Advances in the Treatment of Chronic Hepatitis C Gregory T Everson, MD Professor of Medicine Director 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:Centocor Stock/Ownership:Source, HepQuant LLC Management: HepQuant LLC Research 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 Geno 1 HVL > 800,000 IU/ml Geno 2 & 3 Geno 1 LVL Approximately 2/3 cases of GT1 infection in the US are due to the GT1a subtype.

Natural History of HCV InfectionMildModerateSevere 15%-45%55%-85% Acute HCV Infection RecoveryRecovery Chronic HCV Infection Chronic Hepatitis C CirrhosisCirrhosis Hepatocellular Carcinoma End-Stage Liver Disease Liver Transplantation DeathDeath There are an estimated 3 to 5 million cases of chronic hepatitis C in the US.

Hepatitis C Testing for Anyone Born During : New CDC Recommendations If you were born during (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 SVR Sustained Virologic Response Undetectable HCV RNA - 3 months (SVR12) or 6 months (SVR24) after Treatment The Primary Objective of Therapy for Chronic Hepatitis C

SVR Equates with CURE Swain MG, et al. Gastroenterology 2010;139:

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 % of Patients Achieving SVR 1991Year of FDA Approval 2002

Triple Therapy The Current Standard-of-Care for HCV Genotype 1 First Generation Protease Inhibitors Telaprevir Boceprevir with Peginterferon/Ribavirin

Past and Current Treatment for HCV GT1 % of Patients Achieving SVR 1991Year of FDA Approval

Predictors of SVR with TT in Treatment 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-Naïve SVR by IL28B Polymorphism % SVR CC CT TT ∆ = 18% ∆ = 50%

Boceprevir (BOC): Treatment-Naïve SVR by IL28B Polymorphism % SVR CC CT TT ∆ = 9 to 27% ∆ = 50%

IL28b Polymorphism in Treatment-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-Naïve SVR by Log 10 HCV RNA Decline during Lead-In with PR % SVR SPRINT-2 Study. N Engl J Med 2011;364:

Lead-In in Treatment-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 Log 10 decline in HCV RNA during Lead-in - < 1 Log 10 decline is NOT a Stop Guideline

Extended Rapid Virologic Response (eRVR)

Extended Rapid Virologic Response eRVR 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 patients 1 )  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 patients 2 ) 1ADVANCE. N Engl J Med 2011;364: ILLUMINATE. N Engl J Med 2011;365: SPRINT-2. N Engl J Med 2011;364:

eRVR and Treatment Duration ILLUMINATE study of Telaprevir – 65% Achieved eRVR % SVR ILLUMINATE Study. N Engl J Med 2011;365:

Stage of Fibrosis

Impact of Stage of Fibrosis Telaprevir and Boceprevir: Treatment-Naive SVR (%) Jacobson IM, et al. ADVANCE trial. N Eng J Med 2011;364: Sherman KE, et al. ILLUMINATE trial. N Engl J Med 2011;365: Poordad F, et al. SPRINT-2 trial. N Engl J Med 2011; 364: * 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. Diverticulitis GT1a, F3, IL28b CT No 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. Stopped all Meds due to Diverticulitis HCV RNA Positive 30 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. Stopped all Meds due to Diverticulitis R155K Detected HCV RNA Positive HCV RNA negative

Complex Treatment Algorithms

Telaprevir: Treatment-Naïve Patients Triple Therapy with TPV+P+R For 12 weeks Additional 12 weeks of P+R* Additional 36 weeks of P+R eRVR HCV RNA negative At Weeks 4 & 12 NO eRVR Slow 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-In With 4 weeks P+R Triple Therapy with BOC+P+R For additional 24 weeks* No additional Treatment* (28 weeks total) Additional 8 weeks of BOC+P+R and 12 weeks P+R Treatment* (48 weeks total) eRVR’ 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 <1log 10 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 % 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, 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

Median Hemoglobin (g/dL) 0 Weeks Anemia during triple therapy with Telaprevir or Boceprevir CHC PegIFN+RBV CHC PegIFN+RBV+ TPV CHC PegIFN+RBV+BOC McHutchison JG et al, N Engl J Med Poordad F, et al. Hepatology 2010;52(Suppl.):402A Bacon, B, et al. Hepatology 2010; 52(Suppl):430A This Slide courtesy of X Forns, MD Modified 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 X Oral Drug X IV Kidney P-gp → Urine CYP3A4 → Metabolism Liver P-gp → Bile CYP3A4 → Metabolism Intestine P-gp → Int Lumen CYP3A4 → Metabolism Drug X Systemic Exposure Increases IS Meds Statins Benzodiazepines Antipsychotics? E-mycins Anticonvulsants HIV PIs, NNIs α-Adren Blkrs Ca ++ -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: Tacrolimus

Ratio AUCs for Drug (w/wo TPV) From tables in Prescribing Information for INCIVEK, May 2011 Kiser J, et al. Review and Management of DDIs with Boceprevir and Telaprevir. Hepatology 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: – FDA: – Other Online Resources – – – – 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  Ribavirinup to 6/d  Telaprevir6/d x 3 months  Boceprevir12/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:

Timelines PR PR + 1 st Gen DAA PR + 2 nd Gen DAA IFN-Free Regimens 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) % of Pts with HCV RNA (<10 IU/mL) weeks Increased potency also reduces risk for emergence of resistant viral variants – e.g., MK-5172 is active 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. Stopped all Meds due to Diverticulitis R155K Detected WT HCV RNA Positive 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) % HCV RNA <10 IU/mL Lok A, et al. RVR/cEVR presented at AASLD SVR12 presented EASL N Engl J Med 2012;366: Daclatasvir 60 mg qd, Asunaprevir 600 mg bid, 24 weeks treatment. All breakthroughs Occurred in Patients with G1a

QUAD (or QUINT) Therapy When all else fails!

QUAD in the Treatment of G1 Null Responders BMS /BMS PR (n=10), 24 Weeks of Rx % HCV RNA <10 IU/mL Lok A, et al. N Engl J Med 2012;366: mg qd, mg bid; SVR at week24 post-Rx

Optimistic Results in Phase 2 Trials % 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 Lok AS, et al. Preliminary Study of two antiviral agents for Hepatitis C Genotype 1. N Engl J Med 2012;366: 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: 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 Everson GT, et al. An Interferon-Free, Ribavirin-Free 12-Week Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS Yielded SVR4 of 94% in Treatment-Naïve Patients with Genotype (GT) 1 Chronic Hepatitis C Virus (HCV) Infection. AASLD 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 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 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 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 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 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 % of Patients with SVR 1991 Yr of FDA Approval

Future Treatment for HCV GT2 & 3 % of Patients with SVR 1991 Yr of FDA Approval

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