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Hépatites Virales C et B et Infection par le VIH
37
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Page 1: Benhamou Hcv Hiv Du 2009

Hépatites Virales C et B et Infection par le VIH

Page 2: Benhamou Hcv Hiv Du 2009

Causes de décès d’origine infectieuse dans le monde (2000)

HIV – HBV – HCV : TOP 10

MaladiesMaladiesInfections respiratoiresInfections respiratoiresVIHVIHDiarrhéesDiarrhéesTuberculoseTuberculoseMalaria Malaria RougeoleRougeoleHépatite BHépatite BPertussisPertussisTétanos néonatalTétanos néonatalHépatite CHépatite C

Décès par anDécès par an~3,5 million~3,5 million~3,0 million~3,0 million~2,2 million~2,2 million~2,0 million~2,0 million~1-3 million~1-3 million

~888,000~888,000~750,000~750,000 ~355,000~355,000~300,000~300,000

~ 250,000~ 250,000 Source : CDC, WHO, UNICEF, UNAIDSSource : CDC, WHO, UNICEF, UNAIDS

Page 3: Benhamou Hcv Hiv Du 2009

Viral hepatitis in HIV-infected patients

Hepatotoxicity

of anti-retroviral therapies

Progression to

Cirrhosis

Mortality

Prevalence

Active consideration for treatment of hepatitis

?Controversies

?Accelerated

Higher compare to HBV mono-infected

Major cause of death

7%-10%20%-35%

HBVHCV

Page 4: Benhamou Hcv Hiv Du 2009

Hépatite Chronique C Chez les Patients

Co-infectés par le VIH

Page 5: Benhamou Hcv Hiv Du 2009

Influence of HIV on HCV

• Major cause of mortality

• More severe liver lesions vs HCV mono-infected

• Higher HCV RNA

Page 6: Benhamou Hcv Hiv Du 2009

No influence of HCV/HBV on response to HAART : EuroSIDA cohort

Konopnicki D et al. AIDS. 2005;19:593-601.

HIV RNA <400 copies/ml 50% rise in CD4

10

30

50

70

0 3 6 9 12

10

30

50

70

HCV

Page 7: Benhamou Hcv Hiv Du 2009

Mortalité chez les patients VIH en FranceÉtude du groupe GERMIVIC

Influence du VIH sur le VHC Mortalité liée à l’atteinte hépatique

Caboub et al, CID 2001; Rosenthal et al, AIDS 2003.

0102030405060708090

100

1995 1997 2001 2003

%

Mortalité Globale Mortalité liée au Sida Mortalité liée au foie CHC

8

91,6

1,56,9

2

84,5

6,6 8,8

1

48,7

14,3

36,7

1

47

12,6

40,4

Page 8: Benhamou Hcv Hiv Du 2009

Impact of HAART on liver related mortality

Qurishi N et al, Lancet 2003

Days of observation

500040003000200010000

Surv

ival

1.1

0.9

0.7

0.5

0.3

p < 0,0001

HAART

ARV

Untreated

6000 6000500040003000200010000

1.1

0.9

0.7

0.5

0.3

p < 0,018

HAART

ARV

UntreatedSurv

ival

Global Mortality Liver Mortality

Days of observation

Page 9: Benhamou Hcv Hiv Du 2009

Progression to cirrhosisinfluence of alcohol and immune

status

0

1

2

3

4

5 10 15 20 25 30 35 40

CD4<200/µLOH>50 g/j

CD4 <200/µLOH <50 g/j

CD4 >200/µLOH<50 g/j

HIV-OH<50 g/j

Benhamou et al. Hepatology 1999;30:1054-1058

Estimated duration of HCV infection

Fibrosis(METAVIR)

Page 10: Benhamou Hcv Hiv Du 2009

Timing for Anti-HCV and ARV initiation

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

- ARV recommended- ARV before anti-HCV

HIV/HCVHIV mono-infected

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

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

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

ARV recommended< 200 CD4 cells/µL

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

Page 11: Benhamou Hcv Hiv Du 2009

Treatment of chronic hepatitis C

Genotype 2/3 Genotype 1/4

< 800 000 UI/mL > 800 000 UI/ml

PEG IFN2 (a:180 /b:1.5 µg)RBV 800 mg48 w

Fibrosis: >2

HCV RNA

Fibrosis: 0/1

PEG IFN2 (a:180 /b:1.5 µg)RBV 1000-1200 mg48 w

Rx differed

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

Page 12: Benhamou Hcv Hiv Du 2009

PEG IFN/RBVVirological response

29%

38%

14%

29%

15%21%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

ACTG APRICOT RIBAVIC

EOT SVR

GT 1GT 4

80%

64%68%

73%

53%

31%

62%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

ACTG APRICOT Laguno RIBAVIC

EOT SVR

GT 1/4 GT 2/3

RBV 800 mg 24 weeks

Torriani F et al. NEJM 2004. Carrat F et al. JAMA 2004. Laguno C ett al. AIDS 2004. Chung R. NEJM. 2004

