Hépatites Virales C et B et Infection par le VIH
Yves Benhamou Dominique Thabut
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 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 – 2% HBV – 1% HBV-HCV – 1% other causes
Hépatite Chronique C Chez les Patients
Co-infectés par le VIH
3 Questions
1. La fibrose progresse-t-elle plus vite ? 2. Le traitement est-il différent du traitement chez
un patient non-VIH ? 3. Nouvelles molécules anti-VHC
Questions
1. La fibrose progresse-t-elle plus vite ? 2. Le traitement est-il différent du traitement chez
un patient non-VIH ? 3. Nouvelles molécules anti-VHC
Poynard, T. et al. J Hepatol 2003;38:257-265
4,682 patients
180 HIV-HCV 701 Alcohol 812 HBV 382 Hemochromatosis 2,313 HCV 93 Steatosis BMI>25 200 PBC
1.00
0 20 40 60 80
Haz
ard
func
tion
Age in years
Progression to cirrhosis
Influence of CD4 cell count and HIV-RNA liver fibrosis progression
Modified from Brau et al. J Hepatol 2006; 44(1):47–55.
274 HIV/HCV-‐koinfizierte Pa;enten
Fibrosis-‐Progressionrate (IshFU/year)
0,08
0,14
0,22
0,12
0,16
0,20
1,18
0,10
0,155
0,121
n=124 n=150
p=0,004
CD4 <350
CD4 >350
CD4 (cells/mm3) HIV-‐RNA (copies/mL)
0,123
0,162
0,121 0,118
n=100 n=88 n=53 n= 83
p=0,005 p=0,89
CD4 < 500 CD4 > 500
HIV-‐RNA <400
HIV-‐RNA >400
HIV-‐RNA <400
HIV-‐RNA >400
IshFU/year – Ishak-‐Fibrosis-‐units per year
Impact of ART liver-associated mortality in HIV/HCV-coinfected patients
Overall mortality
Surveillance period (days) 5.000 4.000 3.000 2.000 1.000
1,1
0,9
0,7
0,5
0,3
*p < 0,0001
Patients on HAART*
Patients on ART
untreated patients
6.000 6.000 5.000 4.000 3.000 2.000 1.000 0
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 progression
Increased by:
• Age • Male sex • Alcohol consump_on • HIV-‐infec_on, low CD4, HIV viral load • Immunosuppression • Insulin resistance • Severe Steatosis (?) • Necroinflammatory ac_vity 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
How fast is an HIV/HCV coinfected patient progressing to liver cirrhosis?
• Problem: few „paired-biopsy“ studies, time of infection unclear, small patient numbers, is fibrosis progression a linear process?
Trials with HIV/HCV coinfected patients on fibrosis progression rate (FPR):
• Benhamou et al.: 0.15 FU/year (i.e. time to liver cirrhosis (TLC): 27 years)
• Macias et al.: median time between biopsies: 3.3 years, fast progression rate 0.46 FU/year (i.e. time to liver cirrhosis (TLC): 8.7 years)
• Case reports about rapid FPR after acute HCV infection in HIV patients: Fierer et al: 4.3 +/- 2.7 FU/year
• Sterling et al.: No difference in fibrosis progression in well-controlled HIV coinfection
compared to HCV monoinfection!
Benhamou et al., Hepatology 1999;30:1054-1058 Macías et al., Hepatology. 2009;50(4):1056-1063 Fierer et al., J Infect Dis. 2008 Sep 1;198(5):683-686 Sterling et al., Clin Gastroenterol Hepatol. 2010 Aug 20
SVR = regression, NR = progression ?
