TRÊS MANHÃS NA SANTA CASA
25 de Setembro de 2009 . Rio de Janeiro - RJ
HEPATITE CRÔNICA B
HBeAg Negativo: Cirrótico e
Não Cirrótico - Conduta
Dr. Carlos Eduardo Brandão Mello
Professor Associado – Doutor e Livre Docente
Escola de Medicina e Cirurgia do Rio de Janeiro - UNRIO
Hospital Universitário Gaffrèe e Güinle - Unidade de Doenças do Fígado
Faculdade de Medicina – UFRJ - Disciplina de Gastroenterologia
ACADEMIA NACIONAL DE MEDICINA
A HEPATOLOGIA NOS DIAS DE HOJE
CENTENÁRIO DO PROFESSOR T. FIGUEIREDO MENDES
25 de Agosto 2011 . Rio de Janeiro – RJ
HEPATITE CRÔNICA B
NOVAS OPÇÕES TERAPÊUTICAS
Dr. Carlos Eduardo Brandão Mello
Professor Associado – Doutor e Livre Docente
Escola de Medicina e Cirurgia do Rio de Janeiro - UNIRIO
Hospital Universitário Gaffrèe e Güinle - Unidade de Doenças do Fígado
Faculdade de Medicina – UFRJ - Disciplina de Gastroenterologia
A Descoberta do Antígeno Austrália
O que aprendemos sobre as hepatites
virais desde 1965?
•1965
Blumberg
•Antigeno
Australia
•1971
Prince
•Hepatite não-CMV,
EBV ou HBV
•1973
Feinstone
Hepatite
•1975
•Feinstone
•HPT, sem evidência
de HAV or HBV
Infecciosa
HBV
• PTH
•HAV
• NANBH
Identificação do virus responsável
pela Hepatite NANB : Anos 1980
•1983
Hollinger
•Virus NANB
descoberto de ter
envelope lipidico
•1987/1989
• Feinstone/ Houghton
Virus NANB / descoberto de
ter 30–60 nm de diametro/
Descoberta do HCV
Testes com ALT e Anti-HBc nos
bancos de sangue
Impacto Global da Hepatite B
2 bilhões com infecção por VHB
Passada / Presente
População mundial
6 bilhões
25 - 40% desenvolvem
insuficiência hepática
cirrose, ou CHC
350 – 400 milhões com
Hepatite B crônica
~1 milhão/ano morrem de doença hepática relacionada ao HBV
10a causa de morte no mundo
WHO 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%
Nordeste
2 - 7%
•
•
CentroCentro-oeste
2 - 7%
•
•
Sul
< 1%
Bensabath G et al 1973, 1985
Fonseca JCF et al, 1983, 19 86, 1987,1988
Gayotto LC et al,1984
Sudeste
<1 - 7%
História Natural da Infecção pelo HBV
Infância
> 95%
Imuno
Tolerância
Adulto
< 5%
Hepatite B
Crônica
Hepatite B
Cirrose
HBeAg-
Crônica
HBeAg+
Portador
Inativo
Courtesy 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.
Fases da Infecção Crônica pelo HBV
Fase de Imunotolerância
HBV- DNA > 105
ALT normal
Fase de ImunoClearence
HBV- DNA em queda
ALT elevada
Fase de Controle Imune
HBV -DNA < 105
ALT normal
Fase de Escape Imune
HBV -DNA > 105
ALT elevada
Fases da Infecção Crônica HBV
Imuno
Tolerancia
<
HBeAg+
HBV DNA
2 x 108 2 x 1011 IU/mL
Fase de Baixa
Replicação
Imuno
Clearance
><
Fase de Reativação
HBeAg-/anti-HBe+ (precore/core promoter variants)
> 2000 IU/mL
< 2000 IU/mL
200,000 - 2 x 109 IU/mL
Slide courtesy of A. S. F. Lok, MD.
>
Fases da Infecção Crônica HBV
Immune
Tolerance
<
Immune
Clearance
HBeAg+
HBV DNA
2 x 108 2 x 1011 IU/mL
Low Replicative
Phase
><
Reactivation
Phase
HBeAg-/anti-HBe+ (precore/core promoter variants)
> 2000 IU/mL
< 2000 IU/mL
200,000 - 2 x 109 IU/mL
ALT
Slide courtesy of A. S. F. Lok, MD.
>
Fases da Infecção Crônica HBV
Immune
Tolerance
<
Immune
Clearance
Reactivation
Phase
HBeAg-/anti-HBe+ (precore/core promoter variants)
HBeAg+
HBV DNA
2 x 108 2 x 1011 IU/mL
Low Replicative
Phase
><
> 2000 IU/mL
< 2000 IU/mL
200,000 - 2 x 109 IU/mL
ALT
Normal/HC
Leve
HC Moderada/Grave
Cirrose
Slide courtesy of A. S. F. Lok, MD.
Normal/ HC Leve
Cirrose inativa
HC Moderada/Grave
Cirrose
>
Fases da Infecção Crônica HBV
Immune
Tolerance
<
Immune
Clearance
Reactivation
Phase
HBeAg-/anti-HBe+ (precore/core promoter variants)
HBeAg+
HBV DNA
2 x 108 2 x 1011 IU/mL
Low Replicative
Phase
><
> 2000 IU/mL
< 2000 IU/mL
200,000 - 2 x 109 IU/mL
ALT
Normal/mild
CH
Moderate/severe CH
Cirrhosis
HBeAg+
chronic hepatitis
Slide courtesy of A. S. F. Lok, MD.
Normal/mild CH
Moderate/severe CH
Inactive cirrhosis
Cirrhosis
Inactive-carrier state
HBeAgchronic hepatitis
>
Níveis de HBV DNA e Progressão
de Doença Hepática – Estudo Reveal
1991-1992:
3851 pacientes HBsAg +
Taiwan
2004
77 excluídos: cirrose < 6 meses
Avaliação Cirrose
n = 3774
Avaliação CHC
n = 3851
42115 pacientes/ano
seguimento
43993 pacientes/ano
seguimento
Cirrose: 395 (10.5%)
CHC: 176 (4.5%)
Chen, et al. EASL 2005
Iloeje, et al. EASL 2005
Níveis de HBV DNA e
Incidência de Cirrose
Risco Relativo
10
HBeAg Neg
8
8,6
HBeAg Pos
6,2
6
4,9
4
2,6
2
1,9
1
0
HBV DNA
< 10 4
104 – 105
> 105
Copias/mL
* Ajustado por sexo, idade, anti HCV, tabagismo e álcool.
