THE USE OF TRIPLE THERAPY IN SPECIAL POPULATIONS (HIV, OLT)

Transcription

1 Massimo Puoti Dept. of Infectious Diseases AO Ospedale Niguarda Cà Granda Milan, Italy THE USE OF TRIPLE THERAPY IN SPECIAL POPULATIONS (HIV, OLT) 14 TH AISF Pre-meeting course: HCV treatment: the new scenario in the era of Direct-acting Antiviral Agents (DAAs) Rome February 22 nd 2012 Aula Magna Università di Roma Sapienza. P.le A. Moro 5 Course Directors: R. Bruno, Pavia and P. Caraceni, Bologna

2 Massimo Puoti SC MALATTIE INFETTIVE AO OSPEDALE NIGUARDA, Ca GRANDA MILANO Il sottoscritto dichiara di aver avuto negli ultimi 12 mesi conflitto d interesse in relazione a questa presentazione per collaborazioni occasionali come: advisor o relatore in own events o docente in corsi per personale interno o percettore di grants di ricerca o investigator in RCT con: MSD, JANSSEN CILAG, ROCHE, GILEAD SCIENCES, BMS, BOEHRINGER INGELHEIM, e che la presentazione contiene discussione di farmaci in studio o ad uso off-label Boceprevir, Telaprevir, Daclatasvir, TMC-435, BI ,ITX 5061

3 The use of triple therapy in special populations: HIV and OLT Challenges: Two unmet medical needs: High HCV prevalence Accelerated progression of chronic Hep C significant cause of reduced survival Disappointing results with SOC Life sparing concurrent treatment with consistent DDI

4 The use of triple therapy in HIV+ Rationale DDI Studies Provisional clinical guidelines

5 The use of triple therapy in HIV+ Rationale DDI Studies Provisional clinical guidelines

6 Causes of death in the Swiss HIV Cohort study Ruppik M. et al. Changing patterns of causes of death in the SHCS CROI Poster # 789. Available at:

7 Achieving Sustained Virologic Response: Impact on Long-Term Outcomes in HIV/HCV-Coinfection GESIDA 3603 Cohort: 711 pts treated for HCV Long-Term Outcome Rate (per 100 person/years) 0.46* (0.06,1.65) Overall Mortality 3.12 (2.16,4.37) 0.23 (0.01,1.27) 1.65 (0.98,2.16) Liver-Related Mortality 4.33 (3.16,5.8) 0.23 (0.01,1.27) 0 (0,0.84) Liver Decompensation 0.83 (0.38,1.58) Hepatocarcinoma 0 (0,0.84) 1.02 (0.50,1.82) Liver Transplantation Achieved SVR Did not achieve SVR 0.23 (0.01,1.27) 0.93 (0.44,1.70) New AIDS Conditions *P=0.003, P=0.028, P<0.001, and P=0.034 versus not attaining a sustained virologic response. n=711 HIV/HCV-coinfected patients receiving interferon (peg or conventional) + ribavirin. Berenguer J. et al. Hepatology 2009.

8 Prevalence of HCV genotypes in patients from the MASTER COHORT (stratified by the date of 1st HIV Ab+) HCV-RNA out of 3177 tested: 71% Prevalence (%) Distribution of HCV G1 subtypes HCV Genotype 1a: 59% HCV Genotype 1b: 27% HCV G1 not subtyped or mixed: 13% G: genotype Year Presented by G. Carosi at the 7th International Workshop on HIV & Hepatitis Co-infection, June

9 Summary of Results From Coinfection Trials Study N Treatment SVR (%) All GT 1 GT non-1 RIBAVIC 412 PEG IFN α-2b + RBV * 44 IFN α-2b + RBV ACTG 133 PEG IFN α 2a + RBV IFN α -2a + RBV APRICOT 860 PEG IFN α 2a + RBV IFN α -2a + RBV LAGUNO 93 PEG IFN α-2b + W/B RBV IFN α-2b + W/B RBV PRESCO 389 PEG IFN α-2a + W/B RBV G1 48 w 31 72w 52 G2 24 w 67 48w 82

