Transcript Document

What’s New in Hepatitis C
Diana L. Sylvestre, MD
University of CA, San Francisco
OASIS Clinic, Oakland, CA
Disclosure Information
What’s New In Hepatitis C
Diana 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
What’s Not New
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 caseby-case basis, and that active injection drug
use in and of itself not be used to exclude
such patients from antiviral therapy.”
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 caseby-case basis, and that active injection drug
use in and of itself not be used to exclude
such patients from antiviral therapy.”
HCV Virology
 + ssRNA:Flavivirus
 1012 virions/day
 Frequent mutations and no proofreading
 Results in HCV variants called quasispecies
Lee W et al. Drugs. 2004;64(7):693-700.
HCV Prevalence by Selected Groups
United States
87%
Hemophilia
Injection drug users
79%
30%
HIV patients
Hemodialysis
10%
STD clients
6%
Gen population adults
3.5%
Surgeons, PSWs*
2%
Pregnant women
1%
0.3%
Military personnel
0
10
20
30
40
50
60
70
80
90
100
Average Percent Anti-HCV Positive
* 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.
What’s Not New
Heroin-associated Mortality
Hser, Y. I., et al. (2001) Arch Gen Psychiatry, 58, 503-8.
HCV Testing: ALT
100%
80%
n = 1042, with 4 or more serum ALT
level measurements during 25 months of follow-up
60%
43%
42%
40%
15%
20%
0%
Persistently
normal
ALT
Intermittently
elevated
ALT
Inglesby TV et al. Hepatology. 1999;29:590-596.
Persistently
elevated
ALT
HCV Screening Test:
Has the patient been exposed?
Antibody-based EIA
Not diagnostic of active infection
Remains positive after
spontaneous clearance or
treatment-related cure
Viral Tests: Does the patient
actually have HCV?
Qualitative PCR
Quantitative PCR
Is HCV present?
How much HCV is present?
Genotype
What type of HCV is present?
What IS New
Relative Importance of Risk Factors for
Hepatitis C
Remote (>15 yrs ago)
Recent (<15 yrs ago)
Injection Drug Use
Transfusion
Transfusion
Injection Drug Use
Unknown
Other*
Unknown
Sexual
Other*
Sexual
* Nosocomial, occupational, perinatal
Adapted from CDC Hepatitis Slide Kit http://www.cdc.gov/ncidod/diseases/hepatitis/slideset
What’s new in testing
IL-28B
Noninvasive tests for liver
fibrosis
APRI
 {(AST/upper normal AST)/platelet count} x 100
 Predicts fibrosis >1.5; and cirrhosis >2.0
 Low 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)
Fibrosure
Fibroscan
New medications
Boceprevir
NS3/4A protease inhibitor
Indicated for genotype 1 HCV in combination with
peg-interferon and ribavirin
800 mg (4 pills) tid with light meal
Treatment algorithm:4 week peg IFN + ribavirin
lead in
Triple therapy for 24-44 weeks
Duration of treatment 28 – 48 weeks based on
response and previous treatment
CYP 3A4: lots of interactions
RESPOND-2: SVR Rates With
Boceprevir vs. Prior Response

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
100
Previous partial response
SVR (%)
80
60
40
75
69
Previous relapse
52
40
29
20
7
0
n/N = 23/57 72/105
30/58 77/103
BOC RGT
BOC/PR48
Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.
2/29
15/51
PR48
Telaprevir
NS3/4A protease inhibitor
Indicated for genotype 1 HCV in combination
with peg-interferon and ribavirin
750 mg (2 pills) tid with 20g fat
Treatment algorithm:
Triple therapy for 12 weeks
Complete 24-48 week treatment with pegIFN
+ riba
CYP 3A4: lots of interactions
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
T12/PR48
Previous
Relapsers
100
83*
LI T12/PR48
Pbo/PR48
Previous Partial
Responders
Previous Null
Responders
88*
SVR (%)
80
59*
60
54*
40
29*
24
15
20
n/N=
0
33*
121/145
124/141
16/68
29/49
26/48
Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.
4/27
5
21/72
25/75
2/37
*P < .001 vs Pbo/PR48
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.
The Pipeline
Phase 3, early 2013
Sponsor
NS3/4A Pis
NS5A
replication
complex inh
Abbott
ABT-450/r
ABT-267
BMS
Asunaprevir
Daclatasvir
Boerhinger
Ingelheim
Faldaprevir
Gilead
Jansen
Non-nuc
NS5B Pol
inh
Riba
ABT-333
RBV
RBV
GS5885
Simeprevir
Nucleotide
NS5B poly
inh
Sofosbuvir
PEG
PEG
RBV
RBV
PEG
ATOMIC trial
ATOMIC trial
Abbott
Abbott
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.
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.
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.
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.
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.
Summary
 New tests
 IL-28B
 Noninvasive fibrosis tests
 New medications
 Improved outcomes – genotype 1
 More challenging
 Impressive pipeline
 Interferon-free regimens
 Better tolerability
 Shorter duration
 Improved response
 Elimination of HCV?
From: Scott J____ <[email protected]>
Subject: Former Patient
To: [email protected]
Date: Thursday, June 18, 2009, 10:48 AM
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 I
had 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.
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.