Iloeje et al. EASL 2005
Curva de Distribuição Sobrevida
Mortalidade Decorrente de Hepatopatia Crônica
e sua relação com Carga Viral HBV-DNA Basal
HBV DNA (-)
1.00
HBV DNA Baixa
1.6 x 103 - < 105 cp/mL
RR = 1.5 (0.2-11.8)
0.96
0.92
HBV DNA Alta
> 105 cp/mL
RR = 13.4 (1.9-97.1)
0.88
0.84
0.80
0
1
2
3
4
5
6
7
8
Tempo Sobrevida (Anos)
Chen G et al. 55th AASLD, 2004. Abstract 1362
9
10
11
12
Níveis de HBV DNA e Incidência
de Carcinoma Hepatocelular
1400
1150
Incidência CHC
porr 100,000
1200
952
1000
800
600
315
400
200
145
113
< 300
300 - <103
103 - 104
104 - 105
>105
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)
--
NS
< .005
< .001
< .001
0
HBV DNA
(cópias/ mL)
RR
(95% CI)
p
Chen, et al. EASL 2005
HBV e Risco de CHC
Incidencia % Cumulativa
12
HBsAg(+), HBeAg(+)
(RR = 60.2)
10
8
6
4
2
HBsAg+, HBeAg(RR = 9.6)
0
HBsAg-, HBeAg0
1
2
3
4
5
Ano
Yang HI, et al. N Engl J Med. 2002;347:168-174.
6
7
8
9
10
Curva de Distribuição de Sobrevida
Mortalidade por CHC de Acordo com
a Carga Viral do HBV Basal
1.00
HBV DNA (-)
0.96
HBV DNA Baixa
1.6 x 103 - < 105 cp/mL
RR = 1.8 (0.5-5.8)
0.92
0.88
HBV DNA Alta
> 105 cp/mL
RR = 9.9 (3.2-31.0)
0.84
0.80
0
1
2
3
4
5
6
7
8
Tempo de Sobrevida (Anos)
Chen G et al. 55th AASLD, 2004. Abstract 1362
9
10
11
12
HEPATITE CRÔNICA B:
ALT E RISCO DE COMPLICAÇÕES
N= 3233
Seguimento médio 46.8 meses
Yuen et al. 2005
Papel da Biópsia Hepática em Pacientes
com ALT Normal e Alta Carga Viral
70
Estágio de Fibrose por Grupo de ALT
estagio 0
estagio 1
estagio 2
estagio 3
estagio 4
Pacientes, %
60
50
40
30
20
24%
10
0
PNALT
(n = 57)
Lai et al. AASLD 2005. Abstract 67571.
ALT 1-1.5 ULN
(n = 23)
ALT > 1.5 ULN
(n = 110)
Infecção Crônica pelo HBV:
População Alvo para Tratamento
Tratamento indicado:Hepatite crônica B ativa
– Maior benefício (para aqueles com maior risco de
progressão da doença)
– Maior chance de resposta aos agentes disponíveis
“Atividade” definida por:
– ALT/AST Elevada
– Atividade Necro-inflamatória na biopsia
– Títulos elevados de HBV-DNA
Objetivos da Terapia em Pacientes
com 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 Óbito
Suppressão Sustentada
da 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 Tratamento
HCB HBeAg-positivo (wild type)
– Soroconversão HBeAg é Fundamental
– Supressão Sustentada do HBV-DNA para níveis baixos ou
indetectaveis
– Normalização da ALT
– Redução da atividade necro-inflamatória na biopsia
HCB HBeAg-negativo (mutantes pre-core e core promoter)
– Soroconversão de HBeAg não é o objetivo final
– Supressão Sustentada do HBV-DNA para níveis baixos ou
indetectaveis
– Normalização da ALT
– Redução da atividade necro-inflamatória na biopsia
Indicação de Tratamento na Hepatite B
HBeAg
HBV DNA
(copias/mL)
ALT
+
< 105
Normal
≥ 105
Normal
+
≥ 105
Elevada
–
< 104
Normal
≥ 104
Normal
≥ 104
Elevada
+
–
–
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87-106.
Conduta
Monitorar, sem
tratamento
Considerar biópsia;
tratar se houver
doença ativa
Tratar
Monitorar, sem
tratamento
Considerar biópsia;
tratar se houver
doença ativa
Tratar
Tratamento da Cirrose pelo HBV
Compensada
HBV DNA (copias/mL)
Algoritmo US[1]
Guideline AASLD
[2]
< 104[1] OU < 105[2]
Tratar ou monitorar
Monitorar
≥ 104[1] OU ≥ 105[2]
Tratamento a longo prazo
Tratamento a longo prazo
HBeAg status positivo ou negativo
Descompensada
HBV DNA (copias/mL)
< 103 OU ≥ 103[1]
≥ 105 (ou inferior)[2]
HBeAg status positivo ou negativo
1. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87-106.
2. Lok AS, et al. Hepatology. 2004;39:857-861.
Conduta[1,2]
Tratamento a longo prazo
referenciar para transplante
AASLD Guidelines for Chronic
Hepatitis B Treatment Initiation
•HBeAg Negative
•HBeAg Positive
•ALT < 1 x ULN
ALT > 2 x ULN
•Monitor patient
•ALT < 1 x ULN
ALT > 2 x ULN
•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
•HBV DNA
•Consider biopsy if persistent
•2000-20,000 IU/mL
•or > 40 yrs; treat if needed
•Consider biopsy; treat if needed
•Lok AS, et al. Hepatology. 2007;45:507-539.
Tratamento para Hepatite Crônica B: 2011
•1992
•1998
•2002
•2005
•2006
• IFN
alfa
•LAM
•ADV
•ETV
• LdT
•PegIFN alfa-2a
•“A Nova Era”
•Terapia Oral
•2008 e Além…
•TDF
•Clevudina*
•Combinação?
Algoritmo de Tratamento da
Hepatite B HBeAg Positivo: 2011
•HBeAg positivo
•HBV DNA
•HBV DNA
•< 20,000 IU/mL
•≥ 20,000 IU/mL
•ALT normal
•ALT elevada
Não tratar
Monitorar a cada 6-12
meses
Monitorar ALT cada 3-12
meses (imuno tolerante)
Consider e biópsia, se
> 35-40 anos e tratar se
houver doença significativa
Tratar até
Soroconversão HBeAg
ETV, TDF e
Peg-IFN são as primeiras
opções
•Keeffe EB, et al. DDW 2008. SP198. Keeffe EB, et al. Clin Gastroenterol Hepatol.
2006;4:936-962.
•100
•Not head-to-head trials; different patient populations and trial designs
•76
•80
•67
• (%)
• Pacientes com HBV DNA Indetectavel
Resposta Virologica em Pacientes HBeAg+
(HBV-DNA Indetectável* na Semana 48-52)
•60
•69
•60
•40-44
•40
•20
•0
•0-16
•PLB
•25
•21
•LAM
•ADV
•ETV
•LdT
•TDF •PegIFN
•*By PCR based assay (LLD ~ 50 IU/mL) except for some LAM studies.
•Adapted from Lok AS, et al. Hepatology. 2007;45:507-539. Heathcote EJ,
et al. AASLD 2007. Abstract LB6.
•PegIFN +
LAM
Resposta Virológica em Pacientes HBeAg+
(Soroconversão HBeAg na Semana 48-52)
•HBeAg
HBeAg Seroconversão (%)
•Pacientes
Pacientes Obtiveram
•100
•Not head-to-head trials; different patient populations and trial designs
•80
•60
•40
•32*
•16-21
•20
•PLB
•21
•12
•4-6
•0
•21
•22
•LAM
•ADV
•ETV
•LdT
•27
•TDF •PegIFN
•*Response 6 months after stopping treatment.
