Dr. Marcelo Silva Hospital Universitario Austral

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1 Dr. Marcelo Silva Hospital Universitario Austral
Curso de Medicina Interna Asociación Medica Hepatitis B Dr. Marcelo Silva Hospital Universitario Austral

2 Impacto Global de la HBV
millones de portadores crónicos del (>75% en Asia y Africa) 15-40% progresarán a cirrosis y/ó HCC Una de las causas más importantes de cirrosis y HCC en el mundo. Causa del 80% de los HCC en Americanos de orígen asiático y del 30% a 50% de los HCC en pacientes sin cirrosis Segundo, solo atrás del tabaco, como causal de muerte asociada a cancer Es responsable directo de 500,000 a millón de muertes anuales Sorrell MF, et al. Ann Intern Med. 2009;150: World Health Organization. HBV fact sheet. Conjeevaram HS, et al. J Hepatology. 2003;38(suppl 1):s90-s103. Stanford Asian Liver Center. For hepatitis B and liver cancer patients. Bosch FX, et al. Clin Liver Dis. 2005;9: World Health Organization. Global alert and response: hepatitis B—Introduction.

3 HBV: Un solo Virus o Más de Uno?
Al menos 8 genotipos identificados Variantes Salvajes Mutantes espontáneas Precore Promotor del core Variantes mutantes generadas por anti virales orales HBV, hepatitis B virus. Hepatitis B virus is a single virus; however, it behaves as many viruses because there are numerous variants that must be considered when evaluating patients for potential treatment. For example, there are 8 well-documented genotypes, and viruses can be further categorized according to the absence or presence of mutations: wild-type virus, naturally occurring mutants including the precore and the basal core promoter mutants, and drug-resistant mutants that are selected during therapy.

4 Hepatitis B: Distribución Geográfica de Genotipos
A, B, C, D, G B, C D H A, D, E F HBV, hepatitis B virus. This map shows the geographic distribution of HBV genotypes. As noted earlier, in Asia, most patients are infected with genotypes C and B. In the United States, several genotypes are well represented. A, B, C, D Liaw YF, et al. Liver Int. 2005;25: Chu CJ, et al. Gastroenterology. 2003;125:

5 Hepatitis B: Impacto Clínico de los Genotipos
HBV Gt bien caracterizados (A-H) Gt A asociado a hepatopatia de menor importancia, menor progresión que Gt C Gt A menos chance de desarrollar HCC Gts A y B mejor respuesta al IFN que los Gts C y D Gt F ? HBV, hepatitis B virus; HCC, hepatocellular carcinoma; IFN, interferon. As mentioned, there are at least 8 HBV genotypes that represent genetic variants of the virus and are designated A through H. In Asia, genotypes B and C are the most prevalent. Among the US Korean population, it is interesting to note that I have not seen any HBV genotypes other than C. The statistics from Korea demonstrate approximately 95% prevalence of genotype C, but in my experience in the United States, essentially 100% of Korean patients with HBV infection have genotype C infection. There are certain clinical characteristics associated with these genotypes: Genotype B is associated with less-active disease, slower disease progression, and a lower incidence of HCC than genotype C. Genotypes A and B respond better to interferon therapy than genotypes C and D. Thus, patients who have genotypes A and B may be considered to have more treatment options. Kramvis A, et al. J Viral Hepat. 2005;12:

6 Hepatitis B: Variantes Virales
Variantes Salvajes: HBeAg (+) Mutación Precore: (27% de los pacientes de USA)[1] Impiden la producción de HBeAg, por lo tanto son HBeAg (-) Mutación promotor del Core: (44% de los pacientes de USA)[1] Inhibe parcialmente la producción de HBeAg, HBeAg (+)/(-) Mutaciones inducidas por Antivirales Orales: YMDD: inducidos por Lamivudina ( 20%/año)[2,3] N236T y A181V: inducidos por Adefovir (0% al 1er año, 3% al 2 año, 11% al 3er año, 18% al 4 año, y 29% al 5 año)[4] HBeAg, hepatitis B e antigen. In addition to wild-type HBV, which is usually hepatitis B e antigen (HBeAg) positive, there are 2 types of naturally occurring variants with high prevalence. Mutation in the precore region of the genome accounts for approximately 27% of HBV infections in the United States. Mutation in this region abolishes HBeAg production. Core promoter mutation results in downregulation of HBeAg production and is found in approximately 44% of US cases of HBV infection. As mentioned earlier, there are also treatment-induced mutations that can have important implications for the management of HBV infection, including YMDD, induced by lamivudine at a rate of approximately 20% per year during lamivudine therapy, as well as N236T and A181V induced by adefovir. 1. Chu CJ, et al. Hepatology. 2003;38: Chang TT, et al. J Gastroenterol Hepatol. 2004;19: Lok AS, et al. Gastroenterology. 2003;125: Hadziyannis SJ, et al. Gastroenterology. 2006;131:

7 Hepatitis B: Modos de Transmisión
A través de exposición a sangre y/ó fluidos corporales Encontrado en semen, saliva, mucosa vaginal, lágrimas pero en niveles 1000-veces menores que en suero No encontrado en orina, sudoración, o materia fecal Para infectar requiere de solución de continuidad de membrana mucosa y piel HBV, hepatitis B virus. Transmission of HBV occurs via exposure to blood and bodily fluids and requires a break in the skin or mucus membrane. The virus is found in semen, saliva, vaginal mucus, and tears, but at levels 1000-fold lower than in serum. It is not found in urine, sweat, or stool and cannot be transmitted through casual contact. 7

