Massimo Puoti Dept. of Infectious Diseases AO Ospedale Niguarda Cà Granda Milan, Italy. Treatment with DDA in special populations

Transcription

1 Massimo Puoti Dept. of Infectious Diseases AO Ospedale Niguarda Cà Granda Milan, Italy Treatment with DDA in special populations

2 Massimo Puoti. SC Malattie Infettive AO Ospedale Niguarda Ca Grnada Il sottoscritto dichiara di aver avuto negli ultimi 12 mesi conflitto d interesse in relazione a questa presentazione Membro occasionale di asvisory boards e/o speaker in own events e/o docente in corsi interni e/o investigator e/o reasearch grants per BMS, Gilead sciences, Abbvie, Viiv, Boheringer Ingelheim, MSD, Roche, Janssen, Vertex, Novartis, e che la presentazione contiene discussione di farmaci in studio o ad uso off-label Telaprevir, Boceprevir, Faldaprevir, Sofosbuvir, Simeprevir

3 Special Populations Cirrhosis HIV+ Liver Transplant recipients Cryoglobulinemia ESRD 3

4 Special Populations Cirrhosis HIV+ Liver Transplant recipients Cryoglobulinemia ESRD 4

5 Cirrhosis Rationale SVR < 50% in HCV G1 Increased survival, lower decompensation rate and lower indìcidence of HCC after SVR ( Bruno S Hepatology 2007; 46: ) Schedules 12 PEG RBV TLV + 36 w PEG RBV (Incivo SPC) 4 PEG RBV + 44w PEG RBV BOC (Victrelis SPC)

6 Cirrhosis: Efficacy Study Naïve Relapsers Partial Responders Telaprevir Phase III Studies 1-2 Boceprevir Phase III Studies % (F4) 59% (F3-F4) 84% (F4) 42% 83% (F3-F4) CUPIC _ 71% Telaprevir 6 (SVR 12) CUPIC _ 52% Boceprevir 6 (SVR 12) Expanded 85% Access TPV 7 (HCVRNA undetectable at 12 weeks) 85% (HCVRNA undetectable at 12 weeks) 34% (F4) 46% (F3-F4) 29% (SVR12) 31% (SVR 12) 77% (HCVRNA undetectable at 12 weeks) Null Responders 14% (F4) 1/2 68% (HCVRNA undetectable at 12 weeks) 1. Marcellin P, et al. J Hepatol 2011; 54 (Suppl 1): S Pol S, et al. Hepatology 2011;54(Suppl. S1):374A 3. Buti M. AASLD Poordad F, et al. N Engl J Med 2011;364: Bacon BR, et al. N Engl J Med 2011;364: Vierling J et al AASLD Hezode C et al EASL 2013 Submitted 7. Colombo M et al AASLD 2013 Poster LB -15

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8 Bruno S et al J Hepatol 2013; 58:

9 Cirrhosis: Safety Study % SAE % Severe Infections, Liver Decompensations, Deaths Telaprevir Phase III Studies Boceprevir Phase III Studies CUPIC Telaprevir 45% (at 16 w) CUPIC Boceprevir 33% (at 16 w) 7% 0 5% 0 11,1% (at 16 w) 5,9% (at 16 w) Telaprevir EAP 14% 0,5% 1. Marcellin P, et al. J Hepatol 2011; 54 (Suppl 1): S Pol S, et al. Hepatology 2011;54(Suppl. S1):374A 3. Poordad F, et al. N Engl J Med 2011;364: Bacon BR, et al. N Engl J Med 2011;364: Vierling J et al AASLD Hezode C et al EASL 2013 Submitted 7. Colombo M et al AASLD 2013 Poster LB -15

10 CUPIC: Risk of occurrence of death or severe complications Factors Albumin > 3.5 g/dl Albumin < 3.5 g/dl Platelet count > Platelet Count < % 4.8% 7.1% 40.6% Hezode C et al EASL 2013 Submitted

