HEPATITIS C IN 2014

Lisa M. Chirch, M.D.Assistant Professor of Medicine

University of Connecticut Health Center

A Local Performance Site of the New England AETC

Disclosures

• None

Objectives

• Describe epidemiology, transmission, and clinical presentation of Hepatitis C infection

• Understand and implement new testing and screening recommendations

• Apply relevant data from recent publications regarding treatment of chronic hepatitis C infection

Hepatitis C - Chapter 3 - 2012 Yellow Book | Travelers' Health | CDCwwwnc.cdc.gov

Magnitude of the Problem• Nearly 4 million persons in United States

infected• Approximately 35,000 new cases yearly• Acute infections on the rise since 2010• <10% chronically infected patients are

treated• Leading cause of

Chronic liver disease Cirrhosis Liver cancer Liver transplantation

http://www.cdc.gov/ncidod/diseases/hepatitis/c/fact.htm.

“Silent Epidemic”

NHANES survey: estimated unidentified HCV infections – 43%

May 2011: U.S. Viral Hepatitis Action PlanFederal platformEducate providers and communitiesIncrease awareness, testing and linkage to

care USPSTF has aligned with CDC on testing

recommendations – Grade B

Ronald Valdiserri – DHHS Deputy Assistant Secretary; The Liver Meeting 2013

Hepatitis C, a Silent Killer, Meets Its Match

November 4, 2013

Sources of Infection with HCV

Indications for HCV screening?

• HIV• IDU• History of chronic HD, transfusion, blood

product or organ transplant prior to 1992• Unexplained persistent elevation in ALT (?

RNA)• and….

Hepatitis C: Screening guidelines

• CDC 2012:• Recommendations for the Identification of

Chronic Hepatitis C Virus Infection Among Persons Born During 1945–1965

• Recommendations and Reports, August 17, 2012

…one-time testing without prior ascertainment of HCV risk for persons born during 1945 -1965, a population with a disproportionately high prevalence of HCV infection and related disease.

2013: Update of Guidance for Clinicians and Laboratories

• MMWR May 2013• Availability of rapid test for HCV antibody

(OraQuick)– Fingerstick or venipuncture– CLIA waiver by FDA in 2011

• Discontinuation of the RIBA HCV • Recommended testing sequence:

MMWR May10, 2013

Question

A 50 year old female with a history of HTN and DM is referred to you after her primary care physician performed hepatitis C antibody testing as part of routine evaluation, which was positive. She would like you to explain the chances that she does NOT have chronic hepatitis C infection. What do you tell her?A) 0%B) 15%C) 50%D) 75%E) 99%

Answer

A 50 year old female with a history of HTN and DM is referred to you after her primary care physician performed hepatitis C antibody testing as part of routine evaluation, which was positive. She would like you to explain the chances that she does NOT have chronic hepatitis C infection. What do you tell her?A) 0%B) 15%C) 50%D) 75%E) 99%

Hepatitis C Virus InfectionNatural History

Stable80% (68%)

HCCLiver failure25% (4%)

Slowlyprogressive75% (13%)

Resolved15% (15%)

Acute HCV

Cirrhosis20% (17%)

Chronic HCV85% (85%)

HCC, hepatocellular carcinoma

Hepatitis C VirusGenotypes in the USA

All others1%

Type 310%

Type 217%

Type 172%

McHutchinson JG, et al. N Engl J Med. 1998;339:1485-1492.

Management of Chronic HCV

Disease SeverityResponse to Therapy

AST/ALTBilirubinAlbuminPro-time (INR)Platelet countLiver histologyTransient Elastography

ALTHCV RNAHCV genotypeLiver histology

IL28B

IL28B:gene coding for IFN-λ3, associated with IFN sensitivity –C/C genotype (vs C/T or T/T) associated with

favorable response to HCV treatment in pts treated with PEG/ribavirin

Clark PJ, Am J Gastroenterol Oct 2010

HCV RNA and Liver HistologyFibrosis

Genotype

NoFibrosis

PortalFibrosis

BridgingFibrosis

Cirrhosis

Serum HCV RNA does not correlate with level of fibrosis

0

2

4

6

8

Lo

g H

CV

RN

A(c

op

ies/

mL

)

1

2

3

4

Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.