-‐1
0
1
2
3
4
0 5 10 15 20
Time (yr)
Fibrosis stage (M
etavir fib
rosis u
nits)
Untreated (n=29)
SVR (n=34)
NR/R (n=63)
Ingiliz, Benhamou et al., J Hepatol, submiged, under review
Progression de la fibrose chez les coinfectés VIH-VHC: résumé
• Dépend des facteurs habituels progression fibrose + statut VIH/CD4
• Dépend du TTT antirétroviral • Vitesse plus rapide que chez les monoinfectés ? • Dépend de la réponse virologique au TTT anti-VHC
Questions
1. La fibrose progresse-t-elle plus vite ? 2. Le traitement est-il différent du traitement chez
un patient non-VIH ? 3. Nouvelles molécules anti-VHC
Treatment for HCV in 2010
Ribavirin tablets
Ribavirin capsule
Peg-‐Interferon alfa-‐2a
Peg-‐Interferon alfa-‐2b
180µg/week
1,5µg/kg/week
800-‐1200mg/d
800-‐1200mg/d
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
Traiter + tôt ?
Etudes Bithérapie chez les Co-Infectés
Chung RT. NEJM 2004; Torriani FJ. NEJM 2004; Carrat F. JAMA 2005; Laguno M, AIDS 2004, Nunez M et al. Hepatology 2006
0
10
20
30
40
50
60
70
80
Ribavic ACTG Apricot Laguno PRESCO
Tous
G1
G2 -‐ G3
High doses Ribavirin +++ (15 mg/Kg)
European guidelines for the treatment of HIV-HCV coinfection
EACS guidelines, version 5-2
Traiter + longtemps
Side effects of treatment Pitfalls in HIV/HCV coinfection
• AZT (anemia) • ddI (mitochondrial toxicity) • d4T (mitochondrial toxicity) • ABC (ribavirin pharmacokinetics): plus faible SVR ? (dose Riba
adaptée au Poids)
0 4 5 11 12 Interferon/ribavirin therapy
Sev
erity
6 7 8 9 10 1 2 3
Fatigue Flu-like syndrome
Psychiatric side effects(Depression)
Anemia / Leukopenia / Thrombopenia
weeks
IL 28B polymorphism
IL28B polymorphism: IL28B and ethnicity
Ge et al. Nature 2009 Suppiah et al., 2009 Tanaka et al., 2009
Rallon et al. #165LB, CROI 2010
IL-28B genotypes and treatment response (VIH-VHC)
P<0.001
IL28B Genotype
CC CT/TT 0
25
50
75
100
%SV
R
P=0.02
IL28B Genotype
CC CT/TT 0
25
50
75
100
%SV
R
CC CT/TT
IL28B Genotype
Pineda et al. #656, CROI 2010 Nattermann et al. #164, CROI 2010
Pineda et al., abstract #656, CROI 2010
IL-28B genotype and treatment response - Influence of HCV genotype -
Acute hepatitis C
Acute 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 cases Prevalence chronic HCV/HIV14,15
25%: 185.500
-UK3,4 552 -Germany5 157 -France6,7 117 -Netherlands8 81 -Swiss9 23 -Italy10 21
Australia11: 28 cases Prevalence chronic HCV/HIV16
< 1%: 1.000
USA1,2: 54 cases Prevalence chronic HCV/HIV12-14
15 – 30%: 180.000 – 360.000
Monitoring 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 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
Traitement du VHC chez les coinfectés VIH-‐VHC: Résumé
• Traitement + précoce • + fortes doses de Riba • Traitement + long
• Eviter Abacavir, DDI, DDT et AZT
• Statut IL28B important
• Prévalence du VIH si hépatite aiguë C +++
Questions
1. La fibrose progresse-t-elle plus vite ? 2. Le traitement est-il différent du traitement chez
un patient non-VIH ? 3. Nouvelles molécules anti-VHC
Trials with HCV protease inhibitors HIV/HCV coinfected patients
1 Recruiting Safety and Efficacy of Telaprevir in Combination With Peginterferon Alfa-2a
and Ribavirin in Subjects Co-Infected With Hepatitis C Virus (HCV) and HIV Conditions: Hepatitis C; HIV InfectionsInterventions: Drug: telaprevir or matching placebo Biological:peginterferon alfa-2a; Drug: ribavirin (fixed dose); Drug: ribavirin (weight-based dose)
2 Completed VX-950-TiDP24-C134: Drug-drug Interaction Trial Between Combination of Efavirenz and Tenofovir Disoproxil Fumarate and Different Dosages of Telaprevir on Healthy Volunteer Conditions: Hepatitis C; HCV; HIV; AIDS Intervention: Drug: Efavirenz; Tenofovir disoproxil fumarate; Telaprevir
3 Completed
VX-950-TiDP24-C124: A Phase I Trial to Investigate the Potential Pharmacokinetic Interactions Between Telaprevir and Darunavir/Ritonavir and Between Telaprevir and Fosamprenavir/Ritonavir at Steady-state. Conditions: Hepatitis C; HIV Intervention: Drug: Telaprevir; Darunavir; Ritonavir; Fosamprenavir
4 Recruiting A Phase 2b, Safety and Efficacy Study of Boceprevir in Patients Coinfected With HIV and Hepatitis C (P05411 AM3) Conditions: HIV Infections; Hepatitis C; HCV Infection Interventions: Drug: PEG2b plus ribavirin followed by placebo; Drug: PEG2b plus ribavirin followed by boceprevir/PEG2b/ribavirin
Clinicaltrials.gov, 11.11.2010
Interactions with ritonavir?
