Advances in the Treatment ofChronic Hepatitis C

Gregory T Everson, MDProfessor of MedicineDirector of Hepatology

University of Colorado Denver

Disclosures

Advisory Boards: Roche/Genentech, Merck, Vertex, BMS, GlobeImmune, Abbott, Eisai, Novartis, Pfizer, Gilead, Biotest, Tibotec/Janssen

Consulting: Roche-Genentech, Novartis, BMS, Eisai,Kadmon, Vertex, Abbott, Biotest, Tibotec/Janssen

DSMB: CentocorStock/Ownership: Source, HepQuant LLCManagement: HepQuant LLCResearch Grants: Roche/Genentech, Schering-Plough/Merck,

Vertex, GlobeImmune, Gilead, Novartis, BMS, Pfizer, Source, Eisai, GSK, Pharmassett,Ortho Biotech, Tibotec/Janssen, Amgen, Medtronic, Abbott

Primer on HCV

Worldwide Prevalence of HCV

WHO, Wkly Epidemiol Rec, 2000

Genotype and Viral Load in US

50%

24%

22%4%

Geno 1 HVL> 800,000 IU/ml

Geno 2 & 3

Geno 1 LVL

Approximately 2/3 cases of GT1 infection in the USare due to the GT1a subtype.

Natural History of HCV Infection

Mild Moderate Severe

15%-45% 55%-85%

Acute HCV InfectionAcute HCV Infection

RecoveryRecovery Chronic HCV InfectionChronic HCV Infection

Chronic Hepatitis CChronic Hepatitis C

CirrhosisCirrhosis

Hepatocellular CarcinomaHepatocellular CarcinomaEnd-Stage Liver DiseaseEnd-Stage Liver Disease

Liver TransplantationLiver Transplantation DeathDeath

There are an estimated 3 to 5 million cases of chronic hepatitis C in the US.

Hepatitis C Testing for Anyone Born During1945-1965: New CDC Recommendations

If you were born during 1945-1965 (baby boomer), talk to

your doctor about getting tested for Hepatitis C. The only

way to know if you have Hepatitis C is to get tested.

Early detection can save lives.

Reasons for this recommendation:1. Baby boomers – represent 75% of cases in US). 2. This one-time testing may prevent more than 120,000 deaths.3. Most cases are undiagnosed - testing would find 800,000 new cases.4. There have been recent advances in treatment.

Source: CDC. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945–1965. MMWR 2012;61(No. RR–4).

Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born

during 1945–1965*

• Adults born during 1945–1965 should receive one-time testing for HCV without prior ascertainment of HCV risk.

• All persons with identified HCV infection should receive a brief alcohol screening and intervention as clinically indicated, followed by referral to appropriate care and treatment services for HCV infection and related conditions.

Source: CDC. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945–1965. MMWR 2012;61(No. RR–4).

Case

A baby boomer is screened for HCV and HCV-Ab is positive. You order a polymerase-chain-reaction-based test for HCV RNA quantification. What is the likelihood

that the HCV RNA will be positive?

1. 0%

2. ~ 25%

3. ~ 50%

4. ~ 75%

5. 100%

A baby boomer is screened for HCV and HCV-Ab is positive. You order a polymerase-chain-reaction-based test for HCV RNA quantification. What is the likelihood

that the HCV RNA will be positive?

1. 0%

2. ~ 25%

3. ~ 50%

4. ~ 75%

5. 100%

The HCV RNA is positive. Standard laboratory tests are normal except for ALT 85 IU/mL. Further evaluation reveals HCV genotype 1a, advanced fibrosis (F3), and

IL28B genotype CT. Given these factors, what would you advise for treatment?

1. None

2. Silymarin (milk thistle)

3. Peginterferon alone

4. Peginterferon + Ribavirin

5. Peginterferon + Ribavirin + DAA

The HCV RNA is positive. Standard laboratory tests are normal except for ALT 85 IU/mL. Further evaluation reveals HCV genotype 1a, advanced fibrosis (F3), and

IL28B genotype CT. Given these factors, what would you advise for treatment?

