Transcript Document

A summary of state of the art in non-invasive diagnosis
of liver disease, liver transplantation, and treatments on
the horizon for hepatitis virus coinfected patients
XVII International AIDS Conference,
Session Room 11, HIV and Hepatitis Virus
Co-infection, Mexico City, Thursday,
August 7th, 2008
Jürgen Rockstroh
Department of Medicine I
University of Bonn, Germany
Hot topics in co-infection
 Non-invasive diagnosis of liver
disease
 Liver transplantation in co-infection
• Inclusion/exclusion criteria
• Outcome
 Treatments on the horizon for
hepatitis virus coinfected patients
Limitations of liver biopsy
 Acceptability
 Cost
• Euro 1000 per biopsy
 Morbidity
• Significant haemorrhage up
to 0.7%
• Mortality up to 0.03%
 Reliability
• Length of biopsy
• Inter- and intra-observer
variability
• Assumes uniform disease
process
Blood tests
•
Matrix related:
PIIINP, collagen type IV, laminin
Hyaluronic acid, MMP, TIMP
•
Non matrix related:
AST, ALT, gamma GT
Bilirubin, prothrombin, platelets
Gammaglobulins, ferritin
Alpha 2 macroglobulin, haptoglobin
Apo A1, cholesterol, HOMA
Fibrotest in practice in
HIV/HCV co-infected patients
 PPV 86% for F4
 NPV 93% for <F1
 Avoid liver biopsy in
55% with an
accuracy of 89%
Fibrotest: alpha2-macroglobulin,
haptoglobin, apolipoprotein A1,
GGT, bilirubin (age and gender
adjusted)
Myers, R.P. et al., AIDS 2003;17:721-725
APRI:AST/platlets
Transient elastography
(Fibroscan®, Echosens, Paris)
Thresholds >7.9 kPa for ≥F2,
10.3kPa for ≥F3, 11.9 kPa for F4
Panos G et al., WAC 2008; THAB0203
Elastography in HIV/HCV
co-infected patients
De Lédinghen, V. et al., Journal of Acquired Immune Deficiency Syndrome 2006;41(2):175-179
Elastography in clinical practice:
What are the limitations?






Results investigator dependant
BMI > 28 kg/m2
Inter- and intra-observer differences highest
for F0 fibrosis
Ascites
Effect of hepatic steatosis
Effect of hepatic inflammation
Fraquelli, M. et al.,Gut 2007; 56:968-973
Management of HCV infected patients
Hepatitis C Ab +ve
Hepatitis C PCR to confirm active infection
+ perform HCV genotype
Tests of liver
function/status
(Bilirubin / ALT / AST / ALK
Phos / Albumin / PT)
Liver ultrasound
(to be performed
every 6 months)
Exclude other associated
liver disease
(Autoimmune, metabolic,
HBV, HDV)
Stage Liver Fibrosis
Perform non-invasive
marker testing
(serological
markers/fibroscan)
Concordance
Liver Biopsy
Discordance
Expert decision on need to treat
Adapted from the Body and the
Liver Program 2008
Hot topics in co-infection
 Non-invasive diagnosis of liver
disease
 Liver transplantation in co-infection
• Inclusion/exclusion criteria
• Outcome
 Treatments on the horizon for
hepatitis virus coinfected patients
Hepatitis – Liver transplantation
Indications over time in Europe 1988-2000
100%
80%
60%
40%
20%
0%
68-8081 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 2000
Alcoholic cirrhosis: 5819
Primary biliary cirrhosis: 2931
Virus associated cirrhosis: 8025
Survival probability
HIV coinfection Shortens the Survival of Patients with HCVrelated Decompensated Cirrhosis
1.0
.8
Survival among HCV-infected
individuals with and without
HIV coinfection
p=<0.001
HIV-negative
.6
.4
HIV-positive
.2
0.0
0
10
20
30
40
50
60
70
HCV/HIV 54%
Months
No. at risk
HIV-negative 1037
HIV-positive 180
619 429
75
46
313 208
30 19
HCV
125year years years
74% 61% 44%
133
11
62
5
40%
25%
9
3
Pineda JA et al. Hepatology. 2005, 41:779-89
Liver transplantation and HIV-Infection
 In the pre-HAART era :
1
• No difference in immediate postoperative survival between
HIV+ and HIV- patients
• Long-term high mortality rate due to infections and AIDSrelated complications
• Rapid progression of HIV to AIDS
 In the HAART era²:
• No difference in postoperative survival between HIV+ and
HIV- patients
• Survival worse for low CD4-counts (<100/µl), post OLTX
antiretroviral intolerance, VL > 400 copies/ml and HCV
infection
1) Tzakis AG et al., Transplantation 1990;49:354-358
2) Ragni MV et al, J Infect Dis 2003;188:1412-1420
Are you willing to perform organ transplantations
in HIV+ patients ?
case to case
20%
no comment
2%
no
39%
yes
39%
Query in 87 centers in Germany in 2002
Frühauf et al. Chirurg 2004; 7: 681 - 686
HIV Criteria for OLT: European and U.S.A.