• Telaprevir and Boceprevir protease inhibitors appear to be metabolized by cytochrome enzymes.
• Telaprevir and Boceprevir can be ‘boosted’ by low dose ritonavir in vitro.
• Only rat and in vitro data available – no published human data
Kempf AAC (2007) 18:163-167
Known and an_cipated DDIs between an_retrovirals and an_-‐HCV drugs in current use and the HCV protease inhibitors in Phase III development
Drug-Drug-Interactions (DDIs)
Adapted from Seden K, et al. J An_microb Chemother 2010; 65:1079-‐85; Ashby J, et al. HIV 10; Glasgow; November 7-‐11, 2010; Abst. O315.
Hepa;;s C Therapies
Current Agents Protease Inhibitors (Phase III trials)
PEG-‐IFN Ribavirin Telaprevir Boceprevir
PIs
NNRTIs
NRTIs
Entry Inhibitors
Integrase Inhibitors
No clinically significant interac5on, or interac5on unlikely based on knowledge of drug metabolism
Poten5al interac5on that may require close dose monitoring, altera5on of dosage or 5ming of administra5on
Interac5on likely, do not use or use with cau5on
1
4 4 2
5 5
1 = atazanavir/ritonavir
2 = didanosine, zidovudine
3 3 = emtricitabine, lamivudine, tenofovir 4 = zidovudine
5 = maraviroc
6 6 = raltegravir
Nouvelles molécules anti-VHC: Résumé
• Essais encore en cours
• Interactions probables avec TTT anti-VIH mais peu dans les nouvelles classes de médicaments
Coinfection VIH-VHC: Résumé
• Fréquent • Foie: cause importante de mortalité • Pronostic modifié par HAART • Traitement anti-VHC +++
• Pronostic qui sera révolutionné par les nouvelles molécules anti-VHC
Hépatite Chronique B Chez les Patients
Co-infectés par le VIH
En France
P(HBsAg) = 0.68%
Enquête Assurance Maladie / InVS, 2005
Patients VIH+
P(HBsAg) = 7% Avec ADN-VHB + = 48.5%
(Enquête un jour donné 2004, BEH June 2005)
L’infection VIH modifie l’histoire naturelle de l’infection virale B
1. Diminution de la clairance virale spontanée = plus de risque de passage à la chronicité (25 %) Gatanaga et al. EJCMID 2000
2. Augmente les niveaux de Charge Virale 3. Accélère la fibrogenèse et le temps d’évolution
vers la cirrhose
Hyung j Hepatol 2006
Chronic Hepatitis B Influence of HBV DNA
REVEAL Study: cumula_ve incidence cirrhosis
Iloeje,U.H. et al. Gastroenterology 2006
4,5% 5,9%
9,8%
23,5%
36,2%
105-106 cop/ml
>106 cop/ml
<104 cop/ml
104-105 cop/ml
Perte charge virale = objectif principal du traitement
VHB monoinfecté
1. Charge virale > 2 000 UI/mL (10 000 cp/mL) Ou ALAT > Normale
ET 2- Score METAVIR ≥ A2 ou ≥ F2
Indications de TTT anti-VHB chez le VIH + larges si nécessité de TTT anti-VIH
Une bonne molécule pour le traitement de la co-‐infec;on VI/VHB
1. Une molécule DUALE: efficace sur les deux virus
2. PUISSANTE EFFICACITE ANTIVIRALE 3. HAUTE BARRIERE GENETIQUE:
traitement qui est peu sensible aux variations
génétiques de sa cible
Molécules anti-VHB
IFN 1983
Tenofovir (antiVIH)
2002
Peg IFN 2005
Adefovir 2003
Lamivudine 1999
Entecavir 2006
Telbivudine 2007
Molécules anti-VHB
IFN 1983
Tenofovir (antiVIH)
2002
Peg IFN 2005
Adefovir 2003
Lamivudine 1999
Entecavir 2006
Telbivudine 2007
Ténofovir AMM 2008
Antiviral activity of different Nucleos(t)id-Analogues HBV-DNA < LOD Week 48 / 52
0
10
20
30
40
50
60
70
80
90
100
HBe-Ag pos. HBe-Ag neg.
