Prof. Carlos Eduardo Brandão.pdf - Academia Nacional de Medicina

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Prof. Carlos Eduardo Brandão.pdf - Academia Nacional de Medicina

TRÊS MANHÃS NA SANTA CASA25 de Setembro de 2009 . Rio de Janeiro - RJHEPATITE CRÔNICA BHBeAg Negativo: Cirrótico eNão Cirrótico - CondutaDr. Carlos Eduardo Brandão MelloProfessor Associado – Doutor e Livre DocenteEscola de Medicina e Cirurgia do Rio de Janeiro - UNRIOHospital Universitário Gaffrèe e Güinle - Unidade de Doenças do FígadoFaculdade de Medicina – UFRJ - Disciplina de Gastroenterologia


ACADEMIA NACIONAL DE MEDICINAA HEPATOLOGIA NOS DIAS DE HOJECENTENÁRIO DO PROFESSOR T. FIGUEIREDO MENDES25 de Agosto 2011 . Rio de Janeiro – RJHEPATITE CRÔNICA BNOVAS OPÇÕES TERAPÊUTICASDr. Carlos Eduardo Brandão MelloProfessor Associado – Doutor e Livre DocenteEscola de Medicina e Cirurgia do Rio de Janeiro - UNIRIOHospital Universitário Gaffrèe e Güinle - Unidade de Doenças do FígadoFaculdade de Medicina – UFRJ - Disciplina de Gastroenterologia


A Descoberta do Antígeno Austrália


O que aprendemos sobre as hepatitesvirais desde 1965?•1965 •1971 •1973 •1975BlumbergPrince Feinstone •Feinstone•AntigenoAustralia•Hepatite não-CMV,EBV ou HBVHepatiteInfecciosa•HPT, sem evidênciade HAV or HBVHBV• PTH •HAV • NANBH


Identificação do virus responsávelpela Hepatite NANB : Anos 1980•1983 •1987/1989Hollinger•Virus NANBdescoberto de terenvelope lipidico• Feinstone/ HoughtonVirus NANB / descoberto deter 30–60 nm de diametro/Descoberta do HCVTestes com ALT e Anti-HBc nosbancos de sangue


Impacto Global da Hepatite B2 bilhões com infecção por VHBPassada / Presente25 - 40% desenvolveminsuficiência hepáticacirrose, ou CHCPopulação mundial6 bilhões350 – 400 milhões comHepatite B crônica~1 milhão/ano morrem de doença hepática relacionada ao HBV10 a causa de morte no mundoWHO Fact Sheets, disponíveis no site www.who.int. Acessado em: 24 de setembro de 2004.Conjeevaram, et al. J Hepatology. 2003;38:S90-S103.Lee. N Engl J Med. 1997;337:1733-1745. Lok. N Engl J Med. 2002;346:1682-1683.


Prevalência do HBV no Brasil (população em geral)Norte(ocidental)0,8 - 28,6%••Norte(oriental)1 - 7%•Nordeste2 - 7%Centro-oesteoeste2 - 7%••Sudeste


História Natural da Infecção pelo HBVInfância> 95%ImunoTolerânciaAdulto< 5%Hepatite BCrônicaCirroseHepatite BCrônicaHBeAg-HBeAg+PortadorCourtesy of W. Ray Kim, MD.Chen DS, et al. J Gastroenterol Hep. 1993;8:470-475.Seeff L, et al. N Engl J Med. 1987;316:965-970.Inativo


Fases da Infecção Crônica pelo HBVFase de ImunotolerânciaHBV- DNA > 10 5ALT normalFase de ImunoClearenceHBV- DNA em quedaALT elevadaFase de Controle ImuneHBV -DNA < 10 5ALT normalFase de Escape ImuneHBV -DNA > 10 5ALT elevada


Fases da Infecção Crônica HBVImunoToleranciaHBeAg+HBeAg-/anti-HBe+ (precore/core promoter variants)< > HBV DNA2 x 10 8 -2 x 10 11 IU/mLImunoClearance200,000 - 2 x 10 9 IU/mLFase de BaixaReplicação< 2000 IU/mLFase de Reativação> 2000 IU/mLSlide courtesy of A. S. F. Lok, MD.


Fases da Infecção Crônica HBVImmuneToleranceHBeAg+HBeAg-/anti-HBe+ (precore/core promoter variants)< >HBV DNA2 x 10 8 -2 x 10 11 IU/mLImmuneClearance200,000 - 2 x 10 9 IU/mLLow ReplicativePhase< 2000 IU/mLReactivationPhase> 2000 IU/mLALTSlide courtesy of A. S. F. Lok, MD.


Fases da Infecção Crônica HBVImmuneToleranceHBeAg+HBeAg-/anti-HBe+ (precore/core promoter variants)< >HBV DNA2 x 10 8 -2 x 10 11 IU/mLImmuneClearance200,000 - 2 x 10 9 IU/mLLow ReplicativePhase< 2000 IU/mLReactivationPhase> 2000 IU/mLALTNormal/HCLeveHC Moderada/GraveCirroseNormal/ HC LeveCirrose inativaHC Moderada/GraveCirroseSlide courtesy of A. S. F. Lok, MD.


Fases da Infecção Crônica HBVImmuneToleranceHBeAg+HBeAg-/anti-HBe+ (precore/core promoter variants)< > HBV DNA2 x 10 8 -2 x 10 11 IU/mLImmuneClearance200,000 - 2 x 10 9 IU/mLLow ReplicativePhase< 2000 IU/mLReactivationPhase> 2000 IU/mLALTNormal/mildCHModerate/severe CHCirrhosisNormal/mild CHInactive cirrhosisModerate/severe CHCirrhosisHBeAg+chronic hepatitisSlide courtesy of A. S. F. Lok, MD.Inactive-carrier stateHBeAgchronichepatitis


Níveis de HBV DNA e Progressãode Doença Hepática – Estudo Reveal1991-1992:3851 pacientes HBsAg +Taiwan200477 excluídos: cirrose < 6 mesesAvaliação Cirrosen = 377442115 pacientes/anoseguimentoCirrose: 395 (10.5%)Avaliação CHCn = 385143993 pacientes/anoseguimentoCHC: 176 (4.5%)Chen, et al. EASL 2005Iloeje, et al. EASL 2005


Níveis de HBV DNA eIncidência de Cirrose10HBeAg Neg8,6Risco Relativo86421HBeAg Pos2,61,96,24,90HBV DNA < 10 4 10 4 – 10 5 > 10 5Copias/mL* Ajustado por sexo, idade, anti HCV, tabagismo e álcool.Iloeje et al. EASL 2005


Mortalidade Decorrente de Hepatopatia Crônicae sua relação com Carga Viral HBV-DNA BasalCurva de Distribuição Sobrevida1.000.960.920.880.840.80HBV DNA (-)HBV DNA Baixa1.6 x 10 3 - < 10 5 cp/mLRR = 1.5 (0.2-11.8)HBV DNA Alta> 10 5 cp/mLRR = 13.4 (1.9-97.1)0 1 2 3 4 5 6 7 8 9 10 11 12Tempo Sobrevida (Anos)Chen G et al. 55th AASLD, 2004. Abstract 1362


Níveis de HBV DNA e Incidênciade Carcinoma Hepatocelular140012001150Incidência CHCporr 100,0001000800600400315952200HBV DNA(cópias/ mL)0145 113< 300 300 - 10 5RR(95% CI)1.0(ref)0.9(0.5-1.9)2.4(1.3-4.5)7.2(4.0-12.9)11.6(6.7-19.9)p -- NS < .005 < .001 < .001Chen, et al. EASL 2005


HBV e Risco de CHCIncidencia % Cumulativa1210864200 1 2 3 4 5 6 7 8 9 10AnoHBsAg(+), HBeAg(+)(RR = 60.2)HBsAg+, HBeAg-(RR = 9.6)HBsAg-, HBeAg-Yang HI, et al. N Engl J Med. 2002;347:168-174.


