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Hepatitis and travellers 15.04.11 isom


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Hepatitis and travellers 15.04.11 isom

  1. 1. Hepatitis and travel Dr Peter Noone, HSE Dublin NE Area
  2. 2. Travel risk/100,000 travellers per month to a developing countryLöscher T, Keystone JS,Steffen R, Vaccination of travellers against hepatitis A & B, J of Travel Medicine 1999; 6:107-114 . Incidence of health problems duringa month in a developing country.
  3. 3. Major and minor killers: global impact viewed on a ‘Richter’ (logarithmic) scale 7 Tobacco HIV Infant/child ARI & diarrhoeal dis Malaria HBV + HCV 6 Road accidents Measles Non-HIV tuberculosis RSV, Rota virus Influenza Dengue 5 10,000-foldViruses Hospital infection difference in H Papilloma v 4 Suicide impact West Nile virus 3 SARS Ebola Polio 2 Hanta virus vCJD 1 Log 10 Weiss & McMichael, 2004
  4. 4. Impact and incidence of vaccine-preventable diseases in travellers to developing countries. CFR = case-fatality rate.
  5. 5. Type of Traveller• The Business Traveller,• The Backpacker,• The Package Tourist,• The Overseas aid worker/missionary.• The HCW
  6. 6. Viral Hepatitis - Overview Type of Hepatitis A B C D ESource of faeces blood/ blood/ blood/ faecesvirus blood-derived blood-derived blood-derived body fluids body fluids body fluidsRoute of percutaneous percutaneous percutaneoustransmission faecal-oral permucosal permucosal permucosal faecal-oralChronic no yes yes yes noinfectionPrevention pre/post- pre/post- blood donor pre/post- Ensure exposure exposure screening; exposure safe immunisation immunisation risk behaviour immunisation; drinking modification risk behaviour modification water
  7. 7. These naming conventions can lead to confusion later, e.g.,Viral hepatitis is caused by at least 6 different viruses E n t e r ic a lly“ In f e c t io u s ” A Et r a n s m i t t e d V ir a l F, G , NANB ? O the r * h e p a t it i s P a r e n t e r a lly “ S e rum” B Ct r a n s m i t t e d D* 10-20% of cases of presumed viral hepatitis are still not accounted for
  8. 8. Hepatitis A• Epidemic jaundice described by Hippocrates• Differentiated from hepatitis B in 1940s• Serologic tests developed in 1970s• Most frequently reported type of hepatitis in the US
  9. 9. Hepatitis A Virus• Picornavirus (RNA)• Humans are only natural host• Stable at low pH• Inactivated by high temperature, formalin, chlorine
  10. 10. G e o g r a p h ic D is t r ib u t io n o f H A V In f e c t io nAnti-HAV Prevalence High Intermediate Low Very Low
  11. 11. Basic Water Supply
  12. 12. Hepatitis A—United States, 1966-2002 70000 60000 Vaccine 50000 LicensedCases 40000 30000 20000 10000 0 1966 1970 1974 1978 1982 1986 1990 1994 1998 2002
  13. 13. Hep A reports UKLaboratory reports of hepatitis A, England, Wales, and Northern Ireland: 1998 – 2007
  14. 14. Hep A in IrelandNumber of cases 2009: 52,Crude notification rate: 1.2/100,000No. of cases 2008: 42,
  15. 15. Hepatitis A Epidemiology• Reservoir Human, Endemic• Transmission Faeco-oral• Temporal pattern None• Communicability 2/52 before to 1/52 after onset
  16. 16. Declining Hepatitis A Rates – The Bad News 100 1980 80 1990Proportion Of Americans 60 SusceptibleTo Hepatitis A 40 (%) 20 0 20s 30s 40s 50s 60s 70s Age (Years) Data from NHANES II and III.
  17. 17. Consequences Of Adult Hepatitis A And B Infections HepA HepBSymptoms of overt hepatitis 73%-90% 41%Hospitalization 10%-26% 16%-19%Acute liver failure 2-15 per 1000 7.3 per 1000Liver transplant 1-3 per 1000 1.7 per 1000Post-transplant survival 7-14 years 7-14 yearsCase fatality rate (acute illness) 1-9 per 1000 4 per 1000Probability of chronic infection 0% 5%-8% Berge et al. Hepatology. 2000;31:469. Fendrick et al. Arch Pediatr Adolesc Med. 1999;153:126. Margolis et al. JAMA. 1995;274:120.