10 The use of triple therapy in HIV+ Rationale Liver diseases are the 1 st cause of death in HIV+ SVR is associated with reduced mortality HCV G1 is the most prevalent in Italy SVR after SOC in HIV/HCV is disappointing ( 14-39%)

11 The use of triple therapy in HIV+ Rationale DDI Studies Provisional clinical guidelines

12 Characteristics of New anti HCV drugs potential for DDI with antiretrovirals Directly Acting Antivirals (DAA) Host proteins Targeted Antivirals (HTA) Class 1 st Gen NS3 inhib. 2 nd Gen NS3 inhib. 3 rd Gen NS3 Inhib. Nuc NS 5B inhib 1 st gen. Nuc NS5B inhib. 2 nd gen No Nuc NS5B inhib. NS5A inhib. Cycl ophi llin Inhi bi. Intefe ron lambd a NRTI DDI with Antiretrovirals NNRTI PI RAL

13 Pharmacokinetic Interactions Between Telaprevir and Antiretrovirals TVR dose ARV TVR AUC TVR C min ARV AUC ARV C min TVR 750mg tid ATV/r 0.80 ( ) 0.85 ( ) 1.17 ( ) 1.85 ( ) DRV/r 0.65 ( ) 0.68 ( ) 0.60 ( ) 0.58 ( ) FPV/r 0.68 ( ) 0.70 ( ) 0.53 ( ) 0.44 ( ) LPV/r 0.46 ( ) 0.48 ( ) 1.06 ( ) 1.14 ( ) RAL ( ) 1.78 ( ) TVR 1125mg tid EFV TDF 0.82 ( ) 0.75 ( ) 0.82 ( ) 1.10 ( ) 0.90 ( ) 1.17 ( ) TVR 1500mg bid EFV TDF 0.80 ( ) 0.52 ( ) 0.85 ( ) 1.10 ( ) 0.89 ( ) 1.06 ( ) ARV: antiretroviral; ATV: atazanavir; DRV: darunavir; EFV: efavienz FPV: fosamprenavir; LPV: lopinavir; r: ritonavir; TDF: tenofovir van Heeswijk R, et al. 51st ICAAC Abstract A1-1738a van Heeswijk R, et al. CROI Abstract 119

14 Pharmacokinetic Interactions Between Boceprevir 800 mg tid and Antiretrovirals ARV BOC AUC BOC C max BOC C min ARV AUC ARV C max ARV C min ATV/r Unchanged Not reported Unchanged - 49% DRV/r - 32% Not reported Not reported % % - 59% LPV/r - 45% Not reported Not reported - 43% EFV (90% CI) - 19% (11-25) -8% ( ) - 44% (26-58) + 20% (15-26) +11% (2-20) Not reported TDF +8% (2-14%) +5% (- 2+12) Not reported +5% (1-9)* +32% (19-45%) Not reported RAL Unchanged? ARV: antiretroviral; ATV: atazanavir; DRV: darunavir; EFV: efavienz FPV: fosamprenavir; LPV: lopinavir; r: ritonavir; TDF: tenofovir Modified from Kassera C, et al. CROI Abstract 118 and MSD Dear Doctor letter February 6th 2012

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16 The use of triple therapy in HIV+ Rationale DDI Liver diseases are the 1 st cause of death in HIV+ SVR is associated with reduced mortality HCV G1 is the most prevalent in Italy SVR after SOC in HIV/HCV is disappointing ( 14-39%) There are major DDI with antiretrovirals: Treatment with BOC is not indicated in HIV+ ARV drugs use is restricted in candidates for Telaprevir; Telaprevir dose adjustment is required with EFV

17 The use of triple therapy in HIV+ Rationale DDI Studies Provisional clinical guidelines

18 Phase 2 studies with HCV PI in HIV/HCV Naggie S et al. Submitted 2011

19 Studies with DAA in HIV+ Efficacy

20 Virologic Breakthroughs Boceprevir 1 Telaprevir 2 HIVRNA breakthrough 2 on placebo 2 on ATZ/RTV None HCVRNA breakthrough None 7 patients EFV 4 out of 16 at weeks 4 (n=1), 8 (1), 12 (2) ATZ /RTV 3 out of 15 at weeks 4 (1), 8 (1), 12 (1) 1. Sulkowski M et al. IDSA Sherman KE et al. AASLD 2011

