The document discusses the prevalence of hepatitis C and B viruses globally as well as their coinfection rates with HIV. It examines how HIV coinfection may accelerate liver fibrosis progression for hepatitis C and the importance of antiretroviral therapy in reducing liver-related mortality. New direct-acting antiviral drugs against hepatitis C virus are promising but treatment for HIV/hepatitis coinfection remains challenging due to drug interactions and side effects.
HIV, Hepatitis B and C Global Prevalence and Liver Disease Risk
1. Hépatites Virales C et B
et Infection par le VIH
Yves Benhamou
Dominique Thabut
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 HCV
– 2% HBV LR
Non Liver
– 1% HBV-HCV Related (LR) HBV 10%
86% other 14%
– 1% other causes 1%
2%
1%
The D:A:D study Arch Intern Med 2006;166:1632-1641
5. 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
6. 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
7. 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
10. Impact of ART liver-associated mortality in HIV/HCV-
coinfected patients
Overall mortality Liver-associated mortality
Cumulative survival Cumulative survival
1,1 1,1
*p < 0,0001 *p < 0,018
Patients on HAART*
0,9 Patients on HAART*
0,9
Patients on ART
Untreated patients
0,7 0,7
0,5 0,5
Patients on ART
untreated patients
0,3 0,3
1.000 2.000 3.000 4.000 5.000 6.000 0 1.000 2.000 3.000 4.000 5.000 6.000
Surveillance period (days) Surveillance period (days)
Bonn cohort (1990–2002) Predictors of liver-associated mortality
285 HIV/HCV-coinfected
No HAART
patients
low CD4-count
age
Qurishi
et
al.
Lancet
2003:
362(9379):
1708–1713.
11. 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
12. 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
14. 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
15. 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
16. Treatment for HCV in 2010
Peg-‐Interferon
alfa-‐2a
Ribavirin
tablets
180µg/week
800-‐1200mg/d
Peg-‐Interferon
alfa-‐2b
Ribavirin
capsule
1,5µg/kg/week
800-‐1200mg/d
17. Timing for Anti-HCV and ARV Initiation
HIV mono-infected HIV/HCV Traiter + tôt ?
< 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
18. Etudes Bithérapie chez les Co-Infectés
High doses Ribavirin +++ (15 mg/Kg)
80
70
60
50
Tous
40
G1
30
G2
-‐
G3
20
10
0
Ribavic
ACTG
Apricot
Laguno
PRESCO
NEJM 2004; Nunez M et al. Hepatology 2006
19. European guidelines for the treatment of HIV-
HCV coinfection
Traiter + longtemps
EACS guidelines, version 5-2
20. Side effects of treatment
Pitfalls in HIV/HCV coinfection
Anemia / Leukopenia / Thrombopenia
Fatigue
Severity
Flu-like syndrome
Psychiatric side effects(Depression)
0 1 2 3 4 5 6 7 8 9 10 11 12 weeks
Interferon/ribavirin therapy
• AZT (anemia)
• ddI (mitochondrial toxicity)
• d4T (mitochondrial toxicity)
• ABC (ribavirin pharmacokinetics): plus faible SVR ? (dose Riba
adaptée au Poids)
28. Antiviral therapy of AHC
Week 4 Week 12
HCV-RNA
24 weeks
negative*
peg-IFN +
RBV (AII)
HCV-RNA Drop HCV-RNA
48 weeks
positive* ≥ 2 log10
< 2 log10
Stop Therapy
*evidence based on using a 615 IU/ml cutoff to define negative HCV-RNA
Courtesy: Martin Vogel, Germany
29. 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 +++
30. 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
31. Trials with HCV protease inhibitors HIV/HCV
coinfected patients
1 Safety and Efficacy of Telaprevir in Combination With Peginterferon Alfa-2a
Recruiting 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
32. 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
33. Drug-Drug-Interactions (DDIs)
Known
and
an_cipated
DDIs
between
an_retrovirals
and
an_-‐HCV
drugs
in
current
use
and
the
HCV
protease
inhibitors
in
Phase
III
development
No
clinically
significant
interac5on,
or
interac5on
unlikely
based
Hepa;;s
C
Therapies
on
knowledge
of
drug
metabolism
Protease
Inhibitors
Poten5al
interac5on
that
may
require
close
dose
monitoring,
Current
Agents
(Phase
III
trials)
altera5on
of
dosage
or
5ming
of
administra5on
PEG-‐IFN
Ribavirin
Telaprevir
Boceprevir
Interac5on
likely,
do
not
use
or
use
with
cau5on
PIs
1
1 =
atazanavir/ritonavir
NNRTIs
2 =
didanosine,
zidovudine
NRTIs
2
3
4
4
3 =
emtricitabine,
lamivudine,
tenofovir
4 =
zidovudine
Entry
5
5
5 =
maraviroc
Inhibitors
Integrase
6
6 =
raltegravir
Inhibitors
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.
