Jrgen Rockstroh

1
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

2
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

3
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

4
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

5
Fibrotest in practice in HIV/HCV co-infected
patients

• PPV 86 for F4
• NPV 93 for ltF1
• Avoid liver biopsy in 55 with an accuracy of 89

Fibrotest alpha2-macroglobulin, haptoglobin,
apolipoprotein A1, GGT, bilirubin (age and gender
adjusted) APRIAST/platlets
Myers, R.P. et al., AIDS
200317721-725
6
Transient elastography (Fibroscan, Echosens,
Paris)

• Thresholds gt7.9 kPa for F2, 10.3kPa for F3,
  11.9 kPa for F4

Panos G et al., WAC 2008 THAB0203
7
Elastography in HIV/HCV co-infected patients
De Lédinghen, V. et al., Journal of Acquired
Immune Deficiency Syndrome 200641(2)175-179

8
Elastography in clinical practiceWhat are the
limitations?

• Results investigator dependant
• BMI gt 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 56968-973
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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)
Liver Biopsy
Discordance
Concordance
Adapted from the Body and the Liver Program 2008
Expert decision on need to treat
10
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

11
Hepatitis Liver transplantation
Indications over time in Europe 1988-2000
12
HIV coinfection Shortens the Survival of Patients
with HCV-related Decompensated Cirrhosis
Survival among HCV-infected individuals with and
without HIV coinfection
plt0.001
Pineda JA et al. Hepatology. 2005, 41779-89
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Liver transplantation and HIV-Infection

• In the pre-HAART era1
• No difference in immediate postoperative survival
  between HIV and HIV- patients
• Long-term high mortality rate due to infections
  and AIDS-related 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 (lt100/µl), post
  OLTX antiretroviral intolerance, VL gt 400
  copies/ml and HCV infection

1) Tzakis AG et al., Transplantation
199049354-358 2) Ragni MV et al, J Infect Dis
20031881412-1420
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Are you willing to perform organ transplantations
in HIV patients ?
Query in 87 centers in Germany in 2002
Frühauf et al. Chirurg 2004 7 681 - 686
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HIV Criteria for OLT European and U.S.A.
Recommendations
Spain1
Italy2
U.K.3
Germany4
U.S.A.5
Some No gt100 Yes
No lt1 yr. No gt100/gt200 Yes
No after IR-cART gt100/gt200 Yes
Some No gt100 Yes
Some No gt100 Yes

• C events
• OIs
• Neoplasms
• CD4 count
• VL BDL

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.
DCDecompensated 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.
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Clinical data of liver transplanted HIV patients
in the Bonn cohort
Last follow up
On the OLTX list
Mean follow-up 56mths
1) Vogel M et al., Liver Transpl
2005111515-1521 2) Woijcek K et al., AIDS
2007211363-1365
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Impact of HIV on survival after liver
transplantation in the HAART era
Figure 1 Comparision of survival between HIV
(n138) and HIV- (n30520) after LT
Figure 2 Comparision of survival between HIV/HCV
and HIV-/HCV vs HIV-/HCV- after LT
Mindikoglu A et al., Transplantation
200885359-368
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Would you stop HAART to avoid liver toxicity? No
Bruno et al. J Acquir Immune Defic Syndr. 2007
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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

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Treatment Options for Chronic Hepatitis B
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TDF for the Treatment of HBeAg-Negative and
HBeAg-Positive Chronic Hepatitis B Week 72 TDF
Data and Week 24 Adefovir Dipivoxil Switch Data
(Studies 102 and 103)
5 Years
Open-label
Double Blind
Tenofovir 300 mg
Tenofovir 300 mg
Study 102 N250Study 103 N176
RANDOMIZATION 21

Adefovir 10 mg
Tenofovir 300 mg
Study 102 N125Study 103 N90

Week 240 Liver Biopsy
Week 72
Week 48 Liver Biopsy
Pre-treatment Liver Biopsy
Marcellin P, et al., EASL 2008 Oral
1602.Heathcote J, et al., EASL 2008 Oral
1593.
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Patients with HBV DNA lt 69 IU/ml (400
c/mL)Persistent virologic response
HBe Ag positive (study 103)
HBe Ag negative (Study 102)
91
Randomized Double Blind
Randomized Double Blind
Open Label TDF
79
88
P0.315
76
(P0.617)
Open Label TDF
Heathcote J, et al. EASL 2008 Oral 1593
Marcellin P, et al. EASL 2008 Oral 1602
PVR ITT Anaylsis Patients who discontinued for
administrative reasons with HBV DNA lt400c/ml were
excluded for visits after discontinuation
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New Oral Small Molecule Antivirals in Development
for the Treatment of HCV
Drug name Drug class Preclinical Phase I Phase
II Phase III
X
MK-0608 (Merck)
Nucleoside polymerase inhibitor
X
R7128 (Pharmasset Roche)
Nucleoside polymerase inhibitor
X
NIM811 (Novartis)
Cyclophilin inhibitor
X
ITMN-191 (InterMune Roche)
Protease inhibitor
X
MK-7009 (Merck)
Protease inhibitor
X
BI12202 (Boehringer)
Protease inhibitor
X
BI 1220 (Boehringer)
Nucleosite polymerase inhibitor
X
R1626 (Roche)
Nucleoside polymerase inhibitor
X
Cyclophilin inhibitor
DEBIO-025 (Debiopharm)
X
X
Telaprevir (Vertex Pharmaceuticals)
Protease inhibitor
Boceprevir (Schering-Plough)
Protease inhibitor
X
X
TMC435350 (Tibotec Medivir)
Protease inhibitor
Adapted from Manns MP et al. Nat Rev Drug
Discovery. 20076991-1000.
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PROVE1 Telaprevir PegIFN/RBV in
Treatment-Naive HCV GT 1 Patients
Weeks
24
0
48
72
12
60
36
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
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PROVE 1 Treatment Response Rates (ITT)
undetectable HCV-RNA lt 10 IU/ml
Treatment,
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)
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
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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 Peg-IFN/RBV
  treatment
• Treatment discontinuation through Week 12 due to
  adverse events were 18 in the TVR-based
  treatment arms and 4 in the control arm

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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

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