•Adapted from Lok AS, et al. Hepatology. 2007;45:507-539. Heathcote EJ,
et al. AASLD 2007. Abstract LB6.
•27*
•24
•PegIFN +
LAM
Algoritmo de Tratamento da
Hepatite B HBeAg Negativo:2011
•HBeAg negativo
•HBV DNA
•HBV DNA
•< 2000 IU/mL
•≥ 2000 IU/mL
•ALT
normal
Não tratar
Monitorar cada
•ALT
elevada
6-12 meses
Monitorar ALT e HBV DNA,
ou considerar biópsia, se ALT
estiver flutuante e tratar se
houver doença significativa
•Keeffe EB, et al. DDW 2008. Abstract 198.
Tratamento a longo
prazo ( ETV, TDF,
ou PegIFN são as
opções de primeira linha
Recomendações para o Tratamento
Inicial em Pacientes HBeAg-Negativo
HBV DNA, IU/mL
ALT, x ULN*
Estágio/Grau da
Doença
Terapia Primeiralinha
AASLD 2007[1]
US Algorithm 2008[2]
EASL 2009[3]
> 20,000‡
> 2000
≥ 2000
1a>2
>1
>1
Necroinflamação Moderada/Grave
e/ou Fibrose significativa
ADV,† ETV,
pegIFN
ETV, TDF,
pegIFN
ETV, TDF,
pegIFN
*Persistent (> 3-6 mos). †TDF not FDA approved at time of publication. ‡ Consider liver
biopsy 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 treatment
based on individual’s age, health status, and stage of infection/disease
1. Lok A, et al. Hepatology. 2007;45:507-539. 2. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:13151341. 3. EASL HBV Guidelines. Journal of Hepatology. 2009;50:227-242.
Resposta Virológica em Pacientes HBeAg(HBV-DNA Indetectavel* na Semana 48-52)
•100
•HBV
HBV DNA (%)
•Patients
Patients With Undetectable
•Not head-to-head trials; different patient populations and trial designs
•90
•88
•80 •~ 70
•60
•93
•87
•63
•51
•40
•20
•0
•LAM
•ADV
•ETV
•LdT
•TDF •PegIFN
•*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. AASLD
2007. Abstract LB2.
•PegIFN +
LAM
HBV-DNA Indetectável* em Pacientes HBV
Após 1 Ano de Tratamento
Not head-to-head trials; different patient populations and trial designs
Indetectavel* HBV DNA (%)
HBeAg Positivo
HBeAg Negativo
100
100
76
80
67
60
40
88
91
ETV
LdT
TDF
80
60-73
60
60
40-44
20
90
51-63
40
20
13-21
0
0
LAM
ADV
ETV
LdT
TDF
LAM
ADV
*By PCR-based assay (LLD ~ 50 IU/mL) except for some LAM studies.
Lok A, et al. Hepatology. 2007;45:507-539. EASL HBV Guidelines. Journal of Hepatology. 2009;50:227-242.
••Patients (%)
Seroconversão do HBeAg Durante
a Continuidade do Tratamento
•Not head-to-head trials; different patient populations and trial designs
•100
•100
•LAM
•ADV
•80
•80
•60
•40
•40
•20
•22
•47
•50
•20
•12
•0
•100
•ETV
•80
•60
•31
•37
•21
•1
•LdT
•80
•47*
•40
•0
•48
•40
•29
•0
•100
•20
•60
•60
•40
•20
•2
•3 •4 •5
•Years of Therapy
•0
•23
•1
•29
•2
•3 •4 •5
•Years of Therapy
•*(ETV-022 + ETV-901) 16% additional to 31% HBeAg seroconversion in ETV-022 (Year 2).
•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.
Normalização da ALT e Melhora
Histológica Após 1 Ano de Tratamento
HBeAg Positivo
Outcome, %
LAM
ADV
ETV
LdT
TDF
Normalização da ALT
41-75
48
68
77
69
Melhora Histológica
49-56
53
72
65
74
Outcome, %
LAM
ADV
ETV
LdT
TDF
Normalização da ALT
60-79
72
78
74
77
Melhora Histológica
60-66
64
70
67
72
HBeAg Negativo
*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-2a
na HCB HBeAg-neg
•PEGASYS +/– LAM (N=230)
30
•27
•Pacientes
Pacientes (%)
25
20
•LAM (N=85)
•24
•P=0.042
•18
•16
•17
15
•P=0.021
•11
10
•7
5
•2
0
•ALT normal
•<20,000 cp/mL
•<400 cp/mL
•~4,000 IU/mL
•<~100 IU/mL
•Modified ITT analysis, missing data = non response
•Clearence do
•HBsAg
•Marcellin et al, EASL 2008
•Valor Preditivo da Redução dos Níveis de HBsAg (48ª
Semana) no Clearance do HBsAg ao final de 3 anos
• Pacientes com
clearance HBsAg(%)
•Redução do HBsAg
100
90
80
70
60
50
40
30
20
10
0
• do BL a semana 48
•RR = 14.6 (95% CI 5.5 – 38.5)
•P<0.0001
•42%
•3%
•11/26
•>2 log IU/mL
•5/172
•<2 log IU/mL
•Títulos de HBsAg
100
90
80
70
60
50
40
30
20
10
0
•na semana 48
•RR = 22.8 (95% CI 8 –
649)
•P<0.0001
•52%
•2%
•12/23
•<10 IU/mL
•
•4/171
•>10 IU/mL
Brunetto et al. EASL 2008
•Taxa de Resposta Sustentada ao PEG-IFNα2a de acordo com o qHBsAg na semana
12 de tratamento de 156 pacientes
•Níveis de HBsAg
•Níveis HBsAg
•≤1500 IU/mL (n=61)
•>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 HBV
DNA 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 in
SVR* 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 Analógos
por 48 semanas na HBC HBeAg (-) virgens de tratamento
•*Collation of currently available data – not from head-to-head studies
•%
% Pacienets com HBV DNA <LDQ
•(LLQ of HBV DNA assays: 300-400 copies/ml)
•100%
•80%
•88%
•90%
•91%
•LdT
•ETV
•TDF
•72%
•63%
•60%
•51%
•40%
•20%
•0%
•PEG
PEG--IFN
•LAM
•ADV
•Adapted from EASL CPG HBV, J Hepatol 2009, in press
•
3-anos ETV na HCB HBeAg-neg –
•Re-Tratamento Resposta Virológica
•ETV-901
•100 •94%
•93%
•80
•60
•40
•94%
•83%
•Off-treatment
treatment >60 days
•Proporção
Proporção de pacientes (%)
HBV DNA <300 copias/mL
•ETV-027
•91%
•95%
•59%
•20
•4%
•0
•EOD†
•n=
93/99
Baseline
4/99
Sem 12
56/95
Sem 24
79/95
Sem 48 Sem 72 Sem 96
84/90
72/77
Sem 144
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
Percentagem de Pacientes
Adefovir Para Pacientes HBeAg-Negativo
Resposta Virológica e Bioquímica
100
HBV DNA
< 1000 copias/mL
77% 78%
80
68% 71%
67%
Normalização da
ALT
75% 72%
75%
69%
67%
60
40
20
0
48
96
144 192 240
48
96
144 192 240
Duração Tratamento (Semanas)
n=
69
58
69
65
55
64
53
64
Hadziyannis S, et al. EASL. 2005. Abstract 492. Hadziyannis S, et al. AASLD 2005. Abstract LB14.
