10/21/2016. Susanna Naggie, MD, MHS Associate Professor of Medicine Duke University Durham, North Carolina. Learning Objectives

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1 A Crash Course on the AASLD/IDSA Hepatitis C Virus Infection Treatment Guidelines: What s New Susanna Naggie, MD, MHS Associate Professor of Medicine Duke University Durham, North Carolina FORMATTED: 1/3/16 Financial Relationships With Commercial Entities Dr Naggie has received research support paid to her institution from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Inc, Janssen Therapeutics, Tacere, Merck & Co, Inc, and Vertex Pharmaceuticals, Inc. In the past 2 years she has served as a scientific advisor to Merck & Co, Inc. (Updated 1/2/16) She divested from all personal financial conflict in 1/1/215 due to her Co-Chair position in the AASLD/IDSA Guidance Panel. Slide 2 of 46 Learning Objectives After attending this presentation, learners will be able to: Describe the recent changes to the AASLD/IDSA hepatitis C virus infection treatment guidelines with focus on therapeutics Summarize the studies that support the changes to the guidelines Describe differences in treatment by genotype and presence of cirrhosis Describe treatment of special populations including relevant drug interactions Slide 3 of 46 1

2 Objectives Discuss the recent changes to the AASLD/IDSA Guidelines with focus on therapeutics Discuss the studies supporting the changes to the guidelines Discuss differences in treatment by genotype and presence of cirrhosis Discuss treatment of special populations including relevant drug interactions HIV/HCV Co-infection 2

3 Testing and Monitoring Prior to therapy Staging of hepatic fibrosis Drug interactions Labs: Within 12 weeks: CBC, INR, HFP (tbili, AST, ALT), GFR Any time prior to start: HCV genotype, subtype and quant RNA Cirrhosis calculate Child Pugh score Protease inhibitors contraindicated in decomp (CP B/C) Resistance associated polymorphism (RAP) for some regimens/patients HIV antibody HBV sag, cab, sab Testing and Monitoring HBV co-infection HBV serologies for all Vaccinate those susceptible If sag + check DNA, consider tx Active HBV meeting AASLD criteria should be started on therapy Low or undetectable HBV DNA can be monitored HBV DNA and HFP? Isolated cab + OR cab+/sab+ Reassuring reports Sulkowski et al and Wang et al, Case #1 53 y/o AA man with HIV/HCV on stable dolutegravir/abacavir/lamivudine with suppressed HIV and CD He has never received therapy for HCV and his non invasive markers of liver disease agree that he does not have cirrhosis or severe fibrosis. He is GT 1b and has normal renal function. His HCV RNA is 2.3 million IU/mL. 3

4 What is the recommended length of therapy for this patient? 2% 1. 6 weeks 9% 2. 8 weeks 85% weeks 2% weeks 2% weeks Recommended regimens for treatment-naïve patients with HCV genotype 1 without cirrhosis Elbasvir/grazoprevir (except GT1a with NS5A RAV) 12 (16) I, A Ledipasvir/sofosbuvir 12 I, A Paritaprevir/r/ombitasvir + dasabuvir + ribavirin, GT 1a 12 I, A Paritaprevir/r/ombitasvir + dasabuvir, GT 1b 12 I, A Simeprevir + sofosbuvir 12 I, A Daclatasvir + sofosbuvir 12 I, B Alternative Why isn t 8 weeks of LDV/SOF Recommended? % HCV MONO LDV/SOF Tx Naïve, No cirrhosis: ION HCV RNA <6 million IU/mL 8 weeks 121/123 (98%) 12 weeks 129/131 (98%) RBV +RBV 8 weeks 2 relapse (4.5%) RBV 12 weeks 3 relapse (1%) % HIV/HCV COINFECTION Tx Naïve : ALLY 2 (DCV/SOF) /83 12 weeks 1 relapse (1%) /44 8 weeks 1 relapse (25%) ION 3 Kowdley et al. NEJM 215; ALLY 2 Wyles et al. NEJM 215 4

