Temas no resueltos en Hepatitis B · 2015. 11. 12. · Temas no resueltos en Hepatitis B Jose Luis...

Temas no resueltos en Hepatitis B

Jose Luis Calleja Panero Profesor Titular de Medicina

Servicio de Gastroenterologia y Hepatología Universidad Autonoma de Madrid

2012

Agenda

• Metodos no invasivos para evaluar la fibrosis

• Cohortes de vida real

• Hepatocarcinoma en pacientes tratados

• Reactivación en pacientes inmunodeprimidos

• Nuevas opciones terapéuticas • PEG- IFN + Tenofovir

• TAF

2

FibroScan®

Fraquelli M, et al. Gut 2007; 56:967-973. Castéra L, et al. Gastroenterology 2005; 128:343-50

TE − Dual Cut-off for Diagnosing Fibrosis in Treatment-naïve HBV Patients

Significant fibrosis (F≥2)

Cut-off kPa

Sensitivity %

Specificity %

-LR

+LR

≤6.2 94 93 0.10 1.7

Cut-off kPa

Sensitivity %

Specificity %

-LR

+LR

≤9.4 100 82 0 5.5

EXCLUDING

Cut-off kPa

Sensitivity %

Specificity %

-LR

+LR

>9.4 55 95 0.5 11

Cirrhosis (F4) Cut-off

kPa

Sensitivity %

Specificity %

-LR

+LR

>13.1 75 93 0.3 11.2

CONFIRMING

Significant fibrosis (F≥2)

Cirrhosis (F4)

Viganò et al, AP&T 2011

5 5 Viganò. Aliment Pharmacol Ther 2011

El doble umbral o cut-off de la elastometría

Algunos estudios sugieren que valores de la elastometría ≥9,4 kPa

proporcionan una elevada precisión diagnóstica (>90%) de fibrosis

significativa, mientras que los valores ≤ 6,2 kPa descartarían con la

misma precisión diagnóstica (>90%) el diagnóstico de fibrosis

significativa.

Lèdinghen et al. AP&T 2013;37:979-988

Impacto de la valoración de la fibrosis mediante métodos no invasivos en la

supervivencia en pacientes con hepatitis B

N=600 pacientes con hepatitis crónica B Tasa de supervivencia a 5 años Necesidad de trasplante hepático a los 5 años

Hombres 64%

Edad 42 años

Portadores inactivos 36%

Supervivencia 94,1%


Impacto de la valoración de la fibrosis mediante elastografía transitoria en la



Impacto de la valoración de la fibrosis mediante BIOPSIA HEPÁTICA en la



Impacto de la valoración de la fibrosis mediante APRI y FIB-4 en la supervivencia en

pacientes con hepatitis B

10

Unlike HCV, APRI and FIB-4 do not correctly classify fibrosis stage in a large

number of patients with chronic HBV Kim WR, EASL, 2014, Poster #661

Distribution of APRI and FIB-4 Scores by Ishak Fibrosis Scores from 575 Biopsies

APRI and FIB-4 vs. Histology in CHB Patients in TDF Clinical Trials

Studies 102/103 ‡

APRI ≤0.5 Ishak 0–2; APRI >2.0 Ishak 5–6 FIB-4 <0.6=Ishak 0–1; FIB-4 >3.25=Ishak 4–6

Utilidad ARFI (Acoustic Radiation Force Impulse Imaging mode elastography) en Hepatitis B

• N=114

• F0: 33; F1: 49; F2: 19; F3: 8, F4: 5

Estadio de Fibrosis ARFI TE

>F1 0,66 0,78

>F2 0,73 0,82

>F3 0,79 0,88

>F4 0,94 0,94

p=ns

Cut-off: Descarta F2 (ARFI <1.03) Confirma F2 (ARFI > 1,39)

Friedrich-Rust et al. JVH 2013;20:240-248

Métodos no-invasivos EN Hepatitis B

FIBROTEST

MR elastography

Yin M. Clin Gastro Hepatol 2007;5:1207-1213

2,3 kPa 3,0 kPa 3,25 kPa 4,2 kPa 6,15 kPa

2,74 kPa 3,2 kPa 3,7 kPa 4,33 kPa

N=63 Hombres 44 Mujeres 19

Coeficiente de correlación

Fibrosis 0,94 p<0.0001

Esteatosis 0,15 p=0,23

Inflamación 0,13 p=0,28

Venkatesh et al. Eur Radiol 2013

Utilidad de la Elastografía por resonancia magnética en el diagnóstico de la fibrosis en Hepatitis B

