Download - Hepatitis and travellers 15.04.11 isom
Hepatitis and travel
Dr Peter Noone,
HSE Dublin NE Area
Travel risk/100,000 travellers per month to a developing country
Löscher T, Keystone JS,Steffen R, Vaccination of travellers against hepatitis A & B, J of Travel Medicine 1999; 6:107-114. Incidence of health problems during
a month in a developing country.
2
HIV
Dengue
H Papilloma v
Ebola
Hanta virus
West Nile virus
Tobacco
Malaria
Non-HIV tuberculosis Road accidents
3
5
6
Influenza
Polio
SARS
vCJD
Measles HBV + HCV
4
Log 10
RSV, Rota virus
7
Hospital infection
Suicide
Major and minor killers: global impact viewed on a ‘Richter’ (logarithmic) scale
Weiss & McMichael, 20041
Viruses
Infant/child ARI & diarrhoeal dis
10,000-fold difference in impact
Impact and incidence of vaccine-preventable diseases in travellers to developing countries. CFR = case-fatality rate.
Type of Traveller
• The Business Traveller,
• The Backpacker,
• The Package Tourist,
• The Overseas aid worker/missionary.
• The HCW
Viral Hepatitis - OverviewViral Hepatitis - Overview
AA BB CC DD EESource ofvirus
faeces blood/blood-derived
body fluids
blood/blood-derived
body fluids
blood/blood-derived
body fluids
faeces
Route oftransmission faecal-oral
percutaneouspermucosal
percutaneouspermucosal
percutaneouspermucosal faecal-oral
Chronicinfection
no yes yes yes no
Prevention pre/post-exposure
immunisation
pre/post-exposure
immunisation
blood donorscreening;
risk behaviourmodification
pre/post-exposure
immunisation;risk behaviourmodification
Ensure safe drinking water
Type of HepatitisType of Hepatitis
These naming conventions can lead to confusion later, e.g., Viral hepatitis is caused by at least 6 different viruses
DD
““Infectious”Infectious”
““Serum”Serum”
Viral Viral hepatitishepatitis
AA
NANBNANB
BB
EntericallyEntericallytransmittedtransmitted
ParenterallyParenterallytransmittedtransmitted
EE
CC
F, G,F, G,? Other *? Other *
* 10-20% of cases of presumed viral hepatitis are still not accounted for
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
Hepatitis A Virus
• Picornavirus (RNA)
• Humans are only natural host
• Stable at low pH
• Inactivated by high temperature, formalin, chlorine
Geographic Distribution of HAV Infection
Geographic Distribution of HAV Infection
Anti-HAV Prevalence
High
Intermediate
Low
Very Low
Basic Water Supply
0
10000
20000
30000
40000
50000
60000
70000
1966 1970 1974 1978 1982 1986 1990 1994 1998 2002
Cas
es
Hepatitis A—United States, 1966-2002
VaccineLicensed
Hep A reports UK
Laboratory reports of hepatitis A, England, Wales, and Northern Ireland: 1998 – 2007
Hep A in Ireland
Number of cases 2009: 52,Crude notification rate: 1.2/100,000No. of cases 2008: 42,
Hepatitis A Epidemiology
• Reservoir Human, Endemic
• Transmission Faeco-oral
• Temporal pattern None
• Communicability 2/52 before to 1/52 after onset
Declining Hepatitis A Rates – The Bad News
0
20
40
60
80
100
20s 30s 40s 50s 60s 70s
1980
1990
Proportion Of Americans Susceptible
To Hepatitis A(%)
Age (Years)
Data from NHANES II and III.
Consequences Of Adult Hepatitis A And B Infections
Berge et al. Hepatology. 2000;31:469.Fendrick et al. Arch Pediatr Adolesc Med. 1999;153:126.Margolis et al. JAMA. 1995;274:120.
