Professor Stephen Locarnini

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Chronic Hepatitis B Is There Light at the End
of the Tunnel ?

• Professor Stephen Locarnini
• Victorian Infectious Diseases Reference
  Laboratory,
• North Melbourne, Victoria 3051,
• AUSTRALIA
• www.vidrl.org.au/publications/hep_updates.htm

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Treatment Endpoints in Chronic Hepatitis B
Potential Treatment Endpoints in Chronic
Hepatitis B
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HBeAg Seroconversion At 1 Year
6 months off of treatment
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HBeAg Loss At 1 Year
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DNA Response in HBeAg- Studies _at_ 1yr
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Annual Prevalent Resistance Rates for Lamivudine,
Adefovir, Entecavir, Emtricitabine and Telbivudine
amodified and updated from CL Lai et al 2003 and
NW Leung et al 2001bfrom S Locarnini et al 2005
Hadziyannis S et al 2005. NEJM
3522673.cfrom RP Perrillo et al 2005 and
Colonno et al 2006 dIn the LAM comparator arm,
the percentage was only 8 based on a complex
case definition of antiviral drug
resistance/treatment failure. One would thus
expect a comparable relative levele of 10-12
based on genotypic resistance compared with
Lamivudine (25 per annum).e Lok A McMahon
B 2007 Hepatology 45 507 .
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The Issue of Selecting for Drug-Resistant HBV
During Antiviral Therapy

• Most Virologists have the view that monotherapy
  with
• nucleos(t)ide analogs will inevitably
  create
• BIOLOGICAL MONSTERS
• Still most Hepatologists use monotherapy with
• nucleos(t)ide analogs on the basis of
• A CLINICAL COMPROMISE

from Prof Alfredo Alberti EASL 2006
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Drug-Resistance During Antiviral Therapy for HBV
The evolving role of the Clinical Hepatologist
THE PAST (a single NUC available)
Fatally resigned to resistance
THE PRESENT (2-3 NUCs available)
Busy in monitoring for early detection of
resistance and salvage therapy
THE FUTURE (more drugs and more data)
Hoping for a more relaxed approach with
optimised combination
FIRST
DO NOT HARM !!!
from Prof Alfredo Alberti EASL 2006
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Where To From Here?Is There a Light at the End
of the Tunnel?Is it Combination Therapy?
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Combination Antiviral Therapies

• Complementary and/or mutually exclusive
  resistance pathways
• Principal of rapid maximal suppression
• Superiority of combinations requires testing in
  CH-B
• Proof of principle exists from HIV treatment
• Viral kinetics during treatment may facilitate
  understanding

S. Lewin et al. 2001 Hepatology 341012.
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Antiviral Drug Combinations

• Minuses
• Unpredictable interactions
• Synergistic toxicity
• Selection for multiple resistance
• Antagonism
• Cost
• Registration issues

• Pluses
• Reduced dose frequency
• Reduced chance of resistance
• Synergistic antiviral effect
• Reduced toxicity

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Preventing Lamivudine Resistance with de novo
Combination Therapy
100
After 1- year therapy
80
60
Incidence of resistance ()
34
40
21
20
18
20
12
11
5
2
1
0
LAM
LAM
LAM
LAM
LAMADV
LAMPeg
LAMPeg
LAMLdT
LdT
Sung 1
Marcellin 2
Lau 3
Lai 4
3 Lau et al. Hepatology 2004 4 Lai et al.
Hepatology 2003
1 Sung et al. J Hepatol 2003 2 Marcellin et al.
NEJM 2004
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In the Patients with an Indication to Treatment
with HBV Inhibitors (naive or LAM-R)

• The combination of lamivudine and adefovir does
  not improve antiviral efficacy compared to
  monotherapy BUT considerably delays the onset of
  clinical resistance and preserves the use of
  alternative molecules in the future.
• The combination of emtricitabine and adefovir
  significantly improves antiviral efficacy
  compared to monotherapy, and is being further
  assessed in phase II trials.
• The combination of telbivudine and lamivudine
  may increase the rate of viral resistance over
  monotherapy with telbivudine.

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Combination Therapy for Chronic Hepatitis B Open
Issues

• What and how to combine (?)
• PEG-IFN plus a nucleos(t)ide analog
• Two or more nucleot(s)ide analogs
• Other combinations
• When to combine (?)
• In all cases
• Depending on virological profile
• Depending on disease stage

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Combination Therapy For HBVPros vs Cons
Pros PEG-IFN NUCs synergistic antiviral
immunomodulatory effects NUC NUC higher
antiviral potency, less resistance, with a strong
theoretical rationale , also derived from HIV
lesson Cons Limited evidence-based data
supporting improved clinical efficacy High
Costs Safety and compliance issues
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Combination Therapy for Chronic Hepatitis B Aims

• Allows sustained viral suppression
• Lowers incidence of HBV resistance
• Should theoretically improve treatment endpoints
  of
• HBeAg seroconversion
• HBsAg seroconversion
• What is the basis of the disconnect between
  viral load suppression and HBeAg/HBsAg
  seroconversion?

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Is There Light at the End of the Tunnel ?

• Do we need a Biomarker??

