Hepatitis B Cure: from discovery to regulatory endpoints ...regist2.virology-education.com/2017/4HBV/02_Zoulim.pdf · Hepatitis B Cure: from discovery to regulatory endpoints in HBV

Hepatitis B Cure: from discovery to regulatory endpoints in HBV clinical research

A summary of the AASLD/EASL statement

Fabien Zoulim

Service d’hépatologie, Hospices Civils de Lyon

INSERM U1052, Cancer Research Center of Lyon

Université de Lyon

From viral suppression to cure

UNTREATED

Liver

Blood

Rc-DNA

HBsAg

ccc-DNA

HBV-DNA

Normal Cirrhosis Hepatocellular

carcinoma

Liver

Blood

Rc-DNA

HBsAg

ccc-DNA

NUCs


carcinoma

Risk of HCC reduced

(after 5 yrs)

but not eliminated

Liver

Blood

ccc-DNA Liver

Blood

NMEs NMEs“Cure”

Direct Antiviral Agents

Immunomodulatory

strategies


carcinoma

Zoulim & Levrero

Is HBV Cure Possible?

Can treatment accomplish what nature can’t?

HBV persists in persons who have recovered from acute hepatitis B

with HBsAg to anti-HBs seroconversion

• Reactivation of HBV replication can occur during potent

immunosuppressive therapy

• Transmission of HBV is possible when these livers are

transplanted

• Long-lasting rigorous immune response to HBV possibly from

continued stimulation by residual virus

Barriers to eradicating HBV

cccDNA reservoirLong t1/2Continuous replenishmentNot affected by NAs and IFN

Integrated forms

Defective CD8+ responses

Defective B cell responses

Inefficient innate response

HBV persistence Defective immune responses

Locarnini, S. & Zoulim, F. et al. (2016) Global strategies are required to cure and eliminate HBV infectionNat. Rev. Gastroenterol. Hepatol.

Persistence of intrahepatic viral DNA synthesis duringTenofovir therapy (HIV-HBV cohort)

Boyd et al, J Hepatol 2016

New round of infection and/or replenishment of the cccDNA pool occurdespite « viral suppression »

HBsAg Loss Decreases Subsequent Risk of HCC

Liu J, Gut 2014; 63: 1648

Hazard ratio for HCC after seroclearance

during follow up

• HBeAg 0.63

• HBV DNA 0.24

• HBsAg 0.18

after adjustment for age, gender ALT

Among HBeAg- lifetime cumulative

incidence of HCC for those with

clearance of

• Both HBV DNA and HBsAg 4.0%

• HBV DNA only 6.6%

• Neither 14.2%

REVEAL study 2964 HBsAg+, no cirrhosis

HBsAg

loss

Antivirals

Cure

Immunotherapy

Discovery

Clinical development

Access to care

Revill & Zoulim, Nature Reviews Gastro & Hepatol 2016; Zoulim, EASL ILC 2016

NUCs“Polymerase inhibitors”

plasma

membrane

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

“exhaustion”

“high antigen load”PD-1

CD8+

T cell

Dysfunctional

T-cell response Insufficient

B-cell response

B cell

Lack of impact of current antivirals on cccDNA

Interferon a

Levrero et al, Current Opinion Virology, 2016

Immune modulation

• Toll-like receptors agonists

• Anti-PD-1 mAb

• Vaccine therapy

RNA

interference

NUCs“Polymerase inhibitors”

Targeting

cccDNA

Entry inhibitors

CpAMs

“Capsid inhibitors”

plasma

membrane

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

Inhibitors

of HBsAg

release “exhaustion”

“high antigen

load” PD-1

CD8+

T cell

Dysfunctional

T-cell response Insufficient

B-cell response

B cell

The main targets & drug discovery efforts

Revill & Zoulim, Nature Reviews Gastro & Hepatol 2016 ; Levrero et al, Current Opinion Virology, 2016

The introduction of novel compounds for chronic hepatitis B necessitates:

1) a standardized appraisal of the efficacy and safety of these treatments,

2) definitions of new or additional endpoints to inform clinical trials.

To move the field forward, and to expedite the pathway from discovery toregulatory approval, a workshop with key stake holders was held inSeptember 2016 to develop a consensus on treatment endpoints to guidethe design of clinical trials aimed at hepatitis B cure.

AASLD/EASL HBV Treatment Endpoints Workshop: From Discovery to Regulatory Approval

September 8-9, 2016, in Alexandria, VA.Chairs: A. Lok, F. Zoulim, G Dusheiko, M Ghany

Lok et al, Hepatitis B Cure: From Discovery to Regulatory Approval; Hepatology / J Hepatol joint publication; 2017

Definition of cure

Therapy

HB

V D

NA

ch

an

ge f

rom

base

lin

e (

log

10

c/m

L)

0.0

-1.0

-2.0

-3.0

-4.0

+1.0

Time

HBsAg

HBVDNA

cccDNA

SERUM

LIVER

+/- Anti-HBsAb


Partial Cure

Functional Cure

Complete Cure

Sterilizing Cure

Virologic Cure vs. Liver (Clinical) Cure

Partial Cure

HBsAg+, HBV DNA UD

cccDNA+, integrated HBV DNA+

Functional Cure

HBsAg-, HBV DNA UD

cccDNA+, integrated HBV DNA+

Sterilizing Cure

HBsAg-, anti-HBs+, HBV DNA UD

cccDNA & integrated HBV DNA eliminated

Decreased necroinflammation

Fibrosis persists

HCC risk persists

Regression of fibrosis

HCC risk decreases

Restoration of liver to normal

HCC risk eliminated

??