5%-8%0%Probability of chronic infection
1-9 per 1000
7-14 years
1-3 per 1000
2-15 per 1000
10%-26%
73%-90%
HepA
4 per 1000Case fatality rate (acute illness)
7-14 yearsPost-transplant survival
1.7 per 1000Liver transplant
7.3 per 1000Acute liver failure
16%-19%Hospitalization
41%Symptoms of overt hepatitis
HepB
0
2
4
6
8
10
12
14
16
18
20
<5 5-14 15-24 25-39 40+Age group (yrs)
Ra
teHepatitis A Incidence* by Age Group
*rate per 100,000 population. 1997 data.
Age-specific Mortality Due to Hepatitis A
Age-specific Mortality Due to Hepatitis A
Age group(years)
Case-Fatality(per 1000)
<5 3.05-14 1.6
15-29 1.630-49 3.8
>49 17.5TotalTotalTotalTotal 4.14.1
Source: Viral Hepatitis Surveillance Program CDC Atlanta, 1983-1989
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
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
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.
Concentration of Hepatitis A Virus
in Various Body Fluids
Concentration of Hepatitis A Virus
in Various Body Fluids
Source: Viral Hepatitis and Liver Disease 1984;9-22J Infect Dis 1989;160:887-890
Faeces
Serum
Saliva
Urine
Bod
y F
lui d
Bod
y F
lui d
Infectious Doses per mlInfectious Doses per ml
100 102 104 106 108 1010
Other8%
Unknown 45%
Outbreak 4%
Daycare 2%
IDU6%
MSM10%
Int'l travel 5%
DC contact6%
Sexual/household 14%
Hepatitis A—United States, 1990-2000Risk Factors
Source: NNDSS/VHSP
Hepatitis A Vaccines
• Inactivated whole virus
• Avaxim (Sanofi Pasteur MSD)
• HAVRIX (GlaxoSmithKline)
• Paediatric and adult formulations
• Licensed for persons >2 years
• Epaxal (MASTA)
Hepatitis A Vaccine Immunogenicity
• 95% seropositive after one dose
• 100% seropositive after two doses
• >97% seropositive after one
• 100% seropositive after 2 doses
Adults
Children (>2 years) and Adolescents
Van Damme P, Banatvala J, Fay O et al. Hepatitis A booster vaccination: is there a need? Lancet 2003: 362:
1065-71
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.
Hepatitis A Vaccines
FFoorrmmuullaattiioonn HHAAVVRRIIXX VVAAQQTTAA AAVVAAXXIIMM
PaedsAge
Dose
1-16 yrs
0.5ml
2-17 yrs
0.5ml
<16yrs
Notrecommended
AdultAge
Dose
>16 yrs
1.0ml
>18yrs
1.0ml
>16yrs
0.5ml
Hepatitis A Vaccine Efficacy Studies
Hepatitis A Vaccine Efficacy Studies
JAMA 1994;271:1363-4N Engl J Med 1992;327:453-7
VaccineSite/Age Group N
VaccineEfficacy(95% CI)
HAVRIX(SKB)2 doses360 EL.U.
Thailand1-16 yrs
38,157 94%(79%-99%)
VAQTA(Merck)1 dose25 units
New York2-16 yrs
1,037 100%(85%-100%)
Hepatitis A Vaccines
• 1 dose
• Booster dose 6-18/12 after first dose
• 1 dose
• Booster dose 6-18/12 after first dose
Adult
Children and Adolescent
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
Hepatitis A Vaccine Recommendations
• International travellers
• MSM,
• IVDU’s
• Persons who have clotting-factor disorders
• Persons with occupational risk
• Persons with chronic liver disease, including HCV
Hepatitis A Serologic Testing
• Not indicated for children
• May be considered for some adults and older adolescents
• Not indicated
Prevaccination
Postvaccination
Hepatitis A Vaccine Adverse Reactions
• Pain at injection site
• Systemic reactions not common
• No serious adverse reactions reported
Hepatitis A VaccineContraindications and Precautions
• Severe allergic reaction to a vaccine component or following a prior dose
• Moderate or severe acute illness
Hepatitis A Vaccine 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.
