Benhamou du co infection 2012

Hépatites Virales C et B et Infection par le

VIH

Benhamou Yves

HIV, Hepatitis B and C: global prevalence HIV, Hepatitis B and C: global prevalence

1. WHO Factsheets HBV, HCV, HIV; 2. Alter MJ. J Hepatol 2006; 44(Suppl.1): S6-S9.

350.000.000

170.000.000

33.000.000

2-4.000.000

4-5.000.000

Facteurs pronostiques chez les patients co-infectés VIH-VHC : résultats de la cohorte HEPAVIH (1)

• Cohorte prospective multicentrique française (ANRS CO13 HEPAVIH) ayant inclus 1 175 patients co-infectés (inclusions de 01/2006 – 12/2008)

• Sous-étude incluant les patients avec FibroScan®, suivi suffisant et sans décompensation antérieure : n = 886 (75 %)

• Suivi moyen 23 mois

• Évènements – Décompensation hépatique (n = 10)– Décès toutes causes confondues (n = 36)

• Causes hépatiques : 27 %• Causes liées au VIH : 19 %• Autres : 42 %• Inconnues : 11 %

Sogni P, AASLD 2011, Abs. 246 actualisé

5


Complications hépatiques ou décès toutes causes confondues (à 5 ans : 10 %)Décès toutes causes confondues (à 5 ans : 7 %)Décès de cause hépatique (à 5 ans : 2 %)

Courbes et estimations actuarielles

0 6 12 18 24 30 36 42 48 54 60 660

40

30

20

10

Mois

Pro

babi

lité

(%)


6


Variables RR ajustés IC 95 % pÂge 1,459 1,029 – 2,068 0,034

Albuminémie 0,891 0,807 – 0,983 0,021

Taux de plaquettes 0,464 0,265 – 0,813 0,007

FibroScan® 1,300 1,125 – 1,503 < 10-3

Facteurs associés à la survenue d’une complication hépatique ou d’un décès de cause hépatique (analyse multivariée)

Facteurs associés à la survenue d’une complication hépatique ou d’un décès toutes causes confondues (analyse multivariée)

Variables RR ajustés IC 95 % pAlbuminémie 0,910 0,855 – 0,968 0,003

FibroScan® 1,209 1,085 – 1,347 0,001

Stades CDC (C versus A-B) 2,302 1,095 – 4,839 0,028


7

Hépatite Chronique C Chez les Patients

Co-infectés par le VIH

Fibrosis progression

Poynard, T. et al. J Hepatol 2003;38:257-265

4,682 patients

180 HIV-HCV701 Alcohol812 HBV382 Hemochromatosis2,313 HCV 93 Steatosis BMI>25200 PBC

1.00

0 20 40 60 80

Haza

rd fu

nctio

n

Age in years

Progression to cirrhosisProgression to cirrhosis

Impact of ART liver-associated mortality in HIV/HCV-Impact of ART liver-associated mortality in HIV/HCV-coinfected patientscoinfected patients

Overall mortality

Surveillance period (days)5.0004.0003.0002.0001.000

1,1

0,9

0,7

0,5

0,3

*p < 0,0001

Patients on HAART*

Patients on ART

untreated patients

6.000 6.0005.0004.0003.0002.0001.0000

Liver-associated mortality

*p < 0,018

Patients on HAART*

Patients on ART

Untreated patients

Cumulative survival

Surveillance period (days)

1,1

0,9

0,7

0,5

0,3

Predictors of liver-associated mortality No HAART low CD4-count age

Bonn cohort (1990–2002) 285 HIV/HCV-coinfected

patients

Qurishi et al. Lancet 2003: 362(9379): 1708–1713.

Cumulative survival

Chronic Hepatitis C - Fibrosis progressionChronic Hepatitis C - Fibrosis progression

Increased by:

• Age• Male sex• Alcohol consumption• HIV-infection, low CD4, HIV viral load• Immunosuppression• Insulin resistance• Severe Steatosis (?)• Necroinflammatory activity in liver biopsy• Non-response to interferon therapy

Mohsen et al., Gut 2003;52:1035-1040.Benhamou et al., Hepatology 1999;30:1054-1058.Macías et al., Hepatology. 2009;50(4):1056-1063

SVR = regression, NR = progression ?SVR = regression, NR = progression ?