How to Stage

Hepatitis C Virus InfectionLiver Biopsy

• Only test that can accurately assess–Severity of inflammation

–Degree of fibrosis

• Determines–Risk for developing cirrhosis in future

–Need for therapy

–Need for ongoing therapy when initial treatment has failed

Sampling error of liver biopsy

Serum Markers of Liver Fibrosis

Fibroscan

Validity of Fibroscan Versus Biopsy

Poynard T, et al. Lancet. 1997;349:825-832.

HCV Fibrosis Progression Effect of Alcohol

Alcohol intake> 50 g/day*< 50 g/day

*50 g is equal to approximately 3.5 drinks

< 10 11-20 21-30 31-40 > 40

Duration of Infection (Years)

4.0

3.0

2.0

1.0

0

Fib

rosi

s S

core

Fibrosis Progression in HCVEffect of Steatosis

2% 4% 7%

18%

6%18%

30% 33%

0

20

40

60

80

100

< 5% 5%-10% 11%-30% > 30%

Percentage of Steatosis at Initial Biopsy

Cu

mu

lati

ve P

rob

abil

ity

of

Fib

rosi

s P

rog

ress

ion

(%

)

Year 4

Year 6

Fartoux L, et al. Hepatology. 2005;41:82-87.

Cumulative Probability of Fibrosis According to Level of Steatosis

Chronic Hepatitis C VirusExtrahepatic Manifestations

• Nonspecific antibodies• Essential mixed

cryoglobulinemia• Glomerulonephritis• Porphyria cutanea

tarda• Leukocytoclastic

vasculitis

• Mooren’s corneal ulcer

• Non-Hodgkin’s lymphoma

• Autoimmune thyroiditis

• Diabetes mellitus• Sjögren’s syndrome

HCV Treatment Goals

Goals of treatment for chronic HCV Viral eradication (undetectable viral load) Delay progression of fibrosis Prevent decompensation, HCC, and death

Best indicator of successful treatment is sustained virologic response (SVR)

Sustained virologic response

SVR: serum HCV RNA is undetectable based on a quantitative HCV RNA assay with lower limit of detection of 50 IU/mL or less at 24 weeks after treatment ends

SVR 12: …12 weeks after treatment ends RVR EVR

Treatment of Chronic HCVPeginterferon and Ribavirin

0

20

40

60

80

100

1 2-3

Genotype

Su

stai

ned

Vir

olo

gic

Res

po

nse

(%

)

PegIFN-2a/RBVPegIFN-2b/RBV

Fried MW, et al. N Eng J Med. 2002;347:975-982. Manns MP, et al. Lancet 2001;358:958-965.

Interferon

• Flu-like symptoms: fatigue, headache, myalgias

• Dose-related myelosuppression– Reversible with dose reduction (cost?)– Use of G-CSF and erythropoietin

• Depression: risk assessment prior to therapy initiation– 35-40%– Management with SSRIs and TCAs

Months

Inci

den

ce/S

ever

ity

Depression

Fatigue

Influenza-like symptoms

Time Course of Treatment-Associated Psychiatric Adverse

Effects

1 2 3 400

20

40

60

80

100

Dan A, et al. J Hepatol. 2006;44:491-498. Constant A, et al. J Clin Psychiatry. 2005;66:1050-1057.

Ribavirin

Nucleoside analog Inhibits inosine monophosphate dehydrogenase Potentiates purine analogs, ie didanosine Immune modulator, shift from Th2 to Th1 response

Teratogenic both men and women must use contraception

during and for 6 months after treatment Dose-dependent hemolytic anemia Increased risk for lactic acidosis

HCV Life Cycle and DAA Targets

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

Receptor bindingand endocytosis

Fusion and

uncoating

Transportand release

(+) RNATranslation

andpolyprotein processing

RNA replication

Virionassembly

Membranousweb

ER lumen

LD

LDER lumen

LD

NS3/4 protease inhibitors

NS5B polymerase inhibitors

Nucleoside/nucleotideNonnucleoside

*Block replication complex formation, assembly

NS5A* inhibitors

Simple Regimen

Short duration, simple, straightforward stopping rules

What Are the Key Elements of an Ideal HCV Regimen?