Estudio HEBEST

Calleja JL. Gastroenterol Hepatol, 2013 (A)

1. Evaluar el grado de seguimiento de las guías de la EASL en el manejo

del paciente con infección crónica por VHB no tratado

2. Describir el perfil clínico, virológico, bioquímico e histológico de

pacientes con infección crónica por VHB no tratados en condiciones

de práctica clínica habitual

3. Recogida retrospectiva en 19 hospitales españoles mediante historia

clínica

http://www.congresoaeeh.com/Res%C3%BAmenesnbsp.aspx

Estudio HEBEST: Resultados

586 incluidos

475 analizables

16 pacientes

excluidos por edad,

fecha última visita

anterior a Feb 2009 o

ausencia de datos 95 pacientes excluidos

por ingesta alcohol

> 50 g diarios y/o

< 2 determinaciones de

ADN-VHB o ALT

Estudio HEBEST: Resultados

Estudio HEBEST Lesión Hepática según ALT y ADNVHB

ADNVHB ≥2.000 UI/mL y ALT ≥40 U/L

ADNVHB <2.000 UI/mL y ALT ≥40 U/L

ADNVHB ≥2.000 UI/mL y ALT <40 U/L

ADNVHB <2.000 UI/mL y ALT <40 U/L

Lesión hepática significativa

Zona gris

No lesión hepática

19 19

Guía EASL: Indicaciones de tratamiento

TRATAR

TODAS HCB (HBeAg + y HBeAg -)

DNA VHB > 2000 UI/mL

+

ALT > LSN

+

HISTOLOGÍA (+)*

+

+


+

ALT > LSN

+

HISTOLOGÍA (+)*

+

+

ALT valor normal


+

ALT > x2 LSN

+

HISTOLOGÍA

+

HISTOLOGÍA (no necesaria)

(*) HISTOLOGÍA (+): Necroinflamación moderada - grave y /o fibrosis moderada

Posible tratamiento

recomendable procedimiento

no invasivo para descartar cirrosis

TRATAR

TODAS HCB (HBeAg + y HBeAg -)


+

ALT > LSN

+

HISTOLOGÍA (+)*

+

+


+

ALT > LSN

+

HISTOLOGÍA (+)*

+

+

ALT valor normal

HISTOLOGÍA (+)* Lesión hepática

Leve (A1F1)

Guía AEEH: Indicaciones de tratamiento

Seguimiento obligatorio

Se puede considerar el tto

Agenda






• TAF

20

Agenda






• TAF

21

22

Baseline Characteristics N=400

Overall Median Age, years (Q1–Q3) 44 (34–54)

≥ 65 years, % (n) 8.75% (35)

Male, % (n) 69% (275)

HBeAg–, % (n) 68% (265/389)

ALT>ULN1, Overall, % (n) 55% (209/383)

Treatment naïve, % (n) 46% (183)

TDF monotherapy, % (n) 91% (365)

1. ALT upper limit of normal, ULN: Male ≤ 43 U/L, female ≤ 34 U/L

Geographic Origin

* Turkey: 19%

3-year real life study of 400 treatment-naïve and -experienced patients with CHB from 33 German centers

GEMINIS

Prospective, Multicenter Observational Real-Life Study of TDF for CHB

‡

Petersen J, EASL, 2014, Oral #122

23

HBsAg loss:seroconversion

6:6 in HBeAg-positive

5:0 in HBeAg-negative

2 cases of HCC reported over 3 years

7 pregnancies

– TDF during all trimesters (5/7), 2nd and 3rd trimester (1/7), 1st trimester (1/7)

– All newborns were HBsAg-negative and healthy

Renal function remains stable over 36 months

Petersen J, EASL, 2014, Oral #122

After 3 years in real-life practice, TDF was effective with a favorable safety profile

Prospective, Multicenter Observational Real-Life Study of TDF for CHB

GEMINIS ‡

Timescales not linear

24

Sin experiencia de tratamiento

M12

<20–2K

<2K–200

M3 M6 M24 M36

<200–20

<2–20K

<2M–200K

<20–2M

<200–20M

≥200M

**

**

*

*

*

*

*

***

Con experiencia de tratamiento

M12 M

<20–2K

<2K–200

M3 M6 M24 M36

<200–20

<2–20K

<2M–200K

<20–2M

<200–20M

≥200M

*

**

***

Petersen J et al. EASL 2014; Presentación oral nº 122

La falta de cumplimiento terapéutico se definió como >3 dosis omitidas/mes

Las tasas de respuesta en ensayos clínicos con A.N. se reflejan en estudios en el mundo real