Ingiliz, Benhamou et al., J Hepatol, submitted, under review

Current treatment for HCV

Timing for Anti-HCV and ARV initiation

HIV mono-infected HIV/HCV

< 200 CD4 cells/µL ARV recommended

- ARV recommended- ARV before anti-HCV

> 200 CD4 cells/µL and < 350 CD4 cells/µL

ARV possible : - High HIV RNA and - Rapid CD4 decline

> 350 CD4 cells/µL and< 500 CD4 cells/µL

Monitor - Monitor HIV- Anti-HCV recommended (if indicated)

Adapted from IAS–USA panel guidelines. Yeni P. at al. JAMA, 2004

CD4>350 :• Fibrosis progression rate is reduced• CD4 decline to « dangerous » level if anti-VHC is initiated

Alberti et al. 1st ECCC. J Hepatol. 2005

Nunez et al. AIDS Res Hum Retroviruses 2007; 23(8): 972-982.

SVR (%)

0

100

80

60

40

20

Total389

End of treatment (EOT)Sustained virological response (SVR)

GT1191

GT2/3152

SVR defined as undetectable HCV RNA 24 weeks after end of treatment

49,6%

67,3%

35,6%

55%

72,4%

90,1%

32,6%

41%

GT4152

262 193 106 68 137 110 19 15

HCV genotype patients n=

PRESCO (ITT analysis): virological response, PRESCO (ITT analysis): virological response, genotypegenotype

n=

European guidelines for the treatment of HIV-HCV European guidelines for the treatment of HIV-HCV coinfectioncoinfection

EACS guidelines, version 5-2

PEG IFN/RBV : Specific AE• Liver decompensation : 10% of cirrhotic pts

• Pl., Bilirubin, P alc, Hb and ddI• Compensated cirrhosis: No ddI, Monitoring +++

• Mitochondiral toxicity (1%-3%)• ddI (d4T) (RR x23)• No ddI – (d4T ?)• Monitor : Amylase, lipase, lactic acid

• Anemia : Hb <8 g/dL : 3.8%• AZT (RR x2)• Use EPO

• Neutropenia : Neutrophils <750: 2-11%• Use GCSF

Alberti A et al. 1st ECCC. J Hepatol. 2005 .Torriani F et al. NEJM 2004. Carrat F et al. JAMA 2004. Chung R et al. NEJM. 2004

IL 28B polymorphism

Pineda et al., abstract #656, CROI 2010

IL-28B genotype and treatment responseIL-28B genotype and treatment response- Influence of HCV genotype -- Influence of HCV genotype -

Telaprevir/PEG IFN/RBV chez des patients co-infectés VIH-VHC – Analyse à 6 mois (1)

• Etude randomisée, multicentrique, phase II, patients G1 co-infectés VIH naïfs de traitement VHC

Sherman KE, AASLD 2011, Abs. LB8 actualisé

*ART : anti-rétroviraux, PR : PEG-IFNα-2a 180 μg/sem + RBV 800-1200 mg/j

Partie A : sans ART

Partie B : ART* (EFV/TDF/FTC ou ATV/r + TDF + FTC ou 3TC)

RVSSuivi(n = 7)

(n = 6)

(n = 31)

(n = 16)

S0 S12 S24 S48 S72

TVR + PR PR

PRPlacebo + PR

TVR + PR PR

PRPlacebo + PR

S36

Schéma de l’étude

18

Known and anticipated DDIs between antiretrovirals and anti-HCV drugs in current use and the HCV protease inhibitors in Phase III development

Drug-Drug-Interactions (DDIs)Drug-Drug-Interactions (DDIs)

Adapted from Seden K, et al. J Antimicrob Chemother 2010; 65:1079-85; Ashby J, et al. HIV 10; Glasgow; November 7-11, 2010; Abst. O315.

