Actualización en Hepatitis B Manejo de la resistencia de drogas antivirales Dr. Ezequiel Ridruejo. -Centro de Educación Médica e Investigaciones Clínicas.

Presentación del tema: "Actualización en Hepatitis B Manejo de la resistencia de drogas antivirales Dr. Ezequiel Ridruejo. -Centro de Educación Médica e Investigaciones Clínicas."— Transcripción de la presentación:

1 Actualización en Hepatitis B Manejo de la resistencia de drogas antivirales
Dr. Ezequiel Ridruejo. -Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno “CEMIC” -Hospital Universitario Austral 21º Reunión Anual de Unidades Centinela 15 de Octubre de 2012

2 Manejo de la resistencia de drogas antivirales
Definición Situación Prevención Recomendaciones de Tratamiento LAM-R AVD-R ETV-R

3 Objetivos de Tratamiento de la Hepatitis B
Prevención de las complicaciones clínicas a largo plazo (ej, cirrosis, HCC, muerte) supresión duradera del HBV DNA Remisión de la enfermedad hepática Objetivo primario del tratamiento Reducción sostenida del HBV DNA a niveles bajos o indetectable Objetivos secundarios del tratamiento Disminución o normalización de ALT Pérdida o seroconversión HBeAg Pérdida o seroconversión HBsAg Mejoría de la histología hepática ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma. The ultimate goal of hepatitis B treatment is to prevent long-term negative clinical outcomes such as cirrhosis and liver cancer in patients with chronic hepatitis B. Treatment aims to reduce morbidity and mortality from hepatitis B by maintaining durable suppression of hepatitis B viral DNA. Remission of existing liver disease is a further goal of therapy in some patients. The primary treatment endpoint used to define optimal activity is a sustained decrease in serum HBV DNA to low or undetectable levels. The multiple secondary treatment endpoints include Decreasing or normalizing serum alanine aminotransferase (ALT), a marker of hepatic inflammation Loss or seroconversion of hepatitis B e antigen (HBeAg) Loss or seroconversion of hepatitis B surface antigen (HBsAg) Improvement in liver histology All of these goals can be measured in routine clinical practice. 3 3

4 Definiciones de Resistencia Antiviral a NUC
Término Definición BreakthroughVirológico ↑ HBV DNA por 1 log10 (10-veces) por encima del nadir luego de alcanzar respuesta virológica , con tto continuo Rebote Virológico ↑ HBV DNA a > 20,000 IU/mL o encima de niveles pre-tto luego de alcanzar respuesta virológica , con tto continuo BreakthroughBioquímico ↑ ALT por encima del LSN luego de alcanzar normalización, con tto continuo Resistencia Genotípica Detección de mutaciones en estudios in vitro que confieren resistencia al NUC administrado Resistencia Fenotípica Confirmación in vitro que la mutación detectada disminuye la susceptibilidad (demostrada por un aumento en las concentraciones inhibitorias) al NUC administrado Manifestaciones de Resistencia Antiviral Rebote Virológico 8 Flare de Hepatitis 6 Breakthrough Virológico HBV DNA (log10 UI/mL) ALT (U/L) 4 Resistencia Genotípica Breakthrough Bioquímico LSN ALT, alanine aminotransferase; HBV, hepatitis B virus; NA, nucleos(t)ide analogue; ULN, upper limit of normal. Virologic breakthrough is defined as an increase in HBV DNA > 1 log10 IU/mL above the nadir in a patient who has already achieved a virologic response. Viral rebound is defined as an increase in HBV DNA to > 20,000 IU/mL or above the pretreatment level after achieving a virologic response on continued treatment. Both virologic breakthrough and virologic rebound may be associated with biochemical breakthrough. Here, there is an associated increase in ALT to a level above the upper limits of normal after achieving normalization during continued treatment. Genotypic resistance refers to the detection of mutations that are known to confer resistance to particular oral agents. Phenotypic resistance is a decrease in drug susceptibility, as determined by tests that show that the agent is no longer able to inhibit viral replication. 2 -1 1 2 3 Años Lok AS, et al. Hepatology. 2009;50:

5 Consecuencias de Resistencia Antiviral en Hepatitis B Crónica
Resultado Descripción Virológico Reducción tasas de seroconversión HBeAg[1] Breakthrough virológico y el rebote[2] Bioquímico Breakthrough bioquímico [2] Histológico Progresión histológica de la enfermedad [2,3] Clínica Flare hepatitis y descompensación [4,5] Recurrencia post trasplante [6] Salud Publica Desarrollo poblacion HBV multi-resistente Transmisión de HBV resistente [7] Alteración en HBsAg, potencial fallo de vacuna [8] 1. Leung NW, et al. Hepatology. 2001;33: Dienstag JL, et al. Gastroenterology. 2003;124: Liaw YF, et al. N Engl J Med. 2004;351: Yuen MF, et al. J Hepatol. 2003;39: Nafa S, et al. Hepatology. 2000;32: 6. Mutimer D, et al. Gut. 2000;46: Thibault V, et al. AIDS. 2002;16: 8. Torresi J, et al. Virology. 2002;293:

6 Prevención y Monitoreo de la Resistencia
Evitar tratamiento innecesario Usar antiviral potente que tenga baja tasa de resistencia Cambiar a otro tratamiento en los pacientes que no tengan respuesta primaria Monitoreo Control HBV DNA (PCR) cada 3-6 meses durante el tratamiento Controlar la compliance con la medicación en pacientes breakthrough virológico ¿Confirmar la resistencia antiviral con análisis genotípico? HBV, hepatitis B virus; PCR, polymerase chain reaction Resistance monitoring is an important element in the care of patients receiving oral nucleos(t)ide analogues. Risk of resistance can be reduced by avoiding the unnecessary use of treatment in patients who do not require therapy. Oral agents associated with low rates of drug resistance are preferred. Alternatively, drugs should be used in combination. Finally, switching to an alternative therapy should be considered in patients with primary nonresponse, that is, failure, to reduce HBV DNA by > 2 log10 IU/mL at 24 weeks. Patients on treatment should have serum HBV DNA evaluated by PCR every 3-6 months. Patients who experience virologic breakthrough or relapse should be counseled about medication compliance. If virologic breakthrough or relapse is confirmed, the patient will also require genotypic testing. Lok AS, et al. Hepatology. 2009;50:

7 Evolución del Tratamiento HBV
Schering-Plough PPT Template 4/12/2017 6:59 AM Evolución del Tratamiento HBV Peg-Interferón alfa-2a/b Entecavir Lamivudina Tenofovir 1990 1998 2002 2005 2006 2008 Interferón alfa-2b Adefovir Telbivudina HBV, hepatitis B virus. The hepatitis B treatment landscape is changing. In the early 1990s, the only treatment available for HBV was interferon alfa-2b. This agent was given for a short period, and only a few patients responded to treatment. In 1998, the first oral nucleoside analogue, lamivudine, was introduced, followed fairly rapidly by the nucleotide analogue adefovir. Standard interferon alfa-2b was then replaced by peginterferon alfa-2a, which was administered via once-weekly injections as opposed to daily treatment. Other nucleoside and nucleotide analogues, that is, entecavir, telbivudine, and tenofovir, soon followed. 7

8 Primera elección de Tratamiento HBV 2012
Schering-Plough PPT Template 4/12/2017 6:59 AM Primera elección de Tratamiento HBV 2012 Peg-Interferón alfa-2a/b Entecavir Tenofovir 1990 1998 2002 2005 2006 2008 HBV, hepatitis B virus. The hepatitis B treatment landscape is changing. In the early 1990s, the only treatment available for HBV was interferon alfa-2b. This agent was given for a short period, and only a few patients responded to treatment. In 1998, the first oral nucleoside analogue, lamivudine, was introduced, followed fairly rapidly by the nucleotide analogue adefovir. Standard interferon alfa-2b was then replaced by peginterferon alfa-2a, which was administered via once-weekly injections as opposed to daily treatment. Other nucleoside and nucleotide analogues, that is, entecavir, telbivudine, and tenofovir, soon followed. 8