11 Population Rationale Schedule Cirrhotics Maximal cost effectiveness due to higher morbidity and mortality in the short term SVR increased survival but < 50% in HCV G1 Extended treatm. duration Efficacy Lower Stopping rules and Lead in to maximize cost eff. Safety Worse: caution with Albumin < 4 g/dl and/or PLT< / mm 3 Challenges Safety: Infections and decompensation 11

12 PILLAR/ASPIRE: Simeprevir + PegIFN/RBV in Pts With GT1 HCV, F3/4 Fibrosis Subanalysis of randomized, placebo-controlled phase IIb trials of simeprevir (protease inhibitor) Relatively high SVR24 rates in pts with advanced fibrosis In ASPIRE, 4/13 (31%) F4 null responders achieved SVR24 Placebo + PR Simeprevir 150 mg QD + PR SVR24 (%) SVR24 by METAVIR Score 79 5/ 15/ 1/ 38/ 0/ 24/ n/n = n/n = PILLAR Naive, F ASPIRE Tx Exp d, F3 + F4 62 ASPIRE Tx Exp d, F4 Only SVR24 (%) SVR24 by Prior IFN Response in Pts With F3/F4 0/ / 26 Relapser 10 1/ / 21 Partial Responder 0/ / 21 Null Responder Poordad F, et al. AASLD Abstract 83. Reproduced with permission.

13 SOUND-C2 Subanalysis: Efficacy of Treatment in Patients With Cirrhosis Among 33 cirrhotic patients, outcomes with faldaprevir + BI RBV similar to noncirrhotic patients SVR12 rates higher in GT1b vs GT1a HCV Higher rate of discontinuations and SAEs with TID dosing Cirrhosis No cirrhosis GT1a GT1b SVR12 (%) n/ N = 52 11/ / / / / / 43 SVR12 (%) n/ N = 43 3/ / / / 5 Cirrhosis 0/ / / / / / 43 No Cirrhosis 11 2/ / 25 BI Dosing Duration (wks) RBV TID 16, 28, 40 + BID 28 + TID 28 - TID 16, 28, 40 + BID 28 + TID 28 - TID 16, 28, 40 + BID 28 + TID 28 - Soriano V, et al. AASLD Abstract 84. Reproduced with permission.

14 Ribavirin + Sofosbuvir + PEGIFN Overall data and data in F4: Summary of Fusion (201 HCVG2&3 experienced), Fission (500 HCV G2&3 naives), Positron (207 HCV G2/3 IFN intolerant) and Neutrino (327 HCV G1&4-6 naives) Studies Gilead Science Press Releases: November 18 th 2012; February 4 th & February 20 th 2013

15 Special Populations Cirrhotics HIV+ Liver Transplant recipients Cryoglobulinemia ESRD 15

16 Special Populations: HIV+ Liver disease main cause of death in HIV+ 1 HCV associated with renal and bone comorbidities 2 SVR to anti HCV Tx associated with increased survival 3 SVR in HCV G1 < 50% 4 HCV G1 > 50% of HIV/HCV coinfected 5

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18 Boceprevir in HCV/HIV co-infection: undetectable HCV RNA over time PR BOC/PR Patients with undetectable HCV RNA (%) n/n= 3/34 3/64 5/34 27/64 8/34 38/64 11/34 47/64 10/34 42/64 37/61 9/34 3 patients with SVR 4 have not reached FUPW12 and were not included in the analysis At TW12, there were no marked differences in CD4 count or % of subjects with HIV RNA <50 copies/ml in the treatment groups Sulkowski M, et al. CROI 2012

19 Proportion of patients with advanced fibrosis (F3/F4 or S4/S6) in HIV/HCV coinfected patients enrolled in previous studies with PR and in DAA Phase 2 studies * * S5 and S6 only