Definition of cure


• The vast majority (87.9%) of survey respondents selected functional cure

(sustained HBsAg loss) as the goal for new HBV therapies.

Advantages: easy to assess, associated with improved clinical outcomes &

lower rates of disease reactivation, and once achieved, no further requirement

for therapy.

• Less consensus regarding the necessity of achieving anti-HBs

seroconversion

• Discussion: is elimination or silencing of cccDNA a mandatory criterion

for functional cure ? uncertainties whether new therapies in development

can silence or clear cccDNA, as well as pragmatic difficulties in

measuring cccDNA.

• Partial cure: acceptable intermediary step toward functional cure (more

achievable in the short-term, reduction in clinical outcomes, and could

expedite drug development).

Durability of HBsAg Loss in Patients

Treated with NUC ± PEG-IFN

0

20

40

60

80

100

120

All With anti-HBs Without anti-HBs

Yes No

HBsAg loss confirmed ≥24 weeks apart

74 patients with HBsAg loss during NUC +/- PEG-IFN treatment

Chan H, EASL 2017

Yes No

>95% durable if HBsAg loss confirmed ≥24 weeks apart,

seroconversion to anti-HBs not important

Efficacy endpoints for clinical trials

• The use of a biochemical endpoint is problematic because of the lack of a standardized definition of normal ALT.

• With increasing prevalence of obesity and non-alcoholic fatty liver disease, failure to normalize ALT may not necessarily indicate ongoing liver inflammation induced by HBV.

• Non-invasive assessments of liver fibrosis have replaced liver biopsies in assessing liver disease in clinical practice and a histological endpoint would no longer be practical or necessary for assessing functional cure.

• Liver biopsies may be required in proof-of-concept studies to confirm a novel mode of action and/or to validate noninvasive surrogate markers of antiviral activity.


Efficacy endpoints: clearance of HBsAg

• For both antiviral and immune modulatory therapy trials, suppression of serum HBV DNA to undetectable and loss of HBsAg were ranked as the most important primary efficacy endpoint for phase 2 and phase 3 trials

• No consensus whether the kinetics of decline in HBsAg level can predict ultimate HBsAg loss

• The most appropriate time to assess the primary efficacy endpoint for phase 3 trials of novel antiviral or immune modulatory therapies should be month 6 post-treatment, i.e. durable response

• For Phase 2 studies: depends on the MoA of the drug


Diagnostic assays for new markers to determine therapeutic efficacy

• There was consensus on the need for standardized assays toprovide mechanistic insights into the effects of novelantiviral or immune modulatory agents and to have newsurrogate markers to assess HBV “cure”


pgRNAEncapsidated

pgRNARc-DNA cccDNA

Subgenomic

RNAsExosomes

Nu

cle

us

Cyto

pla

sm

Extr

ac

ell

ula

r / seru

m

sphere

filament

qHBsAgDane particles cir HBV-RNAs HBcrAg

HBeAgDNA free

particles

Dane

particles

HBV RNA

particles

Subgenomic RNAspgRNA

Testoni, Levrero & Zoulim, Seminars Liver Dis 2017

Allweiss et al, ANRS-DZIF-ICE-HBV consortium For cccDNA standardization

NUC

cccDNA drug

CpAM

Testoni and Zoulim, Hepatology 2015

Need for standardized clinical immunology assays

• Goals of TxRestoration of T cell activityRestoration of B cell functionsBoosting innate immunty• Clinical assays needed for: Phenotypic characterization of patientsMonitoring of immune activity of novel TxICE-HBV immunology working group

Assessment of safety and stopping rules

• The remarkable safety profile of current NAs imposes a stringent requirement for the safety of new HBV therapies.

• A unique concern in the development of hepatitis B therapies is the risk of severe hepatitis flares, which can result in hepatic decompensation and death. The U.S. FDA has explicit recommendations on managing drug induced liver injury; however, these recommendations do not apply to patients with underlying liver disease

• Transient hepatitis flares are not always harmful and may portend immune clearance of infected hepatocytes

• Severe flares: accompanied by increase in bilirubin or prothrombin time and flares in patients with cirrhosis

• Any death or liver transplantation, hepatic decompensation, irreversible autoimmunity, or incidence of severe hepatitis flare in >5% of patients could prompt a halt


Design of clinical trials for HBV cure

• Combination of antiviral and immune modulatory therapies most likely needed.

• Antiviral activity and safety of individual new agents used as monotherapy, and drug interactions should be first established before progressing to combination therapy trials.

• However, demonstration of efficacy as a monotherapy need not be required.

• Randomized controlled trials needed to establish efficacy (heterogeneity of the natural course of CHB).

• Trials should aim to demonstrate superiority of the investigational therapy

• Initially conduct trials in treatment-naïve HBeAg-(+) patients with active disease or in virally suppressed patients. Proof of principle and safety to be established first in patients without cirrhosis.


Summary and recommendations

• A functional cure (sustained loss of HBsAg with or without anti-HBs seroconversion) after a finite course of novel therapies in a higher proportion of patients than currently achieved with existing treatments, is an attainable goal.

• Need for surrogate markers for cure to assist clinical trials

• Limited proof-of-concept monotherapy studies to evaluate safety and antiviral activity should be conducted prior to proceeding to combination therapy.

• The safety of any new curative therapies will be paramount given the excellent safety of currently approved NAs.


• Collaboration between Academia, Industry, Regulatory Agencies and Stakeholders

• International HBV cure programs

HBV cure: An attainable goal within the next decade !

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Documents

Hepatitis B Cure: from discovery to regulatory endpoints ...regist2.virology-education.com/2017/4HBV/02_Zoulim.pdf · Hepatitis B Cure: from discovery to regulatory endpoints in HBV