Professor Massimo Puoti

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2 THIRD JOINT CONFERENCE OF BHIVA AND BASHH 2014 Professor Massimo Puoti Niguarda Ca Granda Hospital, Milan, Italy 1-4 April 2014, Arena and Convention Centre Liverpool

3 THIRD JOINT CONFERENCE OF BHIVA AND BASHH 2014 Professor Massimo Puoti Niguarda Ca Granda Hospital, Milan, Italy COMPETING INTEREST OF FINANCIAL VALUE > 1,000: Speaker Name Prof Massimo Puoti Statement Abbvie, BMS, Boehringer Ingelheim, Gilead Sciences, Janssen, MSD, Roche, Date April April 2014, Arena and Convention Centre Liverpool

4 Massimo Puoti Dept. of Infectious Diseases AO Ospedale Niguarda Cà Granda Milan, Italy Hepatitis C: when to treat and when to wait

5 Disclosures I have received fees for talks in own events &/orinternal courses &/or participation in temporary advisory boards &/or resarch grants from: Abbvie, BMS, Boehringer Ingelheim, Gilead Sciences, Janssen, MSD, Vertex, ViiV. In this presentation there are data on off label use of approved drugs and about investigational drugs not approved in humans

6 Treat now or wait? Considerations What is the likelihood of SVR and tolerability with currently approved therapies? What are the morbidity/mortality risks of deferring treatment to a later date? What are the potential benefits (efficacy, safety and convenience) of future therapies? SVR = CURE What is the motivation for the patient to undergo therapy?

7 Treat now or wait? Considerations What is the likelihood of SVR and tolerability with currently approved therapies? What are the morbidity/mortality risks of deferring treatment to a later date? What are the potential benefits (efficacy, safety and convenience) of future therapies? What is the motivation for the patient to undergo therapy?

8 SVR rates (%) Telaprevir and Boceprevir Phase II trials in G1 HCV/HIV1 co-infected treatment naїves Sulkowski et al Ann Int Med Sulkowski MS, et al.lancet Inf Dis Variable Telaprevir Study Boceprevir Study Not on cart 7 0 CD4 & HIVRNA >500 & HIVRNA< > 300 & HIVRNA < 50 c/ml >200 & HIVRNA <50 c/ml 28/38 10/22 37/61 9/34 No new safety signal compared to mono-infected patients

9 ANRS studies Telaprervih (HC26) and Boceprevih (HC 27) SVR24 in HIV/HCV PR experienced treated with PR + TEL (69) or BOC (62) 4 weeks lead in + 44 w standard + 24 additional weeks if HCVRNA w8 > 15 UI/mL Cotte L et al. CROI 2014; Poizot Martin I. et al CROI 2014

10 SVR in HIV/HCV G2 and G3 treated with PEGIFN + RBV in an Italian observational cohort study The Opera study Puoti M et al. Antiviral Therapy in press

11 High levels of SVR to PR in HCV/HIV with RVR independently from IL28 SNP, Fibrosis stage and Treatment duration RVR in 54% of HIV+/HCV G 2/3 Mandorfer et al. AIDS 2013

12 Prevalence and Predictive value of RVR ( HCVRNA undetectable at the 4 th week of triple therapy ) with anti HCV PI in HCV+/HIV- Setting Treatment %RVR SVR in pts with RVR HCVG1 Naïve Relapser & NR F0-F2 1 PR + BOC 889 / % HCVG1 Naïve Relapser & NR F3-F4 1 PR + BOC 120/278 43% HCV G1 Naive 2 PR + TEL 422/583 72% HCV G1 Relapsers 3 PR + TEL 201/251 80% HCV G1 PR 3 PR + TEL 56/84 67% 766/889 86% 106/120 89% 365/420 87% 183/201 91% 38/56 68% HCVG1 NR 3 PR + TEL 42/130 32% 28/42 68% 1 Vierling JM et al. EASL 2013; 2 Sarrazin et al HepDART 2013; 3Berg T, et al. Hepatology 2011;54(Suppl. S1):375A

