Hépatites Virales C et B et Infection par le

VIH

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

The D:A:D study Arch Intern Med 2006;166:1632-1641

1%

1%

14%

2%

10%

86%

Non Liver Related (LR)

LR

HCV

HBV

other

Liver-related (LR) deaths Liver-related (LR) deaths in 23 441 HIV+ from developed countriesin 23 441 HIV+ from developed countries

• 76 893 person-years of follow-up in 23 441 HIV+

• 1246 deaths (5.3%; 1.6 per 100 person- years);

• 14.5% were from liver-related causes:– 10% HCV– 2% HBV – 1% HBV-HCV– 1% other causes

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 f

un

ctio

n

Age in years

Progression to cirrhosisProgression to cirrhosis

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

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

Current treatment for HCV

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

11

44 4422

55 55

11 = atazanavir/ritonavir

22 = didanosine, zidovudine

33 33 = emtricitabine, lamivudine, tenofovir

44 = zidovudine

55 = maraviroc

66 66 = raltegravir

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%49,6%

67,3%67,3%

35,6%35,6%

55%55%

72,4%72,4%

90,1%90,1%

32,6%32,6%

41%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=n=

European guidelines for the treatment of HIV-HCV European guidelines for the treatment of HIV-HCV coinfection GT 2, 3 and 4coinfection GT 2, 3 and 4

EACS guidelines, version 5-2

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 -

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

1515

Study Design

• Two-arm study, double-blinded for BOC, open-label for PEG2b/RBV• 2:1 randomization (experimental: control)• Boceprevir dose 800 mg TID

• 4-week lead-in with PEG2b/RBV for all patients• PEG-2b 1.5 µg/kg QW; RBV 600-1400 mg/day divided BID

• Control arm patients with HCV-RNA ≥ LLOQ at TW 24 were offered open-label PEG2b/RBV+BOC via a crossover arm

Weeks 12 24 28 48 72

PEG2b+RBV 4 wk

Placebo + PEG2b + RBV44 wk

Boceprevir + PEG2b + RBV44 wk

Follow-upSVR-24 wk

Follow-upSVR-24 wk

PEG2b+RBV 4 wk

Arm 1

Arm 2

Futility Rules

1616

8.814.7

23.532.4 29.4 26.5

4.7

42.2

59.4

73.465.6

60.7

0

20

40

60

80

100

4 8 12 24 EOT SVR12

Treatment Week

PR B/PR

%

HC

V R

NA

Un

det

ecta

ble

3/34 3/64 5/34 27/64 8/34 38/64 11/34 47/64

Virologic Response Over Time†

10/34 9/3442/64 37/61

† Three patients undetectable at FW4 have not yet reached FW12 and were not included in SVR12 analysis.

1717

SVR-12 by PI Regimen on Day 1

† Excludes 2 patients not yet at FW12 but undetectable at FW4.

†† Excludes 1 patient not yet at FW12 but undetectable at FW4.

*Includes saquinavir, fosamprenavir and tipranavir

PR B/PR

Atazanavir/r 8/13 (62%) 12/18† (67%)

Lopinavir/r 0/10 (0%) 10/15†† (67%)

Darunavir/r 0/5 (0%) 8/12 (67%)

Other PI/r* 0/3 (0%) 4/7 (57%)

1818

Summary of Safety

PR (N=34)

B/PR(N=64)

Any AE 34 (100) 63 (98)

Serious AEs 7 (21) 11 (17)

Death 0 0

Treatment-related treatment-emergentAEs

34 (100) 61 (95)

Study discontinuation due to an AE 3 (9) 13 (20)

Any drug modification due to an AE 8 (24) 18 (28)

All data shown as number (%) of patients.

1919

Most Common Adverse Events With a Difference of ≥10% Between Groups

PR (N=34)

B/PR(N=64)

Anemia 26% 41%

Pyrexia 21% 36%

Asthenia 24% 34%

Decreased appetite 18% 34%

Diarrhea 18% 28%

Dysgeusia 15% 28%

Vomiting 15% 28%

Flu-like illness 38% 25%

Neutropenia 6% 19%

Part A: no ARTPart A: no ART

PR48 (control)

PR SVR24

Pbo + PR

T/PR TVR + PR SVR24

PR

PR48 (control)

PR SVR24

Pbo + PR

T/PR TVR + PR SVR24

PR

Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC)Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC)

