what’s new in hepatitis c diana l. sylvestre, md university of ca, san francisco oasis clinic,...
TRANSCRIPT
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What’s New in Hepatitis C
Diana L. Sylvestre, MDUniversity of CA, San FranciscoOASIS Clinic, Oakland, CA
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Disclosure InformationWhat’s New In Hepatitis CDiana Sylvestre, MD
I have the following financial relationships to disclose:
Speaker’s Bureau for Merck
I will discuss the following off label use and/or investigational use in my presentation:
Treating drug users for hepatitis C
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What’s Not New
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NIH Consensus Statement on HCV, 2002
“HCV therapy has been successful even when the patients have not abstained from continued drug or alcohol use... Thus, it is recommended that treatment of active injection drug use be considered on a case-by-case basis, and that active injection drug use in and of itself not be used to exclude such patients from antiviral therapy.”
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NIH Consensus Statement on HCV, 2002
“HCV therapy has been successful even when the patients have not abstained from continued drug or alcohol use... Thus, it is recommended that treatment of active injection drug use be considered on a case-by-case basis, and that active injection drug use in and of itself not be used to exclude such patients from antiviral therapy.”
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HCV Virology
Lee W et al. Drugs. 2004;64(7):693-700.
+ ssRNA:Flavivirus
1012 virions/day
Frequent mutations and no proofreading Results in HCV variants called
quasispecies
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HCV Prevalence by Selected GroupsUnited States
0.3%
1%
2%
3.5%
6%
10%
30%
79%
87%
0 10 20 30 40 50 60 70 80 90 100
Hemophilia
Injection drug users
Surgeons, PSWs*
Hemodialysis
Average Percent Anti-HCV Positive
Gen population adults
Military personnel
STD clients
Pregnant women
* PSWs (personal-service workers) are individuals whose occupations involve close personal contact with clients (e.g., hairdressers, barbers, estheticians, cosmetologists, manicurists, pedicurists, massage therapists).Adapted from CDC Hepatitis Slide Kit http://www.cdc.gov/ncidod/diseases/hepatitis/slideset.
HIV patients
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What’s Not New
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Heroin-associated Mortality
Hser, Y. I., et al. (2001) Arch Gen Psychiatry, 58, 503-8.
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HCV Testing: ALT
42% 43%
15%
0%
20%
40%
60%
80%
100%
Inglesby TV et al. Hepatology. 1999;29:590-596.
Persistentlynormal
ALT
Persistentlyelevated
ALT
Intermittentlyelevated
ALT
Pat
i ent
s w
ithP
rior
I llic
itD
rug
Use
n = 1042, with 4 or more serum ALT level measurements during 25 months of follow-up
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HCV Screening Test: Has the patient been exposed?
Antibody-based EIANot diagnostic of active infectionRemains positive after spontaneous clearance or treatment-related cure
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Quantitative PCR
How much HCV is present?
Qualitative PCR
Is HCV present?
Viral Tests: Does the patient actually have HCV?
Genotype
What type of HCV is present?
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What IS New
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Relative Importance of Risk Factors for Hepatitis C
Remote (>15 yrs ago) Recent (<15 yrs ago)
Transfusion
Sexual
Other*
Unknown
TransfusionInjection Drug Use
Unknown
Other*Sexual
Injection Drug Use
* Nosocomial, occupational, perinatalAdapted from CDC Hepatitis Slide Kit http://www.cdc.gov/ncidod/diseases/hepatitis/slideset
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What’s new in testing
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IL-28B
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Noninvasive tests for liver fibrosis
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APRI {(AST/upper normal AST)/platelet count} x 100Predicts fibrosis >1.5; and cirrhosis >2.0Low chance of fibrosis if < 0.5
FIB-4 (age x AST)/ (platelet count x ALT)Predicts fibrosis >1.0 and cirrhosis > 3.25
Note: all platelet counts in 1000’s ( ie 100K = 100)
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Fibrosure
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Fibroscan
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New medications
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Boceprevir
NS3/4A protease inhibitorIndicated for genotype 1 HCV in combination with peg-interferon and ribavirin
800 mg (4 pills) tid with light mealTreatment algorithm:4 week peg IFN + ribavirin lead in
Triple therapy for 24-44 weeksDuration of treatment 28 – 48 weeks based on response and previous treatment
CYP 3A4: lots of interactions
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40
52
7
6975
29
0
20
40
60
80
100
BOC RGT BOC/PR48 PR48
Previous partial response
Previous relapse
n/N = 23/57 72/105 30/58 77/103 2/29 15/51
SV
R (
%)
SVR rates with boceprevir-based triple therapy higher among previous relapsers vs previous partial responders to pegIFN/RBV therapy (previous null responders excluded from study)
– Both groups had higher SVR rates vs pegIFN/RBV alone
Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.