59
55
•ADV mono por 5 anos em pacientes HBeAg-:
Avaliação Histológica
•Necro-inflamação
•Fibrose
•Pacientes
Pacientes (%)
•100
•80
•Piora
•60
•Inalterado
•40
•Melhora
•20
•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
5% dos pacientes tiveram
perda do HBsAg no 5o ano
> 50% obtiveram regressão
da fibrose em pontes ou
cirrose no 5o ano
redução ≥ 1-ponto no escore
de fibrose (Ishak)
– 4o Ano: 55%
– 5o Ano: 71%
Percentagem de Pacientes
Resultados a Longo Prazo do Tratamento Com
Adefovir em Pacientes HBeAg-Negativo
Ano 4
100
80
65
67
70
69
60
40
20
0
n
Hadziyannis S, et al. AASLD 2005. Abstract LB14.
Ano 5
HBV DNA
< 3 log10 copias/mL
30
55
ALT Normal
40
55
Níveis de HBV-DNA durante o follow-up em
Respondedores bioquímicos sustentados após
parar o tratamento com ADV
•>10,000 copias/mL
•100%
•90%
•25%
•34%
•30%
•43%
•80%
•50%
•70%
•60%
•100%
•79%
•HBV-DNA
não detectavel
•31%
•14%
•50%
•33%
•40%
•17%
•70%
•40%
dos
pacientes
•30%
•43%
•20%
•44%
•33%
•10%
•0%
•0
•Detectavel
<10,000 copias/mL
•33%
•30%
•21%
•<10,000
•0%
•c/mL
c/mL
•1
•2
•6
•12
•18
•22
•MESES DE FOLLOW-UP
•Hadziyannis S. et al, AASLD 2006
2-anos TDF vs ADV na HCB HBeAg-neg.
(análise por ITT)
•100
• < 400 cp/ml (95%CI)
• % Pacientes com HBV DNA
•TDF
•91%
•89%
•90
•TDF
•80
•TDF
•70
•P=0.672
•18% LAM Exp:
•60
• 93%
•50
• 96%
•40
•ADV
•30
•20
•10
•Randomized Double Blind
•Open Label
•0
•0
•8
•16
•24
•32
•40
•48
•56
•64
•72
•80
•88
•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 Viral
Resistência Genotípica
= emergência de uma nova substituição de amino ácido na presença
de droga com consequente diminuição da suscetibilidade à mesma
Resistência Fenotípica
= diminuição no nível de suscetibilidade comparado com a cepa
selvagem, usualmente expressa como ‘fold change’
Droga Antiviral
Emergência de resistência à droga
HBV DNA
log10
nadir
Tempo
Eva Wolf. HIV Medicine 2005; Chapter 9:311–313
Adapted from: Locarnini S, et al. Antivir Ther 2004; 9:679–693
1 log10
Viral breakthrough ou
Rebote Virológico
= aumento confirmado de
HBV DNA ≥ 1 log10 do nadir
plasmático
Resistência Genotípica, Rebote Virológico e Rebote
Bioquímico: Definições do NIH
Rebote
Virológico
Rebote
Bioquímico
1 log10
Nadir
ALT (UI/L)
DNA do VHB (log10 cópias/
s/mL
Detecção
de resistência
genotípica
1 x LSN
Medicamento antiviral
Tempo
Lok A e cols. Program of the 2006 Management of Hepatitis B Virus Meeting: 2006, Bethesda, EUA.
Análogo de nucleos(t)ídio
Resistência
clínica
Resistência
virológica
DNA
Resistência
genotípica
Limite de
detecção
Início
1 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 cirrose
Perrillo RP, et al. Hepatology. 2002;36:186-194. Leung NW, et al. Hepatology. 2001;33:1527-1532.
Incidência de Resistência em Pacientes
virgens de Analógos Nucleos(t)ídicos
•80
•70
•67
•Pacientes
Pacientes (%)
•60
•49
•38
•40
•29
•24
•20
•18
•17
•11
•3
•0
•0
•LAM
•ADV
•4
•?
•LDT
•0.5 •1.2
•1.2
•0.2 •1.2
•ETV
•0 •0
•?
•TDF
•adaptado da EASL CPG HBV, J Hepatol 2009, in press
Menor Resistência à Lamivudina com
Suppressão Precoce do HBV
Pacientes, %
100
HBVDNA Serico no 6o Mes vs
Resistencia a Lamivudina no 61o Mes
80
64%
60
40
20
0
32%
8%
< 200
13%
< 3 log10
(n = 23)
< 4 log10
(n = 41)
> 4 log10
(n = 118)
(n = 12)
Nivel Serico de HBVDNA no 6o Mes (copias/mL)
Yuen et al. Hepatology. 2001; 34:785-791.
Menor Resistência com Supressão
Precoce do HBV DNA
100
80
Patients (%)
Serum HBV DNA at Week 48
vs Adefovir Resistance by
Week 144
Serum DNA at Month 6 vs
Lamivudine Resistance by
Month 61
67
64
60
40
20
0
32
8
< 200
(n = 12)
26
13
4
< 3 log10
(n = 23)
< 4 log10 > 4 log10
(n = 41) (n = 118)
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.
< 3 log10
(n = 80)
3-6 log10
(n = 31)
> 6 log10
(n = 3)
Week 48 HBV DNA (copies/mL)
Supressão Profunda e Precoce da Viremia
Correlaciona-se com Resposta Sustentada Maior
Patients PCR Negative
at Follow-up
up (%)
PegIFN alfa-2a at
Week 72 HBeAgPatients
100
LAM at Week 52
HBeAg+
Patients
ETV at Week 52
HBeAg+ Patients
96
LdT at Week 52
HBeAg+ Patients
95
84
80
60
61
50
40
33
31
20
20
0
n = 70
< 400
c/mL
106
≥ 400
c/mL
HBV DNA at Week 12
146
317
< QL ≥ QL
160
153
< QL ≥ QL
HBV DNA at Week 24
Zeuzem S. EASL 2006. Abstract 51. Farci P, et al. J Hepatol. 2005;
42(suppl 2):175. Yurdaydin C, et al. EASL 2006. BMS symposium.
203
255
< QL ≥ QL
•4-anos de ADV+LAM em 94 Cirróticos LAM-R,
Complicações relacionadas ao Fígado
100
80
60
•CHC
•Descompensação
40
20
•15%
•0%
0
0
6
12
18
24
30
36
42
48
•Pacientes •94
•Com risco •94
•92
•94
•89
•93
•86
•89
•68
•71
•53
•58
•46
•51
•27
•30
•10
•10
•Meses
•Lampertico P. et al, Gastroenterology 2007
ADV Monoterapia: Troca vs Adição em
Pacientes Cirróticos Resistentes à LAM
Características
Baseline
Final deTratamento
P Value
Adefovir Monoterapia (n = 18)
ALT, IU/L
HBV DNA, copias/mL
262
57
.001
2.4 x 108
2.3 x 105
< .001
Adefovir + Lamivudina (n = 10)
ALT, IU/L
HBV DNA, copias/mL
246
35
.013
1.57 x 108
4.36 x 104
.005
Liaw Y, et al. J Viral Hepat. 2006;13:250-255.