1. None

2. Silymarin (milk thistle)

3. Peginterferon alone

4. Peginterferon + Ribavirin

5. Peginterferon + Ribavirin + DAA

Treatment

The Goal of Treatment is SVRSustained Virologic Response

Undetectable HCV RNA - 3 months (SVR12) or6 months (SVR24) after Treatment

The Primary Objective ofTherapy for Chronic Hepatitis C

SVR Equates with CURE

Swain MG, et al. Gastroenterology 2010;139:1593-1601.

Established Benefits of SVR

1. Probably “Cured” of HCV infection – chance for late relapse <1%.

2. Halts progression of liver disease.

3. Reduces risk for HCC – although patients with bridging fibrosis or cirrhosis may develop HCC after SVR and still need to be screened.

4. HCV-related extrahepatic manifestations disappear or are ameliorated

5. Health-related (HCV) Quality of Life Improves

Past and Current Treatment for HCV GT2 & 3

1629

69 6680

0

20

40

60

80

100

IFN 24 IFN 48 IFN/RBV 24 IFN/RBV 48 PEG/RBV 24

% of Patients Achieving SVR

1991 Year of FDA Approval 2002

Triple TherapyThe Current Standard-of-Care for

HCV Genotype 1

First Generation Protease Inhibitors

TelaprevirBoceprevir

with Peginterferon/Ribavirin

Past and Current Treatment for HCV GT1

27

1628

40

75

0

20

40

60

80

100

IFN 24 IFN 48 IFN/RBV 24 IFN/RBV 48 PEG/RBV 48 TT-TPV

% of Patients Achieving SVR

1991 Year of FDA Approval 2002 2011

Predictors of SVR with TT inTreatment Naïve Patients

Interferon Sensitivity IL28B Polymorphism HCV RNA decline during Lead-In with

PEG/RBV

On-treatment (TT) Response (eRVR)

Stage of Fibrosis

IL28b Polymorphism

Telaprevir (TPV): Treatment-NaïveSVR by IL28B Polymorphism

64

90

25

71

23

73

0

20

40

60

80

100

PR TPV-based

% SVR

CC CT TT CC CT TT

∆ = 18%

∆ = 50%

Boceprevir (BOC): Treatment-NaïveSVR by IL28B Polymorphism

78 82 80

28

6571

27

55 59

0

20

40

60

80

100

PR BOC-RGT BOC-48

% SVR

CC CT TT CC CT TTCC CT TT

∆ = 9 to 27%

∆ = 50%

IL28b Polymorphism inTreatment-Naïve

1. Highly predictive when treatment is peginterferon plus ribavirin (PR)

2. Less predictive when treatment has higher chance of success in CT and TT polymorphisms – less predictive when treatment is triple therapy.

Lead-In

Boceprevir Trial of Treatment-Naïve(SPRINT-2)

Boceprevir (BOC): Treatment-NaïveSVR by Log10 HCV RNA Decline during Lead-In with PR

4

2838

51

81 79

0

20

40

60

80

100

PR BOC-RGT BOC-48

< 1 Log10 Decline ≥ 1 Log10 Decline

% SVR

SPRINT-2 Study. N Engl J Med 2011;364:1195-1206.

Lead-In inTreatment-Naïve

1. Predicts likelihood of SVR with Boceprevir-based triple therapy

2. SVR is still greater than 30% in the patients treated with triple therapy who have < 1 Log10 decline in HCV RNA during Lead-in - < 1 Log10 decline is NOT a Stop Guideline

Extended Rapid Virologic Response(eRVR)

Extended Rapid Virologic ResponseeRVR Identifies the “Super” Responders who can Stop Early

Two components of eRVR HCV RNA <10 IU/mL at Week 4 of Triple Therapy (RAPID) HCV RNA <10 IU/mL subsequently (EXTENDED)