* Cada burbuja representa n=1 sin cumplimiento terapéutico ** Cada burbuja representa n=1 pausa de TDF >1 mes *** La burbuja representa n=6, 2 sin cumplimiento terapéutico y 4 LIC=200 UI/mL

GEMINIS: Estudio multicéntrico en Alemania, no intervencional,

de TDF en la práctica clínica: datos de 3 años

* La burbuja representa n=1 pausa de TDF >7 días

** La burbuja representa n=2 sin cumplimiento terapéutico

*** La burbuja representa n=2, 1 sin cumplimiento terapéutico y

1 LIC 200 UI/mL

25

Baseline Characteristics N=440

Age Median (years) 45

Male (%) 71%

Liver Biopsy (%) 67%

METAVIR score F3/F4 33%

HBeAg status (%) HBeAg -

HBeAg +

74%

26%

HBV DNA (mean IU/mL)

HBeAg +

HBeAg -

6.6 x 107 IU/mL

3.4 x 106 IU/mL

ALT (mean U/L) 67

VIREAL TDF in Treatment-Naïve or -Experienced CHB Patients in Real Life Practice

3-year efficacy and tolerability data of TDF treatment in real-life patients (N=440) in France

Marcellin P, et al. EASL, 2012; Poster #530

‡

26 Pageaux G-P, EASL, 2014, Poster #1061

TDF in Treatment-Naïve or -Experienced CHB Patients in Real Life Practice

94–97% HBV DNA undetectable, with no difference between TN and TE

Overall HBsAg-loss: 12 (2.7%)

3 cases of HCC reported over 3 years

In real life practice, 3 years of TDF therapy was associated with high virologic

response, very low number of HCC cases, and a favorable safety profile

VIREAL

Virologic Response Rates

97%

n=110 n=119

94%

n=101 n=189 n=171 n=158 Pa

tie

nts

wit

h H

BV

-DN

A

<6

9IU

/mL

(%

)

‡

Overall Population (N=440) eGFR ≥ 60 and < 90 (n=98)

eGFR ≥ 90 (n=238) eGFR ≥ 30 and < 60 (n=24)

27

Long-Term Efficacy of TDF in Previously Treated and Naïve Patients

CIBERHEP

Baseline characteristics of 370 CHB patients treated for a median of 116 weeks (range 12–295) from 48 Spanish centers

‡

Tabernero D, EASL, 2014, Poster #1058

28

0 48 96 144 192 0

30

60

90

120

150

180

210

MD

RD

(m

l/m

in/1

.73m

2)

Week

Tabernero D, EASL, 2014, Poster #1058

Long-Term Efficacy of TDF in Previously Treated and Naïve Patients

CIBERHEP

Analysis of safety and efficacy of TDF in 370 CHB patients treated for a median of 116 weeks (range 12–295) from 48 Spanish centers

Viral suppression was similar between treatment-naïve and -experienced

patients, with HBeAg loss occurring more in naïve patients

HBsAg loss: 4 (1 seroconversion)

HBeAg Negative HBeAg Positive

23 19

Naïve, N TE, N

19 17

14 13

3 8

65 48

Naïve, N TE, N

50 40

26 33

13 25

‡

Agenda


• Tratamiento combinado PEG-IFN + Tenofovir




29

Hosaka T et al. Hepatology 2013;58:98-107

Reducción significativa de CHC con ETV comparado con controles en pacientes cirróticos

Control ETV LAM

HCC

Duración del tratamiento (años)

Ta

sa

acu

mu

lad

a d

e C

HC

(%

)

0 1 2 3 4 5

0

20

30

40

50

10

11,4%

20,9%

2,6%

28,5%

4,3%

19,7%

7,0%

6

7,0%

22,2%

38,9%

4,8%

12,2%

Cirrosis

Prueba del orden logarítmico :

ETV frente a LAM: P=0,043

ETV frente a control: P<0,001

LAM frente a control: P=0,019

Sin cirrosis

1,6% 3,6%

2,5% 0%

0 1 3 5 2 4 6

Ta

sa

acu

mu

lad

a d

e C

HC

(%

)

