HEPATITIS VIRALES

A B C D E Tipo de Hepatitis Fuente del heces sangre/ sangre/ sangre/ virus H-derivados H-derivados H-derivados Fl corporales Fl corporales Fl corporales Via de fecal-oral percutánea percutánea percutánea fecal-oral transmisión mucosa mucosa mucosa Infección no si si si no crónica Prevención immunización immunización screening immunización asegurar pre/post- pre/post- donantes; pre/post- agua exposición exposición modificación exposición potable modificación modificacion conductas de riesgo conductas de riesgo conductas de riesgo

Determinación de Transaminasas (TGO y TGP) SOSPECHA DE HEPATITIS AGUDA No más estudios Hepatitis Aguda A Aguda B Elevadas IgM anti VHA (+) HBs Ag (+) Ambos (-) IgM anti core Hepatitis Aguda B Se descarta IgM anti VHA HBs Ag Normales (+) (-) CMV IgG IgM

HEPATITIS A EPIDEMIOLOGIA MANEJO DE CONTACTOS PREVENCION

HEPATITIS A VIRUS This is an electron micrograph of HAV that causes hepatitis A. See the next slide for specifics about this virus.

HEPATITIS A VIRUS RNA Picornavirus Serotipo único Causa enfermedad aguda o infección asintomática No desarrolla infección crónica Anticuerpos protectivos confieren inmunidad de por vida. Hepatitis A is caused by HAV, a 27-nm ribonucleic acid (RNA) agent that is classified as a picornavirus. Only one serotype has been observed among HAV isolates collected from various parts of the world. HAV causes both acute disease and asymptomatic infection. HAV does not cause chronic infection. Total antibody to HAV develops in response to infection and confers lifelong immunity from future HAV infection.

HEPATITIS A EPIDEMIOLOGIA DESARROLLO SOCIO-ECONOMICO BROTES DISTRIBUCION GLOBAL EDAD DE ADQUISICION ENDEMICIDAD

GEOGRAPHIC DISTRIBUTION OF HEPATITIS A VIRUS INFECTION HAV infection prevalence is high or intermediate in the areas noted in red, blue, and green. Hepatitis A vaccine is recommended for persons who travel or work in these areas. Yellow indicates the areas where HAV infection prevalence is low (including the United States). HAV infection prevalence is very low in the areas shown in tan. Note: This slide has been generalized from available data.

HEPATITIS A PATRONES DE TRANSMISION Edad pico de infección Transmisión Endemicidad Riesgo Alto Bajo/alto Primera infancia Persona a persona; Brotes poco comunes Moderado Alto Infancia tardía/ Adultos jóvenes Persona a persona; agua y alimentos brotes Bajo Bajo Adultos jóvenes Persona a persona; Worldwide, four different patterns of HAV transmission can be defined on the basis of age-specific seroprevalence data. In general, these transmission patterns correlate with socioeconomic and hygienic conditions. In many developing countries where environmental sanitation is generally poor, nearly all children have evidence of prior HAV infection. In these highly endemic areas, outbreaks rarely occur, but the frequency of clinically recognized disease due to HAV infection varies. In some areas, disease rates might be high because of the pervasiveness of the virus in the environment. As hygienic conditions improve, transmission shifts to older age groups and the incidence of clinically evident disease increases. In most industrialized countries, low levels of endemic HAV transmission occur. Because most of the population is susceptible to HAV infection in these industrialized countries, clinically apparent disease is recognized and outbreaks occur. In a few countries, primarily in Scandinavia, hepatitis A outbreaks are uncommon, and nearly all HAV transmission occurs among illegal drug users and travelers to high or intermediate endemic areas. Agua y alimentos brotes Muy bajo Bajo adulto Viajeros, poblaciones de riesgo

HEPATITIS A CARACTERISTICAS CLINICAS Ictericia <6 yrs <10% 6-14 yrs 40%-50% >14 yrs 70%-80% Complicaciones (raras) Hepatitis fulminante Hepatitis colestática Hepatitis bimodal Formas severas sobre hepatopatias crónicas Período de incubación Promedio 30 dias Rango 15-50 dias Secuelas No The average incubation period for hepatitis A is 30 days, with a range of 15 to 50 days. Patients characteristically have abrupt onset of symptoms which can include fever, malaise, anorexia, nausea, abdominal discomfort, dark urine, and jaundice. The severity of clinical disease associated with HAV infection increases with increasing age; jaundice occurs among less than 10% of children younger than 6 years of age, 40%-50% of older children, and 70%-80% of adults. Complications of hepatitis A include fulminant hepatitis, in which the case fatality rate can be greater than 50% despite medical interventions such as liver transplantation; cholestatic hepatitis, with very high bilirubin levels that can persist for months; and relapsing hepatitis, in which exacerbations can occur weeks to months after apparent recovery. Chronic infection does not occur following HAV infection.