Pan-Genotypic

Regimen can be used across all genotypes

Highly Effective

High efficacy in traditionally challenging

populations (ie, poor IFN sensitivity, cirrhosis)

Safe and Tolerable

Few or easily manageable adverse

effects

All Oral

PegIFN/RBV replaced with alternate backbone

with low chance of resistance

Easy Dosing

Once daily, low pill burden

HCV Therapy: Past, Present and Future

Interferon

Ribavirin

Pegylatedinterferons

Proof of concept

for DAA (PI)

Suppression of HCV with DAA combination

(PI + NI)

Telaprevir and

boceprevir

Curability of HCV without

interferon

Frequent curability of

diverse populations without IFN

Approval of simeprevir and sofosbuvir with IFN

First approved IFN-free therapy: SOF + RBV for GT2/3

IFN-free DAAcombinations (GT1)

Potential approval ofother DAAs

with IFN

1990 2000 2005 2010 2011 2012 2013 2014 2015-

Telaprevir - PROVE

McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

0

20

40

60

80

100

Wk 4

Pat

ien

ts (

%)

12-wk TVR + 48-wk pegIFN/RBV (n = 79)

12-wk TVR + 24-wk pegIFN/RBV (n = 79)

59*

Wk 12 Wk 24 Wk 48

12-wk TVR + pegIFN/RBV (n = 17)

Control (n = 75)

81*

11

81*

71 68

45

80

N/A

57 57

71

SVR Relapse

N/A

47

65

N/A

35

61†

41

67‡

33

2

23

6

Undetectable HCV RNAN/A, not applicable. *P < .001 vs control. †P = .02 vs control. ‡P = .002 vs control.

Summary of Key Conclusions• 12-week course of TVR with 24 or 48 weeks of

pegIFN/RBV increased SVR rates in treatment-naive patients infected with genotype 1 HCV vs 48 weeks of pegIFN/RBV alone

• TVR also resulted in higher rate of RVR and lower relapse rate compared with pegIFN/RBV

• TVR increased rate of treatment discontinuation due to adverse effects, predominantly anemia, rash, rectal symptoms (FIARRHEA)

• Small subset experienced virologic breakthrough with protease resistance mutations

McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

No Free LunchTreatment is more effective but much more

difficult

Jordan Feld, MD, MPH. Toronto Western Hospital Liver Centre

Other Issues With PI-Based Therapy

Pill burden Food requirement

CYP3A4PI metabolites

Drug-drug interactions

Resistance

BOC = 12/dayRBV = 4-7/day

TVR = 6/dayRBV = 4-7/day

20 grams of fat…

• Breakfast Ideas– 2-egg omelet with 1 ounce shredded cheese; oatmeal with 1

ounce nuts and ½ tablespoon butter; toast with 2 tablespoons unsalted peanut butter and glass of 2% milk; bagel with 2 tablespoons cream cheese and glass of whole milk 1 egg and 1-3 sausage links (check sausage label, need 15 g fat)

• Lunch / Dinner– 6 ounces salmon; ½ box prepared macaroni and cheese; 3

tablespoons of 2 cups of canned chili with meat; sandwich with 3 slices bologna; 1½ beef hot dogs; 1 chicken leg and thigh with skin; burrito with beans, cheese, and guacamole; 2 pork chops; french fries, medium order; quarter-pound hamburger or double cheeseburger

Drug–Drug Interactions a Clinical Challenge With Current Therapy

Several drugs contraindicated; many more require dose adjustment or cautionDrug Class Contraindicated With BOC[1] Contraindicated With TVR[2]

Alpha 1-adrenoreceptor antagonist

Alfuzosin Alfuzosin

Anticonvulsants Carbamazepine, phenobarbital, phenytoin

N/A

Antimycobacterials Rifampin Rifampin

Ergot derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine

Dihydroergotamine, ergonovine, ergotamine, methylergonovine

GI motility agents Cisapride Cisapride

Herbal products Hypericum perforatum (St John’s wort) Hypericum perforatum

HMG CoA reductase inhibitors Lovastatin, simvastatin Lovastatin, simvastatin

Oral contraceptives Drospirenone N/A

Neuroleptic Pimozide Pimozide

PDE5 inhibitor Sildenafil or tadalafil when used for tx of pulmonary arterial hypertension

Sildenafil or tadalafil when used for tx of pulmonary arterial hypertension

Sedatives/hypnotics Triazolam; orally administered midazolam

Orally administered midazolam, triazolam

1Boceprevir [package insert]. November 2012. 2. Telaprevir [package insert]. October 2012.