Mortalidade por CHC de Acordo coma Carga Viral do HBV BasalCurva de Distribuição de Sobrevida1.000.960.920.880.840.80HBV DNA (-)HBV DNA Baixa1.6 x 10 3 - < 10 5 cp/mLRR = 1.8 (0.5-5.8)HBV DNA Alta> 10 5 cp/mLRR = 9.9 (3.2-31.0)0 1 2 3 4 5 6 7 8 9 10 11 12Tempo de Sobrevida (Anos)Chen G et al. 55th AASLD, 2004. Abstract 1362


HEPATITE CRÔNICA B:ALT E RISCO DE COMPLICAÇÕESN= 3233 Seguimento médio 46.8 mesesYuen et al. 2005


Papel da Biópsia Hepática em Pacientescom ALT Normal e Alta Carga Viral70Estágio de Fibrose por Grupo de ALTPacientes, %605040302024%estagio 0estagio 1estagio 2estagio 3estagio 4100PNALT(n = 57)ALT 1-1.5 ULN(n = 23)ALT > 1.5 ULN(n = 110)Lai et al. AASLD 2005. Abstract 67571.


Infecção Crônica pelo HBV:População Alvo para Tratamento Tratamento indicado:Hepatite crônica B ativa– Maior benefício (para aqueles com maior risco deprogressão da doença)– Maior chance de resposta aos agentes disponíveis “Atividadedefinida por:– ALT/AST Elevada– Atividade Necro-inflamatória na biopsia– Títulos elevados de HBV-DNA


Objetivos da Terapia em Pacientescom Infecção Crônica pelo HBV• Erradicação da infecção– Soroconversão HBsAg e HBeAg– HBV DNA Indetectável• Prevenir complicações da doença hepática– Progressão histológica para cirrose– Doença hepatica descompensada– Carcinoma Hepatocelular


Objetivos Primários Tratamento Hepatite B:Prevenção de Cirrose, CHC e ÓbitoSuppressão Sustentadada Replicação Viral HBV•Impacto da supressão viral na evolução da doença hepática A Supressão Viral Prolongada é associada a:– Redução na necroinflamação, fibrose, e cirrose– Redução na descompensação hepática– Redução nas taxas de CHC– Redução na mortalidade


Objetivos Finais do TratamentoHCB HBeAg-positivo (wild type)– Soroconversão HBeAg é Fundamental– Supressão Sustentada do HBV-DNA para níveis baixos ouindetectaveis– Normalização da ALT– Redução da atividade necro-inflamatória na biopsiaHCB HBeAg-negativo (mutantes pre-core e core promoter)– Soroconversão de HBeAg não é o objetivo final– Supressão Sustentada do HBV-DNA para níveis baixos ouindetectaveis– Normalização da ALT– Redução da atividade necro-inflamatória na biopsia


Indicação de Tratamento na Hepatite BHBeAg+HBV DNA(copias/mL)ALT< 10 5 NormalCondutaMonitorar, semtratamento+Considerar biópsia;≥ 10 5Normal tratar se houverdoença ativa+ ≥ 10 5 Elevada Tratar––< 10 4 Normal≥ 10 4NormalMonitorar, semtratamentoConsiderar biópsia;tratar se houverdoença ativa– ≥ 10 4 Elevada TratarKeeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87-106.


Tratamento da Cirrose pelo HBVCompensadaHBV DNA (copias/mL) Algoritmo US [1] Guideline AASLD [2]< 10 4[1] OU < 10 5[2] Tratar ou monitorar Monitorar≥ 10 4[1] OU ≥ 10 5[2] Tratamento a longo prazo Tratamento a longo prazoHBeAg status positivo ou negativoDescompensadaHBV DNA (copias/mL) Conduta [1,2]< 10 3 OU ≥ 10 3[1]≥ 10 5 (ou inferior) [2]Tratamento a longo prazoreferenciar para transplanteHBeAg status positivo ou negativo1. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87-106.2. Lok AS, et al. Hepatology. 2004;39:857-861.


AASLD Guidelines for ChronicHepatitis B Treatment Initiation•ALT < 1 x ULN•HBeAg PositiveALT > 2 x ULN•ALT < 1 x ULN•HBeAg NegativeALT > 2 x ULN•Monitor patient •HBV DNA •HBV DNA •HBV DNA•> 20,000 IU/mL •< 2000 IU/mL •≥ 20,000 IU/mL•Treat if persistent •Monitor patient •Treat if persistent•ALT 1-2 x ULN•ALT 1-2 x ULN•HBV DNA > 20,000 IU/mL•Consider biopsy if persistent•or > 40 yrs; treat if needed•Lok AS, et al. Hepatology. 2007;45:507-539.•HBV DNA•2000-20,000 IU/mL•Consider biopsy; treat if needed


Tratamento para Hepatite Crônica B: 2011•1992•1998 •2002 •2005•2006•2008 e Além…• IFNalfa•LAM•ADV•ETV• LdT•PegIFN alfa-2a•“A Nova Era”•Terapia Oral•TDF•Clevudina*•Combinação?


Algoritmo de Tratamento daHepatite B HBeAg Positivo: 2011•HBeAg positivo•HBV DNA•< 20,000 IU/mL•HBV DNA•≥ 20,000 IU/mL Não tratar Monitorar a cada 6-12meses•ALT normal Monitorar ALT cada 3-12meses (imuno tolerante) Consider e biópsia, se> 35-40 anos e tratar sehouver doença significativa•Keeffe EB, et al. DDW 2008. SP198. Keeffe EB, et al. Clin Gastroenterol Hepatol.2006;4:936-962.•ALT elevada Tratar atéSoroconversão HBeAgETV, TDF ePeg-IFN são as primeirasopções


Resposta Virologica em Pacientes HBeAg+(HBV-DNA Indetectável* na Semana 48-52)• Pacientes com HBV DNA Indetectavel• (%)•100•80•60•40•20•0•Not head-to-head trials; different patient populations and trial designs•0-16•PLB•40-44•21•Adapted from Lok AS, et al. Hepatology. 2007;45:507-539. Heathcote EJ,et al. AASLD 2007. Abstract LB6.•76•67 •69•60•*By PCR based assay (LLD ~ 50 IU/mL) except for some LAM studies.•25•LAM •ADV •ETV •LdT •TDF •Peg-IFN•Peg-IFN +LAM


Resposta Virológica em Pacientes HBeAg+(Soroconversão HBeAg na Semana 48-52)•Pacientes Obtiveram(%)•100•HBeAg Seroconversão (%)•80•60•40•20•0•Not head-to-head trials; different patient populations and trial designs•4-6•PLB•16-21•12•21•*Response 6 months after stopping treatment.•22 •21•32*•27•27*•24•LAM •ADV •ETV •LdT •TDF •Peg-IFN•Peg-IFN +LAM•Adapted from Lok AS, et al. Hepatology. 2007;45:507-539. Heathcote EJ,et al. AASLD 2007. Abstract LB6.


Algoritmo de Tratamento daHepatite B HBeAg Negativo:2011•HBeAg negativo•HBV DNA•< 2000 IU/mL•HBV DNA•≥ 2000 IU/mL Não tratar Monitorar cada6-12 meses•ALTnormal Monitorar ALT e HBV DNA,ou considerar biópsia, se ALTestiver flutuante e tratar sehouver doença significativa•ALTelevada Tratamento a longoprazo ( ETV, TDF,ou PegIFN são asopções de primeira linha•Keeffe EB, et al. DDW 2008. Abstract 198.