8 Hepatitis B: Candidatos a Screening
Personas nacidas en areas de endemicidad intermedia y alta (≥ 2% prevalencia) Hijos de inmigrantes de areas de endemicidad alta (≥ 8%; solo si no fueron vacunados al nacer) Convivientes o parejas sexuales de portadores del HBV Personas que usaron drogas EV Personas con parejas sexuales múltiples ó historia de ETS Homosexuales Internos de correccionales Individuos con ALT/AST elevadas crónicamente Individuuos infectados con HIV/HCV Pacientes en hemodialsis Pacientes previamente al inicio de tratamiento inmunosupresor Todas las mujeres embarazadas Infantes nacidos de madres portadoras HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; CHB, chronic hepatitis B. Do we need to screen everyone for HBV? No, we do not. The US Centers for Disease Control and Prevention recommend that persons born in high and intermediate endemic areas, that is, a 2% or higher HBV prevalence, need to be screened. According to these recommendations, US-born children of immigrants from high endemic areas need to undergo screening only if they were not vaccinated as infants in the United States. However, in my opinion, these children still need to be screened even if they have been vaccinated because some of them might have had transmission of the virus from the mother if the mother was a carrier. This concern is something to keep in mind. Other individuals who should be screened include: Individuals with chronically elevated alanine aminotransferase (ALT) or aspartate aminotransferase levels. Very often, fatty liver is the cause, but they must be screened because some of those people are HBV carriers. Persons who have been infected with HIV or hepatitis C virus (HCV) because they are at high risk for having HBV infection. Patients undergoing dialysis. Patients undergoing chemotherapy. If such patients have a history of infection, even if it is a silent infection or inactive disease, during immunosuppression, the virus may reactivate. Therefore, they must be screened, and if they are carriers, they may need prophylaxis with antivirals before initiating chemotherapy. All pregnant women. Infants born to HBV carrier mothers regardless of their ethnic background. Household contacts and sexual contacts of HBV carriers. Persons who have injected drugs. Persons with multiple sexual partners or a history of sexually transmitted diseases. Men who have sex with men. Inmates of correctional facilities. Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8): Lok AS, et al. Hepatology. 2009;50:

9 Hepatitis B: Candidatos a Screening Se debe hacer en individuos nacidos en áreas de prevalencia Intermedia y Alta HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen. This map shows the global nature of HBV infection. Korea, China, Indochina, and sub-Saharan Africa are all areas with a high prevalence, meaning 8% or higher, of chronic carriers of this virus. More recent statistics show that the prevalence of hepatitis B surface antigen (HBsAg) positivity in Korea has been decreasing significantly over time and is currently less than 8%.[1] However, in certain areas of China it is more than 15%[2] and in Vietnam it is easily greater than 10%.[3] References 1. Park NH, Chung YH, Lee HS. Impacts of vaccination on hepatitis B viral infections in Korea over a 25-year period. Intervirology. 2010;53:20-28. 2. Tanaka M, Katayama F, Kato H, et al. Hepatitis B and C virus infection and hepatocellular carcinoma in China: a review of epidemiology and control measures. J Epidemiol. 2011;21: 3. Nguyen VT. Hepatitis B infection in Vietnam: current issues and future challenges. Asia Pac J Public Health. 2010;[Epub ahead of print]. HBsAg Prevalencia ≥ 8% (alta) HBsAg Prevalence 2% to 7% (intermedia) < 2% (baja) Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.

10 Hepatitis B: Algoritmo de Screening
Determinar HBsAg Positivo Negativo HC x HBV* Determinar anti-HBs Negativo (No anticuerpos) Positivo (Anticuerpos presentes) HBV, hepatitis B virus. How do we screen for HBV infection? The first step is to assess HBsAg status. If it is positive, the person has hepatitis B and needs to be evaluated for possible treatment. If it is negative, assess for antibody to HBsAg (anti-HBs); if it is positive, the person has antibody-protective immunity and does not require any additional follow-up. However, if the person tests negative for anti-HBs antibody, they should be vaccinated. Evaluar para tratamiento Vacunar Inmune al HBV *Tiempo de detección de HBsAg para hacer diagnóstico de hepatitis crónica es de 6 meses. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6: 10

11 Hepatitis B: Marcadores Serológicos
HBsAg Marcador de infección crónica cuando se detecta en suero por período > 6 meses Anti-HBs Marcador de inumidad HBeAg Marcador de activa replicación viral y alta infectividad Anti-HBe Aparece en las fases de recuperación tanto como de reactivación de la enfermedad Anti-HBc Marcador de infección pasada o presente HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen. This slide lists the serologic markers of HBV infection. Hepatitis B surface antigen is a marker of chronic HBV infection when it persists in the serum for longer than 6 months. Anti-HBs is the marker of immunity, and HBeAg is the index of active viral replication and high infectivity. Antibody to HBeAg (anti-HBe) is present in the recovery phase or the reactivation phase of HBV infection that will be discussed on the next slide. Antibody to the HBV core antigen, or anti-HBc, is a marker of past or possibly current infection.

12 Hepatitis B: Determinación del HBV DNA
Indica hepatitis crónica cuando es positivo luego de 6 meses de haberse detectado la infección aguda Ayuda a diferenciar estado de portador inactivo (< 2000 IU/mL) vs infección resuelta (no detectable) vs reactivación variantes core-precore Crucial para monitorear respuesta al tratamiento Elevaciones durante el tratamiento: variantes resistentes Niveles basales elevados de HBV DNA: baja respuesta al IFN Los niveles de HBV DNA son reportados en IU/mL (standard) ó copias/mL Conversión: 1 IU/mL = ~ 5 copias/mL HBV, hepatitis B virus. HBV DNA indicates chronic hepatitis when the individual is still HBV DNA positive 6 months after diagnosis of acute infection and can help to differentiate the various phases of HBV infection. HBV DNA is the key tool for monitoring response to therapy. An increase in HBV DNA during treatment to which a patient is adherent indicates emergence of resistant variants. The standard measure of HBV DNA is international units per mL (IU/mL), but copies per mL is often cited, and an approximate conversion factor of 1 IU/mL to 5 copies/mL can be used. Adapted from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2: 12

