The document discusses three key points: 1) Hepatitis C and B viruses and HIV have a large global prevalence, infecting hundreds of millions of people worldwide. 2) Coinfection of HIV and hepatitis viruses can accelerate liver disease. A study of over 23,000 HIV-positive individuals found that liver-related causes accounted for 14.5% of deaths. 3) Acute hepatitis C infection among HIV-positive men who have sex with men is an emerging issue, with hundreds of reported cases in the United States, Europe, and Australia. Monitoring HCV RNA levels can help determine if antiviral therapy is needed.

1. Hépatites Virales C et
B et Infection par le
VIH

2. HIV, Hepatitis B and C: global prevalence
350.000.000
170.000.000
33.000.000
2-4.000.000
4-5.000.000
1. WHO Factsheets HBV, HCV, HIV; 2. Alter MJ. J Hepatol 2006; 44(Suppl.1): S6-S9.

3. Liver-related (LR) deaths
in 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 10%
HCV
– 2% HBV 86% 14%
1%
– 1% HBV-HCV Non Liver 2%
– LR
1% other causes Related (LR) 1%
HBV
other
The D:A:D study Arch Intern Med 2006;166:1632-1641

4. Hépatite Chronique C
Chez les Patients
Co-infectés par le VIH

5. Fibrosis progression

6. Progression to cirrhosis
1.00
4,682 patients
Hazard function
180 HIV-HCV
701 Alcohol
812 HBV
382 Hemochromatosis
2,313 HCV
93 Steatosis BMI>25
200 PBC
0 20 40 60 80
Age in years Poynard, T. et al. J Hepatol 2003;38:257-265

8. SVR = regression, NR = progression ?
Ingiliz, Benhamou et al., J Hepatol, submitted, under review

9. Current treatment for HCV

10. Drug-Drug-Interactions (DDIs)
Known and anticipated DDIs between antiretrovirals and anti-HCV drugs in current use and the
HCV protease inhibitors in Phase III development
No clinically significant interaction, or interaction unlikely based
Hepatitis C Therapies
on knowledge of drug metabolism
Protease Inhibitors Potential interaction that may require close dose monitoring,
Current Agents
(Phase III trials) alteration of dosage or timing of administration
PEG-IFN Ribavirin Telaprevir Boceprevir Interaction likely, do not use or use with caution
PIs 1
1 1 = atazanavir/ritonavir
1
NNRTIs
2 = didanosine, zidovudine
2
NRTIs 2
2 3
3 4
4 4
4 3 = emtricitabine, lamivudine, tenofovir
3
4 = zidovudine
4
Entry
5
5 5
5 5 = maraviroc
5
Inhibitors
Integrase
6
6 6 = raltegravir
6
Inhibitors
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.

11. PRESCO (ITT analysis): virological response,
genotype
End of treatment (EOT)
SVR (%)
Sustained virological response (SVR)
100
90,1%
90,1%
80
72,4%
72,4%
67,3%
67,3%
60
55%
55%
49,6%
49,6%
40 41%
41%
35,6%
35,6%
32,6%
32,6%
20
n= 262 193 106 68 137 110 19 15
0
HCV genotype Total GT1 GT2/3 GT4
patients n= 389 191 152 152
SVR defined as undetectable HCV RNA 24 weeks after end of treatment
Nunez et al. AIDS Res Hum Retroviruses 2007; 23(8): 972-982.

12. European guidelines for the treatment of HIV-HCV
coinfection GT 2, 3 and 4
EACS guidelines, version 5-2

13. IL-28B genotype and treatment response
- Influence of HCV genotype -
Pineda et al., abstract #656, CROI 2010

14. 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

15. Study Design
Weeks 12 24 28 48 72
PEG2b
Placebo + PEG2b + RBV Follow-up
Arm 1 +RBV
44 wk SVR-24 wk
4 wk
PEG2b
Boceprevir + PEG2b + RBV Follow-up
Arm 2 +RBV
44 wk SVR-24 wk
4 wk
Futility Rules
• 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
15