21 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 24/64 8/32 35/62 11/32 43/61 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. IDSA 2011: Abstract LB-37

22 Telaprevir in HCV/HIV co-infection: RVR and ervr by ART regimen No ART EFV+TDF+FTC ATV/r+TDF+FTC 68 RVR 61 ervr Patients (%) T/PR PR T/PR PR n/n= 5/7 12/16 9/15 0/6 0/8 0/8 4/7 12/16 7/15 0/6 0/8 0/8 RVR: rapid virologic response=undetectable HCV RNA at Week 4 ervr: extended rapid virologic response=undetectable HCV RNA at Weeks 4 and 12 Sherman KE, et al. Hepatology 2011;54(Suppl. S1): Abstract LB-8

23 Telaprevir + PR vs PR in HIV+: interim analysis at 4 and 12 weeks vs data from phase III Illuminate trial in HIV Sulkowski M et al. CROI 2011 abs 146LB

24 Telaprevir in HCV/HIV co-infection: undetectable HCV RNA at Week 24 by ART regimen No ART EFV+TDF+FTC ATV/r+TDF+FTC 71 (27/38) 55 (12/22) P=0.5 Patients with undetectable HCV RNA (%) T/PR PR n/n= 6/7 11/16 10/15 2/6 4/8 6/8 Roche COBAS TaqMan HCV test v2.0, LLOQ=25 IU/mL, LOD=10 IU/mL Sherman KE, et al. Hepatology 2011;54(Suppl. S1): Abstract LB-8

25 Studies with DAA in HIV+ Safety

26 Boceprevir in HCV/HIV co-infection: patient disposition n (%) PR BOC/PR Treated 34 (100) 64 (100) Discontinued during treatment phase Due to AE Due to treatment failure 14 (41) 3 (9) 11 (32) 16 (25)* 9 (14) 3 (5) Completed treatment phase 1 (3) 2 (3) Ongoing 19 (56) 46 (72) *Four subjects in the BOC/PR group discontinued treatment for reasons unrelated to AE or treatment failure; AE: adverse event Sulkowski M, et al. IDSA 2011: Abstract LB-37

27 Boceprevir in HCV/HIV co-infection: most common AEs with a difference of 10% between groups* % PR (n=34) BOC/PR (n=64) Neutropenia 3 13 Dysgeusia Vomiting Pyrexia Headache Decreased appetite *A difference of 10% for patients in the BOC/PR group when compared with PR Sulkowski M, et al. IDSA 2011: Abstract LB-37

28 Boceprevir in HCV/HIV co-infection: summary of hematologic AEs n (%) PR (n=34) BOC/PR (n=64) Anemia AEs Serious AEs AEs leading to discontinuation Grade 2 (8.0 to <9.5 g/dl) Grade 3 (6.5 to <8.0 g/dl) Erythropoietin use Transfusions Neutropenia AEs Grade 3 (<0.75 x 10 9 /L) Grade 4 (<0.5 x 10 9 /L) 9 (26) 2 (6) 1 (3) 7 (21) 1 (3) 7 (21) 2 (6) 1 (3) 3 (9) * 19 (30) 1 (2) 1 (2) 10 (16) 3 (5) 17 (27) 4 (6) 8 (13) 10 (16) * *To maintain blinding in this continuing study, the table only shows data where events occurred in 1 patient in each treatment group Sulkowski M, et al. IDSA 2011: Abstract LB-37

29 Telaprevir in HCV/HIV co-infection: SAEs and premature discontinuations Part A Part B No ART EFV+TDF+FTC ATV/r+TDF+FTC n PR (n=6) T/PR (n=7) PR (n=8) T/PR (n=16) PR (n=8) T/PR (n=15) SAEs* Reason for discontinuation Discontinuation due to HCV futility rule, n Discontinuation of TVR only due to AE, n (due to jaundice) Discontinuation of all study drugs due to AE (overall treatment phase), n Due to cholelithiasis Due to hemolytic anemia *One additional patient had an SAE of pneumococcal pneumonia reported after the Week 4 safety follow-up visit Reported as severe AE, occurred at Week 3; Patient had Grade 3 hemoglobin, also experienced Grade 4 hemoglobin (SAE of hemolytic anemia); AE: adverse event; SAE: serious AE Sherman KE, et al. Hepatology 2011;54(Suppl. S1): Abstract LB-8

