Disclosure. HCV Update & Case-Based Scenarios in Hepatitis C HCV AT THE CUTTING EDGE. Kristen Marks, MD Weill Cornell Medical College New York, NY

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1 HCV Update & Case-Based Scenarios in Hepatitis C HCV AT THE CUTTING EDGE Kristen Marks, MD Weill Cornell Medical College New York, NY Final Disclosure Dr Marks has received grants and research support from AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Inc, Merck and Janssen Therapeutics. 1

2 Lack of Awareness and Associated Deaths Virus Prevalence % of Population Unaware of Infection Status HBV 800, million HCV million About 65% 3,000 About 75% 12,000 HIV 1.1 million About 21% 14,016 Deaths in 2006 Related to Infection Sources: CDC; Lin et al, 2007; Hagan et al 2006 Current CDC recommendations for HCV screening Screen once (no risk assessment) Adults born Signs of liver disease (persistently elevated ALT) Uncertain Long term sexual partner of HCV+ STIs or multiple sex partners Intranasal drug use Tattooing/bodypiercing MMWR 2012;61. MMWR 2009;58. MMWR 1998;47. Screen based on risk for exposure HIV-infected Past or present injection drug use Received clotting factor concentrates prior to 1987 or other blood products made prior to July1992 or from known HCV+ Ever on chronic hemodialysis Received tissues/organs prior to July1992 Infants of HCV-infected mothers Occupational exposures (needle stick or mucosal blood exposure) 2

3 SVR (%) 6/5/2015 Of people living with HIV in the US: 1 in 3 are co-infected with HCV & 1 in 20 are co-infected with HBV HCV Therapeutics Timeline 1970s Non A, non B hepatitis 1989 HCV identified Consensus IFN BILN-2061 Phase 1b In vitro Boceprevir Telaprevir Peg-IFNa-2b HCV replication You are here IFN-free GT1 DAA regimens IFN a-2b IFN a-2a IFN a-2b + RBV HCV replicons Peg-IFNa-2a Peg-IFNa-2a in HCV/HIV 2015 Sofosbuvir Simeprevir Daclatasvir (EU) Sofosbuvir/ledipasvir Relative misery 3

4 Newer strategy for HCV therapy: Direct acting antivirals target life cycle ---PREVIR Protease inhibitors e.g. telaprevir, boceprevir, faldaprevir, simeprevir, danoprevir, asunaprevir, paritaprevir ---BUVIR Polymerase inhibitors Nucleos(t)ide analogs: e.g. tegobuvir, sofosbuvir, Non-nucs: e.g. deleobuvir, dasabuvir ---ASVIR NS5A inhibitors e.g. daclatasvir, ledipasvir, ombitasvir NUC NUC + + PI NS5A +/- RBV +/- RBV Currently used combinations of DAA classes PI + NS5A NUC-SPARING HIV Toxicity Resistance Renal insufficiency Drug-drug interactions Affordability PI + NS5A + nonnuc NUC-SPARING HCV Affordability Provider preference Renal insufficiency Avoid RBV Drug-drug interactions Toxicity Resistance +/- RBV 4

5 Approved Drug Regimens PEG RBV SOF RBV SOF RBV +/- SMV SOF LDV SOF DAC* SOF RBV +/- PTV/ DAS r OMV Interferon PegIFN Ribavirin ribavirin ribavirin +/-ribavirin +/-ribavirin Nucs sofosbuvir sofosbuvir sofosbuvir sofosbuvir sofosbuvir Protease inhibitors simeprevir Paritaprevir /ritonavir NS5A ledipasvir daclatasvir ombitasvir Non-Nucs dasabuvir *approved in EU Summary of relative efficacy for various studies of Initial Treatment by regimens and genotypes: APPROVED DRUGS RBV +/- PEG RBV +/- PTV/ RBV RBV RBV SMV LDV DAS r SOF SOF SOF SOF SOF OMV GT1 GT2 GT3 x12w x12w X24w X12w* x(8-)12w X12w* 89% (261/292) 80% if cirrhosis 97% including T- E, cirrhosis 97% (38/39) GT4 96% (27/28) only 10% T-exp ~68-76% 93-95% (69/73, 101/109) 83-93% if cirrhosis 56-61% (102/128, 60/98) 21-34% if cirrhosis 59% 10/17 SVR 93%* Overall *24 wks if cirrhosis >95% >95% *24 wks if cirrhosis N/A N/A N/A N/A 93% (98/105) 92% if cirrhosis N/A 60% N/A 93% 14/15 SVR 95% 19/20) >95% 42/42 RBV 40/44 no RBV 5