HBV
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.
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
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
Hepatitis B Virus Infection
•40% of world’s population had contact with or are carriers of HBV, 2 billion infected,
•>350 million chronic carriers worldwide
•Established cause of chronic hepatitis and cirrhosis, 600,000 death in 2002.
•Human carcinogen—cause of up to 80% of hepatocellular carcinomas.Banatvala J et al “Lifelong protection against Hepatitis B; role of vaccine immunogenicity in immune memory”,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.
•In Europe & US chronic infection with HBV, affects about 1-3% of the population,
• In Africa and Asia, rate may be >10% and will remain so for many decades,
• Immigrants from the high incidence areas will carry the same risk of HBV carriage as the population in their country of birth,
• ~ 1/3 of HCV and a variable number of HIV patients have occult HBV infection,
•Before widespread vacc of HCWs, >12,000 HCWs per year were infected 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. MMWR Morb Mortal Wkly Rep 1989;38(suppl 6):1–37.
HBV infection (2)
Hepatitis B Virion, Dane particle and HBsAG
From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 66, published by Mosby Philadelphia,,
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
Hepatitis B Epidemiology
• Reservoir Human. Endemic
• Transmission Bloodborne
Subclinical casestransmit
• Communicability 1-2 months beforeand after onset ofsymptoms
Chronic carriers
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.
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
Clinical outcomes of Hepatitis B infections
From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 62, published by Mosby Philadelphia,,
0
10
20
30
40
50
60
70
80
90
100
Birth 1-6 mo 7-12 mo 1-4 yrs 5+ yrs
Age of infection
Car
rier
ris
k (%
)Risk of Chronic HBV Carriage by
Age of Infection
M Ramsay, HPA UK
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
HBsAg Prevalence
8% - High
2-7% - Intermediate
<2% - Low
Geographic Distribution of Chronic HBV Infection
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
Epidemiology of Hepatitis B in Ireland
Figure 1: Notifications of Hepatitis B (acute and chronic) 2004-2009
Risk of Traveller Exposure HBV
Source
HBV
HBeAg +
HBeAg -
HCV
HIV
Risk
22.0-30.0%
1.0-6.0%
1.8%
0.3%
Risk of Bloodborne Virus Transmission after Occupational Percutaneous Exposure
Bloodborne Pathogen TrainingBloodborne Pathogen Training
Risk
22.0-30.0%
1.0-6.0%
1.8%
0.3%
Concentration of Hepatitis B Virus
in Various Body Fluids
Concentration of Hepatitis B Virus
in Various Body Fluids
High ModerateLow/Not
Detectable
blood semen urineserum vaginal fluid feces
wound exudates saliva sweat
tearsBreast milk
Acute Hepatitis B Virus Infection with RecoveryAcute Hepatitis B Virus Infection with RecoveryAcute Hepatitis B Virus Infection with RecoveryAcute Hepatitis B Virus Infection with Recovery
Typical Serologic CourseTypical Serologic Course
Weeks after ExposureWeeks after Exposure
TiterTiter
Symptoms
HBeAg anti-HBe
Total anti-HBc
IgM anti-HBc anti-HBsHBsAg
0 4 8 12 16 20 24 28 32 36 52 100
Progression to Chronic Hepatitis B Virus Infection
Progression to Chronic Hepatitis B Virus InfectionTypical Serologic CourseTypical Serologic Course
Weeks after ExposureWeeks after Exposure
TiterTiter
IgM anti-HBc
Total anti-HBc
HBsAg
Acute(6 months)
HBeAg
Chronic(Years)