Recomendações para o TratamentoInicial em Pacientes HBeAg-NegativoAASLD 2007 [1] US Algorithm 2008 [2] EASL 2009 [3]HBV DNA, IU/mL > 20,000 ‡ > 2000 ≥ 2000ALT, x ULN* 1 a > 2 > 1 > 1Estágio/Grau daDoençaTerapia PrimeiralinhaADV, † ETV,pegIFNNecroinflamação Moderada/Gravee/ou Fibrose significativaETV, TDF,pegIFNETV, TDF,pegIFN*Persistent (> 3-6 mos). † TDF not FDA approved at time of publication. ‡ Consider liverbiopsy if > 2000 IU/mL and treat if moderate/severe inflammation and/or fibrosis found.Criteria for HBV DNA, ALT and disease stage/grade must all be met– If not, guidelines recommend monitoring and consideration of treatmentbased on individual’s age, health status, and stage of infection/disease1. Lok A, et al. Hepatology. 2007;45:507-539. 2. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. 3. EASL HBV Guidelines. Journal of Hepatology. 2009;50:227-242.


Resposta Virológica em Pacientes HBeAg-(HBV-DNA Indetectavel* na Semana 48-52)•Patients With Undetectable•HBV DNA (%)•Not head-to-head trials; different patient populations and trial designs•100•80•60•40•20•0•~ 70•51•90•88•93•63•*By PCR based assay (LLD ~ 50 IU/mL) except for some LAM studies.•Adapted from Lok AS, et al. Hepatology 2007;45:507-539. Marcellin P, et al. AASLD2007. Abstract LB2.•87•LAM •ADV •ETV •LdT •TDF •Peg-IFN•Peg-IFN +LAM


HBV-DNA Indetectável* em Pacientes HBVApós 1 Ano de TratamentoIndetectavel* HBV DNA (%)100806040200Not head-to-head trials; different patient populations and trial designsHBeAg Positivo6740-4413-2110076 8060 60-736051-634020*By PCR-based assay (LLD ~ 50 IU/mL) except for some LAM studies.HBeAg Negativo90 88 910LAM ADV ETV LdT TDF LAM ADV ETV LdT TDFLok A, et al. Hepatology. 2007;45:507-539. EASL HBV Guidelines. Journal of Hepatology. 2009;50:227-242.


Seroconversão do HBeAg Durantea Continuidade do Tratamento•Patients (%)•Not head-to-head trials; different patient populations and trial designs•100•100•LAM•ADV•80•80•60•40•20•0•100•80•60•40•20•0•22•21•29•31•40•ETV•37•47•47*•50•1 •2 •3 •4 •5•Years of Therapy•Chang TT, et al. J Gastro Hepatol. 2004;19:1276-1282. Lok AS et al. Gastroenterol. 2003;125:1714-1722. Chang TT, et al. N Engl J Med.2006;354:1001-1010. Chang TT, et al. Hepatology. 2006;44(suppl 1):229A. Marcellin P, et al. N Engl J Med. 2003;348:808-816.Marcellin P, et al. Hepatology. 2006;44(suppl 1):548A. Lai CL, et al, Hepatology. 2005;42(suppl 1):748A.Lai CL, et al. Hepatology. 2006;44(suppl 1):222A. Han S, et al. AASLD 2007. A938.•60•40•20•0•100•*(ETV-022 + ETV-901) 16% additional to 31% HBeAg seroconversion in ETV-022 (Year 2).•80•60•40•20•0•12•23•29•LdT•48•1 •2 •3 •4 •5•Years of Therapy


Normalização da ALT e MelhoraHistológica Após 1 Ano de TratamentoHBeAg PositivoOutcome, % LAM ADV ETV LdT TDFNormalização da ALT 41-75 48 68 77 69Melhora Histológica 49-56 53 72 65 74HBeAg NegativoOutcome, % LAM ADV ETV LdT TDFNormalização da ALT 60-79 72 78 74 77Melhora Histológica 60-66 64 70 67 72*Significant variation in the baseline HBV DNA and ALT between trials.Lai CL, et al. N Engl J Med. 1998;339:61-68. Dienstag JL, et al. N Engl J Med. 1999;341:1256-1263.Lau GK, et al. N Engl J Med. 2005;352:2682-2695. Chang TT, et al. N Engl J Med. 2006;354:1001-1010.Lai CL, et al. N Engl J Med. 2007;357:2576-2588. Marcellin P, et al. N Engl J Med. 2003;348:808-816.Marcellin P, et al. 2008;359:2442-2455.


•Resposta Sustentada após 4 anos de Follow-up Peg-IFN α-2ana HCB HBeAg-neg3025•27•24•PEGASYS +/– LAM (N=230)•LAM (N=85)•Pacientes (%)20151050•18•16•ALT normal •


•Valor Preditivo da Redução dos Níveis de HBsAg (48ªSemana) no Clearance do HBsAg ao final de 3 anos• Pacientes comclearance HBsAg(%)1009080706050403020100•Redução do HBsAg• do BL a semana 48•RR = 14.6 (95% CI 5.5 – 38.5)•P2 log IU/mL •


•Taxa de Resposta Sustentada ao PEG-IFNα2a de acordo com o qHBsAg na semana12 de tratamento de 156 pacientes•Níveis de HBsAg•≤1500 IU/mL (n=61)•Níveis HBsAg•>1500 IU/mL•(n=95)•An HBsAg cut-off of 1500 IU/mL at week 12 resulted in a PPV of 39%, 31% and 23% for achieving HBVDNA levels ≤10,000 copies/mL, ≤400 copies/mL and HBsAg clearance 4 years post treatment.•The corresponding NPV were 88%, 92% and 96%, respectively•Marcellin et al, AASLD 2008


•48-wk PEG alpha 2a for HBeAg-neg patients: kinetics of HBV DNA and qHBsAg inSVR* and REL•HBV DNA levels•HBsAg levels•REL•REL•SVR•SVR•SVR (N=12): HBV DNA < 70 cp/ml at week 48 and 72•REL (n=18): HBV DNA < 70 at week 48•Moucari et al, Hepatology 2009


•48 semanas de PEG IFNα-2a para HBeAg (-) :•Níveis séricos de HBsAg na Semana 12 e 24•Moucari et al, Hepatology 2009


Resposta Virológica c/ Terapia com Analógospor 48 semanas na HBC HBeAg (-) virgens de tratamento•*Collation of currently available data – not from head-to-head studies•(LLQ of HBV DNA assays: 300-400 copies/ml)•% Pacienets com HBV DNA


• 3-anos ETV na HCB HBeAg-neg –•Re-Tratamento Resposta Virológica•ETV-027•ETV-901•Proporção de pacientes (%)HBV DNA 60 days•93% •94% •95%•91%•83%•59%•4%•EOD † Baseline Sem 12 Sem 24 Sem 48 Sem 72 Sem 96 Sem 144•n= 93/99 4/99 56/95 79/95 84/90 72/77 67/74 54/57 ‡• † EOD= end-of-dosing‡10 patients who remained on treatment at the Week 144 of ETV-901 visit had missing PCR samples•D. Shouval et al , AASLD 2008


Adefovir Para Pacientes HBeAg-NegativoResposta Virológica e BioquímicaPercentagem de Pacientes10080604020068%HBV DNA< 1000 copias/mLNormalização daALT77% 78%75%71% 72%75%67% 67% 69%48 96 144 192 240 48 96 144 192 240Duração Tratamento (Semanas)n = 69 58 69 65 55 64 53 64 59 55Hadziyannis S, et al. EASL. 2005. Abstract 492. Hadziyannis S, et al. AASLD 2005. Abstract LB14.


