Updates in Treatment of Hepatitis C

Gene LeSage, MD, FACP, AGAF

Objectives

• • • HCV epidemiology, risk factors, diagnosis and prognosis Interferon (IFN) and Ribavirin (RBV) based therapy Direct acting anti-viral (DAA) therapies

HCV Epidemiology

• • • • Nearly 3% of worldwide population has chronic HCV infection [1,2] – Most common blood-borne infection in United States [3] Up to 75% unaware of HCV infection until liver disease or cancer develops many yrs later [4] HCV infection associated with multiple disease processes [5] – Including liver disease, diabetes, B-cell proliferative disorders, depression, and cognitive disorders Diminishing HCV infection rates, morbidity through prevention an important ongoing public health initiative 1. Lavanchy D. Liver Int. 2009;29:74-81. 2. Shepard CW, et al. Lancet Infect Dis. 2005;5:558-567.

3. IOM. Hepatitis and Liver Cancer. NA Press. 2010. 4. Mitchell AE, et al. Hepatology. 2010;51:729-733. 5. Jacobson IM, et al. Clin Gastroenterol Hepatol. 2010;8:1017-1029.

• • • • • • • •

Hepatitis C Virus Infection

Population at Risk

Transfusion of blood products before 1992 Intravenous drug use Nasal inhalation of cocaine Chronic renal failure on dialysis Incarceration Occupational exposure to blood products Transplantation of an organ/tissue graft from an HCV positive donor Body piercing and potentially tattoo Centers for Disease Control and Prevention. Hepatitis C fact sheet. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/c/fact.htm. Accessed February 1, 2006.

Routes of Transmission

Injecting drug use 60% Sexual 15% Transfusion 10% (before screening) Occupational 4% Other 1%* Unknown 10% * Nosocomial; iatrogenic; perinatal Source: Centers for Disease Control and Prevention

Hepatitis C Virus

Diagnostic Testing

Specifications

Mode of detection Sensitivity Specificity Detection postexposure Use

Diagnostic Test Type Serologic Virologic

Antibodies Virus > 95% Variable 2-6 months > 98% > 98% 2-6 weeks Screening Confirmation

HCV Infection - Liver Biopsy • • Only test that can accurately assess – – Severity of inflammation Degree of fibrosis Determines the following – – – Risk for developing cirrhosis in future Need for therapy Need for ongoing therapy when initial treatment has failed

Hepatitis C Virus

Response to Acute Infection

200 150 + HCV RNA + 100 Resolution Chronic 50 0 0 6 12 Month 18 24

Illustration by Mitchell L. Shiffman, MD.

Prevalence of Anti-HCV, United States, 1999-2002 (NHANES)

Overall prevalence: 1.6% (4.1 million) 3% 2% 1% 0% 8% 7% 6% 5% 4% Men Women Born ~1945-1965 Age Group (years)

Armstrong et al. AASLD 2004.

HCV to HCC Pyramid

HCC Cirrhosis

1% (1% –3%/y) 15% (10% –30%/y)

Chronic Hepatitis

90% (60% –95%/y)

HCV Infection

Graphic courtesy of Dr. H.B. El-Serag.

100% 25 y

Liver Cancer Has the Fastest Growing Death Rate in the United States

Trends in US Cancer Mortality Rates All Other Cancers (Average) Corpus & Uterus, NOS Testis Lung & Bronchus (Female) Esophagus Thyroid Liver -2 -1.5

-1 -0.5

0 0.5

1 1.5

Annual Percent Change (1994–2003) NOS = not otherwise specified.

National Cancer Institute. Seer Summary Figures and Tables. Available at: http://seer.cancer.gov/csr/1975_2003/results_merged/topic_graph_trends.pdf. Accessed on October 17, 2008.

2

Chronic Hepatitis C Infection

Progression to Cirrhosis

Mild 15%-33% Moderate Severe Cirrhosis A Cirrhosis C HCC 20%-33% 0 10 20 Years 30 40

Shiffman ML. Viral Hepatitis Rev. 1999;5:27-43.

50

Established Risk Factors for Progression of Fibrosis and Cirrhosis

 Male gender  Longer duration of infection  Age >40 years at time of infection  Alcohol excess  >50 gm/day - men  >30 gm/day - women  Persistently elevated ALT levels  HIV, HBV coinfections  Organ transplantation

Poynard T, Lancet 1997 349:825-32 Mathurin P, Hepatology 1998 27:868-72 Benhamou J, Hepatology 1999 30:1054-8

Newly-Recognized Risk Factors for HCV Disease Progression

  

Menopausal status Cannabis Insulin resistance



Obesity, metabolic syndrome

No fibrosis 23%

Chronic HCV Infection Normal vs Elevated Serum ALT

Portal 26% Bridging 6% Cirrhosis 6% Portal 20% Bridging 13% Cirrhosis 18% Mild 39% No fibrosis 16% Mild 33% Normal ALT Elevated ALT

Shiffman ML, et al. J Infect Dis. 2000;182:1595-1601.

