Download - Benhamou du co infection 2012
Hépatites Virales C et B et Infection par le
VIH
Benhamou Yves
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
Facteurs pronostiques chez les patients co-infectés VIH-VHC : résultats de la cohorte HEPAVIH (1)
• Cohorte prospective multicentrique française (ANRS CO13 HEPAVIH) ayant inclus 1 175 patients co-infectés (inclusions de 01/2006 – 12/2008)
• Sous-étude incluant les patients avec FibroScan®, suivi suffisant et sans décompensation antérieure : n = 886 (75 %)
• Suivi moyen 23 mois
• Évènements – Décompensation hépatique (n = 10)– Décès toutes causes confondues (n = 36)
• Causes hépatiques : 27 %• Causes liées au VIH : 19 %• Autres : 42 %• Inconnues : 11 %
Sogni P, AASLD 2011, Abs. 246 actualisé
5
Sogni P, AASLD 2011, Abs. 246 actualisé
Complications hépatiques ou décès toutes causes confondues (à 5 ans : 10 %)Décès toutes causes confondues (à 5 ans : 7 %)Décès de cause hépatique (à 5 ans : 2 %)
Courbes et estimations actuarielles
0 6 12 18 24 30 36 42 48 54 60 660
40
30
20
10
Mois
Pro
babi
lité
(%)
Facteurs pronostiques chez les patients co-infectés VIH-VHC : résultats de la cohorte HEPAVIH (2)
6
Sogni P, AASLD 2011, Abs. 246 actualisé
Variables RR ajustés IC 95 % pÂge 1,459 1,029 – 2,068 0,034
Albuminémie 0,891 0,807 – 0,983 0,021
Taux de plaquettes 0,464 0,265 – 0,813 0,007
FibroScan® 1,300 1,125 – 1,503 < 10-3
Facteurs associés à la survenue d’une complication hépatique ou d’un décès de cause hépatique (analyse multivariée)
Facteurs associés à la survenue d’une complication hépatique ou d’un décès toutes causes confondues (analyse multivariée)
Variables RR ajustés IC 95 % pAlbuminémie 0,910 0,855 – 0,968 0,003
FibroScan® 1,209 1,085 – 1,347 0,001
Stades CDC (C versus A-B) 2,302 1,095 – 4,839 0,028
Facteurs pronostiques chez les patients co-infectés VIH-VHC : résultats de la cohorte HEPAVIH (3)
7
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 fu
nctio
n
Age in years
Progression to cirrhosisProgression to cirrhosis
Impact of ART liver-associated mortality in HIV/HCV-Impact of ART liver-associated mortality in HIV/HCV-coinfected patientscoinfected patients
Overall mortality
Surveillance period (days)5.0004.0003.0002.0001.000
1,1
0,9
0,7
0,5
0,3
*p < 0,0001
Patients on HAART*
Patients on ART
untreated patients
6.000 6.0005.0004.0003.0002.0001.0000
Liver-associated mortality
*p < 0,018
Patients on HAART*
Patients on ART
Untreated patients
Cumulative survival
Surveillance period (days)
1,1
0,9
0,7
0,5
0,3
Predictors of liver-associated mortality No HAART low CD4-count age
Bonn cohort (1990–2002) 285 HIV/HCV-coinfected
patients
Qurishi et al. Lancet 2003: 362(9379): 1708–1713.
Cumulative survival
Chronic Hepatitis C - Fibrosis progressionChronic Hepatitis C - Fibrosis progression
Increased by:
• Age• Male sex• Alcohol consumption• HIV-infection, low CD4, HIV viral load• Immunosuppression• Insulin resistance• Severe Steatosis (?)• Necroinflammatory activity in liver biopsy• Non-response to interferon therapy
Mohsen et al., Gut 2003;52:1035-1040.Benhamou et al., Hepatology 1999;30:1054-1058.Macías et al., Hepatology. 2009;50(4):1056-1063
SVR = regression, NR = progression ?SVR = regression, NR = progression ?
Ingiliz, Benhamou et al., J Hepatol, submitted, under review
Current treatment for HCV
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
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%
67,3%
35,6%
55%
72,4%
90,1%
32,6%
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=
European guidelines for the treatment of HIV-HCV European guidelines for the treatment of HIV-HCV coinfectioncoinfection
EACS guidelines, version 5-2
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
IL 28B polymorphism
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 -
Telaprevir/PEG IFN/RBV chez des patients co-infectés VIH-VHC – Analyse à 6 mois (1)
• Etude randomisée, multicentrique, phase II, patients G1 co-infectés VIH naïfs de traitement VHC
Sherman KE, AASLD 2011, Abs. LB8 actualisé
*ART : anti-rétroviraux, PR : PEG-IFNα-2a 180 μg/sem + RBV 800-1200 mg/j
Partie A : sans ART
Partie B : ART* (EFV/TDF/FTC ou ATV/r + TDF + FTC ou 3TC)
RVSSuivi(n = 7)
(n = 6)
(n = 31)
(n = 16)
S0 S12 S24 S48 S72
TVR + PR PR
PRPlacebo + PR
TVR + PR PR
PRPlacebo + PR
S36
Schéma de l’étude
18
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
1
4 42
5 5
1 = atazanavir/ritonavir
2 = didanosine, zidovudine
3 3 = emtricitabine, lamivudine, tenofovir4 = zidovudine
5 = maraviroc
6 6 = raltegravir
Telaprevir/PEG IFN/RBV chez des patients co-infectés VIH-VHC – Analyse à 6 mois (2)
Réponse virologique à 6 mois
AR
N V
HC
indé
tect
able
(%)
Sans ART EFV/TDF/FTC ATV/r/TDF/FTC Total
0
20
40
60
80
100
6/7
86
75 7167
11/16 10/15 27/38n/N = 2/6
33
5055
75
4/8 6/8 12/22
T/PR PR
Sherman KE, AASLD 2011, Abs. LB8 actualisé
19
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-RNA
HCV-RNA
wait: cont´d controls
throughout week 48
Initial presentation
acute HCV
2 log10
negative
< 2 log10
positive
Treatment
Treatment
Week 4
Week 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*
Stop Therapy
peg-IFN +
RBV (AII)
< 2 log10
24 weeks
Drop HCV-RNA
2 log10
Week 4 Week 12
HCV-RNA
positive*48 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 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
02468
10121416
1995 1997 2001 2003
ESLD related death % of total death
7
21
4238
05
1015202530354045
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)
HIV/HBeAg+ LAM-R PEG-IFN 2a + ADV
0123456789
Baseline 12 24 48 72
Weeks
Seru
m H
BV
DNA (l
og
copi
es/m
L)
PEG-IFN2a + ADV
0
20
40
60
80
100
Weeks
Seru
m A
LT (I
U/L)
PEG-IFN2a + ADV
HBV DNA ALT
Ingliz P. et al, Antiviral Therapy 2008
N=17
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 therapyPr
opor
tion
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 experiencedTota
l
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+ LAM-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
Patie
nts
(%)
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 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