Recommendations
C events
- OIs
- Neoplasms
Spain1
Italy2
Some*
No
No <1 yr.
No
CD4 count
>100
VL BDL**
Yes
U.K.3 Germany4 U.S.A.5
No after
IR-cART
>100+/>200 >100+/>200
Yes
Yes
Some*
No
Some*
No
>100
>100
Yes
Yes
* Spain: TB, PCP or candidasis; USA: candidiasis or PCP but currently only PML, cryptosporidiosis and vKS are
exclusion criteria; Germany: PML, HIV-Leukencephalopathy** If VL was detectable, post-OLT suppression predicted in
all cases. +DC=Decompensated cirrhosis; PHT: portal hypertension.
1Miró,
EIMC, 2005; 2Centro Nazionale Trapianti, 2004; 3Brook, HIV Med. 2005/2006; 4German consensus guidelines in press,
5CCTAT, Am J Transplant, 2004.
Clinical data of liver transplanted HIV+ patients in
the Bonn cohort
Age
[Years]
43
34
52
57
58
31
31
56
36
Transmission
Risc
Haemophilia
MSM
MSM
MSM
Haemophilia
Haemophilia
Haemophilia
MSM
Haemophilia
CDC
CD4
A2
A1
A3
A3
A3
A3
C3
B3
B2
[/µl]
210
*50%
223
162
168
239
320
517
250
MELD
CD4
HIV-RNA
Follow-Up
15
HU
HU
25
n.A.
16
15
18
17
[/µl]
497
429
386
84
143
297
129
448
480
[cop/ml]
< 50
52801
< 50
n.d.
< 50
< 50
246
< 50
< 50
[months]
living – 77
living - 127
living – 70
dead - 3
living - 73
living - 53
living - 45
living – 26
living - 33
On the OLTX list
1) Vogel M et al., Liver Transpl 2005;11:1515-1521
2) Woijcek K et al., AIDS 2007;21:1363-1365
Last follow up
Mean follow-up 56mths
Impact of HIV on survival after liver
transplantation in the HAART era
Figure 1: Comparision of survival between HIV+
(n=138) and HIV- (n=30520) after LT
Figure 2: Comparision of survival between
HIV/HCV and HIV-/HCV vs HIV-/HCV- after LT
Mindikoglu A et al., Transplantation 2008;85:359-368
Would you stop HAART to avoid liver
toxicity? = No
Bruno et al. J Acquir Immune Defic Syndr. 2007
Hot topics in co-infection
 Non-invasive diagnosis of liver
disease
 Liver transplantation in co-infection
• Inclusion/exclusion criteria
• Outcome
 Treatments on the horizon for
hepatitis virus coinfected patients
Treatment Options for Chronic
Hepatitis B
Approved for HBV
(FDA/EMEA)
•Interferon alfa-2b
•Peginterferon alfa-2a
•Lamivudine
•Adefovir
•Entecavir
•Telbivudine
•Tenofovir DF
Unlabelled
Phase III
•Emtricitabine
Investigational
Phase III
•Clevudine
Phase II
•Pradefovir
•Valtorcitabine
•Amdoxovir
•ANA 380
•Racivir
TDF for the Treatment of HBeAg-Negative and HBeAgPositive Chronic Hepatitis B: Week 72 TDF Data and Week
24 Adefovir Dipivoxil Switch Data (Studies 102 and 103)
RANDOMIZATION 2:1
5 Years
Double Blind
Open-label
Tenofovir 300 mg
Tenofovir 300 mg
Study 102 N=250
Study 103 N=176
Adefovir 10 mg
Tenofovir 300 mg
Study 102 N=125
Study 103 N=90
Pre-treatment
Liver Biopsy
Marcellin P, et al., EASL 2008; Oral # 1602.
Heathcote J, et al., EASL 2008; Oral # 1593.