RESPOND-2: SVR Rates With Boceprevir vs. Prior Response
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Telaprevir
NS3/4A protease inhibitor Indicated for genotype 1 HCV in combination with
peg-interferon and ribavirin750 mg (2 pills) tid with 20g fatTreatment algorithm:
Triple therapy for 12 weeksComplete 24-48 week treatment with pegIFN + riba
CYP 3A4: lots of interactions
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REALIZE: SVR Rates With Telaprevir vs. Prior Response
SVR rates with telaprevir-based triple therapy higher among previous relapsers vs previous partial responders vs null responders to pegIFN/RBV
– All groups had higher SVR rates vs pegIFN/RBV alone
Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.
100
0
60
SV
R (
%)
80
40
Previous Relapsers
Previous Partial Responders
n/N=
Previous Null Responders
*P < .001 vs Pbo/PR48
4/2729/49 26/482/37
21/72 25/7516/68121/145 124/141
20
83*88*
24
59* 54*
15
29*33*
5
T12/PR48 Pbo/PR48LI T12/PR48
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Drug-drug interactions
Methadone CYP 3A4, 2B6, 2D6
Buprenorphine CYP 3A4, 2C8
TVR levels vs. methadone/buprenorphine BVR levels vs. methadone/buprenorphine Methadone vs TVR/BVR Buprenorphine vs. TVR/BVR
Van Heeswijk, R, Vandevoorde, A, et al. The pharmacokinetic interaction between methadone and the investigational HCV protease inhibitor telaprevir. 46th Annual Meeting of the European Association for the Study of the Liver 2011, Abstract 654. Victrelis Package Insert, 2012.
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The Pipeline
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Phase 3, early 2013
Sponsor NS3/4A Pis NS5A replication complex inh
Nucleotide NS5B poly inh
Non-nuc NS5B Pol inh
Riba PEG
Abbott ABT-450/r ABT-267 ABT-333 RBV
BMS Asunaprevir Daclatasvir
Boerhinger Ingelheim
Faldaprevir RBV PEG
Gilead GS5885 Sofosbuvir RBV
Jansen Simeprevir RBV PEG
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ATOMIC trial
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ATOMIC trial
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Abbott
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Abbott
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Treatment as prevention
Magiorkinis G, Sypsa V, et al. Integrating phylodynamics and epidemiology to estimate transmission diversity in viral epidemics. PLoS One, 2013;9(1):e1002876.
Durier, N, Nguyen, C, and White, LJ. Treatment of hepatitis C as prevention: a modeling case study in Vietnam. PLoS One, 2012;7(4):e34548.
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Increasing treatment coverage
Durier, N, Nguyen, C, and White, LJ. Treatment of hepatitis C as prevention: a modeling case study in Vietnam. PLoS One, 2012;7(4):e34548.
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Increasing treatment coverage
Durier, N, Nguyen, C, and White, LJ. Treatment of hepatitis C as prevention: a modeling case study in Vietnam. PLoS One, 2012;7(4):e34548.
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Treating earlier
Durier, N, Nguyen, C, and White, LJ. Treatment of hepatitis C as prevention: a modeling case study in Vietnam. PLoS One, 2012;7(4):e34548.
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Treating earlier
Durier, N, Nguyen, C, and White, LJ. Treatment of hepatitis C as prevention: a modeling case study in Vietnam. PLoS One, 2012;7(4):e34548.
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SummaryNew tests
IL-28B Noninvasive fibrosis tests
New medications Improved outcomes – genotype 1More challenging
Impressive pipeline Interferon-free regimensBetter tolerabilityShorter duration Improved response
Elimination of HCV?
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From: Scott J____ <[email protected]>Subject: Former PatientTo: [email protected]: Thursday, June 18, 2009, 10:48 AM
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Dear Dr. Sylvestre and Staff ,
I am unsure if you remember me or not. In 2005 I took the hep C treatment at your clinic, but had to quit the chemotherapy earlier than planned, as Ihad an opportunity to move to Arkansas. I have had several tests done, the last being a few weeks ago, and the results are still good; no hep C detected !
I have been off of drugs for almost 4 years now, have a wife and a 17 month old son in Arkansas. I am working a good job, and starting college in the fall to get a degree to teach high school English. It feels like a good way to give back to the community.
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I wanted to write and say thank you, from the bottom of my heart. I was in a very bad place, and had made some incredibly bad choices and would probably be dead without your help . It blows my mind how lucky I was to receive treatment for both my addiction and my Hep C, for free. Incredible that both are in remission at this point, I couldn't have done it without you.
So thank you again, I cannot express the warmth I feel for you in my soul. You helped me save myself, and at a time when I thought there was no hope for me.
Sincerely , S____ J_____PS I have sent a picture of me and my son, Amis, hiking in the Ozark mountains.
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