GT2/3,

Rx

48 w

Page 13: Benhamou Hcv Hiv Du 2009

APRICOT(overall SVR 40%)

PRESCO(overall SVR 50%)

Pat

ien

ts (

%)

all 48 weeks therapy

HIV-pos; low RBV dose

0

10

30

40

Geno 1 Geno 3

29%

62%

50

20

n=176 n=95

Geno 1 Geno 3

36%

72%

n=191

24, 48 or 72 weeks therapy

HIV-pos; weight-based RBV

n=152

Ramos et al. J Viral Hepat (in press)

Page 14: Benhamou Hcv Hiv Du 2009

Impact of HCV RNA on SVR

61 63

18

61

0

20

40

60

80

100

≤800,000n=46

>800,000n=130

≤800,000n=28

>800,000n=67

Prop

ortio

n of

pat

ient

s

Torriani F et al. NEJM. 2004.

GT 1 GT 2/3

21 (43 %)49> 5000 cp/mL

23 (35 %)6650-5000 cp/mL

72 (42 %)173< 50 cp/mL

HIV RNA

90 (47 %)216≥ 350 /µL

26 (36 %)72< 350 /µL

8 (47 %)17< 200/µLCD4

SVRN

Cooper D. et al, XV AIDS Conference

HCV RNA

Liver evaluatio

n for

GT1, high H

CV RNA

Page 15: Benhamou Hcv Hiv Du 2009

APRICOTSVR according to Rx exposure

*Patients violated the rule if ≥1 of the three targets were not achieved Opravil M. et al. 45th ICAAC 2005; Abstract 2038

39%

SV

R r

ate

(%)

SV

R r

ate

(%)

≥80/80/80exposure

0

10

20

30

40

50

11%

<80/80/80exposure*

62

29%

Allpatients

n = 176 114

69%

SV

R r

ate

(%)

SV

R r

ate

(%)

≥70/70/70exposure

0

20

40

60

80

100

26%

<70/70/70exposure*

27

59%

Allpatients

n = 111 84

GT1 GT2/3

Page 16: Benhamou Hcv Hiv Du 2009

VR n (%) PPV (%) NPV (%)

G1 G2/3 G1 G2/3 G1 G2/3

119 (68)

83 (87)

39 70

93

92

71 (40)

76 (80)

58 74

90 84

Week 4

≥1 log10 drop

≥2 log10 drop

HCV RNA -ve 22 (13)

35 (37)

82

94

79

57

148 (84)

89 (94)

34

66 96

100

110 (63)

84 (88)

45

70

98

100

60 (34)

68 (72)

70

82

92

89

log10 drop

Week 12

≥1 log10 drop

≥2

HCV RNA -ve

Torriani F, et al. 45th ICAAC 2005; Abstract 1024

APRICOT

Page 17: Benhamou Hcv Hiv Du 2009

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

Page 18: Benhamou Hcv Hiv Du 2009

CONCLUSION

• HCV coinfection: X30 in HIV vs general population

• HCV coinfection major cause of mortality and

morbidity in HIV population

• Less than 20% of the Patients have received anti-

HCV therapy in Europe

• Coinfected patients should be actively considered for

HCV therapy

Page 19: Benhamou Hcv Hiv Du 2009

Hépatite Chronique B Chez les Patients

Co-infectés par le VIH

Page 20: Benhamou Hcv Hiv Du 2009

VHB et VIH

• Prévalence de HBsAg x10 chez les VIH+ vs VIH-

• Contamination sexuelle et UDIV• Virus sauvage/virus pre core: 80% / 15%

• Réactivation en cas d’immunodepression sévère

• HCB plus sévère chez les patients VIH

• Dépistage et prévention (vaccination)

Page 21: Benhamou Hcv Hiv Du 2009

HIV/CHB CoinfectionInfluence of HAART

• Increases duration of HBV by improving survival

• Increases the risk of ALT flares related to

– Immune restoration– Hepatotoxicity

• (Severe) reactivation– Low CD4– ARV discontinuation– LAM resistance

• Inhibition of HBV replication associated with histological improvement (LAM, FTC, TDF)

• LAM reduces liver decompensation

?