13 BOC retrospective analysis: summary of SAEs according to fibrosis stage in HCV+/HIV- F0 1 F3 4 F4* n (%) PR (N=389) BOC (N=868) PR (N=39) BOC (N=139) PR (N=31) BOC (N=112) Any AE 380 (98) 862 (99) 39 (100) 138 (99) 31 (100) 112 (100) SAE 32 (8) 99 (11) 3 (8) 21 (15) 3 (10) 18 (16) Death 4 (1) 3 (<1) Study drug discontinuation due to AE 56 (14) 116 (13) 2 (5) 17 (12) 3 (10) 16 (14) Dose modification due to AE 83 (21) 301 (35) 16 (42) 57 (41) 13 (42) 44 (39) *Includes patients included in SPRINT-1 Patients deaths are also included in this category CHC: chronic hepatitis C Bruno S, et al. J Hepatol 2013;58:479 87

14 TVR Pbo-controlled Phase II and III studies: summary of AEs during TVR/Pbo phase Patients (%) T12/PR (750 mg q8h) (N=1346) Skin and subcutaneous tissue disorders Pbo/PR48 (N=764) Leading to discontinuation of all study drugs* (%) Pruritus (SSC) Rash (SSC) Gastrointestinal disorders Nausea <0.5 Diarrhea <0.5 Hemorrhoids 12 3 <0.5 Anorectal discomfort 8 2 <0.5 Anal pruritus 6 1 <0.5 Blood and lymphatic system disorders Anemia (SSC) *Discontinuation of all study drugs in the T12/PR arms (analysed within SSC for rash and anemia) Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM pdf

15 Antiretroviral therapy in candidates for PEG IFN + RBV + TPV/BOC/SMV/FDV/SOF. CLASS TELAPREVIR BOCEPREVIR SIMEPREVIR FALDAPREVIR *120/ 240 mg SOFOSBUVIR NRTI AZT, ddi, d4t: NO WITH PR / ABC: TDF; AUC increased 30% FTC, LAM PI ATZ/R; ^ Cthrough incresaed 30% ^ DRV/R LPV/R,, FPV/R, NNRTI EFV * NVP RPV ETV; #Etravirine AUC - 23% # INI RAL/DOL Elvitegravir/cobicistat No data No data No data CCR5 I MAR:150 mg bid withtel No data No data

16 What is the likelihood of SVR and tolerability with currently approved therapies? SVR 61-72% in Naïve & Relapsers G1 with PR + BOC/TVR SVR 24-80% in non responders G1 with PR + BOC/TVR SVR > 85% in naïve G1 with RVR to PR + BOC/TVR 56-65% in Naïve HCV G2/3 with PR SVR > 85% in Niave HCVG2/3 with RVR 23% in HCV G4 with PR Low tolerability additionally decreased by the addition of TVR/BOC Limitation of concurrent cart treatment options

17 Treat now or wait? Considerations What is the likelihood of SVR and tolerability with currently approved therapies? What are the morbidity/mortality risks of deferring treatment to a later date? What are the potential benefits (efficacy, safety and convenience) of future therapies? SVR = CURE What is the motivation for the patient to undergo therapy?

18 Impact of HCV coinfection on HIV disease, response to treatment and associated comorbidities HCV impact on HIV natural history and cart response is controversial 1 Two recent papers demonstrated lower virological and immunological response in HCV+ and also in HCV+/HCVRNA+ vs HCV+/HCVRNA- 2,3. Worsening effect of HCV on kidney related to HCVRNA reactivity in HCVAb+ 4 Association between HCV infection and osteoporotic fractures in HIV+ 5,6 Association between HCV coinfection and neurocognitive impairment in HIV and improvement of neurognitive impairment after SVR in HCV+/HIV- 7,8 1 Pulido F et al AIDS reviews 2012; 2 Hua L. et al. AIDS 2013; 3 Poter M AIDS 2010; 4 Mocroft A et al. PLoS One. 2012; 5 Lo Re V et al. Hepatology 2012;56; 6 Maalouf NM et al J Bone Min Res Bing S JAIDS 2012 ; 8 Kraus MR et al Hepatology

