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7/27/2011
Disclaimer
Jonathan Moorman, M.D., Ph.D.
Professor, Infectious Diseases
Quillen College of Medicine
July, 2011
NEITHER THE PUBLISHER NOR THE AUTHORS ASSUME ANY LIABILTY FOR ANY INJURY AND OR DAMAGE TO PERSONS OR PROPERTY ARISING FROM THIS WEBSITE AND ITS CONTENT
Disclosures
To discuss
 Grant funding from NIH/NIAID
 Overview of the problems
 Clinical trials with Gilead, GSK, and Wyeth/Pfizer
 What we think might be going on….
 Novel pathways
 Novel treatments
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Co-infection: A Significant
Problem
 HIV affects 40 million globally and about 1 million in the
U.S.
 HCV affects 200 million globally and 4 million in the U.S.
 Prevalence of co-infection varies from 4% to greater than
90% depending on the population
 In IV drug users and hemophiliacs, the prevalence has been
as high as 98%
 MSM sexually-acquired HCV appears to occur in the
setting of high risk exposures (STDs, traumatic intercourse)
Sulkowski MS. J Hepatol 2008; 48: 353‐367. HIV and HCV: more similar than you might think
HIV
Genome
Transmission
Viral kinetics Viral load
Major target
Latency
Goal of therapy
Drug resistance








ss
ssRNA
N retrovirus
et ov us
Sexual/IVDU
Massive production
Correlates well with
disease
T cell
Yes
Viral suppression
Occurs
WHY PERSISTENCE?
HCV








ss
ssRNA
N flavivirus
av v us
IVDU>>sexual
Massive production
Correlates poorly with
disease
Liver but…..?
No
Viral eradication
Occurs
Kim AY and Chung RT. Gastroenterology 2009; 137: 795‐814.
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WHY PERSISTENCE?
New Targets for chronic viral infection: the negative infection: the negative
immunoreceptors
Immune exhaustion
Arlene H Sharpe, E John Wherry, Rafi Ahmed & Gordon J Freeman. Nature Immunology 8, 239 ‐ 245 (2007).
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Frazier AD, Zhang CL, Ni L, Ma CJ, Zhang Y, Wu XY, Atia AN, Yao ZQ, Moorman JP.
Viral Immunol. 2010 Oct;23(5):487‐95.
PD‐1 and HIV
PD‐1 and HCV
 PD‐1 expression on HIV‐specific T cells is associated with T cell exhaustion and disease progression (Day et al. Nature 2006; 443: 350‐354)
 Immune dysfunction was reversible in HIV
Immune dysfunction was reversible in HIV‐specific specific CD8+ T cells (Trautmann et al. Nat Med 2006; 12:1198‐1202.)
 Blocking PD‐1 in an SIV model enhanced SIV‐specific immunity (Velu et al. Nature 2009; 458: 206‐210.)
Ma CJ, Ni L, Zhang Y, Zhang CL, Wu XY, Atia AN, Thayer P, Moorman JP, Yao ZQ.
Immunology. 2011 Mar;132(3):421‐31.
PD‐1 modulates regulatory T cells and suppresses T‐cell responses in HCV‐
associated lymphoma.
Ni L, Ma CJ, Zhang Y, Nandakumar S, Zhang CL, Wu XY, Borthwick T, Hamati A, Chen XY, Kumaraguru U, Moorman JP, Yao ZQ.
Immunol Cell Biol. 2010 Oct 26. [Epub ahead of print]
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Ma CJ, Ni L, Zhang Y, Zhang CL, Wu XY, Atia AN, Thayer P, Moorman JP, Yao ZQ.
Immunology. 2011 Mar;132(3):421‐31.
New Targets: the Tim‐3 story
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Differential expression of TIM-3 on the surface of T cells regulates susceptibility to viral
infection or development of autoimmune injury.
HCV and Tim‐3: T cells
 Up‐regulation on HCV‐specific T cells*  Blockade is associated with improved CD4+ and CD8+ functions*
 Dual expression of Tim‐3/PD‐1 on T cells has been D l i f Ti
/PD T ll h b
described in co‐infected patients and correlates with progression of liver disease+
•Golden‐Mason et al. J Virol 2009; 83: 9122‐9130.
•+Vali et al. Eur J Immunol 2010; 40: 2493‐2505.
Hafler D A , Kuchroo V J Exp Med 2008;205:2699-2701
Tim‐3 in monocytes
P=0.0012
P<0.001
P=0.1878
P=0.0017
P<0.001
% of Tim‐3+ CD1
14+ M/MØ
P<0.001
P<0.001
P<0.001
% of IL12+ CD14+ M/M
MØ
PD-1
Naïve Activated
Naïve Activated
Naïve Activated
Naïve Activated
Healthy Subjects Chronic HCV Patients 6
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Defining an Initial Virologic Response
 EVR: HCV RNA ↓ ≥ 2 logs or Undetectable at Week 12
HCV RNA (log10 IU//mL)
8
PegIFN/RBV
7
6
5
2 log decline
4
3
2
EVR
1
66% SVR; 48 w
Limit of detection
RVR
SVR
0
0 4 8 12 18 24 30 36 42 48 54 60 66 72 78
Weeks
Initial Treatment of Chronic HCV - Predicting
SVR Over Time
Defining an Initial Virologic Response
 RVR: HCV RNA Undetectable at Week 4
100
5
2 log decline
4
SVR (%
%)
HCV RNA (log10 IU/mL)
90
GT 1[1]
GT 2-3[2]
