexualAssault If offender is HBsAg positive or status is unknown and victim is unimmunized: If offender has acute HBV infection - give HBIG and hepatitis B vaccine. If offender has chronic HBV infection – give vaccine. Dr. Hugo Abel Pinto Ramírez 119
- 120. Healthcare Worker –Pre-Exposure Vaccination Administer vaccination series. Obtain postvaccination serology at 1-2 months after completion of series. If anti-HBs levels are > 10 mIU/mL, employee is a responder. If anti-HBs levels are < 10 mIU/mL, employee is a non-responder. Revaccinate and repeat serology. Dr. Hugo Abel Pinto Ramírez 120
- 121. Postvaccination Serology Testing- Infants born to HBsAg positive mothers. Persons at high risk of occupational exposure. Persons who are immunocompromised and at continued risk of infection. Persons receiving clotting factors. Dr. Hugo Abel Pinto Ramírez 121
- 122. Postvaccination Testing Persons who were tested 1-2 months after completion of series and had anti-HBs levels > 10 mIU/mL should not receive any further testing. Dr. Hugo Abel Pinto Ramírez 122
- 123. Approved Therapies forHBV Infection Interferons Interferon alpha 2b (5 million units qd or 10 million units TIW for 12-24 weeks) Pegylated interferon alpha 2a (180 ug once/week for 48 weeks) Nucleoside analogues Lamivudine (100 mg qd) Entecavir (0.5 mg qd; 1 mg if lamivudine resistance) Nucleotide analogues Adefovir (10 mg qd) Dr. Hugo Abel Pinto Ramírez 123
- 124. Hepatitis B Surveillance Acute Hepatitis B is an urgently reportable condition. It must be reported by phone to the health department within 24 hours. Chronic Hepatitis B is a reportable condition and must be reported to health department within 7 days. Perinatal Hepatitis B is a reportable condition and must be reported to health department within 7 days. Dr. Hugo Abel Pinto Ramírez 124
- 125. Hepatitis D Virus Dr. Hugo Abel Pinto Ramírez 125
- 126. HDV Transmission Percutanous exposures injecting drug use Permucosal exposures sex contact Dr. Hugo Abel Pinto Ramírez 126
- 127. Geographic Distribution ofHDV Infection Taiwan Pacific Islands HDV Prevalence High Intermediate Low Very Low No Data Source: Centers for Disease Control and Prevention
- 128. Hepatitis D -Clinical Features Coinfection severe acute disease low risk of chronic infection Superinfection usually develop chronic HDV infection high risk of severe chronic liver disease Dr. Hugo Abel Pinto Ramírez 128
- 129. HBV - HDVCoinfection Symptoms ALT Elevated anti-HBs Titer IgM anti-HDV HDV RNA HBsAg Total anti-HDV Time after Exposure
- 130. HBV - HDVSuperinfection Jaundice Symptoms Total anti-HDV ALT Titer HDV RNA HBsAg IgM anti-HDV Time after Exposure
- 131. GRACIAS POR SU ATENCIÓN Para ver otros temas relacionados: Visite: Blog SIN BANDERA http://hugopintoramirez.blogspot.mx/ Visite: http://www.slideshare.net/HugoPinto4 Dr. Hugo Abel Pinto Ramírez 131
Editor's Notes
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- #17 24 Antibody production in response to HAV infection results in lifelong immunity to hepatitis A and, presumably, to HAV infection. Vaccination of a person who is immune because of prior infection does not increase the risk of adverse events. In populations that are expected to have high rates of prior HAV infection, prevaccination testing might be considered to reduce costs by avoiding vaccination of persons who have prior immunity. Testing of children is not indicated generally because of their expected low prevalence of infection. For adults, the decision to test should be based on the expected prevalence of immunity , the cost of vaccination compared with the cost of serologic testing (including the cost of an additional visit), and the likelihood that testing will not interfere with initiating vaccination. For example, if the cost of screening (including laboratory and office visits) is one third the cost of the vaccine series, then screening potential recipients in populations where the prevalence of infection is likely to be greater than 33% should be cost-effective. Persons for whom prevaccination testing will likely be most cost-effective include adults who were born in or lived for extensive periods in geographic areas that have a high endemicity of HAV infection , older adolescents and young adults in certain population groups (i.e., Native Americans, Alaska Natives, and Hispanics) , and adults in certain groups that have a high prevalence of infection (e.g., injecting drug users[IDU]). In addition, the prevalence might be high enough among all older U.S.-born adults to warrant prevaccination testing. Commercially available tests for total anti-HAV should be used for prevaccination testing.