  18. 18. Hepatitis A Incidence* by Age Group 20 18 16 14 12 Rate 10 8 6 4 2 0 <5 5-14 15-24 25-39 40+ Age group (yrs) *rate per 100,000 population. 1997 data.
  19. 19. Age-specific Mortality Due to Hepatitis A A g e g r o u pC a s e - F a t a l i t y ( ye a r s ) ( p e r 10 0 0 ) <5 3.0 5-14 1.6 15-29 1.6 30-49 3.8 >49 17.5 Total 4.1 Source: Viral Hepatitis Surveillance Program CDC Atlanta, 1983-1989
  20. 20. Hepatitis A Pathogenesis• Entry into mouth, incub 15-50 days,• Viral replication in the liver• Virus present in blood and faeces 10-12 days after infection• Virus excretion may continue for up to 3/52 after onset of symptoms
  21. 21. Hepatitis A Clinical Features• Incubation period 28 days (range 15-50 days)• Illness not specific for hepatitis A• Likelihood of symptomatic illness directly related to age• Children generally asymptomatic, adults symptomatic
  22. 22. Hepatitis A: Significant Public Health Issue• On average, infected adults lose 27 days of work1• Between 11% and 22% of patients are hospitalized1• Annual costs of hepatitis A estimated at $488.8 million2• On average, in the United States, 1 person dies every 4 days as a result of acute liver failure from hepatitis A1 1. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep. 1999;48(RR-12):1. 2. Berge et al. Hepatology. 2000;31:469.
  23. 23. C o n c e n t r a t io n o f H e p a t it is A V ir u s in V a r io u s B o d y F lu id s FaecesB odyF lu id Serum Saliva Urine 100 102 104 106 108 1010 In f e c t io u s D o s e s Source: Viral Hepatitis and Liver Disease m l p e r 1984;9-22 J Infect Dis 1989;160:887-890
  24. 24. epatitis A—United States, 1990-200 Risk Factors Sexual/household 14% Intl travel 5% MSM Unknown 10% 45% IDU 6% Daycare 2% Outbreak Other 4% 8% Source: NNDSS/VHSP DC contact 6%
  25. 25. Hepatitis A Vaccines• Inactivated whole virus• Avaxim (Sanofi Pasteur MSD)• HAVRIX (GlaxoSmithKline)• Paediatric and adult formulations• Licensed for persons >2 years• Epaxal (MASTA)
  26. 26. Hepatitis A Vaccine Immunogenicity Adults • 95% seropositive after one dose • 100% seropositive after two doses Children (>2 years) and Adolescents • >97% seropositive after one • 100% seropositive after 2 dosesVan Damme P, Banatvala J, Fay O et al. Hepatitis A booster vaccination: is there a need? Lancet 2003: 362:1065-71
  27. 27. Twinrix• Combination hepatitis B (adult dose) and hepatitis A vaccine (paediatric dose)• Schedule: 0, 1, 6-12 months• Approved for persons >16 years, (TWINRIX PAEDIATRIC ® (Glaxo SmithKline) this can be used from 1 year up to and including 15 years of age.• Not recommended for post exposure vaccination.
  28. 28. Hepatitis A VaccinesFormulation HAVRIX VAQTA AVAXIMPaedsAge 1-16 yrs 2-17 yrs <16yrsDose 0.5ml 0.5ml Not recommendedAdultAge >16 yrs >18yrs >16yrsDose 1.0ml 1.0ml 0.5ml
  29. 29. H e p a t it is A V a c c in e E f f ic a c y S t u d ie s Vaccine Site/Age EfficacyVaccine Group N (95% CI)HAVRIX® Thailand 38,157 94%(SKB) 1-16 yrs (79%-99%)2 doses360 EL.U.VAQTA ™ New York 1,037 100%(Merck) 2-16 yrs (85%-100%)1 dose25 unitsJAMA 1994;271:1363-4N Engl J Med 1992;327:453-7
  30. 30. Hepatitis A VaccinesAdult• 1 dose• Booster dose 6-18/12 after first doseChildren and Adolescent• 1 dose• Booster dose 6-18/12 after first dose Hepatitis A booster vaccination: is there a need?. The Lancet, Volume 362, Issue 9389, Pages 1065-1071 P. Van Damme, J. Banatvala, O. Fay, S. Iwarson, B. McMahon, K. Van Herck, D. Shouval, P. Bonanni, B. Connor, G. Cooksley
  31. 31. Hepatitis AVaccine Recommendations• International travellers• MSM,• IVDU’s• Persons who have clotting-factor disorders• Persons with occupational risk• Persons with chronic liver disease, including HCV
  32. 32. Hepatitis A Serologic TestingPrevaccination • Not indicated for children • May be considered for some adults and older adolescentsPostvaccination • Not indicated
  33. 33. Hepatitis AVaccine Adverse Reactions• Pain at injection site• Systemic reactions not common• No serious adverse reactions reported
  34. 34. Hepatitis A VaccineContraindications and Precautions • Severe allergic reaction to a vaccine component or following a prior dose • Moderate or severe acute illness
  35. 35. Hepatitis AVaccine Recommendations• Travellers to high- or intermediate- risk countries• Protected by 4 weeks after dose• Give concurrent IG for travel in <4 weeks or travellers who are immunocomprimised.
