Case #1. Case #1. Case #1: Audience vote VS. The Great Debate: When to Treat HCV in our HIV coinfected patients

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1 Case #1 The Great Debate: When to Treat HCV in our HIV coinfected patients Medical Management of AIDS December, 2012 Moderated by George Beatty,MD 35 year old African American man, CD , HIV RNA <40 copies/ml, on Atripla HCV treatment naïve, HCV RNA 500,000 IU/ml Genotype 1a, IL28b genotype T/T (least favorable) Biopsy: Fibrosis Stage 2 (scale 0-4), Inflammation Grade 1 (scale 0-4) No other comorbidities, including psychiatric In terms of HCV treatment readiness: I ll do whatever you say, Doc Case #1 Treat him now with 48 weeks of Pegylated Interferon/Ribavirin + HCV Protease inhibitor (e.g.telaprevir) VS. Wait until more potent agents, less toxic agents are available? Case: 35 yo man, HCV Treatment Naïve, Genotype 1a, IL28B genotype T/T (least favorable), Fibrosis Stage 2. HIV well controlled on Atripla Case #1: Audience vote Case: 35 y.o. man, HCV Treatment Naïve, Genotype 1a, IL28B genotype T/T (least favorable), Fibrosis Stage 2. HIV well controlled on Atripla 1

2 Argument to Treat Now Percent of patients with HCV RNA Undetectable No ART EFV/TDF/FTC ATV/r+TDF+FTC/3TC n/n = 6/7 12/16 10/15 25/37 2/6 4/8 6/8 12/22 Telaprevir + PR PR Sherman KE et al Abstract LB-8, AASLD 2011 Argument to Wait Argument to Wait 48 weeks of PEG/RBV + Telaprevir 12 weeks of 3-4 oral drugs % 45% N=76 N=44 SVR12 TVR (n=38) PEG/RBV (n=22) Dieterich D, et al. CROI 2012, Abstract 46. Kowdley AASLD 2012 IL28b T/T: up to 25% worse SVR compared to C/C (Advance Study) No data yet to support response guided therapy in HIV+ Therefore 48 weeks Relatively young patient with intermediate fibrosis He can afford to wait and will spare himself a year of toxicity by doing so 2

3 Rebuttal: Treat Now Rebuttal: Wait to treat Case #1 Audience vote, post-debate Case: 35 y.o. man, HCV Treatment Naïve, Genotype 1a, IL28B genotype T/T (least favorable), Fibrosis Stage 2. HIV well controlled on Atripla Case #2 60 year old Caucasian man, CD , HIV RNA < 40 copies/ml on Raltegravir/Epzicom Treatment naïve, HCV Genotype 3a, HCV RNA 1.2 million IU/ml, HCV infection since the 1970 s? Ultrasound: no evidence of cirrhosis Mild depression, well controlled on SSRI, no other comorbidities. I ll do whatever you recommend, except stick a needle in my liver! 3

4 Case #2, Audience vote Argument to Treat now Case: 60 y.o. man, HCV treatment naïve, Genotype 3a, no cirrhosis by imaging, HIV well controlled on raltegravir+ Epzicom Study Cohort RIBAVIC ACTG APRICOT PRESCO Carrat F JAMA Chung R NEJM Torriani FJ NEJM 2004 Rx Peg IFN α-2b RBV 800mg QD Peg IFN α-2a RBV 600mg 800mg QD Peg IFN α-2a RBV 800mg QD Peg INF α-2a RBV 1000mg (<75kg) or RBV 1200mg (>75kg) QD Sustained Virologic Response Rate Genotype 1 Genotype non-1 Genotype 1 Genotype non-1 Genotype 1 Genotype non-1 Genotype 1 Genotype non-1 4 Nunez M AIDS Research and Human Retroviruses Rodriguez-Torres AASLD 2009 # % 15% 43% 27% 14% 73% 40% 29% 62% 50% 35% 72% Argument to Treat now Treating at a younger age associated with better cure rates Argument to wait No urgency to treat? No cirrhosis on ultrasound- poor test No comment about platelet count Mild depression- SSRI Genotype 2/3: SVR lower in HIV HCV: 43-73% Genotype 3: SVR lower than genotype 2 All oral DAA >90% in genotype 2/3 Mauss CROI 2012 #763 4

