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HAV HBV HCV HDV HEV
HAV HBV HCV HDV HEV TTV HGV/GBV-C SENV HFV CMV EBV
( / / ) (1947, MacCallum) HAV HBV (1974-76) ENANBH (1850S) HAV NANBH (1965,Blumberg) (1973, Feinstone) HCV 5-1-1 clone (1977,Mosley) HBV (1970, Dane) (1988,Hoµghton) SEN-V TTV (1997, Nishizawa) ENANBH (1980S) HDV (1983, Rizzetto) Next virus? HFV HGV/GBV-C (1995, Nishizawa) ( 1983, Balayan ) HEV 20 (Epidemic jaundice) 1943 JAMA(Catarrhal jaundice) 1942 Voget Cameron 1947 MacCallum1973 WHO (1988, Purcell) HEV (1991, Reyes) HEV? (1995, Clayson) HEV (1997,Meng)
HAV/HBV/HCV/HDV HAV HEV HBV HCV HDV
Order Family Genus Type Species Mono -negavirales Caudovirales Nidovirales ( ) ICTV classification Picornaviridae ( RNA ) Arenaviridae ( ) Enterovirus Rhinovirus Hepatovirus () Cardiovirus Aphthovirus Parechovirus Arenavirus Ophiovirus Tenuivirus Deltavirus Poliovirus Human rhinovirus A Hepatitis A virus Encephalomyocarditis virus Foot-and-mouth disease virus Human parechovirus Lymphocytic choriomeningitis virus Citrus psorosis virus Rice stripe virus Hepatitis delta virus Hepeviridae Hepevirus Hepatitis E virus Hepadnaviridae ( DNA ) Flaviviridae () Orthohepadnavirus Avihepadnavirus Flavivirus Pestivirus Hepacivirus Hepatitis B virus Duck hepatitis B virus Yellow fever virus Bovine viral diarrhea virus Hepatitis C virus
Viral hepatitis(b15-b19) in ICD-10
WHO 140 / 20 3.5 1.7 1001/3
12090/10 10 1.2
Annual reported hepatitis cases in China 1800000 1600000 1400000 1200000 1000000 800000 600000 400000 200000 0 140 120 100 80 60 40 20 0 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 1.33 million cases in 2006 2006-11
Annual reported morbidity in China
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HAV 60 1 20 100 5 121 20
Pathogenesis of enteroviruses
15~5030 0.2%~0.4%
HAV 1~21~2
-HAV IgM -HAV IgM HAV HAV -HAV IgG -HAV IgG HAV ALT HAV 1 2 3 4 6 12 24-1 HAV
Anti-HAV prevalence High Intermediate Low Very low CDC, 1999
90% 20 1 2 4~12 15 1
HAIG 90% 3~5 HAIG
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Hepatitis E (HEV), (>50 ), 30~70% ;?!, 40 (15~60 ) (1~5%) (20%, ) ; ;
?! HEV HEV HEV HEV HEV HEV () ( ) SPF 3-7 14-20DPI HEV RNA 11% 43.5% HAV HEV 2003 Lancet 3HEV RNA 2003 J Gen Virol: HEV RNA; 2003 8 2003 5
the Program for Monitoring Emerging Diseases 4 13 341 >24,3 33 6 25 1995-433 111 1996 1166 27 13
HEV
Genome organization of HEV Methyl transferase RDRP Polycysteine region Transmemberane Sequence ORF3 Hydrophobic Region ORF1 Papain like cysteine protease Helicase ORF2 Signal peptide rhev Particle HEV HEV 7.5kb, 3
