Coinfection treatment in the era of DAAs. Latest data on DDIs: clinical approaches with telaprevir and darunavir

Massimo Puoti Dept. of Infectious Diseases AO Ospedale Niguarda Cà Granda Milan, Italy Coinfection treatment in the era of DAAs. Latest data on DDIs: clinical approaches with telaprevir and darunavir

Coinfection treatment in the era of DAAs. Rationale for treating HCV in PLHIV Results with PR + DAA IFN Free Treatments Rationale and potential impact in PLHIV Preliminary Results EASL Guidelines and recommendations on HCV treatment in PLHIV Challenges Deferral Access to treatment

Coinfection treatment in the era of DAAs. Rationale for treating HCV in PLHIV Results with PR + DAA IFN Free Treatments Rationale and potential impact in PLHIV Preliminary Results EASL Guidelines and recommendations on HCV treatment in PLHIV Challenges Access to treatment Deferral

Rationale for Treatment of HCV co-infection in Persons Living with HIV (PLHIV) Liver diseases ( Decomp Cirrhosis and HCC) are the most frequent cause of death in HIV in southern Europe 1 Mortality in HCV/HIV unchanged from cart availability concurrent mortality due to liver disease 2 HCVRNA persistence impairs response to cart 3 HCV RNA presence enhances renal 4,5, bone 6,7 and CNS 8 comorbidities in HIV HIV accelerates progresson of HCV disease 9 SVR is associated with a decrease in liver related, AIDS related and non liver related non AIDS related mortality in HIV/HCV 10 1. Weber R, et al HIV Medicine 2013; 2. Ioannou V, et al HEPATOLOGY 2013; 3. Potter M, et al. AIDS 2010; 4. Peters L, et al AIDS 2012; 5 Mocroft A, et al. PLoS One. 2012; 6 Lo Re V, et al. Hepatology 2012;56; 7 Maalouf NM, et al J Bone Min Res 2013; 8 Bing S et al JAIDS 2012 ; 9 Thein H, et al. AIDS 2008;22; 10 Berenguer J,et al CID 2012;

Coinfection treatment in the era of DAAs. Rationale for treating HCV in PLHIV Results with PR + DAA IFN Free Treatments Rationale and potential impact in PLHIV Preliminary Results EASL Guidelines and recommendations on HCV treatment in PLHIV Challenges Access to treatment Deferral

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<1000.000 > 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

SVR24 (%) SVR12 (%) ANRS studies TelapreVIH (HC26) and BocepreVIH (HC 27) SVR in HIV HCV treatment experienced patients Telaprevir Boceprevir 69 27 5 15 21 42 27 34 12 64 20 18 21 39 25 32 27 SVR24 in HIV/HCV PR experienced treated with PR + TVR (69) or BOC (62); 4 weeks lead in + 44 weeks standard + 24 additional weeks if HCV RNA at Week 8 >15 UI/mL Cotte L et al. CROI 2014; Poizot Martin I. et al CROI 2014

HCV therapy in HIV/HCV co-infected patients: UNITE interim analysis Ongoing, Phase III single-arm trial in 185 HCV treatment-naïve or experienced patients receiving anti-retroviral therapy for HIV-1 SVR12 SVR24 PR Treatment-naïve or prior relapsers TVR bid + PR ervr+ ervr SVR12 SVR24 PR Prior null or partial responders TVR bid + PR PR SVR12 SVR24 Week 0 12 24 36 48 60 72 Interim analysis on 147 patients with available SVR12 data TVR 1125 mg bid + PR (RBV at 800 mg/day) for 12 weeks followed by PR up to Week 24 (treatment-naïve/relapsers with ervr) or to Week 48 (all other patients) For patients receiving efavirenz-based ARV TVR was administered1125 mg three times daily Hare CB, et al. HepDART 2013. Abstract 64

Patients achieving SVR12 (%) UNITE: rates of SVR12 by prior treatment response 100 80 60 67 68 60 62 40 39 20 0 55/82 15/22 9/23 12/20 91/147 Treatment-naïve Prior relapser Prior null responder Prior partial responder Total The most common reported AEs were fatigue (51%), rash (40%), pruritus (37%), nausea (35%), anemia (32%), headache (29%), diarrhea (23%), insomnia (20%) and neutropenia (17%) Hare CB, et al. HepDART 2013. Abstract 64