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

Page 22: Benhamou Hcv Hiv Du 2009

Influence of HIV on HBVHIV in HBsAg positive patients (compared to HBV mono-

infected):

– Increases the risk of chronicity after HBV contamination

– Reduces the seroconversion rates to anti-HBe and anti- HBs

– Increases HBV replication

– Increases reactivation rate (related to CD4 decline)

– Accelerates fibrosis progression

– Increases the risk of liver decompensation, HCC and liver deathBodsworth, 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. RR 8.3 (4.8-14.3) ; Di Martino, Gastroenterol 2002 ; Colin : Hepatol 1999 ; Di Martino, Gastroenterol ;

Perillo, Ann Int Med 1986 ; McDonald, J Hepatol 1987 ; Colin, Hepatology 1999 ; Gilson, AIDS 1997

Page 23: Benhamou Hcv Hiv Du 2009

<.0001

<.0001

N=54

2 (2-2)29.6%

134.7

N=469

1 (1-2)16

130.1

Liver biopsy*

Fibrosis (median)- Cirrhosis (%)

Inflammation (median)- A2/3 (%)

<.000162.1%37.8HBVDNA> 6 log (%)

<.000134.8%17.1LAM-R HBV (%)

<.000178.8%49.9HBeAg + (%)

NS57 (47-74)29.1

50 (45-56)26.7

Median ALTALT< 2xULN (%)

PHIV positiveN=164

HIV negativeN=504

Assessed by the METAVIR scoring system.

HBsAg+ vs HBsAg+/HIVGHPS cohort

Benhamou et al CROI 2005

Page 24: Benhamou Hcv Hiv Du 2009

Liver Mortality Rate (per 1000 PY)MACS

0

2

4

6

8

10

12

14

16

HIV-/HBV- HIV-/HBV+ HIV+/HBV- HIV+/HBV-

Thio et al. Lancet 2004

Page 25: Benhamou Hcv Hiv Du 2009

0

0.25

0.50

0.75

1

0 75 150 225 300

Follow up (months)

Pro

po

rtio

n o

f p

atie

nts

fre

e

Of

live

r d

eco

mp

ensa

tio

nHIV – (n=504)

HIV + (n=164)

P=0.004

Liver decompensation in HBsAg+

Benhamou et al. CROI 2005

Page 26: Benhamou Hcv Hiv Du 2009

Anti-HBV therapy

• Objective: Decrease liver inflammation and fibrosis progression

• Criteria for anti-HBV initiation:– HBV DNA

• AgHBe+ > 20 000 UI/ml• AgHBe- > 2000 UI/ml

– Histology• METAVIR A≥2 F≥2

Thresholds based on HBV mono-infected knowledgeMay be used in HIV/HBV co-infected patients

Page 27: Benhamou Hcv Hiv Du 2009

HIV/HBV: Treatment

Licensed for Treatment of CHB

• Lamivudine

• Adefovir dipivoxil

• Entecavir*

• IFN/Pegylated IFN

Licensed for Treatment of HIV Only with Demonstrated Anti-HBV Activity

• Tenofovir DF

• Emtricitabine

* USA

Page 28: Benhamou Hcv Hiv Du 2009

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0 4 8 12 20 28 36 44 52

Time in Weeks

Me

dia

n c

ha

ng

e in

log

HB

V D

NA

Lamivudine Placebo

Serum HBV DNA

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

HIV/HBVLamivudine

-2.7 log10 copies/mL

Page 29: Benhamou Hcv Hiv Du 2009

Lo

g10

HB

V D

NA

24 22 20 20 1733 33 33 33 3310 10 10 7 7

FTC HBV+HIVFTC HBV

d4T HBV+HIV

FTC is not licensed for the treatment of HBV.Raffi F. IAS Conference, July 13-16, 2003, Abstract # 215.

