HBV and HCV management in HIV coinfected patients

1
HBV and HCV management in HIV co-infected
patients

• Sanjay Bhagani
• Dept of Infectious Diseases/HIV Medicine, Royal
  Free Hospital
• Academic Dept of Infection, UCL
• London, UK

2
Overview

• HCV
• New Rx
• Acute HCV
• Fibrosis Progression
• PegIFN and Ribavirin responses and predictors
• Maximising responses
• HBV
• Burden of disease
• Impact of lamivudine montherapy
• Role PegIFN/Entacavir/Telbivudine
• Current Rx algorithm

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HCV targets for therapy
Receptor binding and endocytosis
Transport and release
Fusion and uncoating
() RNA
Virion assembly
Every step of the life cycle offers a variety of
potential targets for novel drug classes
Translation and polyproteinprocessing
RNA replication
NS2NS3 proteinase
NS3 protease
4A
E2
C
NS4B
NS5A
E1
p7
NS2
NS3
NS5B
Serine protease domain
RNA-dependent RNA polymerase
Core
Core
Envelope
1. Lindenbach BD Rice CM. Unravelling
hepatitis C virus replication from genome to
function. Nature 2005436933-938
5
New Drug classes in the pipeline

• Protease inhibitors
• Polymerase inhibitors
• Nucleosides
• Non-nucleosides
• Others
• Entry inhibitors
• Cyclophilin inhibitors
• Alpha-glucosidase inhibitors
• NS5A inhibitors
• siRNA
• Immune modulators

6
Some new oral small molecule ARVs in development
for the treatment of HCV
Drug name Drug class Preclinical Phase I Phase
II Phase III
MK-0608 (Merck)
Nucleoside polymerase inhibitor
X
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
R1626 (Roche)
Nucleoside polymerase inhibitor
X
Cyclophilin inhibitor
DEBIO-025 (Debiopharm)
X
Telaprevir (Vertex Pharmaceuticals)
X
Protease inhibitor
x
Boceprevir (Schering-Plough)
Protease inhibitor
X
TMC435350 (Tibotec Medivir)
Protease inhibitor
Adapted from Manns MP et al. Nat Rev Drug
Discovery. 20076991-1000.
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New Agents - many unknowns

• No clinical studies in HIV (as yet)
• Efficacy with very high viral loads
• Potential for rapid emergence of resistance and
  cross-resistance
• Drug-drug interactions
• Side-effect profiles
• Etc,.

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New epidemic of Acute HCV among HIV MSM-beyond
Europe....
Europe UK2,3,4 Germany5 France6,7
Netherlands8 Switzerland9
Italy10 Belgium11
1. Luetkemeyer JAIDS 2006 2. Danta AASLD 2008
3. Jones 4th Works. HIV Hep. Coinf. 2008 4.
Fisher CROI 20075. Stand 01/2009 6.Gambotti
Euro Surveill 2005 7. Larsen AASLD 2007 8. van
de Laar JID 20079. Rauch CID 2005 10. Gallotta
4th Works. HIV Hep. Coinf. 2008 11. pers.com.
12. Matthews , CID 2009
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HIV/HCV complex immune interactions
Klenerman P, Kim A. PLOS Med 2007 4 1608-1614
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Effect of HAART on progression to ESLD a
meta-analysis
PRE-HAART
POST-HAART
Thien, H et al. AIDS 2008 22 1979-1991
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Insulin Resistance/NASH and hepatic fibrosis in
HIV/HCV co-infected patients
Sterling R, at al. Hepatology 2008
Merchante N, et al., Gut 2009
See Poster WePEB218
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HCV/HIV TREATMENT OUTCOMES
Genotype 1
Genotype 3
SVR 14-38
SVR 44-73
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Genotype 1 Mono- vs. Co-infected
SVR predicted by RVR Gender Liver Fibrosis
Tural, et al Antiviral Therapy, 2008
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ACUTE HCV/HIV Virological Responses
Bhagani HIV/Hepatitis co-infection 2007
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Predictors of response

• Host
• Acute infection
• Younger age
• Lack of stage 3/4 fibrosis
• Ethnicity
• Low BMI
• Lack of hepatic steatosis
• High CD4
• Lack of insulin resistance?