0

20

30

40

50

10

Duración del tratamiento (años)

3,2% 4,9%

Prueba del orden logarítmico:

ETV frente a LAM: P=0,126

ETV frente a control: P=0,440

LAM frente a control: P=0,879

31 Papatheodoridis GV, EASL, 2014, Poster #1075

PAGE-B: Risk Score for HCC Development in Caucasian CHB Patients

Seven-center, cohort study aimed to develop and validate an accurate HCC-risk score in Caucasian CHB patients receiving ETV or TDF

1619 adult Caucasians with CHB ± compensated cirrhosis received ETV or TDF for ≥ 12 months

HCC developed in 56/1619 (3.5%) patients with either therapy

– Incidence: 1.12 (0.86–1.46)/100 patient-years

PAGE-B risk score constructed by applying points for age, gender, and platelets

Patients’ characteristics Univariate Multivariate

HR P-value HR P-value

Age (per 5-year increase) 1.4 <0.001 1.3 0.001

Gender (M vs F) 4.3 0.015 3.9 0.024

BMI (per 1 kg/m2) 1.1 0.183

PegIFN in the past, Y vs N 0.3 0.041

NUC(s) before ETV/TDF, Y vs N 0.5 0.087

ALT, IU/L 1.0 0.239

Platelets, x103/mm3

100,000-199,000 vs. ≥200,000

<100,000 vs ≥200,000

7.5

25.9

0.001

<0.001

5.2

16.2

0.008

<0.001

HBeAg status, (Neg. vs. Pos.) 1.6 0.378

HBV DNA, log10 IU/mL 0.9 0.152

Cirrhosis, Y vs N 6.8 <0.001

Virological remission, Y vs N 0.7 0.480

‡

32 Papatheodoridis GV, EASL, 2014, Poster #1075

PAGE-B, based on patient age, gender, and platelets represents a simple to use HCC-risk score for Caucasian CHB patients receiving ETV or TDF

PAGE-B: Risk Score for HCC Development in Caucasian CHB Patients

Validation Dataset Derivation Dataset

Page B Risk Score <6

Page B Risk Score 6–10

Page B Risk Score >10

0

0.05

0.10

0.15

0.20

0.25

0.30

Cu

mu

lati

ve P

rob

ab

ilit

y o

f H

CC

0 1 2 3 4

Years Since NUC Initiation

5

0

0.05

0.10

0.15

0.20

0.25

0.30

0 1 2 3 4 5

Years Since NUC Initiation

Age (years) Gender Platelets

(/mm3)

16-29: -4 Female: 0 ≥200,000: 0

30-39: -2 Male: 5 100,000-

199,999: 6

40-49: 0 <100,000: 11

50-59: 2

60-69: 4

≥70: 6

Construction of the Risk Score PAGE-B Risk Score for HCC

‡

Kim WR et al. Cancer 2015; doi:10.1002/cncr.29537

REACH-B es un calculador de riesgo que se ha desarrollado solo en pacientes no cirróticos y que por lo tanto puede infravalorar el riesgo en pacientes cirróticos; CU-HCC: Puntuación de CHC de la Universidad China; GAG-HCC: Guía con edad, sexo, ADN VHB, mutaciones en el promotor del core y cirrosis; PAGE-B: Plaquetas, edad y sexo en hepatitis crónica B; REACH-B: Estimación del riesgo de CHC en hepatitis crónica B

Incidencia prevista de CHC utilizando puntuaciones de riesgo frente a casos reales

• Seguimiento a largo plazo de 7,4 años en estudios de registro de TDF (N=641) comparado con la tasa prevista de CHC de 3 nuevos modelos

• Los modelos de riesgo predijeron puntuaciones similares, que fueron superiores de forma constante a los 14 casos de CHC que se produjeron durante el seguimiento (N=404)

• A pesar de la supresión viral con TDF sigue habiendo riesgo de CHC

• Necesidad de una monitorización constante de CHC

Observados REACH-B CU-HCC GAG-HCC

PAGE-B

35

30

25

20

15

10

5

0 0 1 2 3 4 5 6 7 8

Años

Nú

me

ro a

cu

mu

lad

o d

e c

aso

s

de

CH

C

Agenda






• TAF

34

35 Buti M, EASL, 2014, Poster #1040

29 patients were randomized

TDF: 14

Observation: 15

All HBV DNA undetectable

No statistically significant difference in renal function between two groups at baseline and 6 months follow-up

