Temas no resueltos en Hepatitis B · 2015. 11. 12. · Temas no resueltos en Hepatitis B Jose Luis...
Transcript of 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%
Lèdinghen et al. AP&T 2013;37:979-988
Impacto de la valoración de la fibrosis mediante elastografía transitoria en la
supervivencia en pacientes con hepatitis B
Lèdinghen et al. AP&T 2013;37:979-988
Impacto de la valoración de la fibrosis mediante BIOPSIA HEPÁTICA en la
supervivencia en pacientes con hepatitis B
Lèdinghen et al. AP&T 2013;37:979-988
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
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 (+)*
+
+
DNA VHB > 2000 UI/mL
+
ALT > LSN
+
HISTOLOGÍA (+)*
+
+
ALT valor normal
DNA VHB > 20000 UI/mL
+
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 -)
DNA VHB > 2000 UI/mL
+
ALT > LSN
+
HISTOLOGÍA (+)*
+
+
DNA VHB > 2000 UI/mL
+
ALT > LSN
+
HISTOLOGÍA (+)*
+
+
ALT valor normal
HISTOLOGÍA (+)* Lesión hepática
Leve (A1F1)
Guía AEEH: Indicaciones de tratamiento
Seguimiento obligatorio
Se puede considerar el tto
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
20
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
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
• Metodos no invasivos para evaluar la fibrosis
• Tratamiento combinado PEG-IFN + Tenofovir
• Cohortes de vida real
• Hepatocarcinoma en pacientes tratados
• Reactivación en pacientes inmunodeprimidos
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
• 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
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
• 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
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