6 IDSA/AASLD/IAS-USA Easl REMAINING TREATMENT CHALLENGES G1 with drug interactions G1 DAA combo failures G3 + cirrhosis ESRD When to do resistance testing Acute HCV treatment 6

7 CASE 1 62 y.o. African American M with HIV & HCV Geno 1b and cirrhosis, HCV RNA 1.8 million IU/mL HCV Hx: Treatment naïve IFN unwilling in past Cirrhotic based on Bx 6 yrs ago No decompensation events EGD no varices MRI no HCC Other med hx includes: HIV: well controlled on ARVs HTN, CAD (s/p stents) CRCL 55 HOW DO YOU CHOOSE A REGIMEN? 7

8 Minimum to Know Pre-Treatment HCV genotype/subtype Stage of fibrosis Cirrhosis - yes/no If yes, compensated? (e.g., ascites, encephalopathy, etc) Method? Liver biopsy Transient elastography Laboratory biomarkers Imaging Prior HCV treatment? Response? DAA used? Medications To check for drug interactions Interferon eligibility and/or willingness Comorbidities Patient preference Child-bearing potential of patient/partner Ribavirin is a teratogen HIV/Hepatitis C helpline Interferon PEG RBV SOF PegIFN RBV SOF RBV +/- SMV SOF LDV SOF RBV +/- PTV/ DAS r OMV Ribavirin ribavirin ribavirin +/-ribavirin +/-ribavirin Nucs sofosbuvir sofosbuvir sofosbuvir sofosbuvir sofosbuvir Protease inhibitors simeprevir Paritaprevir /ritonavir NS5A ledipasvir daclatasvir ombitasvir Non-Nucs Approved Drug Regimens DAC* SOF dasabuvir *approved in EU 8

9 Summary of relative efficacy for various studies of Initial Treatment by regimens and genotypes: APPROVED DRUGS RBV +/- PEG RBV +/- PTV/ RBV RBV RBV SMV LDV DAS r SOF SOF SOF SOF SOF OMV GT1 GT2 GT3 x12w x12w X24w X12w* x(8-)12w X12w* 89% (261/292) 80% if cirrhosis 97% including T- E, cirrhosis 97% (38/39) GT4 96% (27/28) only 10% T-exp ~68-76% 93-95% (69/73, 101/109) 83-93% if cirrhosis 56-61% (102/128, 60/98) 21-34% if cirrhosis 59% 10/17 SVR 93%* Overall *24 wks if cirrhosis >95% >95% *24 wks if cirrhosis N/A N/A N/A N/A 93% (98/105) 92% if cirrhosis N/A 60% N/A 93% 14/15 SVR 95% 19/20) >95% 42/42 RBV 40/44 no RBV G1B + CIRRHOSIS + RX-NAÏVE: IFN FREE OPTIONS IDSA/AASLD/IAS-USA Recommended: Ledipasvir/sofosbuvir x 12 weeks (just 12 wks given rx-naïve) Daily fixed-dose combination of paritaprevir /ritonavir/ombitasvir plus twice-daily dosed dasabuvir + RBV x 12 weeks (RBV included in 1b in patients with cirrhosis) Sofosbuvir plus simeprevir +/- RBV x 24 weeks (given cirrhosis) Easl Options: Ledipasvir/sofosbuvir + RBV x 12 weeks (RBV included in patients with cirrhosis) OR Ledipasvir/sofosbuvir x 24 wks if cannot take RBV Daily fixed-dose combination of paritaprevir /ritonavir/ombitasvir plus twice-daily dosed dasabuvir + RBV x 12 weeks (RBV included in 1b patients with cirrhosis) Sofosbuvir plus simeprevir + RBV x 12 weeks (RBV included in patients with cirrhosis) OR Sofosbuvir plus simeprevir x 24 weeks if cannot take RBV Sofosbuvir plus daclatasvir + RBV x 12 weeks (RBV included in patients with cirrhosis) OR Sofosbuvir plus daclatasvir x 24 wks if cannot take RBV 9

