Hépatites virales B et C: actualitésscientifiques

Dakar, 11.05.2016

Gilles Wandeler, MD MSc

Burden of HIV and viral hepatitis

Mortality in annualdeath rate

Matthews et al. J Clin Virol 14

Burden of HIV and viral hepatitis

Burden of HIV and viral hepatitis

Numbers are in millions of individuals

HIV accelerates liver injury caused by HBV infectionLiver mortality is 18x higher in HIV/HBV vs. HBV

Plan

Numbers are in millions of individuals

• Dépistage• Fibrose hépatique• Réponse au TDF• Nouveaux TX et

cure

• Guidelines OMS• DAA et santé

publique

HBV in the general population

Schweitzer et al. Lancet 2015

HBV prevalence among HIV-infectedpopulations

Stabinski et al. JAIDS 2015

49 studies from 16 countries (2005-13)

Median HIV/HBV-coinfection prevalence: Overall: 7.8% (range: 0%-28.4%)West Africa: 11.5%Southern Africa: 5.4%East Africa: 4.1%

HBV infection in the IeDEA network

IeDEA-Southern Africa (n=2,000)IeDEA-West Africa (n=2,000)

HBsAg+: 13%

HBsAg+: 9%

HBsAg+: 15%

HBsAg+: 19%

HBsAg+: 13%

Ongoing studies in HIV cohorts and key populations:

- HBV and HCV virology

- Liver fibrosis assessment

HBsAg+: 11%

Det. DNA: 66%

Geno: A1: 49%, E: 49%

HBsAg+: 8%

Det. DNA: 76%

Geno: A1: 70%, E: 23%

Implementation: HBV screening uptake

HBsAg screening uptake in Africa: results fromchart review of 3,000 patients starting ART

Coffie et al. abstract 565, CROI 2016

HBsAg screening uptake in Africa: results fromchart review of 3,000 patients starting ART

Coffie et al. abstract 565, CROI 2016

Central andSouth America: 9 sites7 countries

Africa:36 sites18 countries

Asia:10 sites7 countries

Screening and management of HIV/HBV-coinfection: urgent need for programmatic data!

(To be presented at AIDS 2016, Durban)

HBV screening guidelines

HBeAg(+) HBeAg(-) / anti-HBe(+)

ALT

HBV DNA

Minimal CH Moderate to severe CH Moderate to severe CHRemission

Cirrhosis

Immunotolerant

phase

Immuno-active

phase

Inactive phase

Low replication Reactivation phase

Cirrhosis

109-1012 IU/mL >2000-<109 IU/mL <2000 IU/mL >2000 IU/mL

Inactive cirrhosis

Treatment indicated Treatment indicated

HBsAg

Occult infection

EASL Clinical Practice Guidelines, J Hepatol 2012

HBV natural history

Specificities of HBV in Africa: natural history and transmission

50-90% 5% Chronic infection

Hepatitis B Disease Progression

1. CDC. HBV FAQs for health professionals. 2. Torresi J, et al. Gastroenterology. 2000;118(2 suppl 1):S83-S103. 3. Fattovich G, et al. Hepatology. 1995;21:77-82. 4. Seaberg EC, et al. Clin Transpl. 1998:17-37.

Acute Infection

ChronicInfection

Cirrhosis Death

30% of chronically infected

individuals[2]

23% of patients decompensate within 5 yrs of developing cirrhosis[3]

Liver Cancer (HCC)

Chronic hepatitis B is the 6th leading cause of liver transplantation in the US[4]

Liver Transplantation

Liver Failure(Decompensation)

HBV DNA and immune response = engine

ALT/Histological Activity Index (inflammation) = train speed

Fibrosis stage = distance from canyon

Multivariate analysis of factors associated with significant liver fibrosis

n/N OR (95% CI) p

Antigen HBs Negative

Positive

36/733

7/74

1

2.6 (1.0 – 6.4)

0.04

Alcohol use, (AUDIT-c score) <4

≥4 – 6

≥6

25/536

11/237

7/34

1

0.3 (0.1 – 2.5)

4.6 (1.8 – 11.4)

<10-2

HIV/HBV and HBV therapy

HBV-monoinfection HIV/HBV-coinfection

WHO HIV guidelines 2015

EASL guidelines J Hepatol 2012

WHO HBV guidelines 2015

Anti-HBV drugs

Nucleosides

Nucleotides

TDF*

ADV

ETV*

LAM* FTC*

Genetic barrier

TBV

*Anti-HIV activity

PegIFN

HBV treatment: tenofovir for all?