9 Primera elección de Tratamiento HBV 2012
Análogos Nucleós(t)idos (NUC) Peg-Interferón Seguridad & tolerancia Eficacia (potencia) Duración finita Seguridad & tolerancia Eficacia (potencia) Each class of antiviral agents has advantages and disadvantages. The oral agents have demonstrated a relatively good safety and tolerability profile, as well as high rates of efficacy and potency. The barrier to resistance is variable among agents. They offer a good durability of response. Pegylated interferon has demonstrated efficacy in this patient population, particularly in patients who are HBeAg positive. Duration of peginterferon therapy is finite, with most patients undergoing a maximum of 48 weeks of treatment. However, safety and tolerability are greater concerns with the use of peginterferon than with oral agents. Barrera a la resistencia (durabilidad)

10 Herencia del Tratamiento HBV Resistencia a NUC
Schering-Plough PPT Template 4/12/2017 6:59 AM Herencia del Tratamiento HBV Resistencia a NUC Entecavir Lamivudina Tenofovir 1990 1998 2002 2005 2006 2008 Adefovir Telbivudina HBV, hepatitis B virus. The hepatitis B treatment landscape is changing. In the early 1990s, the only treatment available for HBV was interferon alfa-2b. This agent was given for a short period, and only a few patients responded to treatment. In 1998, the first oral nucleoside analogue, lamivudine, was introduced, followed fairly rapidly by the nucleotide analogue adefovir. Standard interferon alfa-2b was then replaced by peginterferon alfa-2a, which was administered via once-weekly injections as opposed to daily treatment. Other nucleoside and nucleotide analogues, that is, entecavir, telbivudine, and tenofovir, soon followed. 10

11 Tasa de Resistencia con Agentes Orales en Pacientes Naïve
No son trials head-to-head; diferentes poblaciones de pacientes y diseño de trials Año 1 Año 2 Año 3 Año 4 Año 5 Año 6 Generación De Drogas 1era LAM 24% 38% 49% 67% 70% ADV, adefovir; ETV, entecavir; LAM, lamivudine; LdT, telbivudine; TDF, tenofovir. Exposure to oral anti-HBV agents presents a risk of evolving drug resistance. Cumulative rates of resistance differ between agents, with higher rates reported with the use of older agents. In nucleos(t)ide-naive patients, treatment with lamivudine was associated with relatively high rates of resistance: 24% at Year 1, rising to 70% by Year 5. Reported rates of resistance were lower with use of the second-generation drugs adefovir and telbivudine. Data on telbivudine are limited to 2 years of follow-up, at which point resistance was reported in 17% of patients on first-line therapy. The cumulative rate for adefovir was 29% at Year 5. The resistance profile of the third-generation agents entecavir and tenofovir is different. For tenofovir, 3-year follow-up of naive patients found no evidence of emergent resistance. For entecavir, the rate of resistance in comparable populations remained low: 1.2% at Year 6 of therapy. For more information, go online to ADV 0% 3% 11% 18% 29% 2da LdT 4% 17% ETV 0.2% 0.5% 1.2% 1.2% 1.2% 1.2% 3era TDF 0% 0% 0% EASL. J Hepatol. 2009;50: Tenny DJ, et al. EASL Abstract 20. Marcellin P, et al. AASLD Abstract 481. Heathcote E, et al. AASLD Abstract 483.

12 Tasa de Resistencia con Agentes Orales en Pacientes Naïve
100 80 70 60 Tasa Acumulada de Resistencia (%) 40 29 One major challenge with oral antivirals is the potential for resistance. This slide shows the 5-year cumulative incidence rate of resistance among previously nucleos(t)ide-naive individuals receiving oral antiviral therapy. With lamivudine, 70% of these people will develop resistance within 5 years—a very high proportion of patients. The 5-year cumulative incidence of resistance with adefovir is 29%, whereas the 2-year cumulative incidence is 17% with telbivudine. Both entecavir and tenofovir have very high barriers to resistance, with only 1.2% and 0% cumulative incidence of resistance through Year 5, respectively. This is a major reason why these 2 agents are preferred as first-line therapy for hepatitis B. 17 20 1.2 Lamivudina[1] Adefovir[1] Telbivudina*[1] Entecavir[1] Tenofovir[2] *Telbivudina: tasa determinada a Año 2. 1. EASL. J Hepatol. 2009;50: 2. Marcellin P, et al. AASLD Abstract 1375.

13 Mutaciones Resistencia Primaria HBV
Proteina Terminal Spacer Pol/RT RNasaH 1 183 349 (rt1) 692 (rt344) 845 aa F_V_LLAQ YMDD I(G) II(F) A B C D E Resistencia LAM rtA18IT/V rtM204V/I Resistencia LdT rtA181T/V rtM204I Resistencia ADV/TDF* rtA181T/V rtN236T Resistencia ETV rtI169T rtL180M rtM204V rtM250I/V rtT184S/A/I/L/G/C/M rtS202G/C/I *Basado en datos in vitro y en cambio de tratamiento luego de aparición de resistencia genotípica a ADV. Allen MI, et al. Hepatology. 1998;27: Qi X, et al. EASL Abstract 57. Tenney D, et al. Antimicrob Agents Chemother. 2004;48: Telbivudine [package insert]. Locarnini S. IDRW Abstract P2. Qi X, et al. Antivir Ther. 2007;12: van Bommel F,et al. AASLD Abstract 960.

14 Barrera Genética El numero de sustituciones necesarias para desarrollar resistencia antiviral primaria a drogas LAM/LdT: rtM204I ADV: rtN236T ETV: se necesitan por lo menos 2 mutaciones: rtL180M + rtM204V + un de rtT184 o rtS202 o rtM250

15 ¿Qué Determina Tasa de Resistencia? Potencia vs Barrera Genética
Potencia es solo una parte de la ecuación LAM y LdT son potentes con baja barrera genética y altas tasas de resistencia ETV y TDF son potentes con alta barrera genética y bajas tasas de resistencia ADV es menos potente pero con alta barrera genética y bajas tasas de resistencia Barrera genética es probablemente tan importante como la potencia

16 Potencia Antiviral Relativa
Tratamiento HBV 2012 1998 2002 2005 2006 2008 LAM ADV ETV TDF LdT Potencia Antiviral Relativa Barrera Genética * ? *Numero de mutaciones necesarias para resistencia antiviral primaria a drogas.