•ADV mono por 5 anos em pacientes HBeAg-:Avaliação Histológica•Necro-inflamação•Fibrose•100•Pacientes (%)•80•60•40•20•Piora•Inalterado•Melhora•0•Ano 4•Ano 5•Ano 4•Ano 5•(n=22)•(n=24)•(n=22)•(n=24)•*Maior do que ou iqual a 2 pontos de melhora no escore de Knodell sem piora na fibrose•Hadziyannis S et al, Gastroenterology 2006


Resultados a Longo Prazo do Tratamento ComAdefovir em Pacientes HBeAg-Negativo5% dos pacientes tiveramperda do HBsAg no 5 o anoPercentagem de Pacientes> 50% obtiveram regressãoda fibrose em pontes ou80cirrose no 5 o ano65 67 7069redução ≥ 1-ponto no escorede fibrose (Ishak)– 4 o Ano: 55%– 5 o Ano: 71%1006040200Ano 4 Ano 5HBV DNA< 3 log 10 copias/mLALT Normaln 30 55 40 55Hadziyannis S, et al. AASLD 2005. Abstract LB14.


Níveis de HBV-DNA durante o follow-up emRespondedores bioquímicos sustentados apósparar o tratamento com ADV•100%•>10,000 copias/mL•90%•80%•50%•43%•25%•34%•30%•Detectavel


2-anos TDF vs ADV na HCB HBeAg-neg.(análise por ITT)• % Pacientes com HBV DNA• < 400 cp/ml (95%CI)•100•90•80•70•60•50•40•30•20•10•0•TDF•TDF•TDF•ADV•Randomized Double Blind•Open Label•0 •8 •16 •24 •32 •40 •48 •56 •64 •72 •80 •88 •96•91%•89%•P=0.672•18% LAM Exp:• 93%• 96%•Semanas no Estudo•TDF-TDF •N= •250 •245 •243 •248 •247 •242 •243 •234•ADV-TDF •N= •125 •125 •124 •120 •123 •123 •122 •122•Marcellin P, et al., AASLD 2008; Oral # 146.


Conceitos de Resistência ViralResistência Genotípica= emergência de uma nova substituição de amino ácido na presençade droga com consequente diminuição da suscetibilidade à mesmaResistência Fenotípica= diminuição no nível de suscetibilidade comparado com a cepaselvagem, usualmente expressa como ‘fold change’Droga AntiviralEmergência de resistência à drogaHBV DNAlog 10nadir1 log 10Viral breakthrough ouRebote Virológico= aumento confirmado deHBV DNA ≥ 1 log 10 do nadirplasmáticoTempoEva Wolf. HIV Medicine 2005; Chapter 9:311–313Adapted from: Locarnini S, et al. Antivir Ther 2004; 9:679–693


Resistência Genotípica, Rebote Virológico e ReboteBioquímico: Definições do NIHDetecçãode resistênciagenotípicaReboteVirológicoReboteBioquímicoDNA do VHB (log 10 cópias/ s/mLNadir1 log 10ALT (UI/L)1 x LSNMedicamento antiviralTempoLok A e cols. Program of the 2006 Management of Hepatitis B Virus Meeting: 2006, Bethesda, EUA.


Análogo de nucleos(t)ídioResistênciavirológicaResistênciaclínicaDNAResistênciagenotípicaLimite dedetecçãoInício1 ano 2 anos 3 anos


Conseqüências da Resistência Viral Recidiva viral ( HBV DNA ) Elevação das aminotransferases (ALT) Menor taxa de seroconversão do HBeAg Perda da melhora histológica Descompensação clinica Prognóstico pior se houver cirrosePerrillo RP, et al. Hepatology. 2002;36:186-194. Leung NW, et al. Hepatology. 2001;33:1527-1532.


Incidência de Resistência em Pacientes•80virgens de Analógos Nucleos(t)ídicos•70•67•60•Pacientes (%)•40•20•24•38•49•18•29•17•11•0•3 •4•0.5 •1.2•?•0•0.2•1.2 •1.2•0 •0 •?•LAM •ADV •LDT •ETV •TDF•adaptado da EASL CPG HBV, J Hepatol 2009, in press


Menor Resistência à Lamivudina comSuppressão Precoce do HBV100HBVDNA Serico no 6 o Mes vsResistencia a Lamivudina no 61 o MesPacientes, %80604032%64%208%13%0< 200 < 3 log 10 < 4 log 10 > 4 log 10(n = 12) (n = 23) (n = 41) (n = 118)Nivel Serico de HBVDNA no 6 o Mes (copias/mL)Yuen et al. Hepatology. 2001; 34:785-791.


Menor Resistência com SupressãoPrecoce do HBV DNAPatients (%)1008060402008< 200(n = 12)Serum DNA at Month 6 vsLamivudine Resistance byMonth 6113< 3 log 10(n = 23)32< 4 log 10(n = 41)Month 6 HBV DNA (copies/mL)Yuen M, et al. Hepatology. 2001; 34(4):785-791.Locarnini S, et al. J. Hepatology 2005;42(suppl 2):17.64> 4 log 10(n = 118)Serum HBV DNA at Week 48vs Adefovir Resistance byWeek 1444< 3 log 10(n = 80)263-6 log 10(n = 31)67> 6 log 10(n = 3)Week 48 HBV DNA (copies/mL)


Supressão Profunda e Precoce da ViremiaCorrelaciona-se com Resposta Sustentada MaiorPatients PCR Negativeat Follow-up (%)100806040200PegIFN alfa-2a atWeek 72 HBeAg-Patients6131HBV DNA at Week 12LAM at Week 52HBeAg+PatientsZeuzem S. EASL 2006. Abstract 51. Farci P, et al. J Hepatol. 2005;42(suppl 2):175. Yurdaydin C, et al. EASL 2006. BMS symposium.8420ETV at Week 52 LdT at Week 52HBeAg+ Patients HBeAg+ Patients96 95n = 70 106 146 317 160 153 203 255< 400c/mL≥ 400c/mL< QL ≥ QL < QL ≥ QL < QL ≥ QL50HBV DNA at Week 2433


•4-anos de ADV+LAM em 94 Cirróticos LAM-R,Complicações relacionadas ao Fígado100806040•CHC•Descompensação200•15%0 6 12 18 24 30 36 42 48 •Meses•0%•Pacientes•Com risco•94 •92 •89 •86 •68 •53 •46•94 •94 •93 •89 •71 •58 •51•27•30•10•10•Lampertico P. et al, Gastroenterology 2007


ADV Monoterapia: Troca vs Adição emPacientes Cirróticos Resistentes à LAMCaracterísticas Baseline Final deTratamento P ValueAdefovir Monoterapia (n = 18) ALT, IU/L 262 57 .001 HBV DNA, copias/mL 2.4 x 10 8 2.3 x 10 5 < .001Adefovir + Lamivudina (n = 10) ALT, IU/L 246 35 .013 HBV DNA, copias/mL 1.57 x 10 8 4.36 x 10 4 .005Liaw Y, et al. J Viral Hepat. 2006;13:250-255.


Adefovir para a Infecção Crônica peloHBV Resistente à LamivudinaEvoluçãoAlteração média na carga viral,copias/mL Semana 16 Semana 48HBV DNA < 1000 copias/mL naSemana 48, %Adefovir(n = 19)-3.11-4.00Lamivudina(n = 19)0.00-0.31Adefovir+Lamivudina(n = 20)-2.95-3.4626 0 35Peters MG, et al. Gastroenterology. 2004;126:91-101.


ADV vs ADV + LAM para Pacientescom Resistência à LAMMedian: 18 Months(Range: 12-30)Individuals withchronic HBV infectionon lamivudine therapywith lamivudineresistance(N = 52)Switch to Adefovir(n = 29)Lamivudine maintained + Adefovir(n = 23)Marzano A, et al. AASLD 2006. Abstract 113.


ADV vs ADV + LAM para Pacientescom Resistência à LAM Nonsignificant trend toward better efficacy outcomes withcombination therapy– Better responses in both groups for individuals with lowerbaseline viral loadOutcome at Month 18, % Adefovir Adefovir +LamivudineP ValueComplete virologic response* 55 83 NS HBV DNA < 5 log 10 copies/mL atbaseline HBV DNA > 5 log 10 copies/mL atbaseline100 100 NS38 81 < .05ALT normalization 80 91 NS*Undetectable HBV DNA by PCR.Marzano A, et al. AASLD 2006. Abstract 113.