Week 48
Liver Biopsy
Week 72
Week 240
Liver Biopsy
% Patients with HBV DNA < 69 IU/ml (400 c/mL)
Persistent virologic response*
HBe Ag positive (study 103)
HBe Ag negative (Study 102)
100
100
Open Label TDF
Randomized Double Blind
90
79%
70
76%
60
50
40
(P=0.617)
30
70
50
40
30
20
10
10
0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
P=0.315
60
20
0
88%
80
Percentage (%)
Percentage (%)
80
Open Label TDF
0
4
8
12
16
20
24
88
170
90
171
Heathcote J, et al. EASL 2008; Oral #1593
28
32
36
40
44
48
52
56
60
64
68
72
Weeks on Study
Weeks on Study
ADV N= 90
TDF N= 176
91%
Randomized Double Blind
90
87
164
ADV N= 125
TDF N= 250
124
243
123
246
Marcellin P, et al. EASL 2008; Oral #1602
* PVR ITT Anaylsis: Patients who discontinued for administrative reasons with
HBV DNA <400c/ml were excluded for visits after discontinuation
124
243
76
New Oral Small Molecule Antivirals in Development
for the Treatment of HCV
Drug name
Drug class
Preclinical Phase I Phase II Phase III
MK-0608 (Merck)
Nucleoside polymerase inhibitor
R7128 (Pharmasset & Roche)
Nucleoside polymerase inhibitor
NIM811 (Novartis)
Cyclophilin inhibitor
ITMN-191 (InterMune & Roche)
Protease inhibitor
X
X
X
MK-7009 (Merck)
Protease inhibitor
X
BI12202 (Boehringer)
Protease inhibitor
X
BI 1220 (Boehringer)
Nucleosite polymerase inhibitor
X
X
X
R1626 (Roche)
Nucleoside polymerase inhibitor
X
DEBIO-025 (Debiopharm)
Cyclophilin inhibitor
X
Telaprevir (Vertex Pharmaceuticals)
Protease inhibitor
X
Boceprevir (Schering-Plough)
Protease inhibitor
X
TMC435350 (Tibotec & Medivir)
Protease inhibitor
Adapted from Manns MP et al. Nat Rev Drug Discovery. 2007;6:991-1000.
X
PROVE1: Telaprevir + PegIFN/RBV in TreatmentNaive HCV GT 1 Patients
(n=75)
Placebo +
Peg-IFN + RBV
Peg-IFN + RBV
(n=17)
TVR +
Peg-IFN + RBV
Follow-up
(n=79)
TVR +
Peg-IFN + RBV
Peg-IFN + RBV
(n=79)
TVR + Peg-IFN
+ RBV
Control group
Weeks
0
12
Follow-up
Follow-up
Peg-IFN + RBV
24
36
Follow-up
48
60
72
Dosing: Peg-IFN = Peg-IFN alfa-2a 180 µg/week, RBV = RBV 1,000 or 1,200 mg/day,
TVR = TVR 750 mg q8h
McHutchinson J et al., EASL 2008; Oral #4
PROVE 1: Treatment Response Rates (ITT);
undetectable HCV-RNA < 10 IU/ml
Week 4
Undetectable
(RVR)
Week 12
Undetectable
SVR
Relapse
PegIFN/RBV/placebo 48
wks
(n = 75)
11
45
41
23 (8/35)
TVR/PegIFN/RBV 12 wks¶
(n = 17)
59
71
35
6 (3/51)
TVR/PegIFN/RBV 12 wks 
PegIFN/RBV 12 wks¶
(n = 79)
81
68
61*
2 (1/41)
TVR/PegIFN/RBV 12 wks 
pegIFN/RBV 36 wks
(n = 79)
81
80
67**
33 (3/9)
Treatment, %
*P
= .02 vs pegIFN/RBV/placebo 48 weeks, **P = .001 vs pegIFN/RBV/placebo 48 weeks.
¶Only
subjects who met the RVR criterion and stopped at 12 or 24 total weeks of treatment.
McHutchinson J et al., EASL 2008; Oral #4
Safety and tolerability in PROVE-1
 The most common adverse events
reported more frequently than placebo
were gastrointestinal events, skin events
(rash, pruritus) and anemia
 Other adverse events reported were similar in
type and frequency to those seen with PegIFN/RBV treatment
 Treatment discontinuation through Week 12
due to adverse events were 18% in the TVRbased treatment arms and 4% in the control
arm
Summary
 Non invasive markers for assessing liver disease in
coinfection can be used; in unclear cases or discordant
results liver biopsy remains the gold standard
 HCV/HIV coinfected patients show a faster progression to
cirrhosis and increased liver-related mortality
 OLTX is a treatment option in advanced liver disease and
needs to be considered
 New drugs for HCV therapy are emerging promising
shorter PegIFN/RBV treatment durations but challenges
remain
• Drug-drug interactions
• Resistance development
• tolerability