17 Prevalence and Impact of Antiviral Resistance in Naïve CHB Patients
Study to determine prevalence of antiviral drug resistance mutations in naïve CHB patients and impact of mutations on response to NA treatment Methods: 203 NA-naive CHB patients ( ) Antiviral drug resistance tested by direct sequencing Polymerase gene sequences compared to consensus sequence of respective HBV genotype using HBV database ( No-Treatment (n=121) Subsequent Treatment (n=82) P Age 39 44 0.005 Male 55% 73% 0.007 Race Caucasian 19% 34% 0.11 Asian 70% 56% African American 7% 6% Other 3% 4% ALT (U/L) 58 ± 110 136 ± 199 0.002 HBeAg Positive 26% 59% <0.001 HBV DNA (log10 IU/mL) 4.5 ± 1.9 6.7 ± 1.8 KEY Message: The prevalence of antiviral resistance HBV mutations in NA-naïve patients is low and when present as minor variant do not impact response to NA treatment. These data support current recommendation that resistance testing not needed prior to start of NA in CHB Background and Aims: The prevalence of antiviral drug resistance mutations in patients (pts) with CHB who have not been exposed to nucleos(t)ide analog (NA) treatment has been reported to vary from 0 to 57%. The impact of pretreatment antiviral drug resistance mutations in nucleos(t)ide na ve pts on treatment response is not clear. The aims of this study were to determine the prevalence of antiviral drug resistance mutations in nucleos(t)ide na ve CHB pts and the impact of these mutations on response to subsequent NA treatment. Methods: Serum samples from 157 nucleos(t)ide-na ve CHB pts were tested for antiviral drug resistance Polymerase (P) gene mutations using line probe assay (INNO-LiPA) as well as direct sequencing. Results were compared with sequences from 2,526 pts in an HBV database ( 71 pts subsequently received NA treatment, virological responses between pts with and without baseline P gene mutations were compared. Results: Of the 157 pts in this study, 64% were male, mean age was 41 years, 63% were Asian, 46% were HBeAg positive, mean HBV DNA was 5.8 log 10IU/mL. Signature antiviral resistance mutations (rtS202S/G, rtM250M/I, rtA181A/T, rtM204M/V) were detected by INNO-LiPA in 4 (2.5%) pts but not by direct sequencing. Novel HBV P gene mutations were found in 13 pts (8.3%) by direct sequencing, rtT225S was the most common (1.9%) followed by rtV112A (1.3%). Variants at polymorphic sites were observed in 33 pts (21%), the most common sites were rt219 (5.7%) and rt135 (3.2%). 71 pts subsequently received treatment: entecavir (n=33), lamivudine (n=15), tenofovir (n=11), adefovir (n=8) and combination of NA (n=4). These pts were divided into 4 groups: G1 - 3 pts with pre-existing signature drug resistance mutations (2 received entecavir and 1 adefovir), G2 - 4 pts with pre-existing novel P gene mutations (rtP64Q, rtL209V, rtK212N, rtQ215S), G3 - 13 pts with polymorphic changes, and G pts with conserved sequences. At month 6 on treatment, mean decrease in HBV DNA in G1, G2, G3, and G4 was 3.7, 4.2, 4.3, and 4.2 log 10IU/mL, respectively (p=0.80). At month 12 on treatment, HBV DNA was undetectable in 100%, 100%, 81.2%, and 60.5% in these 4 groups (p=0.18). ALT normalization at months 6 and 12 was not significantly different among the 4 groups. Conclusions: The prevalence of antiviral drug resistance HBV mutations among pts who have never been exposed to NA treatment is low. Line probe assay is more sensitive in detecting minor variants than direct sequencing but the presence of P gene mutations as a minor variant does not impact the response to subsequent treatment. Chotiyaputta W, et al. 61st AASLD; Boston, MA; October 29-November 2, 2010; Abst. 427.

18 Distribution of Antiviral Resistance in Naïve CHB Patients
Results: 4 (2%) had signature antiviral resistance mutation (INNO-Lipa): rtA181A/T, rtM204M/V, rtS202S/G, and rtM250M/I (1 each) None had resistance mutations by direct sequencing Associated S Gene Changes No Associated S Gene Changes KEY Message: The prevalence of antiviral resistance HBV mutations in NA-naïve patients is low and when present as minor variant do not impact response to NA treatment. These data support current recommendation that resistance testing not needed prior to start of NA in CHB Background and Aims: The prevalence of antiviral drug resistance mutations in patients (pts) with CHB who have not been exposed to nucleos(t)ide analog (NA) treatment has been reported to vary from 0 to 57%. The impact of pretreatment antiviral drug resistance mutations in nucleos(t)ide na ve pts on treatment response is not clear. The aims of this study were to determine the prevalence of antiviral drug resistance mutations in nucleos(t)ide na ve CHB pts and the impact of these mutations on response to subsequent NA treatment. Methods: Serum samples from 157 nucleos(t)ide-na ve CHB pts were tested for antiviral drug resistance Polymerase (P) gene mutations using line probe assay (INNO-LiPA) as well as direct sequencing. Results were compared with sequences from 2,526 pts in an HBV database ( 71 pts subsequently received NA treatment, virological responses between pts with and without baseline P gene mutations were compared. Results: Of the 157 pts in this study, 64% were male, mean age was 41 years, 63% were Asian, 46% were HBeAg positive, mean HBV DNA was 5.8 log 10IU/mL. Signature antiviral resistance mutations (rtS202S/G, rtM250M/I, rtA181A/T, rtM204M/V) were detected by INNO-LiPA in 4 (2.5%) pts but not by direct sequencing. Novel HBV P gene mutations were found in 13 pts (8.3%) by direct sequencing, rtT225S was the most common (1.9%) followed by rtV112A (1.3%). Variants at polymorphic sites were observed in 33 pts (21%), the most common sites were rt219 (5.7%) and rt135 (3.2%). 71 pts subsequently received treatment: entecavir (n=33), lamivudine (n=15), tenofovir (n=11), adefovir (n=8) and combination of NA (n=4). These pts were divided into 4 groups: G1 - 3 pts with pre-existing signature drug resistance mutations (2 received entecavir and 1 adefovir), G2 - 4 pts with pre-existing novel P gene mutations (rtP64Q, rtL209V, rtK212N, rtQ215S), G3 - 13 pts with polymorphic changes, and G pts with conserved sequences. At month 6 on treatment, mean decrease in HBV DNA in G1, G2, G3, and G4 was 3.7, 4.2, 4.3, and 4.2 log 10IU/mL, respectively (p=0.80). At month 12 on treatment, HBV DNA was undetectable in 100%, 100%, 81.2%, and 60.5% in these 4 groups (p=0.18). ALT normalization at months 6 and 12 was not significantly different among the 4 groups. Conclusions: The prevalence of antiviral drug resistance HBV mutations among pts who have never been exposed to NA treatment is low. Line probe assay is more sensitive in detecting minor variants than direct sequencing but the presence of P gene mutations as a minor variant does not impact the response to subsequent treatment. Chotiyaputta W, et al. 61st AASLD; Boston, MA; October 29-November 2, 2010; Abst. 427.