10 NO CIRRHOSIS CIRRHOSIS EASL guidelines 62 y.o. African American M with HIV & HCV Geno 1b and cirrhosis, HCV RNA 1.8 million IU/mL. Treatment naïve for HCV. Doing well on truvada/atazanavir/r. Does not want to switch ARVS. Which regimen would you use? 47% A. Sofosbuvir/ledipasvir x 12 wks B. Sofosbuvir + simeprevir x 24 wks 28% 25% C. Paritaprevir /ritonavir/ombitasvir + dasabuvir + RBV x 12 weeks Sofosbuvir/ledipasvir x 1... Sofosbuvir + simeprevir x.. Paritaprevir /ritonavir/... 10

11 DRUG-DRUG INTERACTIONS WITH DAAS Acid-reducing drugs Anti-epileptics Antiretrovirals Amiodarone Lipid-lowering drugs CURRENT MEDICATIONS Rosuvastatin Atenolol Aspirin Nitroglycerin as needed (has not used in months) Tenofovir/emtricitabine Atazanavir/ritonavir 11

12 Potential for drug-drug interactions between DAAs and ARVs* PTV/OMV/r/DAS SOF/LDV SOF+DAC SOF+RBV Potential for drug-drug interactions between SOF/LED and ARVs LDV TDF HIV PI/r TDF??TDF? Options for patients on TDF + boosted-pi Change TDF Change PI Await another HCV regimen If combo required close monitoring recommended 12

13 *CrCl >60 to be eligible for study Naggie, CROI, 2015 RBV-free arm with less side effects and dose modifications Combined safety data from 3 ION studies 13

14 Pill Burden LABS PRIOR TO RX HCV RNA 1.7 million IU/mL CR 1.9 (prior 1.4) UA ++glucose ++protein SWAPPED OUT TDF/FTC for dolutegravir CR normalized 14

15 62 y.o. African American M with HIV & HCV Geno 1b and cirrhosis, HCV RNA 1.7 million IU/mL. Treatment naïve for HCV. Doing well on atazanavir/r +dolutegravir. H/o TDF renal toxicity. WhIch regimen would you use? 45% A. Sofosbuvir/ledipasvir x 12 wks B. Sofosbuvir + simeprevir x 24 wks 28% 27% C. Paritaprevir /ritonavir/ombitasvir + dasabuvir + RBV x 12 weeks Sofosbuvir/ledipasvir x 1... Sofosbuvir + simeprevir x.. Paritaprevir /ritonavir/... CASE 1 SWITCHEROO-1 WHAT IF HE WAS G1A? G1A + CIRRHOSIS + RX-NAÏVE: IFN FREE OPTIONS IDSA/AASLD/IAS-USA Recommended: Ledipasvir/sofosbuvir x 12 weeks (just 12 wks given rx-naïve) Daily fixed-dose combination of paritaprevir /ritonavir/ombitasvir plus twice-daily dosed dasabuvir x x 24 weeks (1a + cirrhosis) Sofosbuvir plus simeprevir +/-RBV x 24 weeks (given cirrhosis) Easl Options: Ledipasvir/sofosbuvir + RBV x 12 weeks (RBV included in patients with cirrhosis) OR Ledipasvir/sofosbuvir x 24 wks if cannot take RBV Daily fixed-dose combination of paritaprevir /ritonavir/ombitasvir plus twice-daily dosed dasabuvir + RBV x 24 weeks (1a + cirrhosis) Sofosbuvir plus simeprevir + RBV x 12 weeks (RBV included in patients with cirrhosis) OR Sofosbuvir plus simeprevir x 24 weeks if cannot take RBV Sofosbuvir plus daclatasvir + RBV x 12 weeks (RBV included in patients with cirrhosis) OR Sofosbuvir plus daclatasvir x 24 wks if cannot take RBV 15

16 62 y.o. African American M with HIV & HCV Geno 1b and WITHOUT cirrhosis, HCV RNA 1.7 million IU/mL. Treatment naïve for HCV. Doing well on atazanavir/r +dolutegrevir. H/o TDF renal toxicity. WhIch regimen would you use? 44% A. Sofosbuvir/ledipasvir x 12 wks B. Sofosbuvir/ledipasvir x 8 wks C. Paritaprevir /ritonavir/ombitasvir + dasabuvir x 12 wks 25% 31% Sofosbuvir/ledipasvir x 1... Sofosbuvir/ledipasvir x 8... Paritaprevir /ritonavir/... CASE 2: 45 y.o. Caucasian M with HCV genotype 1a HCV hx: St 2 on fibrosure, no stigmata of cirrhosis HCV RNA 9.5 million IU/ml HCV Treatment-naive HIV history distant h.o AZT monotherapy h/o ARV intolerance: efavirenz rash, ABC hypersensitivity reaction doing well x many years on TDF/FTC + darunavir/r 16

