Pierluigi Toniutto Clinica di Medicina Interna Azienda Ospedaliero Universitaria Udine

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1 Pierluigi Toniutto Clinica di Medicina Interna Azienda Ospedaliero Universitaria Udine Il sottoscritto dichiara di non aver avuto negli ultimi 12 mesi conflitto d interesse in relazione a questa presentazione e che la presentazione non contiene discussione di farmaci in studio o ad uso off-label

2 CURRENT ANTIVIRAL THERAPY FOR HCV GENOTYPE 1 CHRONIC HEPATITIS Pierluigi Toniutto Medical Liver Transplant Section University of Udine

3 WHY TREAT CHRONIC HEPATITIS C? The disease Common, chronic, and frequently progressive Complications are becoming more common [1,2] Liver failure, HCC First indication for liver transplantation in Europe and US The treatment Viral cure, or SVR, is achievable SVR associated with histologic improvement and gradual regression of fibrosis [3] SVR reduces risk for mortality [4], liver failure and HCC, improves survival [5,6] [1] Kanwal F, et al. Gastroenterology. 2011;140: [2] Shaw JJ, et al. Expert Rev Gastroenterol Hepatol. 2011;5: [3] Poynard T, et al. Gastroenterology. 2002;122: [4] Van de Meer et al. JAMA [5] Craxi A, et al. Clin Liver Dis. 2005;9: [6] Shiratori Y, et al. Ann Intern Med. 2005;142:

4 MILESTONES IN THERAPY OF GENOTYPE 1 HCV CHRONIC HEPATITIS 100 Peginterferon Direct-acting antivirals Standard interferon 1991 Ribavirin IFN 6 mos IFN 12 mos IFN/RBV 6 mos IFN/RBV 12 mos PegIFN 12 mos PegIFN/ RBV 12 mos PegIFN/ RBV/ DAA Adapted from US FDA Antiviral Drugs Advisory Committee Meeting; April 27-28, 2011; Silver Spring, MD.

5 TWO PROTEASE INHIBITORS APPROVED FOR GT1 HCV INFECTION COMBINED WITH PR Protease Inhibitor Recommendations Administration Boceprevir 800 mg TID (every 7-9 hrs) [1,2] Naive to previous therapy Previous treatment failure Compensated cirrhosis Response-guided therapy Take with food All patients initiate therapy with 4-wk pegifn/rbv lead-in phase After completion of lead-in phase, boceprevir should be added to continued pegifn/rbv for wks Telaprevir 750 mg TID (every 7-9 hrs) [2,3] Naive to previous therapy Previous treatment failure Compensated cirrhosis Response-guided therapy Take with food (not low fat) All patients initiate therapy with 12-wk period of triple therapy with telaprevir plus pegifn/rbv Followed by wks of pegifn/rbv 1. Boceprevir [US package insert]. July Ghany MG, et al. Hepatology. 2011;54: Telaprevir [US package insert]. October 2012.

6 ADDITION OF BOC OR TVR TO PEGIFN/RBV IMPROVES SVR IN GENOTYPE 1 PATIENTS PegIFN + RBV BOC/TVR + pegifn* + RBV SVR (%) Treatment Naive [1,2] Relapsers [3,4] 7-15 Partial Responders [3,4] 5 Null Responders [4,5] *BOC was administered with pegifn-α2b; TVR was administered with pegifn-α2a in these trials. 1. Poordad F, et al. N Engl J Med. 2011;364: Jacobson IM, et al. N Engl J Med. 2011;364: Bacon BR, et al. N Engl J Med. 2011;364: Zeuzem S, et al. N Engl J Med. 2011;364: Bronowicki JP, et al. EASL Abstract 11.