  36. 36. HBV
  37. 37. Hepatitis B• The first recognition of public health importance of HBV infection by direct inoculation of blood or blood products was first documented by Lurman in Bremen, Germany, in 1883, during a smallpox immunisation campaign. Thousands received vaccine that had been prepared from human lymph.• Of 1,289 shipyard workers who received this vaccine, 191 (15%) developed jaundice several weeks to 8 months later; jaundice did not occur among unvaccinated workers.• Lurman, A. 1855. Eine icterus Epidemic. Berlin Klin. Wochenschr. 22:20–23.
  38. 38. Hepatitis B• Epidemic jaundice described by Hippocrates in 5th century BCE• Jaundice reported among recipients of human serum and yellow fever vaccines in 1930s and 1940s• Australian antigen described in 1965• Serologic tests developed in 1970s
  39. 39. Hepatitis B Virus• Hepadnaviridae family (DNA)• Numerous antigenic components• Humans are only known host• May retain infectivity for at least 1 month at room temperature
  40. 40. Hepatitis B Virus Infection•40% of world’s population had contact withor are carriers of HBV, 2 billion infected,•>350 million chronic carriers worldwide•Established cause of chronic hepatitis andcirrhosis, 600,000 death in 2002.•Human carcinogen—cause of up to 80% ofhepatocellular carcinomas.Banatvala J et al “Lifelong protection against Hepatitis B; role of vaccine immunogenicity in immunememory”,Vaccine 2001;19:877-885.Goldstein ST, Zhou F, Hadler SC, Bell BP, Mast EE, Margolis HS. A mathematical model to estimate globalhepatitis B disease burden and vaccination impact. Int J Epidemiol 2005;34(6):1329.
  41. 41. HBV infection (2)•In Europe & US chronic infection with HBV, affects about 1-3% ofthe population,• In Africa and Asia, rate may be >10% and will remain so for manydecades,• Immigrants from the high incidence areas will carry the same riskof HBV carriage as the population in their country of birth,• ~ 1/3 of HCV and a variable number of HIV patients have occultHBV infection,•Before widespread vacc of HCWs, >12,000 HCWs per year wereinfected in U.S. in the pre-vaccine era.Guidelines for prevention of transmission of human immunodeficiency virus and hepatitis B virus to health-care and public-safety workers. MMWRMorb Mortal Wkly Rep 1989;38(suppl 6):1–37.
  42. 42. Hepatitis B Virion, Dane particle and HBsAG From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 66, published by Mosby Philadelphia,,
  43. 43. Hepatitis B Clinical Features• Incubation period 6 weeks to 6 months (average 120 days)• Non-specific prodrome of fever, malaise, headache, myalgia• Illness not specific for hepatitis B• At least 50% of infections asymptomatic
  44. 44. Hepatitis B Epidemiology• Reservoir Human. Endemic• Transmission Bloodborne Subclinical cases transmit• Communicability 1-2 months before and after onset of symptoms Chronic carriers
  45. 45. HBV Diagnosis• A battery of serological tests are used for the diagnosis of acute and chronic hepatitis B infection.• HBsAg - used as a general marker of infection.• HBsAb - used to document recovery and/or immunity to HBV infection.• anti-HBc IgM - marker of acute infection.• anti-HBcIgG - past or chronic infection.• HBeAg - indicates active replication of virus and therefore infectiveness.• Anti-HBe - virus no longer replicating. However, the patient can still be positive for HBsAg which is made by integrated HBV.• HBV-DNA - indicates active replication of virus, more accurate than HBeAg especially in cases of escape mutants. Used mainly for monitoring response to therapy.
