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Hepatitis B, C, and Beyond
John Scott, MD, MSc
Feb 20, 2007
Harborview Medical Center
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HCV/HIV Coinfection
• When?
• With what?
• What next?
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Case #1
• 45 yo W man w/ B2 HIV, CD4 count 390, HIV load 100,000 copies/ml
• HCV+, GT 1a, HCV RNA 3 million IU/ml
• ALT 67 U/L, normal synthetic function
• PTSD, depression, 20 yr h/o IDU, clean for 6 months
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What to treat first?
HIV?
Or HCV?
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Why is HCV such a concern in HIV+ patients?
• Common coinfection
• Complicates HAART
• Can lead to rapid progression of liver disease and death
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Mitochondrial Toxicity of ART: Ribavirin and DDI Drug Interaction
• ddI is contraindicated in cirrhosis and should be avoided in less severe liver disease.
• Ribavirin appears to potentiate ddI mitochondrial toxicity -> increases intracellular accumulation of ddI
• FDA warning (9/27/02) of combination• Dose dependent?• DDI and advanced liver disease likely a greater
risk than the DDI/RBV drug combination itself
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Other issues
• d4T associated w/ acute/chronic steatosis
• Tipranavir can cause hepatotoxicity in 5-20%, dose dependent
• More hepatotoxicity in recently started NVP, high dose ritonavir (>200 mg)
• More frequent anemia in pts on AZT (26% vs. 8%) and neutropenia (52% vs. 31%) for pts receiving IFN + RVN
Sulkowski et al. AIDS 2005Sulkowski M. AASLD 2006
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Impact of HIV on HCV
Cirrhosis Decompensation
Makris
Soto
Pol
Benhamou
Combined
0.76 1.0 2.07 10.83
Eyster
Telfer
Makris
Lesens
Combined
0.61 1.0 6.14 175.32
Graham CID 2001Relative Risk (95% CI)
A B
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Liver Disease has Emerged as a Major Cause of Death in the HAART Era
Bica Clin Infect Dis 2001; Puoti JAIDS 2000; Soriano Eur J Epidemiol 1999; Soriano PRN Notebook 2002; Martin-Carbonero AIDS Res Human Retrovirus 2001
0
10
20
30
40
50
60
Mo
rtal
ity
(%)
Death from end-stage liver disease (ESLD) as a% of all deaths among HIV patients
Italy (Brescia) Spain (Madrid) USA (Boston)
13%
35%
5%
12%
45%
50%Pre-HAART era
HAART era
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Liver-related mortality:
#1 cause of non-AIDS deaths
14.5% deaths
2/3 Hep C
D:A:D Study. Arch Intern Med 2006; 166:1632-41
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Effect of HCV on Mortality in HIV Patients: Harborview HIV Clinic, 1997-2005
At risk (events):
HIV alone 1461(46)1268(26)1025(27) 775 (16) 520 (3) 286 (2) 37
HIV/HCV coinfect 373 (17) 325 (12) 257 (13) 190 (7) 131 (9) 63 (2) 9
0.00
0.25
0.50
0.75
1.00
Pro
port
ion
Sur
vivi
ng
0 500 1000 1500 2000 2500 3000Time(days)
HCV negativeHCV positive
p<0.001
Kaplan Meier Survival Analysis, by HCV Status
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Cause of Death in Harborview HIV Clinic Patients with HCV
14
19
15
9
3
0
2
4
6
8
10
12
14
16
18
20
Hepatic-related
HIV-related Other Unknown Accident
Cause of Death
Nu
mb
ers
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Decreased cirrhosis with HAART
Untreated
PI Treated
P<0.001
Benhamou et al. Hepatology 2001; 34:283-7
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Decreased liver-related mortality with HAART
Qurishi et al. Lancet 2003; 362:1708-13
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Back to Case #1
• 45 yo W man w/ B2 HIV, CD4 count 390, HIV load 100,000 copies/ml
• HCV+, GT 1a, HCV RNA 3 million IU/ml
• ALT 67 U/L, normal synthetic function
• PTSD, depression, 20 yr h/o IDU, clean for 6 months
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Considerations and Recommendations
• Efficacy of HCV tx not affected by CD4 count
• IFN causes mean CD4 decline of 140 cells/ml
• Immune reconstitution syndrome?