30 Telaprevir in HCV/HIV co-infection: most common AEs PR (n=22) T/PR (n=38) Any AE, % Most common AEs,* % Fatigue Pruritus 9 39 Headache Nausea Rash Diarrhea Dizziness Pyrexia 9 21 Depression 9 21 Neutropenia Anemia Vomiting 9 18 Myalgia Chills Insomnia Decreased appetite Weight decreased *Regardless of severity and reported in 15% of patients in total T/PR or PR groups during overall treatment phase Grouped term for related dermatologic AEs, no severe rashes were reported Grouped term for related anemia AEs, 4 patients (1 Part A, 3 Part B) received an erythropoietin-stimulating agent Pruritus, headache, nausea, rash, pyrexia, depression, insomnia, decreased weight and abdominal pain occurred with >10% higher frequency in T/PR vs PR group Bilirubin AEs with ATV/r more frequent in T/PR vs PR groups (27% vs 0%, respectively) Hyper-bilirubinemia was primarily unconjugated Sherman KE, et al. Hepatology 2011;54(Suppl. S1): Abstract LB-8

31 Telaprevir in HCV/HIV co-infection: pharmacokinetics Telaprevir pharmacokinetics were comparable across ART regimens Pharmacokinetics of ARVs showed modest changes when co-administered with T/PR Ratio to reference (%) TVR pharmacokinetics* EFV-based ART ATV/r-based ART C min C avg C max ART pharmacokinetics (C min ) PR T/PR ATV EFV Tenofovir (given with EFV) Tenofovir (not given with EFV) *Ratio of mean concentration with ART (test) versus no ART (reference) Ratio of median C min after (test) versus before (reference) anti-hcv treatment ARV: antiretrovrial; C min : minimum plasma concentration; C avg : average plasma concentration C max : maximum plasma concentration Sherman KE, et al. Hepatology 2011;54(Suppl. S1): Abstract LB-8

32 Summary: studies with boceprevir or telaprevir in HCV/HIV co-infection HCV-HIV co-infected naïve patients had higher rates of HCV response with BOC/PR and TPV/PR compared to PR alone Preliminary safety data in co-infected patients showed a profile consistent with that observed in mono-infected patients No unexpected trends in CD4 counts or HIV RNA level Sulkowski M, et al. IDSA 2011: Abstract LB-37 Sherman KE, et al. Hepatology 2011;54(Suppl. S1): Abstract LB-8

33 The use of triple therapy in HIV+ Rationale DDI Studies Provisional clinical guidelines

34 Antiretroviral therapy in candidates for PEG IFN + RBV + TPV. BOCEPREVIR IS NOT INDICATED FOR USE IN PATIENTS WHO ARE INFECTED WITH BOTH HIV-1 AND CHRONIC HCV. CLASS Antiretrovirals TELAPREVIR NRTI AZT, ddi, d4t Avoid coadministration ABC: No data Potential interaction with UDP-glucuronyl tranferase TDF FTC, LAM. No Data but no potential interactions Combine with caution Can be combined Can be combined PI LPV/R, DRV/R, FPV/R, Avoid coadministration ATZ/R Can be combined NNRTI EFV 1125 mg tid NVP RPV ETV: Data expected soon on ETV and RPV Avoid coadministration II RAL Can be combined

35 Telaprevir: Treatment schedule in HIV+ 750 mg (two 375-mg tablets) q8hr with food (not low fat; standard fat meal is 21 g) If on Efavirenz based ART :1125 (three 375-mg tablets) q 8 hr with food ( not low fat; standard fat meal is 21g) TVR + PR PR ervr: HCVRNA undetectable at 4 & 12 weeks: useful to reinforce patients adherence but not for Response Guided Therapy Time Point Criterion Stopping Rule Wk 4 or 12 HCV RNA > 1000 IU/mL Discontinue all therapy Wk 24 Detectable HCV RNA Discontinue PR Any Discontinuation of PR for any reason Discontinue TVR Telaprevir [package insert]. May EMA. Telaprevir [package insert] 2011.