FTC HBV+HIV

d4T HBV+HIV

FTC in Chronic HBV (FTCB-102)

HIV/HBVFTC

Page 30: Benhamou Hcv Hiv Du 2009

4

5

6

7

8

9

10

0 12 24 36 48

ETV PBO

5.56

HB

V D

NA

(lo

g1

0 c

op

ies/

ml)

9.19

4.79

5.63

Weeks

RDZ double binded phase All the patients: ETV 1.0 mg

HIV/HBV LAM-R: ETV

Pessoa et al. ICAAC 2005

Page 31: Benhamou Hcv Hiv Du 2009

HB

V D

NA

(lo

g10

co

pie

s/m

l)

- 6.2 log10 c/ml p<0.001*

-7.0

-6.0

-5.0

-4.0

-3.0

-2.0

-1.0

0.0

0 24 48 72 96 120 144 168 192

ADV (weeks)

- 5.9 log10 c/ml p<0.001*

- 4.7 log10 c/ml P<0.001* - 5.5 log10 c/ml

p<0.001*

31 29 31 30 31 29 27†27n = 35

†27 patients remain on study

* p<0.001 Wilcoxon Sign Rank Test

Benhamou et al, Lancet, 2001 & J Hepatol in press

HBV DNA HBV DNA (< 2.6 log(< 2.6 log1010 copies/ml) copies/ml) 8/358/35

HBeAg negativationHBeAg negativation 3/33*3/33*

HBe seroconversion HBe seroconversion 2/33*2/33*

HIV/HBV LAM-RADV

Page 32: Benhamou Hcv Hiv Du 2009

Median (Q1-Q3) HBV DNA in HBeAg+ (n=72)

Benhamou Y, et al. Hepatology 2006 (in press)

HIV/HBVTDF

Months of TDF

*Roche Cobas Amplicor, LLQ 200 copies/mL

Page 33: Benhamou Hcv Hiv Du 2009

Peters M et al. CROI 2005.

-7

-6

-5

-4

-3

-2

-1

0

0 12 24 36 48

ADVTDF

HB

V D

NA

(lo

g 10 c

/mL)

*

ADV 25 24 23 20 18 17

TDF 27 26 23 18 17 18

HIV/HBVADV vs TDF

*Roche Cobas Amplicor, LLQ 200 copies/mL

Page 34: Benhamou Hcv Hiv Du 2009

NoyesyesYES?YesPoorAnti HIV activity

?

49%

?

3.6

wt, preC, LAM-R??

24

51

ETV*

wt, preC, LAM-R

wt, preC LAM-R

wt, preCwt, preCwt, preCAnti-HBV activity

ADV*TDF*FTCLAMIFN

33-50%

35-66%

7%

4 - 5.4

48-144

35

?

12-20%

9%

26%**

12-24

87

???Histological improvement

??30-50%ALT response

4%?11%HBe seroconv.

4.432.7HBV DNA decline (log cp/ml)

24-484848Duration (weeks)

20033215No. of patients

* Added to LMV in the majority of the cases. ** < 6log copies/ml

HIV/HBV: anti-HBV therapy

Wong DK et al. Gastroenterology 1995. Di Martino V et al. Gastroenterology 2002. Dore GJ et al. J Infect Dis 1999.Benhamou Y et al. Hepatology 1996. Pessoa W et al. CROI 2005. Raffi F et al. 2003 IAS. Peter M et al. CROI 2005..Ristig MB et al. J Infect Dis. 2002. Benhamou Y et al. N Engl J Med. 2003.

Benhamou Y et al. Lancet 2001 and AASLD, 2003

Page 35: Benhamou Hcv Hiv Du 2009

HBV resistance

Lai C et al. N Engl J Med 1998. Leung N et al. J Hepatol 1999. Chang T et al. Antiv Ther 2000. Benhamou Y et al. Hepatology 1999. Benhamou Y et al. Lancet 2001 and AADSL 2003. Data on file. NV-02B-003. Idenix.

HIV/HBV HIV/HBV HBV HBV

0

00

0

0

0

0

50

90

0

4%

024%

18

4%

9

19%24

38

49

67%

0

10

20

30

40

50

60

70

80

90

1

3

LMV

FTC LdT ADV

LMV+L

dTETV

LMV

LMV+A

DV

LMV+T

DF

ETV +

LAM

Years

Patien

ts (%)

Patien

ts (%)

Page 36: Benhamou Hcv Hiv Du 2009

Treatment Algorithm Patients with Compensated Disease

and No indication for HIV therapy

Page 37: Benhamou Hcv Hiv Du 2009

Treatment Algorithm Patients with Compensated Disease

and indication for HIV therapy