HCV RNA effect on Liver Histology & Fibrosis  Serum HCV RNA does not correlate with level of fibrosis

8 6 4 2 Genotype 1 2 3 4 0 No Fibrosis Portal Fibrosis

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

Bridging Fibrosis Cirrhosis

HCV and Alcohol

100 80 60 40 20 0 10 20 30 Years Following Exposure 40

Excessive alcohol intake characterized as > 40 g/day for women and > 60 g/day for men.

Wiley TE, et al. Hepatology. 1998:28:805-809.

HCV HCV + alcohol

Past and Future (Estimated) US Incidence and Prevalence of HCV Infection Decline among IDUs 150 100 50 0 1960 1970 1980 1990 2000 Overall incidence 2010 2020 2030 Graphic courtesy of Centers for Disease Control and Prevention.

The Changing Face of HCV in the US

6,000,000 5,000,000 4,000,000 3,000,000 Ever HCV infected All chronic HCV Acute HCV infection Cirrhosis Peak incidence Peak cirrhosis 2,000,000 1,000,000 0 1950 1960 1970 1980 1990 2000 2010 2020 2030 Yr Reprinted from Gastroenterology, 138, Davis GL, et al, Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression, 513-521, Copyright 2010, with permission from Elsevier.

HCV Life Cycle and DAA Targets

Receptor binding and endocytosis Fusion and uncoating (+) RNA LD Translation and polyprotein ER lumen Membranous web LD

NS5A* inhibitors

*Role in HCV life cycle not well defined Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000. Transport and release ER lumen LD Virion assembly RNA replication Nucleoside/nucleotide Nonnucleoside

Sustained virologic response (SVR) as Clinical Endpoint

• • SVR used as endpoint of successful HCV treatment – Defined as undetectable serum HCV RNA levels 24 wks after end of treatment Achieving SVR results in significant reduction of HCV-associated complications and mortality [1,2]

SVR better No SVR better Genotype 1 Genotype 2 Genotype 3

P < .0001

P = .004

P < .0001

0 0.2

0.4

0.6

0.8

1.0

1.2

1.4

All-Cause Mortality HR (95% CI)

1.6

1.8

2.0

1. Morgan TR, et al. Hepatology. 2010;52:833-844. 2. Backus L, et al. 2010 AASLD. Abstract 213.

HCV Standard of Care Prior to May 2011

 GT1 (most common in US, Europe) least responsive to pegIFN/RBV

PegIFN alfa-2a 180 µg/wk + Weight-Based RBV (1000 or 1200 mg/day) for 48 Wks [2]

100

PegIFN alfa-2b 1.5 µg/kg/wk + RBV 800 mg/day for 48 Wks [1]

100

82

80 80

76

60

54 42

60

56 46

40 40 20 20 0 n = 511

Overall

348

GT1

147

GT2/3

0 n = 453

Overall

298

GT1

1. Manns MP, et al. Lancet. 2001;358:958-965. 2. Fried MW, et al. N Engl J Med. 2002;347:975-982. 140

GT2/3

Suboptimal Virologic Responses

8 7 6 PegIFN/RBV Null response Relapse 5 4 Breakthrough 2 log 10 decline 3 2 1 0 Incomplete treatment 0 4 8 Partial response Limit of detection 12 18 24 30 36 42 48 54 60 66 72 78 Wks McHutchison JG, et al. N Engl J Med. 2009;361:580-593.

Development of Viral Resistance

Drug-susceptible quasispecies Drug-resistant quasispecies

Treatment begins Incomplete suppression

 Inadequate potency  Inadequate drug levels   Inadequate adherence Preexisting resistance

Selection of resistant quasispecies Time

Limitations of PegIFN/RBV

• • • In GT1/4 slow responders variable results achieved by extending therapy to 72 wks [1-4] Few options available for patients who fail pegIFN/RBV [5-8] SVR rates consistently lower among blacks, older patients, individuals with advanced cirrhosis [9,10] 1. Berg T, et al. Gastroenterology. 2006;130:1086-1097. 2. Pearlman BL, et al. Hepatology. 2007;46:1688-1694. 3. Sanchez-Tapias JM, et al. Gastroenterology. 2006;131:451-460. 4. Buti M, et al. Hepatology. 2010;52:1201-1207. 5. Poynard T, et al. Gastroenterology. 2009;136:1618-1628. 6. Pearlman BL, et al. AASLD 2009. Abstract 815. 7. Jensen DM, et al. Ann Intern Med. 2009;150:528-540. 8. Bacon BR, et al. Hepatology. 2009;49:1838-1846. 9. Jacobson IM, et al. Hepatology. 2007;46:982-990. 10. Huang CF, et al. J Infect Dis. 2010;201:751-759.