Adefovir para a Infecção Crônica pelo
HBV Resistente à Lamivudina
Evolução
Adefovir Lamivudina
(n = 19)
(n = 19)
Adefovir
+
Lamivudina
(n = 20)
Alteração média na carga viral,
copias/mL
-3.11
0.00
-2.95
Semana 16
-4.00
-0.31
-3.46
26
0
35
Semana 48
HBV DNA < 1000 copias/mL na
Semana 48, %
Peters MG, et al. Gastroenterology. 2004;126:91-101.
ADV vs ADV + LAM para Pacientes
com Resistência à LAM
Median: 18 Months
(Range: 12-30)
Individuals with
chronic HBV infection
on lamivudine therapy
with lamivudine
resistance
(N = 52)
Marzano A, et al. AASLD 2006. Abstract 113.
Switch to Adefovir
(n = 29)
Lamivudine maintained + Adefovir
(n = 23)
ADV vs ADV + LAM para Pacientes
com Resistência à LAM
Nonsignificant trend toward better efficacy outcomes with
combination therapy
– Better responses in both groups for individuals with lower
baseline viral load
Outcome at Month 18, %
Complete virologic response*
HBV DNA < 5 log10 copies/mL at
baseline
HBV DNA > 5 log10 copies/mL at
baseline
ALT normalization
*Undetectable HBV DNA by PCR.
Marzano A, et al. AASLD 2006. Abstract 113.
Adefovir
Adefovir +
Lamivudine
P Value
55
83
NS
100
100
NS
38
81
< .05
80
91
NS
ADV vs ADV + LAM para Pacientes
HBeAg-Negativo Resistentes à LAM Multicenter cohort study; retrospective/prospective
– Mean follow-up: 33 months
Undetectable HBV DNA* (%)
Adefovir + lamivudine (n = 285)
Adefovir (n = 303)
100
Patients (%)
Year 3 Cumulative Adefovir
Resistance
100
80
80
60
60
P = NS
40
40
20
20
0
0
0
6
12
18
Month
*< 1000 copies/mL.
Lampertico P, et al. AASLD 2006. Abstract LB5.
24
30
36
P < .001
16
0
ADV
(n = 303)
ADV +
LAM
(n = 285)
Resistência Adefovir Não Observada Com
Terapia Combinada de Lamivudina
Incidence of Resistance (%)
Adefovir monotherapy (Study 438)
60
Adefovir + lamivudine (lamivudine resistance
Studies 435 and 460i)*
Study 435: pre- and post-OLT
Study 460i: HIV/HBV
40
30
20
19
11
0
0
0
Year 1
3
0
0
Year 2
Year 3
0
Year 4
Year 5
*2 patients enrolled in Study 435, initially on combination therapy with adefovir + lamivudine, and
subsequently selected adefovir resistance mutation N236T. However, they were on adefovir monotherapy
when 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 HBV
Resistência ä Lamivudina
• Adicionar Adefovir ou Tenofovir
Resistência ä Telbivudina
• Adicionar Tenofovir*
Resistência ao Entecavir
• Adicionar Tenofovir*
• Trocar p/ Tenofovir e adicionar uma 2a droga
Se N236T, adicione lamivudina, entecavir* ou
telbivudina* ou troque para Truvada
Se A181V/T, adicione entecavir* ou troque para
Truvada
Resistência ao Adefovir
Resistência ao Tenofovir *
• Genotipar e fenotipar para determinar o perfil
de resistência cruzada
• Adicionar entecavir*, telbivudina*, lamivudine
ou 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 Lamivudina
Com a Terapia Combinada de Novo
100
Incidence of Resistance After 1 Year of Therapy
Patients (%)
80
60
Sung[1]
Marcellin[2]
40
20
Lai[4]
34
20
21
18
11
2
0
Lau[3]
LAM LAM +
ADV
12
1
LAM LAM +
PegIFN
1. 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.
LAM LAM +
PegIFN
LAM LAM +
LdT
Progressão Retardada da Doença Com
Supressão Continuada : Não-cirróticos
76.3% of lamivudine-treated patients had YMDD mutations at Year 6
– Benefits of treatment reduced for those with YMDD mutations
P = .005
Patients With
Cirrhosis/HCC (%)
14
P = .024
12
10
P = .390
8
6
4
2
0
Lamivudine
(WT)
Yuen MF, et al. AASLD 2005. Abstract 985.
Lamivudine
(YMDD)
Controls
HBV DNA
(log10 copias/mL)
Tenofovir vs Adefovir em Pacientes
com Resistencia a Lamivudina
Adefovir
(10 mg/day)
Tenofovir
(300 mg/day)
Semanas
Van Bommel et al. Hepatology. 2004;40:1421-1425.
Algoritmo para Tratamento da Hepatite Crônica pelo HBV
Avaliação da Resposta Virológica Primária (Semana 12)
Falha Terapêutica Primária
< 1 log redução da CV basal
Resposta Virológica
1 log redução da CV basal
Avaliação da Resposta Virológica (Semana 24)
Resposta Virológica Completa
PCR negativo
Continuar Terapia
e monitorar a cada
6 meses
Resposta Virológica Parcial
> 60 a < 2000 UI ou
> 300 a 10000 copias
Droga com baixa barreira
genética:Adicionar 2ª droga
e monitorar de 6/6 meses
> 2000 UI ou
> 10.000 copias
Droga com alta barreira
genética: monitorar de 3/3
Meses e avaliar na sem.48
c/ Resposta Completa
na sem. 48: Continuar
Keeffe et al. 2007
Ausência de Resposta Virológica
Adicionar droga mais potente
e monitorar de 3/3 meses
s/ Resposta Completa
na sem. 48: adicionar
Roadmap de Acordo com a
Resposta Virológica na Semana 12
•Start treatment
•Week 12
•Assess for primary nonresponse
Primary response
HBV DNA ≥ 1 log10 IU/mL drop
Primary treatment failure
HBV DNA < 1 log10 IU/mL drop
If nonadherent,
Continue
counsel
•Keeffe E, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.
If adherent,
add a more
potent drug
Roadmap de Acordo com a
Resposta 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;
•Add a more potent drug;
•monitor every 6 months
•monitor every 3 months
•Keeffe E, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.
Roadmap de Acordo com a
Resposta Virológica na Semana 24
•Patients with primary response
•Week 24
•Assess early predictors of efficacy
•Partial response
•HBV DNA
•Is there a
•60 to < 2000 IU/mL
•rationale for
•switching?