76
94
67
90
60
88
36
72
25
63
21
51
Tenofovir
Entecavir
Telbivudine
Lamivudine
Pegylated IFN
Adefovir
Lai et al. Hepatology 2005; Lau et al. NEJM 2005,
Chang et al. NEJM 2006, Marcellin et al. NEJM 2003, Marcellin et al. AASLD 2007,
Heathcote et al. AASLD 2007, Kim et al. 2008, Lau AASLD 2008,Chung EASL 2006
Resistance rates in nuc-naive Hepatitis B-patients
No data from direct comparison
Modifiied from: 1. Tenney et al. EASL 2009; Oral 20. J. Hepatol 2009;50(suppl 1), S10.. 2. Chang et al. J Gastroenterol Hepatol 2004;19(11): 1276-‐1282. 3. Hadziyannis et al. Gastroenterology 2006;131(6): 1743-‐1751. 4. Standring et al. J Hepatology 2006; 44(suppl 2): S191. 5. Adapted from: Lai et al. Hepatology 2006; 44(4 suppl 1): 222A. 6. Snow-‐Lampart et al. Hepa55s B and C virus resistance to an5viral therapies 2008;. Poster 5.
Cumula;ve probability (%)
0
100
80
60
40
20
663 1
278 2
149 3
120 4
108 5 (years)
N=
Genotypic ETV-‐Resistance1 HBeAg(+) and (-‐) pa;ents
Cumula;ve probability (%)
0
100
80
60
40
20
183 1
134 2
NA 3
NA 4
60 5 (years)
N=
Genotypic ADV-‐Resistance3 HBeAg(-‐) pa;ents
0,2% 0,5% 1,2% 1,2% 1,2%
Incidence (%)
0
100
80
60
40
20
58 1
58 2
58 3
58 4
5 (years)
N=
Genotypic LVD-‐Resistance2 HBeAg(+) Pa;enten
17%
40% 57%
67%
ND
0 3% 11% 18%
29%
Cumula;ve Incidence (%)
0
100
80
60
40
20
458 222 1
458 222 2
3
4
5 (years)
N=
Virol. breakthrough with genotypic LdT-‐Resistance4,5
4% 3% 22%
9% ND ND ND
HBeAg(+) HBeAg(-‐)
TDF: Un;l week 72 no occurrence of genotypic resistance6
99 6
1,2%
Resistance rates in nuc-naive Hepatitis B-patients
No data from direct comparison
Modifiied from: 1. Tenney et al. EASL 2009; Oral 20. J. Hepatol 2009;50(suppl 1), S10.. 2. Chang et al. J Gastroenterol Hepatol 2004;19(11): 1276-‐1282. 3. Hadziyannis et al. Gastroenterology 2006;131(6): 1743-‐1751. 4. Standring et al. J Hepatology 2006; 44(suppl 2): S191. 5. Adapted from: Lai et al. Hepatology 2006; 44(4 suppl 1): 222A. 6. Snow-‐Lampart et al. Hepa55s B and C virus resistance to an5viral therapies 2008;. Poster 5.