Antiretroviral therapy in candidates for PEG IFN + RBV + TPV/BOC/SMV/FDV/SOF. CLASS TELAPREVIR BOCEPREVIR 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 CCR5 I MAR:150 mg bid withtel No data

Protein displacement interaction Example: Single drug PK Key message Albumin Example: Two drugs X Total drug concentration: 3 Free concentration: 1 Free fraction: 33% Initial in free concentrations are subject to systemic clearance Total drug concentration: 2 Free concentration: 1 Free fraction: 50% Free concentrations are responsible for pharmacologic activity (PD), and are subject to systemic clearance (PK) Displacement trend: Total concentration Free concentration Free fraction LIMITED CLINICAL IMPACT Albumin TVR may be subject to some protein displacement interactions Example: TVR versus methadone

Plasma concentration of unbound TVR (ng/ml) Plasma concentration of total TVR (ng/ml) INSIGHT substudy: Plasma concentration of telaprevir coadministered with darunavir 4000 3500 3000 2500 2000 1500 1000 500 0 1200 1000 800 600 400 200 0 TVR (n=16) 0 1 2 3 4 5 6 7 8 Time (hours) 0 1 2 3 4 5 6 7 8 Time (hours) Bertelsen K, et al. EACS 2013. Poster PE7/11

Plasma concentration of total DRV (ng/ml) INSIGHT substudy: PK of darunavir co-administered with telaprevir Plasma concentration of unbound DRV (ng/ml) DRV alone (n=17) DRV with TVR + PR (n=16) 12000 10000 8000 6000 4000 2000 0 0 4 8 12 16 20 24 Time (hours) 2000 1800 1400 1200 1000 800 600 400 200 0 0 4 8 12 16 20 24 Time (hours) Although reduced, relative comparisons of these data with historical data suggest that the total TVR and DRV concentrations in this study are generally similar to the lowest quartiles observed in prior studies of TVR or DRV for most patients Bertelsen K, et al. EACS 2013. Poster PE7/11

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

High levels of SVR to PR in HCV with RVR independently from IL28 SNP and HIV co-infection 62 HCV 160 HIV HCV Neukam K et al. Journal of Infection 2013

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 /1511 55% 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

Adverse events in combination with Ribavirin (no head to head studies) Drug BOC TVR Tx Duration 28-48 24-48 N pills/n of doses 12/3 6/2-3 Food effect Yes Light snack Yes Fatty meal Anemia ++ ++ Fatigue ++ Dysgeusia ++ Nausea Vomiting + + Diarrhea - + Anorectal signs - ++ Pruritus + Rash Photosensitivity (+) ++ Victrelis EU SmPC; Incivo EU SmPC; Mauss et al Hepatology 2014;

PR + Second generation DAAs in co-infected patients C212 1 HCV treatment-naïve Prior PR relapsers SMV + PR (RGT) PR PR Follow-up Follow-up Partial response Null response Cirrhotic patients (F4) SMV + PR PR Follow-up STARTVerso4 2 FDV 240 mg + PR FDV 240 mg + PR PR PR or follow up (RGT) FDV 120 mg + PR PR or follow up (RGT) SOF + PR 3 GT 1 4 SOF + PR Follow-up SVR4 SVR12 SVR24 Week 12 24 36 48 60 72 1. Dietrich D et al. EACS 2013; 2. Rockstroh J et al EACS 2013 & AASLD 2013 3. Rodriguez-Torres M et al IDSA week; 4. Sulkowski M et al AASLD 2013

C212 study design: Phase III, openlabel, single-arm, international trial HCV treatment-naïve Prior relapse + Partial response Null response Cirrhotic patients (F4) Primary endpoints: SVR12, safety and tolerability Secondary endpoints: virologic response at other time points, meeting RGT criteria* for shortened treatment to 24 weeks, on-treatment failure and relapse rates Primary analysis: RGT * Week SMV 150 mg/pr SMV 150 mg/pr SMV 150 mg/pr 12 24 36 Follow-up Follow-up All patients included in the analysis (N=106) had completed 24 weeks of treatment, or had reached the time point of the primary efficacy endpoint SVR12 (Week 60), or discontinued prior to that point (for those on 48 weeks of treatment) PR PR PR Primary analysis 48 60 72 Follow-up + After PR treatment; *RGT criteria: HCV RNA <25 IU/mL (detectable or undetectable) at Week 4 and undetectable at Week 12 (measured using Roche COBAS TaqMan HCV/HPS assay, v.2) Dieterich D, et al. EACS 2013. Abstract LBPS9/5

