Hépatites Virales C et B et Infection par le VIH

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

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

Hépatite Chronique C Chez les Patients

Co-infectés par le VIH

Influence of HIV on HCV

• Major cause of mortality

• More severe liver lesions vs HCV mono-infected

• Higher HCV RNA

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

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

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

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)

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

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

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

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)

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

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

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

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

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

Hépatite Chronique B Chez les Patients

Co-infectés par le VIH

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)

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

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

<.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

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

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

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

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

-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

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

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

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

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

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

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

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 (%)

Treatment Algorithm Patients with Compensated Disease

and No indication for HIV therapy

Treatment Algorithm Patients with Compensated Disease

and indication for HIV therapy