Hepatitis C Therapies

Current Agents Protease Inhibitors (Phase III trials)

PEG-IFN Ribavirin Telaprevir Boceprevir

PIs

NNRTIs

NRTIs

Entry Inhibitors

Integrase Inhibitors

No clinically significant interaction, or interaction unlikely based on knowledge of drug metabolism

Potential interaction that may require close dose monitoring, alteration of dosage or timing of administration

Interaction likely, do not use or use with caution

1

4 42

5 5

1 = atazanavir/ritonavir

2 = didanosine, zidovudine

3 3 = emtricitabine, lamivudine, tenofovir4 = zidovudine

5 = maraviroc

6 6 = raltegravir

Telaprevir/PEG IFN/RBV chez des patients co-infectés VIH-VHC – Analyse à 6 mois (2)

Réponse virologique à 6 mois

AR

N V

HC

indé

tect

able

(%)

Sans ART EFV/TDF/FTC ATV/r/TDF/FTC Total

0

20

40

60

80

100

6/7

86

75 7167

11/16 10/15 27/38n/N = 2/6

33

5055

75

4/8 6/8 12/22

T/PR PR

Sherman KE, AASLD 2011, Abs. LB8 actualisé

19

Acute hepatitis C

Acute HCV among HIV+ MSMAcute HCV among HIV+ MSM

1.Luetkemeyer JAIDS 2006; 2.Fierer 5th Works. HIV & Hep. Coinf. 2009; 3.Giraudon Sex Transm Infect 2008; 4.Ruf Eurosurveill 2008; 5. Vogel CID 2009; 6.Gambotti Euro Surveill 2005; 7.Larsen AASLD 2007; 8.Urbanus AIDS 2009; 9.Rauch CID 2005; 10.Gallotta 4th Works. HIV & Hep. Coinf. 2008; 11.Matthews CID 2009; 12. Sherman CID 2002; 13: Backus JAIDS 2005; 14: UNAIDS Report 2008; 15: Soriano JID 2008; 16: NCHECR Report 2008.

Europe: 951 casesPrevalence chronic HCV/HIV14,15

25%: 185.500

-UK3,4 552-Germany5 157-France6,7 117-Netherlands8 81-Swiss9 23-Italy10 21

Australia11: 28 casesPrevalence chronic HCV/HIV16

< 1%: 1.000

USA1,2: 54 casesPrevalence chronic HCV/HIV12-14

15 – 30%: 180.000 – 360.000

Monitoring and initiation antiviral therapyMonitoring and initiation antiviral therapy

Decay HCV-RNA

HCV-RNA

wait: cont´d controls

throughout week 48

Initial presentation

acute HCV

2 log10

negative

< 2 log10

positive

Treatment

Treatment

Week 4

Week 12

Courtesy: Martin Vogel, Germany

Antiviral therapy of AHCAntiviral therapy of AHC

*evidence based on using a 615 IU/ml cutoff to define negative HCV-RNA

HCV-RNA

negative*

Stop Therapy

peg-IFN +

RBV (AII)

< 2 log10

24 weeks

Drop HCV-RNA

2 log10

Week 4 Week 12

HCV-RNA

positive*48 weeks

Courtesy: Martin Vogel, Germany

Hépatite Chronique B Chez les Patients

Co-infectés par le VIH

Prevalence of HBsAg+ in HIV Infected Patients

EuroSIDA Cohort (n= 9802) : Patients screened for HBsAg: 5883 (60%)

HBsAg+: 530 (9%)- South: 9.1%

- Central: 9.2%

- North: 9.7%

- East: 6%

Konopnicki D, et al. AIDS. 2005.

Influence of HIV on CHBIn the Pre HAART era, HIV in HBsAg positive patients (compared toHBV mono-infected):

Increased the risk of chronic infection after contamination

Reduced the seroconversion rates to anti-HBe and anti- HBs

Increased HBV replication

Frequent reactivation related to CD4 decline

Accelerated fibrosis progression

Increased risk of liver decompensation, HCC and liver death

Bodsworth, JID 1989 ; Hadler, JID 1991 ; Krogsgaard, Hepatology 1987 ; Bodsworth, JID 1989 ; Gilson, AIDS 1997. Piroth, J Hepatol 2002; Vogel Cancer Res 1991; Corallini Cncer Res 1993 ; Altavilla Am J Pathol 2000 ; Bodsworth, JID 1989 ; Mills,

Gastroenterol 1990 ; Goldin, J Clin Pathol 1990 ; Gilson, AIDS 1997 ; Thio, Lancet 2002 ; Di Martino, Gastroenterol 2002; Colin Hepatol 1999; Perillo, Ann Int Med 1986 ; McDonald, J Hepatol 1987

MortalityLiver-related mortality in 5293 patients (MACS), 1984 /1987–2000

Thio CL, et al. Lancet. 2002;360:1921-1926.