Telaprevir (T12/PR24) HCV RNA <10 IU/mL Weeks 4 through 12 Stop treatment at Week 24 (58% & 65% of patients1) ILLUMINATE, randomized trial of eRVR, 24 vs 48 wks PR

Boceprevir (LI PR4, B24/PR24) HCV RNA <10 IU/mL Weeks 8 through 24 eRVR – Stop treatment at Week 28 (44% of patients2)

1 ADVANCE. N Engl J Med 2011;364:2405-2416. ILLUMINATE. N Engl J Med 2011;365:1014-1024.2 SPRINT-2. N Engl J Med 2011;364:1195-1206.

eRVR and Treatment DurationILLUMINATE study of Telaprevir – 65% Achieved eRVR

92 88

0

20

40

60

80

100

24 Weeks 48 Weeks

% SVR

ILLUMINATE Study. N Engl J Med 2011;365:1014-1024.

Stage of Fibrosis

Impact of Stage of FibrosisTelaprevir and Boceprevir: Treatment-Naive

0

20

40

60

80

100

ADVANCE T12 ADVANCE T8 ILLUMINATEeRVR24

ILLUMINATEeRVR48

SPRINT-2 RGT SPRINT-2 48

F0-F2 F3-F4

SVR (%)

Jacobson IM, et al. ADVANCE trial. N Eng J Med 2011;364:2405-2416.Sherman KE, et al. ILLUMINATE trial. N Engl J Med 2011;365:1014-1024.

Poordad F, et al. SPRINT-2 trial. N Engl J Med 2011; 364:1195-1206.

* Biggest Impact of reducing duration of TPV in ADVANCE, or PR in ILLUMINATE, was in F4 patients.

*

*

Case

The Patient Elects Treatment with Telaprevir-based Triple Therapy. HCV RNA is undetectable from Weeks 1 through 8.

Base Wk 1 Wk 4 Wk 8 Post-Rx Wk4

Post-Rx Wk12

Post-Rx Wk16

Post-Rx Yr2

0

500000

1000000

1500000

2000000

2500000

3000000

Diverticulitis

GT1a, F3, IL28b CTNo viral variants at baseline

HCV RNA negative

HCV RNA (IU/mL)

The patient is admitted to the hospital with fever, LLQ abdominal pain, and leucocytosis. CT confirms sigmoid

diverticulitis and blood cultures were positive for E. coli. Best management includes antibiotic therapy and:

1. Continuation of TPV, PEG, and RBV

2. Continuation of PEG and RBV only

3. Continuation of PEG only

4. Discontinuation of TPV, PEG, and RBV

The patient is admitted to the hospital with fever, LLQ abdominal pain, and leucocytosis. CT confirms sigmoid

diverticulitis and blood cultures were positive for E. coli. Best management includes antibiotic therapy and:

1. Continuation of TPV, PEG, and RBV

2. Continuation of PEG and RBV only

3. Continuation of PEG only

4. Discontinuation of TPV, PEG, and RBV

Pitfalls of Current DAA Rx

• Single DAA – low barrier to resistance• Only indicated for HCV GT1• Complex treatment algorithms• High pill burden• Rx duration of 24 to 48 weeks• Requires PEG/RBV – SEs, AEs, SAEs• Unique SEs, AEs, SAEs• Drug-Drug Interactions

Viral Resistance

Case

TPV, PEG, and RBV are discontinued and HCV RNA is monitored.

Base Wk 1 Wk 4 Wk 8 Post-Rx Wk4

Post-Rx Wk12

Post-Rx Wk16

Post-Rx Yr2

0

500000

1000000

1500000

2000000

2500000

3000000

V36M -T54A -R155K -A156V -

Stopped allMeds due toDiverticulitis

HCV RNAPositive30 IU/mL

HCV RNA negative

After confirming relapse by repeat testing of HCV RNA, a blood sample is analyzed for variants of HCV resistant to TPV.