  46. 46. Clinical outcomes of Hepatitis B infections Figure 66-11. Clinical outcomes of acute hepatitis B infection. (Redrawn from White DO, Fenner F: Medical virology, ed 3, New York, 1986, Academic Press From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 62, published by Mosby Philadelphia,,
  47. 47. Risk of Chronic HBV Carriage by Age of Infection 100 90 80Carrier risk (%) 70 60 50 40 30 20 10 0 Birth 1-6 mo 7-12 mo 1-4 yrs 5+ yrs Age of infection
  48. 48. M Ramsay, HPA UK
  49. 49. Global Patterns of Chronic HBV Infection• High (>8%): 45% of global population – lifetime risk of infection >60% – early childhood infections common• Intermediate (2%-7%): 43% of global population – lifetime risk of infection 20%-60% – infections occur in all age groups• Low (<2%): 12% of global population – lifetime risk of infection <20% – most infections occur in adult risk groups
  50. 50. Geographic Distribution of Chronic HBV Infection HBsAg Prevalence ≥8% - High 2-7% - Intermediate <2% - Low
  51. 51. Worldwide distribution patterns of HBV genotypes and sub-genotypes.Regions with high, intermediate and low endemicity are shown by grey, light grey and white shades respectively.Datta Virology Journal 2008 5:156 doi:10.1186/1743-422X-5-156
  52. 52. Hepatitis B—United States, 1978-2002 Decline among homosexual men 30000 Decline among IV drug users 25000 20000Cases 15000 10000 Hepatitis B vaccine licensed 5000 0 1978 1982 1986 1990 1994 1998 2002
  53. 53. Figure 1: Notifications of Hepatitis B (acute and chronic) 2004-2009 Epidemiology of Hepatitis B in Ireland
  54. 54. Risk of Traveller Exposure HBV
  55. 55. Bloodborne Pathogen TrainingRisk of Bloodborne Virus Transmission after Occupational Percutaneous Exposure Source Risk Risk HBV HBeAg + 22.0-30.0% 22.0-30.0% HBeAg - 1.0-6.0% 1.0-6.0% 1.8% HCV 1.8% 0.3% HIV 0.3%
  56. 56. Risk Factors for Hepatitis B Other 23% Multiple sex partners 24% Household 3% Sex contact 13% MSM IDU 17% 20% CDC Sentinel Sites. 2001 data.
  57. 57. C o n c e n t r a t io n o f H e p a t it is B V ir u s in V a r io u s B o d y F lu id s Low/Not High Moderate Detectable blood semen urine serum vaginal fluid feceswound exudates saliva sweat tears Breast milk
  58. 58. Acute Hepatitis B Virus Infection with Recovery T y p ic a l S e r o lo g ic C o u r s e Symptoms HBeAg anti-HBe Total anti-HBcT it e r HBsAg IgM anti-HBc anti-HBs 0 4 8 12 16 20 24 28 32 36 52 100 We e k s a fte r E xpos ure
  59. 59. Progression to Chronic Hepatitis B Virus Infection T y p ic a l S e r o lo g ic C o u r s e Acute Chronic (6 months) (Years) HBeAg anti-HBe HBsAg Total anti-HBc T it e r IgM anti-HBc 0 4 8 12 16 20 24 28 32 36 52 Years We e k s a fte r E xpos ure
  60. 60. Pathogenesis of HepatitisHBV - Natural History B Modulating Factors in Hepatitis B HOST VIRUS Gender Genotype Age Molecular Variants Immune Response ENVIRONMENT Alcohol HCV, HDV, HIV Carcinogens
  61. 61. Hepatitis B Vaccine1965 Discovery of Australian antigen1973 Successful HBV infection of chimpanzees1981 License of plasma-derived vaccine1986 License of recombinant vaccine1991 Universal infant vaccination (U.S.)1996 Universal adolescent vaccination (U.S).
  62. 62. Hepatitis B Vaccine• Composition Recombinant HBsAg• Efficacy 95% (Range, 80%-100%)• Duration of Immunity >15 years• Schedule 3 Doses• Booster doses not routinely recommendedAre booster immunisations needed for lifelong hepatitis B immunity? European Consensus Group on HepatitisB Immunity.Lancet 2000 Feb 12;355(9203):561-5.
  63. 63. Hepatitis B Vaccine Formulations• HB-Vax II (Sanofi) - 5.0 mcg/0.5 mL (paediatric) - 10 mcg/1 mL (adult) - 40 mcg/1 mL (dialysis)• Engerix-B (GSK) - 10 mcg/0.5 mL (paediatric) - 20 mcg/1 mL (adult)
  64. 64. Protection* by Age Group and Dose Dose Infants** Teens and Adults*** 1 16%-40% 20%-30% 2 80%-95% 75%-80% 3 98%-100% 90%-95% * Anti-HBs antibody titre of 10 mIU/mL or higher ** Preterm infants less than 2 kg have been shown to respond to vaccination less often *** Factors that may lower vaccine response rates are age >40 years, male gender, smoking, obesity, and immune deficiency, HLA type.