13 HBV: Evaluación Clínica de Tests Diagnósticos
54th AASLD Annual Meeting - SHOW 10/27/03 HBV: Evaluación Clínica de Tests Diagnósticos Test HBsAg Anti-HBs Anti-HBc IgM Anti-HBc HBV DNA Infección Aguda, alta infectividad + - Recuperación de infección Inmunización Infección crónica +/- Indefinido* HBsAg, hepatitis B surface antigen. The table on this slide reviews the interpretation of diagnostic testing for HBV infection. Chronic HBV infection is characterized by HBsAg positivity and anti-HBc positivity in the presence or absence of detectable HBV DNA. A patient who has been infected with HBV but has recovered will test negative for HBsAg but positive for anti-HBs and anti-HBc. Acute HBV infection is characterized by HBsAg positivity, anti-HBc positivity, IgM anti-HBc positivity, and detectable HBV DNA. A person who has been vaccinated against HBV will test positive for anti-HBs but negative for anti-HBc and all other markers. Finally, anti-HBc positivity in the absence of any other detectable markers provides an unclear diagnosis and could reflect 1 of 4 possibilities: 1) resolved infection (most likely), 2) false-positive anti-HBc results, 3) “low level” chronic infection, or 4) resolving acute infection. In my experience, anti-HBc positivity in the absence of any other detectable markers occurs relatively frequently among Asian American patients, and the frequency of this finding increases with increasing patient age. For example, I have found isolated anti-HBc positivity in approximately 12% to 14% of patients aged 60 years or older. Most of the time, such patients probably have protective immunity, but the level of immunity is very low and cannot be detected. A very small percentage of these individuals are probably virus carriers, but, again, the level of virus is so low that this is not detectable. My approach is to vaccinate such patients and assess for the development of immunity. Some patients will develop anti-HBs, but some will not. For those who do not develop anti-HBs, we cannot be certain that they are HBV carriers. If such patients will be undergoing chemotherapy or immunomodulatory therapy, I treat them with prophylactic antiviral therapy for HBV. *4 posibildades: 1) infección resuelta (lo más probable), 2) falso-positivo, 3) infección crónica oculta, 4) en proceso de resolver infección aguda. Satellite Symposium - Boston, MA 13

14 HBV: 4 Fases de la Infección Crónica por HBV
Entendimiento actual de la evolución de la infección crónica por HBV HBeAg Anti-HBe Niveles de ALT HBV-DNA ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus. This slide reviews the different phases of HBV infection. Of course, not all HBV carriers will move through these 4 phases uniformly. The first phase of infection is the immune-tolerance phase where the level of HBV DNA is very high because it is the phase when the virus replicates very rapidly and significantly, although the alanine aminotransferase (ALT) is quite normal. Typically, these patients will not complain of any symptoms and will have normal liver function tests. This can be followed by an immune-clearance phase. In this phase of the infection, the virus and the host immune system are at odds, resulting in the ALT fluctuating up and down or remaining high, and the HBV DNA can also fluctuate, but at a fairly high level. This can be followed by an inactive carrier state in which both HBV DNA levels and ALT levels come down to near-normal levels. If a liver biopsy were performed, in this phase, the liver could either be normal or there may be minimal inflammation and fibrosis. These individuals can then experience HBV reactivation, when the HBV DNA and ALT levels again rise, and the patient can be quite symptomatic. The ideal times for treatment or intervention with antiviral drugs are during the phases of high HBV DNA and ALT levels when active inflammation is occurring. Fase Immuno Tolerante Clearance Immune Portador crónico Inactivo Reactivación Hígado Inflamación y fibrosis mínimas Inflamación crónica activa Hepatitis y fibrosis leve Inflamación activa Momento ideal de terapia Yim HJ, et al. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in Hepatology. 2006;43:S173-S181. Copyright © 1999–2012 John Wiley & Sons, Inc. All Rights Reserved.

15 Hepatitis Crónica B HBeAg (-) y sus Diferencias con el Portador Inactivo
Status HBV crónica HBeAg (-) Portador Inactivo HBsAg positivo  Anti-HBe positivo Anti-HBc positivo HBV DNA Niveles fluctuantes de HBV DNA > 2000 IU/mL Niveles de HVB DNA bajos o indetectables < 2000 IU/mL ALT Elevadas, fluctuantes Normal ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen. This slide provides information on how to differentiate between HBeAg-negative chronic hepatitis B and the inactive carrier state. Patients in both phases will be HBsAg positive, anti-HBe positive, and anti-HBc positive; however, HBV DNA levels and ALT levels will differ between the 2 phases. Patients with HBeAg-negative disease will have moderate, often fluctuating serum HBV DNA levels, generally higher than 2000 IU/mL, whereas patients in the inactive carrier state will have low (< 2000 IU/mL) or undetectable serum HBV DNA levels. Likewise, ALT levels will be elevated and often fluctuating in patients with HBeAg-negative chronic HBV infection, whereas patients in the inactive carrier state will have normal ALT levels. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:

16 Hepatitis B: El Estado de Portador Crónico tiene una Fase Dinámica
54th AASLD Annual Meeting - SHOW 10/27/03 Hepatitis B: El Estado de Portador Crónico tiene una Fase Dinámica Después de seroconversión espontánea del HBeAg , sólo el 67% al 80% de los portadores crónicos se mantiene en ésa fase Inmunotolerante Portador Inactivo (No portador sano !!) HCB HBeAg (-) 4% a 20% de los portadores inactivos revierten su estado a HBeAg positivos nuevamente 10% a 20% tiene reactivación luego de años de enfermedad quiescente CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen. It is important to understand that the inactive carrier phase of HBV infection is not static but is instead dynamic. For example, although 67% to 80% of patients who are in the inactive carrier phase remain in this state, 4% to 20% may revert to the immune-tolerant phase, and 10% to 20% may advance to reactivated HBeAg-negative chronic hepatitis B, underscoring that this phase should not be considered a healthy carrier state. When we see patients, it is very difficult to predict who is going to remain in the inactive carrier state and who will revert or advance. Therefore, serial testing is necessary during the inactive carrier state. Seguimiento y testeo serial es imprescindible durante el estadío de “portador inactivo” Lok AS, et al. Hepatology. 2009;50: Satellite Symposium - Boston, MA 16