36 Il 28 b SNP and RVR as predictors of SVR in 64 HIV/HCV G1 pts (54 with RVR) IL28 b Rs RVR NO/all (% 95% CI) All 48/54 (89%; 85-93%) AA 4/14 (29%; 16-40%) AG & GG 2/34 (6%;2-10%) All 6/48 (12%; 8-17%) Rate of SVR RVR YES/all ( % ; 95% CI) 6/54 (11%; 7-15%) 3/3 (100%) 2/3 (67%; 39-94%) 5/6 (83% 68-99%) ALL (%; 95% CI) 8/20 (40%; 29-51%) 4/44 (9%; 5-13%) 12/64 (19%; 14-24%) Puoti M et al. 45 th AISF annual meeting Poster n. 45 February 24 th 2012

37 Management of HIV-HCV coinfected genotype-1 patients according to fibrosis stage and prior treatment outcome: a proposal * Lead in phase Fbrosis stage IL28 & RVR Naïve Experienced Relapsers Partial responders Null responders Undefined F0-F1 At least one predictor P+R Consider P+R+T Defer Defer Defer No Predictors Defer F2-F3 RVR* P+ R P+R+T No RVR F4 Lead in HCVRNA decrease >1 Log Lead in HCVRNA decrease <1 Log P+R+T P+R+T* Defer

38 HIV/HCV studies with Boceprevir on clinical.trial.gov Drug ID Sponsor Design Target population N of subjects (status on Feb ) Boceprevir NCT NIAID Open uncontrolle d Boceprevir NCT NIAID Controlled vs HIV- Boceprevir NCT ARNS Open uncontrolle d Naives + Experienced Naives HIV+ vs Naives HIV- 310 (not yet recruiting) 200 (recruiting) Experienced 80 (recruiting)

39 HIV/HCV studies with Telaprevir in HIV on clinical.trial.gov Drug ID Sponsor Design Target population N of subjects (status on Feb ) Telaprevir NCT VX Vertex Open uncontrolle d (1125 mg bid or tid with EFV) Naïve Experienced 160 (recruiting) Telaprevir NCT VX- 950HPC3008 Tibotec Open uncontrolle d Naïve Experienced 150 (recruiting) Telaprevir NCT VX- 950HPC3005 Janssen Cilag Open uncontrolle d Naïve Experienced F3 F4 500 (recruiting)

40 HIV/HCV studies with other DAA on clinical.trial.gov Drug ID Sponsor Design Target population N of subjects (status on Feb ) TMC435 NCT TMC435- TiDP16-C212 Tibotec Open uncontroled? 100 BI NCT Boehringer Randomized( 12 vs 24 w) Daclatasvir (BMS ) NCT AI BMS Open Uncontrolled Naïve Relapsers 316 Naive 300

41 Rationale DDI Triple therapy in HIV+ Liver diseases are the 1 st cause of death in HIV+ SVR is associated with reduced mortality HCV G1 is the most prevalent in Italy SVR after SOC in HIV/HCV is disappointing ( 14-39%) There are major DDI with antiretrovirals: Treatment with BOC is not indicated in HIV+ ARV drugs use is restricted in candidates for Telaprevir and TPV dose should be increased with EFV Preliminary data HCV-HIV co-infected patients who were previously untreated had higher rates of HCV response with BOC/PR and TPV/PR compared to PR alone Preliminary safety data in co-infected patients showed a profile consistent with that observed in mono-infected patients No unexpected trends in CD4 counts or HIV RNA level Provisional guidelines for use Usage of TPV in selected HIV coinfected patients with adjusted ART possibly in clinical studies