. ( ) (%) 1955~56. 2.9 10.5 1955~56. 1.1 18.0 1973~74. 1.0 20~25 1976~77. 2.0 18.0 1978~82. 5.2 NA 1981~82. 1.2 20~25 1986~88. 12.0 NA 1988~89. 1.14 17.0 1991. 7.9 NA
Non-ABC >25% HEV HEV RT- PCR(+) HEV RT-PCR(+)
HEV HEV HEV HEV
Distribution of Genotypes LEGEND Genotype I Genotype II Genotype III Genotype IV HEV Genotypes
1982 1.27% - 16.4% - (. ) 46.5% - non-abc ( 90 ) 17.2% - (1992) >20 -,1986-88, 12,
IV 3 5
1982 1.27% - 16.4% - (. ) 46.5% - non-abc ( 90 ) 17.2% - (1992) >16 -,1986-88, 12,
HEV --- 9 I IV, III (2006) China
HAV IgM (53.03%) HBsAg (41.08%) 31.12% 19.07% 20.97% 1.80% 1.04% 8.73% HEV IgM (17.55%) 5.98% Others 11.28% (,%) HCV 5 (0.47) HAV+HCV 3 (0.28) HBsAg+HCV 2 (0.19) HCV+HEV 2 (0.19) HBsAg+HCV+HEV 1 (0.09) 106 (10.06)
1 1.67 28 ( ) 3
( ) II I IV III
(%) 1986.9-1988.4 119280/? 0.6 1993.2.18-3.10 11/107 10.3%) NA 1994.4.27-5.15 24/379 6.87%) NA 1995.2.3-3.15 11/92 12.0% 9.1 9/600 1.5%) NA 2001.1.20-3.1 145/1675 (8.7%) 0.7 2003.5
HEV (n=8626)
HEV 2:1 ( ) 15~40 HEV
( ) 16, 46, ( 4767 *) 26, ( 1720 *) * HEV IgM EIA
1. 2. 3.
HEV HEV 127/4767 10/97=0.3% HEV HEV 0.3%
(150bp) 31 4, 4 A D, %/ 3.4~4.1 3.7~14.4 A D IV ( ) A 2004/2005 2004 D 2004/2005 2002/2004 B/C 2002/2005
(HEV IgG) 1.0 50.1 213/425 1.29(1.02 1.64) 61.2 792/1295 1.74(1.24 2.44) 75.9 258/340 0.82(0.48 1.41) 58.0 40/69 <5 1.84(1.16 2.93) 74.6 94/126 5-14 2.82(1.67 4.75) 85.5 124/145 >15 OR 95%CI (%) / 1.0 50.1 213/425 1.29(1.02 1.64) 61.2 792/1295 1.74(1.24 2.44) 75.9 258/340 0.82(0.48 1.41) 58.0 40/69 <5 1.84(1.16 2.93) 74.6 94/126 5-14 2.82(1.67 4.75) 85.5 124/145 >15 OR 95%CI (%) /
IV HEV
2006;193(12):1643-9 IF=4.953) (JKF201001) (2005AA2Z3H20)
-HEV IgM HEV -HEV IgG HEV IgM 10
-HEV5%~26% -HEV17.2% HEV 20%
100 n=8 GMT(IU) 80 60 40 (5IU) 20 0 0 10 20 30 40 50 60 70 80 90 4W Weeks 62W
HAV HEV HAV HEV RNA HEV 27-32nm 27 34nm 20 60 ( ) 3 VP1 3 T=3 20 60 HEV a, B A, B, RNA 7.5kb I,II,III,IV 1
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Global Disease Burden Estimated 2 billion people infected with HBV More than 350 million have chronic HBV infection Approximately 88% of the world's population live in areas where the prevalence of chronic HBV infection is high (>8% HBsAg +) or moderate (2-7% HBsAg +) Estimated 600 000 HBV-related deaths in 2002 Approximately 93% of deaths were the result of chronic infection The worldwide prevalence of HBV infection is falling due not only to vaccine, but to better hygiene and to the AIDS campaign which addresses the dangers of promiscuity and of shared syringes and needles. WHO believe that by 2001 there will be an 80% fall in carrier rate, but the reservoir of those patients already infected will still have to be treated.