7 FURTHER ADVANTAGES OF TRIPLE Vs DUAL ANTIVIRAL THERAPY About 50% of naïve and previous relapsers non cirrhotic patients may be treated with a shorter duration schedule on the basis of their on treatment HCV-RNA decline (RGT) TVR: - eevr (HCV-RNA negative at weeks 4-12 in both naives and previous relapsers), TD 24 weeks (12 weeks for naives RVR carrying IL-28B CC genotypes?) BOC: - HCV-RNA neg at weeks 8-24 in naives, TD 28 weeks - HCV-RNA neg at weeks 8-12 in previous relapsers, TD 36 weeks

8 MAIN DRAWBACKS OF TRIPLE Vs DUAL ANTIVIRAL THERAPY Complexity - Different schedules, different durations Difficult to manage - Side effects and drug to drug interactions - Pill burden: 6 pills/day for TVR and 12 pills/day for BOC (adherence) Costs Availability (in Italy) - Only in certified centres (selected according to regional and non-national rules) - Referral of patients from not authorized centres - Overall access to treatment - Patients parked waiting new antivirals

9 HOW TO SELECT PATIENTS FOR TRIPLE ANTIVIRAL THERAPY General assumptions All patients with HCV related chronic hepatitis should be considered potential candidates for treatment HCV genotype 1 patients who failed dual therapy must be considered potential candidates ONLY for triple therapy On the basis of urgency Priority for patients with sever liver disease (F3-F4) Previous non response to dual therapy On the basis of the probability to respond Less severe disease, favourable predictors of response Comparison with dual therapy success in naives Patient motivation National guidelines (AISF)

10 HOW TO SELECT PATIENTS FOR TRIPLE ANTIVIRAL THERAPY General assumptions All patients with HCV related chronic hepatitis should be considered potential candidates for treatment HCV genotype 1 patients who failed dual therapy must be considered potential candidates ONLY for triple therapy On the basis of urgency Priority for patients with severe liver disease (F3-F4) Comorbidities, age Special situations On the basis of the probability to respond Less severe disease, favourable predictors of response Comparison with dual therapy success in naives National guidelines (AISF)

11 EFFICACY AND SAFETY WORSEN IN ADVANCED LIVER DISEASE Severity of adverse events F0 F1 F2 F3 F4 Probability of cure

12 SVR IN PATIENTS WITH ADVANCED FIBROSIS/CIRRHOSIS BY RESPONSE AT WK 4 IN LEAD- IN ARM Bruno S et al J Hepatol, 2013.

13 REALIZE: SVR RATES WITH TELAPREVIR BY INCREMENTAL RESPONSE AFTER 4 WEEKS OF LEAD-IN Foster et al, J Hepatol 2013;58:488-94

14 LEAD-IN/IFN SENSITIVITY TEST STRATEGY CAN HELP TO DETERMINE WHOM TO TREAT AMONG PATIENTS WITH ADVANCED LIVER DISEASE 4 wks of pegifn/rbv before BOC or TVR Allows assessment of IFN responsiveness Provides useful information regarding likelihood of SVR with addition of DAA Provides insight into tolerability of pegifn/rbv backbone Elucidates hematologic response to pegifn/rbv, especially in these marginal patients; make needed dose adjustments before addition of DAA Helps to make the decision not to treat patients with worse riskbenefit ratio Is IFN sensitivity modifiable? Vitamin D serum levels vitamin D supplementation

15 AISF Recomandation on the management of Triple Therapy (Peg-IFN + Ribavirin + first generation Protease Inhibitors) for genotype 1 chronic Hepatitis C patients Naives: Triple therapy should be scheduled (high priority) for patients with severe fibrosis (METAVIR score F3) to cirrhosis (F4), with compensated liver disease Child-Pugh class A (A1) Previous treatment failure: In Relapser patients, triple therapy should be scheduled (high priority) for severe fibrosis (F3) and cirrhosis (F4) In Partial responders, triple therapy should be scheduled (high priority) for severe fibrosis (F3) and cirrhosis (F4) In Null responders indication to triple therapy has to be considered carefully, considering the low efficacy and the risk of side effects. Published on line April 24, 2013.

16 CUPIC: RISK OF OCCURRENCE OF DEATH OR SEVERE COMPLICATIONS IN CIRRHOTICS TREATED WITH PI Factors Platelet count > /mm 3 Platelet Count < /mm 3 Albumin >3.5 g/dl 3.4% 4.3% Albumin <3.5 g/dl 7.1% 44.1% Portal HTN is key: HVPG>10 mmhg also predictive Hezode C et al J Hepatol 2013; Rutter EASL 2013 Abst 65.