In this interim analysis at 6 months, no HBV reactivation occurred in patients who received TDF prophylaxis

P=0.2

TDF Prophylaxis of HBV Reactivation in Anti-HBc-positive Patients with Hematologic Malignancies Treated with Rituximab

Randomized, prospective, open-label, parallel group study in HBsAg-negative, anti-HBc-positive patients with hematologic malignancy treated with RTX randomized to either TDF or observation for 18 months

PREBLIN

2/15

‡

TDF is not specifically licensed for prophylaxis of HBV Reactivation.

Agenda






• TAF

36

Efficacy: HBsAg Loss in HBeAg+ Patients Efficacy: HBsAg Loss in HBeAg+ Patients

Baseline predictors for HBsAg loss (multivariate)1

– Caucasian race, genotype A or D, ≤4 year of HBV infection, HBsAg level (log10 IU/mL)

1. Marcellin P, et al. J Hepatol. 2014 Jul 18 (ePub ahead of print). 37

Weeks on Study

Cum

ula

tive

Pro

ba

bili

ty F

un

ctio

n E

stim

ate

12.9% (Kaplan-Meier-ITT analysis)

TDF-TDF

Year 1 2 3 4 5 6 7 8

ADV-TDF

38

Virologic Breakthrough and Genotypic Changes

Over 8 Years of TDF Treatment

Corsa, AASLD, 2014, Poster #1707

Studies 102/103

n=16 9.7%

n=42 25.5%

n=39 23.6%

n=68 41.2%

Genotypic Changes

65% patients had no changes from baseline or were unable to be genotyped

Sequence changes in pol/RT were observed in 58/165 patients (35%)

Conserved site changes were not associated with phenotypic resistance to TDF

Adaptado de Allweiss L et al. J Hepatol 2014;60:500-7

Descenso d

el niv

el de A

DN

VH

B

en la s

em

ana

4 (

log

10 U

I/m

l)

Descenso d

el n

ivel

de H

BsA

g

en la s

em

ana

4 (

log

10 U

I/m

l)

-0,5

Evidencia de actividad sinérgica con PEG-IFN + ETV en ratones humanizados

infectados por VHB

AASLD 2014, Boston

HBsAg Loss With Tenofovir Disoproxil Fumarate Plus

Peginterferon Alfa-2a in Chronic Hepatitis B: Results of a Global

Randomized Controlled Trial

Patrick Marcellin1, Sang-Hoon Ahn2, Xiaoli Ma3, Florin A. Caruntu4, Won-Young Tak5,

Magdy Elkashab6, Wan-Long Chuang7, Fehmi Tabak8, Rajiv Mehta9, Joerg Petersen10,

Eduardo B. Martins11, Phillip Dinh11, Amoreena Corsa11, Prista Charuworn11, G. Mani Subramanian11, John G. McHutchison11, Maria Buti12, Giovanni Gaeta13,

George Papatheodoridis14, Robert Flisiak15, Henry L.Y. Chan16 1Hôpital Beaujon, Université Paris-Diderot, Clichy, France; 2Yonsei University College of Medicine, Seoul, South Korea; 3Drexel

University College of Medicine, Philadelphia, PA; 4National Institute for Infectious Diseases “Prof Dr Matei Balș,” Bucharest, Romania; 5Kyungpook National University Hospital, Daegu, South Korea; 6Toronto Liver Centre, Ontario, Canada; 7Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan; 8Istanbul University Cerrahpaşa Faculty of Medicine, Istanbul, Turkey; 9Liver Clinic,

Surat, India; 10University of Hamburg, Germany; 11Gilead Sciences Inc., Foster City, CA; 12Hospital Universitari Vall d'Hebron, Barcelona, Spain; 13Second University of Naples, Italy; 14Athens University Medical School, Athens, Greece; 15Medical University of Bialystok,

Poland; 16The Chinese University of Hong Kong, Hong Kong SAR, Peoples Republic of China

Date of preparation: November 2014

HCV1/IHQ/14-09//1341k © 2014 Gilead Sciences

Start TDF during follow-up if prespecified safety criteria met

Study Design

Randomized, controlled, open-label study (N=740)

