Jose A Lavergne, M.D., F.A.C.P.

Caracteristicas y Epidemiologia de las Hepatitis Virales

Virus Family Type Worldwide Prevalence
A Picornavirus ssRNA Varies by Geography
High prevalence areas: nearly all adults exposed
Low prevalence areas: 33% of populations exposed
B Hepadnaviridae dsDNA 300 million worldwide
High prevalence (China and SoutheastAsia): 10-20% of population
Medium prevalence (Africa and Eastern Europe): 3-5% of population
Low prevalence (North America and Western Europe):<2% of
population
C Flaviviridae ssRNA 100 million worldwide
1-2% of population
D Deltaviridae ssRNA 15 million persons worldwide (-5% with patients with chronic HBV;
most commonly Eastern Europe)
E Calciviridae ssRNA Varies by Geography
High prevalence (India): 40-70% of population
Low prevalence (North America and Europe): 1-5% of population
Virus Age Group Most
Commonly
Infected
Modes of Infection
A Infants and children

Adults
Person-person via fecal oral spread and contaminated food

Same as for children, homosexual activity
B Infants

Children and adults
Perinatal exposure

Sexual activity, intravenous drug use, contaminated instruments , and other
parenteral expsorues

C All patients Vertical and sexual transmission rare but increased in setting of HIV
coinfection

Drug use, other parenteral exposures
D All patients Sexual activity, durg use, other parenteral exposures
E All persons Person-person via fecal-oral spread and contaminated food
Caracteristicas y Epidemiologia de las Hepatitis Virales
Fulminant Hepatic Failure and chronicity rates for Hepatitis viruses
Virus Fulminant Hepatic Failure Chronicity rates
A 0.1% mostly adults

Approximately 30% in patients with
chronic liver disease
Never, regardless of age
B 1% mostly in adults

Approximately 25% in patients with
chronic liver disease
90% when exposed perinatally

50% when exposed as a child

5% when exposed as adult
C Not reported 80%, regardless of age
D Coinfection: 20-25%

Superinfection: uncommon
Coinfection 2%

Superinfection > 90%
E 0.5 4% overall

15-30% if exposure during pregnancy
None regardless of age
Acute Hepatitis Treatment
Acute Hepatitis A and E never develop chronic disease
Only 5% of adults with Acute Hepatitis B develop
Chronic infection
A, B, and E treatment is supportive and to monitor for
signs of acute fulminant hepatic failure
HBV-HDV coinfection and pregnant females with HEV
80% of Acute Hepatitis C progress to Chronic liver
disease
90% HCVRNA undetectable if treated with IFN alfa.
Active treatment for acute hepatitis is only
recommended for Acute HCV
Hepatitis A Prevention: Vaccine vs. Immunoglobulin
Victor J et al. NEJM 2007;157:1685-1694
MMR. March 2008
Coinfection with HAV
NEJM 29;338(5):286-90
MMR. October 19, 2007 / 56(41);1080-1084
Hepatitis B
Infeccion cronica --- Cirrosis y Cancer de
Higado
2 billones de infectados mundialmente (30%)
350 millones con infeccion cronica
1 millon de muertes mundialmente

Hepatitis B
Transmision
Perinatal
Contacto percutaneo o permucoso con
sangre u otros fluidos corporales (semen y
fluidos vaginales)
No por contacto casual
HBV - Epidemiology
Risk of chronic infection
Age at Infection
0
20
40
60
80
100
Neonates Infants Children Adults
%
Risk
Risk of Chronic Infection
Hepatitis B
25% de infectados al nacer mueren de
cancer hepatico o cirrosis
Vacuna (1982)
95% efectiva
Segura y efectiva

Hepatitis B - Vacunacion
Hepatitis B
50-100 veces mas infeccioso que el HIV
Importante riesgo ocupacional para los
trabajadores de la salud.
Vacunacion universal segura y efectiva
Lok AS. Hepatology 2007
Lok AS. Hepatology 2007
HBV - Diagnosis
Acute Infection
0 2 4 6
HBsAg
Anti-HBs
Anti-
HBc
Anti-HBc
IgM
Months
Years
HBeAg
HBV DNA
Anti-HBe
Serological Markers of Acute HBV Infection
Chronic Infection
HBV - Diagnosis
HBV DNA
HBeAg
Months Years
Anti-HBc IgM
Anti-HBc
IgG
Anti-HBe
HBsAg
Serological Markers of Chronic HBV Infection
Serology associated with the different phases of HBV and common
hepatitis B mutants
Serology testing
sAg Anticore eAg Anti-E Antisurface HBV DNA (copies/ml)
Resolved Infection X X X
Wild type infection X X X > 1 000 000
Inactive infection X X X < 100 000
Vaccination X
Mutants forms of HBV:
Pre core X X +/- > 100 000
Surface X X +/- Variable
Core X +/- +/- Variable
HBV DNA -- Incidencia de Cirrosis
Illoeje UH, et al. Gastroenterology 2006;130-678-686
36%
5%
Riesgo de HCC y nivel de HBVDNA
CJ Chen et al. JAMA 2006; 295:65-73
A-G
Correlacion con etnicidad y pais de origen
Asiaticos Genotipo B y C
C > B Reactivacion, severidad, y HCC
Europa Oriental Genotipo D
USA (caucasicos y africo-americanos) Genotipo A
Genotipo A es un fuerte predictor de respuesta a
tratamiento con PEG Interferon.