Adherence to PegIFN/RBV: Essential but Challenging

 Retrospective analysis of pegIFN alfa-2b/RBV trials (N = 511) [1] 100 80 • • Only ~ 60% of US patients adhere to HCV therapy [2] Drug exposure correlates with SVR; ≥ 80% adherence correlates with SVR [1,3]

63

60 40

54 53

• Patient self-report overestimates adherence [4] 20 n = 0 35

17

24 72 75 305 • Adherence wanes over time [4] 10 30 50 70

Adherence Rate (%)

90 1. McHutchison JG, et al. Gastroenterology. 2002;123:1061-1069. 2. Mitra D, et al. Value Health. 2010;13:479-486. 3. Raptopoulou M, et al. J Viral Hepat. 2005;12:91-95. 4. Smith SR, et al. Ann Pharmacother. 2007;41:1116-1123.

Limitations of IFN-based therapy

2. Tolerability and acceptance

100 HCV RNA+ Patients

Ineligible patients, 60%

40 Eligible Patients 28 Start Therapy

Eligible patient refusal, 30%

5 Cures

Patient dropout or nonresponse, 75% Modeled on Falck-Ytter Y. Annals 2002.

IL28B Genotype a Strong Predictor of SVR With PegIFN/RBV in Genotype 1 HCV

Whites (n = 871) Blacks (n = 191) Hispanics (n = 75) Factor Associated With SVR Odds Ratio (95% CI) IL28B rs12979860 genotype (CC vs TT) 5.6

6.1

7.3

Baseline HCV RNA (< vs ≥ 600,000 IU/mL) 2.4

3.0

4.2

5.1

Baseline fibrosis (METAVIR F0-F2 vs F3-F4) 1.1

4.1

0.1

1.0

10.0

Ge D, et al. Nature. 2009;461:399-401.

Direct-Acting Antiviral Agents

• • • Directly target HCV Improve virological response when combined with pegIFN/RBV HCV NS3/4A protease inhibitors (PI) boceprevir and telaprevir approved by FDA, May 2011 [1,2] – Indicated in combination with pegIFN/RBV for treatment of GT1 HCV–infected patients who are untreated or who have failed previous therapy 1. Boceprevir [package insert]. May 2011. 2. Telaprevir [package insert]. May 2011. 3.

Key Factors for Considering Treatment Candidacy for PI-Based Therapy

Factor

Genotype Fibrosis stage Treatment experience

Role

 Boceprevir and telaprevir licensed only for patients with genotype 1 HCV   Individuals with mild or moderate fibrosis have better rates of SVR with PI-based triple therapy than those with advanced fibrosis or cirrhosis SVR rates for individuals with cirrhosis are markedly improved with PI-based therapy vs pegIFN/RBV alone, but SVR rates are still lower than for individuals with F0-F3 fibrosis   Treatment-naive patients and previous relapsers or partial responders to IFN-based therapy have excellent response rates with PI-based therapy Both previous partial responders and previous null responders have lower SVR rates with triple therapy than treatment-naive patients or relapsers. Previous null responders have the lowest SVR rates with triple therapy

Boceprevir and Telaprevir Clinical Trials

• Phase III trials leading to approval – Boceprevir plus pegIFN/RBV • SPRINT-2: treatment-naive patients [1] • RESPOND-2: treatment-experienced patients [2] – Telaprevir plus pegIFN/RBV • ADVANCE: treatment-naive patients [3] • ILLUMINATE: treatment-naive patients [4] • REALIZE: treatment-experienced patients [5] 1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 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. Sherman KE, et al. 2010 AASLD. Abstract LB2. 5. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.

4 8 6

Telaprevir Monotherapy and Development of Resistance

Telaprevir Dosing Telaprevir Dosing 8 Patient 1018 Patient 1002 6 4 2 LOD 0 1 14 Days HCV RNA (>100 IU/mL) Wild type T54A V36A/M Kieffer TL, et al. Hepatology. 2007;46:631-639.