19 Sustained Virological Response to Interferon Plus Ribavirin ReducesOverall, Liver Related and Non Liver-Related Mortality in 1599 Patients Coinfected With HIV and Hepatitis C Virus Overall mortality Liver rel. mortality Non Liver rel. mortality Non Liver rel. Non AIDS mortality 20 Berenguer Clin Inf Dis 2012; 55:

20 Hepatology 2013 Proportion of ALT Values > 2.5 x UNL

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22 The risk of Liver Related Death is < 1% at 10 years in pts with mild fibrosis in EuroSIDA Grint D et al. CROI 2014

23 Priorities for anti HCV treatment: Risk of decompensation of cirrhosis in HIV-HCV coinfected patients with advanced fibrosis 24 Macias J CROI 2013 abstract # 727

24 Benefits From Sustained Virologic Response to Pegylated Interferon Plus Ribavirin in 166 HIV/ Hepatitis C Virus Coinfected Patients With Compensated Cirrhosis Incidence of decompensation Overall mortality 25 Mira J CID 2013:56:

25 Post transplant recurrence of HCV Progression to a fibrosis score F2 HIV(+)/HCV(+) vs HIV(-)/HCV(+) Duclos-Vallèe, Hepatology, vol 47 (2) , 2008

26 Case (N=84) - Control (N=252) Study: Survival After OLT in HCV- Infected Patients According to HIV Status 90% (86-93%) 88% (79-93%) 76% (70-80%) 72% (66-77%) 62% (51-72%) 54% (42-64%) HCV/HIV co-infected HCV mono-infected Mirò J et al Am J Liver Transpl 2012

27 What are the morbidity/mortality risks of deferring treatment to a later date? All treatment-naïve and experienced patients with compensated disease due to HCV should be considered for immediate therapy Treatment deferral may be associated with persistence of the worsening impact of HCV on HIV disease and related comorbidities. Treatment should be prioritized for patients with significant fibrosis (METAVIR score F3 to F4 or Stiffness > 14.5 KPa or FIB4>3,25). In patients with no or mild disease (METAVIR score F0-F1), the indication for and timing of therapy can be individualized on ALT levels and cofactors of liver disease progression. Patients on the transplant list are expected to have a great benefit from anti HCV treatment In patients with decompensated cirrhosis (pre and post liver transplantation) the benefit of SVR could be potentially high but should be assessed both in the short term ( according to the stage of decompensation) and in the long term (concurrent occurrence of HCC)

28 Treat now or wait? Considerations What is the likelihood of SVR and tolerability with currently approved therapies? What are the morbidity/mortality risks of deferring treatment to a later date? What are the potential benefits (efficacy, safety and convenience) of future therapies? What is the motivation for the patient to undergo therapy?

29 What are the potential benefits (efficacy, safety and convenience) of therapies available in the next months?

30 Study Rodriguez Torres M et al IDSA 2013; Dieterich EACS 2013; Rockstroh The Liver Congress 2013 C212 Dietrich D et al. EACS 2013 STARTVERSO4 Rockstroh J et al EACS 2013 & The Liver Congress 2013 PEGIFN + R + SOFO Rodriguez-Torres M et al IDSA week Photon 1 Sulkowski M et al The Liver Congress 2013

31 Study populations in registrative studies in HIV/HCV Genotype 1 Study Telaprevir Boceprevir SIMEPREVIR ( C212) FALDAPREVIR (startverso 4) SOFOSBUVIR + PR SOFOSBIVIR + RBV N Males % 92% 72% 85% 78% 78% 82% Naives n (%) 38 (100%) 64 (100%) 53 (50%) 139 (75%) 19 (100%) 114 (100%) RR n (%) (25%) 0 0 PR n (%) NR n (5) IL28 CC % NR 25% 27% 29% 22% 27% HCV G1a 71% 80% 82% 84% 65% NR F0-F2 n (%) 86% 84% 67% 75% NR NR On cart 82% 100% 88% 97% 100% 98% Cirrhosis 5% 9% * 12% 11% NR 4%

32 Cross comparison between trials SVR 4 in HIV/HCV G1 treated with PR + SOFOSBUVIR or SIMEPREVIR or FALDAPREVIR 4/4 16/18 13/15 178/242 72/88 16/28 7/10 13/15 17/19 169/239 17/19 229/308 Rodriguez Torres M et al IDSA 2013; Dieterich EACS 2013; Rockstroh The Liver Congress 2013

