Kuala Lumpur, Malaysia, 30 June - 3 July 2013 How to manage virologic non- responders, non-genotype 1, relapsers IAS 2013, Session: HCV – Is your patient being left behind? New options and unmet needs., Kuala Lumpur, Malaysia Jürgen K. Rockstroh Department of Internal Medicine I University Hospital Bonn Germany

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Disclosure slide: Jürgen Rockstroh Receipt of grants/research supports: – Gilead Receipt of honoraria or consultation fees: – Abbvie, Abbott, Bionor. BMS, Boehringer, Gilead, GSK, Janssen, Merck, Novartis, Tobira, ViiV

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 How to manage: Virologic non-responders and relapsers

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 EACS guidelines 2012

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Cotte L, et al. 20th CROI; Atlanta, GA; March 3-6, Abst. 36. Telaprevir + PegIFN + RBV in HIV/HCV Co-infected Patients with Virologic Failure on IFN + RBV Complete RVR 8 (HCV-RNA <15 IU/mL): 32 weeks PR phase (Total treatment: 48 weeks) Partial RVR 8 (15 IU/mL <HCV-RNA <1,000 IU/mL) 56 weeks PR phase (Total treatment: 72 weeks) Single Arm, Phase 2 Clinical Trial (Lead in) PegIFN α-2a RBV Telaprevir PegIFN α-2a RBV PegIFN α-2a RBV Follow-upFollow-up Follow-upFollow-up D0W4W8 RVR 8 W16 EVR 16 W48W72 SVR 24 W96 SVR 24 Complete RVR 8 Partial RVR 8

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Cotte L, et al. 20th CROI; Atlanta, GA; March 3-6, Abst. 36. Telaprevir + PegIFN + RBV in HIV/HCV Co-infected Patients with Virologic Failure on IFN + RBV Main Inclusion Criteria – Chronic HCV genotype 1 infection and HIV-1 infection – Previous virological failure after ≥12 weeks PegIFN + RBV ≥600 mg/day – Stable ART for ≥3 months – Authorized antiretrovirals: ATV, ATVr, EFV, RAL, TDF, FTC, 3TC – CD4 ≥200 cells/mm 3 and ≥15%, plasma HIV-RNA levels <50 copies/mL – Liver biopsy <3 years or cirrhosis on any previous biopsy Main Exclusion Criteria – HVB coinfection, HIV-2 infection – Past history of decompensated cirrhosis – Previous null response with cirrhosis Important patient characteristics – F3 16%, F4 23%; HCV GT1a 70%

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Virological response (ITT, n=69) Only 3 patients with partial RVR 8  treatment 72 weeks RVR 8 EVR 16 7 TND 88%

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Telaprevir + Peg-IFN + RBV in HIV/HCV co- infected patients with virologic failure on IFN + RBV: Early virologic response by patient group Cotte L, et al. 20th CROI; Atlanta, GA; March 3-6, Abstract 36 n= ATVr EFV RAL Others F1F2F3F4RR BrkTh PRNR

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Grade 3 – 4 AEs and treatment discontinuations up to W16 N (%), n=69 Grade 3 AEs Blood General GI Cutaneous Neurological Psychiatric Others 18 (26%) 6 (9%) 5 (7%) 2 (3%) 3 (4%) 2 (3%) 1 (1%) 2 (3%) Grade 4 AEs Blood Psychiatric 5 (7%) 4 (6%) 1 (1%) Reasons for treatment discontinuations Psychiatric AEs Cutaneous AEs Others AEs Virological failure 3 (4%) 1 (1%)

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Boceprevir + PegIFN + RBV for HIV-HCV Co-Infected Patients with Previous Virologic Failure on PegIFN + RBV **BOC+ PegIFN + RBV **BOC+ PegIFN + RBV W8 15≤HCV VL- ≤1,000 IU/mL BOC+ PegIFN + RBV W8 15≤HCV VL- ≤1,000 IU/mL BOC+ PegIFN + RBV Weeks * *PegIFN + RBV W12-HCV VL> 1,000 IU/ mL: PegIFN + RBV PegIFN + RBV W12- 15< HCV VL≤ 1,000 IU/ mL BOC+ PegIFN + RBV W12- 15< HCV VL≤ 1,000 IU/ mL BOC+ PegIFN + RBV Follow-up Follow-up Lead- in Phase * PegIFNα2b: 1.5 μg/kg/wk RBV: 800 to 1,400 mg/day ** BOC:800 mg 3 times/ day Stop BOC Stop All Drugs RVR8: % HCV RNA <15 IU/mL EVR16:% HCV RNA <15 IU/mL EPO, G-CSF, TPO-R agonists allowed Pizot-Martin I, et al. 20th CROI; Atlanta, GA; March 3-6, Abst. 37. Study Design HCV VL > 1,000 IU/mL SVR 24 W72 Follow-up W8-HCV VL < 15 IU/ mL: BOC+ PegIFN + RBV SVR 24 W96 W8-HCV VL > 1,000 IU/ mL: PegIFN + RBV Follow-up HCV RNA > 100 IU/mL