  65. 65. Recommended Dose of Hepatitis B Vaccine HB-Vax II Engerix-B Dose (mcg) Dose (mcg)Infants and children 0.5 mL (5) 0.5 mL (10)<11 years of ageAdolescents 11-19 0.5 mL (5) 0.5 mL (10)yearsAdults >18 years 1.0 mL (10) 1.0 mL (20)
  66. 66. Hepatitis B Vaccine Long-term Efficacy • Immunologic memory established following vaccination • Exposure to HBV results in anamnestic anti-HBs response • Chronic infection rarely documented among vaccine respondersAre booster immunisations needed for lifelong hepatitis B immunity?European Consensus Group on Hepatitis B Immunity.Lancet 2000 Feb12;355(9203):561-5.
  67. 67. Management of Non-response to Hepatitis B Vaccine • Complete a second series of three doses or • Give a booster dose and recheck, • Should be given on the usual schedule of 0, 1 and 6 months • Retest 1-2 months after completing the second series
  68. 68. Persistent Non-response to Hepatitis B Vaccine• <5% of vaccinees do not develop anti-HBs after 6 valid doses• May be non-responder or "hypo- responder"• Check HBsAg status• If exposed, treat as non- responder with PEP (HBIG)
  69. 69. Non-response • Age (>40yrs), • Gender, • Obesity (BMI>30), • Smokers, • HLA_DR3+ or -DR7+ halotypes, • Site and route of injection.Zuckerman J et al, “Evaluation of a New Hepatitis B Triple-Antigen Vaccine in Inadequate Responders to Current Vaccine,Hepatology 2001; 34(4)798-802
  70. 70. Twinrix• Combination hepatitis B and hepatitis A vaccine (paediatric dose) (720 ELISA u’s HAV, 20mcgs recomb HBsAG in 1ml)• Schedule: 0, 1, 6-12 months• Approved for persons >16 years• Twinrix paediatric (360 ELISa u’s HAV, 10mcgs recomb HBsAg protein in 0.5ml)• Not recommended for post exposure vaccination
  71. 71. Northdruft H,Zuckerman J, “Accelerated Vaccination Schedules Provide Protection Against Hepatitis A & B in Last Minute Travellers” Vaccine 2002;20:1157-1162. Medicine
  72. 72. Evaluation of Hepatitis B Immune-Response in Elderly, Obese or Medically Compromised Subjects after Vaccination with HAB Combination or Monovalent Hepatitis B Vaccines Chlibek, R, von Sonnenburg F, Van Damme P, et al• response to HBV vacc in elderly, overweight or with medical conditions. Study of 4-yr persistence of anti-HBs and immunological memory to HBV in subjects ≥41 years with these conditions who had received either a combined HAB vaccine or one of two monovalent HBV vaccines.• 596 subjects ≥41-yrs randomised into 3 groups receive Twinrix™, at 0, 1 and 6/12, or one of two different monovalent HBV vaccines (Engerix-B™, or HBVAXPRO™) given at 0, 1 and 6/12 together with a HAV vaccine (at 0 and 6 months).• % with anti-HBs levels (≥10 mIU/ml) 4 yrs after vacc highest in HAB group, lower in Engerix-B and lowest in HBVAXPRO™. 1/12 after challenge HBV dose, the % elderly who mounted anti-HBs antibody ≥10mIU/ml highest in HAB (91.1%), lower in Engerix-B™ (89.1%) and lowest in HBVAXPRO™ group (76.4%).• In elderly, obese or ongoing medical conditions, combined HAB vaccine consistently greater anti-HBs than the other vaccines.• P2-15, NECTM 20010, Hamburg,
  73. 73. Hepatitis B Vaccine Adverse Reactions Infants and Twinrix Adults ChildrenPain at injection site 13%-29% 3%-9%Mild systemic complaints 11%-17% 0%-20%(fatigue, headache)Temperature >99.9°F (37.7°C) 1% 0.4%-6% rare rareSevere systemic reactions
  74. 74. Hepatitis B Vaccine Contraindications and Precautions• Severe allergic reaction to a vaccine component or following a prior dose,• Moderate or severe acute illness,• Hernán MA, Jick DS, Olek MJ, and Jick H, Recombinant hepatitis B vaccine and the risk of multiple sclerosis A prospective study, NEUROLOGY 2004;63:838-842• Numerous studies have evaluated a possible relationship between hepatitis B vaccination and multiple sclerosis. The weight of the available scientific evidence does not support the suggestion that hepatitis B vaccine causes or worsens MS.• ep_b.html
  75. 75. HBV variants with mutations•Vaccine failures with HBV mutations in small surface protein (S) gene(S mutants) in infants who got HBV vaccine or HBIG appropriately andwho have anti-HBs in protective range.•HBV variants resistant to neutralizing anti-HBs, reduce effectivenessof HBV imms programs or accelerate formation of HBV variants?. •But S mutants implicated in perinatally exposed infant vaccine failures usually of maternal origin and not induced by vaccination. •Mothers of infants who responded to vaccine as likely to have sAg variants as mums of infants who did not respond, suggests infections among vaccinated children with S mutants represent immunoprophylaxis failures and infection with maternal viral variants rather than breakthrough infections among successfully vaccinated infants. •Vaccinated chimps are protected from challenge with the most common surface antigen variant .• Commercial assays employing polyclonal anti-HBs detect S mutants,making ongoing surveillance for S mutants possible.