34. Nouvelles molécules anti-VHC: Résumé
• Essais encore en cours
• Interactions probables avec TTT anti-VIH mais peu dans
les nouvelles classes de médicaments
35. 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
37. En France
P(HBsAg) = 0.68% Patients VIH+
P(HBsAg) = 7%
Avec ADN-VHB + = 48.5%
(Enquête un jour donné 2004, BEH June 2005)
Enquête Assurance Maladie / InVS, 2005
38. 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
39. Chronic Hepatitis B
Influence of HBV DNA
REVEAL
Study:
cumula_ve
incidence
cirrhosis
36,2%
Perte charge virale = objectif
principal du traitement
>106 cop/ml
23,5%
105-106 cop/ml
104-105 cop/ml 9,8%
5,9%
<104 cop/ml 4,5%
Iloeje,U.H. et al. Gastroenterology 2006
40. 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
41. 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
44. Antiviral activity of different Nucleos(t)id-Analogues
HBV-DNA < LOD Week 48 / 52
100 94
90 88
90
80 76
72 Tenofovir
70 67
63
60 Entecavir
60
51
50 Telbivudine
40 36
Lamivudine
30 25
21 Pegylated IFN
20
10
Adefovir
0
Lai et al. Hepatology 2005;
HBe-Ag pos. HBe-Ag neg. 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
45. Resistance rates in nuc-naive Hepatitis B-patients
Cumula;ve
probability
(%)
Incidence
(%)
100
Genotypic
LVD-‐Resistance2
100
Genotypic
ETV-‐Resistance1
HBeAg(+)
Pa;enten
80
HBeAg(+)
and
(-‐)
pa;ents
80
67%
60
57%
60
40%
40
40
20
20
17%
0,2%
0,5%
1,2%
1,2%
1,2%
1,2%
ND
0
0
N=
663
278
149
120
108
99
N=
58
58
58
58
1
2
3
4
5
6
(years)
1
2
3
4
5
(years)
Cumula;ve
probability
(%)
Cumula;ve
Incidence
(%)
100
100
Genotypic
ADV-‐Resistance3
Virol.
breakthrough
with
genotypic
80
80
LdT-‐Resistance4,5
HBeAg(-‐)
pa;ents
60
60
HBeAg(+)
HBeAg(-‐)
40
40
29%
22%
20
18%
20
11%
4%
3%
9%
3%
ND
ND
ND
0
0
0
N=
183
134
NA
NA
60
N=
458
222
458
222
1
2
3
4
5
(years)
1
2
3
4
5
(years)
TDF:
Un;l
week
72
no
occurrence
of
genotypic
resistance6
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.
46. Resistance rates in nuc-naive Hepatitis B-patients
Cumula;ve
probability
(%)
Incidence
(%)
100
Genotypic
LVD-‐Resistance2
100
HBeAg(+)
Pa;enten
*
Genotypic
ETV-‐Resistance1
80
HBeAg(+)
and
(-‐)
pa;ents
80
67%
60
57%
60
40%
40
40
20
20
17%
0,2%
0,5%
1,2%
1,2%
1,2%
1,2%
ND
0
0
N=
663
278
149
120
108
99
N=
58
58
58
58
1
2
3
4
5
6
(years)
1
2
3
4
5
(years)
Cumula;ve
probability
(%)
Cumula;ve
Incidence
(%)
100
100
Genotypic
ADV-‐Resistance3
Virol.
breakthrough
with
genotypic
80
80
LdT-‐Resistance4,5
HBeAg(-‐)
pa;ents
60
60
HBeAg(+)
HBeAg(-‐)
40
40
29%
22%
20
18%
20
11%
4%
3%
9%
3%
ND
ND
ND
0
0
0
N=
183
134
NA
NA
60
N=
458
222
458
222
1
2
3
4
5
(years)
1
2
3
4
5
(years)
* TDF:
Un;l
week
72
no
occurrence
of
genotypic
resistance6
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.
47. Entecavir chez le coinfecté VIH-VHC
Patient 1: 31 yo male
1. Sélection de mutations M184V CD4+ 596 cells/mm³ 105
Plasma HIV RNA (c/mL)
sur la Reverse transcriptase du 1010 ETV
Plasma HBV DNA (IU/mL)
VIH … Ne pas utiliser SANS
HAART +++ 108
104
2. Tubulopathie +++ 106 103
3. 80% malades déjà exposés au 104
3TC ... (double dose, 102
résistances ...) 102
101
-36 -30 -24 -18 -12 -6 0 6 12
Months after initiation of ETV
McMahon M, et al. 14th CROI, Los Angeles 2007; #136LB
48. Entecavir chez le coinfecté VIH-VHC
Patient 1: 31 yo male
1. Sélection de mutations M184V CD4+ 596 cells/mm³ 105
Plasma HIV RNA (c/mL)
sur la Reverse transcriptase du 1010 ETV
Plasma HBV DNA (IU/mL)
VIH … Ne pas utiliser SANS
HAART +++ 108
104
2. Tubulopathie +++ 106 103
3. 80% malades déjà exposés au 104
3TC ... (double dose, 102
résistances ...) 102
101
-36 -30 -24 -18 -12 -6 0 6 12
Traitement de choix = Ténofovir Months after initiation of ETV
McMahon M, et al. 14th CROI, Los Angeles 2007; #136LB
49. 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)
50. 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
N
=
102
No
Yes
HBsAg-‐decline
at
week
12?
(n
=
54)
(n
=
48)
<
2
log
≥
2
log
<
2
log
≥
2
log
Degree
of
HBV
DNA
decline
at
week
12
(n
=
20)
(n
=
34)
(n
=
20)
(n
=
28)
Percentage
with
SR*
0%
24%
25%
39%
*SR
=
HBV
DNA
<
10,000
c/mL
(~
2000
IU/mL)
and
normal
ALT
at
Wk
72.
Rijckborst V, et al. EASL 2010. Abstract 8.
51.
52. Coinfection VIH-VHB: Résumé
• Fréquent
• Bon pronostic
• Indications larges de traitement (TTT anti-VIH + VHB)
• Ténofovir = TTT de choix
• Place Peg IFN ?
53. 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