Manifestaciones clínicas HEPATITIS A Manifestaciones clínicas Infección ALT IgM IgG Viremia Respuesta HAV en MF The diagnosis of acute HAV infection is confirmed during the acute or early convalescent phase of infection by the presence of IgM antibodies to HAV (IgM anti-HAV). IgM anti-HAV is generally present 5-10 days before the onset of symptoms and is no longer detectable in the vast majority of patients 6 months later. IgG anti-HAV, which also appears early in the course of infection, remains detectable for the lifetime of the individual and confers lifelong protection against infection. Commercial tests are available for the detection of IgM and total (IgM and IgG) anti-HAV in serum. In infected persons, HAV replicates in the liver, is excreted in bile, and is shed in the stool. Peak infectivity occurs during the 2-week period before onset of jaundice or elevation of liver enzymes, when the concentration of virus in stool is highest. The concentration of virus in stool declines after jaundice appears. Children and infants can shed HAV for longer periods than adults, up to several months after the onset of clinical illness. Chronic shedding of HAV in feces does not occur; however, shedding can occur in persons who have relapsing illness. Viremia occurs soon after infection and persists through the period of liver enzyme (alanine aminotransferase [ALT]) elevation. HAV RNA can be detected in the blood and stool of most persons during the acute phase of infection by using nucleic acid amplification methods, such as PCR, and nucleic acid sequencing has been used to determine the relatedness of HAV isolates. These methods, however, are available in only a limited number of research laboratories and are not used generally for diagnostic purposes. 1 2 3 4 5 6 7 8 9 10 11 12 13 Semanas

CONCENTRACION DE HEPATITIS A VIRUS EN FLUIDOS CORPORALES Heces Suero Fluidos Saliva Urine Feces can contain up to 108 infectious virions per milliliter and are the primary source of HAV. Viremia occurs during the preclinical and clinical phases of illness, and HAV has been transmitted by transfusion (before screening of blood and blood products for HAV was initiated) and by injection drug use. Virus has also been found in saliva and urine during the incubation period in experimentally infected animals, but transmission by saliva or urine has not been reported to occur. 100 102 104 106 108 1010 Dosis infectante por mL Source: Viral Hepatitis and Liver Disease 1984;9-22. J Infect Dis 1989;160:887-890

HEPATITIS A DEFINICION DE CASO - VIGILANCIA Criterio clínico: Enfermedad aguda con: Astenia, dolor abdominal,anorexia,náuseas, vómitos; e Ictericia o elevación de aminotransferasas. Criterio de laboratorio: IgM (anti-HAV) positivo Clasificación de Caso: Confirmado Criterio clínico + laboratorio Criterio clínico con contacto epidemiológico HAV IgM + (50 y 15 días previos al comienzo de los síntomas) Trends in acute viral hepatitis can be monitored through cases reported to surveillance systems using a standard case definition. The surveillance case definition for acute hepatitis A includes both clinical and laboratory criteria. The clinical criteria consist of an acute illness with discrete onset of symptoms AND presentation of jaundice OR elevated liver enzymes. The laboratory criterion is IgM anti-HAV positivity. In addition, the case definition can be met if the person meets the clinical criteria and had an epidemiological link with a person who has laboratory-confirmed hepatitis A (i.e., household or sex contact with an infected person during the 15-50 days before the onset of symptoms). All patients who meet this case definition should be reported to the local or state health department. Case reports of acute hepatitis A are then transmitted weekly by state health departments to CDC via the National Electronic Telecommunications System for Surveillance (NETSS).