  76. 76. Pre-core mutantsDisappearance of HBeAg and rise of anti-HBe is associated with decline in viremia titerand replacement of wild-type HBV by the core promoter mutants and/or precore mutants.However, the core promoter mutants become prevalent even before the rise of anti-HBe.
  77. 77. HBV in Immune-suppressed Subjects Background*• HBV reactivation occurs in up to 50% of HBsAg+ patients and in ~4% anti-HBc+ patients with occult HBV receiving chemotherapy,• ~10% will become icteric and mortality is increased by at least 5% and may reach 70% after a flare,• Clinical reactivation frequently occurs following withdrawal of chemotherapy and emergence of immune recovery (Median onset 16w; Range:4-36w)• There is currently no reliable way to predict severity of HBV reactivation during and after chemotherapy,• However, risk seems to correlate with degree of viral load, use of corticosteroids , degree of immunosuppression, male sex.• *Liang R et al. J Clin Oncology 1999;17:394, Yeo W et al. British J Cancer 2004;90:1306
  78. 78. Reactivation of HBV in Immunosuppressed Patients• A large number of patients undergoing immuno or chemotherapy are still not screened for HBV markers prior to initiation of treatment,• As a result, patients with overt (and also occult) HBV infection are exposed to an unnecessary and usually preventable risk,• Partners of such patients and their treating HCWs maybe exposed to HBV upon reactivation
  79. 79. Patients at Risk for HBV Reactivation• Any patients with overt or occult HBV receiving systemic chemo- radio- or immunotherapy,• Lymphoma, Leukaemia and hematologic malignancies,• Bone marrow (BMT,) peripheral lymphocyte and stem cell transplantation for any cause (incl. Autologous BMT),• Cancer (i.e. breast cancer, gastric cancer, HCC post TACE in HBsAg+ or anti-HBc+ patients),• Liver, renal, heart, lung transplantation,• Systemic diseases (i.e. HIV infection, Crohn’s disease, RA; SLE etc.),• Premature discontinuation of anti-viral therapy in immune suppressed patients
  80. 80. Reactivation of HBV may occur in two defined forms of persistent infection:• Reactivation of HBV in originally asymptomatic, overt HBV, HBsAg(+) patients,• Reactivation of HBV in HBsAg(-) patients with occult HBV infection - OBV (HBV DNA in serum; in hepatocytes or in immune cells (ccc HBV-DNA+, anti-HBc+ or anti-HBc+/anti-HBs+)
  81. 81. Background• HBV reactivation in patients at risk may be asymptomatic orsymptomatic and is associated with cytotoxic orimmunosuppressive treatment, with pregnancy or surgery,• Reactivation may lead to hepatitis, hepatic failure, delays inchemo or immunotherapy (M ~100 days) and decreased survival(4-60%),• Reactivation may occur in >50% in HBsAg+ patients receivingchemotherapy,• Reactivation may also occur spontaneously in up to ~22% of HBVinfected patients who do not receive immunosuppression,• Not all forms of chemotherapy confer an equivalent risk forreactivation,Review: Holbrook E et al. Clin Liver Dis 2007; 11:965
  82. 82. Treatment• Interferon - for HBeAg +ve carriers with chronic active hepatitis. Response rate is 30 to 40%. – alpha-interferon 2b (original) – alpha-interferon 2a (newer, claims to be more efficacious and efficient)• Lamivudine - a nucleoside analogue reverse transcriptase inhibitor. Well tolerated, most patients will respond favorably. However, tendency to relapse on cessation of treatment. Another problem is the rapid emergence of drug resistance.• Adefovir – less likely to develop resistance than Lamivudine and may be used to treat Lamivudine resistance HBV. However more expensive and toxic• Entecavir – most powerful antiviral known, similar to Adefovir• Successful response to treatment will result in the disappearance of HBsAg, HBV-DNA, and seroconversion to HBeAg.