HBV Tratamiento Metas
HBeAg (+)
HBeAg (-)
Perdida del HBeAg
Aparicion de AntiHBe
Conversion a status inactivo
Normalizacion de Aminotransferasas hepaticas
Perdida de HBVDNA detectable
Mejoria de la histologia hepatica
Reducir el riesgo de Carcinoma Hepatocelular
Perdida de HBsAg
Convertir una infeccion activa a una inactiva
EB Keefe, et al. Clin Gastroenterol Hepatol 2008;6:1315-1341
EB Keefe, et al. Clin Gastroenterol Hepatol 2008;6:1315-1341
JL Dienstag. NEJM 2008; 359:1486-1500

Terapias Antivirales for HBeAg+
HBV PEG IFN alfa
PEG IFN alfa semanal por 6-12 meses
Genotype A - 50% seroconversion (EAg to Anti-E)
HBVDNA, EAg y AntiE al finalizar , 3 meses y 6 meses
post tratamiento
No ventaja a combinacion con antivirales orales
No iniciar antivirales orales hasta 6 meses post
tratamiento.
JL Dienstag. NEJM 2008; 359:1486-1500
Oral Antivirales HBeAg+
EAg a AntiE (seroconversion) depende de HBVDNA no
detectable
META = Supresion completa de HBVDNA
HBV DNA no detectable a 6-12 meses
Continuar 6-12 meses post seroconversion
HBVDNA detectable a 6-12 meses = Agregar otro antiviral
con diferente sitio de accion
Site 1 Site 2 Site 3
Lamivudine

Adefovir


Tenofovir
Telbivudine
Emtricitabine
Entevavir
Oral Antivirales HBeAg (-)
No pueden seroconvertir (Precore mutant)
Tratamiento es por vida
Oral antivirales
Supresion completa de HBVDNA
Agregar un antiviral adicional si HBVDNA es
detectable a 6-12 meses
EB Keefe, et al. Clin Gastroenterol Hepatol 2008;6:1315-1341
Terapias Antivirales para HBeAg-
EB Keefe, et al. Clin Gastroenterol Hepatol 2008;6:1315-1341
EB Keefe, et al. Clin Gastroenterol Hepatol 2008;6:1315-1341
EB Keefe, et al. Clin Gastroenterol Hepatol 2008;6:1315-1341
Liaw Y. NEJM 2004;351:1521-1531
Disease progression
Increase in Child-Pugh
Score
Diagnosis de HCC
Efecto de Lamivudine
en Progresion de
Cirrosis y HCC
HBV Profilaxis en Quimioterapia
Reactivacion de HBV 14-50%
HBV cronica que reciben quimioterapia
(cytotoxicos) o immunosupresores (Infliximab).
Aumento de ALTs, histologica inflamacion, y (en
pocos casos) falla hepatica.



Recomendacion: HBsAg (+)/ AntiHBc
Lamivudine 1 semana antes , y por > 1 yr despues
de terminar.