19 Impact of Antiviral Resistance on Treatment of Naïve CHB Patients
CHB Patients with Subsequent HBV Treatment (n=82) 82/203 patients received HBV therapy 3 had pre-existing signature P gene mutations 8 had pre-existing other P gene mutations Virologic Response rates similar between patients with signature, other and no P gene mutations Conclusions: Prevalence of antiviral resistance HBV mutations in NA-naïve patients is low Pre-existing mutations (as minor variant) do not impact response to NA treatment Data support current recommendation that resistance testing not needed prior to start of NA in CHB Pre-existing P Gene Mutations Signature Other No P value Number of Patients 3 8 71 At Baseline HBV DNA (log10 IU/mL) 5.7 ± 2.2 6.2 ± 2.0 6.8 ± 1.7 0.46 ALT (IU/L) 106 ± 36 147 ± 201 137 ± 205 0.87 Medications Lamivudine 2 13 0.94 Adefovir 1 6 Entecavir 4 34 Tenofovir 14 Telbivudine 8 7 6 4 2 5 3 1 9 12 18 24 30 Months on Treatment Mean HBV DNA (log10 IU/mL) Effect of Preexisting P Gene Mutations on Treatment Outcomes 36 3 8 71 3 7 54 0 5 29 0 3 13 Signature P Gene Mutations Other P Gene Mutations No P Gene Mutations Number of Patients Evaluated Signature P Gene Mutations KEY Message: The prevalence of antiviral resistance HBV mutations in NA-naïve patients is low and when present as minor variant do not impact response to NA treatment. These data support current recommendation that resistance testing not needed prior to start of NA in CHB Background and Aims: The prevalence of antiviral drug resistance mutations in patients (pts) with CHB who have not been exposed to nucleos(t)ide analog (NA) treatment has been reported to vary from 0 to 57%. The impact of pretreatment antiviral drug resistance mutations in nucleos(t)ide na ve pts on treatment response is not clear. The aims of this study were to determine the prevalence of antiviral drug resistance mutations in nucleos(t)ide na ve CHB pts and the impact of these mutations on response to subsequent NA treatment. Methods: Serum samples from 157 nucleos(t)ide-na ve CHB pts were tested for antiviral drug resistance Polymerase (P) gene mutations using line probe assay (INNO-LiPA) as well as direct sequencing. Results were compared with sequences from 2,526 pts in an HBV database ( 71 pts subsequently received NA treatment, virological responses between pts with and without baseline P gene mutations were compared. Results: Of the 157 pts in this study, 64% were male, mean age was 41 years, 63% were Asian, 46% were HBeAg positive, mean HBV DNA was 5.8 log 10IU/mL. Signature antiviral resistance mutations (rtS202S/G, rtM250M/I, rtA181A/T, rtM204M/V) were detected by INNO-LiPA in 4 (2.5%) pts but not by direct sequencing. Novel HBV P gene mutations were found in 13 pts (8.3%) by direct sequencing, rtT225S was the most common (1.9%) followed by rtV112A (1.3%). Variants at polymorphic sites were observed in 33 pts (21%), the most common sites were rt219 (5.7%) and rt135 (3.2%). 71 pts subsequently received treatment: entecavir (n=33), lamivudine (n=15), tenofovir (n=11), adefovir (n=8) and combination of NA (n=4). These pts were divided into 4 groups: G1 - 3 pts with pre-existing signature drug resistance mutations (2 received entecavir and 1 adefovir), G2 - 4 pts with pre-existing novel P gene mutations (rtP64Q, rtL209V, rtK212N, rtQ215S), G3 - 13 pts with polymorphic changes, and G pts with conserved sequences. At month 6 on treatment, mean decrease in HBV DNA in G1, G2, G3, and G4 was 3.7, 4.2, 4.3, and 4.2 log 10IU/mL, respectively (p=0.80). At month 12 on treatment, HBV DNA was undetectable in 100%, 100%, 81.2%, and 60.5% in these 4 groups (p=0.18). ALT normalization at months 6 and 12 was not significantly different among the 4 groups. Conclusions: The prevalence of antiviral drug resistance HBV mutations among pts who have never been exposed to NA treatment is low. Line probe assay is more sensitive in detecting minor variants than direct sequencing but the presence of P gene mutations as a minor variant does not impact the response to subsequent treatment. Chotiyaputta W, et al. 61st AASLD; Boston, MA; October 29-November 2, 2010; Abst. 427.

20 Manejo de HBV Resistente: 2009
Tratamiento Estrategia Resistente a Lamivudina Agregar adefovir o tenofovir Suspender lamivudina y cambiar a tenofovir/emtricitabina* Resistente a Adefovir Agregar lamivudina† Suspender adefovir y cambiar a tenofovir/emtricitabina* Cambiar a/o agregar entecavir*† Resistente a Entecavir Cambiar a tenofovir o tenofovir/emtricitabina* Resistente a Telbivudina‡ Suspender telbivudina y cambiar a tenofovir/emtricitabina Resistente a Tenofovir§ Puede agregar entecavir, telbivudina, lamivudina, o emtricitabina AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of the Liver; HBV, hepatitis B virus. Lamivudine resistance is common and occurs in up to 70% of patients after 5 years of lamivudine monotherapy. Patients with lamivudine resistance can be managed either by adding adefovir or tenofovir to lamivudine therapy or by switching from lamivudine to the combination of tenofovir/emtricitabine. For patients with adefovir resistance, the recommended options include adding lamivudine to adefovir, although the durability of this regimen is not established, especially in patients who have had previous lamivudine exposure. The alternatives are to stop adefovir and switch to tenofovir/emtricitabine or to switch to or add entecavir. In patients with entecavir resistance, the recommended strategy is to switch to tenofovir or to the combination tenofovir/emtricitabine. Telbivudine-resistant patients are managed in the same manner as lamivudine-resistant patients. Although management of tenofovir resistance is not addressed in the AASLD guidelines, the European Association for the Study of the Liver guidelines recommend that such cases have genotypic and phenotypic testing performed by an expert laboratory before considering the addition of 1 of the other oral agents. *En coinfectados HIV; poca experiencia en no HIV. †Durabilidad de la supresión viral, especialmente en pacientes con resistencia a lamivudina previa. ‡Sin datos clínicos disponibles. §No evaluado en las guías AASLD; EASL 2009 recomienda análisis genotípico y fenotípico para establecer perfil de resistencia cruzado. Lok AS, et al. Hepatology. 2009;50: EASL. J Hepatol. 2009;50:

21 Manejo de HBV Resistente: 2012
Tratamiento Estrategia Resistente a Lamivudina Agregar adefovir o tenofovir Suspender lamivudina y cambiar a tenofovir/emtricitabina* Resistente a Adefovir Agregar lamivudina† Suspender adefovir y cambiar a tenofovir/emtricitabina* Cambiar a/o agregar entecavir*† Resistente a Entecavir Cambiar a tenofovir o tenofovir/emtricitabina* Resistente a Telbivudina‡ Suspender telbivudina y cambiar a tenofovir/emtricitabina Resistente a Tenofovir§ Puede agregar entecavir, telbivudina, lamivudina, o emtricitabina AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of the Liver; HBV, hepatitis B virus. Lamivudine resistance is common and occurs in up to 70% of patients after 5 years of lamivudine monotherapy. Patients with lamivudine resistance can be managed either by adding adefovir or tenofovir to lamivudine therapy or by switching from lamivudine to the combination of tenofovir/emtricitabine. For patients with adefovir resistance, the recommended options include adding lamivudine to adefovir, although the durability of this regimen is not established, especially in patients who have had previous lamivudine exposure. The alternatives are to stop adefovir and switch to tenofovir/emtricitabine or to switch to or add entecavir. In patients with entecavir resistance, the recommended strategy is to switch to tenofovir or to the combination tenofovir/emtricitabine. Telbivudine-resistant patients are managed in the same manner as lamivudine-resistant patients. Although management of tenofovir resistance is not addressed in the AASLD guidelines, the European Association for the Study of the Liver guidelines recommend that such cases have genotypic and phenotypic testing performed by an expert laboratory before considering the addition of 1 of the other oral agents. *En coinfectados HIV; poca experiencia en no HIV. †Durabilidad de la supresión viral, especialmente en pacientes con resistencia a lamivudina previa. ‡Sin datos clínicos disponibles. §No evaluado en las guías AASLD; EASL 2012 recomienda análisis genotípico y fenotípico para establecer perfil de resistencia cruzado. Lok AS, et al. Hepatology. 2009;50: EASL. J Hepatol. 2012;55:

22 TDF en Pacientes tratados con NUC: HBV DNA no detectable* a 12 Meses
P = NS P = NS P =.001 100 100 92 92 90 90 85 80 73 70 HBV DNA no detectable* a 12 Meses, % 60 50 40 30 30 20 10 Todos HBeAg positivo HBeAg negativo HBV Wild-type Mutaciones YMDD ADV-r No ADV-r n = Sin breakthrough virologico durante el periodo de follow-up, independiente de la presencia de ADV-R al inicio de TDF * HBV DNA < 400 copias/mL (< 69 UI/mL) Van Bommel F, et al. Hepatology 2010;51:73–80.