17 Hepatitis B: Progresión de la Hepatopatía
54th AASLD Annual Meeting - SHOW 10/27/03 Hepatitis B: Progresión de la Hepatopatía HCC 30% de los infectados crónicos[2] Infección Aguda Infección Crónica Cirrosis Trasplante Muerte > 90% de los infantes progresan a HC de los adultos inmunocopententes progresan a HC[1] Once a person becomes infected with HBV, how does the disease progress? Do all infected individuals become chronic carriers? Once they become chronic carriers, do they all develop cirrhosis? Do they all develop liver cancer? The answer to these questions is no, but depending on when one becomes infected, the rate of progression to chronic infection varies. More than 90% of infected infants progress to chronic disease, whereas less than 5% of infected immunocompetent adults progress to chronic disease. Once chronic infection develops, up to 30% will eventually develop liver cirrhosis, which can then progress to liver cancer or liver failure. An interesting feature of chronic HBV infection is that some people may bypass the cirrhotic phase and develop liver cancer without ever having cirrhosis. This characteristic differentiates this disease from hepatitis C, which is an RNA virus that can lead to liver cirrhosis from which liver cancer develops. Hepatitis B is a DNA virus, and it acts as a direct carcinogen that causes liver cancer. For this reason, chronic carriers of the virus need to be screened for liver cancer even at younger ages. Descompensación hepática La infección crónica por HBV es la 6ta causa de trasplante en USA[4] 23% de los pacientes se descompensan dentro de los 5 años del diagnóstico de cirrosis[3] 1. CDC. HBV FAQs for health professionals. 2. Torresi J, et al. Gastroenterology. 2000;118(2 suppl 1):S83-S Fattovich G, et al. Hepatology. 1995;21: Seaberg EC, et al. Clin Transpl. 1998:17-37. Satellite Symposium - Boston, MA 17

18 54th AASLD Annual Meeting - SHOW
10/27/03 Hepatitis B: Evolución de la Infección en Función de la Edad de la Infección 100 100 Predominantemente en adultos en países occidentales 90% 80 80 Predominantemente en infección neonatal en Asia 60 60 Infección sintomática autolimitada (%) Infección crónica (%) 40 40 HBV, hepatitis B virus. The graph on this slide shows the chronic infection rate (green line) and the rate of symptomatic infection (orange line) according to the age of HBV transmission. As noted on the previous slide, 90% of individuals who are infected at the time of birth, which is the predominant timing of transmission in Asia, end up becoming chronic carriers. Individuals infected at age 20 years or older, however, have a less than 5% likelihood of becoming a chronic carrier. In Western countries, transmission predominantly occurs during adulthood. The rate of symptomatic infection follows an opposite pattern in that those who are infected at an early age generally have no symptoms, and the likelihood of symptomatic infection increases with the age of transmission. 25% al 30% 20 Infección crónica Infección autolimitada 20 < 5% RN 1-6 Meses 7-12 Meses 1-4 Años Adolescentes y Adultos Stanford Asian Liver Center physician’s guide to hepatitis B: a silent killer. Satellite Symposium - Boston, MA 18

19 Diferencias Epidemiológicas y Clínicas de Acuerdo al Area Geográfica
Caracteristicas Asia/Africa Sub-Sahara USA/UE Endemicidad Alta Baja Edad de Infección RN, toddler Adulto joven Modo primario de transmisión Perinatal, horizontal Percutaneo, sexual Cronicidad Común Rara Riesgo de cirrosis Alto Bajo Riesgo de HCC HCC, hepatocellular carcinoma. This shows geographic differences in the epidemiologic and clinical characteristics of HBV infection. The most common timing of infection among highly endemic regions such as Asia and sub-Saharan Africa is at birth or while a toddler, and the primary modes of transmission are perinatal and horizontal. Chronicity is very common and the risk of cirrhosis and liver cancer in these populations is much higher than, for example, North American and Western European populations. Mast EE, et al. MMWR Recomm Rep. 2006;55:1-33. Custer B, et al. J Clin Gastroenterol. 2004;38(10 suppl):S158-S168.

20 HBV: Factores Determinantes de Progresión Factores del Medio Ambiente
Factores del Huésped Mayor edad Género masculino Raza Via de contagio Co-infeccíón con HDV, HCV ó HIV, NASH Factores del Medio Ambiente Alcohol Tabaco Aflatoxinas Factores del Huésped Alta carga viral basal Genotipos C,D,F Variantes mutantes del core-precore McMahon BJ. Hepatology 2009;49:S45-S55.