Lamivudine Placebo
Tasa de Hepatitis 9.2% (o-20%) 54% (33-67%)
Tasa de HBV
reactivacion
8.7% (0-24%) 37% (29-56%)
Kohrt HE.Aliment Pharmacol Ther 24:1003-1016
Prevalence
HCV - Epidemiology
United States
Anti-HCV positive 3.9 million (1.8%)
HCV RNA positive 2.7 million (1.4%)
Worldwide 170 million ( 3%)
Alter MJ et al., New Engl J Med 1999; 341:556
Lavanchy D & McMahon B, In: Liang TJ & Hoofnagle JH (eds.)
Hepatitis C. New York: Academic Press, 2000:185
Prevalence
HCV - Epidemiology
Heintges, T., Hepatology 1997; 26:521
10 to 20
5 to 10
2 to 5
1 to 2
0 to 1
HCV Ab
pos (%)
Worldwide Prevalence
Worldwide Prevalence
HCV - Epidemiology
Risk Factors
for Hepatitis C
Injection
Drug Use
Multiple
Sexual Partners
Clotting Factor
Treatment Prior
to 1987
Long-Term
Hemodialysis
Blood
Transfusion
or Organ
Transplant
Prior to 1992
Birth from
Infected Mother
Mass Injections
and Traditional
Practices
Risk Factors for Hepatitis C
HCV - Epidemiology
Prevalence In Groups at Risk
Recipients of clotting factors before 1987 75 - 90%
Injection drug users 70 - 85%
Long-term hemodialysis patients 10%
Individuals with > 50 sexual partners 10%
Recipients of blood prior to 1990 5%
Infants born to infected mothers 5%
Long-term sexual partners of HCV positive 1 - 5%
Health workers after random needlesticks 1 - 2%
CDC, MMWR 1998;47(No. RR-19):1
Prevalence In Groups at Risk
CDC, 1995
HCV - Epidemiology
Incidence of Acute Hepatitis C
Has Declined in the U.S.
Surrogate tests
on donors
0
5
10
15
20
82 84 86 88 90 92 94 95
Year
Cases per
100,000
Anti-HCV test
Decline among
injection drug users
Incidence of Acute Hepatitis C Has Declined in the U.S.
HCV - Natural History
Outcome Following Hepatitis C
Infection
Acute hepatitis C
Chronic infection
Chronic hepatitis
Cirrhosis
Time
(yr)
55 - 85%
70%
20%
10
20 30
Decompensation
HCC
1 - 4%/yr
4 - 5%/yr
Outcome Following Hepatitis C Infection
Factores Claves que influyen en la
decision tomar tratamiento
Predictores de la probabilidad de obtener SVR
Stadio de Fibrosis
Severidad de actividad necroinflamatoria
Presencia de contraindicaciones absolutas or relativas a
tratamiento
Embarazo o intencion de concepcion
Enfermedad Autoinmune Activa
Enfermedad Cardiovascular significativa
Enfermedad Psiquiatrica activa
Convulsiones no-controladas
Citopenias severas- incluyendo necesidad por transfusion
Motivacion del paciente a tomar tratamiento.
Pretreatment Factors Associated with reduced
likelihood of achieving SVR
Host Viral Disease-specific
African American Race Genotype 1 Advanced fibrosis score
Latino ethnicity High HCV RNA Steatosis
Older age HIV coinfection
Male sex
Insulin resistance
High BMI
HCV Genotypes
Genotype 1 70% infected patients in USA
Lower SVR with current treatment
Treated for at least 48 weeks
Genotype 2- 3 30% of infected patients in USA
More common in Europe (Austrians) and Japanese
Higher SVR with current treatment
Genotype 4 Egypt and Middle East
Genotype 5 Southern Africa
Genotype 6 Southeast Asia
4
HCV - Treatment
Sustained Virological Response (SVR)
0 24 48 72
0
50
100
150
0
6
12
ALT
HCV RNA
200
18
Weeks
ALT
(IU)
HCV RNA
(IU/ml)
Treatment
Sustained virological response (SVR)
Peg- IFN
(180 ug or 1.5
ug/kg)
Weekly +
Weight base
RBV
(13-15
mg/kg)
RVR
WK 4
WK 12
No
RVR
24 wks
If baseline VL <400,000 IU/ml and low
Fibrosis score
Complete EVR
HCV RNA < 50 IU/ml
Partial EVR
2-log decline
No EVR Stop
72 wks
48 wks
48 wks
HCV Genotype 1
Genotype 2-3
Peg-IFN
180 ug or
1.5 ug/kg
weekly +
Ribavirin
800 mg/d

Response Weeks of
assessment
Interpretation Management
implications
RVR 4 HCV RNA < 50 IU/ml
predicts 90% SVR
Duration of
treatment of 12-16
weeks can be
considered
No RVR 4 HCV RNA > 50 IU/ml
predicts SVR < 50%
Consideration o
treatment duration
longer than 24
weeks
HBV - Therapy
Effect of IFN on Survival and HCC
Development
0
25
50
75
%
Cumulative
incidence
100
0 2 4 6 8 10 12
Years of follow-up
Treated group
Control group
Survival
p = 0.018
HCC
p = 0.013
Lin SM, Hepatology 1999; 29:971
Effect of interferon treatment on survival and hepatocellular carcinoma (HCC) development
Conclusiones
Las Hepatitis virales son un problema importante de salud
mundial.
Hepatitis A y E son infecciones agudas que no progresan a
cronicidad y cuya propagacion depende de las condiciones
de higiene en la comunidad.
Hepatitis A es prevenible mas alta mortalidad en adultos
y pacientes con enfermedad hepatica cronica
Hepatitis B y C son causas importantes de mortalidad y
morbilidad por falla hepatica y cancer.
Vacunacion es una forma segura y eficaz (y mucho mas
economica) de atacar la hepatitis B.
Hay opciones de tratamiento para las formas cronicas de
hepatitis B y C, las cuales actualmente se encuentran en
evolucion.
Conclusiones
Acute Hepatitis C should be treated with IFN alfa por
el alto riesgo de avanzar a cronicidad
Los niveles de viremia y genotipos de HBV y HCV son
importantes al momento de decidir tratamiento.