42 The use of triple therapy in OLT Rationale DDI Study

43 The use of triple therapy in OLT Rationale DDI Study

44 N. of adults with 1 st LT: 1204; Non viral indications : 436

45 Outcome of HCV post-transplant Gane E LT 2008;14:S36-44.

46 Natural History of Recurrent HCV Decompensation in Recurrent Cirrhosis Rate of Decompensation 100% 75% 50% 25% 0% *Once cirrhosis present in allograft 3 y survival < 10% 42% 4% 62% 9% Years Recurrent HCV-cirrhosis Berenguer, 2000 Non-transplant HCV-cirrhosis Fattovich, 1997

47 Rationale for DAAs treatment of recurrent chronic hep C in liver transplant recipients HCV infection remains the most common indication for orthotopic Liver Transplantation in Italy Most patients are viremic at time of liver transplantation Hepatitis C recurrence after OLTx is universal and results in accelerated progression of fibrosis to cirrhosis in 20% at 5 years and 50% at 10 years Allograft HCV recurrence with subsequent liver failure is the one of the most common reason for decreased allograft survival in HCV infected patients HCV genotype 1 is the most common genotype in Italy 47

48 The use of triple therapy in OLT Rationale DDI Study

49 49

50 Pharmacokinetic Interactions Between Telaprevir and Immunosuppressants Telaprevir is expected to have a significant effect on both cylcosporine and tacrolimus as they are substrates of CYP3A and P-gp 1 Calcineurin Inhbitor Cyclosporine 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 Single doses of cyclosporine or tacrolimus had no major effect on telaprevir pharmacokinetics According to Drug metabolism interaction with sirolimus and everolimus could be expected C max : maximum plasma concentration Garg et al Hepatology 2011; 54: 20-7

51 The use of triple therapy in OLT Rationale DDI Study

52 Preliminary data from a pilot study on efficacy and safety of TPV based triple therapy of Hep C recurrence in Liver transplant recipients Study population 7 LT recipients with HCV recurrence 3mo - 6 yrs post Tx aged yrs; 1/7 F4 6/7 F0-2 Immunosuppressive therapy: TAC ½ of pre Tx dose once weekly with TDM every other day in first 2 weeks. TAC dose resumed 5 days after Telaprevir withdrawal with gradual escalation Schedule of Anti HCV Tx 6/7 triple therapy; 1/7 TPV add on PEG (6: 2a; 1: 2b) + RBV mg/d 52Mantry PS et al Global Antiviral Journal, Volume 7, Suppl. 1 (HEPDART 2011) : 90

53 Preliminary data from a pilot study on efficacy and safety of TPV based triple therapy of Hep C recurrence in Liver transplant recipients Efficacy: 1 NR + 4/7 ervr + 2/7 cevr Safety: 1 deceased ( Pneumonia + ARDS) with 3 hospitalization and 4 transfusion 3 at least 1 hospitalization ( 2 infections: 2 UTI 1 with sepsis) 5/7 blood transfusions ( 2 or more) Conclusions: TAC dose adjustment with intensive monitoring no toxicity or rejection Rapid HCV suppression Substantial side effects should be discussed with pts. 53Mantry PS et al Global Antiviral Journal, Volume 7, Suppl. 1 (HEPDART 2011) : 90

54 HIV/HCV studies with DAA in Liver Transplant Recipients Drug ID Sponsor Design Target population N of subjects (status on Feb ) ITX 5061 (HCV entry inhibitor) NCT University of Birmingham Phase I Open Label Liver transplant recipients 20 Telaprevir NCT VX Vertex Phase II Open Label 1125 bid Stable LT recipients assuming Sirolimus + PDN 75 Boceprevir ANRS HC 29 BOCEPRETRAN SPLANT ANRS Phase II Open Label Cirrhosis LT candidates MELD < 18 64

55 Triple therapy in OLT Rationale DDI HCV infection most common indication for OLT in Italy Universal Hepatitis C recurrence with accelerated progression to cirrhosis and significantly deceased allograft survival HCV genotype 1 is the most common genotype in Italy Significant DDI with calcineurin and mtor inhibitors: calcineurin dose adjustments as in HIV+ OLT taking Pi based ART Study No data to define any provisional guideline Studies with careful surveillance for safety are urgently needed