anti-HBe
0 4 8 12 16 20 24 28 32 36 52 Years
HBV - Natural HistoryHBV - Natural History
Modulating Factors in Hepatitis BModulating Factors in Hepatitis B
HOSTGender
AgeImmune Response
HOSTGender
AgeImmune Response
VIRUSGenotype
Molecular Variants
VIRUSGenotype
Molecular Variants
ENVIRONMENTAlcohol
HCV, HDV, HIVCarcinogens
ENVIRONMENTAlcohol
HCV, HDV, HIVCarcinogens
Pathogenesis of Hepatitis B
1965 Discovery of Australian antigen
1973 Successful HBV infection of chimpanzees
1981 License of plasma-derived vaccine
1986 License of recombinant vaccine
1991 Universal infant vaccination (U.S.)
1996 Universal adolescent vaccination (U.S).
Hepatitis B Vaccine
Hepatitis B Vaccine
• Composition Recombinant HBsAg
• Efficacy 95% (Range, 80%-100%)
• Duration ofImmunity >15 years
• Schedule 3 Doses
• Booster doses not routinely recommended Are booster immunisations needed for lifelong hepatitis B immunity? European Consensus Group on Hepatitis B Immunity.Lancet 2000 Feb 12;355(9203):561-5.
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)
90%-95%98%-100%3
75%-80%80%-95%2
20%-30%16%-40%1
Teens and Adults***Infants**Dose
Protection* by Age Group and Dose
* 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.
Hepatitis B VaccineLong-term Efficacy
• Immunologic memory established following vaccination
• Exposure to HBV results in anamnestic anti-HBs response
• Chronic infection rarely documented among vaccine responders
Are booster immunisations needed for lifelong hepatitis B immunity? European Consensus Group on Hepatitis B Immunity.Lancet 2000 Feb 12;355(9203):561-5.
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
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)
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
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
Northdruft H,Zuckerman J, “Accelerated Vaccination Schedules Provide Protection Against Hepatitis A & B in Last Minute Travellers” Vaccine 2002; 20:1157-1162. Medicine
Evaluation of Hepatitis B Immune-Response in Elderly, Obese or Medically Compromised Subjects after Vaccination with HAB Combination or Monovalent
Hepatitis B VaccinesChlibek, 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,
Hepatitis B VaccineAdverse Reactions
Pain at injection site
Mild systemic complaints(fatigue, headache)
Temperature >99.9°F (37.7°C)
Severe systemic reactions
Adults13%-29%
11%-17%
1%
rare
Infants and Children3%-9%
0%-20%
0.4%-6%
rare
Twinrix
Hepatitis B VaccineContraindications 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.
• http://www.cdc.gov/vaccinesafety/Vaccines/multiplesclerosis_and_hep_b.html
•Vaccine failures with HBV mutations in small surface protein (S) gene (S mutants) in infants who got HBV vaccine or HBIG appropriately and who have anti-HBs in protective range.•HBV variants resistant to neutralizing anti-HBs, reduce effectiveness of 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.
HBV variants with mutations
Pre-core mutants
Disappearance of HBeAg and rise of anti-HBe is associated with decline in viremia titer and 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.
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
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
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
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+)
Background
• HBV reactivation in patients at risk may be asymptomatic or symptomatic and is associated with cytotoxic or immunosuppressive treatment, with pregnancy or surgery,
• Reactivation may lead to hepatitis, hepatic failure, delays in chemo or immunotherapy (M ~100 days) and decreased survival (4-60%),• Reactivation may occur in >50% in HBsAg+ patients receiving chemotherapy,
• Reactivation may also occur spontaneously in up to ~22% of HBV infected patients who do not receive immunosuppression,
• Not all forms of chemotherapy confer an equivalent risk for reactivation,
Review: Holbrook E et al. Clin Liver Dis 2007; 11:965
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.