ADV vs ADV + LAM para PacientesHBeAg-Negativo Resistentes à LAM- Multicenter cohort study; retrospective/prospective– Mean follow-up: 33 monthsPatients (%)Undetectable HBV DNA* (%)100Adefovir + lamivudine (n = 285)100Adefovir (n = 303)8080604020P = NS00 6 12 18 24 30 36*< 1000 copies/mL.MonthLampertico P, et al. AASLD 2006. Abstract LB5.6040200Year 3 Cumulative AdefovirResistance16ADV(n = 303)P < .0010ADV +LAM(n = 285)


Resistência Adefovir Não Observada ComTerapia Combinada de LamivudinaIncidence of Resistance (%)60402000 0Adefovir monotherapy (Study 438)Adefovir + lamivudine (lamivudine resistanceStudies 435 and 460i)*Study 435: pre- and post-OLTStudy 460i: HIV/HBV3011Year 1 Year 2 Year 3 Year 4 Year 5019030*2 patients enrolled in Study 435, initially on combination therapy with adefovir + lamivudine, andsubsequently selected adefovir resistance mutation N236T. However, they were on adefovir monotherapywhen adefovir resistance mutation was detected.Lee YS, et al. Hepatology. 2006;43:1385-1391. Lampertico P, et al. AASLD 2006.Abstract LB5. Schiff E, et al. Liver Transpl. 2007;13:349-360. Hepsera [package insert].Foster City, Calif: Gilead Sciences; 2006.


Manuseio da Resistência do HBVResistência ä Lamivudina• Adicionar Adefovir ou TenofovirResistência ä Telbivudina• Adicionar Tenofovir*Resistência ao EntecavirResistência ao AdefovirResistência ao Tenofovir *• Adicionar Tenofovir*• Trocar p/ Tenofovir e adicionar uma 2a droga Se N236T, adicione lamivudina, entecavir* outelbivudina* ou troque para Truvada Se A181V/T, adicione entecavir* ou troque paraTruvada• Genotipar e fenotipar para determinar o perfilde resistência cruzada• Adicionar entecavir*, telbivudina*, lamivudineou mude para Truvada•*the long-term safety of these combinations is unknown•**not seen so far•adaptado da EASL CPG HBV, J Hepatol 2009, in press


Prevenção da Resistência à LamivudinaCom a Terapia Combinada de Novo100Incidence of Resistance After 1 Year of TherapyPatients (%)806040200Sung [1] Marcellin [2] Lau [3] Lai [4]20 182 1342111 12LAM LAM + LAM LAM + LAM LAM + LAMADVPegIFN PegIFNLAM +LdT1. Sung J, et al. J Hepatol. 2003;38(suppl 2):25-26.2. Marcellin P, et al. N Engl J Med. 2004;351:1206-1217.3. Lau G, et al. Hepatology. 2004;40:171A.4. Lai C, et al. Hepatology. 2003;38:262A.


Progressão Retardada da Doença ComSupressão Continuada : Não-cirróticos 76.3% of lamivudine-treated patients had YMDD mutations at Year 6– Benefits of treatment reduced for those with YMDD mutationsPatients WithCirrhosis/HCC (%)14121086420Lamivudine(WT)P = .390P = .005Lamivudine(YMDD)P = .024ControlsYuen MF, et al. AASLD 2005. Abstract 985.


Tenofovir vs Adefovir em Pacientescom Resistencia a LamivudinaHBV DNA(log 10 copias/mL)Adefovir(10 mg/day)Tenofovir(300 mg/day)SemanasVan Bommel et al. Hepatology. 2004;40:1421-1425.


Algoritmo para Tratamento da Hepatite Crônica pelo HBVAvaliação da Resposta Virológica Primária (Semana 12)Resposta Virológica1 log redução da CV basalFalha Terapêutica Primária< 1 log redução da CV basalAvaliação da Resposta Virológica (Semana 24)Resposta Virológica CompletaPCR negativoResposta Virológica Parcial> 60 a < 2000 UI ou> 300 a 10000 copiasAusência de Resposta Virológica> 2000 UI ou> 10.000 copiasContinuar Terapiae monitorar a cada6 mesesDroga com baixa barreiragenética:Adicionar 2ª drogae monitorar de 6/6 mesesDroga com alta barreiragenética: monitorar de 3/3Meses e avaliar na sem.48Adicionar droga mais potentee monitorar de 3/3 mesesc/ Resposta Completana sem. 48: Continuars/ Resposta Completana sem. 48: adicionarKeeffe et al. 2007


Roadmap de Acordo com aResposta Virológica na Semana 12•Start treatment•Week 12•Assess for primary nonresponsePrimary responseHBV DNA ≥ 1 log 10 IU/mL dropPrimary treatment failureHBV DNA < 1 log 10 IU/mL dropContinueIf nonadherent,counselIf adherent,add a morepotent drug•Keeffe E, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.


Roadmap de Acordo com aResposta Virológica na Semana 24•Patients with primary response•Week 24•Assess early predictors of efficacy•Complete response•HBV DNA negative by PCR•Partial response•HBV DNA•60 to < 2000 IU/mL•Inadequate response•HBV DNA ≥ 2000 IU/mL•Continue therapy;•monitor every 6 months•Add a more potent drug;•monitor every 3 months•Keeffe E, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.


Roadmap de Acordo com aResposta Virológica na Semana 24•Patients with primary response•Week 24•Assess early predictors of efficacy•Antiviral: low geneticbarrier•Add a second drug withoutcross-resistance•Partial response•HBV DNA•60 to < 2000 IU/mL•Antiviral: high geneticbarrier•Monitor every 3 months;continue to ≥ 48 weeks•Is there a•rationale for•switching?•Antiviral: suboptimalantiviral potency•Monitor every 3 months;continue to 48 weeks*•*If incomplete response at 48 weeks, add a more potent noncross-resistant antiviral.•Keeffe E, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.


Tratamento da Hepatite B: SumárioOpções Terapêuticas Disponíveis: PegIFN, LAM, ADV, ETVPegIFN somente em pacientes compensadosPegIFN apresenta eficácia superior à LAMEntecavir apresenta eficácia superior à LAMResistência ocorre com todos os agentes orais; exceto o PegIFNAdefovir e entecavir nunca foram comparados face a facePegIFN vs adefovir ou entecavir não avaliado


Current Treatment Options for Hepatitis BIOM Report: Burden of HBV Disease 1 15% to 25% risk of early death caused by liver cancer orend-stage liver disease among patients with chronicHBV infection 2,3 WHO global HBV estimates 3– ~ 2 billion people ever infected with HBV– ~ 350 million people living with chronic HBV infection– ~ 600,000 deaths annually caused by HBV-related liverdisease or HCC1. Institute of Medicine. Hepatitis and liver cancer: a national strategy for prevention and control ofhepatitis B and C. 2010. 2. Beasley R et al. In: Hollinger FB, Margolis H, Lemon SM, editors. Viralhepatitis and liver disease. Proceedings of the 1990 international symposium on viral hepatitis andliver disease: contemporary issues and future prospects. 1991. 3. WHO. Hepatitis B fact sheet.clinicaloptions.com/hep•75


Current Treatment Options for Hepatitis BNatural History of HBV InfectionEarlyChildhood> 95%ImmuneToleranceAdulthood< 5%HBeAg-ChronicHepatitis BCirrhosisHBeAg+ChronicHepatitis BInactiveCarrierCourtesy of W. Ray Kim, MD.Chen DS et al. J Gastroenterol Hepatol. 1993;8:470-475.Seeff L et al. N Engl J Med. 1987;316:965-970.clinicaloptions.com/hep•76