21 Incidencia acumulativa de HCC al final de 13 años (%)
Hepatitis B: Alta Carga Viral basal, uno de los factores de riesgo para desarrollo de HCC REVEAL estudio de cohorte longitudinal (3653 pacientes HBsAg +): Incidencia acumulativa de HCC luego de seguimiento de 13 años en relación al HBV DNA basal 50 40 30 20 10 1.30 1.37 3.57 12.17 14.89 <300 300 to <104 104 a <105 105 a <106 ≥106 HBV DNA basal (copias/mL) Incidencia acumulativa de HCC al final de 13 años (%) Chen CJ, et al. JAMA 2006;295:65–73. 21

22 Cuando empezar tratamiento de la HBV?
Beneficios Riesgos Eventos adversos Resistencia a las Drogas Chances de: Progresión sin tratamiento Respuesta en el largo plazo Edad, y preferencia del paciente y costos HBV, hepatitis B virus; HCC, hepatocellular carcinoma. The determination of whether to initiate HBV therapy requires weighing the benefits against the risks. The key risks include the potential for adverse effects of the drug and development of drug resistance. By contrast, immediate benefits of the antiviral treatment would be suppression of HBV DNA and, hopefully, normalization of ALT and liver function. Long-term benefits could include prevention of liver cirrhosis from this chronic infection and possibly the prevention of hepatoma. So, we have to really consider the likelihood of adverse outcome without treatments and the potential for treatment to prevent them. Individually, we must consider the risk of cirrhosis and HCC in the patient in the next years. Chances de progresión sin tratamiento Actividad y estadío de la hepatopatía al momento de la presentación Riesgo de cirrosis/HCC en los próximos años Chances de beneficio en el largo plazo con el tratamiento

23 Objetivos de Tratamiento de HBV
Prevenir la necesidad de trasplante, de muerte por Cirrosis, y de HCC... Como conseguir ese objetivo? Supresión De DNA-HBV Normalización de ALT Mejora histológica Seroconversión de HBeAg / HBsAg del DNA-HBV

24 Que información necesitamos para determinar necesidad de tratamiento?
HBeAg ALT HBV DNA Histología Historia Familiar? Otros factores pronósticos: edad, género, raza ? ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV hepatitis B virus. What are the key pieces of information needed to determine HBV treatment candidacy? These include HBeAg status, ALT level, HBV DNA level, and liver histology. Family history is not easily quantifiable but is also of interest. Collectively, these are the factors that we have to learn about in detail before we counsel the patient on their need for treatment. We can review each of these individually.

25 Conveniencia de Histología
Biopsia Hepática: Establece estadío antes de inicar tratamiento Ayuda a excluir otras causas de enfermedad hepática Más sensible y específico que el nivore sensitive and acl de ALT Puede ser considerada necesaria para definir el diagnóstico de hepatitis crónica Limitaciones Invasiva Errores de muestra Variabilidad inter-observador ALT, alanine aminotransferase. Liver biopsy is considered the gold standard for evaluating histology; it can establish disease baseline before initiation of therapy and is more sensitive and specific than ALT at accomplishing this. Biopsy results can also be used to help exclude other causes of liver disease. Biopsy may be considered in patients who meet the criteria for chronic hepatitis. However, it has limitations, including the invasive nature, the potential for sampling errors, and some intraobserver variability.

26 Tratamiento de la Hepatitis Crónica B
Guias* HBeAg Positivo HBeAg Negativo HBV DNA, IU/mL ALT EASL 2012[1] > 2000 > VN† ALEH 2011[3] AASLD 2009[2] > 20,000 ≥ 2 x VN o (+) biopsia ≥ 2, ,000 PBH: A2 / F2. Todos los criterios (HBV DNA, ALT e histología) deben reunirse. 1. EASL. J Hepatol. 2012; in press. 2. Lok et al. Hepatology. 2009; 3. Gadano et al. Acta Gastro 2011 26

27 HBV: Otras poblaciones a tratar
Independientemente de HBV DNA y ALT Rápido deterioro de la función hepática. Cirrosis compensada: DNA > 2,000 IU/mL (AASLD) DNA detectable (EASL, ALEH) Cirrosis descompensada (DNA detectable) Portadores de HBV sometidos a tratamiento inmunosupresor Recurrencia post-trasplante. 1. EASL. J Hepatol. 2012; in press. 2. Lok et al. Hepatology. 2009; 3. Gadano et al. Acta Gastro 2011 27

28 A quien tratar ? No es una pregunta a quién tratar y a quién no. Sino cuando tratar,…… si monitorear ahora y tratar después. Todos los portadores crónicos son eventuales candidatos a recibir tratamiento en algún momento en base a: Cambios en el stautus de replicación/actividad/estadío Recordar que los mismos suelen ser dinámicos a lo largo del tiempo Acceso a terapias novedosas que optimicen el tratamiento actual HBV, hepatitis B virus. To summarize, all HBV carriers are potential treatment candidates, and the key question becomes when to treat. A patient who is not a treatment candidate right now can be a treatment candidate in the future because of changes in the level of HBV DNA, ALT, and/or the activity of disease as seen from liver histology. In addition, if new and improved treatments become available, it may alter whom we consider to be treatment candidates.

29 Disminución de la Replicación: Beneficios
Histología antes del tto. Histología tras 3a. c/ NA Regresión de la fibrosis Schiff, AASLD 2000 Schiff, DDW 2009 Placebo n=215 Lamivudina n=436 5 10 15 20 25 % HCC Años de tratamento 1 2 3 Disminución del riesgo de HCC Liaw et al, N. Engl. J. Med. 2004 Años de seguimiento 1.0 0.8 0.6 0.4 0.2 2 3 4 5 6 7 1 Aumento de la sobrevida HBeAg (+) 8 10 12 14 HBeAg (-) Niederau et al, 1996 Papatheodoridis et al, 2001

30 Hepatitis B: Tratamientos Aprobados
Schering-Plough PPT Template 4/1/2017 8:17 AM Hepatitis B: Tratamientos Aprobados Peginterferon alfa-2a Entecavir Lamivudine Tenofovir 1990 1998 2002 2005 2006 2008 Interferon alfa-2b Adefovir Telbivudine *Aprobados por FDA y EMEA 30

31 2013: Fármacos aprobados contra HBV
2 tipos de interferon- 5 tipos de análogos Lamivudina Entecavir Telbivudina Adefovir Tenofovir IFN convencional IFN peguilado Nucleosídos Nucleotídos 31