Deaths from Vaccine-Preventable Diseases Diphtheria Pneumococcus Tetanus Pertussis Polio Meningococcus Measles Rotavirus Yellow Fever Hib Hepatitis B 4 Million Deaths to Be Prevented (2000 estimates)
Epidemiology of Chronic Infection Most HBV infections occur in perinatal period/early childhood Infections at this early age lead to high proportion chronic infections Large proportion of chronic infections unrecognized and lead to longterm complications (cirrhosis and HCC) ~21% of HBV-related deaths result from infection in perinatal period ~48% from infection in early childhood (age <5 years)
25% 80%~90%
HBV (Dane )HBV 42nm 22nm HBV HBsAg 22nm 40nm ~ 500nm
HBV HBVDNA 3200 4 S C P X S SS1 S2 HBV HBsAg pre-sl pre-s2 C CC HBcAg HBeAg P DNA Xx HBxAg 8 A-H
HBV -HBsAg a,d/y,w(1-4)/r, q(+/-) Adw2,4;ayw1-4;adrq+ adrq- ayr
Distribution of HBV genotypes and HBsAg subtypes across the world HBV genoty HBsAg Geographical distribution pe A adw2 Europe, North America, Africa ayw1 Africa B adw2 Far East ayw1 Far East C Adrq- Pacific adr/ayr adw adr Far East Japan, Indonesia Far East, Pacific D ayw4 United States ayw2/ay w3 Worldwide E ayw4 Africa F adw2 South America adw4 ayw4 Polynesia, Alaska, Central and South America South America
HBsAg -HBs HBcAg -HBc e HBeAg -HBe HBV HBV HBV Pre-S1 Pre-S2 x HBV-DNA DNA
DNA HBV -HBc -HBc IgM HBsAg HBeAg -HBe -HBs ALT HBV 1 2 3 4 5 6 7 8 24-2
Tests Results Interpretation Tests Results Interpretation HBsAg anti-hbc anti-hbs HBsAg anti-hbc anti-hbs HBsAg anti-hbc anti-hbs Interpretation of the Hepatitis B Panel susceptible immune due to natural infection immune due to hepatitis B vaccination HBsAg anti-hbc IgM anti-hbc anti-hbs HBsAg anti-hbc IgM anti-hbc anti-hbs HBsAg anti-hbc anti-hbs acutely infected chronically infected four interpretations possible * * 1. May be recovering from acute HBV infection. 2. May be distantly immune and test not sensitive enough to detect very low level of anti-hbs in serum. 3. May be susceptible with a false anti-hbc. 4. May be undetectable level of HBsAg present in the serum and the person is actually a carrier.
HBV DNA -HBs
HBV HBV 1 5 10% 30%~50% 1 80%~90% 1~4 30%~50% 1% 5%~10% HBV HBsAg 6 HBV -HBs -HBc 60% 30% 2% HBsAg
HBV HBV HBsAg HBeAg
Concentration of HBV in body fluids High Moderate Low / not detectable Blood Serum Wound exudates Semen Vaginal fluid Saliva Urine Feces Sweat Tears Breast milk
Transmission of HBV Transmitted by exposure to HBV-infected blood or serous body fluid (serum, wound exudates, semen, vaginal fluid) Mode of transmission: Person-to-person Direct Indirect (via infected object) Cannot be transmitted though intact skin or mucous membranes Extremely infectious - 100 times more infectious than HIV Sexually transmitted disease
Parenteral Transmission of HBV Receipt of infected blood or blood products Use of contaminated medical instruments and injection equipment in health care settings Use of contaminated injection equipment by injection drug users Use of contaminated equipment for tattooing, ritual scaring, acupuncture, body piercing, body scarring
80% HBV HBV
HBV-HBs HBV 50%~60% 70%
1992 HBsAg 9.75%8.08%10.49% 30~40 HBsAg
WHO Strategy 1991 WHO 2002 3151 WHO Priorities for hepatitis B immunization in order of importance are: routine infant vaccination; prevention of perinatal HBV transmission (the birth dose); catch-up vaccination for older age groups. Vaccination of infants and children is highest priority for hepatitis B programs
3 doses of hepatitis B vaccine 90% 95% effective in preventing HBV infection and chronic sequelae To prevent perinatal HBV transmission, 1st dose vaccine should be given within 24 hours after birth the birth dose
1986 1992
Hepatitis B Vaccine Made from HBsAg by genetic engineering (no human blood products are used in current vaccines) Hep B is given to infants because It can prevent onset of chronic disease in infants and Adult vaccination has been operationally difficult The vaccine can be given in a variety of schedules, usually with DPT1, DPT2, and DPT3 Among the safest of EPI vaccine The only cancer and STD vaccine available (hepatoma) Now HPV!