20 Antiretroviral therapy in candidates for PEG IFN + RBV + TPV. CLASS Antiretrovirals TELAPREVIR BOCEPREVIR NRTI AZT, ddi, d4t Avoid coadministration Avoid Coadministration ABC: No data Potential interaction with UDPglucuronyl tranferase Combine with caution Combine with caution TDF Can be combined Can be combined FTC, LAM. No Data but no potential interactions Can be combined PI LPV/R, DRV/R, FPV/R, Avoid coadministration Can be combined ATZ/R Can be combined NNRTI EFV 1125 mg tid NVP Avoid coadministration RPV Can be Combined Can be combined ETV Can be combined Combine with caution II RAL Can be combined Can be combined ^ Potential interaction with UDP-glucuronyl tranferase; * Rilpivirine AUC +79% check QT Etravirine AUC - 23%: caution in patients with history of multiresistance

21 Population Rationale HIV+ HCV Main cause of Death SVR incrased survival Rapid progression Associated with comorbidities Poor response to SOC in HCV G1 HCV G1 > 50% HIV/HCV Schedule Efficacy Safety Challenges Extended treatm. duration Similar to HIV- Similar to HIV- Few data in easy to treat pts. Limitation of concurrent cart regimen 21

22 Treatment of HIV/HCV: the future Protease Inhibitors Danoprevir Asunaprevir TMC 4335 BI 1335 Simeprevir GS 9256 ABT-450/R Polymerase Inhibitors Nucleosides/ tides Non Nucleosides NS5A inhibitors Mericitabine Sofosbuvir Tegobuvir Filibuvir BI-7127 ANA-598 VX-222 VCH-759 ABT-333 Daclatasvir IDX 184 ABT-267 Phase III studies in HIV + initiated DDI with cart completed

23 Special Populations Cirrhosis HIV+ Liver Transplant recipients Cryoglobulinemia ESRD 23

24 LT recipients Rationale Rapid progression Low response to SOC in HCV G1

25 Background: telaprevir increases exposure to immunosuppressants (CYP3A4 & P-gp substrates) Calcineurin Inhbitor Cyclosporine A Tacrolimus C max AUC t 1/2 1.3-fold increase 9.4-fold increase 4.6-fold increase 70-fold increase From hours From hours Significant immunosuppressant dose reductions and prolongation of the dosing intervals will be required Close monitoring of immunosuppressant blood levels, renal function and immunosuppressant related side effects are recommended when co-administered with telaprevir Garg V, et al. Hepatology 2011;54:20 7; Telaprevir EU SmPC

26 Background: boceprevir increases exposure to immunosuppressants (CYP3A4 & P-gp substrates) Calcineurin Inhbitor Cyclosporine A Tacrolimus C max AUC t 1/2 2-fold increase 10-fold increase 2.6-fold increase 17-fold increase From hours From hours Boceprevir co-administration significantly increased blood concentrations of cyclosporine and tacrolimus Therapeutic medicine monitoring is recommended when administering boceprevir with CYP3A4/5 substrates that have a narrow therapeutic window (e.g., tacrolimus, cyclosporine) Individual patients may require additional titration of their immunosuppressant dosage when boceprevir is started or stopped to ensure clinically effective blood levels Hulskotte EGJ, et al. Global Antivir J 2011;7(Suppl. 1):110; Boceprevir EU SmPC

27 Triple Therapy post LT Pooled analysis 8 AASLD abstracts 1 paper 204 post LTx patients Triple treatment 81% Telaprevir 19% Boceprevir Disease stage & previous treatment > 50% with F3-F4 or FCH > 50% experienced Immunosuppression: Cya 62% Tac 32% Syrolimus 6% 48 weeks of therapy Burton J et al. AASLD 2012 #211, Pungpapong S et al. AASLD 2012 #10; Coilly A et al AASLD 2012 #9; Aqel B et al AASLD 2012 # 706; Mantry PS et al. AASLD 2012, # 712; Koning L et al. AASLD 2012 #209; Nar S et al AASLD 2012 #720; Kuo PY et al. AASLD 2012 #719; Werner CR et al Liver Transpl 2012

28 Triple therapy post LT 30% stopped 2/3 Futility 1/3 AE 3% Death 20% Breakthrough & Relapse 70/165 Burton J et al. AASLD 2012 #211, Pungpapong S et al. AASLD 2012 #10; Coilly A et al AASLD 2012 #9; Aqel B et al AASLD 2012 # 706; Mantry PS et al. AASLD 2012, # 712; Koning L et al. AASLD 2012 #209; Nar S et al AASLD 2012 #720; Kuo PY et al. AASLD 2012 #719; Werner CR et al Liver Transpl 2012

