Download New Frontiers in HIV/HCV Therapy

New Frontiers in HIV/HCV Therapy
Todd S Wills, MD
USF ETAC, Infectious Disease Specialist
USF ETAC, Infectious Disease Specialist
Potential Areas of Advancement in HIV/HCV Therapy /
h
•
•
•
•
Response guided therapy
Response‐guided
therapy
Predictive Biomarkers
S ifi C
Specific HCV antiviral therapy
i i l h
Other new drugs
HCV Response Guided Therapy
HCV Response Guided Therapy
• Using
Using the rate of virologic response to predict the rate of virologic response to predict
success of therapy
• Using rate of response to determine duration Using rate of response to determine duration
of therapy
Response Guided Therapy in HCV Monoinfection
Levin AASLD, Nov 2‐6, 2007, Boston, MA Response Guided Therapy in HCV Monoinfection
Levin AASLD, Nov 2‐6, 2007
Response‐Guided Therapy in HIV/HCV C i f i
Coinfection
• Van den Eynde et al. Clin Infect Dis. (2009) 48 (8): y
f
(
) ( )
1152‐1159
• 60 HIV/HCV coinfected patients • 24 weeks of therapy for patients with Rapid
Virologic Response (RVR)
• 48 weeks of therapy for Early Virologic
Response (EVR)
• 60 weeks of therapy for partial EVR
• Termination of treatment for null response
p
Response Guided Therapy – All Patients
Response Guided Therapy All Patients
ETR – End of Treatment Treatment
Response
SVR – Sustained Virologic Response
RR – Relapse Rate
Van den Eynde et al. Clin Infect Dis. (2009) 48 (8): 1152‐1159
Response Guided Therapy ‐ RVR
Response Guided Therapy Van den Eynde et al. Clin Infect Dis. (2009) 48 (8): 1152‐1159
Response Guided Therapy ‐ EVR
Response Guided Therapy Van den Eynde et al. Clin Infect Dis. (2009) 48 (8): 1152‐1159
IL‐28B Polymorphism and Treatment Response
• Polymorphisms
Polymorphisms near the IL
near the IL‐28B
28B gene are gene are
strong predictors of both spontaneous clearance of HCV and response to treatment
clearance of HCV and response to treatment
Percentage of SVR by genotypes for IL‐28B region
DL Ge et al. Nature 461, 399‐401 (2009)
Rate of SVR and IL‐28 region C‐allele
frequency in diverse ethnic groups
DL Ge et al. Nature 461, 399‐401 (2009) Interleukin 28B (IL‐28B) Polymorphism and Treatment Response in Coinfection
i
i f i
• Nattermann J, et al. 2010 CROI Abstract #164
J et al 2010 CROI Abstract #164
• 183 Co infected patients versus healthy and monoinfected controls
– C/C genotype SVR rates 58.1%
– C/T 58.1%
C/T 58 1%
– T/T 40.6%; P =0.041 ITPA deficiency protects against clinically significant decline in Hb concentration induced by HCV anti‐viral treatment
concentration induced by HCV anti viral treatment
J Fellay et al. Nature, 1‐4 (2010) Potential HCV antiviral targets
5’
Internal
ribosomal
entry site
C
RNA
binding
site
E1
E2/NS1
Envelope
glyco‐
proteins
NS2
Signal
peptide
NS3
NS4A
NS4B
Serine protease/
helicase
telaprevir, boceprevir
l
i b
i
NS5A
NS5B
RNA dependent
RNA polymerase
3’
Telaprevir and Boceprevir
and Boceprevir
• Both target HCV serine proteases
Both target HCV serine proteases
– Common resistance mutations and cross resistance described
resistance described
•
•
•
•
•
Telaprevir NS3/NS4 protease inhibitor
B
Boceprevir
i NS3 protease inhibitor
NS3
t
i hibit
Studies in HCV monoinfection are complete
Studies in HIV/HCV co‐infection ongoing
Potential FDA review within 6‐12
Potential FDA review within 6
12 months
months
Telaprevir with PEGIFN and Ribavirin in treatment naïve patients ‐
ï
i
HCV Genotype 1
HCV ‐
G
1
80
PROVE 1 (USA) n =
250
PROVE 2 (Europe) n
= 334
334
SUSTA
TAINED VIRA
AL RESPONSEE (%)
70
60
50
40
30
20
10
0
PR48
T12PR12
T12PR24
1. McHutchison et al, NEJM 2009; 2. Hezode et al, NEJM 2009
T12PR48
Telaprevir for previously treated (PEGIFN / ribavirin) HCV Genotype 1
ib i i ) HCV G
1
SUSTA
TAINED VIRA
AL RESPONSEE (%)
80
All patients n =
453
Non‐responders n
= 260
Relapsers n =
162
70
60
50
40
30
20
10
0
PR48 McHutchison et al, NEJM 2010
T12PR24
T12PR48
Telaprevir Response in Previously Treated Patients
McHutchison, J. et al. New England Journal of Medicine. 362(14):1292‐1303, April 8, 2010.
Adverse Events Leading to Telaprevir Discontinuation
McHutchison, J, et al. New England Journal of Medicine. 360(18):1827‐1838, April 30, 2009.
Boceprevir in Treatment Naïve HCV Genotype 1
in Treatment Naïve HCV Genotype 1
Kwo PY et al. The Lancet ‐
PY et al The Lancet 28 August 2010 ( Vol. 376, Issue 9742, Pages 705‐716 ) 28 August 2010 ( Vol 376 Issue 9742 Pages 705 716 )
Kwo PY et al. The PY et al The
Lancet ‐ 28 August 2010 ( Vol. 376, Issue 9742, Pages 705‐716 ) SVR Based on 4‐week Viral Load reduction in
reduction in Boceprevir
treatment Naïve Trial
Naïve Trial
Primary mutations conferring resistance to NS3/4A protease inhibitors
hb
.
Soriano V et al. Clin Infect Dis. 2009;48:313‐320
Binding sites for HCV polymerase inhibitors
Soriano V et al. Clin Infect Dis. 2009;48:313-320
Main features of new specifically targeted hepatitis C virus drugs.
Soriano V et al. Clin Infect Dis. 2009;48:313‐320
The Direct Acting HCV Antiviral Pipeline
The Direct Acting HCV Antiviral Pipeline
• 22
22 agents in Phase 1 trials
agents in Phase 1 trials
• 18 agents in Phase 2 trials
• Multiple trials involving combination therapy li l i l i l i
bi i
h
with investigational agents
• Trials are exploring virologic efficacy AND duration of treatment
• All agents are protease or polymerase inhibitors
http://www.hcvadvocate.org/hepatitis/hepC/HCVDrugs_2011.pdf
accessed: January 23, 2011
Indirect Acting HCV Drug Pipeliine
Indirect Acting HCV Drug Pipeliine
• 14 agents in Phase 1 trials
14 agents in Phase 1 trials
• 23 agents in Phase 2 trials
• Mechanisms of action include
Mechanisms of action include
– Immunomodulators
– Oral or alternative interferons
Oral or alternative interferons
– TLR antagonists
– Therapeutic Vaccines
Therapeutic Vaccines
– Interfering RNAs
– Existing Antimicrobials (nitazoxanide)
Existing Antimicrobials (nitazoxanide)
http://www.hcvadvocate.org/hepatitis/hepC/HCVDrugs_
2011.pdf acessed: January 23, 2011