EFV = efavirenz; TDF = tenofovir; FTC = emtricitabine; ATV/r = ritonavir-boosted atazanavir; 3TC = lamivudine; T/TVR = telaprevir 750 mg q8h or 1125 mg q8h (with EFV); Pbo=Placebo; P/Peg-IFN = pegylated interferon alfa-2a (40 kD) 180 µg/wk); SVR = sustained virologic response

EFV = efavirenz; TDF = tenofovir; FTC = emtricitabine; ATV/r = ritonavir-boosted atazanavir; 3TC = lamivudine; T/TVR = telaprevir 750 mg q8h or 1125 mg q8h (with EFV); Pbo=Placebo; P/Peg-IFN = pegylated interferon alfa-2a (40 kD) 180 µg/wk); SVR = sustained virologic response

Study Design: Randomized, Double-blind, Placebo-controlled Trial

240 48 72Weeks 12 36 60

SVR12

SVR12

SVR12

SVR12

1:11:1

2:12:1

n/N =n/N = 5/75/7 11/1611/16 12/15*12/15* 28/3828/38 2/62/6 4/8*4/8* 4/84/8 10/2210/22

SVR at post-treatment week 24 (SVR24)

*Prior to Week 24 visit, 1 patient in this cohort was lost to follow up. SVR24 was imputed based on SVR12 for this patient. *Prior to Week 24 visit, 1 patient in this cohort was lost to follow up. SVR24 was imputed based on SVR12 for this patient.

Pa

tie

nts

wit

h S

VR

(%

)No ART EFV/TDF/FTC ATV/r/TDF/FTC Total

T/PRT/PR PRPR

Most Common Adverse Events: TVR treatment phase (Weeks 1-12)*

*Reported in >15% of patients regardless of severity in total T/PR or PR in overall treatment phase, in bold event occurring at >10% points difference between T/PR group vs PR. ‡ Rash and anemia were defined using a group of related search terms in which the event of highest severity was scored.

N (%) T/PR, N=38 (%) PR, N=22 (%)

Fatigue 15 (39) 9 (41)

Pruritus 13 (34) 1 (5)

Headache 13 (34) 5 (23)

Nausea 12 (32) 4 (18)

Rash‡ 11 (29) 4 (18)

Diarrhea 8 (21) 3 (14)

Dizziness 8 (21) 2 (9)

Pyrexia 7 (18) 2 (9)

Depression 6 (16) 2 (9)

Neutropenia 3 (8) 1 (5)

Anemia‡ 5 (13) 4 (18)

Vomiting 6 (16) 2 (9)

Myalgia 5 (13) 5 (23)

Chills 5 (13) 4 (18)

Insomnia 5 (13) 4 (18)

Decreased appetite 4 (11) 3 (14)

Weight decreased 2 (5) 2 (9)

Events of Special Interest: Overall Treatment Phase

n (%)

T/PR

N=38

PR

N=22

Severe rash 0 (0) 0 (0)

Mild and moderate rash 13 (34) 5 (23)

Any anemia (hemoglobin <10g/dL) 7 (18) 4 (18)

Severe anemia (hemoglobin 7.0-8.9 g/dL or decrease from baseline ≥4.5 g/dL)

11 (29) 5 (23)

Use of erythropoietin stimulating agent 3 (8) 1 (5)

Blood transfusions 4 (11) 1 (5)

Discontinuation due to AE 3 (8) 0 (0)

• No HIV breakthrough; CD4 counts declined in T/PR and PR groups; CD4% unchanged• No HIV breakthrough; CD4 counts declined in T/PR and PR groups; CD4% unchanged• 3 T/PR patients discontinued due to adverse event (3 T/PR)

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-RNADecay HCV-RNA

HCV-RNA HCV-RNA

wait: cont´d controls

throughout week 48

wait: cont´d controls

throughout week 48

Initial presentation

acute HCV

Initial presentation

acute HCV

2 log10

negative

< 2 log10

positive

TreatmentTreatment

TreatmentTreatment

Week 4Week 4

Week 12Week 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*

HCV-RNA

negative*

Stop Therapy Stop Therapy

peg-IFN +

RBV (AII)

peg-IFN +

RBV (AII)

< 2 log10

24 weeks24 weeks

Drop HCV-RNA

2 log10

Drop HCV-RNA

2 log10

Week 4Week 4 Week 12Week 12

HCV-RNA

positive*

HCV-RNA

positive*48 weeks48 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 c

irrh

os

is

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

* 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)

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 therapyP

rop

ort

ion

of

pat

ien

ts L

AM

-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

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

ien

ts (

%)

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 outcomesLAM

N=12

TDF

N=12

TDF+LAM

N=12p

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