23 TDF o TDV/FTC en HBV ADV-R
Tenofovir (n = 52) Emtricitabina/tenofovir (n = 53) 100 81 81 80 69 66 60 HBV DNA < 400 copias/mL (%) 40 20 Semana 24 Semana 48 (ITT) Berg T, et al. Gastroenterology. 2010;139:

24 TDF o TDV/FTC en HBV ADV-R
Mayoría de los pacientes resistentes a adefovir- o lamivudina alcanzaron un HBV DNA < 400 copias/mL en la semana 48 100 92 93 83 79 80 81 79 80 72 60 HBV DNA < 400 copias/mL (%) 40 20 n = 13 90 10 93 25 72 29 68 Si No Si No Si No Si No LAM-R ADV-R LAM-R ADV-R Population Sequencing Line Probe Assay Berg T, et al. Gastroenterology. 2010;139:

25 ETV en Pacientes tratados con NUC
161 ptes. 11 (3–23) meses seguimiento. 104 naïve: 79% HBV DNA negativo. 57 NUC previo: 54 % HBV DNA negativo. LAM-R (HR 0.14; IC 95% 0.04–0.58; p = 0.007). LAM previo (HR 0.81; IC 95% 0.43–1.52; p = 0.52). ADV-R (HR 0.86; 95% CI 0.27–2.71; p = 0.80). ADV previo (HR 0.84; IC 95% 0.43–1.64; p = 0.61). Reijnders JG, et al. J Hepatol 2010;52:493–500.

26 ETV en Pacientes sin vs con LAM
Tratamiento ETV Grupo 1 - Naïve (n=81) [ETV 0.5 mg QD] Grupo 2 - LAM- (n=31) [ETV 0.5 mg QD] Grupo 3 - LAM-R (n=50) [ETV 1.0 mg QD] Mayor respuesta viral completa en grupos 1 y 2 P=0.230 P<0.001 P<0.001 Key point: LAM-R patients have less viral response than naïve and LAM-experienced (but not resistant) patients. Key point: LAM-experienced patients are more likely to have viral breakthrough when treated with ETV. 1435. Prior exposure to lamivudine therapy significantly increases the risk of entecavir-resistant genotypic mutation in chronic hepatitis B patients even if there is no lamivudine resistance..  J. Lee; E. Cho; E. Jang; M. Kwak; S. Yu; J. Yoon; H. Lee; Y. Kim View Pres. Prior exposure to lamivudine therapy significantly increases the risk of entecavir-resistant genotypic mutation in chronic hepatitis B patients even if there is no lamivudine resistance.  J. Lee1; E. Cho1; E. Jang1; M. Kwak1; S. Yu1; J. Yoon1; H. Lee1; Y. Kim1  1. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea, Republic of.  Backgroud: Entecavir (ETV) has an excellent efficacy in nucleos(t)ide analogue (NA)-naïve chronic hepatitis B (CHB) patients. However, antiviral effect of ETV in patients who experienced prior lamivudine (LAM) therapy was not fully evaluated. In this study, we aimed to evaluate the influence of prior exposure to LAM on the development of genotypic resistance for ETV.  Methods: This study included 174 consecutive patients with CHB who started ETV monotherapy at a single tertiary hospital (Seoul, Korea) in The patients were grouped into three groups: NA-naïve patients (group 1, n=81), patients who experienced LAM without development of LAM-resistance (group 2, n=31), and patients who had with LAM-resistance at baseline (group 3, n=62). Groups 1 and 2 were treated with ETV 0.5 mg/day and group 3 was treated with ETV 1.0 mg/day. Results: Overall median treatment duration was 164 weeks (range, 24–231 weeks) and 52.9% were hepatitis B virus (HBV) e antigen-positive. There was no significant difference in baseline liver function and serum HBV DNA levels among three groups. The probabilities of achieving complete virological response were significantly lower in group 3 than groups 1 and 2 (both P<0.05), and virological breakthrough was more frequent in group 2 and 3 than in group 1 (both P<0.05). Genotypic resistance to ETV was more frequently developed in group 3 than in group 2 (hazard ratio=10.5, P=0.036), and in group 2 than in group 1 (hazard ratio=5.541, P=0.045): the probabilities of developing ETV-resistant mutation in group 1, 2, and 3 were 0%, 4% and 39% at week 144. Conclusion: This study indicates that ETV-resistant mutation was developed more frequently in LAM-experienced patients, although they never developed LAM-resistant mutation, as compared to NA-naïve patients. Therefore, clinicians should be cautious about applying ETV monotherapy in LAM-experienced CHB patients regardless of LAM-resistant mutation. No. at risk Group 1 81 54 15 8 5 3 1 Group 2 31 21 9 4 2 Group 3 50 43 30 27 18 6 Lee J, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011; Abst

27 ETV en Pacientes sin vs con LAM: Resistencia
Probabilidad de desarrollar ETV-R en semana 192 mayor en grupos 2 y 3 P=0.203 P=0.028 P=0.004 Key point: ETV resistance occurs more frequently in LAM-experienced (especially those with LAM-R) patients. 1435. Prior exposure to lamivudine therapy significantly increases the risk of entecavir-resistant genotypic mutation in chronic hepatitis B patients even if there is no lamivudine resistance..  J. Lee; E. Cho; E. Jang; M. Kwak; S. Yu; J. Yoon; H. Lee; Y. Kim View Pres. Prior exposure to lamivudine therapy significantly increases the risk of entecavir-resistant genotypic mutation in chronic hepatitis B patients even if there is no lamivudine resistance.  J. Lee1; E. Cho1; E. Jang1; M. Kwak1; S. Yu1; J. Yoon1; H. Lee1; Y. Kim1  1. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea, Republic of.  Backgroud: Entecavir (ETV) has an excellent efficacy in nucleos(t)ide analogue (NA)-naïve chronic hepatitis B (CHB) patients. However, antiviral effect of ETV in patients who experienced prior lamivudine (LAM) therapy was not fully evaluated. In this study, we aimed to evaluate the influence of prior exposure to LAM on the development of genotypic resistance for ETV.  Methods: This study included 174 consecutive patients with CHB who started ETV monotherapy at a single tertiary hospital (Seoul, Korea) in The patients were grouped into three groups: NA-naïve patients (group 1, n=81), patients who experienced LAM without development of LAM-resistance (group 2, n=31), and patients who had with LAM-resistance at baseline (group 3, n=62). Groups 1 and 2 were treated with ETV 0.5 mg/day and group 3 was treated with ETV 1.0 mg/day. Results: Overall median treatment duration was 164 weeks (range, 24–231 weeks) and 52.9% were hepatitis B virus (HBV) e antigen-positive. There was no significant difference in baseline liver function and serum HBV DNA levels among three groups. The probabilities of achieving complete virological response were significantly lower in group 3 than groups 1 and 2 (both P<0.05), and virological breakthrough was more frequent in group 2 and 3 than in group 1 (both P<0.05). Genotypic resistance to ETV was more frequently developed in group 3 than in group 2 (hazard ratio=10.5, P=0.036), and in group 2 than in group 1 (hazard ratio=5.541, P=0.045): the probabilities of developing ETV-resistant mutation in group 1, 2, and 3 were 0%, 4% and 39% at week 144. Conclusion: This study indicates that ETV-resistant mutation was developed more frequently in LAM-experienced patients, although they never developed LAM-resistant mutation, as compared to NA-naïve patients. Therefore, clinicians should be cautious about applying ETV monotherapy in LAM-experienced CHB patients regardless of LAM-resistant mutation. No. at risk Group 1 81 78 73 65 59 31 Group 2 30 29 28 25 23 14 Group 3 50 48 47 44 43 39 26 19 Conclusiones Resistencia a ETV ocurre mas frecuentemente en tratados con LAM (especialmente en LAM-R) Cuidado con el uso de ETV en pacientes que recibieron LAM. Lee J, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011; Abst