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Inclusion/Exclusion Criteria Inclusion – body weight kg – Chronic HCV genotype 1 – Previous virologic failure on PegIFN + RBV – Stable antiretroviral therapy with 3 or more ARV agents among TDF, ABC, FTC, 3TC, ATV (boosted or not), and RAL – CD4+ count ≥200 cells/mm 3 and VL <50 c/mL for ≥6 months – Any fibrosis level on liver bx within past 3 years or any bx showing cirrhosis Exclusion – HBV co-infection – Childs B or C; decompensated cirrhosis – Previous null response with cirrhosis Important patient characteristics – F4 17%; previous null responders 33%, GT1a 78% Pizot-Martin I, et al. 20th CROI; Atlanta, GA; March 3-6, Abst. 37.

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 BOC/IFN/RBV following virologic failure: results by previous response to Peg-IFN + RBV Pizot-Martin I, et al. 20th CROI; Atlanta, GA; March 3–6, Abstract 37 RVR 8 EVR 16

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 BOC/IFN/RBV following virologic failure: Results by ARV regimen Pizot-Martin I, et al. 20th CROI; Atlanta, GA, 2013; Abstract 37 RVR 8 EVR 16

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 F0F1 F2F3 F4 NaiveRelapser Nonresponder Individual decision Individual decision/ triple therapy Defer Triple therapy Individual decision according to disease progression Triple therapy Management of HIV-HCV GT1-co-infected patients (chronic) according to prior treatment outcome Ingiliz P. & Rockstroh J. Liver Int 2012;32:1194–9; EACS guidelines version November 2012

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 EACS guidelines 2012

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 How to manage: Non-genotype 1

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Pivotal RCTs for Peg-IFN/RBV in HIV/HCV co-infection 1. Carrat F, et al. JAMA 2004;292:2839–48; 2. Laguno M, et al. Hepatology 2009;49:22–31; 3. Chung RT, et al. N Engl J Med 2004;351:451–9; 4. Torriani FJ, et al. N Engl J Med 2004;351:438–50; 5. Núñez M, et al. AIDS Res Hum Retroviruses 2007;23:972–82 StudyRegimen SVR (%) G1 or G4 SVR (%) G2 or G3 Take home observations RIBAVIC 1 France (N = 412) Peg-IFN α-2b RBV 800 mg 1744 Low-dose RBV Toxicity with ddI + RBV Failure to suppress HCV RNA at week 4 <460,000 IU/mL → 100% NPV Laguno et al 2 Spain (N =182) Peg-IFN α-2b RBV 800 – 1200 mg 2862 Weight-based RBV → higher SVR Short (24-week) therapy for genotype 2/3 not effective ACTG A USA (N = 133) Peg-IFN α-2a RBV mg 1473 Low-dose RBV Failure to achieve week 12 EVR → 100% NPV ZDV + RBV → more anemia APRICOT 4 International (N = 868) Peg-IFN α-2a RBV 800 mg 2962 Low-dose RBV Decompensation with advanced fibrosis Genotype 1/High HCV RNA –18% SVR PRESCO 5 Spain (N = 389) Peg-IFN α-2a RBV 1000 – 1200 mg 3572 Weight-based RBV → higher SVR No increase in anemia Long (72-week) therapy not well tolerated

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 EACS guidelines 2012

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Ongoing clinical trials in HIV/HCV coinfection PHOTON 1 and 2 Studies: GT1 or 4 HIV/HCV co-infected treatment- naïve (TN) and GT- 2/3 TN and Experienced Subjects with sofosbuvir + RBV weeks

Kuala Lumpur, Malaysia, 30 June - 3 July 2013