Limited Efficacy With Telaprevir and Boceprevir in Some Patient Groups

1. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 3. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 4. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 5. Bronowicki J, et al. EASL 2012. Abstract 11. 6. Zeuzem S, et al. EASL 2011. Abstract 5.

0

20

40

60

80

100

SV

R (

%)

Relapser Naive White/

Nonblack

Null Responder

Naive Black Partial Responder

Cirrhotic Null

Responder

68-75[3,4]

53-62[3,4]

*Pooled TVR arms of REALIZE trial.

75-83[1,2]

40-59[1,2]

29-40[1,5]

14[6]*

42-62[3,4]

NaiveCirrhotic

Question A 44 year old male with a history of prior heroin abuse (clean

for 1 year +) is referred for hepatitis C therapy. His HCV RNA level is 5.2 million IU/mL, genotype 1b, ALT 65, and there are no stigmata or lab values to suggest ESLD. He does have a history of depression and anxiety, requiring mirtazapine and citalopram therapy. How should you proceed?

A) get a liver biopsy – this will help me decideB) He cannot receive therapy due to comorbiditiesC) Treat with just IFN/ribavirin, he will not likely

tolerate a PID) Treat with just telaprevir, he will not likely

tolerate IFNE) wait for something better

Answer A 44 year old male with a history of prior heroin abuse (clean

for 1 year +) is referred for hepatitis C therapy. His HCV RNA level is 5.2 million IU/mL, genotype 1b, ALT 65, and there are no stigmata or lab values to suggest ESLD. He does have a history of depression and anxiety, requiring mirtazapine and citalopram therapy. How should you proceed?

A) get a liver biopsy – this will help me decideB) He cannot receive therapy due to comorbiditiesC) Treat with just IFN/ribavirin, he will not likely

tolerate a PID) Treat with just telaprevir, he will not likely

tolerate IFNE) wait for something better

Standard of Care of Chronic HCV Infection- October 2014

www.hcvguidelines.org

Genotype Regimen Duration Considerations

1 Sofosbuvir + Ledipasvir (FDC)

12 weeks (24 for experienced cirrhotics)

FDA approved, not yet in guidance

1 Sofosbuvir + IFN/RBV

12 weeks Minimal drug interactions

1 Sofosbuvir + Simeprevir +/- RBV

12 weeks Off label to dateFor IFN ineligible

2 Sofosbuvir + RBV 12 weeks

3 Sofosbuvir + RBV 24 weeks

NEUTRINO: SVR12 With Sofosbuvir + P/R According to Genotype and

Fibrosis Level

Lawitz E, et al. EASL 2013. Abstract 1411. N Engl J Med 2013; 368:1878-1887

SV

R12

(%

)

92

80

100

80

60

40

20

0No

CirrhosisCirrhosis

252/273 43/54

SVR12 According to Fibrosis Level

SV

R12

(%

)

8996

100100

80

60

40

20

0GT 1 GT 4 GT 5,6

261/292 27/28 7/7

SVR12 According to Genotype

n/N =

COSMOS: SVR12 in Cohorts 1 and 2 by HCV Subgenotype and Baseline Q80K

Cohort 1 (F0-F2 Nulls)*[1] Cohort 2 (F3-F4 Naives/Nulls)*[2]

1. Sulkowski M, et al. EASL 2014. Abstract O7. 2. Lawitz E, et al. EASL 2014. Abstract O165.

SMV/SOF ±RBV

SVR12 (%)

SMV/SOF +RBV

SMV/SOF+RBV

SMV/SOF SMV/SOF

24 Wks 12 Wks Overall

4/4

7/7

8/9

3/3

7/7

3/3

6/6

12/12

8/9

4/4

4/4

5/6

*Excluding patients who discontinued for nonvirologic reasons.