17 EFFICACY AND SAFETY ARE BETTER IN LESS SEVERE LIVER DISEASE Severity of adverse events F0 F1 F2 F3 F4 Probability of cure

18 IDENTIFICATION OF NAIVE HCV 1 PATIENTS WHO MAY BENEFIT FROM DUAL THERAPY WITH PEG-IFN AND RIBAVIRIN 1210 pts: 287 (24%) with RVR and 467 (39%) with SVR 100% 81% 82% 67% SV R 25% 20% of pts were predicted to have > 80% chance of SVR with dual therapy Andriulli et al. J Hepatol 2013.

19 AISF Recomandation on the management of Triple Therapy (Peg-IFN + Ribavirin + first generation Protease Inhibitors) for genotype 1 chronic Hepatitis C patients Naïve: In patients with fibrosis F0-F2 a 4 weeks PEG/RBV treatment permits to personalize treatment schedule and also to assess patient adherence and tolerance of treatment. Those who achieve an RVR should maintain dual therapy; in patients with detectable HCV-RNA at week 4, the indication to add PI should be evaluated case to case, according to stage of disease and considering the possibility to stop treatment and wait new antiviral drugs (B1) In selected patients with severe fibrosis (F3) and cirrhosis (F4), particularly with severe fibrosis (F3), favourable baseline predictors (IL28B CC genotype or low viral load) or with high risk of side effects with PI, the achievement of RVR may justify to continue dual (PEG/RBV) therapy without addition of PI (B2) Published on line April 24, 2013.

20 AISF Recomandation on the management of Triple Therapy (Peg-IFN + Ribavirin + first generation Protease Inhibitors) for genotype 1 chronic Hepatitis C patients Previous dual treatment failure: In patients with fibrosis F0-F1 independently from previous pattern of non response (REL, PR, NR) triple antiviral therapy should be considered only for selected patients taking into account risk/benefit ratio and - Patient motivation - Comorbidities - Age Published on line April 24, 2013

21 HOW TO SELECT PATIENTS WHO DISCONTINUE TRIPLE THERAPY PREMATURELY FOR LACK OF RESPONSE: THE ROLE OF STOPPING RULES Boceprevir [1,2] Time Point Criteria* Action Wk 12 HCV RNA 100 IU/mL Discontinue all therapy Wk 24 HCV RNA detectable Discontinue all therapy Wk 8 HCV RNA drop <3 log from baseline Discontinue all therapy Telaprevir [2,3] Time Point Criteria* Action Wk 4 or 12 HCV RNA >1000 IU/mL Discontinue all therapy Wk 24 HCV RNA detectable Discontinue pegifn/rbv 1. Boceprevir [US package insert]. July Ghany MG, et al. Hepatology. 2011;54: Telaprevir [US package insert]. October AISF Clinical Guidelines; 2013.

22 MAJOR SIDE EFFECTS DURING AVT Dual therapy (Peg-IFN + RBV) - asthenia, headache, nausea, fever, musculo-skeletal pain - anemia, neutropenia - decline in mood, irritability, insomnia - rash Triple therapy (Peg-IFN + RBV + DAA) - TVR: pruritus, rash, anemia, gastro-intestinal disorders - BOC: fatigue, anemia, nausea, diarrhoea, dysgeusia, neutropenia Pegintron EU SmPC; Pegasys EU SmPC; Rebetol EU SmPC; Jacobson IM, et al. NEJM 2011; Sherman KE, et al. NEJM 2011; Zeuzem S, et al. NEJM 2011; Telaprevir EU SmPC; Poordad F, et al. NEJM 2011; Bacon BR, et al. NEJM 2011; Boceprevir EU SmPC

23 ANEMIA MANAGEMENT Ribavirin dose reduction mg at a time - Possibly when HCV-RNA negative Epoetin - Can allows to maintain the dose of RBV - Use if Hb <10 g/dl - Recommended dose: IU/week - *Associated with thromboembolism (3%) - Halving dose if Hb increases by 1 g/week or 2 g/month - Discontinue if Hb >12 g/dl Blood transfusion if Hb <8 g/dl Do not suspend RBV and continue treatment with Peg-IFN + DAA (high risk of resistance) Do not reduce DAA dose (high risk of resistance) *Poordad F et al Gastroenterology in press.