Base Wk 1 Wk 4 Wk 8 Post-Rx Wk4

Post-Rx Wk12

Post-Rx Wk16

Post-Rx Yr2

0

500000

1000000

1500000

2000000

2500000

3000000

V36M - -T54A - -R155K - +A156V - -

Stopped allMeds due toDiverticulitis

R155KDetected

HCV RNAPositive

HCV RNA negative

Complex Treatment Algorithms

Telaprevir: Treatment-Naïve Patients

TripleTherapy

withTPV+P+R

For12 weeks

Additional12 weeks of

P+R*

Additional36 weeks of

P+R

eRVRHCV RNA negative

At Weeks 4 & 12

NO eRVRSlow Responder**

HCV RNA is quantified at weeks 4, 8, 12 while the

patient is taking TPV – to evaluate for viral response

and resistance.

TPV is stopped if there is evidence of rebound in HCV

RNA.Treatment is discontinued if HCV

RNA is >1000 IU/mL at week 4 or 12 or detectable at week 24

* FDA recommends extending P+R for 36 weeks in patients with cirrhosis.** Slow responder is RNA positive at week 4 but RNA negative prior to or at week 24.

Boceprevir: Treatment-Naïve Patients

Lead-InWith

4 weeksP+R

TripleTherapy

withBOC+P+R

For additional24 weeks*

Noadditional

Treatment*

(28 weeks total)

Additional8 weeks of

BOC+P+R and 12 weeks P+RTreatment*

(48 weeks total)

eRVR’8 - 24 wk RNA neg

NO eRVR’Slow Responder

HCV RNA at Weeks 4, 8, 12, 24 while the patient is taking BOC – to evaluate for viral response and resistance.

All treatment is discontinued if either HCV RNA >100 IU/mL at wk 12

or HCV RNA detectable at wk 24

The drop in HCV RNA predicts likelihood of

responding to subsequent triple therapy with BOC.

Patients with <1log10 decrease (Poor response)

have SVR ~30%.

* Cirrhotic patients and Poor Responders are treated for 44 weeks BOC+P+R, regardless of eRVR’.** Slow responders are RNA positive at week 8 but RNA negative prior to or at week 24.

Unique Side Effects

Telaprevir and Rash

Can be nasty (DRESS, S-J syndrome)!

Occurs in over 50% of patients, mild in most cases (hydroxyzine, topicals)

Telaprevir discontinued in 5 - 10% due to rash. Systemic steroids may be required. All treatment stopped in 1-2% due to rash.

Ribavirin Rash

Telaprevir – Mild to Moderate Rash

Telaprevir – Moderate to Severe Rash

December 19, 2012. The U.S. Food and Drug Administration (FDA) received reports of serious skin reactions, some fatal, in patients taking the hepatitis C drug Incivek (telaprevir) in combination with the drugs peginterferon alfa and ribavirin (Incivek combination treatment). Significantly, some patients died when they continued to receive Incivek combination treatment after

developing a worsening, or progressive rash and systemic symptoms (symptoms affecting the entire body). As a result, FDA is adding a boxed

warning to the Incivek drug label stating that Incivek combination treatment must be immediately stopped in patients experiencing a rash with systemic symptoms or a progressive severe rash. Consideration should also be given to stopping any other medications that may be associated with serious skin reactions. Typical systemic symptoms and signs may include fever, nausea,

diarrhea, mouth sores or ulcers, facial swelling (edema), red or inflamed eyes, or swelling or inflammation of the liver (hepatitis). All patients with

serious skin reactions should also receive urgent medical care.

Black Box Warning – Severe Rash

Telaprevir and Anal Pain

Ring of Fire! Aggravating.

Occurs in about 20% of patients, mild in most, occasionlly severe. Topical lidocaine, steroid supporitories. May respond to amitryptyline?

Typically have not stopped treatment due to this.