- #18 25 Post-vaccination testing is not indicated because of the high rate of vaccine response among adults and children. In addition, testing methods that have the sensitivity to detect low, but protective, anti-HAV concentrations after vaccination are not approved for routine diagnostic use in the United States.
- #19 Periodic outbreaks among users of illicit drugs and men who have sex with men have been recognized in the United States, Canada, Europe, and Australia for many years. Since 1996, when the ACIP made the first recommendations for the use of hepatitis A vaccine, routine vaccination of persons at increased risk of infection or its consequences has been recommended. However, these recommendations have not been widely implemented. Hepatitis A vaccination is also recommended, instead of or in addition to IG for persons who travel to areas of high or intermediate hepatitis A endemicity (see slide 10). Other groups for whom hepatitis A vaccination is recommended include persons who have clotting factor disorders and persons with chronic liver disease because of the increased risk of more severe symptoms with hepatitis A.
- #20 The complete set of guidelines for the treatment of patients who have sexually transmitted diseases (STDs) were developed by CDC after consultation with a group of professionals knowledgeable in the field of STDs who met in Atlanta on September 26-28, 2000. Included in the guidelines is language that stresses that hepatitis A and hepatitis B vaccinations are critical in the care of men who have sex with men.
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- #45 WHO estimates that 170 million persons or 3 % of the world’s population are infected with hepatitis C and 3 to 4 million persons are newly infected each year. The prevalence of HCV in some countries in Africa, the Eastern Mediterranean, South East Asia and Western Pacific is high compared to some countries in Europe and North America. According to the National Health and Nutrition Examination Survey of 1988 to 1994, the NHANES survey, and other population-based surveys, nearly 2% of Americans test positive for the hepatitis C antibody. This prevalence corresponds to an estimated 4 million Americans infected with HCV.
- #46 After initial exposure, HCV RNA can be detected in blood with 1 to 3 weeks and is present at the onset of symptoms. Antibodies to HCV are detected by enzyme immunoassay (EIA) in only 50 to 70 percent of patients at onset of symptoms, increasing to more than 90 percent after 3 months. Acute infection can be severe but rarely is fulminant. Symptoms are uncommon but can include malaise, weakness, anorexia, and jaundice. Symptoms usually subside after several weeks as ALT levels decline. Persons with acute HCV infection typically are either asymptomatic or have a mild clinical illness., 60%-70% have no discernible symptoms; 20%-30% might have jaundice; and 10% might have non-specific symptoms (eg, anorexia, malaise, or abdominal pain). After acute infection, 15%-25% of persons appear to resolve their infection without sequelae as defined by sustained absence of HCV RNA in serum and normalization of ALT levels. Chronic HCV infection develops in most persons, with persistent or fluctuation in ALT elevations indicating active liver disease.
- #48 Based on studies conducted in the last decade since the publication by Kiyosawa et al., it has become possible to formulate an algorithm of the natural history of hepatitis C using data from a combination of prospective studies of posttransfusion and long-term follow-up of patients with established HCV infection. 75%-85% of patients will become chronically infected. Over a variable time period 10-20 years, 20% of patients will develop cirrhosis.
- #49 Based on studies conducted in the last decade since the publication by Kiyosawa et al., it has become possible to formulate an algorithm of the natural history of hepatitis C using data from a combination of prospective studies of posttransfusion and long-term follow-up of patients with established HCV infection. Of the 20% of cirrhotic patients, approximately 6% of patients can be expected to develop hepatic decompensation per year , 4% will develop HCC per year, and 3% to 4% per year can be expected to die or require liver transplantation.