HBIG 3~6 HBsAg HBeAg 6 24
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NANB 1989 HCV (HCC) WHO3% 1.7 HCV
50nm 6 HCV ( 1a 2b 3c ) 1 HCV 70 HCV quasispecies
Genome NS3 / NS5B RNA RNA HCV
6-7 2-26 26 ( ) (<20%) 60%-85% Agerelated 10%-70% <5%-20% Mortality from CLD 1%-5%
HCV Symptoms +/- anti-hcv HCV RNA Titer ALT Normal 0 1 2 3 4 5 6 1 2 3 4 Years Months Time after Exposure
HCV Symptoms +/- anti-hcv HCV RNA Titer ALT Normal 0 1 2 3 4 5 6 1 2 3 4 Years Months Time after Exposure
HCV -HCV HCV -HCV -HCV HCV RNA HCV RNA
HCV Resolved Exposure (Acute phase) 15% (15) 85% (85) Stable Chronic 80% (68) Slowly Progressive 20% (17) Cirrhosis 75% (13) HIV and Alcohol 25% (4) HCC Transplant Death
HCV
HCV
1% 1%~2.4% 2.5%~4.9% 5% 1515
World Health Organization, 1999. (1.7-2.0 ) US 3-44 M Americas 12-15 15 M Western Europe 5 M Africa 30-40 M Eastern Europe 10 M Far East Asia 60 M South East Asia 30-35 35 M Australia 0.2 M
1a, 1b 2a, 2b, 3a 1b 2a, 2b, 2c, 3a 4 4 1b, 3a 2a 1b, 6 1b 3b 5a 1b, 3a
-HCV3.2% 3.6% 2.9% 2.5% 2.7% 3.2% 3.3% 3.8% 4.6% -HCV 1 2.0% 50 59 3.9% HCV 1b 2a 1b 1a 2b 3b6
-HCV ALT1993 HCV HCV HCV RNA
Comparison between HBV and HCV
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1977 HBcAg HBV HBcAg delta 1980 HBV HBV HBsAg HBsAg
RNA 36~43nm HDV RNA HDAg HBV HBsAg HDV RNA 1.7kb HDV DNA HDV HBV
Schematic representation of viral particles found in serum of HBV - HDV infected people Infectious HBV particle: Infectious HDV particle: 42 nm outer envelope containing lipid and three forms of HBsAg 27 nm nucleocapsid containing 180 copies of core protein and reverse transcriptase and HBV DNA 36-43 nm outer envelope containing lipid and three forms of HBsAg 19 nm nucleocapsid containing 60 copies of delta antigen and HDV genomic RNA Empty noninfectious particles: 22 nm filaments and spheres made of lipid and mainly one form of HBsAg
HDV HDV/HBV HDVHBV HDV/HBV HBV HDV 80% HDV 60%~70% 5~10
-HDV HDV -HDV HDV RNA HDAg HDV HDV
HDV HBV
HDV 1000 HBsAgHDV HBV HDV HDV
HBsAg HDV