2 0 1 R155K/T 36/155 A156V/T 36/156 Days 14 LOD

Phase III SPRINT-2: Boceprevir + PegIFN/RBV in GT 1 Tx-Naive Patients

 Randomized, placebo-controlled trial

Wk 4 Wk 28 Wk 48

Treatment-naive patients with genotype 1 HCV (2 cohorts: N = 938 nonblack and 159 black) PR* (n = 316, 52) PR* (n = 311, 55) BOC + PR* (n = 316 nonblack, 52 black) BOC + PR*

Follow-up

PR* (n = 311 nonblack, 55 black) PR* (n = 311 nonblack, 52 black) *BOC 800 mg q8h; pegIFN alfa-2b 1.5 µg/kg/wk; weight-based RBV 600-1400 mg/day.

† Undetectable HCV RNA at Wk 4 of BOC treatment (ie, at Wk 8) and at all subsequent assays.

Poordad F, et al. N Eng J Med. 2011;364:1195-1206.

Follow-up Follow-up Follow-up Wk 72

SPRINT-2: Response Rates According to Race

4-wk PR → response-guided BOC + PR 100 Nonblack Patients P < .001

80 67 68 60 40 40 20 0 n = 211 213 125 SVR 9 8 21 18 Relapse 23 37 Poordad F, et al. N Eng J Med. 2011;364:1195-1206.

4-wk PR → 44-wk BOC + PR 100 Black Patients 48-wk PR 80 60 42 P = .04

P = .004

53 40 23 20 0 22 29 SVR 12 17 12 3 6 Relapse 14 2

Phase III RESPOND-2: Boceprevir in GT 1 Previous Nonresponders to PegIFN/RBV

Wk 36 Wk 48 Wk 4 Wk 8

PR* (n = 162) BOC + PR* (n = 162)

Follow-up †

PR*

Follow-up †

Treatment experienced patients with GT 1 HCV (N = 403) PR* (n = 161) BOC + PR* (n = 161) PR* (n = 80)

Follow-up † Follow-up †

*BOC 800 mg TID; pegIFN alfa-2b 1.5 µg/kg/wk; weight-based RBV 600-1400 mg/day.

† Follow-up for 24 wks after completion of therapy. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.



RESPOND-2: SVR Rates With Boceprevir-Based Therapy by Previous 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

40

29

20 0

7

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.

Phase III ADVANCE: Telaprevir + PegIFN/RBV in GT 1 Tx-Naive Patients

 Randomized, placebo-controlled trial

Wk 8 Wk 12 Wk 24

TVR + PR* (n = 364) eRVR † : PR* PR* Treatment-naive patients with GT 1 HCV (N = 1088) TVR + PR* (n = 363) eRVR † : PR* PR* PR* (n = 361) *TVR 750 mg q8h; pegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day.

† eRVR = undetectable HCV RNA at Wks 4 and 12.

Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

Wk 48 Follow-up Follow-up Follow-up Follow-up Follow-up Wk 72

ADVANCE: Overall SVR and Relapse Rates

100 80 60 40 P < .0001 for both treatment arms vs control 69 75 44 20 0 n = 250 271 SVR 158 Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

T8PR24/48 (n = 364) T12PR24/48 (n = 363) PR48 (n = 361) n = 28 9 28 9 27 Relapse 64

REALIZE: Telaprevir in GT1 Treatment Experienced Patients

Randomized 2:2:1; stratified by HCV RNA and previous response Wk 4

Telaprevir 750 mg q8h + PR* (n = 266)

Wk 12

Placebo +

PR*

Wk 16

Patients with GT1 HCV who previously failed pegIFN/RBV (N = 632) Placebo +

PR*

(n = 264) Telaprevir 750 mg q8h + PR*

Placebo + PR*

(n = 132) *PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.

PR* PR* PR*

Wk 48

24-wk follow-up for SVR

REALIZE: SVR Rates With Telaprevir Based Therapy by Previous 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

LI T12/PR48

Previous Partial Responders

Pbo/PR48

Previous Null Responders

100

88* 83*

80 60

59* 54*

40

24

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

26/48

15

4/27

29*

21/72

33*

25/75

5

2/37 *P < .001 vs Pbo/PR48

Patients Who Are Not Candidates for PI-Based Therapy

• • • Patients with previous serious adverse events leading to premature pegIFN/RBV treatment discontinuation Contraindications for boceprevir and telaprevir therapy – Pregnant women or men whose female partners are pregnant – Coadministration with other drugs highly dependent on CYP3A4/5 for clearance and for which elevated plasma concentrations associated with serious/life-threatening events – When coadministered with potent CYP3A4/5 inducers where significantly reduced boceprevir or telaprevir plasma concentrations may be associated with reduced efficacy Safety and pharmacokinetics of the PIs have not been studied in patients with decompensated cirrhosis or in liver transplant recipients