- #51 Statistics from the Centers for Disease Control indicate that approximately 4 million Americans are infected with HCV, and of these, an estimated 2.7 million have chronic HCV infection. Chronic liver disease is the tenth leading cause of death among American adults and accounts for approximately 25,000 deaths each year, or 1% of all deaths in the United States. HCV accounts for an estimated one-third of HCC cases in the United States. HCC rarely occurs in the absence of cirrhosis or advanced fibrosis. The incidence of HCV-related HCC continues to rise in United States and worldwide, in part because of the increasing numbers of persons who have been chronically infected for decades, the presence of comorbid factors, and the longer survival of persons with advanced liver disease due to improved management of complications. Hepatitis C also is now the most common reason for liver transplantation in the United States.
- #54 Extrahepatic Manifestations of HCV Patients with chronic HCV can present with extrahepatic manifestations or syndromes considered to be of immunologic origin, such as rheumatoid symptoms, keratoconjunctivitis sicca, lichen planus, glomerulonephritis, lymphoma, and essential mixed cryoglobulinemia. Cryoglobulins have been detected in the serum of up to one-half of patients with chronic hepatitis C, but the clinical features of mixed cryoglobulinemia are uncommon. Chronic hepatitis C is also related to porphyria cutanea tarda. Psychological disorders including depression have been associated with HCV infection in up to 20 to 30 percent of cases Management of Hepatitis C. NIH Consensus Statement, 2002. P 7-8 [Ref. 4.1]
- #62 The course of acute hepatitis C is variable, although elevations in serum ALT levels, which often take on fluctuating patterns, are its most characteristic feature. Normalization of ALT levels may occur and suggests full recovery, but this is frequently followed by ALT elevations that indicate progression to chronic liver disease. Patients with HCV infection typically are asymptomatic or have nonspecific symptoms and may have mild-to-moderate elevations of ALT. After acute infection, 15% to 25% of patients appear to resolve their infection without sequelae as defined by sustained absence of HCV RNA in serum and normalization of ALT levels. Chronic HCV infection develops in most patients with persistent or fluctuating ALT levels, but in 30% to 40% of patients with chronic infection, ALT levels are normal. Similarly, a comparable proportion of patients who test positive for the hepatitis C antibody, as many as 42%, may have ALT levels that are less than 2 times the upper limit of normal. Since the results of a single ALT determination cannot exclude ongoing hepatic disease, any degree of abnormality in ALT levels warrants further evaluation, and long-term follow-up of patients with HCV infection is required to determine their clinical outcome or prognosis.
- #63 Many people infected with HCV are unaware of the route of exposure, the risk of transmission, and the severity of HCV-related liver disease. A recent study assessed the primary routes of HCV transmission in an asymptomatic population of volunteer blood donors, studied their sexual partners and/or family members, and correlated their positivity for anti-HCV with evidence of chronic liver disease. Among the blood donors who tested positive for HCV RNA, 56% had biochemical evidence of liver disease at the initial evaluation; that is, they had at least one elevated ALT measurement. When the follow-up period was included in the analysis, the percentage of volunteers with elevated ALT levels increased to 69%. During follow-up, most HCV-positive individuals had either persistently normal ALT levels (31%), or peak levels no more than twice the upper limit of normal (42%). ALT levels were more than twice the upper limit of normal in 15% of the participants and more than three times the upper limit of normal in 12%. Among the 77 volunteers positive for HCV RNA who underwent liver biopsy, five had severe chronic hepatitis or cirrhosis, 66 had mild-to-moderate chronic hepatitis, and six had no evidence of hepatitis.
- #64 Liver biopsy provides a unique source of information on fibrosis and assessment of histology. Liver enzymes have shown little value in predicting fibrosis. Extracellular matrix tests can predict severe stages of fibrosis but cannot consistently classify intermediate stages of fibrosis. Moreover, only liver biopsy provides information on possible contributions of iron, steatosis, and concurrent alcoholic liver disease to the progression of chronic hepatitis C toward cirrhosis. Although unexpected etiologies of liver disease are rarely discovered on liver biopsies from patients undergoing evaluation of chronic hepatitis C, the information obtained on liver biopsy allows affected individuals to make more informed choices about the initiation or postponement of antiviral treatment. Thus, the liver biopsy is a useful part of the informed consent process. Adult or pediatric patients with persistently normal or slightly elevated ALT levels and minimal or no fibrosis on liver biopsy may be reassured of a favorable prognosis and decide to defer antiviral therapy in the light of treatment side effects. Since a favorable response to current antiviral therapy occurs in 80 percent of patients infected with genotype 2 or 3, it may not always be necessary to perform liver biopsy in these patients to make a decision to treat. The usefulness of a pretreatment liver biopsy in this group as well as those with other genotypes requires further study. In general, a baseline assessment of liver histology offers a valuable standard for subsequent comparisons. However, the appropriate interval for subsequent evaluations is yet to be determined.