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qHBeAg

• Fried, AASLD, 2005 (abs 182)
• (lt 30.7 IU/ml - 54)
• HBeAg titre followed on treatment as a predictor
  of HBeAg seroconversion
• Wk12
• Wk24
• HBeAg titre gt 100 IU at 24 weeks - NPV 96
  (superior utility cf VL)

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qHBeAg

• Predictor of seroconversion on therapy
• Superior to VL - esp during NA therapy?
• Predictor of innate immune activation?
• FTCB-201 data
• Definition of HBeAg titre in the context of
  therapy-related virological and immunological
  changes is needed
• Limitation
• lack of a commercially available assay with a
  wide dynamic range
• lack of a widely available international
  reference standard
• NOW - VIDRL (PE IU/ml)
• Available as a translational tool

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Intrahepatic HBV DNA New Insight on Viral ccc DNA
Persistence During Natural History of Chronic
Hepatitis B and Adefovir Dipivoxil Therapy

• B. Werle1, S Bowden2, S. Locarnini2, K.
  Wursthorn3, J. Petersen3,
• G. Lau4, C Trepo1, P Marcellin5, Z Goodman6, W.
  Delaney5,
• S. Xiong5, C. Brosgart5, S-S Chen7, C. Gibbs7
  and F. Zoulim1

1 Inserm Unit 271, Lyon, France 2Victorian
Infectious Diseases Reference Laboratory, N.
Melbourne, Australia 3Universitaetsklinikum
Hamburg-Eppendorf, Hamburg, Germany 4Queen Mary
Hospital, Hong Kong 5Inserm Unite 481 and
Hopital Beaujon, Clichy, France, 6Armed Forces
Institute of Pathology, Washington DC, USA,
7Gilead Sciences, Foster City, CA USA
Gastroenterology (2004) 126 1750
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Natural History
Monitoring of cccDNA levels in the different
phases of chronic HBV infection

• HBeAg patients had significantly higher cccDNA
  (90-fold) and total HBV DNA (147- fold) levels
  compared to HBeAg- patients. (plt0.001, Wilcoxon
  tests)
• Werle-Lapostolle, Bowden, Locarnini et al
  Gastroenterology (2004)

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Reductions in Serum HBV DNA, Total Intrahepatic
HBV DNA and ccc DNA During ADV Therapy
ADV-treated (n 22)
Median (Log10 copies/mL Log10 copies/cell)

• 48 weeks of ADV resulted in median reductions of
  
• 4.6 log in serum HBV DNA
• 1.9 log in total intrahepatic HBV DNA
• 0.84 log in cccDNA
• No significant reductions in placebo patients

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HBV cccDNA Levels as a Predictor of Sustained
Virological Response

• IFN LMV combination vs LMV monotherapy
  (patients 47)
• Evaluated serum HBV load, intrahepatic HBV DNA
  and cccDNA as predictors of response

Sung et al (2005) Gastroenterology 128 1890
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ROC Curve of Log Serum HBV DNA, Intrahepatic DNA
and cccDNA for SVR
cccDNA levels give the highest predictive value
for SVR
Sung et al (2005) Gastroenterology 128 1890
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Future Directions

• Prevention of Drug Resistance -- Two Basic
  Approaches (Richman Hepatology 2000 32
  866-867)
• Not to treat
• -- Is a reversible decision
• -- Is a decision to postpone
• -- Risk benefit strategy of postponing inadequate
  monotherapy to permit its later incorporation in
  a combination regimen
• Treat more effectively, thereby preventing
  replication
• -- Use of combination chemotherapy
• -- Guided by viral dynamic/kinetic studies
  
• -- Phase 2 elimination problem (LMV IFN a)
• (Lewin et al. Hepatology 2001 341012)

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Future Directions (cont)

• Salvage Approach
• Management option
• Continue LMV
• Stop LMV - often associated with hepatic flare
• Switch to another agent
• DRUGS WITHOUT CROSS-RESISTANCE
• Add another agent
• Adefovir dipivoxil - PROBABLY
• Entecavir - ?
• Develop better treatment strategies
• IFNs/PEG-IFNs

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ADV Added to LAM in LAM-Resistant Patients
Virological Response by Resistance Definition
3-6 log HBV-DNA at baseline virologic
breakthrough
6-8 log HBV-DNA at baseline
Clinical breakthrough
Patients with undetectable HBV-DNA
gt8 log HBV DNA at baseline
plt0.0001
Months
(Lampertico et al., Hepatology 2005421414-1419)
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Very Early Add-on Therapy to Keep Viral Load as
Low as Possible
Drug A
Drug A high genetic barrier Drug B different
cross-resistance profile
Drug A Drug B
Serum HBV DNA (Log10 copies/mL)
Month of therapy
From Zoulim, F. 2006
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Conclusions

• Current emerging patterns of antiviral drug
  resistance to HBV Pol are complex
• Primary resistance mutations across groups A181V
  and M204I
• Broad clusters of compensatory mutations during
  Lamivudine therapy (rtV214A, rtQ215S Vs
  rtI169TrtV173L Vs rtT184S) compromising future
  salvage therapy options (Adefovir, Tenofovir,
  Entecavir)
• Requirement for HBV Pol sequencing to determine
  profile of LMV resistance
• need for interactive database programs to guide
  rescue therapy

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Future Needs for the Management of HBV Drug
Resistance

• Algorithm for the use of viral load genomic
  assays in the monitoring of antiviral therapy
• Management of drug resistance best strategies to
  rescue drug resistance with long-term treatment
  end-points
• Prevention of drug resistance
• Treatment strategy trials de novo combination
  versus early add-on therapy
• Drugs without cross-resistance
• Long-term endpoints

From Zoulim, F. 2006
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