– Stratified by screening HBeAg status and HBV genotype

Inclusion criteria

– HBeAg+ and HBV DNA ≥20,000 IU/mL; HBeAg- and HBV DNA ≥2,000 IU/mL

– ALT >54 and ≤400 U/L (men); ALT >36 and ≤300 U/L (women)

– No bridging fibrosis or cirrhosis on liver biopsy or by transient elastography

41

0 48 120 72

TDF + PEG

TDF+PEG → TDF

24

n=186

n=184

n=185

n=185 PEG

16

TDF

Week

Baseline Characteristics

42

TDF+PEG 48 wk

n=186

TDF+PEG 16 wk

→TDF 32 wk

n=184

TDF 120 wk

n=185

PEG 48 wk

n=185

Mean age, y 38 37 36 38

Male, % 68 65 65 64

Asian, % 76 73 76 74

Genotype, n (%)

A 17 (9) 16 (9) 14 (8) 14 (8)

B 50 (27) 51 (28) 49 (27) 53 (29)

C 78 (42) 79 (43) 78 (42) 79 (43)

D 39 (21) 36 (20) 41 (22) 38 (21)

E–H 2 (1) 2 (1) 3 (2) 1 (<1)

HBeAg positive, n (%) 108 (58) 106 (58) 110 (60) 108 (58)

Mean HBV DNA, log10 IU/mL (SD) 7.1 (1.5) 7.1 (1.5) 7.0 (1.5) 6.9 (1.6)

Mean HBsAg, log10 IU/mL (SD) 3.9 (0.8) 3.8 (0.8) 3.9 (0.8) 3.8 (0.8)

Mean ALT, U/L (SD) 121.2 (180.8) 112.2 (94.4) 100.9 (67.7) 106.6 (91.5)

All baseline characteristics similar (p>0.05).

Results: Change in Serum HBsAg Levels

Me

an

Ch

an

ge

Fro

m B

ase

line

(lo

g10 IU

/mL

)

Efficacy: On-Treatment Changes in HBsAg Levels at Week 48

3 patients who were re-treated at Week 48 were excluded from Week 48 calculations.

Error bars represent 95% confidence intervals. 43

48

TDF+PEG 16 wk

→TDF 32 wk

TDF + PEG 48 wk

-0.3 log

PEG 48 wk

TDF 120 wk

-0.5 log

-0.8 log

-1.1 log

p<.001

p=.016

p<.001

Efficacy: HBsAg Loss Over Time (Week 48)

44

Pa

tie

nts

w

ith

HB

sA

g L

oss,

Ka

pla

n-M

eie

r E

stim

ate

(%

)

0.10

0.09

0.08

0.07

0.06

0.05

0.04

0.03

0.02

0.01

0.00

48 weeks

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72

Week

0.15

0.14

0.13

0.12

0.11

72 weeks

7.3%

0%

2.8%

2.8% TDF + PEG 16 wk →TDF 32 wk

PEG 48 wk

TDF 120 wk

TDF + PEG 48 wk

Results: HBsAg Loss Over Time (Week 72)

45

Pa

tie

nts

w

ith

HB

sA

g L

oss,

Ka

pla

n-M

eie

r E

stim

ate

(%

)

0.10

0.09

0.08

0.07

0.06

0.05

0.04

0.03

0.02

0.01

0.00

48 weeks

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72

Week

0.15

0.14

0.13

0.12

0.11

72 weeks

7 patients had HBsAg seroreversion on or after Week 48 (4 [TDF + PEG 48 wk],

3 [TDF + PEG 16 wk →TDF 32 wk])

– 5/7 had ≤1 week of therapy after HBsAg loss

TDF + PEG 16 wk →TDF 32 wk

TDF + PEG 48 wk 9.0%

0%

2.8%

2.8%

p=0.003

p<0.001

p=NS

p=NS PEG 48 wk

TDF 120 wk

Overall Safety

46

TDF + PEG 48 wk

n=186

TDF + PEG 16 wk

→TDF 32 wk

n=184

TDF 120 wk

n=185

PEG 48 wk

n=185

TDF re-treatment, n (%) 100 (54) 100 (54) N/A 112 (61)

TDF re-treatment TDF re-treatment TDF re-treatment

No Yes No Yes No Yes

Total D/C from the study, n 32 2 31 6 26 30 2

Total AEs leading to D/C of

study drug, n/N (%) 8/186 (4) 1/100 (1) 4/184 (2) 1/100 (1) 0/185 (0) 14/185 (8) 0/112 (0)

Serious AEs, n/N (%) 21/186 (11) 7/100 (7) 18/184 (10) 3*/100 (3) 12/185 (7) 18/185 (10) 5/112 (5)

Grade 3–4 AEs, n/N (%) 26/186 (14) 5/100 (5) 17/184 (9) 5/100 (5) 11/185 (6) 27/185 (15) 6/112 (5)

*1 patient had grade 1 hepatic encephalopathy with hepatic flare after drug D/C that resolved following TDF re-treatment.