•Antiviral: low genetic
barrier
•Antiviral: high genetic
barrier
•Antiviral: suboptimal
antiviral potency
•Add a second drug without
cross-resistance
•Monitor every 3 months;
continue to ≥ 48 weeks
•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: Sumário
Opções Terapêuticas Disponíveis: PegIFN, LAM, ADV, ETV
PegIFN somente em pacientes compensados
PegIFN apresenta eficácia superior à LAM
Entecavir apresenta eficácia superior à LAM
Resistência ocorre com todos os agentes orais; exceto o PegIFN
Adefovir e entecavir nunca foram comparados face a face
PegIFN vs adefovir ou entecavir não avaliado
Current Treatment Options for Hepatitis B
IOM Report: Burden of HBV Disease1
15% to 25% risk of early death caused by liver cancer or
end-stage liver disease among patients with chronic
HBV infection2,3
WHO global HBV estimates3
– ~ 2 billion people ever infected with HBV
– ~ 350 million people living with chronic HBV infection
– ~ 600,000 deaths annually caused by HBV-related liver
disease or HCC
1. Institute of Medicine. Hepatitis and liver cancer: a national strategy for prevention and control of
hepatitis B and C. 2010. 2. Beasley R et al. In: Hollinger FB, Margolis H, Lemon SM, editors. Viral
hepatitis and liver disease. Proceedings of the 1990 international symposium on viral hepatitis and
liver disease: contemporary issues and future prospects. 1991. 3. WHO. Hepatitis B fact sheet.
clinicaloptions.com/hep
•75
Current Treatment Options for Hepatitis B
Natural History of HBV Infection
Early
Childhood
> 95%
Immune
Tolerance
Adulthood
< 5%
HBeAgChronic
Hepatitis B
Cirrhosis
HBeAg+
Chronic
Hepatitis B
Inactive
Carrier
Courtesy 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 B
AASLD CHB Guidelines: Treatment Candidacy
for HBeAg-Positive Patients
HBsAg Positive
HBeAg Positive
ALT < 1 x ULN
ALT 1-2 x ULN
ALT > 2 x ULN
HBV DNA < 20,000 IU/mL HBV DNA > 20,000 IU/mL HBV DNA > 20,000 IU/mL
Q 3-6 mos ALT
Q 3 mos ALT
Q 1-3 mos ALT, HBeAg
Q 6-12 mos HBeAg
Q 6 mos HBeAg
Treat if persistent
Consider biopsy if
persistent or age > 40
Liver bx optional
Immediate Rx if jaundice or
Rx as
needed
Lok AS, McMahon BJ. Hepatology. 2009;50:661-662.
Chronic
Hepatitis B: Update 2009, decompensated
Lok ASF,
McMahon BJ, www.aasld.org. Copyright@2009. American Association for the Study of Liver
Diseases, Reproduced with permission of the American Association for the Study of Liver Diseases. clinicaloptions.com/hep
•77
Current Treatment Options for Hepatitis B
AASLD CHB Guidelines: Treatment Candidacy
for HBeAg-Negative Patients
HBsAg Positive
HBeAg Negative
ALT < 1 x ULN
HBV DNA < 2000 IU/mL
Q 3 mos ALT x 3,
then Q 6-12 mos if
ALT still < 1 X ULN
ALT 1-2 x ULN
ALT ≥ 2 x ULN
HBV DNA 2000-20,000 IU/mL HBV DNA ≥ 20,000 IU/mL
Q 3 mos ALT and HBV DNA
Treat if persistent
Consider biopsy if persistent
Liver biopsy optional
Rx as needed
Lok 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 Liver
Diseases, Reproduced with permission of the American Association for the Study of Liver Diseases.
clinicaloptions.com/hep
•78
Current Treatment Options for Hepatitis B
Treatment Criteria for Chronic Hepatitis B:
Comparison of Liver Society Guidelines
Recommended HBV DNA and ALT levels outlined in the
following table
Liver Society
Guidelines*
HBeAg Positive
HBeAg Negative
HBV DNA, IU/mL
ALT
HBV DNA, IU/mL†
ALT
EASL 20091
> 2000
> ULN‡
> 2000
> ULN‡
APASL 20082
≥ 20,000
> 2 x ULN‡
≥ 2000
> 2 x ULN‡
> 20,000
> 2 x ULN§ or
positive biopsy
≥ 20,000
≥ 2 x ULN§ or
positive biopsy
AASLD
20093
*Although ALT and HBV DNA are primary tests used to determine treatment candidacy, the levels of
elevation 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 a
cutoff for treatment.
‡Laboratory
§30
normal.
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 B
The Twin Pillars of HBV Therapy
PROFOUND VIRAL
AVOIDANCE
SUPPRESSION
OF RESISTANCE
Jacobson IM. J Hepatol. 2008;48:687-691.
clinicaloptions.com/hep
•80
Current Treatment Options for Hepatitis B
The Goal of HBV Therapy
Long-term
Viral Suppression
Improved Clinical Outcomes
Requires finite course of therapy in some patients
– HBeAg seroconversion
Long-term treatment in others
– HBeAg-positive without seroconversion
– HBeAg-negative
clinicaloptions.com/hep
•81
Current Treatment Options for Hepatitis B
Goals of Hepatitis B Treatment
Prevention of long-term negative clinical outcomes (eg, cirrhosis,
HCC, death) by durable suppression of HBV DNA
Remission of liver disease
Primary treatment endpoint
– Sustained decrease in serum HBV DNA level to low or undetectable
Secondary treatment endpoints
– Decrease or normalize serum ALT
– Induce HBeAg loss or seroconversion
– Induce HBsAg loss or seroconversion
– Improve liver histology
clinicaloptions.com/hep
•82
Current Treatment Options for Hepatitis B
HBV Treatment Landscape in 2011
Peginterferon alfa-2a
Entecavir
Lamivudine
1990
Interferon alfa-2b
1998
2002
Adefovir
2005
Tenofovir
2006
2008
Telbivudine
clinicaloptions.com/hep
•83
Current Treatment Options for Hepatitis B
Treatment Guidelines: Recommendations for
First-line Therapy
HBeAg Positive or Negative Chronic HBV
Preferred
Alternative
Not Preferred
Tenofovir DF
Adefovir
Lamivudine
Entecavir
Telbivudine*
Peg-IFN alfa-2a
*HBV DNA must be undetectable at 24 weeks to continue
Lok 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 B
Undetectable* HBV DNA After
1 Year of Treatment
Undetectable* HBV DNA (%)
Not head-to-head trials; different patient populations and trial designs
HBeAg Positive
100
76
80
60
60
HBeAg Negative
100
80
67
88
90
93
60-73
63
51-63
60
40-44
40
20
40
25
13-21
20
0
LAM ADV LdT
ETV TDF
PegIFN
0
LAM ADV
LdT
ETV
TDF PegIFN
*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 B
HBeAg Loss and Seroconversion in HBeAg+
Patients After 1 Year of Treatment
Not head-to-head trials; different patient populations and trial designs
HBeAg Loss
Outcome (%)
100
100
80
80
60
60
40
17-32
24
26
HBeAg Seroconversion
30
40
21
20
20
22
12-18
22-27
23
21
21
LdT
ETV
TDF
NA
0
LAM ADV LdT
ETV TDF
PegIFN
0
LAM ADV
Lok 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 Engl
J Med. 2008;359:2442-2455. Janssen HL et al. Lancet. 2005;365;123-129.