HEPATITIS A TRANSMISION Contacto personal cercano (convivientes, pareja sexual, guarderias) Agua y alimentos contaminados. Exposición con sangre (raro) (usuarios de drogas EV, transfusiones) Transmission of HAV generally occurs when susceptible persons put anything in their mouths that has been contaminated with the feces of an infected person. Close personal contact is the most common mode of HAV transmission, as demonstrated by infections among household and sex contacts of persons with hepatitis A and among children in day-care center outbreaks. Contaminated food and water can also serve as vehicles of HAV transmission. HAV transmission can occur when an infected food handler directly handles uncooked or cooked foods. Outbreaks have also been reported in association with foods contaminated before wholesale distribution, such as fresh vegetables contaminated at the time of harvesting or processing. HAV transmission can occur as a result of blood exposures such as injecting drug use or blood transfusion because viremia can occur prior to the onset of illness in infected persons. Screening of blood products for HAV has essentially eliminated the already extremely low risk associated with transfusion.

FACTORES DE RIESGO ASOCIADOS CON HEPATITIS A, 1990-2000, EEUU From 1990 through 2000, the most frequently reported source of infection was personal contact (household or sex) with an infected person (14%). Two percent of cases involved a child or employee in day-care; 6% of cases were a contact of a child or employee in day-care; 5% of cases reported recent international travel; and 4% of cases reported being part of a recognized foodborne outbreak. Injection drug use was a reported risk factor in 6% of cases; men who have sex with men represented 10% of cases. Forty-six percent of reported hepatitis A cases could not identify a risk factor for their infection. Note: Risk factor percentages rounded to nearest percent Source: NNDSS/VHSP

HEPATITIS A PREVENCION Higiene (lavado de manos) Saneamiento (fuentes de agua potable) Vacuna Hepatitis A (pre-y post-exposición) Immuno globulina (pre- y post-exposición) Good hygienic practices and adequate sanitation are important elements in the prevention of HAV infection, particularly in the developing world. However, hepatitis A vaccine is the key component in the overall strategy to prevent HAV infection in the United States. Immune globulin is also available for pre-exposure and post-exposure prophylaxis.

HEPATITIS A, VACUNAS Virus desarrollados en cultivo de líneas celulares (MRC-5) Producto purificado inactivado con formalina. Adsorbido en hidroxido de aluminio. In the United States, highly immunogenic and efficacious inactivated hepatitis A vaccines were first licensed in 1995 by the Food and Drug Administration (FDA). These vaccines are prepared by methods similar to those used for inactivated poliovirus vaccine. Cell culture-adapted virus is propagated in human fibroblasts, purified from cell lysates by ultrafiltration and exclusion gel chromatography or other methods, inactivated with formalin, and adsorbed to an aluminum hydroxide adjuvant.

HEPATITIS A VACUNAS Altamente inmunogénica: 97%-100% de los niños, adolescentes y adultos tienen niveles protectivos luego de 1 mes de la primera dosis ; 100% luego de la segunda dosis. Altamente eficaz: 94%-100% de los niños adquieren protección frente a una dosis. The two inactivated vaccines licensed in the United States, HAVRIX® * (manufactured by GlaxoSmithKline) and VAQTA® * (manufactured by Merck & Co., Inc.), are highly immunogenic. Approximately 97%-100% of children, adolescents, and adults develop protective levels of antibody within 1 month after the first dose of vaccine; essentially 100% of vaccinees develop protective antibody with high geometric mean concentrations after completing the two-dose series. The vaccines are highly efficacious: In published studies, 94%-100% of children were protected against clinical hepatitis A after receiving the equivalent of one dose. *Use of trade names is for identification only and does not imply endorsement by the Public Health Service or the U.S. Department of Health and Human Services.