  83. 83. Efficacy of current drug regimens eAg +ve eAg -veDrug HBeAg HBV DNA HBV DNA seroconversion negative at negative at at Yr 1, % Yr 1, % Yr 1, %Interferon 18 37 60-70Lamivudine 18 40-44 60-70Adefovir 12 21 51Entecavir 21 67 90Peg-IFNa-2a 27 25 63Telbivudine 23 60 88
  84. 84. Rates of resistanceDrug Resistance %Interferon noneLamivudine 23 at Yr 1 71 at Yr 4Adefovir 0 at Yr 1 30 at Yr 5Entecavir < 1 in naïve at Yr 4 40 in Lam-r at Yr 4Peg IFNa-2a noneTelbivudine 22 in HBeAg +ve at Yr 2 9 in HBeAg -ve at Yr 2
  85. 85. Key Points:Screening for HBV markers is mandatory in allpatients scheduled for chemo- or immuno-therapy,• Immunization against HBV should be completed as soon aspossible (non-response must be investigated for occult HBV),• Early pre-emptive anti-viral treatment is superior to treatment atonset of reactivation,• It is highly recommended to continue treatment for 6-12 monthsafter completing chemo or immuno therapy,• Awareness regarding the risk of HBV reactivation must bestrengthened , especially among oncologists, haematologists andtransplant surgeons
  86. 86. HCV
  87. 87. HCV Epidemiology•HCV single-stranded RNA 170 million chronicallyinfected with HCV. 4 million people HCV in US,•HCV causes 17-20% of acute hepatitis cases in the US,•CDC -150,000 new cases per year. Highest prevalencehaemophiliacs and IVDU. Before plasma screening HCVaccounted for 90% of post transfusion hepatitis cases.•HCV is the most common cause of chronic viral hepatitisin the US. About 80% of people infected progress tochronic HCV infection
  88. 88. H e p a t it is C V ir u s c a p s id e n v e lo p r o t e a s e /h e RNA- RNA pe lic a s e d e p e n d e n tp o l y m e r a s e p ro te i c 2 n 33 c - 10 2 c 05’ 3’ c o E1 E2 NS NS NS NS re 2 3 4 5 h y p e r v a r ia b le r e g io n
  89. 89. Course of clinical HCV WEDEMEYER ET AL. HEPATOLOGY, May 2004
  90. 90. HCV Transmission• HCV can be transmitted parenterally, perinatally, and sexually. Most reliably through transfusion of infected blood or blood products, transplantation of organs from infected donors, and sharing contaminated needles among IVDU’s.• NSI among HCW’s place them at significant risk of infection. Incidence of HCV infection in HCW with history of needle-stick exposure to infected blood approaches 6%.• There is a 0.4-1% chance of developing irreversible liver injury from a needle-stick infection in this setting.
  91. 91. Trials evaluating treatment for acute HCV Study Type Nos SC n (%) Regimen Time of therapy SVR (%) Jaeckel et al Non- 44 N/A A Immediately, average 89 days post 98 randomised exposure Gerlach et al “ 60 24 (52) B 10-26 months from symptom onset 80 Kamal et al Randomised 54 5 (9) C 12 wks from symptom onset or 1St +ve 83 HCV RNA Nomura et al “ 30 0 D 8 wks from symptom onset 87 Pimstone et al Non- 10 3 (30) E 14 wks from exposure 100 randomised Rocca et al “ 16 1 (6) F Immediately, <70 days post exposure 92 Wiegand et al Non- 60 N/A G Immediately 95 randomised Santantonio et “ 28 11 (38) G 12 wks from symptom onset 94 al Broers et al “ 27 5 (19) G 100±82 days from symptom onset or 57 63±53 days from 1st +ve HCV assay Delwaide et al “ 28 N/A H Immediate, average110 ±44days post 75 exposure Adapted from Zekry et al. Journal of Hepatology 2005; 42: 293-296
  92. 92. HCV Infection Testing Algorithm for Diagnosis of Asymptomatic Persons 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 Evaluation (e.g. PCR, ALT) Evaluation Negative PCR, Positive PCR, Normal ALT Abnormal ALTSource: MMWR 1998;47 (No. RR 19)
  93. 93. Acute HCV• HCV infection is mostly asymptomatic (66-80%), incub 15-150 days,• Spontaneous viral clearance in 1- 30% 8-12 weeks post exposure,• Clearance can be predicted by rate of viral load decline,• Higher clearance rates reported in children, young adults particularly young women and persons with jaundice,• Up to 80% risk of going on to developing chronic disease with up to >20% risk of developing HCC,• Therapy once disease established improving but not completely effective in some genotypes,• Once disease is established response to treatment is reduced.Jaeckel E, et al “Treatment of Acute Hepatitis C with interferon Alpha-2B,N Eng J Med,2001; 345(20):1452-1456.