Viral status

N HIV HBsAgLiver-related mortality (n)

Liver death (1000 pers/yr) P

3093 – – 0 0.0

139 – + 1 0.8 0.04

2346 + – 35 1.7 <0.0001

213 + + 26 14.2 <0.0001

5293 62 1.1

Liver related mortalityX 19 HBV/HIV vs HBV (RR:18; 73,1-766,1; P<0,001)

Impact of HIV Infection on Progression to HBV-Related Cirrhosis

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10

Follow-up (years)

% o

f cirr

hosi

s

HIV negative

HIV positive

p=0.005

Di Martino V et al. Gastroenterology. 2002.

Influence of HAART

• Increases duration of HBV by improving survival

• Increases the risk of ALT flares related to – Immune restoration– Hepatotoxicity– Reactivation

• ARV discontinuation• HBV resistance

• Inhibition of HBV replication(LAM – FTC – ADV)

– Histological improvement

? Proia et al. Am J Med 2000. Wit et al. JID 2002. Benhamou et al. J Hepatol 2005. Bruno et al. Gastroenerol 2002.

Bonacini et al. Gastroenterol 2002. Puoti et al. Antiviral Ther 2004. Gouskos AIDS 2004

Liver-related mortality (1995-2003 - GERMIVIC Cohort)

12.6

14.3

6.6

1.5

02468

10121416

1995 1997 2001 2003

ESLD related death % of total death

7

21

4238

05

1015202530354045

1995 1997 2001 2003

ESLD related death: % of HBsAg+

Rosenthal E, et al. J Viral Hep. 2007.

HIV/HBV Co-infection Mortality

* Improvement defined as ≥1 point reduction ** Worsening defined as ≥ 1 point increase

Median METAVIR F at Baseline = 2

Improved *

Worsened **

N = 15 12

33%50%

20% 8%

-30%

-10%

10%

30%

50%

70% Week 48 Week 192

Benhamou Y et al. J Hepatol 2005.

Impact of Anti-HBV Therapy on Liver Fibrosis

F0-F1 F2 F3-F4

F0-F1 (n=8)

8 0 0

F2(n=17)

7 6 4

F3-F4(n=13)

1 1 11

Median time F. up : 29.5 months

ADV TDF

Lacombe, et al. CROI 2009, Abstract 815.

Treatment of HBV in HIV Co-infected Patients

Licensed for

HIV HBV

Interferon (IFN) Lamivudine (LAM) Emtricitabine (FTC) Entecavir (ETV) Telbivudine (LDT) Adefovir dipivoxil (ADV) Tenofovir disoproxil fumarate (TDF)

HIV/HBeAg+ LAM-R PEG-IFN 2a + ADV

0123456789

Baseline 12 24 48 72

Weeks

Seru

m H

BV

DNA (l

og

copi

es/m

L)

PEG-IFN2a + ADV

0

20

40

60

80

100

Weeks

Seru

m A

LT (I

U/L)

PEG-IFN2a + ADV

HBV DNA ALT

Ingliz P. et al, Antiviral Therapy 2008

N=17

Median change in serum HBV DNAHIV/HBeAg+ Naïve Pts

Dore GJ, et al. J Infect Dis. 1999;180:607-613.