Resistance to Protease Inhibitors

• • • • Resistance may develop rapidly with protease inhibitors It is ESSENTIAL that patients take pegIFN/RBV with protease inhibitors NEVER dose reduce a protease inhibitor Always STOP the protease inhibitor if HCV RNA begins to increase

Boceprevir Regimens

• • • Treatment-naive patients – 4-wk

lead-in period

of pegIFN/RBV alone, then

triple therapy

with BOC 800 mg TID + pegIFN/RBV for 24-32 wks • Duration dependent on treatment response* • Followed by

additional 12 wks of pegIFN/RBV alone

for slow responders Previous partial responders and relapsers – 4-wk

lead-in period

of pegIFN/RBV alone, then

triple therapy

with BOC 800 mg TID + pegIFN/RBV for 32 weeks • Followed by

additional 12 wks of pegIFN/RBV alone

for slow responders Previous null responders and all cirrhotic patients – 4-wk

lead-in period

of pegIFN/RBV alone, then

triple therapy

with BOC 800 mg TID + pegIFN/RBV for 44 weeks *Treatment duration covered in detail in next section.

Boceprevir [package insert]. 2011.

Telaprevir Regimens

• • Treatment-naive patients and previous relapsers –

Triple therapy

with TVR 750 mg TID + pegIFN/RBV for 12 wks, followed by 12-36 wks of

pegIFN/RBV alone

• Duration of pegIFN/RBV dependent on treatment response* (except cirrhotics may benefit from full 48-wk course) Previous partial and null responders –

Triple therapy

with TVR 750 mg TID + pegIFN/RBV for 12 wks, followed by 36 wks of

pegIFN/RBV alone

*Treatment duration covered in detail in next section.

Telaprevir [package insert]. 2011.

Pros and Cons of Treating vs Deferring Therapy Once PIs Are Available

  

Treat

Protease inhibitors substantially increase chance of SVR Successful treatment may arrest progression of liver disease (including potential for cirrhosis, HCC, etc) Many patients already “ warehoused warehouse? ” awaiting DAAs, but when is the right time to exit the   

Defer

Current regimens complex, challenging adverse events Potential for better treatment options in future, eg, better response rates, fewer adverse events, shorter duration Risk of resistance if therapy fails; impact on future options?

Study 110: Preliminary Data in HIV/HCV Coinfection

• Higher rates of undetectable HCV RNA at Wks 4 and 12 with telaprevir plus pegIFN/RBV vs pegIFN/RBV alone – Similar results regardless of use of concurrent ART

Undetectable HCV RNA, Wk 4 (ITT)

No ART EFV-based ART 100 80 60 40 20 0 n/N=

71 75 64 70

5/7 12/16 9/14 26/37

Telaprevir + PR

0 0/6

12

1/8

PR

0 0/8

5

1/22 Sulkowski M, et al. 2011 CROI. Abstract 146LB.

Undetectable HCV RNA, Wk 12 (ITT)

ATV/RTV-based ART Total 100 80

71 75 57

60 40 20 0 n/N=

68

5/7 12/16 8/14 25/37

Telaprevir + PR 17

1/6

12

1/8

PR 12

1/8

14

3/22

Select DAAs in Clinical Development

Protease Inhibitors Nonnucleoside polymerase inhibitors Phase I

ABT-450 ACH-1625 GS 9451 MK-5172 VX-985 BI 207127 IDX375

Nucleoside polymerase inhibitors NS5A inhibitors

A-831 PPI-461

Phase II

BMS-650032 CTS-1027 Danoprevir GS 9256 IDX320 Vaniprevir ABT-333 ABT-072 ANA598 BMS-791325 Filibuvir Tegobuvir VX-759 VX-222 IDX184 PSI-7977 RG7128 BMS-790052 BMS-824393 CF102

Phase III

BI 201335 Boceprevir Telaprevir TMC435

Points to remember

• • • Incidence is declining, but prevalence of HCV related cirrhosis will markedly increase in next 10-20 years HCV treatment can induce permanent remission and reduces mortality and morbidly DAAs markedly increases effectiveness of treatment in difficult to treat patients (genotype 1, advanced fibrosis, previously treated and African Americans)