What’s New in Hepatitis C

Diana L. Sylvestre, MDUniversity of CA, San FranciscoOASIS Clinic, Oakland, CA

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

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 case-by-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 case-by-case basis, and that active injection drug use in and of itself not be used to exclude such patients from antiviral therapy.”

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

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

What’s Not New

Heroin-associated Mortality

Hser, Y. I., et al. (2001) Arch Gen Psychiatry, 58, 503-8.

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

HCV Screening Test: Has the patient been exposed?

Antibody-based EIANot diagnostic of active infectionRemains positive after spontaneous clearance or treatment-related cure

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?

What IS New

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

What’s new in testing

IL-28B

Noninvasive tests for liver fibrosis

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)

Fibrosure

Fibroscan

New medications

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

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

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

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

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

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

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.

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?

From: Scott J____ <sc____@gmail.com>Subject: Former PatientTo: oasisclinic@sbcglobal.netDate: 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 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.

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.