Current Treatment Options for Hepatitis BAASLD CHB Guidelines: Treatment Candidacyfor HBeAg-Positive PatientsHBsAg PositiveHBeAg PositiveALT < 1 x ULNHBV DNA < 20,000 IU/mLALT 1-2 x ULNHBV DNA > 20,000 IU/mLALT > 2 x ULNHBV DNA > 20,000 IU/mLQ 3-6 mos ALTQ 6-12 mos HBeAgQ 3 mos ALTQ 6 mos HBeAgConsider biopsy ifpersistent or age > 40Rx as neededQ 1-3 mos ALT, HBeAgTreat if persistentLiver bx optionalImmediate Rx if jaundice ordecompensatedLok AS, McMahon BJ. Hepatology. 2009;50:661-662. Chronic Hepatitis B: Update 2009, Lok ASF,McMahon BJ, www.aasld.org. Copyright@2009. American Association for the Study of LiverDiseases, Reproduced with permission of the American Association for the Study of Liver Diseases.clinicaloptions.com/hep•77


Current Treatment Options for Hepatitis BAASLD CHB Guidelines: Treatment Candidacyfor HBeAg-Negative PatientsHBsAg PositiveHBeAg NegativeALT < 1 x ULNHBV DNA < 2000 IU/mLALT 1-2 x ULNHBV DNA 2000-20,000 IU/mLALT ≥ 2 x ULNHBV DNA ≥ 20,000 IU/mLQ 3 mos ALT x 3,then Q 6-12 mos ifALT still < 1 X ULNQ 3 mos ALT and HBV DNAConsider biopsy if persistentRx as neededTreat if persistentLiver biopsy optionalLok AS, McMahon BJ. Hepatology. 2009;50:661-662. Chronic Hepatitis B: Update 2009, Lok ASF,McMahon BJ, www.aasld.org. Copyright@2009. American Association for the Study of LiverDiseases, Reproduced with permission of the American Association for the Study of Liver Diseases.clinicaloptions.com/hep•78


Current Treatment Options for Hepatitis BTreatment Criteria for Chronic Hepatitis B:Comparison of Liver Society Guidelines Recommended HBV DNA and ALT levels outlined in thefollowing tableLiver SocietyGuidelines*HBeAg PositiveHBeAg NegativeHBV DNA, IU/mL ALT HBV DNA, IU/mL † ALTEASL 2009 1 > 2000 > ULN ‡ > 2000 > ULN ‡APASL 2008 2 ≥ 20,000 > 2 x ULN ‡ ≥ 2000 > 2 x ULN ‡AASLD 2009 3 > 20,000> 2 x ULN § orpositive biopsy≥ 20,000≥ 2 x ULN § orpositive biopsy*Although ALT and HBV DNA are primary tests used to determine treatment candidacy, the levels ofelevation that warrant consideration of treatment are not universally agreed upon.†Some experts recommend in patients older than 40 yrs of age, 2000 IU/mL should be considered as acutoff for treatment.‡Laboratory normal.§30 U/L for men and 19 U/L for women.1. EASL. J Hepatol. 2009;50:227-242. 2. Liaw YF et al. Hepatol Int. 2008;3:263-283.3. Lok AS et al. Hepatology. 2009;50:661-662.clinicaloptions.com/hep•79


Current Treatment Options for Hepatitis BThe Twin Pillars of HBV TherapyPROFOUND VIRALAVOIDANCESUPPRESSIONOF RESISTANCEJacobson IM. J Hepatol. 2008;48:687-691.clinicaloptions.com/hep•80


Current Treatment Options for Hepatitis BThe Goal of HBV TherapyLong-termViral SuppressionImproved Clinical OutcomesRequires finite course of therapy in some patients– HBeAg seroconversionLong-term treatment in others– HBeAg-positive without seroconversion– HBeAg-negativeclinicaloptions.com/hep•81


Current Treatment Options for Hepatitis BGoals of Hepatitis B TreatmentPrevention of long-term negative clinical outcomes (eg, cirrhosis,HCC, death) by durable suppression of HBV DNARemission of liver diseasePrimary treatment endpoint– Sustained decrease in serum HBV DNA level to low or undetectableSecondary treatment endpoints– Decrease or normalize serum ALT– Induce HBeAg loss or seroconversion– Induce HBsAg loss or seroconversion– Improve liver histologyclinicaloptions.com/hep•82


Current Treatment Options for Hepatitis BHBV Treatment Landscape in 2011Peginterferon alfa-2aLamivudineEntecavirTenofovir1990 1998 2002 2005 2006 2008Interferon alfa-2b Adefovir Telbivudineclinicaloptions.com/hep•83


Current Treatment Options for Hepatitis BTreatment Guidelines: Recommendations forFirst-line TherapyHBeAg Positive or Negative Chronic HBVPreferred Alternative Not PreferredTenofovir DF Adefovir LamivudineEntecavir Telbivudine*Peg-IFN alfa-2a*HBV DNA must be undetectable at 24 weeks to continueLok AS et al. Hepatology. 2009;50:661-662. Available at: http://www.aasld.org.Keeffe EB et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.clinicaloptions.com/hep•84


Current Treatment Options for Hepatitis BUndetectable* HBV DNA (%)Undetectable* HBV DNA After1 Year of TreatmentNot head-to-head trials; different patient populations and trial designs10080604020040-44HBeAg Positive13-216067LAM ADV LdT ETV76TDF25Peg-IFN10080604020060-7351-63HBeAg Negative8890LAM ADV LdT ETV93TDF63Peg-IFN*By PCR-based assay (LLD ~ 50 IU/mL) except for some LAM studies.Lok AS et al. Hepatology. 2007;45:507-539. Lok AS et al. Hepatology. 2009;50:661-662.clinicaloptions.com/hep•85


Current Treatment Options for Hepatitis BHBeAg Loss and Seroconversion in HBeAg+Patients After 1 Year of Treatment100Not head-to-head trials; different patient populations and trial designsHBeAg Loss100HBeAg Seroconversion8080Outcome (%)604020017-32242621NA30LAM ADV LdT ETV TDF Peg-IFN6040200222312-18 21 2122-27LAM ADV ETV LdT TDF Peg-IFNLok AS et al. Hepatology. 2007;45:507-539. Lau GK et al. N Engl J Med. 2005;352:2682-2695.Marcellin P et al. N Engl J Med. 2003;348:808-816. Chang TT et al. N Engl J Med.2006;354:1001-1010. Lai CL et al. N Engl J Med. 2007;357:2576-2588. Marcellin P et al. N EnglJ Med. 2008;359:2442-2455. Janssen HL et al. Lancet. 2005;365;123-129.clinicaloptions.com/hep•86


jb3Current Treatment Options for Hepatitis BDurability of HBeAg SeroconversionNot head-to-head trials; different patient populations and trial designsAgentnPosttreatmentTimepointSustained HBeAgSeroconversion, %Peginterferon 1 72 24 wks 82Lamivudine 1-4 61 24 wks7243 52 wks935524 wks5839 40.7 mos*77Adefovir 5 45 150 wks* 91Telbivudine 3 55 52 wks 86Entecavir 2 70 24 wks 77*Median follow-up.1. Lau GK et al. N Engl J Med. 2005;352:2682-2695. 2. Gish RG et al. Gastroenterology.2007;133:1437-1444. 3. Poynard T et al. J Hepatol. 2008;48(Suppl 2):S263-S264. 4. Dienstag JLet al. Hepatology. 2003;37:748-755. 5. Wu IC et al. Clin Infect Dis. 2008;47:1305-1311.clinicaloptions.com/hep•87


Slide 87jb3This is a new slide. Dr. Afdhal, is this what you meant by durability of HBeAg response?jblanchett; 21/10/2010