- #65 The severity of hepatitis is measured in two ways. The amount of inflammation present measure the current immune activity in the liver, and is known as the grade of the disease. When inflammation does not subside, it leads to the destruction of working liver cells. When these cells die, they are replace by scar tissue, a process known as fibrosis. The amount of scarring in the liver is used to determine the stage of hepatitis. The stage of hepatitis represents the amount of liver damage that has been done by the disease. The more scarring that is present in the liver, the less work the liver can do. These five sections of the liver represent increasing levels of fibrosis as defined as the METAVIR staging system. Little effect on liver function is seen during stages 0, 1, and 2. Fibrosis is largely limited, and most of the working cells of the liver stay well supplied with blood and oxygen. By stage 3, however, the scarring has progressed to the point that the function of the liver cells is affected, and blood flow throughout he liver is altered. Fluids and bile may begin to build up in the liver, which begins to discolor. In stage 4, also called cirrhosis, abnormal blood flow may result in a build up of fluid in the abdomen, a condition known as ascites. Failure of the liver cells to function often results in symptoms such as generalized weakness, anorexia, malaise, weight loss, and jaundice.
- #67 First, physicians need to have a high index of suspicion based on the presence of risk factors, not the presence or absence of symptoms. The initial test for suspected HCV infection is an EIA to determine the presence of antibodies to HCV in serum. A positive anti-HCV test by EIA indicates the presence of HCV infection unless additional testing for HCV RNA by qualitative or quantitative PCR assay indicates a lack of viremia. In selected cases, measurement of HCV RNA may be the only positive test indicative of the presence of HCV infection.
- #71 Like thrombolytics, cytokines, growth factors, and adhesion molecules, interferons are native proteins that have widespread applications in the treatment of cardiovascular disease, oncology, organ transplantation, trauma, and immunodeficiency. However, they have several shortcomings. Native proteins are hydrolyzed in the gastrointestinal tract and must be administered parenterally, often in frequent, multiple doses due to their poor stability and short half-lives. After parenteral administration, they are cleared rapidly through renal, hepatic, or splenic mechanisms, and their rate of clearance depends on their size, charge, and other physicochemical factors. As therapy for viral infections, dosing regimens for some native proteins is burdensome to patients and may lead to virologic breakthrough infections. Chemical modification of native proteins is a means of overcoming these difficulties, particularly for proteins that must be administered parenterally for prolonged periods. One of the most promising technologies is modification with polyethylene glycol (PEG), a process known as pegylation.
- #72 Polyethylene glycol (PEG) is a linear, hydrophilic, uncharged, flexible polymer that is available in a variety of molecular weights. It is used as a formulation for a number of pharmaceutical preparations, for example, Adagen ® (Enzon, Inc., Piscataway, NJ). Adagen has been shown to be safe and effective in the treatment of adenosine deaminase (ADA)-deficient severe combined immunodeficiency disease (SCID) for more than 10 years without adverse effects attributable to the PEG polymer. In studies involving over 40 proteins, pegylation has been shown to increase serum half-life, reduce antigenicity and immunogenicity, and reduce protein sensitivity to proteolysis. Schering-Plough has developed a pegylated form of INTRON A (PEG-INTRON) that fulfills all the requirements of a long-acting, once weekly IFN - 2b. PEG-INTRON consists predominantly of a single unit of monomethoxypolyethylene glycol, with an average molecular weight of approximately 12,000 Da, covalently conjugated variously by urethane, carbonate, and oxycarbonyl imidazole linkaged to various amino acids on the IFN - 2b peptide.