EASL. J Hepatol 2012

EASL. J Hepatol 2012

HBV virological response to tenofovir

De Vries et al. Gastroenterology 2010

N=641

N=102

Gordon et al. Hepatology 2013

HBV-monoinfection HIV/HBV-coinfection

TDF for HIV/HBV-coinfection in Africa

Stockdale et al. Clin Inf Dis 2015

Regression of liver fibrosis with TDF

Marcellin et al. Lancet 2013

27 - GILEAD CONFIDENTIAL AND PROPRIETARY DRAFT. FOR INTERNAL USE ONLY. NOT FOR DISTRIBUTION OR PROMOTION.27 - GILEAD CONFIDENTIAL AND PROPRIETARY DRAFT. FOR INTERNAL USE ONLY. NOT FOR DISTRIBUTION OR PROMOTION.

TAF delivers high potency of TDF while minimizing off-target renal and bone side effects

*HIV target cells include lymphocytes and other PMBCs, as well as macrophages.1. Lee W et. Antimicr Agents Chemo 2005;49(5):1898-1906. 2. Birkus G et al. Antimicr Agents Chemo 2007;51(2):543-550. 3. Babusis D, et al. Mol Pharm 2013;10(2):459-66. 4. Ruane P, et al. J Acquir Immune Defic Syndr 2013; 63:449-5. 5. Sax P, et al. JAIDS 2014. 2014 Sep 1;67(1):52-8. 6. Sax P, et al. Lancet 2015 Apr 15 [Epub ahead of print].

HIV TARGET CELL

AMIDATE

ESTER

--

DIANION

GI TRACT

Tenofovir alafenamide

(TAF)

Tenofovir disoproxil

fumarate (TDF)

Tenofovir (TFV) Parent

Nucleotide

T1/2 = 90 min

T1/2 = 0.41 min

PLASMA

TAF25 mg

TDF 300 mg

TFV

TFV

TFV

TFV

HIV

E/C/F/TAF at IAS – Vancouver, July 2015

ConfidentialSlide 28

Treatment Naïve Adults

Truvada Switch

Renal Impairment Switch

Treatment Naïve Adolescents

Studies 292-0104/0111

(N=1,733)E/C/F/TAF vs. STRIBILD

Study 292-0109

(N=1,436)E/C/F/TAF vs. 3rd Agent + Truvada

Study 292-0112

(N=242)E/C/F/TAF, eGFR 30-68 mL/min

Study 292-0106

(N=50)E/C/F/TAF, 12-17 yo

Patient Population Clinical Study

HIV/HBV Co-infectionStudy 292-1249

(N=72)E/C/F/TAF

Study 292-0119

(N=135)E/C/F/TAF + DRV 800mg vs SBR

Phase 3

Regimen Simplification

Phase 3b

J. Gallant (poster)

TAF in HIV/HBV Co-infection

48 Weeks: Favorable safety, HIV/HBV suppression, and liver endpoints

% o

f su

bje

cts

48Wk 0

Study 292-1249 (N=72)HIV <50 c/mL, HBV DNA <9 log10

Switch to E/C/F/TAF

ConfidentialSlide 29

% %

%

%

% %

Gallant et al. IAS 2015

TAF in global HIV treatment scale-up

ConfidentialSlide 33

35 million HIV+

• TAF licensed to WHO Medicines Patent Pool (July 2014)

• 6 generic manufacturers to distribute TAF in 112 countries (September 2014)

40

20

10

30

0

30 million HIV+in developing countries

12 million HIV+on ARVs

7 million HIV+on TDF

2014

35 million HIV+

30 million HIV+in developing countries

21 million HIV+on ARVs1

16 million HIV+on TDF or TAF2

2020

1WHO projection2Gilead projection

• Adherence

– life long for NRTI

• Toxicity with pegylated-IFN

– low (<20%) efficacy, genotype A best

• Cost

– very few countries in high prevalence regions have reimbursement policies

• Drug resistance

– Rare with tenofovir but common with lamivudine

– In China, > 3 x 106 lamivudine resistant cases

• HBsAg-positivity on treatment

Current treatment is inadequate

Two approved classes of drugs are inadequate: low HBsAg loss

253

6 85 6 8

0

20

40

60

80

100

1.0 Yr 1.5-2.0 Yrs

3.0-4.0 Yrs

Pe

rce

nta

ge

with

HB

sA

gL

oss

HBeAg positive

Entecaivr

Tenofovir

PEG-IFN

0 0 04

7 9

0

20

40

60

80

100

1.0 Yr 1.5-2.0 Yrs 3.0-4.0 Yrs

HBeAg negative

< < N

(No head-to-head trials. Different populations and trial designs.Extended Treatment With Nucleos(t)ide Analogues vs. 1 Yr Peginterferon Treatment)

Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Buster EH, et al. Gastroenterology. 2008;135;459-467. Gish R, et al. Gastroenterology. 2007;133:1437-1444. Heathcote J. AASLD 2008. Abstract 158. Heathcote J, et al. AASLD 2009. Abstract 483. Janssen HL, et al. Lancet. 2005;365:123-129.