• Virus
• Genotypes 2/3
• Low viral loads

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APRICOT SVR rates according to exposure
Genotype 1 recipients of peginterferon alfa-2a
plus ribavirin
50
39
40
29
SVR rate ()
30
20
11
10
62
n 176
114
0
80/80/80exposure
lt80/80/80exposure
Allpatients
Patients violated the rule if 1 of the three
targets were not achieved
Opravil M, et al. 45th ICAAC 2005 Abstract 2038
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APRICOT Baseline CD4 Count and Efficacy of
Peg-IFN alpha-2a Plus RBV

• SVR rates analyzed in overall population and
  within genotypes according to baseline CD4 cell
  count quartiles (Q1-Q4)
• Rate of SVR varied according to CD4 cell
  percentage quartile in genotype 1 but not in
  genotypes 2/3

100
73
80
Q1 (2.5 to 19)
69
62
60
Pts With SVR ()
47
Q2 (19.1 to 25.0)
34
40
27
29
16
20
Q3 (25.0 to 32.1)
0
Gt 1 (n 150)
Gt 2/3 (n 78)
Q4 (32.1 to 69.3)
Dieterich D, et al. ICAAC 2006. Abstract H-1888.
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How can we maximise response to therapy?
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Viral Dynamic response to interferon and ribavirin
Pawlotsky Hepatology 2002 32(4)
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Cost Effectiveness of EPO Therapy

• Medical Intervention
• Primary angioplasty vs. thrombolysis
• PegIFN/RBV vs. IFN/RBV
• EPO vs. STD Care

• Incremental cost/QALY
• 13,100
• 15,000 55,000
• 16,433

Spiegel BR, Chen K, Chiou C-F, et al. Clin Gastro
and Hepatology 200531034-42
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Interactions between RBV nucleoside analogues

• AZT ddI d4T
• anemia hepatic
  pancreatitis weight
• decomp. lactic
  acidosis loss

Blanco et al. NEJM 2002 347 1287
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Abacavir and SVR
RBV
ABC
Adenylosuccinatesynthase-lyase
p0.02
p0.03
p0.4
ABV-MP
Adenylate kinase
RBV-MP
CBV-MP
Guanylate kinase
RBV-DP
CBV-DP
Nucleoside diphospho-kinase
RBV-TP
CBV-TP
Mira JA, et al. J Antimicrob Chemother 2008
62(6) 13651373 Medscape www.medscape.com
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Extended duration of therapy?
25
Utilising kinetics to determine length of therapy
mathematical model Genotype 1
End Rx
HCV RNA
36 weeks lt 50 c/ml
Drusano Preston. JID 2004 189 964-970
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Longer Duration of Undetectability on Treatment
Increases Chance for SVR

• Retrospective analysis of genotype 1 patients
  receiving 48 weeks of pegIFN alfa-2a RBV (N
  453)

100
91
80
66
60
45
SVR ()
40
20
2
0
HCV RNA Positive at Week 24
4
12
24
Week Became HCV RNA Negative
Ferenci P, et al. J Hepatol. 200543425-433.
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Treatment of Chronic HCVExtending Therapy
80
EOT
60
61
SVR
52
HCV RNA (-)
40
45
Extending the duration of therapy reduced relapse
from 47 to 13
32
20
0
48
72
Weeks of Treatment
Sanchez-Tapias et al. AASLD 2004. Abstract 126.
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Results (On Treatment analysis)
p0.04
p0.004
56
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• 270 mcg vs. 180 mcg PegIFN alpha 2a R
  (1000mg/1200mg) for 4 weeks followed by 180mcg
  R
• No difference in RVR or EVR
• Also see Poster WePEB223