HEPATITIS A ESTUDIOS DE EFICACIA Lugar/ Groupo etario Eficacia (95 % Cl) Vacuna N Ò HAVRIX Thailandia 38,157 94% (GSK) 1-16 a (79%-99%) 2 dosis 360 EL.U. The efficacy of HAVRIX® * was evaluated in a double-blind, controlled, randomized clinical trial in Thailand among 38,157 children 1-16 years of age living in an area with high endemic rates of hepatitis A. Following two doses of vaccine (360 EL.U. per dose) given 1 month apart, the efficacy of vaccine in protecting against clinical hepatitis A was 94% (95% confidence interval [CI], 79%-99%). A double-blind, placebo-controlled, randomized clinical trial using VAQTA® * was conducted among 1,037 children 2-16 years of age living in a single U.S. community with a high rate of hepatitis A. Within 18 days following one dose (25 U) of vaccine, the efficacy in protecting against clinical disease was 100% (95% CI, 85%-100%). *Use of trade names is for identification only and does not imply endorsement by the Public Health Service or the U.S. Department of Health and Human Services. VAQTA Ò   New York 1,037 100% (Merck) 2-16 a (85%-100%) 1 dosis 25 units JAMA 1994;271:1363-4; N Engl J Med 1992;327:453-7 17

HEPATITIS A VACUNAS DOSIS RECOMENDADAS Volumen 2-Dosis Vacuna Edad Dosis (mL) (meses) HAVRIX ® # 2-18 720 (EL.U.*) 0.5 0, 6-12 >18 1,440 1.0 0, 6-12 VAQTA ® ## 2-18 25 (U**) 0.5 0, 6-18 >18 50 1.0 0, 6-18 * EL.U. – Enzyme-linked immunosorbent assay (ELISA) units ** Units # has 2-phenoxyethanol as a preservative ## has no preservative Both HAVRIX® and VAQTA® should be administered intramuscularly into the deltoid. A needle length appropriate for the vaccinee’s age and size should be used. HAVRIX® is available in two formulations, and the formulation differs according to the person’s age: for persons 2-18 years of age, 720 EL.U. per dose in a two-dose schedule; and for persons greater than 18 years of age, 1,440 EL.U. per dose in a two-dose schedule. VAQTA® is also licensed in two formulations, and the formulation differs according to the person’s age: for persons 2-18 years of age, 25 U in a two-dose schedule; and for persons greater than 18 years of age, 50 U per dose in a two-dose schedule.

VACUNA HEPATITIS A SEGURIDAD Efectos adversos más comunes: Dolor en el sitio de inyección 50% Cefalea 15% Debilidad 7% No efectos severos atribuidos a la vacuna. Seguridad en el embarazo no está determinada, bajo riesgo. Contraindicaciones: reacción adversa severa a la dosis previa o componente de la vacuna No precauciones especiales en huéspedes inmunocomprometidos. Soreness at the site of injection is the most commonly reported side effect of hepatitis A vaccination (50%). Headache and malaise were reported by 15% and 7% of vaccinees, respectively. Reviews of data from multiple sources for more than 5 years did not identify any serious adverse events among children or adults that could be definitively attributed to hepatitis A vaccine. The safety of the vaccine will continue to be assessed through ongoing monitoring of data from the Vaccine Adverse Events Reporting System (VAERS) and other surveillance systems. The safety of hepatitis A vaccination during pregnancy has not been determined; however, because hepatitis A vaccine is produced from inactivated HAV, the theoretical risk to the developing fetus is expected to be low. The risk associated with vaccination should be weighed against the risk of hepatitis A in women who might be at high risk for exposure to HAV. Hepatitis A vaccine should not be administered to persons with a history of a severe reaction to a dose of hepatitis A vaccine or allergy to a vaccine component. Because hepatitis A vaccine is inactivated, no special precautions are needed when vaccinating immunocompromised persons.

DURACION DE LA PROTECCION POST- VACUNA HEPATITIS A Persistencia de anticuerpos: 5-8 años (niños y adultos) Eficacia: No casos reportados en niños vacunados a 5-6 a de seguimiento. Modelos matemáticos de declinación de anticuerpos sugieren niveles protectivos por al menos 20 años. Otros mecanismos contribuyen, como la memoria celular. Among adults and children, studies have demonstrated that detectable antibody persists for at least 5-8 years after completing the vaccination series. Although data regarding long-term efficacy are limited, no cases among vaccinated children were observed in one community at 5-6 years of follow-up. Estimates of antibody persistence derived from mathematical models of antibody decline indicate that protective levels of anti-HAV persist for at least 20 years. Whether other mechanisms such as cellular memory also contribute to long-term protection is unknown.