17 45 y.o. Caucasian M with HCV genotype 1a, HCV RNA 9.5 million IU/ml, HCV Rx-naïve, Normal CrCL. Doing well on TDF/FTC + darunavir/r. WhIch regimen would you use? A. Switch ARVS and use sofosbuvir/ledipasvir x 12 wks B. Switch ARVS and use sofosbuvir + simeprevir x 12 wks C. Switch ARVs and use Paritaprevir /ritonavir/ombitasvir + dasabuvir + RBV x 12 wks D. Switch ARVS and use sofosbuvir + daclatasvir once approved E. Leave ARVS and use sofosbuvir + daclatasvir once approved Switch ARVS and use sof... 14% 11% Switch ARVS and use sof... Switch ARVs and use Par... 7% Switch ARVS and use sof... 3% Leave ARVS and use sofo... 66% SOF + DAC for HIV/HCV Wyles, EASL,

18 SOF + DAC for HIV ALLY-2 Wyles, EASL, 2015 CASE 3: 51 y.o. African American W with HCV G1a and ESRD HCV hx: Fibroscan 13.5 kpa (c/w cirrhosis), sonogram some nodularity No prior treatment HCV RNA 190,000 IU/mL HIV-uninfected ESRD on hemodialysis, never evaluated for renal transplant 18

19 51 y.o. African American W with HCV G1a and ESRD on HD, cirrhosis, treatment-naïve Which regimen would you use? A. Sofosbuvir/ledipasvir x 12 wks B. Sofosbuvir + simeprevir x 24 wks 21% 28% 31% 19% C. Paritaprevir/ritonavir/ombitasvir + dasabuvir + RBV x 12 weeks D. Grazoprevir/elbasvir once approved Sofosbuvir/ledipasvir x 1... Sofosbuvir + simeprevir x.. Paritaprevir/ritonavir/o... Grazoprevir/elbasvir onc... DAA STUDY in ESRD EASL,

20 Grazoprevir/elbasvir in HIV/HCV Rx Naive EASL, 2015 CASE 4: 70 y.o. Indian female with HCV genotype 3 + cirrhosis HCV hx: Dx 10 years ago in india Risk factor: blood transfusions 80's after having hysterectomy Cirrhotic as per biopsy 2011 Previously treated with peg IFN/RBV; non-responder HIV-uninfected Substance abuse history negative Residing in the US x 7 years 20

21 Current Medications Atorvastatin St. John s wort Labs GLUC: 118 CR: 0.65 ALB: 3.2 ALT: 87 AST: 96 GGT: 77 Total Bili: 1.0 Direct Bili: 0.3 WBC: 2.9 HGB: 11.9 HCT 35.6 PLAT: 79 HCV RNA: 650,980 iu/ml HCV GT: 3a 21

22 Summary of relative efficacy for various studies of Initial Treatment by regimens and genotypes: APPROVED DRUGS RBV +/- PEG RBV +/- PTV/ RBV RBV RBV SMV LDV DAS r SOF SOF SOF SOF SOF OMV GT1 GT2 GT3 x12w x12w X24w X12w* x(8-)12w X12w* 89% (261/292) 80% if cirrhosis 97% including T- E, cirrhosis 97% (38/39) GT4 96% (27/28) only 10% T-exp ~68-76% 93-95% (69/73, 101/109) 83-93% if cirrhosis 56-61% (102/128, 60/98) 21-34% if cirrhosis 59% 10/17 SVR 93%* Overall *24 wks if cirrhosis >95% >95% *24 wks if cirrhosis N/A N/A N/A N/A 93% (98/105) 92% if cirrhosis N/A 60% N/A 93% 14/15 SVR 95% 19/20) >95% 42/42 RBV 40/44 no RBV 70 W with HCV G3, cirrhosis and IFN-experience. Which regimen would you use? A. Sofosbuvir + RBV x 12 wks B. Sofosbuvir + RBV x 24 wk C. Sofosbuvir + PegIFN + RBV x 12 wks D. Sofosbuvir + daclatasvir x 12 wks 46% 22% 15% 16% Sofosbuvir + RBV x 12 wks Sofosbuvir + RBV x 24 wk Sofosbuvir + PegIFN + RBV.. Sofosbuvir + daclatasvir... 22