32 Schering-Plough PPT Template
4/1/2017 8:17 AM PEG-IFN. Seroconversión del HBeAg después de fin de tratamiento (Sem 48) 100 90 Seguimiento (Semana 72) 80 70 60 P < .001 Seroconversión HBeAg (%) 50 P = .023 40 32 30 27 19 20 10 PegIFN (n = 271) PegIFN + LAM (n = 271) LAM (n = 272) Seroconversión HBsAg : 3% grupo pegIFN / 0% grupo LAM (P = .001) Lau GK, et al. N Engl J Med. 2005;352: 32

33 Supresión viral en pacientes HBeAg-neg post-tratamiento con PegIFN-2a ± LAM
100 90 80 70 60 Pacientes con HBV DNA ≤ 400 copias/mL (%)* 50 40 30 18 17 20 13 13 10 1 2 3 4 Años posteriores a la finalización del tratamiento *~ 80 IU/mL, los datos perdidos se consideran pacientes no respondedores Marcellin P, et al. AASLD Abstract Marcellin P, et al. EASL Abstract 53. Marcellin P, et al. EASL Abstract 103.

34 Predictores de respuesta a IFN
Basal Intra-Tratamiento Edad Bajo nivel de HBV DNA ALT basal > 2-3 LSN Actividad inflamatoria +++ Genotipo A o F (?) Sin cirrosis, sin HIV IL28b ? ALT flares Niveles de HBV DNA HBeAg cuantitativo HBsAg cuantitativo

35 Respuesta 6 meses post-tto de acuerdo a HBsAg en Sem 12
Peg-IFN: Niveles de HBsAg en Sem 12 asociados a respuesta virológica en HBeAg+ Respuesta 6 meses post-tto de acuerdo a HBsAg en Sem 12 The NEPTUNE study showed that the highest rate of HBeAg seroconversion 6 months post-treatment was achieved with the licensed regimen of peginterferon alfa-2a (PEG-IFNα-2a) (180 µg for 48 weeks; 36.2%). We investigated the association of sustained response with on-treatment HBsAg levels, which has been identified as being predictive of response in the phase 3 study of PEG-IFNα-2a. Methods: HBeAg-positive patients receiving PEG-IFNα-2a (180 µg for 48 weeks) during NEPTUNE (with HBsAg data available at baseline and weeks 12, 24 and 48 of treatment) were included. HBsAg was quantified using the Elecsys HBsAg II quant assay. Rates of sustained response were assessed according to HBsAg cut-off levels at week 12 and week 24 identified in analysis of the phase 3 study (< 1500, ,000 and >20,000 IU/mL). Results: Of 114 patients with available HBsAg data, 37.6% achieved HBeAg seroconversion 6 months post-treatment. On-treatment HBsAg decline from baseline was more pronounced in these patients (-1.34 log10 IU/mL at week 48) than in non-responders (-0.61 log10 IU/mL at week 48). HBsAg < 1500 IU/mL was reached by 27% and 40% of patients at weeks 12 and 24, respectively, and was associated with highest rates of sustained response (table). Patients with HBsAg >20,000 IU/mL at weeks 12 or 24 did not achieve sustained response. Conclusions: This study confirmed the association between on-treatment HBsAg levels and sustained response, validating positive predictive values for HBsAg < 1500 and < 20,000 IU/mL. Patients with HBsAg levels >20,000 IU/mL by week 12 or 24 are unlikely to achieve sustained response with 48 weeks of PEG-IFNα-2a and may be considered for discontinuation of therapy. NEPTUNE, Gane E. 46th EASL 2011 35

36 Buena respuesta en sem 12-24
Tratamiento de Hepatitis B con PegIFN La determinación cuantitativa de HBsAg en semana 12 es una herramienta para predecir respuesta Pobre respuesta en sem 12 Buena respuesta en sem 12-24 Interrumpir tto Continuar tto Lij-Yuen Chan J Hepatol 2011

37 Elementos centrales en la elección de Análogos de Nucleos(t)idos
Potencia Barrera genética 37

38 Carga viral Drogas antivirales Espacio extracelular Hepatocito
Persistencia viral Reactivación Recaída post -AN cccDNA Reparación Transcripción Denudamiento viral HBV se une a los receptores de membrana y penetra en la celula Drogas antivirales Traducción en proteínas Espacio extracelular Hepatocito Ensamblaje del core y empaqueta miento del RNA Carga viral HBV Replication Pathway HBV virus replication takes place predominantly in hepatocytes and to a lesser extent in stem cells in the pancreas, bone marrow, and spleen. Viral replication consists of a number of complex phases: The uncoated virion enters the host cell and its genome is delivered to the cell nucleus. It is here that the viral genome is converted to covalently closed circular (ccc) DNA – a minichromosome that serves as the viral transcription template. Using this template, RNA is translated to yield viral proteins. Additionally, the 3.5-kb RNA acts as a pregenomic template for the reverse transcription to negative-strand DNA. In turn, the negative-strand DNA becomes the template for the transcription of positive-strand DNA. Nucleocapsid and envelope proteins assemble around the viral genome, forming capsids that bud from the cell membrane. Clinically, the reverse transcription phase is important since some antiretroviral drugs (originally developed for treatment of HIV) also are effective against HBV and are currently used to treat chronic hepatitis B. Replication is also clinically important because the enzyme responsible for transcription (the HBV polymerase) has low replication fidelity. The low fidelity can cause mutations that give rise to variant strains of the virus. This development can present a problem during ongoing drug therapy if the new variants are resistant to the drug. Therefore, preventing HBV replication as much as possible should result in a reduced probability of mutagensis and a decreased rate of patients developing drug-resistant HBV strains. It should be noted that the existence of multiple genotypes adds to the complexity of HBV. Ganem D, Prince AM. Hepatitis B virus infection--natural history and clinical consequences. N Engl J Med Mar 11;350(11): Síntesis de DNA – por TR Ensamblaje de la nucleocápsode y de la envoltura Síntesis de DNA + por polimerasa 38

39 Los Análogos de Nucleós(t)idos (AN) disminuyen la incidencia de HCC
Incidencia acumulativa de HCC (%) 100 NA treatment (+) n = 117 NA treatment (-) n = 117 80 Of the 117 patients receiving NA therapy: 18 con LAM 28 con LAM y ADV 71 con ETV† 60 40 20 1 2 3 4 5 6 7 8 9 10 Tratamiento: Años NA(+) 117 117 115 108 96 77 56 32 16 10 7 NA(-) 117 117 115 111 106 100 85 73 67 54 47 En 234 pacientes Japoneses con HBV: La tasa de HCC fue mayor en el grupo de no tratados (p = ) †ETV no esta indicada para la prevención de HCC en pacientes con Hepatitis Crónica por HBV Kumada T, et al. J. Hepatology 2013:58;427–33.