16. Virologic Response Over Time†
100 PR B/PR
% HCV RNA Undetectable
80 73.4
65.6
59.4 60.7
60
42.2
40 32.4 29.4 26.5
23.5
20 14.7
8.8
4.7
3/34 3/64 5/34 27/64 8/34 38/64 11/34 47/64 10/34 42/64 9/34 37/61
0
4 8 12 24 EOT SVR12
Treatment Week
†
Three patients undetectable at FW4 have not yet reached FW12 and were not included in SVR12 analysis.
16

17. SVR-12 by PI Regimen on Day 1
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%)
† 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
17

18. Summary of Safety
PR B/PR
(N=34) (N=64)
Any AE 34 (100) 63 (98)
Serious AEs 7 (21) 11 (17)
Death 0 0
Treatment-related treatment-emergent
34 (100) 61 (95)
AEs
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.
18

19. Most Common Adverse Events With a
Difference of ≥10% Between Groups
PR B/PR
(N=34) (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%
19

20. Study Design: Randomized, Double-blind,
Placebo-controlled Trial
Part A: no ART
SVR24
T/PR TVR + PR PR SVR12
1:1
PR48 SVR24
Pbo + PR PR SVR12
(control)
Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC)
SVR24
T/PR TVR + PR PR SVR12
2:1
PR48 SVR24
Pbo + PR PR SVR12
(control)
Weeks 0 12 24 36 48 60 72
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

21. SVR at post-treatment week 24 (SVR24)
No ART EFV/TDF/FTC ATV/r/TDF/FTC Total
Patients with SVR (%)
n/N = 5/7 11/16 12/15* 28/38 2/6 4/8* 4/8 10/22
T/PR PR
*Prior to Week 24 visit, 1 patient in this cohort was lost to follow up. SVR24 was imputed based on SVR12 for this patient.

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

23. Events of Special Interest: Overall Treatment Phase
T/PR PR
n (%) N=38 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
11 (29) 5 (23)
or decrease from baseline ≥4.5 g/dL)
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
• 3 T/PR patients discontinued due to adverse event (3 T/PR)

24. Acute hepatitis C

25. Acute HCV among HIV+ MSM
USA1,2: 54 cases Europe: 951 cases
Prevalence chronic HCV/HIV14,15
Prevalence chronic HCV/HIV12-14 25%: 185.500
15 – 30%: 180.000 – 360.000
-UK3,4 552
-Germany5 157
-France6,7 117
-Netherlands8 81
-Swiss9 23
-Italy10 21
Australia11: 28 cases
Prevalence chronic HCV/HIV16
< 1%: 1.000
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.

26. Monitoring and initiation antiviral therapy
Initial presentation
Initial presentation
acute HCV
acute HCV
< 2 log10
Week 4
Week 4 Decay HCV-RNA
Decay HCV-RNA Treatment
Treatment
≥ 2 log10
positive
Week 12
Week 12 HCV-RNA
HCV-RNA Treatment
Treatment
negative
wait: cont´d controls
wait: cont´d controls
throughout week 48
throughout week 48
Courtesy: Martin Vogel, Germany

27. Antiviral therapy of AHC
Week 4
Week 4 Week 12
Week 12
HCV-RNA
HCV-RNA
24 weeks
24 weeks
negative*
negative*
peg-IFN +
peg-IFN +
RBV (AII)
RBV (AII)
HCV-RNA
HCV-RNA Drop HCV-RNA
Drop HCV-RNA
48 weeks
48 weeks
positive*
positive* ≥ 2 log10
≥ 2 log10
< 2 log10
Stop Therapy
Stop Therapy
*evidence based on using a 615 IU/ml cutoff to define negative HCV-RNA
Courtesy: Martin Vogel, Germany

28. Hépatite Chronique B
Chez les Patients
Co-infectés par le VIH

29. 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.

30. Influence of HIV on CHB
In the Pre HAART era, HIV in HBsAg positive patients
(compared to
HBV 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
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,
• Increased risk of liver decompensation, HCC and liver
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
death

31. Mortality
Liver-related mortality in 5293 patients (MACS), 1984 /1987–2000
Viral status
Liver-related Liver death
N HIV HBsAg mortality (n) (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 mortality
X 19 HBV/HIV vs HBV (RR:18; 73,1-766,1; P<0,001)
Thio CL, et al. Lancet. 2002;360:1921-1926.