Lai CL, et al. N Engl J Med. 2006;354:1011-1020. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Marcellin P, et al. AASLD 2008. Abstract 146. Shouval D, et al. J Hepatol. 2009;50:289-295. Marcellin P, et al. AASLD 2009. Abstract 481. Brunetto M, et al. EASL 2008. Abstract.

Therapy

HB

V D

NA

ch

an

ge

fro

m b

as

eli

ne

(lo

g 1

0c

/mL

)

0.0

-1.0

-2.0

-3.0

-4.0

+1.0

Time

New treatment concepts for a functional cure of HBV infection

HBsAg

HBVDNA

cccDNA

SERUM

LIVER

The main differences between HIV, HBV and HCV

H

HBV1,2

Host cell

cccDNA

Host DNA

Integrated DNA

Nucleus

H

HIV1

Host cell

Host DNA

Proviral DNA

Nucleus

H

HCV1,3

Host cell

Host DNA

Nucleus

HCV RNA

Life-long suppression of viral replication

Definitive viral clearanceand SVR

Long-term suppression of viral replication

Adapted from 1. Sorriano V, et al. J Antimicrob Chemother 2008;62:1-4. 2. Locarnini S and Zoulim F. Antiviral Therapy 2010;15 (suppl 3):3-14. 3. Sarrazin C and Zeuzem S. Gastroenterology 2010;138:447-462.

HBV cure

Durantel et al. J Hepatol 2016

New HBV antiviral drug classes

Durantel et al. J Hepatol 2016

What May a HBV Curative Regimen Look Like?

cccDNAinhibitor

Anti-HBVNucleos(t)ide

Agent to prevent viral spread, cccDNA re-amplification

Agents to activate antiviral immunity orrelieve repression of the system

Selective agent to deplete or perturb cccDNA

Immuneactivator

+

+

HBV antigen inhibition

Agents to inhibit other components in the HBV life cycle [entry or cell-spread, capsid, HBX, HBsAg]

+

Adapted from S. Locarnini

http://www.who.int/hepatitis/publications/hepatitis-c-guidelines-2016

Pre-clinical

Phase I

Phase II

Phase III

FDA approval

DAA combinationsNuc-Polymerase inhibitors

Non-Nuc-Polymerase inhibitors

NS3/4A protease inhibitors

Others

NS5A-inhibitor inhibitors

Vedroprevir(Gilead)MS-5172

(MSD)

Simeprevir(Janssen)

Boceprevir(MSD)

Telaprevir(Vertex)

Sovaprevir(Achillion)

Danoprevir(Roche)

Faldaprevir(BMS)

ABT-450(AbbVie)

Asunaprevir(BMS)

ACH-3102 (Achillion)

GSK-2336805(GlaxoSmithKline

MK-8742(MSD)

PPI-688(Presidio)

ABT-333(AbbVie)

BI-207127(Boehr.Ingl.)Ledipasvir

(Gilead)

ABT-267(AbbVie)

Daclatasvir(BMS)

Tegobuvir(Gilead)

ABT-072(AbbVie)

BMS-791325(BMS)

TMC-647055(Janssen)

Mericitabine(Roche)

Sofosbuvir(Gilead)

VX-135(Vertex)

SofosbuvirSimeprevir

SofosbuvirLedipasvirABT-450r/

ABT-267/ABT-333

FaldaprevirBI-207127)

Miravirsen miR-122(Santaris)

DaclatasvirVX-125

AsunaprevirDaclatsivir

SimeprevirTMC-647055

DaclatasvirSimeprevir

Contexte: la révolutiondu TX anti-HCV

Curing HCV: population level impact

Individual level cure rate Population level cure rate (if no increase in treatment uptake)

Pop

ula

tio

n S

VR

(%

)

PEG-IFN +RBV

DAA combinations

Ind

ivid

ual

SV

R (

%)

Thomas DL. Lancet 2010;376:1441‒2.

Concerted efforts will be needed to improve HCV diagnosis and treatment rates

6

5

4

3

2

1

00 20 40 60 80 100

Diagnosis rate (%)

Tre

atm

en

t ra

te (

%)

France

Germany

Austria

England

Spain

Czech Republic

Egypt

Turkey

Brazil

Portugal

Belgium

Switzerland

Denmark

Canada

Australia

Sweden

• Note: size of bubble depicts viraemic HCV prevalence.Dore GJ, et al. J Viral Hepat 2014;21(Suppl 1):1–4.

Merci pour votre attention

Abstracts CROI disponibles à l’adresse

http://www.croiconference.org

Abstracts EASL disponibles à l’adresse

http://ilc-congress.eu/ilc-2016-barcelona

Consulter le site NATAP pour les les présentations oraleshttp://www.natap.org