5 I heard 8 weeks works well and it is under used? PRO Baseline viral load can predict decrease risk of relapse Real World Cohorts TRIO 242/254 (95%) TARGET 15/154 (97%) 1 HIV/HCV patient GECCO 175/191 (92%) 27/28 HIV/HCV (97%) Cheaper CON Baseline viral load is not the only predictor Real World Cohorts VA greater failure for 8 weeks in black veterans Women more likely to get 8 weeks Only ~4% of TARGET eligible got 8 weeks under use? Good medical decision making? Failure = resistance 65% Terrault et al, AASLD 215; Ingiliz et al, CID 216; Afdhal et al, AASLD 215; Backus et al. AASLD 215 Gender as a predictor of SVR: ION3 O brien et al, OFID 215 Lets take another look at ION Relapse weeks 12 weeks 24 weeks Black Non Black Wilder et al, Hepatology 216 5

6 And what about NS5A resistance? Baseline RAV <1 fold Baseline RAV >1 fold No RAV at Baseline /12 24/29 185/192 8 weeks LDV/SOF Sarrazin et al, Gastroenterology 216 Baseline NS5A RAV in the 5 failures L31M (19.25%) L31M (25.45%) Y93N (15.37%) Q3Y (2.4%) Q3H (1.16%) Y93H (3.6%) M28T (93.52%) M28A (6.9%) HCV GT 1a 1a 1a 1a 1a Based on available data, shortening treatment to less than 12 weeks is Not Recommended for HIV-infected patients (see HIV/HCV coinfection section), African-American patients, or those with known IL28B polymorphism CT or TT. (Wilder, 216); (O'Brien, 214) For others, it should be done at the discretion of the practitioner.? Add NS5A resistance? What if the patient had cirrhosis what is the recommended length of therapy for this patient? 71% weeks 6% weeks % 3. 2 weeks 24% weeks 6

7 Recommended regimens for treatment-naïve patients with HCV genotype 1 with compensated cirrhosis Elbasvir/grazoprevir (except GT1a with NS5A RAV) 12 (16) I, A* Ledipasvir/sofosbuvir 12 I, A Paritaprevir/r/ombitasvir + dasabuvir + ribavirin, GT 1a 24 I, A Paritaprevir/r/ombitasvir + dasabuvir, GT 1b 12 I, A Simeprevir + sofosbuvir 24 II, B Daclatasvir + sofosbuvir 24 IIa, B *for 16 week + RBV regimen rating is IIa, B; Alternative Alternative regimens are those that are effective but have, relative to Recommended regimens, potential disadvantages, limitations for use in certain patient populations, or less supporting data than Recommended regimens. In certain situations, an Alternative regimen may be an optimal regimen for a specific patient situation. Recommended regimens for PEG-IFN/RBV treatment- Exp patients with HCV genotype 1 without cirrhosis Elbasvir/grazoprevir (except GT1a with NS5A RAV) 12 (16) I, A Ledipasvir/sofosbuvir 12 I, A Paritaprevir/r/ombitasvir + dasabuvir + ribavirin, GT 1a 12 I, A Paritaprevir/r/ombitasvir + dasabuvir, GT 1b 12 I, A Simeprevir + sofosbuvir 12 I, A Daclatasvir + sofosbuvir 12 I, B Alternative 7