5 All orals HCV monoinfection DAC and SOF (7977)* 24 week SVR 93% One relapse Gen 3: SVR when SOC added 24w Response not related to IL28B, RBV or subtype Nucleotide analogue mg QD + RBV for 12 wks^ All patients in all arms had undetectable HCV RNA w4 Needed RBV but not Peg IFN 100% SVR12 in all RBV-containing arms SVR24 in 100% naive (n = 20); 80% Rx experienced Rebuttal: Treat Now * Sulkowski AASLD 2012: ^ GANE AASLD 2011 EASL 2012 Case #2: Audience vote, post debate Rebuttal: Wait to treat Case: 60 y.o. man, HCV treatment naïve, Genotype 3a, no cirrhosis by imaging, HIV well controlled on raltegravir+ Epzicom 5

6 Case #3 48 y.o. Latina woman, CD4 388, HIV RNA < 40 copies/ml on Atazanavir/ritonavir + Truvada Genotype 1b, HCV RNA 750,000 IU/ml, IL28b genotype C/T (intermediate) PEG/RBV 4 years ago, stopped after 12 weeks due to < 2 log 10 HCV RNA drop (null response), tolerated reasonably well Imaging now suggestive of early cirrhosis, biopsy Fibrosis stage 3-4, no history of decompensation No other signficant comorbidities Case #3, Audience vote Case: 48 y.o. woman, prior null responder, HCV Genotype 1b, Fibrosis stage 3-4, IL28b C/T (intermediate). HIV well controlled on Atazanavir/ritonavir + Truvada Argument to Treat Now HCV and HIV coinfected Select who to treat Moderate to severe fibrosis F3-4 No decompensation Controlled HIV Encourage Adherence Avoid alcohol % SVR REALIZE (Telaprevir) RESPOND-2 (Boceprevir) No Clinical Benefit to Lead- in was Observed Nulls excluded n=121/145 n=124/141 n=16/68 n=29/49 n=26/48 n=4/27 n=21/72 n=25/75 n=2/37 T/PR No LI T/PR LI PR Control Relapsers Partial Responders Null Responders Bacon et al. NEJM

7 Argument to Wait Baseline N=578 Cirrhosis (n=143) No cirrhosis (n=435) Mean age 54 (8) 50 (9) Male, n (%) 104 (73) 294 (68) VL (SD) 6.57 (0.53) 6.56 (0.58) STRATIFICATION by Prior PR response, n (%) Null 51 (36) 113 (26) Partial 29 (20) 79 (18) Relapser 63 (44) 243 (56) Patients achieving SVR, n/n (%) Pooled T/PR 57/117 (49) 249/348 (72) PR alone 2/26 (8) 17/87 (20) Cirrhosis No Cirrhosis Rash 43% 27% Pruritus 55% 35% Anemia 44% 27% Discontinuation 15% 11% SVR to TVR/PEG/RBV in prior null responder cirrhotics:14% Linear Macrocyclic Cross- resistance of NS3 Protease Inhibitors Telaprevir Boceprevir Narlaprevir Danoprevir MK TMC 435 BI V36A/M T54S/A V55A Q80R/K R155K/T/Q/P A156S A156/V/T D168A/V/T/H * * * * * V170A/T/L Rebuttal: Treat Now *Mutations associated with in vitro resistance but not described in patients. Susser S et al. Hepatology. 2009;50: ; Sarrazin C, Zeuzem S. Gastroenterology. 2010;138:

8 Case #3, Audience vote, post-debate Rebuttal: Wait to treat Case: 48 y.o. woman, prior null responder, HCV Geno 1b, Fibrosis stage 3-4, IL28b C/T (intermediate). HIV well controlled on Atazanavir/ritonavir + Truvada 8