33 Photon study: Sofosbuvir + Ribavirin in HIV/HCV Dieterich D et al. APASL 2014

34 Cross comparison between trials SVR 4 after treatment with PR + Simeprevir, Faldaprevir and Sofosbuvir + R + P for hepatitis C naïve pts.: Comparison beteween data in HIV + vs HIV- 78/124 87/ /145 28/42 295/327 17/19 IN THE DAA ERA HIV+ WILL NOT BE A SPECIAL POPULATION WITH AN UNMET NEED 414/ / /521 42/53 Gane EJ EASL 2013 ; Jacobson IM NEJM 2013; Lawitz E et al NEJM 2013; Ferenci F et al EASL 2012 Manns MP et al EASL 2012 Jacobson EASL 2012 Rodriguez Torres M et al IDSA 2013; Dieterich EACS 2013; Rockstroh The Liver Congress 2013

35 Antiretroviral therapy in candidates for PEG IFN + RBV + TPV/BOC/SMV/FDV/SOF. CLASS DACLATASVIR *30 mg/60mg/ 90 mg SIMEPREVIR FALDAPREVIR *120/ 240 mg SOFOSBUVIR NRTI AZT, ddi, d4t: no with PR orr / ABC: TDF; AUC increased 30% FTC, LAM PI ATZ/R; ^ Cthrough incresaed 30% * DRV/R No data LPV/R,, FPV/R, No data NNRTI EFV * NVP No data RPV No data ETV; #Etravirine AUC - 23% No data INI RAL/DOL Elvitegravir/cobicistat No data No data No data CCR5 I MAR:150 mg bid withtel No data No data

36 % of treated patients with SVR 12 (95% CI) Cross comparison between trials SVR 12 in HCV+/HIV- G1 Naïve Cirrhotics treated with PEG + RBV + SOFO (12 w) or SIME (48 w) or FDV (48w) SOFO G1 CIRR SIME G1 CIRR FALDA G1 CIRR Lawitz et al NEJM 2013; Jensen et al AASLD 2013 Yoshida et al. AASLD 2013;

37 PR TVR vs PR SMV in HCV+/HIVnon responders Reddy KR et al APASL 2014

38 Jacobson IM, et al. AASLD 2013, Washington DC. #LB-3 Sofosbuvir + Simeprevir + RBV for 12 weeks in HCV+/HCV

39 Sofosbuvir + Daclatasvir + Ribavirin for weeks in 167 HCV G1 HIV- (32 F4) Sulkowski M et al NEJM 2014

40 Treatment of HIV/HCV coinfection AASLD guidelines 2014

41 Naïve or Relapsers Treatment of HIV/HCV coinfection AASLD guidelines 2014 Eligible to Interferon Yes Yes PR + Sofo 12 w alt. [IB] No HCVG1* HCV G2 HCV G3 HCV G4 PR + Sime 24-48w [IIaC] Sofo + R [IB] Sofo + Sime + Riba [IIaC] Sofo + R (cirrh 16 w) [IB] Sofo + R 24 w [I B] PR+ Sofo 12 w [IIaB] PR + Sime 24-48w Sofo + R 24 w [IIaC] No Yes No Sofo + Sime + R [IIaC] PR + Sofo 12 w [IIaB] Sofo + R 12 w (16w cirrh.) [IB] PR + Sofo 12 w [IIaA] Sofo + R 24 w [IIaB] PR + Sofo 12 w [IIaB] Sofo + R 24 w [IIaC] * F0-F2 watchful waiting unti IFN free combo with more data from registrative studes will be available

42 What are the potential benefits (efficacy, safety and convenience) of therapies available in the next year?

43 Abbvie 3D combo + R in HIV- HCV Genotype 1 ( 1a + 1b; experienced + naives) stratified according to the presence of cirrhosis Kowdley et al. NEJM 2014; Lawitz et al AASLD 2013; Abbvie Press Release Jan 31 st 2014