Current Treatment Options for Hepatitis BOutcome (%)Other Outcomes in HBeAg+ PatientsAfter 1 Year of TreatmentNot head-to-head trials; different patient populations and trial designs1008060404841-757768 6872 74655349-56 50-8039 38~ 90~ 8069LAMADVLdTETVTDFPeg-IFN200ALT*No/short duration Normalization consolidation tx among ImprovementLAM- and ETV-treated Durability* pts; most ptstreated with ADV and LdT had consolidation.Lok AS et al. Hepatology. 2009;50:661-662.HistologicNA NA 1 0 0 2 3.2 3Response HBsAg Lossclinicaloptions.com/hep•88


Current Treatment Options for Hepatitis BOther Outcomes in HBeAg-NegativePatients After 1 Year of TreatmentNot head-to-head trials; different patient populations and trial designsOutcome (%)100 LAMADV80604072 74 78 76676460-79 60-6638707248LdTETVTDFPeg-IFN200ALTHistologic< 10~ 5NA3 NAResponse~ 20NormalizationLok AS et al. Hepatology. 2009;50:661-662.ImprovementDurabilityclinicaloptions.com/hep•89


Current Treatment Options for Hepatitis BHBeAg-Positive Patients Treated Upto 5 Years With EntecavirProportion of Patients Achieving HBV DNA < 300 copies/mL through 5 YrsPatients (%)ETV-022Overall CohortHBeAg-Positive ETV Long-term Cohort(ETV-022 → ETV-901)Yr 1Yr 1 Yr 2 Yr 3 Yr 4 Yr 51008389 91 948067605540200n = 236/354 80/146 116/140 116/131 98/108 88/94Han S-H et al. Hepatology. 2008;48(Suppl S1):705A.clinicaloptions.com/hep•90


Current Treatment Options for Hepatitis BTenofovir Pivotal Study 103 (HBeAg Positive):Three-Year Viral Suppression (Not ITT)(%) Patients withHBV DNA < 400 copies/mL1009080706050403020100Randomized Double-BlindOpen-Label TDF0 24 48 72 96 120 144Weeks on StudyIncludes 17 patients who had HBV DNA


Current Treatment Options for Hepatitis BHBeAg Seroconversion Rates OverTime in HBeAg-Positive PatientsNot head-to-head trials; different patient populations and trial designsHBeAg Seroconversion (%)80604020•Extended Treatment With Nucleos(t)ide Analogues* vsLimited Duration (1 Yr) Peginterferon Treatment21 2222-2701.0 Yr 1.5-2.0 Yrs 3.0-4.0 Yrs*With sustained undetectable HBV DNA.312629-32392635EntecavirTenofovirPeginterferon1.Chang TT et al. J Viral Hepat. 2009;16:784-789. 2. Chang TT et al. Hepatology. 2006;44(Suppl S1):229A.3. Lau GK et al. N Engl J Med. 2005;352:2682-2695. 4. Marcellin P et al. N Engl J Med. 2008;359:2442-2455.5. Buster EH et al. Gastroenterology. 2008;135;459-467. 6. Heathcote EJ et al. Hepatology. 2008;48(Suppl S1):376A.7. Heathcote EJ et al. Hepatology. 2009;50(Suppl S4):533A. 8. Janssen HL et al. Lancet. 2005;365;123-129.clinicaloptions.com/hep•92


Current Treatment Options for Hepatitis BHBsAg Loss Over Time inHBeAg-Positive PatientsNot head-to-head trials; different patient populations and trial designs100•Extended Treatment With Nucleos(t)ide Analogues* vsLimited Duration (1 Yr) Peginterferon TreatmentHBsAg Loss (%)80 EntecavirTenofovir60Peginterferon40202 3 5 5 6 68 8NA01.0 Yr 1.5-2.0 Yrs 3.0-4.0 Yrs*With sustained undetectable HBV DNA.1. Chang TT et al. N Engl J Med. 2006;354:1001-1010. 2. Marcellin P et al. N Engl J Med. 2008;359:2442-2455.3. Buster EH et al. Gastroenterology. 2008;135;459-467. 4. Gish R et al. Gastroenterology. 2007;133:1437-1444.5. Heathcote EJ et al. Hepatology. 2008;48(Suppl S1):376A. 6. Heathcote EJ et al. Hepatology. 2009;50(Suppl S4):533A.7. Janssen HL et al. Lancet. 2005;365:123-129.clinicaloptions.com/hep•93


Current Treatment Options for Hepatitis BPredictors of HBsAg Loss inHBeAg-Positive Patients Race: whites > nonwhites 1 Genotype 1-3– Nucleos(t)ide analogues: A and D– Peginterferon: A Decline in HBsAg level during first 24 wks withnucleos(t)ide analogues 1 HBeAg negative at or within 26 wks of completingpeginterferon treatment 31. Heathcote EJ et al. J Hepatol. 2009;50(Suppl 1):S330. 2. Gish RG et al. J Viral Hepat.2010;17:16-22. 3. Buster EH et al. Gastroenterology. 2008;135:459-467.clinicaloptions.com/hep•94


Current Treatment Options for Hepatitis BUndetectable HBV DNA Over Time inHBeAg-Negative PatientsNot head-to-head trials; different patient populations and trial designsUndetectable HBV DNA (%)100806040200•*Single-center study.•Extended Treatment With Nucleos(t)ide Analogues vsLimited Duration (1 Yr) Peginterferon Treatment90 93 100*918763NA15 161 Yr 2 Yrs 3 YrsEntecavirTenofovirPeginterferon1. Lok AS, McMahon BJ. Hepatology. 2009;50:661-662. 2. Marcellin P et al. Hepatology. 2008;48(Suppl S1): 370A. 3.Marcellin P et al. Hepatology. 2009;50(Suppl S4):532A. 4. Marcellin P et al. Gastroenterology. 2009;136:2169-2179. 5.Baqai S et al. Hepatology. 2009;50(Suppl S4):530A. 6. Lai CL et al. Hong Kong International Liver Congress 2006.clinicaloptions.com/hep•95


Current Treatment Options for Hepatitis BHBsAg Loss Over Time inHBeAg-Negative PatientsNot head-to-head trials; different patient populations and trial designs100•Extended Treatment With Nucleos(t)ide Analogues* vsLimited Duration (1 yr) Peginterferon TreatmentPatients (%)80 EntecavirTenofovir60Peginterferon40200947< 1 0< 1 0NA 01.0 Yr 1.5-2.0 Yrs 3.0-4.0 Yrs*With sustained undetectable HBV DNA.1. Lai CL et al. N Engl J Med. 2006;354:1011-1020. 2. Marcellin P et al. N Engl J Med. 2008;359:2442-2455. 3.Marcellin P et al. Hepatology. 2008;48(Suppl S1):370A. 4. Shouval D et al. J Hepatol. 2009;50:289-295. 5. Marcellin Pet al. Hepatology. 2009;50(Suppl S4):532A. 6. Brunetto M et al. J Hepatol. 2008;48(Suppl 2):S254.clinicaloptions.com/hep•96


Current Treatment Options for Hepatitis BThe First Branch Point in ChoosingWhat to Treat WithDecision to treatIFN(Peg-IFN alfa-2a)Nucleos(t)ideanaloguesclinicaloptions.com/hep•97


Current Treatment Options for Hepatitis BWhen to Consider Peg-IFN Favorable predictors ofresponse 1,2 Specific patient– Low HBV DNA*demographics 1,2– High ALT*– Genotype A or B > C or D 3-5– Generally young people– Young women wantingpregnancy in near future– Genotype A or B > C or D 3-5 – Young women wanting*Also predictive of response to nucleos(t)ide analogues.– Absence of comorbidities Patient preference 1,2 Concomitant HCVinfection1. Lok AS et al. Hepatology. 2009;50:661-662. 2. Lok AS. Hepatology. 2010;52:743-747.3. Janssen HL et al. Lancet. 2005;365;123-129. 4. Lau GK et al. N Engl J Med. 2005;352:2682-2695. 5. Flink HJ et al. Am J Gastro. 2006;101:297-303.clinicaloptions.com/hep•98