No deaths occurred during the study.

Conclusions

1. Combination therapy with TDF plus PEG for 48 weeks led to higher rates of HBsAg

loss compared with either monotherapy in CHB patients without cirrhosis

– Duration of PEG therapy is important

2. The TDF + PEG combination was well tolerated

Future perspectives

a) Consolidation therapy after HBsAg loss may be important

b) Identify patient characteristics associated with response.

47

48

TDF Alone or in Combination with ETV in Patients with

ETV-Resistant CHB

Lim, AASLD, 2014, Oral #231

IN-US-174-0202 Trial Study Group

Multicenter, randomized trial of TDF monotherapy (n=45) and TDF+ETV

combination (n=45) in CHB patients with genotypic resistance to ETV

Study Week

% o

f P

ati

en

ts w

ith

HB

V D

NA

<15 I

U/m

L

0 4 12 24 36 48

10 20 30 40 50 60 70 80 90 100

TDF TDF+ETV

P >0.99 at 48 weeks

0

73%

71%

No significant difference between groups for virologic response

Minimal incidence of virologic breakthrough (1 patient in TDF group; associated with poor adherence)

Marked decrease in preexisting resistance mutations

No additional resistance mutation 45 45

3 2 0

1020304050

TDF TDF+ETV TDF TDF+ETV

Before Baseline At 48 Week

• No additional or novel resistance mutations were detected at Week 48

TDF monotherapy may be a reasonable option for rescue

therapy of patients infected with ETV-resistant HBV

% of Patients with Virologic Response

(HBV DNA < 15 IU/mL)

Number of Patients with Any

Detectable HBV Resistance Mutations

49

Next-Generation Delivery System of Tenofovir

TAF

N

N

N

N

NH2

OP

O

OO

O

O

O

OO

O

N

N

N

N

NH2

OP

O

HOOH

N

N

N

N

NH2

OP

O

NH OO

O

Tenofovir

Disoproxil Fumarate Tenofovir

Tenofovir

Alafenamide

LYMPHOID CELLS/

HEPATOCYTES PLASMA GUT

TFV

TFV

TFV-MP

TFV-DP

TDF/TFV TDF

TFV TDF TAF

TAF

Cathepsin A

CES1

TAF TAF

♦ Improved stability in plasma:

– Enhanced delivery of active form

(TFV-DP) to hepatocytes

– Lower doses are used; systemic

exposures of TFV reduced

‡

Agarwal K et al. AASLD 2013, Poster # 973

Murakami E et al. HepDART 2013, Abstract 104 CES1 = carboxylesterase 1; DP= di-phosphate; MP= mono-phosphate.

50

T im e (H o u rs )

Me

an

TF

V P

las

ma

C

on

ce

ntr

ati

on

(n

g/m

L)

0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4

0

5 0

1 0 0

1 5 0

2 0 0

2 5 0

3 0 0

T A F 8 m g (n = 1 0 )

T A F 2 5 m g (n = 1 0 )

T A F 4 0 m g (n = 1 1 )

T A F 1 2 0 m g (n = 1 0 )

T D F 3 0 0 m g (n = 1 0 )

T im e (H o u rs )

Me

an

TA

F P

las

ma

C

on

ce

ntr

ati

on

(n

g/m

L)

0 1 2 3 4 5 6 7 8

0

1 0 0

2 0 0

3 0 0

4 0 0

5 0 0

6 0 0

7 0 0

8 0 0

9 0 0

1 0 0 0

1 1 0 0

T A F 8 m g (n = 1 0 )

T A F 2 5 m g (n = 1 0 )

T A F 4 0 m g (n = 1 1 )

T A F 1 2 0 m g (n = 1 0 )