- #73 3 Derivatization of protein-based therapeutics with polyethylene glycol (pegylation) can often improve pharmacokinetic and pharmacodynamic properties of the proteins and thereby, improve efficacy and minimize dosing frequency. Polyethylene glycol (PEG) is a linear, hydrophilic, uncharged, flexible polymer that is available in a variety of molecular weights. It is used as a formulation for a number of pharmaceutical preparations, for example, Adagen ® (Enzon, Inc., Piscataway, NJ). Adagen has been shown to be safe and effective in the treatment of adenosine deaminase (ADA)-deficient severe combined immunodeficiency disease (SCID) for more than 10 years without adverse effects attributable to the PEG polymer. In studies involving over 40 proteins, pegylation has been shown to increase serum half-life, reduce antigenicity and immunogenicity, and reduce protein sensitivity to proteolysis. Schering-Plough has developed a pegylated form of INTRON A (PEG-INTRON) that fulfills all the requirements of a long-acting, once weekly IFN - 2b. PEG-INTRON consists predominantly of a single unit of monomethoxypolyethylene glycol, with an average molecular weight of approximately 12,000 Da, covalently conjugated variously by urethane, carbonate, and oxycarbonyl imidazole linkaged to various amino acids on the IFN - 2b peptide.
- #74 This cartoon depicts the effect of increased peg-size on half-life. PEG molecules range in molecular weight from 300 to 4000 Daltons can be arranged in linear or branched chains. The extent to which pegylation modifies the pharmacokinetic and pharmacodynamic profile of a native protein depends on the structure and size of the PEG molecule (x-axis) and the site of attachment of the PEG chain. In general, the larger the PEG chain, the greater the extension of the protein’s half-life (y-axis). The 12 kDa molecule promotes high biological activity along with enhanced pharmacokinetic behavior. Choosing a single 12 kilodalton polyethylene glycol (PEG) molecule was key to designing the pegylation strategy for interferon -2b. A smaller polymer 5 kilodalton would have had an inadequate effect on the clearance of the molecule, whereas larger PEGs 20 kilodalton (PEG) decrease the activity of the molecule and are more difficult to clear from the body.PEG conjugation increases the serum half-life and thereby prolong patient exposure to interferon -2b without altering the biologic potency to the protein. The underlying interferon is still the active antiviral agent. Since size and attachment position of the PEG molecule can affect biologic activity of the protein. PEG-INTRON ® was designed to deliver the most “active” pegylated interferon alfa-2b to suppress the virus over a full one-week period.
- #75 This cartoon depicts the effect of increased peg-size on activity. As the peg size increases (molecular weight) less activity is observed. This is most likely due to stearic hindrance (ie the molecules ability to bind to the receptor). The 12 kDa molecule promotes high biological activity along with enhanced pharmacokinetic behavior. Choosing a single 12 kilodalton polyethylene glycol (PEG) molecule was key to designing the pegylation strategy for interferon -2b. A smaller polymer 5 kilodalton would have had an inadequate effect on the clearance of the molecule, whereas larger PEGs 20 kilodalton (PEG) decrease the activity of the molecule and are more difficult to clear from the body. The relationship between PEG size, activity, and half life can be expressed on a simple equation, with half-life increasing and antiviral activity decreasing directly with PEG size. Grace et al have with the experiments described in the previous slides demonstrated that the site (Cys1, His34, Lys31, Lys83, Lys121, Lys131, and Lys134) and size (5 kD, 12 kD, 20 kD, or 30 kD) of pegylation affects the interferon alpha specific activity. The highest antiviral activity was observed with 5kD, the lowest residual translocation was observed with the 30 kD. Note that as the peg attached to alfa-2b increases in size (5 kD to 30 kD), for pegylated isomers, the antiviral activity decreases. The trend of decreasing activity associated with increasing PEG size suggests that a putative mechanism-of-action may reside with the interaction and binding of IFN- to the IFNAR1/IFNAR2 heterodimeric receptor. The underlying interferon is still the active antiviral agent. Since size and attachment position of the PEG molecule can affect biologic activity of the protein. PEG-INTRON ® was designed to deliver the most “active” pegylated interferon alfa-2b to suppress the virus over a full one-week period.