Anemia

Telaprevir and Boceprevir

Med

ian

Hem

og

lob

in (

g/d

L)

0

Weeks

4 8 12 16 20 24

11

12

13

14

15

8

9

10

Anemia during triple therapy withTelaprevir or Boceprevir

CHC PegIFN+RBV

CHC PegIFN+RBV+ TPV

CHC PegIFN+RBV+BOC

McHutchison JG et al, N Engl J Med. 2010

Poordad F, et al. Hepatology 2010;52(Suppl.):402ABacon, B, et al. Hepatology 2010; 52(Suppl):430A

This Slide courtesy of X Forns, MDModified by GTE

Management of Anemia

Step 1: RBV Dose Reduction

Step 2: EPA therapy

Step 3: Transfusion

Step 4: Discontinuation of TPV or BOC

Drug-Drug Interactions(CNIs)

Drug XOral

Drug XIV

KidneyP-gp → Urine

CYP3A4 → Metabolism

LiverP-gp → Bile

CYP3A4 → Metabolism

IntestineP-gp → Int Lumen

CYP3A4 → Metabolism

Drug X SystemicExposureIncreases

IS MedsStatins

BenzodiazepinesAntipsychotics?

E-mycinsAnticonvulsants

HIV PIs, NNIsα-Adren BlkrsCa++-Ch Blkrs

Impact of BOC or TPV on Drug X

X

X

X

X

X

X

Kiser J, et al. Review and Management of Drug Interactions with Boceprevir and Telaprevir. Hepatology 2012;55:1620-8

Garg V, et al. Effect of Telaprevir on the PK of CSA and TAC. Hepatology 2011;54:20-27.

Tacrolimus

0

1

2

3

4

5

6

7

8

9

Ratio AUCs for Drug (w/wo TPV)

From tables in Prescribing Information for INCIVEK, May 2011Kiser J, et al. Review and Management of DDIs with Boceprevir and Telaprevir. Hepatology 2012.

Drug X AUC Ratio w/wo TPV

Management

• Dose Adjust DRUG X

• Adjust Duration between doses of DRUG X

• Monitor Closely– Drug Levels– Laboratory Parameters– Clinical Assessment of the Patient

Resources for DDIs

• Outstanding – University of Liverpool (David Back, Editorial Board, EASL reps); sponsored by Janssen, MSD, Roche, Vertex:– http://www.hep-druginteractions.org

• FDA:– http://www.fda.gov/Drugs/DrugSafety/

• Other Online Resources –– http://www.drugs.com/drug-interactions/html– http://www.merckmedicus.com/pp/us/hep– Epocrates– Micromedex, Lexicomp and Others

Goals of Future Treatments Improve rates of SVR to 100% Activity against all HCV genotypes and subtypes Simplify treatment algorithms Extend treatment to the “difficult to treat”, “difficult to cure”

Eliminate side effects Eliminate peginterferon Eliminate ribavirin Avoid rash, anemia, anal pain, and dysgeusia Reduce drug-drug interactions

Reduce complexity and pill burden by avoiding - Injections (shots) 24, up to 48, total Ribavirin up to 6/d Telaprevir 6/d x 3 months Boceprevir 12/d from 24 to 44 wks

Reduce treatment duration

Reduce costs

What’s on the Horizon?

HCV Proteins and their Functions

Charles M. Rice, PhD. Top Antivir Med 2011;19:117-120.

Timelines

2011 2013 2015 2017

PR

PR + 1st Gen DAA

PR + 2nd Gen DAA

IFN-FreeRegimens

QUAD or QUINT Rescue

Simiprevir

Inhibitor of NS3/4a Protease

Daclatasvir

Inhibitor of NS5a Protein

Sofusbivir

Inhibitor (Nuc) of NS5b Polymerase

Regimens of DAA + PEG/RBV(Virologic Responses in Rx-Naïve Patients with HCV GT1)

BOC MCB TPV DAC DNV SMV FDP SOF ABT0

20

40

60

80

100

50

6065

78 79 8287

92100

% of Pts with HCV RNA (<10 IU/mL) weeks 4 - 12

Increased potency also reduces risk for emergence of resistant viral variants – e.g., MK-5172 isactive in vitro against common variants with resistance to TPV or BOC.