T A FT F V

♦ TAF PK (Cmax and AUClast) were dose proportional1

♦ Reduction in TFV exposures (AUCinf) with TAF relative to TDF 300 mg

which varied inversely by dose:

– 92% reduction in circulating TFV levels with TAF 25 mg

♦ TAF PK in CHB similar to results in HIV patients and healthy subjects

1slopes 1.03 and 1.01, respectively (Power Model) Agarwal K et al. AASLD 2013. Poster #973

TAF and TFV Pharmacokinetics (day 1)

‡

51

Phase 1b Study Design

Randomized, open-label, active-controlled

– Stratified by HBeAg status Included patients with CHB (HBsAg+ ≥6 months)

– HBV DNA ≥2 x 103 IU/mL

– ALT ≤10 x ULN

– CLCr (Cockcroft-Gault) ≥70 mL/min

– No evidence of cirrhosis 12 sites (Australia, Canada, New Zealand, UK, USA)

Baseline Wk 8 Wk 4

TAF 8 mg (n=10)

TAF 25 mg (n=10)

TAF 120 mg (n=10)

TDF 300 mg (n=10)

CHB

Treatment naïve

(N=50)

TAF 40 mg (n=10)

Off treatment

follow-up

Ra

nd

om

ize

d 1

:1:1

:1:1

Agarwal K et al. AASLD 2013. Poster #973

‡

52

Phase 1B Results: HBV DNA Declines Over 28 Days

♦ No differences in viral declines over range of TAF 8 mg to 120 mg

♦ Viral suppression over 4 weeks with TAF was similar to TDF

TAF

Study Day

‡

TAF 8 mg (n= 10)

TAF 40 mg (n=10)

TAF 120 mg (n=11)

TDF 300 mg (n=10)

TAF 25 mg (n=10)

Study Day

Mea

n H

BV

DN

A (

Log

10 I

U/m

L)

Agarwal K et al. AASLD 2013, Poster # 973

GS-US-320-0101 - Clinicaltrials.gov NCT01671787

53

HBV Phase 3 Program

2 phase 3, randomized, double-blind studies

Primary endpoint (non inferiority margin of 10%)

– HBV DNA <29 IU/mL at Week 48

Secondary endpoints

– Bone mineral density

– Renal parameters

TAF 25 mg

TDF 300 mg

2:1 randomization Open-label

TAF

Week 96 Week 144

(Year 3)

Study 1

HBeAg+

N=864

Study 2

HBeAg-

N=390

‡

GS-US-320-0108 – Clinicaltrials.gov NCT01940341

GS-US-320-0110– Clinical trials.gov NCT01940471

TAF

Inmunomodulación

•Agonistas receptores de

Toll-like e.g.

GS-9620

•Anti-PD-1 mAb, e.g.

BMS-936559

CYT107

GI13000

Inhibidores entrada

• Lipopéptidos, e.g.

Myrcludex-B

Inhibición de

formación de

ADNccc

Inhibición de ensamblaje de

nucleocápsida, e.g. Bay 41-4109,

NVR1221

Inhibidores

polimerasa:

•Análogos nucleósidos,

e.g. amdoxovir,

MIV-210

•No-nucleósidos, e.g.

LB80380

Inhibidores liberación

HBsAg, e.g. REP 9AC Interferencia ARN,

e.g. ARC-520

Estadio de desarrollo: preclínico, clínico

Futuro del Tratamiento VHB Fármacos en Desarrollo

Zoulim F. Antiviral Res, 2012 Zoulim F. Gastroenterology, 2013

Inmunomodulador

Potente inhibidor de polimerasa

Prevenir entrada y propagación

Inhibidor ADNccc

Inhibidor de entrada/liberación

Suprimir la replicación

Beneficio potencial

¿Vislumbramos con esto el tratamiento del VHB en Europa en el futuro?

Conclusiones

• Se debe utilizar los métodos no invasivos para evaluar la fibrosis

en TODOS los pacientes con hepatitis B

• Las cohortes de vida real confirman la eficacia y seguridad de los

tratamientos antivirales de última generación

• Necesitamos mas conocimientos sobre el riesgo de HCC en

pacientes infectados por Hepatitis B

• La reactivacion de la infección por VHB es una situación grave

evitable en su mayoria de casos

• Necesitamos nuevos tratamientos para la infección por VHB

Temas no resueltos en Hepatitis B · 2015. 11. 12. · Temas no resueltos en Hepatitis B Jose Luis...

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