PegIFN
clinicaloptions.com/hep
•86
jb3
Current Treatment Options for Hepatitis B
Durability of HBeAg Seroconversion
Not head-to-head trials; different patient populations and trial designs
Agent
n
Posttreatment
Timepoint
Sustained HBeAg
Seroconversion, %
Peginterferon1
72
24 wks
82
Lamivudine1-4
55
61
43
39
24 wks
24 wks
52 wks
40.7 mos*
58
72
93
77
Adefovir5
45
150 wks*
91
Telbivudine3
55
52 wks
86
Entecavir2
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 JL
et al. Hepatology. 2003;37:748-755. 5. Wu IC et al. Clin Infect Dis. 2008;47:1305-1311.
clinicaloptions.com/hep
•87
Slide 87
jb3
This 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 B
Other Outcomes in HBeAg+ Patients
After
1
Year
of
Treatment
Not head-to-head trials; different patient populations and trial designs
100
~ 90
Outcome (%)
~ 80
77
80
72 74
68 68
49-56
48
41-75
69
65
60
40
LAM
ADV
LdT
ETV
TDF
Peg-IFN
53
39
50-80
38
20
0
NA NA
ALT
Histologic
Response
Normalization
Improvement
Durability*
*No/short duration
consolidation tx among
LAM- and ETV-treated
pts; most pts
treated with ADV and LdT had consolidation.
Lok AS et al. Hepatology. 2009;50:661-662.
1 0 0 2 3.2 3
HBsAg Loss
clinicaloptions.com/hep
•88
Current Treatment Options for Hepatitis B
Other Outcomes in HBeAg-Negative
Patients
After
1
Year
of
Treatment
Not head-to-head trials; different patient populations and trial designs
LAM
ADV
LdT
ETV
TDF
Peg-IFN
Outcome (%)
100
80
60
72 74
78 76
60-66
60-79
64
67
70 72
48
38
40
~ 20
20
< 10
~5
0
ALT
Histologic
Normalization
Improvement
Lok AS et al. Hepatology. 2009;50:661-662.
NA 3 NA
Response
Durability
clinicaloptions.com/hep
•89
Current Treatment Options for Hepatitis B
HBeAg-Positive Patients Treated Up
to 5 Years With Entecavir
Proportion of Patients Achieving HBV DNA < 300 copies/mL through 5 Yrs
ETV-022
Patients (%)
Overall Cohort
Yr 1
100
80
HBeAg-Positive ETV Long-term Cohort
Yr 1
(ETV-022 → ETV-901)
Yr 2
Yr 3
Yr 4
83
89
91
Yr 5
94
116/140
116/131
98/108
88/94
67
55
60
40
20
n=
0
236/354
80/146
Han S-H et al. Hepatology. 2008;48(Suppl S1):705A.
clinicaloptions.com/hep
•90
Current Treatment Options for Hepatitis B
Tenofovir Pivotal Study 103 (HBeAg Positive):
Three-Year Viral Suppression (Not ITT)
Randomized Double-Blind
Open-Label TDF
HBV DNA < 400 copies/mL
(%) Patients with
100
95% TDF-TDF
90
91% ADV-TDF
80
70
60
50
40
30
20
10
0
0
24
48
72
96
120
144
Weeks on Study
Includes 17 patients who had HBV DNA <400 copies/mL at week 144 on FTC + TDF
Heathcote EJ et al. Hepatology. 2009;50(Suppl S4):533A.
clinicaloptions.com/hep
•91
Current Treatment Options for Hepatitis B
HBeAg Seroconversion Rates Over
Time in HBeAg-Positive Patients
HBeAg Seroconversion (%)
Not head-to-head trials; different patient populations and trial designs
•Extended Treatment With Nucleos(t)ide Analogues* vs
Limited Duration (1 Yr) Peginterferon Treatment
Entecavir
Tenofovir
Peginterferon
80
60
39
40
20
31
21
22 22-27
26 29-32
35
26
0
1.0 Yr
1.5-2.0 Yrs
3.0-4.0 Yrs
*With sustained undetectable HBV DNA.
1.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 B
HBsAg Loss Over Time in
HBeAg-Positive Patients
Not head-to-head trials; different patient populations and trial designs
HBsAg Loss (%)
100
•Extended Treatment With Nucleos(t)ide Analogues* vs
Limited Duration (1 Yr) Peginterferon Treatment
Entecavir
Tenofovir
Peginterferon
80
60
40
20
2
3
5
5
6
0
1.0 Yr
8
6
1.5-2.0 Yrs
8
NA
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 B
Predictors of HBsAg Loss in
HBeAg-Positive Patients
Race: whites > nonwhites1
Genotype1-3
– Nucleos(t)ide analogues: A and D
– Peginterferon: A
Decline in HBsAg level during first 24 wks with
nucleos(t)ide analogues1
HBeAg negative at or within 26 wks of completing
peginterferon treatment3
1. 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 B
Undetectable HBV DNA Over Time in
HBeAg-Negative Patients
Not head-to-head trials; different patient populations and trial designs
Undetectable HBV DNA (%)
•Extended Treatment With Nucleos(t)ide Analogues vs
Limited Duration (1 Yr) Peginterferon Treatment
100
90
93
80
100*
91
87
Entecavir
Tenofovir
Peginterferon
63
60
40
20
15
16
NA
0
1 Yr
2 Yrs
3 Yrs
•*Single-center study.
1. 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 B
HBsAg Loss Over Time in
HBeAg-Negative Patients
Not head-to-head trials; different patient populations and trial designs
100
•Extended Treatment With Nucleos(t)ide Analogues* vs
Limited Duration (1 yr) Peginterferon Treatment
Entecavir
Tenofovir
Peginterferon
Patients (%)
80
60
40
20
0
<1 0
4
1.0 Yr
<1 0
9
7
1.5-2.0 Yrs
NA 0
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 P
et 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 B
The First Branch Point in Choosing
What to Treat With
Decision to treat
IFN
(Peg-IFN alfa-2a)
Nucleos(t)ide
analogues
clinicaloptions.com/hep
•97
Current Treatment Options for Hepatitis B
When to Consider Peg-IFN
Favorable predictors of
response1,2
– Low HBV DNA*
– High ALT*
– Genotype A or B > C or D3-5
Specific patient
demographics1,2
– Generally young people
– Young women wanting
pregnancy in near future
– Absence of comorbidities
Patient preference1,2
*Also predictive of response to nucleos(t)ide analogues.
Concomitant HCV
infection
1. 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;352:26822695. 5. Flink HJ et al. Am J Gastro. 2006;101:297-303.
clinicaloptions.com/hep
•98
Current Treatment Options for Hepatitis B
The Second Branch Point in Choosing
What to Treat With
Nucleos(t)ide
analogues
Lamivudine
Adefovir
Entecavir
Telbivudine
Tenofovir
clinicaloptions.com/hep
•99
Current Treatment Options for Hepatitis B
Entecavir and Tenofovir Combination
Therapy
52 patients with advanced fibrosis or cirrhosis
Median 3 lines of pretreatment with incomplete response
60% HBeAg positive
No lactic acidosis
%
81
No renal impairment
Median 12 mo
8
42/52
Peterson J et al. Hepatology. 2010;52(Suppl 1):S394-S395.