8 Which regimen does NOT offer a 12 week treatment option without ribavirin for PEG/RBV experienced patient with GT1b infection and cirrhosis? 25% 1. Elbasvir/grazoprevir 18% 2. Ledipasvir/sofosbuvr 38% 3. Paritaprevir/r/ombitasvir + dasabuvir 2% 4. Sofosbuvir/velpatasvir Recommended regimens for PEG-IFN/RBV treatment- Exp patients with HCV genotype 1 with comp cirrhosis Elbasvir/grazoprevir (except GT1a with NS5A RAV) 12 (16) I, A* Ledipasvir/sofosbuvir ± ribavirin 12 (24) I, A Paritaprevir/r/ombitasvir + dasabuvir + ribavirin, GT 1a 24 I, A Paritaprevir/r/ombitasvir + dasabuvir, GT 1b 12 I, A Simeprevir + sofosbuvir 24 II, B Daclatasvir + sofosbuvir 24 IIa, B *for 16 week + RBV regimen rating is I, B; Alternative Cirrhosis requires RBV or longer therapy for some but not all SIRIUS: LDV/SOF+RBV X 12W or LDV/SOF X 24W in TE Cirrhosis Weeks* 12 Weeks 24 Weeks /77 75/77 Elbasvir/Grazoprevir in TE and TN Cirrhosis Cirrhosis TE or TN 12 weeks No 416/443 94% Yes 126/13 97% TE 16 weeks + RBV 61/64 95% 32/32 1% *not arm in SIRIUS shown for historic comparison Poordad et al. EASL 215; Bourliere et al. Lancet ID 215; Reddy et al. Hepatology

9 TURQUOISE-II: Why RBV isn t required with P/r/O/D X12 weeks in Genotype 1b N=6 All patients achieve RVR All patients complete tx SVR 1% /6 6/6 6/6 6/6 RVR EOT SVR4 Feld et al. ISVHLD June 215 Sofosbuvir/velpatasvir in GT All Cirrhosis Treatment Experienced /21 49/49 78/78 117/118 23/24 31/32 Genotype 1a Genotype 1b Feld et al. NEJM 216 Sofosbuvir/velpatasvir in decompensated liver disease (CPB) Weeks 12 Weeks + RBV 24 Weeks /9 82/87 77/9 47/5 53/54 53/55 16/18 14/14 15/16 Overall Genotype 1a Genotype 1b Curry et al. NEJM 216 9

10 Recommended regimens for PI/PEG-IFN/RBV treatment-exp patients with HCV genotype 1 without cirrhosis Ledipasvir/sofosbuvir* 12 I, A Daclatasvir + sofosbuvir 12 IIa, B Elbasvir/grazoprevir + ribavirin (except GT1a with NS5A RAV) IIa, B *also Recommended with RBV for sofosbuvir + RBV ±PEG IFN failures for 12 weeks. Rating IIa, B Recommended regimens for PI/PEG-IFN/RBV treatment-exp patients with HCV genotype 1 with compensated cirrhosis Ledipasvir/sofosbuvir ± ribavirin* I, A Daclatasvir + sofosbuvir ± ribavirin 24 IIa, B Elbasvir/grazoprevir + ribavirin (except GT1a with NS5A RAV) IIa, B *also Recommended for sofosbuvir + RBV ±PEG IFN failures for 24 weeks. Rating IIa, B (also true for simeprevir + sofosbuvir failures) 1

11 Evidence Based Options for Salvage? C SWIFT II: Elbasvir/grazoprevir + SOF + RBV X 12 weeks in Elb/grazo failures (4,6,8 weeks) = 25/25 = 1% With NS5A RAVs = 18/18 = 1% QUARTZ I: PrOD + SOF + RBV X 12 for 1a no cirrhosis (N=14); 24 weeks for 1a with cirrhosis (N=6) 75% with NS5A + other RAV = 13/14 = 93% = 6/6 = 1% Sofosbuvir/velpatasvir + RBV X 24 weeks in SOF/VEL or SOF/VEL/GS 9857 failures Overall = 59/65 = 91% (18 GT3, 14 GT2) GT1 = 33/34 = 97% (including 6 with RAVS) Lawitz et al, EASL 215; Poordad et al. AASLD 215; Gane et al. EASL 216 Recommended regimens for HCV genotype 2 infection with or without CP-A cirrhosis Treatment naive Daclatasvir + sofosbuvir (cirrhosis) 12 (16 24) IIa, B Treatment experienced PEG/RBV Daclatasvir + sofosbuvir (cirrhosis) 12 (16 24) IIa, B Treatment experienced SOF/RBV Daclatasvir + sofosbuvir ± ribavirin 24 IIa, C Sofosbuvir/velpatasvir + ribavirin 12 IIa, C Alternative ASTRAL 2: SOF/VEL vs SOF/RBV 1 8 SOF/VEL SOF/RBV /1 92/96 15/15 14/15 15/15 13/16 4/4 4/4 Cirrhosis No Yes No Yes Treatment Naive Treatment Experienced Foster et al. NEJM