23 G3 + CIRRHOSIS + IFN-EXP IDSA/AASLD/IAS-USA Recommended: Daily sofosbuvir (400 mg) + weight-based RBV x 24 weeks Alternative : Daily sofosbuvir (400 mg) and weight-based RBV plus weekly PEG-IFN X 12 weeks Easl Recommended: Daily sofosbuvir (400 mg) + daclatasvir (40 mg) + weightbased RBV x 24 week (pending further data) Daily sofosbuvir (400 mg) and weight-based RBV plus weekly PEG-IFN X 12 weeks Not recommended because suboptimal response in rx-exp with cirrhosis: Daily sofosbuvir (400 mg) + weight-based RBV x 24 weeks SOFOSBUVIR +RBV for G3 REAL WORLD EXPERIENCE (TARGET COHORT) EASL,

24 SOF+RBV vs SOF+PEG+RBV (BOSON TRIAL) EASL, 2015 SOF + DAC FOR G3 AASLD,

25 LABS Week 4 HGB: 10.6 PLAT: 83K HCV RNA: 2,802 iu/ml Week 8 HGB: 9.8 AST: 32 ALT: 27 HCV RNA: Non detectable What to do about the Hb drop? A. Hold sofosbuvir + RBV B. Dose reduce sofosbuvir C. Dose reduce RBV D. Hold RBV E. Monitor for symptoms 49% 41% 9% 0% 1% Hold sofosbuvir + RBV Dose reduce sofosbuvir Dose reduce RBV Hold RBV Monitor for symptoms 25

26 Week 12 Patient presents saying she has taken last doses! (Pharmacy told her such) BE CLEAR! Aware of language barriers, cognitive issues that may impede proper treatment completion Again, for GT 3 treatment is 24 weeks Week 16 HCV ND; HGB 10.1 WEEK 24 HCV ND; HGB 10.3 WEEK 36 HCV ND; HGB

27 WHAT IF SHE WAS G2? G2 + cirrhosis + IFN-EXP IDSA/AASLD/IAS-USA Recommended: Daily sofosbuvir (400 mg) + weight-based RBV x weeks Alternative : Daily sofosbuvir (400 mg) and weight-based RBV plus weekly PEG-IFN X 12 weeks Easl Options: Daily sofosbuvir (400 mg) + + weight-based RBV x week Daily sofosbuvir (400 mg) and weight-based RBV plus weekly PEG-IFN X 12 weeks Daily sofosbuvir (400 mg) + daclatasvir (60 mg) x 12 weeks After SVR Continued monitoring/managment of cirrhosis EGD to r/o varices HCC screening Counsel how to prevent reinfection 27

28 RESISTANCE TESTING AND G1 Resistance-associated variants (RAVs) are common with failure of DAAs NS5A RAVs persist PI RAVs revert over time Patients with prior Peg/RBV+PI -experience had slightly inferior outcomes in cohorts of patients treated with SOF + SIM NS5A RAVs are relatively common at baseline Significance of these may depend on regimen used SOF/LED x 24 wks for prior SOF/LED failures Lawitz, EASL,

29 ACUTE HCV + GUIDELINES: IFN- FREE OPTIONS IDSA/AASLD/IAS-USA If decision made to treat in acute phase: Owing to high efficacy and safety, the same regimens recommended for chronic HCV infection are also recommended for acute infection. EASL Although no data is available yet: The same dose and durations for patients with chronic HCV can be used, without RBV until new data indicate whether shorter and/or less intensive treatment is sufficient SUMMARY Remarkable advances in terms of HCV treatment tolerability & efficacy Continued efforts being made to make shorter, safer, more effective Continued need for therapies without significant drug interactions & that can be used in varied populations (HIV+, ESRD, opiate substitution, etc) Successful treatment prevents cirrhosis, end stage liver disease, and hepatocellular cancer Challenge now is to scale up efforts to diagnose and treat the millions of people living with HCV 29

30 HCVguidelines.org hepatitisc.uw.edu IASUSA.org nynjaetc.org Thank you Resources 30