32. Impact of HIV Infection on Progression
to HBV-Related Cirrhosis
100
90
80
% of cirrhosis
70
HIV positive
60
50
40 p=0.005
30
20
HIV negative
10
0
0 1 2 3 4 5 6 7 8 9 10
Follow-up (years)
Di Martino V et al. Gastroenterology. 2002.

33. Influence of HAART
• Increases duration of HBV
by improving survival
• Inhibition of HBV replication
• Increases the risk of ALT (LAM – FTC – ADV)
flares related to – Histological improvement
– Immune restoration
?
– Hepatotoxicity
– Reactivation
• ARV discontinuation
• HBV resistance
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

34. Impact of Anti-HBV Therapy on Liver Fibrosis
ADV TDF
Median METAVIR F at Baseline = 2 Median time F. up : 29.5 months
70% Week 48 Week 192
50% F0-F1 F2 F3-F4
30% Improved * F0-F1 8 0 0
50%
33%
(n=8)
10%
F2 7 6 4
8%
-10% 20% (n=17)
Worsened **
-30% N= 15 12
F3-F4 1 1 11
(n=13)
* Improvement defined as ≥1 point reduction
** Worsening defined as ≥ 1 point increase
Benhamou Y et al. J Hepatol 2005. Lacombe, et al. CROI 2009, Abstract 815.

35. 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)  

36. Lamivudine
Median change in serum HBV DNA
HBV resistance to LAM
HIV/HBeAg+ Naïve Pts
1
Proportion of patients LAM-R
0.75
N= 57
0.50
0.25
0 350 700 1050 1400
Days of
lamivudine therapy
Number of patients 57 32 13 6 3
under observation
(LAM 150 mg bid)
Dore GJ, et al. J Infect Dis. 1999;180:607-613. Benhamou Y, et al. Hepatology 1999; 30:1302-06

37. Tenofovir Disoproxil Fumarate
TDF vs. TDF+LAM (48 weeks) TDF + LAM (48 weeks)
TDF TDF+LAM
100
42/50
80 19 / 2 5 LAM LAM
29/50
14 / 2 5
Naive Experience
Patients (%)
60 d
(n=9)
40 9/25
(n=47)
12 / 5 0
20
3 / 5 0 1/ 2 5
0 HBV DNA <15 9 41
DNA<3 AST<45 HBeAg HBsAg UI/mL
log U/L loss loss
Mean time to 49 67
DNA < LOD
(weeks)
Schmutz G, et al. AIDS. 2006. Tuma R, et al. AASLD 2008, Abstract 967.

38. 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
LAM TDF TDF+LAM
W48 outcomes p
N=12 N=12 N=12
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
Matthews G et al. Hepatology 2008

39. Treatment Algorithm
Patients with Compensated Liver Disease and
No Indication for HIV Therapy (CD4 count >350/µL)
HBV DNA
HBV DNA HBV DNA
<2000 IU/mL ≥2000 IU/mL
ALT Elevated
ALT Normal
• No treatment • Monitor ALT every • PEG IFN
3-12 months • LdT (if HBV DNA>LOD at w24 add ADV)
• Monitor every
6–12 months • Consider biopsy • ADV+LdT
and treat if disease
present • Early HAART initiation –TDF+LAM/FTC
ECC Statement. J Hepatol. 2005.
Rockstroh et al. HIV Medicine 2008.

40. Treatment Algorithm
Patients with Compensated Liver Disease and
Indication for HIV Therapy (CD4 count <350/µL)
HBV DNA Patients with
cirrhosis
HBV DNA HBV DNA
≥2000 IU/ml <2000 IU/ml
HAART including
Patients without Patients with TDF+LAM/FTC
HBV-associated HBV-associated
HAART regimen
LAM resistance LAM resistance
of choice
Refer patient for liver
HAART including transplantation
TDF+3T/FTC Substitute one NRTI by
evaluation if
TDF or add TDF*
decompensation
*If feasible and appropriate from the perspective
ECC Statement. J Hepatol. 2005.
of maintaining HIV suppression. Rockstroh et al. HIV Medicine 2008.