4/52
clinicaloptions.com/hep
•100
Current Treatment Options for Hepatitis B
A Simplified Road Map for 2011
Entecavir
or
Tenofovir
48 weeks
HBV DNA
HBV DNA+
(marked decline
and still falling)
Continue to
week 72-96
+
Switch
or add
HBV DNA+
(plateau)
Add second
drug
HBV DNA-
Continue
-
Continue
clinicaloptions.com/hep
•101
Resistance:
Recognition and
Management
•102
Current Treatment Options for Hepatitis B
Methods to Detect HBV Resistance
Commercially Available
Standard
population-
INNO-LIPA
based sequencing
• Less sensitive
• Detects variants present
at 25% of viral population
• Needed to detect “new,”
previously undescribed
substitutions
Research
RFLP
Allelespecific
PCR
• More sensitive
• Detects variants present
at 5% of viral population
• Only detects known
mutations
• Detect variants present at 1%
of the viral population
• Like INNO-LIPA, only detects
known mutations
• Coming soon: ultra deep
sequencing
clinicaloptions.com/hep
•103
Current Treatment Options for Hepatitis B
Summary of Resistance Analyses
of TDF-Treated Patients Through Year 3
Total Patients on Study
Patients > 400 copies/mL
Patients with Resistance
450
400
350
300
250
200
150
100
50
0
400
426
350
364 (85%)
300
250
200
150
100
39 (9%)
24 (6%)
13* (4%)
50
0
0
Year 1
*Includes
389 (91%)
Number of Patients
Number of Patients
450
0
Year 2
0
Year 3
7 patients on FTC+TDF combination therapy
Snow-Lampart A et al. Hepatology. 2009;50(Suppl S4):532A.
clinicaloptions.com/hep
•104
Current Treatment Options for Hepatitis B
Cumulative Rates of Resistance With Oral Agents
in Nucleos(t)ide-Naive Patients
Not 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
•2nd
•3rd
•LAM
24%
38%
49%
67%
•ADV
0%
3%
11%
18%
29%
•LdT
4%
17%
•ETV
•TDF
0.2%
0%
0.5%
1.2%
0%
1.2%
0%
1.2%
0%
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.
70%
1.2%
clinicaloptions.com/hep
•105
Current Treatment Options for Hepatitis B
Cross-Resistance Data for the Most
Frequent Resistant HBV Variants
HBV Variant
(Amino Acid Substitutions)
Level of Susceptibility
Lamivudine Telbivudine
Entecavir
Adefovir
Tenofovir*
S
S
S
S
S
Wild-type
S
S
M204I
R
R
L180M + M204V
R
R
I
S
S
A181T/V
I
S
S
R
S
N236T
S
S
S
R
I
R
R
R
S
S
R
R
R
S
S
L180M + M204V/I ± I169T ± V173L ±
M250V
L180M + M204V/I ± T184G ±
S202I/G
S - Sensitive
I
R
I – Intermediate
(Reduced Susceptibility)
*Resistance to tenofovir has not been described so far
Adapted from EASL Clinical Practice Gudelines: Management of Chronic Hepatitis B.
EASL. J Hepatology. 2009;50:227-42.
R - Resistant
clinicaloptions.com/hep
•106
Current Treatment Options for Hepatitis B
When to Perform Resistance Testing
Virologic breakthrough
– Consider compliance if no resistant mutations present
– Most breakthroughs in ETV and TDF trials have not been
associated with documented resistance
Residual viremia at late stage of treatment when HBV
DNA undetectability would be expected (depends on
drug)
clinicaloptions.com/hep
•107
Current Treatment Options for Hepatitis B
Treatment of Established Resistance
One Drug From Each Class
Nucleotides
Nucleotides
Lamivudine
Adefovir
Telbivudine
Tenofovir
Entecavir
Emtricitabine
(FTC)*
*Available with tenofovir
clinicaloptions.com/hep
•108
Current Treatment Options for Hepatitis B
Management of Patients With
Decompensated Cirrhosis
Preferred therapies
(LAM or LdT) + (ADV or TDF); TDF or ETV
monotherapy*
– Treatment should be coordinated with transplant center
– IFNs should not be used in decompensated cirrhosis
Treatment duration
Life-long treatment recommended
*Clinical data documenting safety and efficacy of TDF or ETV monotherapy in
decompensated cirrhosis are lacking.
Lok AS et al. Hepatology. 2009;50:661-662.
clinicaloptions.com/hep
•109
Current Treatment Options for Hepatitis B
Management of Patients With HIV
Coinfection
HBV/HIV-coinfected pts who require HBV therapy should be treated
1
– Liver biopsy should be considered in patients with fluctuating or mildly
elevated ALT (1-2 x normal)
Not on or Anticipating
Antiretroviral Therapy*
• Treat with antiviral
therapy that does not
target HIV, such as
pegIFN or ADV
• Although LdT does not
target HIV, it should not
be used in this
circumstance
Planning Antiretroviral
Therapy
• Treat with therapies that
are effective against both
viruses: TDF + (FTC or
LAM) preferred (plus ≥ 1
other anti-HIV agent)
Already Receiving
Antiretroviral Therapy
• If regimen does not
include drug active
against HBV, may add
pegIFN or ADV
• If LAM resistance, add
TDF
*DHHS guidelines recommend that any HBV/HIV-coinfected pt in whom HBV treatment is indicated should
initiate a fully suppressive antiretroviral regimen containing 2 drugs with anti-HBV activity.2
1. 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 B
Management of HBV During Chemotherapy or
Immunosuppression
Reactivation of HBV replication common during
immunosuppression/chemotherapy (20% to 50%)
Prophylactic antiviral therapy recommended in HBV carriers at onset
of cancer chemotherapy or immunosuppressive therapy
– If baseline HBV DNA < 2000 IU/mL, continue treatment for
6 mos after
– If baseline HBV DNA > 2000 IU/mL, continue treatment until treatment
endpoints for hepatitis B are reached
Tenofovir or entecavir preferred if treatment for > 12 mos
For patients with anti-HBc but HBsAg-negative:
– Individuallize treatment decisions
– Flare may occur even if anti-HBs present
Lok AS et al. Hepatology. 2009;50:661-662.
clinicaloptions.com/hep
•111
Current Treatment Options for Hepatitis B
Treatment Endpoints
HBeAg+
Seroconversion
Stop 12
months later
HBeAg-
No seroconversion
Continue
Therapy in cirrhotics should be continued
until PCR negative and loss of HBsAg
Keeffe EB et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.
Treat
indefinitely
Change regimen (switch or add)
for incomplete response
clinicaloptions.com/hep
•112
Current Treatment Options for Hepatitis B
Conclusions
Choose agents that confer high potency and excellent
resistance profiles
Follow to assess HBV DNA, chemistries, HBeAg/Ab, and
HBsAg at appropriate intervals (q12 weeks for HBV DNA)
Aim for complete viral suppression in all patients: think about
change if residual viremia present after 1-2 years (sooner if
drug with low genetic barrier to resistance is used)
Resistance unlikely even with late residual viremia but check
for it when change is contemplated or with virologic
breakthrough – do not take compliance for granted
Combination therapy (nucleoside and nucleotide) for
established resistance
Consider entecavir and tenofovir for multiresistant HBV
clinicaloptions.com/hep
•113