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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 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 Virology

 + ssRNA: Flavivirus  10 12 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 Hemophilia Injection drug users HIV patients Hemodialysis STD clients Gen population adults Surgeons, PSWs* Pregnant women Military personnel 10% 6% 3.5% 2% 1% 0.3% 30% 79% 87% 0 10 20 30 40 50 60 70 Average Percent Anti-HCV Positive 80 90 100

* 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% 60% n = 1042

, with 4 or more serum ALT level measurements during 25 months of follow-up

42% 43% 40% 20% 0%

Persistently normal ALT Intermittently elevated ALT Inglesby TV et al.

Hepatology.

1999;29:590-596.

15%

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 Is HCV present?

Quantitative PCR 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) Transfusion Injection Drug Use Transfusion Unknown Other* Injection Drug Use Unknown Other* Sexual 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 80

69 75

Previous partial response Previous relapse 60

52 40

20 0

n/N = 23/57 72/105 30/58 77/103 2/29 15/51

BOC RGT BOC/PR48 PR48

Bacon BR, et al. N Engl J Med. 2011;364:1207-1217 .

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 100

83*

T12/PR48

Previous Relapsers

LI T12/PR48 Pbo/PR48

Previous Partial Responders Previous Null Responders 88*

59*

54* 33*

20 n/N= 0 121/145 124/141 16/68 29/49 26/48 Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.

4/27

29*

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. 46 th 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

Abbott BMS Boerhinger Ingelheim Gilead Jansen

NS3/4A Pis

ABT-450/r Asunaprevir Faldaprevir Simeprevir

NS5A replication complex inh

ABT-267 Daclatasvir GS5885

Nucleotide NS5B poly inh

Sofosbuvir

Non-nuc NS5B Pol inh

ABT-333

Riba

RBV RBV RBV RBV

PEG

PEG PEG

ATOMIC trial

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.

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