100 10093

8895

100 100

88

10096

SMV/SOF ±RBV

SMV/SOF +RBV

SMV/SOF +RBV

SMV/SOF SMV/SOF

24 Wks 12 Wks Overall

6/6

11/11

11/11

4/4

7/7

4/4

5/5

13/14

7/8

3/3

7/8

3/3

18/18

38/40

25/26

100 100 100 100 100100

80

60

40

20

0

100 100

89

100100 100 100 100

89

100 100

83

100 100

89

GT1b GT1a without Q80K GT1a with Q80K

30/30

7/17

24/27

TURQUOISE II: SVR12 With 3 DAAs + RBV in Cirrhotic Pts by HCV Subtype

12 wks24 wks 100 100

Naive Relapse

100 100 85.7100 100 100

PartialResponse

NullResponse

GT1b

Poordad F, et al. EASL 2014. Abstract O163

SV

R12

(%

)

Naive Relapse PartialResponse

NullResponse

GT1a

59/64

14/15

52/56

13/13

11/11

40/50

10/10

39/42

Virologic failure in 17/380 pts (4.5%); relapse more frequent with 12-wk vs 24-wk treatment (12 vs 1 pt), 7/12 relapsers by posttreatment Wk 12 were GT1a null responders

100

80

60

40

20

0

92.292.9 93.3100 100 100

80.0

92.9100

80

60

40

20

0

22/22

25/25

18/18

20/20

6/7 14/14

3/3 10/10

Summary of Investigational HCV AgentsClass Drug Dosing

NS3/4A protease inhibitor ABT-450/RTV 150/100 mg

NS3 protease inhibitor Asunaprevir 200 mg BID

NS3/4A protease inhibitor Faldaprevir 120 mg or 240 mg QD

NS3 protease inhibitor GS-9451 200 mg QD

NS3/4A protease inhibitor MK-5172 100 mg QD

NS3/4A protease inhibitor Simeprevir* 150 mg QD

NS5B nonnucleoside polymerase inhibitor ABT-333 400 mg BID

NS5B nonnucleoside polymerase inhibitor BMS-791325 75 mg or 150 mg BID

NS5B nonnucleoside polymerase inhibitor Deleobuvir 600 mg BID

NS5B nonnucleoside polymerase inhibitor GS-9669 500 mg QD

NS5B nucleotide polymerase inhibitor Sofosbuvir* 400 mg QD

NS5A inhibitor ABT-267 25 mg QD

NS5A inhibitor Daclatasvir 30 mg BID or 60 mg QD

NS5A inhibitor Ledipasvir** 90 mg QD

NS5A inhibitor MK-8742 20 or 50 mg QD

NS5A inhibitor PI-688 200 mg QD

*FDA approved December 2013; **October 2014

Regimen Genotype Mechanism of Action Approximate SVR in naïve/relapsers

Daclatasvir + Sofosbuvir +/- RBV

1,2,3 NS5A/NS5B polymerase 98/92/89%

ION-1,2,3:Sofosbuvir + Ledipasvir (FDC) +/- RBVN Engl J Med. 2014 Apr 11.

1, naïve and previously treated

Polymerase / NS5A 97-99%

Sof/LDV + RBV or GS 9669

1 Polymerase / NS5A inhibitor + non-nuc.

100/100%

SAPPHIRE-I and –II:ABT-450/RTV + ombitasvir + Dasabuvir + RBVN Engl J Med 2014;370:17.

1 Protease/NS5A/NS5B polymerase/ritonavir

>95%

TURQUOISE-II:ABT-450/RTV + ombitasvir + Dasabuvir + RBVN Engl J Med. 2014 Apr 11. [Epub ahead of print]

1, cirrhosis Protease/NS5A/NS5B polymerase/ritonavir

92-96%

C-WORTHY:MK-5172/MK-8742 +/- RBV

1 2nd gen protease, NS5A 90-100

HALLMARK-DUAL: Daclatasvir + asuneprevir

1b NS5A / 2nd gen protease 73-91%

• Enter the Nonspecialist: – Will Evolving Hepatitis C Therapies Reduce

the Need for Specialized Care?– Graham R. Foster, FRCP, PhD - 10/8/2013

“A rapid expansion of patients and providers will mirror improving efficacies and gentler adverse event profiles…the introduction of a single-tablet regimen for HCV therapy—a development that will propel hepatitis C care to its future in nonspecialist providers offices. Information will be the key to overcoming preconceptions about adverse events and regimen complexities, finally allowing nonspecialists to take a central role in caring for HCV-infected patients”.

Parting thoughts

The last word…“Back to the Future”…? The future is

here. Liang and Ghany

“The Costs of Success” Hoofnagle and Sherker

Connecticut Infectious Diseases Society Annual Meeting, New Haven, CT. May 15, 2014