SVR12 (%) C212: SVR12 Primary endpoint 78/106 42/53 13/15 7/10 16/28 SVR12, sustained virologic response 12 weeks after end of treatment Dieterich D, et al. EACS 2013. Abstract LBPS9/5

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

SVR12 (%) SVR12 after treatment with PR + TVR, SMV, FDV and SOF in HCV G1 treatment-naïve patients: HIV + vs HIV HIV + HIV IN THE DAA ERA HIV+ WILL NOT BE A SPECIAL POPULATION WITH AN UNMET NEED 28/38 285/363 42/53 419/521 169/239 414/570 21/23 296/327 87/114 104/159 24 or 48 weeks 24 or 48 weeks 12 or 24 weeks 12 weeks 24 weeks Cirrhosis 10% 13% 11% Excluded Sulkowski M, AASLD 2012; TVR EU SmPC; Dieterich CROI 2014; Rockstroh J et al EACS 2013 & AASLD 2013; Rodriguez Torres M et al IDSA 2013; Naggie CROI 2014; SOF EU SmPC

SIMILAR ADJUSTED SVR12 RATES FOR HIV CO-INFECTED AND HCV MONO-INFECTED PATIENTS : POOLED ANALYSIS OF FALDAPREVIR PHASE III TRIALS 1,554 treatment-naïve or prior relapse patients (HIV-co-infected, N=308) who received FDV plus PR Stepwise logistic regression baseline variables significantly associated with SVR12 Significant variables were included in the model, and the adjusted SVR12 rates of HIV positive and negative patients and differences were calculated based on least squares Dietrich D et al EASL 2014

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 with FDV No data No data

Coinfection treatment in the era of DAAs Rationale for treating HCV in PLHIV Results with PR + DAA IFN Free Treatments Rationale and potential impact in PLHIV Preliminary Results EASL Guidelines and recommendations on HCV treatment in PLHIV Challenges Access to treatment Deferral

Proportion N under follow-up Current and cumulative exposure to anti- HCV treatment in HCV+ in EUROSIDA Calendar year Mocroft A et al. EACS Cologne 2009

Survey Italian database Opera Questionnaire sent to 31 Italian HIV outpatients clinic Population of HCV coinfected 7017 pts ( 33% of all HIV+) 4057 1818

IFN Free DAAs regimens in co-infected patients Photon 1 Study Dieterich D et al. APASL 2014 C-Worthy Study Sukowsky M. et al. EASL 2014 SOFOSBUVIR/LEDIPASVIR FDC study Osinusi A. et al. EASL 2014

SVR with IFN Free DAAs regimens in HIV/HCV co-infected patients * * * SVR 4 114 34 58 26 24 42 17 Dieterich D et al. APASL 2014; Sulkowsky M et al EASL 2014 Osinusi A et al EASL 2014 HCV G 1 HCVG 2 HCVG 3 SOFO + R SOFO + LEDI MK5172/ MK8742 + R SOFO + R

Antiretroviral therapy allowed in studies including Ledipasvir or MK5172/MK 8742 CLASS Ledipasvir MK 5172/MK 8742 MK 8742NRTI AZT, ddi, d4t: no with PR orr ABC: TDF; FTC, LAM PI ATZ/R; DRV/R LPV/R,, FPV/R, NNRTI EFV NVP RPV ETV INI RALTEGRAVIR Elvitegravir/cobicistat CCR5I MARAVIROC

Adverse events in combination with Ribavirin (no head to head studies) Drug BOC TVR SMV FDV SOFO Tx Duration 28-48 24-48 24-48 24-48 12 N pills/n of doses 12/3 6/2-3 1/1 1/1 1/1 Food effect Yes Light snack Yes Fatty meal Anemia ++ ++ Fatigue ++ Dysgeusia ++ Yes Breakfast Minimal Nausea Vomiting + + (+) (+) Yes Breakfast Diarrhea - + - (+) - Anorectal signs - ++ - - - Pruritus + + Rash Photosensitivity (+) ++ + + Victrelis EU SmPC; Incivo EU SmPC; Mauss et al Hepatology 2014; Simeprevir FDA Advisory Committee meeting briefing materials; Janssen data on file; Boehringer Ingelheim data on file; Sulkowsky et al Hepatology 2013; Sovaldi EPAR product information (+/-)