40 HBV DNA indetectable* luego de un año de tratamiento
Schering-Plough PPT Template 4/1/2017 8:17 AM HBV DNA indetectable* luego de un año de tratamiento No son estudios head-to-head; diferencias en las poblaciones de los pacientes y en el diseño de los estudios HBeAg Positivo HBeAg Negativo 100 100 90 91 88 76 80 80 67 60 60-73 60 60 51-63 HBV DNA indetectable *(%) 40-44 40 40 ADV, adefovir; ETV, entecavir; LAM, lamivudine; LdT, telbivudine; TDF, tenofovir. 20 20 13-21 LAM ADV ETV LdT TDF LAM ADV ETV LdT TDF *By PCR-based assay (LLD ~ 50 IU/mL) except for some LAM studies. Lok A, et al. Hepatology. 2007;45: EASL HBV Guidelines. Journal of Hepatology. 2009;50: 40

41 Pilares de tratamiento exitoso con AN
EASL Clinical Practice Guidelines: Entecavir y tenofovir son potentes inhibidores del HBV-DNA con alta barrera genética a la resistencia. Por lo tanto pueden ser utilizados con confidencia como terapia de 1st línea (A1).1 Alta potencia para obtenr máxima supresión viral Alta barrera genética para la resistencia Perfil de seguridad favorable para tratamientos extendidos Adherencia 1. EASL Clinical Practice Guidelines: J Hepatol 2012;57:167–85. 41

42 ETV y TDF son efectivos en estudios de la vida real en pacientes NUC-naive
2,903 pacientes tratados con ETV en estudos de la vida real por un máximo de 60 meses1-6 670 pacientes tratados con TDV en 3 estudios de la vida real por un total de 42 meses7-9 1. Buti M, et al. Eur J Gastroenterol Hepatol 2012;24:535– Zoutendijk R, et al. Hepatology 2011;54:443– Hou J, et al. AASLD 2012, poster Lampertico P, et al. AASLD 2012, poster Mete B, et al. AASLD 2012, poster Seto WK, et al. EASL 2011, poster Lampertico P, et al. AASLD 2012, poster Marcellin P, et al. EASL 2012, poster Petersen J, et al. EASL 2012, poster 537. 42

43 Pacientes en seguimiento
Cohorte Italiana con ETV: 100% de los pacientes naive obtuvieron HBV-DNA no detectable a los 60 meses Estudio prospectivo de la vida real, evaluando seguridad y eficacia a los 5 años de ETV en pacientes NUC-naive Resistencia Sólo un paciente (0.2%) desarrollo resistencia Seguridad Buena en generale Renal: solo dos pacientes tuvieron que reducir la dosis de ETV debido a caída del eGFR † Meses 405 418 391 Pacientes en seguimiento 344 307 259 97 * HBV-DNA no detectable † Una mujer de 78 años con AH y un varón de 48- años con trasplante renal y cirrosis compensada Adapted from Lampertico P, et al. AASLD 2012, poster 366. Available at lampertico.entecavir.treatment.for.nuc.na.field.practice.patients.with.html?history_id= [Accessed April 2013]. 43

44 Baseline characteristics
Cohorte Italiana con ETV: sobrevida libre de complicaciones en pacientes con cirrosis compensada Libres de descompensación 100% 86% Libre de HCC Baseline characteristics (418 NUC-naive patients): Median (range) age: 58 (18 – 82) Cirrhosis: 49% Concomitant diseases: 56% HBeAg(-)ve: 83% Tasa de descompensación/año: 0% Tasa de HCC /año: 2.8% Complication-free survivlal* (%) *Kaplan–Meier estimates. Months Patients at risk 155 153 149 145 135 125 115 105 92 58 20 Adapted from Lampertico P, et al. AASLD 2012, Boston, MA. Poster 366. Available at lampertico.entecavir.treatment.for.nuc.na.field.practice.patients.with.html?history_id= [Accessed April 2013]

45 Cohorte Italiana con ETV: Sobrevida Global y relacionada a hepatica en pacientes con cirrosis compensada Sobrevida relacionada a hepatopatía* 95% 91% Sobrevida Global* Muertes por HCC: 2 pacientes OLT por HCC: 4 pacientes Sobrevida (%) *Kaplan–Meier estimates. OLT = death. Meses Pacientes en riesgo 155 154 151 147 142 133 124 111 98 61 21 Adapted from Lampertico P, et al. AASLD 2012, Boston, MA. Poster 366. Available at lampertico.entecavir.treatment.for.nuc.na.field.practice.patients.with.html?history_id= [Accessed April 2013]