29 Triple therapy post LT -Safety Renal function Creatinine clearance > 50 ml/min Watch for AKI Anemia Lower Ribavirin starting dose 90% of patients required growth factors Transfusion are common Use Lead In regardless of PI Assess Tolerability Adjust PEG IFN & RBV dose Minimize risk of PI discontinuation

30 Triple Therapy post LT Drug-Drug Interactions Stop or switch all non essential meds w/ddi Anti-hypertensive HMG-CoA reductase inhibitors Psych Meds Cya is the easiest Not all patients can be switched Medical instability FCH Renal dysfunction Steroids & Syrolimus have unstudied DDI Mycophenolate no DDI

31 DDI with CNI and mtor Triple therapy post LT Drug Drug Interactions change over time Telaprevir most profound effect 1 st 6 weeks: 0-2 lowest dose 2-6 frequent monitoring increased dose >6 Increased stability dosing > 12 Coming off Koning et al. found decreased dose over time with Boceprevir Reasons: Liver failure improvement in FCH Alterations in Absorption Metabolism O Leary et al AASLD 2012 # 707 Koning et al. AASLD 2012 #209

32 Triple therapy post OLT Summary Triple therapy is being used in very selected LT patients Response Rates: Pooled analysis 204 w 12 70% HCVRNA 56% SVR??? Safety concerns: 3% Deaths Anemia: > 90% growth factors and transfusions Renal function critical AKI Lead in can be helpful DDI Minimize # before starting CNI or mtor may need to be adjusted throughout

33 Population Rationale Schedule LT recipients Rapid progression Poor response to SOC in HCV G1 Extended treatment duration Lead in used in most series Efficacy Safety Challenges Lower Worse Interaction with CNI no data on mtor I. Infections and decompensation 33

34 Unlicensed DAA post LT Emerging data Author Citation DAA Duration/r esult Fontana R Liv Transpl 2012 Fontana R AASLD 2012 # 694 Ouwerkerk AASLD 2012 # 80 Mathias AASLD 2012 #1869 Sofosbuvir + Daclatasvir Daclatasvir + P/R Simeprevir Sofosbuvir 24 weeks/svr 24 w + 4/SVR Subjects Impact on Cya 1 FCH pt None Impact on Tac 1 FCH pt none Healthy Volunteers n. 28 Healthy volunteers n. 40 No clinical impact No clinical impact No clinical impact No clinical impact Ongoing studies with Sofosbuvir + RBV pre and post transplant

35 Rationale Special Populations -ESRD Higher post Renal Transplant mortality in HCV+ pre RT therapy is recommmended 1 pk in ESRD Not clinically significant modification of Telaprevir 2 and Boceprevir 3 Cmax and AUC Studies are ongoing: Dumortier et al J Clin Virol 2012 in press: 3 out of 4 treated with PEG IFN + RBV + TEL HCVRNA undetectable 1. KDIGO Clinical Practice Guidelines for the Prev at wek 12ention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease. Kidn Intern van Heeswijk R, et al. J Hepatol 2011;54(Suppl. 1):S Treitel M. Clin Pharmacokinet Sep 1;51(9):619-28

36 Rationale Special Populations - Cryoglobulinemia Improvement of mild- moderate MC after eradication of HCV infection Poor response in HCV G1 Data ( Triboli E et al. Dig Liv Dis 2013; 45: S10) 24 HCVMC G1 treated with triple BOC + PEGIFN + RBV vs 11 no MC: similar safety but lower response; dramatic effect of Boc introduction on symptoms