FACTORES ASOCIADOS A DISMINUCION DE INMUNOGENICIDAD DISMINUCIóN DE NIVELES DE ANTICUERPOS: Administración conjunta IG Anticuerpos maternos adquiridos pasivamente Edad Enfermedad hepática crónica. DISMINUCION DE LA SEROCONVERSION: HIV Inmunosupresión Transplante hepático. The presence of anti-HAV at the time of vaccination appears to blunt the immune response. Administration of immune globulin (IG) concurrently with the first dose of hepatitis A vaccine did not decrease the proportion of adults who developed protective levels of antibody compared with adults who had been administered hepatitis A vaccine alone, but the geometric mean antibody concentrations (GMCs) among adults who received IG were lower 1 month after completion of the vaccination series than the GMCs of any adults who had been administered hepatitis A vaccine alone. The reduced immunogenicity of hepatitis A vaccine that occurs with concurrent administration of IG does not appear to be clinically significant. IG and hepatitis A vaccine can be given concurrently if indicated. Reduced vaccine immunogenicity also has been observed in infants who had passively-transferred antibody because of prior maternal HAV infection and were administered hepatitis A vaccine according to a number of different schedules. In most studies, all infants developed protective levels of antibody, but the final GMCs were approximately 1/3 to 1/10 those of infants born to anti-HAV-negative mothers. Based on limited data, final antibody concentrations might be lower among older vaccinated persons. Vaccination of adults with chronic liver disease of viral or nonviral etiology produced seroprotection rates similar to those observed in healthy adults. Final antibody concentrations, however, were substantially lower for each group of patients with chronic liver disease than for healthy adults. In some studies, administration of hepatitis A vaccine to persons with HIV infection resulted in lower seroprotection rates and antibody concentrations. Among HIV-infected men, those who responded to hepatitis A vaccination had significantly more CD4+ T lymphocytes at baseline compared with those who did not respond. Being HIV positive, however, is not a contraindication for administering hepatitis A vaccine if the person is in a risk group for whom hepatitis A vaccine is recommended. In one small study, none of the 8 patients who had received a liver transplant responded to hepatitis A vaccination; however, liver transplantation is not a contraindication for administering hepatitis A vaccine.

TEST PRE- VACUNACION Costo de la vacuna. Costo del test serológico. Prevalencia de la infección. Impacto y aceptación de la vacuna. Altamente costo efectiva en grupos de riesgo: Nacidos en áreas endémicas Usuarios de drogas EV Hombres que practican sexo con hombres. 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. 24

TEST POST-VACUNACION No recomendado: Alta respuesta de la vacuna El test comercialmente disponible es de baja sensibilidad. 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. 25

HEPATITIS A PREVENCION IMMUNO GLOBULINA Pre-exposición: Viajeros a áreas de intermedia-alta endemicidad. Post-exposición (hasta 14 días) Siempre Convivientes y contactos íntimos RN de madres con HAV (2 sem antes y 2 sem después del parto) Selectivo Igual fuente de exposición (contaminación de alimentos y/o agua) Escuelas (Brote) Guarderías (1 caso) Centros de salud. IG is a sterile preparation of concentrated antibodies made from pooled human plasma. IG provides protection against hepatitis A through passive transfer of antibody. IG is 80%‑90% effective in preventing clinical hepatitis A when administered before exposure or early in the incubation period after exposure. IG can be used for pre-exposure prophylaxis for travelers to areas of high or intermediate endemicity of hepatitis A, particularly when the planned departure is less than 2-4 weeks later. In this situation, immunity from vaccination might not have developed by the time of departure. Post-exposure prophylaxis with IG is effective if administered within 14 days of exposure. The primary routine indication for post-exposure prophylaxis is for household or other intimate contacts of persons with hepatitis A. In addition, post-exposure prophylaxis might be indicated when hepatitis A cases occur in some institutional settings (e.g., child day-care centers) and after some common source exposures (e.g., persons who ate food prepared by an infected food handler). Local and/or state health departments should be consulted regarding the use of IG for post-exposure prophylaxis in these settings.