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Proposed optimal duration of HCV therapy in
HCV/HIV-coinfected patients.
G2/3
24 weeks therapy
HCV-RNA neg
G1/4
48 weeks therapy
G2/3
HCV-RNA neg
G1/4
72 weeks therapy
gt 2 log drop in HCV-RNA
HCV-RNA pos
Stop
HCV-RNA pos
lt 2 log drop in HCV-RNA
Stop
In patients with baseline low viral load and
minimal liver fibrosis.
Rockstroh et al, EACS Guidelines 2008
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HIV/HCV 2009
Patient Education avoid infection
HIV/HCV co-infection
Early reversal of Immune suppression Use
non-toxic agents
Identify early Rx early/acute
Chronic HCV- Rx Max dose Ribavirin Interactions A
void dose-reductions Kinetics based Rx length
Address Co-factors Alcohol Hepatic
Steatosis Insulin Resistance
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HBV/HIV - Unequal Burden?
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Prevalence of HBV Global Estimates
HBsAg Prevalence
High (8) Intermediate (2 to 8) Low (lt2)
Mast EE, et al. MMWR Recomm Rep.
200655133Custer B, et al. J Clin
Gastroenterol. 200438(10 suppl)S158-S168
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Global HIV/HBV
Thio, C. Hepatology 2009 49(5) s138
See Posters WePEB 227and 237
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Natural history of HBV infection where does
co-infection fit in?
lt 5
gt 95
Immune tolerance
Early childhood
Adulthood
HIV/HBV Increased likelihood
HBeAgChronicHepatitis B
HBeAgChronicHepatitis B
HIV/HBV Higher viral loads
HIV/HBV Increased viral loads Lower
ALT Increased fibrosis
HCC
Inactive carrier
HIV/HBV Reduced seroconversion
Adapted from Chen DS, et al. J Gastroenterol
Hepatol 199384705 Seeff L, et al. N Engl J
Med 198731696570 Thio CL, et al. Lancet
200236019216 Gilson RJ, et al. AIDS
199711597606 Colin JF, et al. Hepatology
199929130610.
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Liver Related Deaths and HCC in HIV effect of
HBV
N822
20 LRD
HIV/HBV
50 HCC
88 cirrhosis
15 HCC
Increased RR With falling CD4 Counts in MSM
Salmon-Ceron D, et al. J Hepatol
200542(6)799-805 Clifford et al. AIDS 2008
22 2135-2141
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Incidence of HBV Resistance in Patients Treated
with LAM in HBV infection vs. HIV/HBV co-infection
LAM1 (YMDD )
LAM2 (YMDD in HIV/HBV)
100
90
Triple HBV mutation twice as common in HIV/HBV3
80
70
53
60
Incidence of Resistance
47
42
40
24
20
0
year 1
year 2
year 3
year 4
1. Lai C.L., et al., Clinical Infectious
Diseases (2003) 36687 2. Benhamou Y et al.
Hepatology 1999 301302-6 3. Matthews GV, et
al. AIDS 200620(6)863-70
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Impact of lamivudine resistance on progression of
liver disease
Patients with severe fibrosis or cirrhosis
25
Placebo (n 215)
YMDDm (n 209) (49)
20
Wild-Type (n 221)
Placebo
21
15
13
Disease Progression,
YMDDm
10
5
5
WT
0
0
6
12
18
24
30
36
Time after Randomization (months)
Liaw, N Engl J Med. 2004
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ADVPEG study

• 18 HIV/HBV eAg patients with LAM-R
• No e-seroconversions
• ALT reduction

Ingiliz P, et al. Antivir Ther 200813895900.
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Entecavir may inhibit HIV-1 replication and
select HIV-1 variants resistant to ARV drugs
Patient 1 31 yo male CD4 596 cells/mm³

• The use of entecavir in HIV/HBV patients
  without HAART needs to be reconsidered

105
Plasma HIV RN
ETV
1010
104
108
A
Plasma HIV RNA (c/mL)
106
103
Plasma HBV DNA (IU/mL)
(copies/ml)
104
102
102
101
12
-36
-30
-24
-18
-12
-6
0
6
Months after initiation of ETV
McMahon M, et al. 14th CROI, Los Angeles 2007
136LB
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Telbuvidine anti-HIV activity?
No in vitro activity against 8 wild-type HIV-1, 2
drug resistant HIV-1 isolates
HIV viral load over time
10000
100
Patient
Patient
Entecavir
Telbivudine
26/2/8LdT and ADVstarted
Ref
Ref
11/11/8LdT re-startedVL 1074
9000
75
8000
50
Inhibition ()
25/11/8LdT 2 wksVL 127
7000
25
29/7/8LdT stoppedVL 127
6000
0
0.01
0.10
1
10
100
0.1
1
10
100
5000
Viral load (copies/mL)
4000
6/5/8VL lt50
3000
100
Patient
Patient
Entecavir
Telbivudine
2000
Ref
Ref
75
1000
50
Inhibition ()
0
25
0
23/10/07
23/11/07
23/12/07
23/01/08
23/02/08
23/03/08
23/04/08
23/05/08
23/06/08
23/07/08
23/08/08
23/09/08
23/10/08
23/11/08
0.01
0.10
1
10
100
0.1
1
10
100
Drug concentration (µM)
Drug concentration (µM)
Low E, et al. CROI 2009P813a.
Avila C, et al. CROI 2009P813b.
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