28 Baseline Characteristics
ETV + ADV vs. ETV Monotherapy in CHB Patients with LAM and ADV Resistance Multi-drug resistance development after sequential nucleos(t)ide therapy in CHB infections remains problematic Efficacy and clinical outcomes of ETV 1.0 mg were compared to ETV plus ADV in CHB patients with multi-drug resistance after sequential LAM and ADV therapy (N=43) Baseline Characteristics ETV (n = 22) ETV + ADV (n = 21) P-value Age (years) 47 0.5555 Liver cirrhosis, n (%) 4 (18.2%) 5 (23.8%) 0.721 HBeAg positivity, n (%) 17 (77.3%) 17 (81.0%) 1.000 Serum HBV DNA (log10 copies/mL) 6.54 6.29 0.357 Serum ALT (IU/L) 45.05 74. 09 0.050 Serum total bilirubin (mg/dL) 1.00 1.02 0.075 PT (INR) 1.04 1.10 0.098 Platelet count (/µL) 182.86 155.29 0.630 Resistance to ADV rtA181V/T 18 (81.8%) 16 (76.2%) 0.641 rtN236T 8 (36.4%) 6 (28.6%) 0.495 Key point ETV + ADV superior to ETV Background  Multi-drug resistance development after sequential nucleos(t)ide therapy emerged as a major clinical concern in chronic hepatitis B (CHB) infections. Therapeutic options are still limited in countries where the reimbursement policy of new antiviral drugs is restricted. Aim of our study is to compare the efficacy and clinical outcomes of entecavir (ETV) 1.0 mg monotherapy with ETV plus adefovir (ADV) combination therapy in CHB patients who developed multi-drug resistance after sequential lamivudine (LAM)-ADV therapy.  Methods A total of 45 CHB patients with the documented presence of genotypic resistance mutation to  ADV after sequential LAM-ADV therapy were enrolled. Of these, 22 patients were treated with ETV 1 mg (ETV group) and 23 patients were treated with ETV 1 mg plus ADV 10 mg combination (ETV/ADV combination group).  Results  There were no significant differences in baseline characteristics except serum ALT levels (45.05 ± in ETV group versus ± in ETV/ADV combination group). After ADV resistance development, median duration of rescue therapy was 19.5 months in the ETV group and 24 months in the ETV/ADV combination group. After 12 months of ETV monotherapy or ETV-ADV combination therapy, mean reduction of serum HBV DNA levels (log10 copies/ml) were 2.36 ± 1.69, and 2.96 ± 1.72 respectively (p=0.049). Virologic response (defined as serum HBV less than 300 copies/ml) occurred in 8 of 22 (36.4%) in the ETV group and 10 of 23 (43.5%) in the ETV/ADV combination group (p=0.626) during the rescue therapy. Virologic breakthrough occurred in 16 of 22 (72.7%) in the ETV group and 3 of 23 (13.0%) in the ETV/ADV combination group (p=0.000) during the rescue therapy. Median time of virologic breakthrough occurrence was 18 months in the ETV group and 12 months in the ETV/ADV group. During the rescue therapy, cumulative rate of virologic breakthrough was significant higher in the ETV group (p=0.001). Genotypic resistance for ETV was detected in 11 of 16 in the ETV group and none of 3 in the ETV/ADV combination group. Cumulative rate of genotypic resistance development for ETV was also significant higher in the ETV group (p=0.000).  Conclusion ETV plus ADV combination therapy was more effective in suppressing serum hepatitis B virus DNA and in preventing antiviral resistance development than ETV monotherapy in CHB patients who developed sequential LMV-ADV resistance. Because tenofovir is still not available in some countries, these results have clinical implications in managing multi-drug resistant CHB infections.  Lee S, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011; Abst

29 ETV + ADV mas efectivo que ETV en LAM-R y ADV-R secuencial
Respuesta Virológica Breakthrough Virológico Resistencia Genotípica a ETV ETV ETV + ADV P Niveles HBV DNA (log10 copias mL) Mes 12 4.26 3.26 0.061 Mes 24 4.49 2.87 0.006 Cambios en niveles de HBV DNA (log10 copias mL) -2.36 -2.94 0.278 -1.98 -2.98 0.097 Respuesta virológica completa 22.7% 28.6% 0.736 20% 30.8% 0.670 P=0.001 P<0.001 ETV ETV ETV + ADV ETV plus ADV combination therapy was more effective in suppressing serum hepatitis B virus DNA and in preventing antiviral resistance development than ETV monotherapy in CHB patients ETV + ADV Conclusión: en pacientes LAM-R y ADV-R, ETV + ADV es más efectivo que ETV solo Lee S, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011; Abst

30 Eficacia de Entecavir vs Tenofovir en Pacientes con Resistencia
Actividad antiviral similar en HBV naïve de NUC; eficacia en variantes resistentes a NUCs difiere Actividad de Acuerdo a la Resistencia Entecavir Tenofovir Resistencia LAM/LdT Disminuida Activa Resistencia ETV -- Resistencia ADV Resistencia TDF ADV, adefovir; ETV, entecavir; HBV, hepatitis B virus; LAM, lamivudine; LdT, telbivudine; TDF, tenofovir. Treatment history must be considered when choosing an oral agent for patients with hepatitis B. For patients who have never received antivirals, both entecavir and tenofovir have proven efficacy with little apparent risk of emergent resistance. In patients with lamivudine or telbivudine resistance, the activity of entecavir is decreased, and risk is increased for developing entecavir resistance. Entecavir remains active in patients who have adefovir or tenofovir resistance. The converse appears to be true for tenofovir: tenofovir is highly effective in patients who have lamivudine and telbivudine resistance and in patients who have entecavir resistance. In patients with adefovir resistance, tenofovir activity is somewhat decreased. Lok AS. Hepatology. 2010;52:

31 Tenofovir + Entecavir en Pacientes HBV Multi-resistentes
Estudio abierto en pacientes que recibieron NUCs; mayoría con resistencia (N=55) Combinación TDF + ETV por ~18 meses  89% HBV DNA no detectable LLoD HBV DNA [UI/mL] Tiempo [Meses] 1010 108 106 104 102 57 BL 3 51 6 48 9 42 12 40 15 34 18 28 21 24 17 27 Reducción Δ 3 log P<0.0001 n= 55 patients followed in an open-label cohort Most with resistance mutations TDF + ETV ~ 18 months 89% achieved undetectable HBV DNA No safety issues Background: Long-term viral suppression is a major goal to prevent hepatic flares in patients with the history of multiple resistant HBV mutations. Aim of this ongoing cohort study was to investigate the efficacy and safety of entecavir (1mg) and tenofovir in treatment experienced patients. Combination therapy was initiated as rescue therapy in 55 adherent HBV-infected patients with multidrug resistant HBV or only partial responses to previous lines of therapy and advanced liver disease. Methods: Open label cohort, investigator initiated study from 10 European referral centers. Quantitative HBV-DNA measurement with LLOD< 69 IU/ml was used. Resistance was determined using Innolipa line-probe-assay DRV3 and direct sequencing. ALT and HBV-DNA were measured at baseline and every 3 months. Results: 55 patients (35 HBeAg positive), median age 49yrs, 3 lines of pretreatment (median, range 1-6) were included. Last treatment before switch to TDF-ETV combination included: 14xADV+LAM, 7xADV+ETV, 4xTDF+LAM, 9xADV, 6xTDF, 13xETV, 1xLdT, 1xLAM. Median ALT at baseline was 1.0ULN (range ), HBV-DNA was 1.5x10^4 IU/ml (range 500-1x10^11 IU/ml). Median treatment duration of combination therapy was 18 months (range 3-57 months, October 2010). Median HBV-DNA level dropped by 3 logs (range 0-8 log; p< ), 49/55 patients became HBV-DNA undetectable, median after 6 months (95%CI month). Probability of reaching complete HBV DNA suppression was not decreased in patients with ADV or ETV resistance. Ongoing viral suppression was accompanied by decline in ALT (median 0.7 ULN; range ; p=0.001). Four patients lost HBeAg (after 15,18,21, and 24 months, respectively), one patient showed HBs-seroconversion. Besides long-term viral suppression (21 and 37 month) two patients showed significant viral rebound. Patients with liver cirrhosis did not develop clinical decomposition, but two patients with cirrhosis and undetectable HBV DNA developed HCC´s. There were no significant clinical side effects reported, especially no induced renal impairment and no lactic acidosis. Discussion: Rescue therapy with entecavir and tenofovir in HBV infected patients harbouring complex viral resistance patterns or showing only partial antiviral responses to preceeding therapies was highly efficient, safe, and well tolerated in patients with advanced liver disease. Resistance analysis of two viral break through patients is ongoing. Petersen J, et al. 46th EASL; Berlin, Germany; March 30-April 3, 2011; Abst. 744.