Lamivudine

(LAM 150 mg bid)

0.25

0.50

0.75

1

0 350 700 1050 1400

Days of lamivudine therapyPr

opor

tion

of p

atie

nts

LAM

-R

N= 57

Number of patients 57 32 13 6 3under observation

Benhamou Y, et al. Hepatology 1999; 30:1302-06

HBV resistance to LAM

Entecavir

• 17 HIV/HBV Pts who received ETV for HBV- Significant reduction in HIV RNA in the

majority of pts

Selection of M184V (HIV RT) following ETV treatment

0

10

20

30

40

50

60

70

ART naïveART experiencedTota

l

Median time M184V 148 days 98 days

% w

ith M

184V

3/7

3/5

6/12

Switch from a TDF to ETV for HBV suppression

- 6 pts switched to ETV because of TDF renal tox

- HBeAg+ and HBV DNA <LOD: 6

- L180M and M204V: 5

Outcome results:

- HBV rebound on ETV: 6

- Median time to rebound: 3 months

- All pts maintained HIV suppression

Hull M, et al. 9th Intl. Congress on Drug Therapy in HIV Infection. Glasgow 2008.Audsley J, et al. 15th CROI, Boston 2008, #63.

ETV 1mg qd 48w = 4.3 log DNA decline in HIV/HBeAg+ LAM-R patients Pessoa et al. AIDS 2008

HIV IsolateNNRTI Multi drug resistant

HIV IsolateSubtype A

Drug ETV LdT

11.67 >600IC50 µMFold change 0.93 >Max

Drug ETV LdT

>600 >Max

IC50 µMFold change

13.211.05

Telbivudine

Avila et al. CROI 2009, Abstract 1002.

• One doubtful case of LdT anti-HIV activity ?

Low et al., CROI 2009. Abstract 813a

• No in vitro anti HIV activity of LdT

ETV LdT

TDF vs. TDF+LAM (48 weeks)

3/50

12/50

29/50

42/50

1/25

9/25

14/25

19/25

0

20

40

60

80

100

DNA<3log

AST<45U/L

HBeAgloss

HBsAgloss

Patie

nts

(%)

TDF TDF+LAM

Schmutz G, et al. AIDS. 2006.

LAM Naive(n=9)

LAM Experienced(n=47)

HBV DNA <15 UI/mL

9 41

Mean time to DNA < LOD (weeks)

49 67

Tuma R, et al. AASLD 2008, Abstract 967.

Tenofovir Disoproxil Fumarate

TDF + LAM (48 weeks)

Matthews G et al. Hepatology 2008

W48 outcomesLAMN=12

TDFN=12

TDF+LAMN=12

p

Median DNA Reduction 4.07 4.57 4.73 .7

DNA <3 log 46% 92% 91% .01

HBeAg loss 3 1 3

Anti-HBe Seroconversion 1 1 3

HBsAg loss 1 1 1

Tenofovir Disoproxil Fumarate

TDF- vs LAM- containing HAART in ARV-naïve HIV/HBeAg+ Co-infected Patients (TICO Study):

Randomized Thai trial (1:1:1) of LAM vs TDF vs LAM/TDF within an EFV-based HAART regimen

Treatment Algorithm Patients with Compensated Liver Disease and

No Indication for HIV Therapy (CD4 count >350/µL)

• No treatment• Monitor every

6–12 months

HBV DNA2000 IU/mL

HBV DNA

HBV DNA<2000 IU/mL

ALT ElevatedALT Normal

• Monitor ALT every 3-12 months

• Consider biopsy and treat if disease present

• PEG IFN• LdT (if HBV DNA>LOD at w24 add ADV)• ADV+LdT• Early HAART initiation –TDF+LAM/FTC

ECC Statement. J Hepatol. 2005.Rockstroh et al. HIV Medicine 2008.

Treatment Algorithm Patients with Compensated Liver Disease and Indication for HIV Therapy (CD4 count <350/µL)

HBV DNA≥2000 IU/ml

HBV DNA<2000 IU/ml

HAART includingTDF+3T/FTC Substitute one NRTI by

TDF or add TDF*

Patients without HBV-associated LAM resistance

Patients with cirrhosis

ECC Statement. J Hepatol. 2005.Rockstroh et al. HIV Medicine 2008.

Patients with HBV-associated LAM resistance HAART regimen

of choice

HAART includingTDF+LAM/FTC

*If feasible and appropriate from the perspective

of maintaining HIV suppression.

Refer patient for liver transplantation

evaluation if decompensation

HBV DNA

Benhamou du co infection 2012

Health & Medicine

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