Laboratory abnormalities in combination with PEGIFN + Ribavirin (no Head to Head studies) Drug BOC TVR SMV FDV SOFO Neutrophils = = = = Lympho = = = = Hb = = = PLT ( ) ( ) = = = Bilirubine = ( ) Direct & indir. Direct Creatinine = = = Uric Acid = = = Triglycerides Cholesterol = = = = Victrelis EU SmPC; Incivo EU SmPC; Mauss et al Hepatology 2014; Simeprevir FDA Advisory Committee meeting briefing materials; Janssen data on file; Boehringer Ingelheim data on file; Sulkowsky et al Hepatology 2013; Sovaldi EPAR product information =

Indications for HCV treatment in HCV/HIV co-infected persons are identical to those in patients with HCV mono-infection (A1). The same treatment regimens can be used in HIV-co-infected patients as in patients without HIV infection, as the virological results of therapy are identical (A1).

EASL GUIDELINES 2014 + RECOMMENDATIONS 2014 F3-F4 Prioritized for treatment ; F2 treatment is justified; F0-F1 individualized treatment Available drugs PR+ TEL, BOC + SOFO, SMV, DCV Naïve or Relapser Eligible to IFN Yes Yes PR + BOC/TEL (efficacy > 85% in RVR) HCV G1 HCV G2 HCV G3 HCV G4 No Yes Informed deferral Any No Informed deferral Yes Yes PR + SOFO/SMV / DCV Yes No SOFO + SMV No No /DCV + RBV SOFO + RBV (2*) No Yes PR response guided therapy (efficacy > 85% in RVR) SOFO+R 12-20w PR+SOFO SOFO+R 24w SOFO + DCV 12-24w PR + SOFO PR + SOFO /SMV/DCV SOFO+R 24w SOFO+SMV SOFO+DCV PR+SOFO/S MV Grade of Evidence: High quality Moderate Low or Very Low

Prevalence of HCV Co-infection in persons living with HIV in EuroSIDA cohort and government debt to GDP ratio in Europe 5957 subjects from EUROSIDA COHORT 33% HCVAb+ North: HCV+ 24,5 % East: HCV+ 47,7 % Central: HCV+22,9 % South: HCV+ 44,9 % Konopnicki D et al.; AIDS. 2005. Rockstroh J et al.; JID 2005

Titanic consideration April 1912: 2223 passengers lifeboat capacity of 1178 32% survivors Courtesy of Raffaele Bruno www. hermstitanic.wikia.com 54

Percentage of Titanic survivors by class % Courtesy of Raffaele Bruno www.titanic.com, 2002 http://www.icyousee.org/titanic.html

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?

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

2014-2015 Where Do We Set The Bar of current options when new treatments are on the way? > 85%

THERAPEUTIC OPTIONS FOR ANTI HCV TREATMENT with > 85% SVR Prototype Only PR + TEL/BOC available HCV G1 without advanced disease Naïve HCV G1 difficult to cure or relapse NR HCV G1 HCV G1 advanced cirrhosis HCV G2 HCV G3 naïve PR PR + TEL/ BOC 24-48 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) Additional options available (next months?) 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 available (next year?) 3D SOFO/LEDI FDC + R Additional value Greater efficacy beter tolerability 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 PR with RVR PR + SOFO or SOFO + R Wait Treat Individual decision based on patient s motivation & clinical need

Conclusions Treatment of HCV in PLHIV is mandatory Good results with 1 st generation DAA improved by 2 nd generation DAA ( better convenience and tolerability) Availability of IFN free combinations will be the turning point Efficacy & tolerability in PLHIV are the same we observe in anti HIV negative Same indications as HIV negative & no need for a specific label for PLHIV with a key consideration about DDI with concurrent cart Guidelines indicate several options according to HCV genotype, previous treatment experience and tolerability of PEGIFN Treatment costs may affect access to treatment we don t want a first class and a third class medicine equity in access to treatment is the only option Informed deferral is challenging and may be pursued with clinical prediction at the individual patient level

Predictions in Medicine Clinical case 1: KR The gerontologist Dr. David Demko in 1990 calculated the projected expiration date for KR. His findings? Average life expectancy: 79 years White male: 2 Has abused every drug known to man: 9 Physiological hardiness: +4 Smokes like a chimney: 8 Likes the whiskey: 4 Promiscuous behavior: 9 Strums righty: +1 Year of brith: 1943 Estimated Life Expectancy: 52 Projected Year of Death: 1995 some doctor told me I had six months to live and I went to their funeral. - Keith Richards