32 OptiB: Virological Response by Baseline Genotypic Resistance
TDF and TDF+LAM were well tolerated with 81% of patients achieving HBV DNA <69 IU/mL by week 48 Virologic response was independent of HBV genotype, LAM-associated mutations and HBeAg status at baseline Virologic response insignificantly decreased if ADV-associated mutations present at baseline (ADV-Rs) Virological Response (HBV DNA <69 IU/ml) According to Baseline Genotypic Analysis 20 40 60 80 100 0% 4 27% Patients % 57% 24 12 69% Baseline 83 85 78 74 Patients 84% 71 Weeks 48 39% 45% 58% 71% ADV-Rs SORs Background and aim: Tenofovir (TDF) displays a potent activity against HBV replication, including lamivudine (LAM)-resistant HBV and patients with incomplete virological response to adefovir (ADV). OptiB was designed to evaluate the long term efficacy and safety of TDF in chronic hepatitis B patients with suboptimal response to ADV or ADV/LAM treatment. Patients and methods: Adults with HBV mono-infection and HBV-DNA >103cp after 48 weeks of ADV±LAM were enrolled and switched to TDF 300 mg daily±LAM. Study endpoints were complete HBV suppression at 24 weeks (primary), early (4-12 weeks) and long term HBV suppression, HBsAg and HBeAg seroconversion, viral resistance and safety surveillance. Genotypic analysis are performed by direct sequencing (TrueGene 2.0) and reverse hybridization (InnoLIPA V3). HBV-DNA is measured using the Roche COBAS TaqMan assay. Results: 91 patients were screened and 85 have been enrolled. 13 (15.3 %) patients were switched from ADV to TDF and 72 (84.7%) to the TDF/LAM combination. 70 (82.4%) were male, median age 54.8 years (range 21-75). 35 (41.2%) patients were HBeAg+ve. Median duration of prior ADV therapy 29.2 months. Baseline median viral load 5.7 log10 UI/ml (range ). 95.8% of patients had resistance mutations at baseline (ADV-R [A181V, N236T, A181V/T+N236T, I233V] in 46.5%; LAM-R [L180M, L180M+M204V/I; M204I] in 56.3%; A181T in 9.9% and ETV-R [S202C/G/I, M250I/V and T184S/A/I/L/G/C/M in 9.9%). 78 and 70 patients have completed 24 and 48 weeks of TDF therapy and evaluation, respectively % and 71.0% of patients had HBV-DNA levels < 69 UI/ml at 24 and 48 weeks of treatment, respectively. 44.2% and 51.6% of patients reached HBV-DNA levels < 12 UI/ml by week 24 and 48, respectively. Virologic response was independent of HBV genotype, LAM-R mutations and HBe-Ag status at baseline, slightly reduced but not significantly different in patients with or without ADV-R mutations at baseline. 9 patients dropped out (1 virological breakthrough, 1 lack of response, 5 due to worsening of liver disease, 2 for SAE). No clinically significant side effects related to TDF were reported. Conclusions: TDF shows significant antiviral activity against HBV in patients who have failed lamivudine and are sub-optimal responders to ADV. Levrero M, et al. 45th EASL; Vienna, Austria; April 14-18, 2010; Abst 32

33 Entecavir + Adefovir Rescue Therapy for Patients with Both Adefovir and Lamivudine Resistance
Study to characterize the virologic response to ETV + ADV for Korean patients with both LAM and ADV resistance Key point: HBV-DNA levels in LAM-R + ADV-R patients decrease using a rescue therapy of ETV + ADV. One-Year Study of Entecavir and Adefovir Combination Therapy for rtA181V/T Mutants in Prior Lamivudine-Resistant Hepatitis B Virus H. Cho2; Y. Kim1; G. Gwak1; M. Choi1; J. Lee1; K. Koh1; B. Yoo1; S. Paik1 1. Division of Gastroenterology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic of. 2. Division of Gastroenterology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea, Republic of. Background/Aims: Recent studies reported the occurrence of amino acid substitutions at position 181 of the HBV polymerase, associated with a viral breakthrough under adefovir (ADV) therapy following lamivudine (LAM) breakthrough. Several in vitro studies reported that rtA181V/T mutants showed decreased susceptibility to LAM and ADV, and remained susceptible to entecavir (ETV) and tenofovir and few clinical data are available about treatment for rtA181V/T mutants in HBV. Unfortunately, tenofovir is not currently available in Korea. The aim of this study was to characterize the virologic response to ETV and ADV for rtA181V/T mutants in prior LAM-resistant HBV. Methods: The clinical records of 24 patients with chronic hepatitis B who had rtA181V/T mutants after ADV therapy following LAM resistance and received ETV and ADV combination therapy for at least 1 year from June 2009 to October 2009 were retrospectively analyzed. Virologic responses were evaluated at three-month intervals after initiation of therapy. Results: All 24 patients (22 males and 2 females, median age 50 years) had prior LAM resistance and 91.7% of patients received ADV monotherapy and 8.3% of patients received LAM and ADV for treatment of LAM resistnace. All patients had rtA181V/T mutants and 50% of patients had rtN236T mutants. 83.3% of patients were HBeAg-positive and median HBV DNA levels were 4.8 (3.0–7.1) log10IU/ml. 25% of patients had liver cirrhosis and 12.5% of patients had hepatocellular carcinoma. Median HBV DNA reduction levels after ETV and ADV combination therapy for rtA181V/T mutants were as follows; 2.0 log10IU/ml at 3months, 2.5 log10IU/ml at 6months, 2.9 log10IU/ml at 9months, and 3.0 log10IU/ml at 12months. Virologic responses at 6 months of ETV and ADV treatment were as follows; complete response (HBV DNA < 60 IU/ml) in 29.2%, partial response (60 IU/ml≤ HBV DNA <2000 IU/ml) in 58.3%, and inadequate response (HBV DNA ≥2000 IU/ml) in 12.5% of patients. Virologic responses at 12months of ETV and ADV treatment were as follows; complete response in 33.3%, partial response in 62.5%, and inadequate response in 4.2% of patients. One patient showed HBeAg loss at 12 months of treatment and no patient showed biochemical breakthrough during treatment. Conclusions: ETV and ADV combination therapy is beneficial for rtA181V/T mutants in prior LAM-resistant hepatitis B virus. Cho H, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011; Abst