HEPATITIS A en ARGENTINA 2005 se notificaron 27.773 casos TASA de 76.6 casos 100.000 hab 2004 se notificaron 61.845 casos TASA de 170.6 casos 100.000 hab 2003 se notificaron 50.399 casos TASA de 139 casos 100.000 hab

HEPATITIS A en ARGENTINA

Hepatitis A. Pcia. Bs. As. 1997 - 2003

RECOMENDACIONES ACIP 1999 VACUNACION EN HEPATITIS A Niños que deben ser vacunados: Quiénes viven en comunidades o países de intermedia – alta endemicidad  20 casos/100,000. Niños que debería ser considerados: Quiénes viven en comunidades o países con un rango de <20 pero  10 casos/100,000 . The current ACIP recommendations, published in 1999, recommend that children living in areas where rates of hepatitis A were at least twice the national average; that is, greater than or equal to 20 cases per 100,000 during the baseline period (1987-1997) should be routinely vaccinated. The ACIP also recommends that routine vaccination be considered for children living in areas where rates of hepatitis A were greater than the national average but lower than twice the national average; that is, rates of at least 10, but fewer than 20 cases per 100,000 during the baseline period (1987-1997).

HEPATITIS A en ARGENTINA RESOLUCION MINISTERIAL N° 653 (Junio 2005) Incorpora la vacuna de Hepatitis A al Calendario Nacional de Vacunación. Se aplicará al año de edad.

¿Quiénes deben vacunarse ? Hombres que practican sexo con hombres. Usuarios de drogas. Viajeros internacionales. Personas con trastornos de la coagulación. Personas con hepatopatía crónica. Riesgo ocupacional. Niños y personal de jardines maternales. Instituciones penitenciarias. Inmunocomprometidos. 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.

HEPATITIS A PREVENCION CAMBIOS PARA EL FUTURO Continuar con la vacunación en niños en forma sostenida. Reducción de la incidencia: Vacunación de adultos de alto riesgo Detección precoz de casos e identificación de brotes Manejo de contactos. Important challenges will be to sustain vaccination in the face of falling disease rates and to continue to improve hepatitis A vaccination coverage among children. Without ongoing vaccination, hepatitis A incidence rates in areas that historically had consistently elevated rates will return to pre-vaccination-era levels because the fundamental epidemiological characteristics that resulted in these elevated rates have not changed. To further reduce incidence, we will need to do a better job of vaccinating adults in high-risk groups. Ultimately, vaccination of all children nationwide can be considered. This final incremental step would be facilitated by the availability of a vaccine that can be used in children younger than 2 years old and a combination vaccine that includes hepatitis A vaccine.

Un Problema Mayor… HEPATITIS B 400,000,000 portadores. 1,000,000 de muertes por año (9na causa). 30% evolución hacia cirrosis. 5-10% evolución hacia hepatocarcinoma.

Factores de riesgo Hepatitis B Heterosexual* (41%) Adiccion EV (15%) Actividad homosexual (9%) Contacto hogareño (2%) Trabajadores de la salud (1%) Otros (1%) Desconocido (31%) * Incluye contacto sexual con casos agudos, portadores, y parejas multiples. Fuente: CDC Sentinel Counties Study of Viral Hepatitis * Incluye contacto sexual con casos agudos, portadores, y parejas multiples. Fuente: CDC Sentinel Counties Study of Viral Hepatitis

HEPATITIS B Hepadnaviridae. Existen varios genotipos virales con diferente distribución geográfica. Características del genoma: pre S-S  HBsAg preC-C  HBcAg y HBeAg ADN viral se integra al genoma con una unión Cerrada Covalente y Circular (cccDNA)

HEPATITIS B – Concentración viral en fluidos corporales Baja / No Alta Moderada detectable sangre semen orina suero fuido vaginal heces exudados de heridas saliva sudor lágrimas leche materna

HEPATITIS B El ciclo de replicación viral no es directamente citotóxico. La respuesta inmune es el principal determinante de la injuria celular. La respuesta de Linfocitos T citotóxicos es determinante en el clearance viral y en la lisis de la célula target.

HEPATITIS B – Curso serológico típico Síntomas HBeAg anti-HBe Total anti-HBc Título anti-HBs HBsAg IgM anti-HBc 4 8 12 16 20 24 28 32 36 52 100 Semanas post-exposición

HEPATITIS B INFECCION AGUDA normalización de ALT y clearance HBsAg en 6 meses. (> 90% de los casos) INFECCION PERSISTENTE persistencia de HBsAg por más de 6 meses.