46 Cohorte Europea con TDF: 97% de los pacientes naive obtuvieron HBV-DNA negativo a los 42 meses
Resistencia Ningún caso de resistencia a la semana 962 Seguridad 13 (4%) pacientes redujeron la dosis de TDF por eventos renales† 3 (1%) paciente D/C TDF por complicaciones renales‡ 7 (2%) pacientes D&C TDF por EAS no- renales Meses Pacientes en seguimiento 271 273 249 162 94 * HBV-DNA no detectable † Caída del eGFR decline en 11, bajo fósforo en dos ‡ Caída del eGFR decline en dos, bajo fósforo en uno 1. Adapted from Lampertico P, et al. AASLD 2012, poster 401. Available at /pietro.lampertico.tenofovir.monotherapy.suppressed.viral.suppression.in.most.html?history_id= [Accessed April 2013]. 2. Lampertico P, et al. Curr Hepatitis Rep 2012;11:90–4. 46

47 Hepatitis B: La terapia prolongada con ETV mejora el estadío de fibrosis
Ishak Fibrosis Score Número de pacientes N = 57 NUC-naive HBeAg(+) y HBeAg(-) de estudios fase 3 Biopsia hepatica en una mediana de 6 años post ETV (rango 3 – 7 años) 88% de los pacientes tuvieron regresión de la fibrosis†, incluyendo 10/57 con fibrosis avanzada o cirrosis (Ishak score ≥ 4) al inicio de la terapia † ≥1-punto en la caída del score de fibrosis de Ishak Adapted from Chang TT, et al. Hepatology 2010;52:886–93. 47

48 Regresión de la cirrosis a los 5 años de ETV
F4 F4 F2 Chang TT, et al. Hepatology 2010;52:

49 Pacientes con cirrosis compensada (n = 89) y descompensada (n = 9)
VIRGIL: La respuesta al ETV se asocia a menor probabilidad de progresión a cirrosis * Eventos: descompensación, HCC ó muerte Pacientes con cirrosis compensada (n = 89) y descompensada (n = 9) 100 80 60 Probabildad del evento* % No virological response 40 Paciente cirróticos recibieron previamente ADV: 31% LAM: 34% p = 0.04 20 Virological response** 48 96 144 Tiempo en semanas **VR defined as HBV-DNA <80 IU/mL. Adapted from Zoutendijk R, et al. Gut 2013;62:760–5.

50 Resumen El ETV y TDF demonstraron una alta tasa de respuesta virológica en pacientes tratados hasta 5 años en estudios de la “vida real”1,2,3 La terapia prolongada con NUC (ETV y TDF) resultó en regresión de la fibrosis4,5 La respuesta virologica está asociada a menores chances de progresión6 En pacientes con cirrosis la supresión en el largo plazo del HBV DNA previene la descompensación y no necesariamente el desarrollo de HCC2 El tratamiento con ETV † reduce la incidencia de HCC comparativamente con los pacientes no tratados7 †ETV no está indicado para prevenir HCC 1. EASL Clinical Practice Guidelines: J Hepatol 2012;57:167– Lampertico P, et al. AASLD 2012, poster Lampertico P, et al. AASLD 2012, poster Chang TT, et al. Hepatology 2010;52:886– Marcellin P, et al. Lancet 2013;381:468– Zoutendijk R, et al. Gut 2013;62:760–5. 7. Hosaka T, et al. Hepatology, 2013 [Epub ahead of print].

51 Vigilancia de HCC en Pacientes con HBV Crónica: Recomendaciones AASLD
Asiáticos varones mayores de 40 años Asiáticos mujeres mayores de 50 años Pacientes con: Cirrosis Historia amiliar de HCC Afroamericanos Aquellos con co-infección con HCV ó HIV, presencia de otra hepatopatía (Fe/NASH), y aquellos con alta carga viral basal AASLD, American Association for the Study of Liver Diseases; HCC, hepatocellular carcinoma; HCV, hepatitis C virus. The American Association for the Study of Liver Diseases recommends HCC surveillance with ultrasound and/or alpha fetoprotein as appropriate for the following persons: Asian men older than 40 years of age Asian women older than 50 years of age Patients with cirrhosis Patients with a family history of HCC African/North American blacks Those with other risk factors such as high HBV DNA, coinfection with HCV or HIV, or presence of other liver disease However, in my practice, we do not restrict HCC screening of Asian patients to those older than a certain age because there are many people younger than these age ranges who develop serious problems. Bruix J, et al. Hepatology. 2011;53:

52 Incidencia de HBV Aguda en EEUU y Relación con la Vacuna (1982-2006)
Vacunación universal de infantes recomendada en 1991 Declinanción de incidencia del 80% 14 Vacunación universal de infantes 12 10 8 Incidencia* 6 HBV, hepatitis B virus; HCC, hepatocellular carcinoma. Vaccination plays a key role in decreasing the burden of the disease. Universal vaccination of infants was started in the United States in The graph on this slide shows that the incidence of acute HBV infection has decreased by 80% in approximately 15 years since universal infant vaccination began. This pattern shows the efficacy of vaccination. 4 2 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 Año *Per 100,000 popblación Wasley A, et al. MMWR Surveill Summ. 2008;57(SS-2):1-24.

53 Impacto de la Vacuna del HBV en la Incidencia de HCC y Mortalidad*
1.0 1.0 0.80 0.8 0.8 0.70 0.57 0.58 0.6 0.6 Per 100,000 niños (6-14 años) Per 100,000 niños (6-14 años) 0.4 0.36 0.4 0.34 HBV, hepatitis B virus. This slide depicts data from Taiwan examining cases of pediatric HCC. The HBV vaccine became available in 1982, and in Taiwan, universal vaccination was implemented in July 1984. From that time, the incidence of HCC cases among children aged 6-14 years decreased by 50% in only 10 years; the pattern is similar for HCC mortality. These data demonstrate the strong benefit of HBV vaccination on clinical outcomes. 0.2 0.2 Tiempo-período Tiempo-período *Nationwide vaccination in Taiwan, implemented July 1984. Chang MH, et al. N Engl J Med. 1997;336:

54 La Vacunación es la mejor estrategia para prevenir la infección por hbv y sus complicaciones

55 Muchas Gracias!!