Case

Two years after triple therapy another blood sample is analyzed for resistant variants of HCV.

Base Wk 1 Wk 4 Wk 8 Post-Rx Wk4

Post-Rx Wk12

Post-Rx Wk16

Post-Rx Yr2

0

500000

1000000

1500000

2000000

2500000

3000000

V36M - - -T54A - - -R155K - + -A156V - - -

Stopped allMeds due toDiverticulitis

R155KDetected

WT

HCV RNAPositive

HCV RNA negative

Within a few weeks of discontinuing Triple Therapy, the patient had relapsed and tested positive for R155K, an

HCV variant with resistance to TPV. On retesting, 2 years after triple therapy, only wild-type and no variant of HCV could be detected. Assuming all options listed below are

available, which re-treatment would be most successful in achieving SVR?

1. Peginterferon/Ribavirin (PR)

2. Telaprevir + PR

3. Boceprevir + PR

4. Simeprevir + PR

5. Sofusbevir + PR

Within a few weeks of discontinuing Triple Therapy, the patient had relapsed and tested positive for R155K, an

HCV variant with resistance to TPV. On retesting, 2 years after triple therapy, only wild-type and no variant of HCV could be detected. Assuming all options listed below are

available, which re-treatment would be most successful in achieving SVR?

1. Peginterferon/Ribavirin (PR)

2. Telaprevir + PR

3. Boceprevir + PR

4. Simeprevir + PR

5. Sofusbevir + PR

IFN-Free Combinations

Dual DAA (Daclatasvir+Asunaprevir)

GT 1 Null Responders to PEG/RBV

DUAL DAA in GT1 Null Responders Daclatasvir + Asunaprevir (n=11)

RVR cEVR EOT SVR120

20

40

60

80

100

63.6

45.5 45.536.4

% HCV RNA <10 IU/mL

Lok A, et al. RVR/cEVR presented at AASLD 2010. SVR12 presented EASL 2011. N Engl J Med 2012;366:216-224 .Daclatasvir 60 mg qd, Asunaprevir 600 mg bid, 24 weeks treatment.

All breakthroughsOccurred in

Patients with G1a

QUAD (or QUINT) Therapy

When all else fails!

QUAD in the Treatment of G1 Null RespondersBMS-790052/BMS-650032 + PR (n=10), 24 Weeks of Rx

RVR cEVR EOT SVR120

20

40

60

80

100

60

100 10090

% HCV RNA <10 IU/mL

Lok A, et al. N Engl J Med 2012;366:216-224.790052 60 mg qd, 650032 600 mg bid; SVR at week24 post-Rx

Optimistic Results in Phase 2 TrialsGT

2/3

SOF

R 12

W

GT2/

3 SO

F DA

C...

GT1b

DAC

ASV

24W

GT1a

DAC

ASV

P...

GT1

CC 5

885

945.

..

GT1

CC 5

885

945.

..

GT1

SOF

DAC

12W

GT1

DAC

ASV

71...

GT1

AA D

tT S

OF

...

GT1

ABT4

50r 2

67...

GT1

Nul

l ABT

450.

..

GT1

Fib

DNV

MER

...

GT1b

Nul

l DAC

A...

GT1

Nul

l DAC

AS.

..

GT1b

FAL

127

R...

GT1a

FAL

127

R...

GT1

SOF

PR 1

2W

GT4

SOF

PR 1

2W

GT6

SOF

PR 1

2W

GT1

SOF

5885

R...

0

20

40

60

80

100

% SVR

Thompson A, et al. Six Weeks of an NS5A Inhibitor (GS-5885) and a Protease Inhibitor (GS-9451) Plus Peginterferon+Ribavirin Achieves High SVR4 Rates in Genotype 1 IL28B CC Treatment-Naïve Hepatitis C Virus Patients: Interim Results of a Prospective, Randomized Trial. AASLD

2012.

