Hépatites Virales C et B et Infection par le VIH

Causes de décès d’origine infectieusedans le monde (2000)

HIV – HBV – HCV : TOP 10

MaladiesMaladiesInfections Infections respiratoiresrespiratoiresVIHVIHDiarrhDiarrh ééesesTuberculoseTuberculoseMalaria Malaria RougeoleRougeoleHHéépatitepatite BBPertussisPertussisTTéétanostanos nnééonatalonatalHHéépatitepatite CC

DDééccèèss par anpar 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~1~1--3 million3 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-infectedpatients

HCV HBV

Prevalence 20%-35% 7%-10%

Mortality Major cause of death Higher compare to HBV mono-infected

Progression toCirrhosis

Accelerated ?

Hepatotoxicityof anti-retroviraltherapies

Controversies ?

Active consideration for treatment of hepatitis

Hépatite Chronique C Chez les Patients

Co-infectés par le VIH

Influence of HIV on HCVInfluence 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

10101010

30303030

50505050

70707070

0000 3333 6666 9999 12121212

10101010

30303030

50505050

70707070

HCV

Mortalité chez les patients VIH en FranceÉtude du groupe GERMIVIC

Influence du VIH sur le VHCMortalité liée à l’atteinte hépatique

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

0

10

20

30

40

50

60

70

80

90

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

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 MortalityGlobal Mortality Liver MortalityLiver Mortality

Days of observation

Progression to cirrhosis

influence of alcohol and immune

status

Progression to cirrhosis

influence of alcohol and immune

status

0

1

2

3

4

5 10 15 20 25 30 35 40

CD4<200/µL

OH>50 g/j

CD4 <200/µLOH <50 g/j CD4 >200/µL

OH<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

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

Treatment of chronic hepatitis C

Genotype 2/3 Genotype 1/4

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

TREAT

Fibrosis: > 2

HCV RNA

Fibrosis: 0/1

TREATRx 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, R

x 48 w

APRICOT(overall SVR 40%)

PRESCO(overall SVR 50%)

Pat

ient

s (%

)

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

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

Pro

port

ion

of p

atie

nts

Torriani F et al. NEJM. 2004.

GT 1 GT 2/3

N SVR

CD4< 200/µL 17 8 (47 %)

< 350 /µL 72 26 (36 %)

≥ 350 /µL 216 90 (47 %)

HIV RNA

< 50 cp/mL 173 72 (42 %)

50-5000 cp/mL 66 23 (35 %)

> 5000 cp/mL 49 21 (43 %)

Cooper D. et al, XV AIDS Conference

HCV RNA

Liver evaluation for

GT1, high HCV R

NA

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 log 10 drop

≥2 log 10 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

log 10 drop

Week 12

≥1 log 10 drop

≥2

HCV RNA -ve

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

APRICOT

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

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

Prevalence of HBsAg + in HIV InfectedPatients

• 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 contamin ation

• Reduced the seroconversion rates to anti-HBe and anti- H Bs

• 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

0

2

4

6

8

10

12

14

16

1995 1997 2001 2003

ESLD related death % of total death

7

21

4238

0

5

1015

20

25

3035

40

45

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)

���� ����

Interferon

Pts αααα-IFNMonths of

therapy CD4HBV DNA

<6 logHBeAg

clearance

McDonald 87 14 2.5-10 6 – – 0

Marcellin 93 10 3-5 4-6 20-858 2 2

Wong 95 12 10 6 No AIDS 1 1

Zylberberg 96 25 6 6 480 ±±±± 234 9 2

Di Martino 02 26 5 6 331 ±±±± 207 7 3

Total 87 19 (26%) 8 (9%)

McDonald. Hepatology. 1987; Marcellin. Gut. 1993; Wong. Gastroenterology. 1995; Zylberberg. Gastroenterol Clin Biol. 1996;Di Martino. Gastroenterology. 2002.

HIV/HBeAg + LAM-RPEG-IFN αααα2a + ADV

0123456789

Baseline 12 24 48 72

Weeks

Ser

um H

BV

DN

A (

log

copi

es/m

L)

PEG-IFN2a + ADV

0

20

40

60

80

100

Basel ine 4 8 12 24 36 40 48 60 72

Weeks

Ser

um A

LT (

IU/L

)

PEG-IFN2a + ADV

HBV DNA ALT

Ingliz P. et al, Antiviral Therapy 2008

N=17

-2.7

-5

-4

-3

-2

-1

0Week 52

Med

ian

Cha

nge

in L

og H

BV

DN

A

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 oflamivudine therapy

Pro

port

ion

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 experienced

Total

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+ LA M-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

Pat

ient

s (%

)

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 DNA≥≥≥≥2000 IU/mL

HBV DNA

HBV DNA<2000 IU/mL

ALT ElevatedALT Normal

• Monitor ALT every 3-12 months

• Consider biopsyand 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 byTDF 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