HEPATITIS B HBV crónica Enfermedad necroinflamatoria crónica del hígado causada por una infección persistente por HBV. Puede presentar Ag e+/e- HBsAg > 6m DNA HBV > 10 5 ALT elevadas Biopsia con necroinflamación >= 4

HEPATITIS B ESTADO DE PORTADOR INACTIVO Infección persistente por HBV sin una significante actividad necroinflamatoria HBsAg > 6m HBV DNA < 10 5 seroconversión anti e ALT normales Biopsia score < 4

HEPATITIS B HBV crónica RESUELTA Infección previa por HBV, sin evidencia bioquímica, histológica ni virológica de infección o enfermedad. Historia de infección aguda o crónica Anti HBsAg HBsAg – ALT normales HBV ADN indetectable

HEPATITIS B EXACERBACION ó FLARE Elevación intermitente de las transaminasas > 10 del valor normal, en más de 2 controles, luego de haber alcanzado valores basales. REACTIVACION Reaparición de la necroinflamación en paciente con HBV resuelta o portación inactiva.

HEPATITIS B Clearance de HBeAg Pérdida de HBeAg en un individuo previamente HBeAg + Seroconversión HBeAg anti e Pérdida de HBeAg y aparició de anti e. Reversión HBeAg Reaparición de HBeAg y en persona previamente HBeAg - y anti e +.

HEPATITIS B HEPATITIS B CRONICA Ag e (-) Mutación core, precore Mutación precore G1896A, abole la producción de Ag e. Es común en genotipo D (Mediterráneo) Mutación core A1762T + G1764A que genera un down regulation de HBeAg.

HEPATITIS B crónica - Evolución Progresión a cirrosis Más frecuente en adultos mayores Ag e(+) y ALT elevadas Cirrosis compensada : sobrevida a 5 años 84 % y a 10 años 68%. Factores pronóstico de descompensación: Age(+) y fallo al IFN. Cirrosis descompensada :sobrevida a 5 años 14% Gastroenterology 1992

HEPATITIS B crónica - Evolución Progresión a Carcinoma Hepatocelular Factores de riesgo: sexo masculino edad > 45 Ag e (+) historia de reversión coinfección HCV cirrosis

HEPATITIS B crónica - Tratamiento OBJETIVOS Supresión de la replicación viral Remisión de la enfermedad hepática END POINTS ALT normales HBV DNA indetectable Clearance Ag e c/s anti e Mejoría histológica

HEPATITIS B crónica - Tratamiento TIPOS DE RESPUESTA Bioquímica Virológica ALT normales ADN – Pérdida Ag e Histológica Completa Mejoría en 2 puntos Todos y pérdida de AgS del score NHI Consensus Workshop on Management HBV 2000

HEPATITIS B crónica - Tratamiento 5 drogas aprobadas por FDA: Interferon(alfa2a) Peg interferon , lamivudine, adefovir dipivoxil, entecavir pueden ser considerados como primera línea de tto.

HEPATITIS B crónica - Tratamiento Interferon Lamivudine Adefovir Pros Duración definida Vía oral SVR prolongada Eventos adversos mínimos Efectivo en LAM-resistant mutants No reporte de resistancia Bajo costo ( basado en 1 año de tto) Baja incidencia de mutaciones Cons SC Tto prolongado indefinido Alto costo Alto riesgo de resistencia en tto prolongado Potencial nefrotoxicidad Eventos adversos frecuentes

Hepatitis B Qué debemos considerar para tratar? Infección crónica Histología Nivel de ADN viral Ag e + ó – Nivel de transaminasas

Hepatitis B Controles en paciente sin tto Hepatograma, tiempo de protrombina, proteinograma electroforético. Ecografía anual Alfa fetoproteína anual Biopsia (no varía por 2 años). Carga viral (cuando pensamos tratar).

Hepatitis B Fármacos en investigación: Telvibudine Clevudine

HEPATITIS C –Aspectos prácticos ¿A quién solicitar el test de Hepatitis C? Transaminasas hepáticas persistentemente elevadas en chequeos de salud. Estudio de esteatosis hepática (higado graso) Personas transfundidas antes de 1992. Personas con antecedentes de consumo de drogas ilícitas IV o inhalatorias. Bancos de sangre. Estudio por “fatiga” o síntomas compatibles con “fibromialgia”.