34 HBV DNA Response Rates for Entecavir + Adefovir Rescue Therapy
Key point: More LAM-R + ADV-R patients demonstrate complete and partial response over time using a rescue therapy consisting of ETV + ADV. One-Year Study of Entecavir and Adefovir Combination Therapy for rtA181V/T Mutants in Prior Lamivudine-Resistant Hepatitis B Virus H. Cho2; Y. Kim1; G. Gwak1; M. Choi1; J. Lee1; K. Koh1; B. Yoo1; S. Paik1 1. Division of Gastroenterology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic of. 2. Division of Gastroenterology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea, Republic of. Background/Aims: Recent studies reported the occurrence of amino acid substitutions at position 181 of the HBV polymerase, associated with a viral breakthrough under adefovir (ADV) therapy following lamivudine (LAM) breakthrough. Several in vitro studies reported that rtA181V/T mutants showed decreased susceptibility to LAM and ADV, and remained susceptible to entecavir (ETV) and tenofovir and few clinical data are available about treatment for rtA181V/T mutants in HBV. Unfortunately, tenofovir is not currently available in Korea. The aim of this study was to characterize the virologic response to ETV and ADV for rtA181V/T mutants in prior LAM-resistant HBV. Methods: The clinical records of 24 patients with chronic hepatitis B who had rtA181V/T mutants after ADV therapy following LAM resistance and received ETV and ADV combination therapy for at least 1 year from June 2009 to October 2009 were retrospectively analyzed. Virologic responses were evaluated at three-month intervals after initiation of therapy. Results: All 24 patients (22 males and 2 females, median age 50 years) had prior LAM resistance and 91.7% of patients received ADV monotherapy and 8.3% of patients received LAM and ADV for treatment of LAM resistnace. All patients had rtA181V/T mutants and 50% of patients had rtN236T mutants. 83.3% of patients were HBeAg-positive and median HBV DNA levels were 4.8 (3.0–7.1) log10IU/ml. 25% of patients had liver cirrhosis and 12.5% of patients had hepatocellular carcinoma. Median HBV DNA reduction levels after ETV and ADV combination therapy for rtA181V/T mutants were as follows; 2.0 log10IU/ml at 3months, 2.5 log10IU/ml at 6months, 2.9 log10IU/ml at 9months, and 3.0 log10IU/ml at 12months. Virologic responses at 6 months of ETV and ADV treatment were as follows; complete response (HBV DNA < 60 IU/ml) in 29.2%, partial response (60 IU/ml≤ HBV DNA <2000 IU/ml) in 58.3%, and inadequate response (HBV DNA ≥2000 IU/ml) in 12.5% of patients. Virologic responses at 12months of ETV and ADV treatment were as follows; complete response in 33.3%, partial response in 62.5%, and inadequate response in 4.2% of patients. One patient showed HBeAg loss at 12 months of treatment and no patient showed biochemical breakthrough during treatment. Conclusions: ETV and ADV combination therapy is beneficial for rtA181V/T mutants in prior LAM-resistant hepatitis B virus. Conclusion: Combination therapy with ETV + ADV is effective for patients with LAM and ADV resistance   Cho H, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011; Abst

35 ADV Add-on Therapy in CHB Patients with LAM Resistance
Study to assess treatment with ADV add-on therapy in CHB patients with LAM resistant HBV (N=559) Predictors for virologic response and ADV resistance also assessed Treatment 28 months (6-130 months), HBeAg(+) 53%,median HBV DNA 5.48 log IU/mL (1.1 to 8.23) HBeAg clearance occurred in 14.5%, seroconversion in 15% and HBeAg loss in 9.5% Overall Cumulative Probability of Complete Virologic Response and ADV Resistance   Purpose We aimed to describe the treatment outcome of adefovir (ADV) add-on therapy in chronic hepatitis B (CHB) patients infected with lamivudine (LAM) resistant hepatitis B virus (HBV). And we also aimed to differentiate the optimal candidate for ADV add-on therapy by verifying the predictors for virologic response and adefovir resistance. Methods From January 2007 to March 2011, CHB patients who were treated with ADV add-on therapy to LAM for more than 12 months due to genotypic and phenotypic resistance to LAM were included. Virologic responses were defined as like these: primary non response (NR), no reduction of HBV DNA by 1log IU/mL at 3 months after treatment; complete virologic response (CVR), undetectable HBV DNA (lower limit of detection 9 IU/mL); partial virologic response (PVR), HBV DNA<2,000 IU/mL; inadequate virologic response (IVR), HBV DNA >2,000 IU/mL; viral breakthrough (BT), HBV DNA increase more than 1 log from nadir. Results A total of 559 patients were included. Duration of LAM treatment was median 28 months (range 6 to 130), HBeAg was positive in 52.6%, and median value of serum HBV DNA was 5.48 log IU/mL (range 1.1 to 8.23). Median duration of follow-up was 30.1 months (range 12 to 56). HBeAg clearance occurred in 14.5%, seroconversion in 15% and HBeAg loss in 9.5%. Overall treatment outcome was recorded as like these: CVR in 70%, PVR in 20%, IVR in 7.9%, primary NR in 0.7%, and viral BT in 1.4%. Cumulative probability of CVR during treatment was 58% at 1year, 69% at 2year, and 76% at 3 year. Multivariate analysis revealed baseline HBV DNA level (OR 0.836, 95% CI , p =0.000) and PCR negativity at 6month (OR , 95% CI , p=0.000) as predictors of CVR. Genotypic resistance to ADV was identified in 10 patients (1.8%). Baseline HBV DNA showed strong association with PCR negativity at 6 month (OR 0.324, 95% CI , p=0.000), and HBV DNA value of 2,000,000 IU/mL was selected as the cut off value with specificity of 90% and negative predictive value of 87.2% for CVR. All 245 patients who met these two criteria, baseline HBV DNA <2,000,000 IU/mL and PCR negativity at 6 month, accomplished CVR and showed no CVR. Conclusions Treatment with ADV add-on therapy for LAM resistant CHB showed CVR rates of 58%, 68%, and 76% at 1year, 2year, and 3 year, respectively. Genotypic resistance to ADV was identified in 10 patients (1.8%). Predictors for CVR were PCR negativity at 6 months of treatment and baseline HBV DNA level. Based on these findings, we suggest that patients with baseline HBV DNA <2,000,000 IU/mL and PCR negativity at 6 month are the best candidates for ADV add-on therapy. Months Months Patients at risk 559 255 121 35 1 Patients at risk 559 483 310 119 Kim Y, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011; Abst

36 ADV Add-on Therapy in CHB Patients with LAM Resistance: Results
Predictors for complete virologic response (CVR) were baseline HBV DNA <2,000,000 IU/mL and PCR negativity at 6 months Conclusion: ADV add-on therapy is effective in LAM-resistant patients Cumulative Probability of Complete Virologic Response and ADV Resistance by Virologic Response (VR) P<0.000 Key points: Treatment with ADV add-on therapy for LAM resistant CHB showed CVR rates of 58%, 68%, and 76% at 1year, 2year, and 3 year, respectively. Genotypic resistance to ADV was identified in 10 patients (1.8%). Predictors for CVR were PCR negativity at 6 months of treatment and baseline HBV DNA level. High viral load also predicted resistance P<0.000 Patients at risk CVR 273 PVR 142 127 48 8 IVR 75 27 1 Patients at risk CVR 273 231 142 55 PVR 124 80 30 IVR 140 129 88 35 Kim Y, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011; Abst

37 Conclusiones Prevención Monitoreo Adecuada elección del paciente
Adecuada elección del tratamiento Monitoreo Diagnóstico temprano

38 Conclusiones (2) Tratamiento LAM-R: TDF ADV-R: ETV o TDF o TDF/FTC
LdT: TDF TDF-R: ETV ETV-R: TDF

39 MUCHAS GRACIAS Dr. Ezequiel Ridruejo. -Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno “CEMIC” -Hospital Universitario Austral 21º Reunión Anual de Unidades Centinela 15 de Octubre de 2012