eAg +ve eAg -ve
Drug HBeAg seroconversion
at Yr 1, %
HBV DNA negative at
Yr 1, %
HBV DNA negative at
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
Efficacy of current drug regimens
Drug Resistance %
Interferon none
Lamivudine 23 at Yr 1
71 at Yr 4
Adefovir 0 at Yr 1
30 at Yr 5
Entecavir < 1 in naïve at Yr 4
40 in Lam-r at Yr 4
Peg IFNa-2a none
Telbivudine 22 in HBeAg +ve at Yr 2
9 in HBeAg -ve at Yr 2
Rates of resistance
Key Points:
Screening for HBV markers is mandatory in allpatients scheduled for chemo- or immuno-therapy,
• Immunization against HBV should be completed as soon as possible (non-response must be investigated for occult HBV),
• Early pre-emptive anti-viral treatment is superior to treatment at onset of reactivation,
• It is highly recommended to continue treatment for 6-12 months after completing chemo or immuno therapy,
• Awareness regarding the risk of HBV reactivation must be strengthened , especially among oncologists, haematologists and transplant surgeons
HCV
HCV single-stranded RNA 170 million chronically
infected 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 prevalence
haemophiliacs and IVDU. Before plasma screening HCV
accounted for 90% of post transfusion hepatitis cases.
HCV is the most common cause of chronic viral hepatitis
in the US. About 80% of people infected progress to
chronic HCV infection
HCV Epidemiology HCV Epidemiology
Course of clinical HCV WEDEMEYER ET AL. HEPATOLOGY, May 2004
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.
75Immediate, average110 ±44days post exposure
HN/A28“Delwaide et al
57100±82 days from symptom onset or 63±53 days from 1st +ve HCV assay
G5 (19)27“Broers et al
9412 wks from symptom onsetG11 (38)28“Santantonio et al
95ImmediatelyGN/A60Non-randomised
Wiegand et al
92Immediately, <70 days post exposureF1 (6)16“Rocca et al
10014 wks from exposureE3 (30)10Non-randomised
Pimstone et al
878 wks from symptom onsetD030“Nomura et al
8312 wks from symptom onset or 1St +ve HCV RNA
C5 (9)54RandomisedKamal et al
8010-26 months from symptom onsetB24 (52)60“Gerlach et al
98Immediately, average 89 days post exposure
AN/A44Non-randomised
Jaeckel et al
SVR (%)Time of therapyRegimenSC n (%)NosTypeStudy
Trials evaluating treatment for acute HCV
Adapted from Zekry et al. Journal of Hepatology 2005; 42: 293-296
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.
http://www.hpsc.ie/hpsc/A-Z/HepatitisHIVAIDSandSTIs/BloodborneVirus/File,4352,en.pdf
http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1227688128096
http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1227688128096
http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1227688128096
HCV in the Health care setting European case-control study * • France, Italy, Spain, Switzerland, UK • 60 cases of occupationally acquired HCV in HCWs January 1993 and December 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 than females) but this factor will need further investigation into its significance. Prevalence of infection in the specific population Volume of inoculums and viral load in source patient Post exposure management.
* Yazdanpanah Y, De Carli G, Migueres B, Lot F, Campins M, Colombo C, et al. Risk Factors for HCV Transmission after Occupational Exposure in Health Care Workers: A European Case-Control Study. Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); Chicago, September 2003: poster no. 1087
YesYes6Collecting rubbish bag – needle protruding
Hollowbore needle
Domestic Assistant (2003)
YesYes7Someone else’s sharpHollowbore needle
Healthcare Assistant (2004)
YesYes7CannulationHollowbore needle
Nurse (2004)
Treatment ongoing
Yes†6Someone else’s sharpHollowbore needle
Nurse (2004)
YesYes8VenepunctureHollowbore needle
Doctor (2003)
YesN/A*8VenepunctureHollowbore needle
Nurse (2003)
YesNK4InjectionHollowbore needle
Dentist (2001)
YesYes8SuturingSolid needleSurgeon (2000)
YesNK16Resuscitation A&EHollowbore needle
Junior Doctor (1996)
Virus cleared
HCW treated
1st test positive (weeks)
ProcedureDevice OccupationOccupation
UK HCV seroconversions in HCW’s
HPA UK Eye of the Needle Report
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
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.