2. Causes de décès d’origine infectieuse
dans le monde (2000)
HIV – HBV – HCV : TOP 10
Maladies Décès par an
Infections respiratoires ~3,5 million
VIH ~3,0 million
Diarrhées ~2,2 million
Tuberculose ~2,0 million
Malaria ~1-3 million
Rougeole ~888,000
Hépatite B ~750,000
Pertussis ~355,000
Tétanos néonatal ~300,000
Hépatite C ~ 250,000
Source : CDC, WHO, UNICEF, UNAIDS
3. Viral hepatitis in HIV-infected
patients
HCV HBV
Prevalence 20%-35% 7%-10%
Mortality Major cause of death Higher compare to
HBV mono-infected
Progression to Accelerated ?
Cirrhosis
Hepatotoxicity Controversies ?
of anti-retroviral
therapies
Active consideration for
treatment of hepatitis
5. Influence of HIV on HCV
• Major cause of mortality
• More severe liver lesions vs HCV
mono-infected
• Higher HCV RNA
6. No influence of HCV/HBV on response to
HAART : EuroSIDA cohort
HIV RNA <400 copies/ml 50% rise in CD4
70
70
50
50
HCV 30
30
10 10
0 3 6 9 12
Konopnicki D et al. AIDS. 2005;19:593-601.
7. Influence du VIH sur le VHC
Mortalité liée à l’atteinte hépatique
Mortalité chez les patients VIH en France
Étude du groupe GERMIVIC
100 91,6
90 84,5
80
70
60
50 48,7 47
%
40,4
40 36,7
30
20 14,3 12,6
10 8 6,9
2
6,6 8,8
1,5 1 1
0
1995 1997 2001 2003
Mortalité Globale Mortalité liée au Sida Mortalité liée au foie CHC
Caboub et al, CID 2001; Rosenthal et al, AIDS 2003.
8. Impact of HAART on liver related
mortality
1.1 Global Mortality
Global Mortality 1.1
Liver Mortality
Liver Mortality
HAART
0.9 HAART
0.9
Survival
ARV
Survival
p < 0,0001 Untreated
0.7 0.7
0.5 ARV 0.5
p < 0,018
Untreated
0.3 0.3
0 1000 2000 3000 4000 5000 6000 0 1000 2000 3000 4000 5000 6000
Days of observation Days of observation
Qurishi N et al, Lancet 2003
9. Progression to cirrhosis
influence of alcohol and immune
status
CD4 <200/µL
CD4 >200/ L
OH <50 g/j
OH<50 g/j
4 CD4<200/ L
OH>50 g/j HIV-
OH<50 g/j
Fibrosis 3
(METAVIR)
2
1
0
5 10 15 20 25 30 35 40
Estimated duration of HCV infection
Benhamou et al. Hepatology 1999;30:1054-1058
10. Timing for Anti-HCV and ARV
initiation
HIV mono-infected HIV/HCV
< 200 CD4 cells/µL ARV recommended
> 200 CD4 cells/µL and ARV possible : - ARV recommended
< 350 CD4 cells/µL - High HIV RNA and - ARV before anti-HCV
- Rapid CD4 decline
> 350 CD4 cells/µL and Monitor - Monitor HIV
< 500 CD4 cells/µL - Anti-HCV recommended
(if indicated)
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 Adapted from IAS–USA panel guidelines. Yeni P. at al. JAMA, 2004
14. r
fo A
a
n
tio RN
l u CV
Impact of HCV RNA on
a
ev h H
r
ve , hi
i 1
L T
g SVR
G
HCV RNA
100
N SVR
CD4
80 GT 1 GT 2/3 < 200/µL 17 8 (47 %)
P ro p o rtio n o f p a tie n ts
61
61 63
60 < 350 /µL 72 26 (36 %)
≥ 350 /µL 216 90 (47 %)
40
18 HIV RNA
20 < 50 cp/mL 173 72 (42 %)
50-5000 cp/mL 66 23 (35 %)
0
> 5000 cp/mL 49 21 (43 %)
≤800,000 >800,000 ≤800,000 >800,000
n=46 n=130 n=28 n=67
Torriani F et al. NEJM. 2004. Cooper D. et al, XV AIDS Conference
15. APRICOT
SVR according to Rx exposure
GT1 GT2/3
50
100
39%
40
SVR rate (%)
SVR rate (%)
80 69%
29%
30 59%
60
20
40
11% 26%
10 20
n= 176 62 114 n= 111 27 84
0 0
All <80/80/80 ≥80/80/80 All <70/70/70 ≥70/70/70
patients exposure* exposure patients exposure* exposure
*Patients violated the rule if ≥1 of the three targets
were not achieved Opravil M. et al. 45th ICAAC 2005; Abstract 2038
18. 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
19. 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
21. 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.