- #76 Studies in the lab have shown that the larger the PEG size, the lesser the clearance. Small molecules such as PEG 5,000 are cleared rapidly. Larger molecules such as PEG 20,000 are cleared slower.
- #81 To achieve the goals, two drugs currently available for the treatment of HCV, interferon alfa and ribavirin. IFNs are natural cellular proteins with various actions, including induction of an antiviral state in their target cells and cytokine secretion, recruitment of immune cells, and induction of cell differentiation. After subcutaneous administration, IFN- a is specifically fixed onto high-affinity receptors at the surface of target cells. IFN-receptor fixation triggers a cascade of intracellular reactions leading to activation of numerous IFN-inducible genes. The products of these genes are the mediators of the various cellular actions of IFN . They are responsible for the antiviral effects of IFN through two distinct but complementary mechanisms: the induction of an antiviral state not specific to the virus in infected cells, which results in a direct inhibition of HCV replication; also, induction of immunomodulatory effects that enhance specific anti-HCV immune responses of the host. Ribavirin is a synthetic guanosine analogue used principally in the past for the treatment of severe respiratory syncitial virus infections in infants. Given alone, ribavirin has not proved to be efficient in chronic HCV infection.29 When added to IFN , ribavirin increases the initial response, i.e. , the ratio of patients who clear HCV RNA during therapy, and markedly reduces relapse rates in these patients. The mechanisms underlying these effects are not yet fully understood. Ribavirin selectively inhibits viral RNA polymerases in vitro . It has been reported to inhibit in vitro the replication of bovine viral diarrhea virus, a pestivirus close to HCV, and to synergize the antiviral effect of IFN in this model. Ribavirin also appears to potentiate the immunomodulatory properties of IFN . The underlying mechanisms are poorly known. It has been suggested that ribavirin could alter the Th1/Th2 balance by causing a shift towards Th1 responses. The greater efficacy of combination therapy with IFN plus ribavirin might also be related to ribavirin ability to suppress HCV-specific IL-10 production.
- #82 The goals of therapy are two-fold: The first is to clear the HCV RNA from peripheral blood. Producing a virologic response to therapy defined as HCV RNA negativity can be achieved with antiviral treatment with interferon based therapies ( ribavirin). This therapy can significantly alter the viral equilibrium, resulting in the decrease in the release of new virions from infected hepatocytes and, to a lesser extent, a decrease in the infection if previously infected hepatocytes. The second to prevent relapse or viral breakthrough. The second goal of therapy is to maintain the response, eg maintaining viral levels below levels of detectability. The optimal time that a patients must remain HCV RNA negative is still under investigation.
- #83 Initiation of IFN therapy results in a characteristic biphasic decline in viral load. This pattern can be seen in almost all patients, with the slope of the second-phase decline being related to the treatment regimen. The first phase rapid decline ( 2days) in HCV viral levels is due to the direct antiviral effect of IFN on virions release. The slower second-phase decline (>3 days) appears to be related to the reduction in the rate of infection of new hepatocytes combined with an increased death rate of infected hepatocytes. The differences in the degree of early viral decline has led researchers to classify patients according to a least 4 distinct patterns of response. Nonresponders, defined as having no decrease in viral load from baseline levels Flat partial responders, defined by a rapid first-phase decrease of 1-2 logs(within 1 to 2 days) but no further decrease Slow partial responders, defined as having a rapid-first-phase decline followed by a very gradual second-phase decrease in viral levels which may or may not become undetectable during treatment Rapid virologic responders, defined as rapid first- and second-slope viral decays with viral levels becoming undetectable fairly soon after initiation of therapy Data has consistently shown that patients demonstrating a rapid viral response have a much higher chance of of becoming a sustained virologic responders. Hence, viral load measurements early in the course of therapy can be used to predict those patients with the greatest likelihood of responding.
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- #111 Vaccine advisory groups that have endorsed this strategy include the Immunization Practices Advisory Committee to the U.S. Public Health Service (ACIP), the American Academy of Pediatrics (AAP), the American Academy of Family Physicians (AAFP), and the American College of Physicians (ACP).
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