24 RASH MANAGEMENT MILD AND MODERATE (grade 1-2 less than 50% of BSA) Continue triple therapy Not reduce TVR Look for systemic symptoms General indication for skin care Anti-histamine for itching Topical steroids Frequent observation to exclude progression SEVERE (grade 3, more than 50% of BSA) Rare Stop TVR Continue Peg-IFN e RBV; discontinue if rash stable or worsens Look for systemic symptoms General indication for skin care Anti-histamine for itching Topical or systemic steroids Cacoub P, et al. J Hepatol 2012

25 RASH MANAGEMENT SEVERE cutaneous adverse reaction (SCAR, grade 4) Associated with systemic symptoms - Extremely rare - Stop immediately all 3 drugs - Patient should be hospitalized (if necessary in ICU) - Exclude a Stevens-Johnson syndrome or DRESS Systemic symptoms fever anorexia lymphoadenopaties facial edema eosinophilia atypical lymphocytes hepatic and renal involvement SJS: Stevens-Johnson Syndrome DRESS: Drug Reaction Eosinophilia Systemic Symptoms TEN: Toxic Epidermic Necrolysis EM: Erythema Multiforme AGEP: Acute Generalized Exanthematous Pustolosis Cacoub P, et al. J Hepatol 2012

26 DYSGEUSIA Telaprevir Not listed as a frequent event Boceprevir - Metallic taste - Contributes to anorexia and weight loss - Naïve: 37 43% (SoC: 13%) - Experienced: 43 45% (SoC: 11%) Taking BOC capsules with chocolate milk seems to help manage dysgeusia in some patients Jacobson IM, et al. NEJM 2011; Poordad F, et al. NEJM 2011; Bacon BR, et al. NEJM 2011; Boceprevir EU SmPC

27 BOTH BOC AND TVR HAVE POTENTIAL FOR MANY DRUG DRUG INTERACTIONS BOC Strong inhibitor of CYP3A4/5 Partly metabolized by CYP3A4/5 Potential inhibitor of and substrate for P-gp TVR Substrate of CYP3A Inhibitor of CYP3A Substrate and inhibitor of P- gp Most drug drug interactions can be overcome by careful survey of the patient s medications and judicious substitutions during HCV therapy (or just during the period of PI-based triple therapy) See:

28 WHO SHOULD BE TREATED NOW? Pts Who Want Tx Want to be cured of disease Personal or social reasons Plans for pregnancy Social support Pts Who Are Eligible for Tx Eligible for pegifn/ RBV Fit for regimen No contraindications Disease stage Pts Who Are Motivated and Understand... Likelihood of response Risks/benefits of treatment Risk of resistance Possibility of shortened therapy What is coming down the line for their genotype

29 WHO SHOULD BE DEFERRED FOR TREATMENT? Patients with mild disease without signs of fibrosis progression (careful monitor of liver function) Patients with advanced liver disease who do not have any other treatment options (decompensated cirrhosis, renal failure and kidney transplant, IFN intolerant) New antivirals are coming but: - For genotype 1, the first therapeutic regimens available will still be based on the use of IFN and RBV (Sofosbuvir, Simeprevir, Faldaprevir) - They will be associated with a probable increment of costs that could be limit their use in all HCV infected patients - Not yet defined the date of their availability in Europe and, more importantly, in Italy - Patients deferred should be carefully informed of the risks, benefits and complexity of deferring treatment

30 SUMMARY BOC or TVR based triple therapy increases SVR rates over pegifn/rbv alone for all genotype 1 patient populations that have been evaluated On-treatment management techniques including application of RGT algorithms and effective management of adverse events maximize treatment outcomes and mitigate treatment failure