Lok AS, et al. Preliminary Study of two antiviral agents for Hepatitis C Genotype 1. N Engl J Med 2012;366:216-224.

Chayama K, et al. Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders. Hepatology 2012;55:742-748.

Sulkowski M, et al. High Rate of Sustained Virologic Response With the All-Oral Combination of Daclatasvir (NS5A Inhibitor) Plus Sofosbuvir (Nucleotide NS5B Inhibitor), With or Without Ribavirin, in Treatment-Naive Patients Chronically Infected With HCV GT 1, 2, or 3. AASLD 2012.

Everson GT, et al. An Interferon-Free, Ribavirin-Free 12-Week Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 Yielded SVR4 of 94% in Treatment-Naïve Patients with Genotype (GT) 1 Chronic Hepatitis C Virus (HCV) Infection. AASLD 2012.

Osinusi A, et al. High Efficacy of GS-7977 in Combination with Low or Full dose Ribavirin for 24 weeks in Difficult to Treat HCV Infected Genotype 1 Patients. AASLD 2012.

Kowdley KV, et al. A 12-week Interferon-free Treatment Regimen With ABT-450/r, ABT 267, ABT-333, and Ribavirin Achieves SVR12 Rates (Observed Data) of 99% in Treatment-naïve Patients and 93% in Prior Null Responders With HCV Genotype 1 Infection. AASLD 2012.

Jacobson IM, et al. Safety and efficacy of ritonavir-boosted danoprevir (DNVr), peginterferon alfa-2a (40KD), and ribavirin with or without mericitabine in HCV genotype 1-infected treatment-experienced patients with advanced hepatic fibrosis: the MATTERHORN study. AASLD

2012.

Lok AS, et al. Sustained Virologic Response in Chronic HCV Genotype (GT) 1-Infected Null Responders With Combination of Daclatasvir (DCV; NS5A Inhibitor) and Asunaprevir (ASV; NS3 Inhibitor) With or Without Peginterferon Alfa-2a/Ribavirin (PEG/RBV) . AASLD 2012.

Zeuzem S, et al. Sustained Virologic Response in Chronic HCV Genotype (GT) 1-Infected Null Responders With Combination of Daclatasvir (DCV; NS5A Inhibitor) and Asunaprevir (ASV; NS3 Inhibitor) With or Without Peginterferon Alfa-2a/Ribavirin (PEG/RBV) . AASLD 2012

Hassenein T, et al. Once Daily Sofosbuvir (GS-7977) plus PEG/RBV In Treatment-Naïve Patients With HCV Genotype 1, 4, and 6 Infection: The ATOMIC Study. AASLD 2012.

Gane E, et al. 100 Percent Sustained Virologic Response Rate (SVR4) for an Interferon-Free Regimen of Sofosbuvir (GS-7977), GS-5885 and Ribavirin in Treatment-Naïve Genotype 1 Hepatitis C Infected Patients. AASLD 2012.

The Promise of Future Treatments

1. Pan-genotypic coverage

2. IFN-Free Regimens (Gilead, Abbott, BMS, Roche/Genentech, BI)

3. Greater Potency – higher rates of SVR

4. Shortened Duration of Treatment

5. Improved Tolerability and Safety

6. Less bone marrow suppression or hemolysis

Perspective

Future Treatment for HCV GT1

2 716

2840

70 85 92 98100

020406080

100

% of Patients with SVR

1991 Yr of FDA Approval 2011 2013 2015

Future Treatment for HCV GT2 & 3

1629

69 6680 90 100 100

020406080

100

% of Patients with SVR

1991 Yr of FDA Approval 2002 2013 2015

The Real Impact Could Be -

1. Reduction in costs of care for HCV

2. Reduction in liver-related death

3. Reduction in Hepatocellular carcinoma

4. Reduction in need for liver transplantation

5. Reduction in autoimmune disorders

6. Reduction in adult-onset diabetes mellitus

7. Reduction in B-cell lymphoma