Cumula;ve probability (%)
0
100
80
60
40
20
663 1
278 2
149 3
120 4
108 5 (years)
N=
Genotypic ETV-‐Resistance1 HBeAg(+) and (-‐) pa;ents
Cumula;ve probability (%)
0
100
80
60
40
20
183 1
134 2
NA 3
NA 4
60 5 (years)
N=
Genotypic ADV-‐Resistance3 HBeAg(-‐) pa;ents
0,2% 0,5% 1,2% 1,2% 1,2%
Incidence (%)
0
100
80
60
40
20
58 1
58 2
58 3
58 4
5 (years)
N=
Genotypic LVD-‐Resistance2 HBeAg(+) Pa;enten
17%
40% 57%
67%
ND
0 3% 11% 18%
29%
Cumula;ve Incidence (%)
0
100
80
60
40
20
458 222 1
458 222 2
3
4
5 (years)
N=
Virol. breakthrough with genotypic LdT-‐Resistance4,5
4% 3% 22%
9% ND ND ND
HBeAg(+) HBeAg(-‐)
TDF: Un;l week 72 no occurrence of genotypic resistance6
99 6
1,2%
*
*
Entecavir chez le coinfecté VIH-VHC
1. Sélection de mutations M184V
sur la Reverse transcriptase du VIH … Ne pas utiliser SANS HAART +++
2. Tubulopathie +++ 3. 80% malades déjà exposés au
3TC ... (double dose, résistances ...)
McMahon M, et al. 14th CROI, Los Angeles 2007; #136LB
Patient 1: 31 yo male CD4+ 596 cells/mm³
Months after initiation of ETV -36 -30 -24 -18 -12 -6 0 6 12
102
1010
108
106
104
ETV
Pla
sma
HB
V D
NA
(IU/m
L)
102
101
105
104
103
Plasm
a HIV
RN
A (c/mL)
Entecavir chez le coinfecté VIH-VHC
1. Sélection de mutations M184V
sur la Reverse transcriptase du VIH … Ne pas utiliser SANS HAART +++
2. Tubulopathie +++ 3. 80% malades déjà exposés au
3TC ... (double dose, résistances ...)
McMahon M, et al. 14th CROI, Los Angeles 2007; #136LB
Patient 1: 31 yo male CD4+ 596 cells/mm³
Months after initiation of ETV -36 -30 -24 -18 -12 -6 0 6 12
102
1010
108
106
104
ETV
Pla
sma
HB
V D
NA
(IU/m
L)
102
101
105
104
103
Plasm
a HIV
RN
A (c/mL)
Traitement de choix = Ténofovir
Reste-t-il une place pour l’IFN peg ?
- Résultats décevants Di Martino V Gastroenterology 2002
- Traitements combinés INF + analogues: décevants
- Etude en cours: EMVIPEG (ANRS)
HBsAg-‐kine;cs and HBV DNA levels for the predic;on of response to PegIFN alfa-‐2a treatment in HBeAg-‐nega;ve pa;ents
• 48 weeks of treatment and 24 weeks of observa_on
Rijckborst V, et al. EASL 2010. Abstract 8.
*SR = HBV DNA < 10,000 c/mL (~ 2000 IU/mL) and normal ALT at Wk 72.
HBsAg-‐decline at week 12?
Degree of HBV DNA decline at week 12
Percentage with SR* 0% 24% 25% 39%
< 2 log (n = 20)
≥ 2 log (n = 34)
< 2 log (n = 20)
≥ 2 log (n = 28)
No (n = 54)
Yes (n = 48)
N = 102
Coinfection VIH-VHB: Résumé
• Fréquent • Bon pronostic • Indications larges de traitement (TTT anti-VIH + VHB) • Ténofovir = TTT de choix • Place Peg IFN ?
Conclusions
• Viral hepa__s coinfec_ons are major factors of mortality and morbidity in the HIV infected popula_on
• It is crucial to determine those pa_ents who are in need for treatment
• Viral and host factors can predict the chance of cure
• DAAs for HCV will soon be available but lack data on HIV coinfec_on
• Tenofovir is the actual agent of choice in HBV coinfec_on