  94. 94. HCV Clinical course• Incubation period is 15-150 days, with symptoms developing anywhere from 5-12 weeks after exposure.• During acute infection with HCV, symptoms may appear similar to those of HBV infection. In up to 80% of cases, however, patients are asymptomatic and do not develop icterus.
  95. 95. Serologic Pattern of Acute HCV Infection with Recovery anti-HCV Symptoms +/- HCV RNATiter ALT Normal 0 1 2 3 4 5 6 1 2 3 4 Months Years Time after Exposure
  96. 96. Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection anti-HCV Symptoms +/- HCV RNATiter ALT Normal 0 1 2 3 4 5 6 1 2 3 4 Months Years Time after Exposure
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  101. 101. HCV in the Health care settingEuropean case-control study *• France, Italy, Spain, Switzerland, UK• 60 cases of occupationally acquired HCV in HCWs January 1993 andDecember 2002)• All cases percutaneous injuries.Risk factors associated with transmission:• -needle having been placed in the source patient’s vein or artery•-deep injury• -Hollow bore needle•-gender of the HCW (males were more likely to have seroconverted thanfemales) but this factor will need further investigation into its significance.Prevalence of infection in the specific populationVolume of inoculums and viral load in source patientPost exposure management.* Yazdanpanah Y, De Carli G, Migueres B, Lot F, Campins M, Colombo C, et al. Risk Factors for HCV Transmissionafter Occupational Exposure in Health Care Workers: A European Case-Control Study. Interscience Conference onAntimicrobial Agents and Chemotherapy (ICAAC); Chicago, September 2003: poster no. 1087
  102. 102. UK HCV seroconversions in HCW’s Occupation Device Procedure 1st test positive HCW Virus (weeks) treated cleared Junior Doctor (1996) Hollowbore Resuscitation A&E 16 NK Yes needle Surgeon (2000) Solid needle Suturing 8 Yes Yes Dentist (2001) Hollowbore Injection 4 NK Yes needle Nurse (2003) Hollowbore Venepuncture 8 N/A* Yes needle Doctor (2003) Hollowbore Venepuncture 8 Yes Yes needle Nurse (2004) Hollowbore Someone else’s sharp 6 Yes† Treatment needle ongoing Nurse (2004) Hollowbore Cannulation 7 Yes Yes needleHealthcare Assistant (2004) Hollowbore Someone else’s sharp 7 Yes Yes needleDomestic Assistant (2003) Hollowbore Collecting rubbish bag 6 Yes Yes needle – needle protrudingHPA UK Eye of the Needle Report
  103. 103. HCV Complications• Acute infection with HCV -fulminant hepatic failure, associated aplastic anaemia.• Approximately 50-85% of patients chronically infected, 29-76% later develop CAH or cirrhosis.• In the US and Europe, chronic HCV infection is the leading indication for liver transplant. Chronic HCV infection causes 10,000 deaths per year in the US.• Chronic HCV infection is also strongly linked to the development of HCC, which usually develops after 30 years
  104. 104. Transmission in HCW• About 65,000 HBV, 16,400 HCV and 1000 HIV infxn in HCWs p.a worldwide from occ exposure,• Risk infxn to HCW from patient>HCW to patient,• Universal imms, PEP, std precautions (including barrier precautions & proper handwashing), appropriate techniques & devices reduce transmission,• Down from 10,000 pa in U.S in 1993 to 400 in 2002,• Transmission of HCV rare and seroprevalence HCV in U.S and UK similar in HCWs to gen pop.• High risk cardiothoracic, ortho, obs&gyn,• Role of precore mutants in 10 published HBV reports in last decade,• HCW to patient HCV infection a proxy for substance misuse.