22. 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
• 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
23. 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.
24. 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.
25. 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
26. HIV/HBV Co-infection Mortality
Liver-related mortality (1995-2003 - GERMIVIC Cohort)
ESLD related death % of total death ESLD related death: % of HBsAg+
16 45 42
14.3 38
40
14 12.6
35
12
30
10
25
21
8 6.6 20
6 15
7
4 10
1.5 5
2
0 0
1995 1997 2001 2003 1995 1997 2001 2003
Rosenthal E, et al. J Viral Hep. 2007.
27. 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%
50%
Improved * F0-F1 8 0 0
33% (n=8)
10%
8%
F2 7 6 4
-10% 20%
(n=17)
Worsened **
-30% N= 15 12 F3-F4 1 1 11
* Improvement defined as ≥1 point reduction
(n=13)
** Worsening defined as ≥ 1 point increase
Benhamou Y et al. J Hepatol 2005. Lacombe, et al. CROI 2009, Abstract 815.
28. 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)
30. HIV/HBeAg+ LAM-R
PEG-IFN α2a + ADV
HBV DNA ALT
N=17
PEG-IFN2a + ADV PEG-IFN2a + ADV
9
S e ru m H B V D N A (lo g
8 100
7
S e r u m A L T (IU /L )
80
c o p ie s /m L )
6
5 60
4
3 40
2 20
1
0 0
Baseline 12 24 48 72
4
8
12
24
36
40
48
60
72
e
lin
Weeks
se
Ba
Weeks
Ingliz P. et al, Antiviral Therapy 2008
31. Lamivudine
Median change in serum HBV DNA
HBV resistance to LAM
HIV/HBeAg+ Naïve Pts
Week 52
Median Change in Log HBV DNA
1
0
Proportion of patients LAM-R
0.75
-1 N= 57
0.50
-2
0.25
-3 -2.7
-4 0 350 700 1050 1400
Days ofamivudine therapy
l
-5 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
32. Entecavir
ETV 1mg qd 48w = 4.3 log DNA decline in HIV/HBeAg+ LAM-R patients
Pessoa et al. AIDS 2008
• 17 HIV/HBV Pts who received ETV for HBV • Switch from a TDF to ETV for HBV
- Significant reduction in HIV RNA in the suppression
majority of pts
- 6 pts switched to ETV because of
Selection of M184V (HIV RT) TDF renal tox
following ETV treatment
ART naïve - HBeAg+ and HBV DNA <LOD: 6
ART experienced - L180M and M204V: 5
70
3/5 Total
60 • Outcome results:
% with M184V
6/12
50 3/7 - HBV rebound on ETV: 6
40
- Median time to rebound: 3 months
30
- All pts maintained HIV suppression
20
10
0
Median time M184V 148 days 98 days
Hull M, et al. 9th Intl. Congress on Drug Therapy in HIV
Audsley J, et al. 15th CROI, Boston 2008, #63. Infection. Glasgow 2008.
33. Telbivudine
• No in vitro anti HIV activity of LdT
HIV Isolate
NNRTI Multi drug resistant
ETV LdT
Drug ETV LdT
IC50 µM 11.67 >600
Fold change 0.93 >Max
HIV Isolate
Subtype A
Drug ETV LdT
IC50 µM 13.21 >600
Fold change 1.05 >Max
• One doubtful case of LdT anti-HIV activity ?
Low et al., CROI 2009. Abstract 813a Avila et al. CROI 2009, Abstract 1002.
34. Tenofovir Disoproxil Fumarate
TDF vs. TDF+LAM (48 weeks) TDF + LAM (48 weeks)
TDF TDF+LAM
100
LAM LAM
42/ 50
Naive Experienced
80 19 / 2 5
(n=9) (n=47)
29/ 50
14 / 2 5
Patients (%)
60
HBV DNA <15 9 41
40 9/ 25
UI/mL
12 / 5 0
20 Mean time to 49 67
3/ 50
1/ 2 5 DNA < LOD
0 (weeks)
DNA<3 AST<45 HBeAg HBsAg
log U/L loss loss
Schmutz G, et al. AIDS. 2006. Tuma R, et al. AASLD 2008, Abstract 967.
35. 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
36. 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.
37. 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
TDF+LAM/FTC
Patients without Patients with
HBV-associated HBV-associated
HAART regimen
LAM resistance LAM resistance
of choice
Refer patient for liver
HAART including transplantation
Substitute one NRTI by
TDF+3T/FTC 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.