12 NS5A testing is recommend for all genotype 3 patients listed below except: 5% 1. Treatment naïve with cirrhosis 33% 2. Treatment experienced without cirrhosis 17% 3. Treatment experienced with cirrhosis Recommended regimens for HCV genotype 3 infection with or without CP-A cirrhosis Treatment naive Sofosbuvir/velpatasvir* 12 I, A Daclatasvir + sofosbuvir* (cirrhosis) 12 (24) I, A Treatment experienced PEG/RBV Sofosbuvir/velpatasvir* (add ribavirin if cirrhosis) 12 I, A Daclatasvir + sofosbuvir* (cirrhosis, with ribavirin) 12 (24) IIa, B Treatment experienced SOF/RBV Daclatasvir + sofosbuvir + ribavirin 24 IIa, C Sofosbuvir/velpatasvir + ribavirin 12 IIa, C * check NS5A resistance, add ribavirin if Y93H is present (for TN only if cirrhosis for TE only if not) ALLY-3(+): DAC + SOF for GT3 ALLY 3: DCV/SOF X 12 weeks Treatment Naïve and Experienced No Cirrhosis Cirrhosis ALLY 3+: DCV/SOF+RBV X 12 or 16 weeks with F3/4 Fibrosis All F3 F Overall TN TE Overall 12 Weeks 16 Weeks Nelson et al. Hepatology 215; Leroy et al. AASLD

13 ASTRAL 3: SOF/VEL vs SOF/RBV SOF/VEL SOF/RBV / /156 4/43 33/45 31/34 22/31 33/37 22/38 Cirrhosis No Yes No Yes Treatment Naive Treatment Experienced Foster et al. NEJM 215 Recommended regimens for HCV genotype 5 and 6 infection with or without CP-A cirrhosis Treatment naïve or Treatment experienced PEG/RBV with or without cirrhosis Sofosbuvir/velpatasvir 12 I/IIa, A/B Ledipasvir/sofosbuvir 12 IIa, B/C Less data in treatment experienced patients Renal Impairment and Post Renal Transplant Treatment should always be discussed with nephro to ensure not transplant candidate GFR>3 same as recommended Exception those with RBV GFR<3 or ESRD Elbasvir/grazoprevir X12W for 1a, 1b, 4 No NS5A testing recommended PrOD X12W for 1b For 2,3,5,6 poor options Post renal transplant LDV/SOF X12 weeks (no RBV required) Renal Direct Acting Antiviral FDA Guidance Supporting Data Clearance Ribavirin YES GFR<5,>3 extensive 4mg alt with 2mg QD; GFR<3 2mg QD ESRD 2mg QD Sofosbuvir YES* No use if GFR<3 limited # Simeprevir NO No dose change limited # Ledipasvir NO No use if GFR<3 none Paritaprevir/r/ombitasvir NO No dose change** limited + dasabuvir # Daclatasvir NO No dose change none Elbasvir/grazoprevir NO No dose change Phase III/FDA # Velpatasvir NO No use if GFR<3 none 13

14 Acute HCV Infection AASLD/IDSA GL Treat as chronic Allow time for clearance (12 16W) EASL GL Four studies SOF/RBV for 6 or 12 weeks LDV/SOF for 6 weeks in either early acute or more typical acute (12 24) Rockstroh et al. CROI 216 What is coming? NS5A Resistance Primer Pregnant Women Children and Adolescents My retirement Questions 14

15 A Crash Course on the AASLD/IDSA Hepatitis C Virus Infection Treatment Guidelines: What s New Susanna Naggie, MD, MHS Associate Professor of Medicine Duke University Durham, North Carolina FORMATTED: 1/3/16 15