HEPATITIS C – Aspectos prácticos ¿A quién solicitar el test de Hepatitis C? Estudios serológicos ante un accidente cortopunzante en profesionales de la salud. (estudios de la fuente y del profesional, basales y de seguimiento). Evaluación pretransplante de órganos del donante y del receptor. Hijos de madres VHC (+). Hemodializados cada 6 meses. Personas sometidas a múltiples procedimientos quirúrgicos o tratamientos médicos con inyectables, tatuajes y/o perforaciones corporales “piercing”.

Hepatitis C Evaluación Inicial Ig G HCV + Test confirmatorios: Inmunobloting PCR HCV

Hepatitis C Genotipificación prevalente en Argentina 1(a,b) 2(a,b) 3

HEPATITIS C -Tratamiento 1. CUIDADOS GENERALES Dieta general (restricción de grasas solo en casos con patología biliar concomitante). Actividad física aeróbica. Listado de medicamentos permitidos y no permitidos (evitar automedicación con AINES). Vacunación contra hepatitis A y B (previo chequeo serológico en los > 20 años). Instrucciones específicas de evitar alcohol o ingesta menor a 10g/día.

HEPATITIS C - Evaluación VIROLÓGICO ARN-VHC Genotipo BIOQUÍMICO GOT/GPT FA/g GT HISTOLÓGICO Grados de necro-inflamación Grados de fibrosis. Ausencia o presencia de cirrosis.

HEPATITIS C crónica 2. TRATAMIENTOS ANTIVIRALES ESPECÍFICOS OBJETIVOS: Reducir la necro-inflamación hepática. Enlentecer o detener el daño hepático progresivo. Reducir el riesgo de carcinoma hepatocelular. Potencial erradicación del virus.

HEPATITIS C - Tratamiento NO ELEGIBLES PARA TRATAMIENTO ANTIVIRAL ACTIVO Pacientes en consumo activo de alcohol o drogas ilícitas. Pacientes con cirrosis descompensada (Child B o C) Pacientes añosos, con enfermedad histológica leve y comorbilidades. Pacientes coinfectados por hepatitis C y HIV, con infección por HIV no controlada.

HEPATITIS C - Tratamiento ELEGIBLES PARA TRATAMIENTO ANTIVIRAL ACTIVO Pacientes con transaminasas elevadas o no (transaminasas normales no indican ausencia de fibrosis) con actividad histológica inflamatoria moderada a severa, en ausencia de contraindicaciones absolutas para tratamiento antiviral específico. Pacientes con Genotipos respondedores se puede ofrecer tto aún con histología favorable , por la alta chance de curación. Conclusiones de las Conferencias de Consenso Internacional sobre Hepatitis C Crónica (NIH, Washington,2002).

Contraidicaciones al uso de Interferón ABSOLUTAS: Antecedentes de psicosis y/o depresión mayor. Leucopenia (PMN < 1500/mm3) y/o trombocitopenia (<80.000/mm3). Transplante de órganos (excepto transplante hepático). Cirrosis descompensada.(Cihld B o C) Convulsiones no controladas. Enfermedad cardiaca descompensada. Enfermedad coronaria inestable Embarazo/anticoncepción no confiable RELATIVAS: Enfermedades autoinmunes. DBT no controlada.

Contraindicaciones al uso de Rrivabirina Hemoglobinopatías (talasemia)/antecedentes de hemólisis. Anemia. Insuficiencia renal crónica. Cardiopatía isquémica. Insuficiencia cardíaca. Embarazo/anticoncepción no confiable.

Hepatitis C Duración y dosis de tratamiento 180 mcg Peg interferon SC 1 vez semanal + 1000/1200 mg día Rivabirina durante 12 meses, en genotipos resistentes(1). 180 mcg Peg interferón SC 1 vez semanal + 800 mg día Rivabirina durante 6 meses, en genotipos sensibles(2 y 3).

HEPATITIS C - Tratamiento La decisión de indicar un ciclo de tratamiento antiviral para Hepatitis C en un paciente es una decisión que comprende la correcta categorización de la hepatopatía del paciente, presencia o no de co-morbilidades y una exhaustiva evaluación para descartar contraindicaciones absolutas para el mismo.

Muchas gracias