66
PegIFN/RBV
7
6
60
59
45
40
20
3
2
91
80
8
RVR
90% SVR; 24 w
Limit of detection
1
SVR
0
0 4 8 12 18 24 30 36 42 48 54 60 66 72 78
Weeks
0
4
24
12
Week Undetectable HCV RNA Achieved
No matter what genotype, achieving RVR is crucial for a SVR
1. Ferenci P, et al. J Hepatology. 2005;43:453-471.
2. Shiffman ML, et al. N Engl J Med. 2007;124-134.
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HCV monoinfection: Sustained Virologic Response With
Peg-interferon and Ribavirin Combination Treatment
Drug
Peginterferon alfa-2a plus
ribavirin
Peginterferon alfa-2b plus
ribavirin
Weight-based dosing
Overall Genotype 1
Genotype 2 or 3
56%
46%
76%
54%
42%
82%
48%
88%
Fried et al. N Engl J Med 2002; 347: 975.
Hadziyannis et al. Ann Intern Med 2004; 140; 346.
New Targets
STAT-C:
Specifically Targeted Antiviral
Therapy for Hepatitis C
 IFN + RBV + small molecule agents specifically inhibit HCV life cycle
 achieve RVRs and increase SVRs from 50 to 80%;
 Pretreatment quasispecies confer resistance to all classes of inhibitors  All therapies will still be IFN‐based
 Sides effect: skin rash, renal toxicity
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Therapies arrived: NS3/4A inhibitors
 The NS3/4a complex acts as
a serine protease to process
the HCV polyprotein
 Peptidomimetic inhibitors
developed
p ((oral))
 Boceprevir
 Telepravir
•McCutshison et al. NEJM 2009; 360:1827.
•Hezode et al. NEJM 2009; 360:1839-1850.
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Summary: Treatment‐naïve, Genotype 1
 Addition of protease inhibitor increases SVR by 1.7 fold
 Boceprevir:
 Telaprevir:
 24 (28) weeks of treatment is effective for many patients
 Adverse events include
 Boceprevir: anemia, dysgusia
 Telaprevir: skin rash, anemia
 Effective in African‐Americans and patients with cirrhosis
 first line treatment for genotype 1 HCV now
Summary
Summary – Treatment‐Experienced Patients
 Boceprevir and telaprevir increase SVR for non‐responders
 48 weeks of treatment
 Probability of SVR depends on prior response to y
p
p
p
PegIFN/RBV
 75 – 85%% in relapsers
 50‐65% in non‐responders (non‐null)
 30% in null‐responders
 Null responders not optimally served by either drug Protease + (nN)Polymerase Inhibitors ± PegIFN +Ribavirin
Genotype 1, treatment‐naïve; 4 weeks of PI+PI; PI+PI+RBV; PI+PI+Peg+RBV
 Protease inhibitor + pegIFN/RBV expected to be the next standard of care for most patients with HCV genotype 1
 Treatment‐naive patients can anticipate SVR rates from 63%‐75%
 Shorter duration for many patients (response‐guided therapy)
 Treatment‐experienced patients can anticipate SVR rates ranging from 29%‐88% depending on response to pegIFN/RBV
9
p
g
p
p g
/
 Side effects:  Boceprevir: anemia, dysgusia
 Telaprevir: rash, anemia
 Resistance in patients who don’t respond to pegIFN/RBV
 New agents are promising, probably with pegIFN + RBV
Zeuzem AASLD 2010 abstract LB‐1
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Summary
 HCV and HIV present similar challenging issues and perhaps underlying immunopathology
 Novel treatments for HCV will likely lead to substantial improvements in sustained virologic responses in both mono‐ and co‐infected populations
 Novel pathways that mediate immune exhaustion are potential targets to improve host responses Thanks….
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John Yao, MD, PhD
Ying Zhang, MD, PhD
Jerry Ma, MD, PhD
Ni Lei, MD, PhD
Ni Lei MD PhD
Chunlan Zhang, MD, PhD
Xiaojun Ji, MD, PhD
Jiamin Wang, MD, PhD
Rose Wu
Ashley Frazier
Antwan Atia, MD
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7/27/2011
Consequences: not just persistence
Vaccine responses in chronic HCV infection
80
*
% CD69+ in CD4+
+ T cells 70
60
IgG
*
a‐PDL‐1
50
40
*
30
20
10
0
HBsAg stimulation a‐CD3/28 stimulation
* p=0.002
A Vaccine (Failure) Model
PD-1
Does having HIV make HCV
worse?
 Co-infected patients had higher HCV RNA viral loads*
 Co
Co-infected
infected patients had more rapid HCV viral replication
and progressed more rapidly and frequently to hepatic
fibrosis and cirrhosis than HIV (-) patients with HCV†
 In a large group of hemophiliacs, progression to liver
failure was more likely and was inversely correlated with
CD4 count‡
*Bonacini et al. J Viral Hepat 1999, 6:405.
†Allory et al. J Infect Dis 2000, 181:442; Benhamou et al. Nat Struct Biol 1999, 6:937.
‡Telfer et al. Med Microbiol Immunol 1994, 183:159.
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HIV/HCV Co‐infection
RR for ESLD 6.14 RR for Cirrhosis 2.07
Sulkowski MS. J Hepatol 2008; 48: 353‐367. Kim AY and Chung RT. Gastroenterology 2009; 137: 795‐814.
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