Current Treatment Options for Hepatitis BThe Second Branch Point in ChoosingWhat to Treat WithNucleos(t)ideanaloguesLamivudine Adefovir Entecavir Telbivudine Tenofovirclinicaloptions.com/hep•99


Current Treatment Options for Hepatitis BEntecavir and Tenofovir CombinationTherapy52 patients with advanced fibrosis or cirrhosisMedian 3 lines of pretreatment with incomplete response60% HBeAg positiveNo lactic acidosis%81Median 12 moNo renal impairment842/52 4/52Peterson J et al. Hepatology. 2010;52(Suppl 1):S394-S395.clinicaloptions.com/hep•100


Current Treatment Options for Hepatitis BA Simplified Road Map for 2011Entecavir or Tenofovir48 weeksHBV DNAHBV DNA+(marked declineand still falling)Continue toweek 72-96HBV DNA+(plateau)Add seconddrugHBV DNA-Continue+Switchor add-Continueclinicaloptions.com/hep•101


Resistance:Recognition andManagement•102


Current Treatment Options for Hepatitis BMethods to Detect HBV ResistanceCommercially AvailableResearchStandardpopulation-based sequencingINNO-LIPARFLPAllelespecificPCR• Less sensitive• Detects variants presentat 25% of viral population• Needed to detect “new,”previously undescribedsubstitutions• More sensitive• Detects variants presentat 5% of viral population• Only detects knownmutations• Detect variants present at 1%of the viral population• Like INNO-LIPA, only detectsknown mutations• Coming soon: ultra deepsequencingclinicaloptions.com/hep•103


Current Treatment Options for Hepatitis BSummary of Resistance Analysesof TDF-Treated Patients Through Year 3Total Patients on Study Patients > 400 copies/mLPatients with Resistance450Number of Patients450400350300250200150100500426389 (91%)364 (85%)39 (9%) 24 (6%) 13* (4%)0 0 0Year 1 Year 2 Year 3400350300250200150100500Number of Patients*Includes 7 patients on FTC+TDF combination therapySnow-Lampart A et al. Hepatology. 2009;50(Suppl S4):532A.clinicaloptions.com/hep•104


Current Treatment Options for Hepatitis BCumulative Rates of Resistance With Oral Agentsin Nucleos(t)ide-Naive PatientsNot head-to-head trials; different patient populations and trial designs•Yr 1 •Yr 2 •Yr 3 •Yr 4 •Yr 5 •Yr 6•Drug•Generation•1st•LAM24%38%49%67%70%•2nd•3rd•ADV•LdT•ETV•TDF0% 3%11%4%0.2%0%17%0.5%0%1.2%0%18%1.2%0%29%1.2%1.2%1. EASL. J Hepatol. 2009;50:227-242. 2. Tenny DJ et al. J Hepatol. 2009;50(Suppl 1):Oral 20.3. Marcellin P et al. Hepatology. 2009;50(Suppl S4):532A. 4. Heathcote EJ et al. Hepatology.2009;50(Suppl S4):533A.clinicaloptions.com/hep•105


Current Treatment Options for Hepatitis BCross-Resistance Data for the MostFrequent Resistant HBV VariantsHBV VariantLevel of Susceptibility(Amino Acid Substitutions)LamivudineTelbivudineEntecavirAdefovirTenofovir*Wild-typeSSSSSM204IRRRISSL180M + M204VRRISSA181T/VISSRSN236TSSSRIL180M + M204V/I ± I169T ± V173L ±M250VL180M + M204V/I ± T184G ±S202I/GI – IntermediateS - Sensitive(Reduced Susceptibility)*Resistance to tenofovir has not been described so farAdapted from EASL Clinical Practice Gudelines: Management of Chronic Hepatitis B.EASL. J Hepatology. 2009;50:227-42.RRRRRRSSSSR - Resistantclinicaloptions.com/hep•106


Current Treatment Options for Hepatitis BWhen to Perform Resistance Testing Virologic breakthrough– Consider compliance if no resistant mutations present– Most breakthroughs in ETV and TDF trials have not beenassociated with documented resistance Residual viremia at late stage of treatment when HBVDNA undetectability would be expected (depends ondrug)clinicaloptions.com/hep•107


Current Treatment Options for Hepatitis BTreatment of Established ResistanceOne Drug From Each ClassNucleotidesLamivudineNucleotidesAdefovirTelbivudineTenofovirEntecavirEmtricitabine(FTC)**Available with tenofovirclinicaloptions.com/hep•108


Current Treatment Options for Hepatitis BManagement of Patients WithDecompensated CirrhosisPreferred therapies (LAM or LdT) + (ADV or TDF); TDF or ETVmonotherapy*– Treatment should be coordinated with transplant center– IFNs should not be used in decompensated cirrhosisTreatment duration Life-long treatment recommended*Clinical data documenting safety and efficacy of TDF or ETV monotherapy indecompensated cirrhosis are lacking.Lok AS et al. Hepatology. 2009;50:661-662.clinicaloptions.com/hep•109


Current Treatment Options for Hepatitis BManagement of Patients With HIVCoinfection HBV/HIV-coinfected pts who require HBV therapy should be treated 1– Liver biopsy should be considered in patients with fluctuating or mildlyelevated ALT (1-2 x normal)Not on or AnticipatingAntiretroviral Therapy*Planning AntiretroviralTherapyAlready ReceivingAntiretroviral Therapy• Treat with antiviral• Treat with therapies that• If regimen does nottherapy that does not are effective against both include drug activetarget HIV, such asviruses: TDF + (FTC or against HBV, may addpegIFN or ADVLAM) preferred (plus ≥ 1 pegIFN or ADV• Although LdT does not other anti-HIV agent) • If LAM resistance, addtarget HIV, it should notTDFbe used in thiscircumstance*DHHS guidelines recommend that any HBV/HIV-coinfected pt in whom HBV treatment is indicated shouldinitiate a fully suppressive antiretroviral regimen containing 2 drugs with anti-HBV activity. 21. Lok AS et al. Hepatology. 2009;50:661-662. 2. DHHS. Available at:http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.clinicaloptions.com/hep•110


Current Treatment Options for Hepatitis BManagement of HBV During Chemotherapy orImmunosuppressionReactivation of HBV replication common duringimmunosuppression/chemotherapy (20% to 50%)Prophylactic antiviral therapy recommended in HBV carriers at onsetof cancer chemotherapy or immunosuppressive therapy– If baseline HBV DNA < 2000 IU/mL, continue treatment for6 mos after– If baseline HBV DNA > 2000 IU/mL, continue treatment until treatmentendpoints for hepatitis B are reachedTenofovir or entecavir preferred if treatment for > 12 mosFor patients with anti-HBc but HBsAg-negative:– Individuallize treatment decisions– Flare may occur even if anti-HBs presentLok AS et al. Hepatology. 2009;50:661-662.clinicaloptions.com/hep•111


Current Treatment Options for Hepatitis BTreatment EndpointsHBeAg+HBeAg-SeroconversionNo seroconversionStop 12months laterContinueTreatindefinitelyTherapy in cirrhotics should be continueduntil PCR negative and loss of HBsAgKeeffe EB et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.Change regimen (switch or add)for incomplete responseclinicaloptions.com/hep•112


Current Treatment Options for Hepatitis BConclusionsChoose agents that confer high potency and excellentresistance profilesFollow to assess HBV DNA, chemistries, HBeAg/Ab, andHBsAg at appropriate intervals (q12 weeks for HBV DNA)Aim for complete viral suppression in all patients: think aboutchange if residual viremia present after 1-2 years (sooner ifdrug with low genetic barrier to resistance is used)Resistance unlikely even with late residual viremia but checkfor it when change is contemplated or with virologicbreakthrough – do not take compliance for grantedCombination therapy (nucleoside and nucleotide) forestablished resistanceConsider entecavir and tenofovir for multiresistant HBVclinicaloptions.com/hep•113

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