44 1456/1518 HIV- (95,9%) SVR12 TN TE SVR 12 % SVR NA 108/ NA 110/ 111 % 99,1 99,1 209/ / ,6 Ion 1 136/865 (15,7%) with cirhrosis Ion 2 88/440 (20%) with cirrhosis 211/ / ,2 107/ ,4 62 failure (4,1%): 35relapses ; 1 breakthrough for bad compliance; 26 (1,7%) lost to follow up or retired consensus NA: data not available 201/ / ,4

45 Second generation NS5a inhibitors: pangenotipic activity and activity against RAVs Cheng G et al EASL 2013; Ng T et al CROI 2014

46 Second generation Protease Inhibitors: Pangenotypic activity and activity against RAVs Ng et al CROI 2014; Lawitz e et al. CROI 2014

47 The future: one pill for all second generation PI and Ns5A inhibitors: (almost) pangenotipic (almost) active against RAV Lawitz E et al CROI 2014

48 Treat now or wait? Considerations What is the likelihood of SVR and tolerability with currently approved therapies? What are the morbidity/mortality risks of deferring treatment to a later date? What are the potential benefits (efficacy, safety and convenience) of future therapies? What is the motivation for the patient to undergo therapy?

49 Clinical Need to be treated Treat now or wait? Clinical assessment Need for treatment but no desire for treatment Need for treatment and desire for treatment Probability of SVR No need for treatment yet and no desire for treatment No need for treatment yet but wants treatment Clinical need Patient Motivation Patient Motivation to be treated Patient Decision

50 Treat now or wait? Considerations What is the likelihood of SVR and tolerability with currently approved therapies? What are the morbidity/mortality risks of deferring treatment to a later date? A GUILTY BYSTANDER : THE THIRD PAYER ( HEALTH CARE INSURANCES, NHS) What are the potential benefits (efficacy, safety and convenience) of future therapies? SVR = CURE What is the motivation for the patient to undergo therapy?

51 Treatment of HIV/HCV coinfection AASLD guidelines 2014 Naïve or Relapse rs Eligible to Interfer on Yes Yes USD HCVG1 HCV G2 HCV G3 HCV G USD USD USD No USD USD USD USD No Yes USD USD No USD Cost of HCV screen and treat strategy in HIV in Italy : HIV/HCV x USD billion USD USD

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53 Delays may be long between approval and availability/reimbursement Approval Reimbursement 15 months TVR BOC France Sweden Germany UK* Austria Finland Denmark Switzerland Norway Scotland Netherlands Luxembourg Israel Spain UK* Belgium Ireland Italy Russia May Sept Dec Jan Dec National reimbursement does not mean product availability due to regional access policies Potential EU approval of IFN-free combinations: access in ? *Telaprevir was available but not reimbursed until UK NICE approval obtained 16 March 2012

54 Where Do We Set The Bar? > 85%

55 THERAPEUTIC OPTIONS FOR ANTI HCV TREATMENT with > 85% SVR Prototype Now Additional options for The next months If available HCV G1 without advanced diseas Naïve HCV G1 difficult to cure or relapse NR HCV G1 HCV G1 advanced cirrhosis HCV G2 HCV G3 naïve PR PR + TEL/ BOC w With RVR (50-60% of pts) PR + BOC/TEL With RVR (50-60% of pts) PR+ BOC/TEL With RVR (< 35% ogfpts) None PR with RVR (75% of pts) PR with RVR 75% of pts) PR + 2 nd w PI 24 w (1b) with RVR (70%) PR + SOFO 12 w (1a/1b) Additional value Greater efficacy better tolerability SIME /DACLA+ SOFO + R? Additional value greater efficacy excellent tolerability but few data SOFO + R SOFO + R HCV G3 experienced No PR SOFO/ SOFO R Additional options for The next years If available 3D SOFO/LEDI FDC + R Additional value Greater efficacy beter tolrability Complete and large data sets Someday somewhere FOR HCV ERADICATION WORLDWIDE SINGLE PILL PANGENOTYPIC COMBINATION OF 2 or 3 DRUGS candidates: SOFO/GS5816 Or MK 8732/MK5172 Or ABT 530/ABT 493 HCV G4 No PR + SOFO or SOFO + R Wait Treat Individual decision based on patient s motivation & clinical need

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