37 Population Cirrhotics HIV+ LT recipients Dialysis pts Cryoglobulinemia Rationale Schedule Efficacy Safety Challenges Maximal cost effectiveness due to higher morbidity and mortality in the short term SVR increased survival but < 50% in HCV G1 Extended treatm. duration Lower Stopping rules and Lead in to maximize cost eff. Worse: caution with Albumin < 4 and/or PLT< Safety: Infections and decompensation HCV Main cause of Death SVR incrased survival Rapid progression Associated with comorbidities Poor response to SOC in HCV G1 Extended treatm. duration Rapid progression Poor response to SOC in HCV G1 Extended treatment duration Lead in used in most series HCV associated with post RT mortality No data HCV eradication Improvement of cryoglobulinemi syndrome As in SPC Similar to HIV- Lower No Data Lower Similar to HIV- Worse No Data Similar Few data in easy to treat pts. Limitation of concurrent cart regimen Interaction with CNI no data on mtor I. Infections and decompensation Dramatic effect on Symptoms and Cryocrit Increase pf cryocriit in lead 37 in phase

38 PEG IFN + RBV + Sofosbuvir vs PEG IFN + RBV in HCV G1 & naives NEUTRINO STUDY NEUTRINO, 327 treatmentnaïve HCV genotype 1, 4, 5 and 6 patients were treated for 12 weeks with sofosbuvir 400 mg once daily in combination with RBV (1,000 or 1,200 mg/day) and peg-ifn (180 μg/week). 17% compensated cirrhosis 89 % HCV G1. Gilead Science Press Release February 4 th 2013

39 NIH SPARE: Interim Data on Sofosbuvir and RBV in Difficult-to-Treat GT1 Pts Subjects primarily GT1a (70%), male (63%), black (83%), IL28B CT/TT (80%) BMI > 30: 48%; advanced liver disease: 23%; HCV RNA > 800,000 IU/mL: 62% Part 1 (early-stage fibrosis) Wk 24 Viral Response, % EOT SVR4 SVR12 Sofosbuvir 400 mg + RBV 1000/1200 mg (n = 10) Part 2 (all stages of fibrosis) Sofosbuvir 400 mg + RBV 600 mg (n = 25) Sofosbuvir 400 mg + RBV 1000/1200 mg (n = 25) In viral kinetic study involving 10 low-dose and 15 full-dose RBV subjects, HCV RNA decrease was rapid with median HCV RNA reduction of 4.14 log 10 IU/mL by Day 7 Both regimens well tolerated and resulted in significant improvement of hepatic inflammation (P <.0001) Osinusi A, et al. AASLD Abstract LB-4.

40 RBV + Sofosbuvir vs PEG IFN + RBV in HCV G2&3 naives FISSION STUDY FISSION study, treatmentnaïve HCV genotype 2 and 3 patients were randomized (1:1) to receive either 12 weeks of sofosbuvir 400 mg once daily plus RBV (1,000 or 1,200 mg/day) (n=256) or 24 weeks of peg-ifn (180 μg/week) plus RBV (800 mg/day) (n=243). 73% HCV G3 20 % compensated cirrhosis Gilead Science Press Release February 4 th 2013

41 Sofosbuvir + Ribavirin in HCV G2 &3 Non responders: Fusion Study HCV genotype 2 or 3 patients who failed prior interferon-based therapy were randomized (1:1) to receive either a 12-week (n=103) or 16-week (n=98) course of sofosbuvir 400 mg once daily plus RBV (1,000 or 1,200 mg/day). 63% HCV genotype 3. 34% Cirrhosis Historical control group: 25% SVR % SVR Gilead Science Press Release February 20 th 2013

42 POSITRON Efficacy of a 12-Week of Sofosbuvir Plus Ribavirin for Chronic Hepatitis C Patients HCV G2 or 3 who are Unable or Unwilling to Take Interferon Study population: HCV G2 or G3 were interferon intolerant, interferon ineligible or unwilling to take interferon randomized (3:1) to receive 12 weeks of either sofosbuvir 400 mg once daily plus weight-based RBV twice daily (n=207) or matching placebo (n=71). 207 patients randomized to the sofosbuvir/rbv arm, 15 percent had compensated cirrhosis (more advanced liver disease) 53 percent were infected with genotype /110 59/97 0/71 Gilead Sciences Press Release Nov