• ACTG study ongoing• CD4<200, treat HIV• CD4>350 and low
HIVL, ideal candidate for HCV tx
• CD4 200-350, tx HIV first or HCV cautiously
Torriani et al. NEJM 2004; 351:438-50Sulkowski MS. J Hepatol 2006; 44: S49-55VA Guidelines. Am J Gastroenterol 2005; 100:2338-54Rockstroh and Spengler. Lancet Inf Dis 2004; 437-44
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HIV/HCV Coinfection TrialsACTG RIBAVIC APRICOT Laguno
# pts 134 412 860 95
% genotype 1 78% 66% 61% 49%
fibrosis score 2.5 2.3 16% cirrhotic 30% st 3 or 4
Mean CD4 475 515 530 560
Overall SVR 27% 26% 40% 44%
SVR GT 1 5% 15% 29% 38%
SVR non-1 30% 43% 62% 53%
d/c rate (ea arm)
12% 42% 30-40% 17%
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Extended treatment for HCV
• Mathematical models show that viral suppression necessary for at least 36 weeks
• HCV monoinfected trial showed that if HCV RNA + at wk 12 but – at wk 24, SVR increased from 17% to 29% with add’l 24 weeks of therapy
• Goal: reduce relapse rateDrusano GL. 2004 J Infect Dis 189:964-70Berg T. 2006 Gastro 130:1086-97.
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Duration of Detectability (DUD)
4 12 24 48 Time (weeks)
RVR
EVR
SlowVR
Detectable
Detectable
Detectable
Undetectable
Undetectable
Undetectable
44 wks
36 wks
24 wks
Ferenci 2005, Fried 2006
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PRESCO
• Ongoing Spanish study of 398 stable coinfected pts (mean CD4 562 cells/mm3)
• All are receiving 180 mcg PegIFNα2a (Pegasys) and wt-based RBV (1000 or 1200 mg/d)
• Comparing extended tx w/ std tx:– 48 weeks for GT non-1– 72 weeks for GT 1
Soriano, et al. AASLD Meeting 2006; Abstract #365
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PRESCO Results
• ITT analysis: overall SVR 49% (71% GT 2,3 and 35% GT 1)
• No significant differences in relapse rates by duration of therapy (26% vs 17%)
• Ribavirin dosage more important than duration of therapy
Soriano, et al. AASLD Meeting 2006; Abstract #365
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Novel Therapies
• Serine protease inhibitors• Polymerase inhibitors• Helicase inhibitors• Antisense therapy• siRNA• Toll-like receptor agonists• Cyclosporine analog• Improved Ribavirin and
Interferon • Therapeutic vaccination
Review: McHutchison JG. 2006 J Hepatol 44:411-21
Specifically Targeted Antiviral Therapy (STAT)
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STAT-C
• Very potent!
• Three potential problems:– Rapid development of resistance– Importance of precise dosing and adherence– Possibility of synergistic side effects
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VX-950 Alone or in Combination with Pegasys: Mean Viral Response
11
00
-2-2
-3-3
-4-4
-1-1
-5-5
-6-6
BB 11 22 4433 55 66 77 88 99 1010 1111 1212 1313 1414Study Time (In Study Time (In Days)Days)
HC
V R
NA
Ch
an
ge f
rom
H
CV
RN
A C
han
ge f
rom
Baselin
e (
Log
Baselin
e (
Log
10
10 I
U/m
L)
IU
/mL)
Pegasys + Pegasys + placeboplacebo
VX-950VX-950
VX-950 + Peg-IFNVX-950 + Peg-IFN
BaselineBaseline
Reesink H et al. EASL. April 26-30, 2006. Reesink H et al. EASL. April 26-30, 2006.
Vienna, Austria. Abstract 737.Vienna, Austria. Abstract 737.Slide courtesy Roche Medical Affairs
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Phenotypic Characterization of Telaprevir-Resistant Variants
• Highly sensitive clonal method– Detect 5% frequency of variants– Performed at days 4, 8, 12, 14– 80 sequences/patient/time point
Wild type T54A V36A/M R155K/T 36/155 A156V/T
Low resistance High resistance
Adapted from Kieffer T, et al. 2006 AASLD, Boston, #92
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Log(10) HC
V R
NA
IU/m
l
Days
8
6
4
2
14
Telaprevir
100
Peginterferon + Ribavirin
LOD = 10 IU/ml
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Log(10) HC
V R
NA
IU/m
l
Days
8
6
4
2
14
Telaprevir +Peg/RVN Peginterferon + Ribavirin
100
Adapted from Kieffer T, et al. 2006 AASLD, Boston, #92
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Liver Transplantation
• Similar survival post-txp b/t HIV+ and HIV- pts transplanted for Hep C– 12 mo survival: 87% vs. 87%– 24 mo survival: 73% vs. 82%– UCSF experience: 15/21 alive w/ mean f/u 33 mos
• No significant HIV clinical, virologic or immunologic disease progression in post-txp patients
• Drug interactions w/ HAART and immunosuppressants• Criteria for eval: CD4>200, HIVL <400, no active OI
– REFER EARLY, MELD score doesn’t predict well
• UCSF
Rockstroh and Spengler. Lancet Inf Dis 2004; 437-44VA Guidelines. Am J Gastroenterol 2005; 2338-54Stock P. AASLD Oral Presentation 2006.