Short Duration DAA Therapy for Hepatitis C: How Short Can We Go?

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1 Short Duration DAA Therapy for Hepatitis C: How Short Can We Go? Shyam Kottilil MD, Ph.D. Institute of Human Virology, University of Maryland, Baltimore, MD HEPDART Kona, HI

2 Disclosures Received research grants paid to the institution from Medimmune Inc, Merck Inc, Arbutus Pharmaceuticals and Gilead Sciences Inc.

3 Objective To evaluate strategies employed to shorten duration of HCV therapy beyond 8 weeks

4 Rationale

5 Mechanism of HCV Clearance Infection Target cell Virions DAA Infected hepatocyte Host Immunity Death Clearance Death/loss

6 Addition of a 3 rd DAA Improves Viral Kinetics Median HCV RNA Decline * p<0.05 * p<0.05 * p<0.05 Sofosbuvir + Ledipasvir Sofosbuvir + Ledipasvir + GS-9669 Sofosbuvir + Ledipasvir + GS-9451 Time (days) Kohli A. Kottilil S. Lancet 385(9973): , 2015

7 Potency of DAA Influences the Need for Host Immunity to Achieve SVR Patients with IL28B CC haplotype have faster decline of HCV to SOF+RBV Kohli A. Kottilil S Hepdart 2013 No difference is observed when more potent LDV + SOF is used

8 HCV specific phenotype 25x10 6 CFSE labeled PBMC Genotype matched HCV peptides Flow cytometry 48 hour incubation CFSE low = proliferation = antigen responsive CD4 CD3 PD-1 Tim-3 CD57 CD8 Live Dead IL-2 IFN-γ TNF-α CTLA-4

9 Live cells and cells responding to antigen are gated for further analysis Live cells *Exclusion Dye Viability dye* Cell division in response to HCV antigen

10 Enhanced Viral Suppression Improves Antiviral Immunity Shrivastava S. Kottilil S.. AASLD 2015

11 O Brien T HEPDART 2015 Precision Medicine for HCV 100% 88%

12 Adherence to DAA therapy drops with duration Petersen Kottilil, Kohli et. al. Hepatology International 2015

13 Shortening Treatment Duration Saves Money Veteran's Administration 2015: 254,000 patients with HCV; 20% cirrhosis

14 The Trials

15 Short Duration HCV Therapy Emmanuel B..Kottilil S. Lau G. (2017) Lancet G&H

16 Predictors of SVR Baseline HCV Viral load HCV genotype 1b Absence of RAVs

17 SODAPI Study

18 Sofosbuvir (SOF, nucleotide NS5B inhibitor) 400 mg once daily Ledipasvir (LDV, NS5A inhibitor) 90 mg once daily Daclatasvir (DCV, NS5A inhibitor) 60 mg once daily Simeprevir (SMV, a protease/ NS3/4 inhibitor) 150 mg once daily Asunaprevir (ASV, a protease/ NS3/4 inhibitor) 100 mg twice daily SODAPI Study Flow Day Plasma HCV RNA < 500 IU/ml by Day 2 GT-1b Noncirrhotic Chinese Patients Patient randomly assigned Group 1: SOF/LDV+ASV Group 2: SOF+DCV+SMV Group 3: SOF +DCV+ASV Group 1: SOF/LDV+ASV N=6 Group 2: SOF+DCV+SMV N=6 Group 3: SOF+DCV+ASV N=6 Follow up Follow up Follow up

19 % Patients with VL<25 IU/mL SODAPI Viral Measurements

20 Future Considerations

21 Effective Retreatment Strategy for Failures: SYNERGY 88.2% 30/ % 32/ % 31/ % 31/ % 31/ % 22/34 2 patients withdrew consent 1 patient relapsed

22 Distribution of HCV genotypes Hajarizadeh, B. et al. (2013) Nat. Rev. Gastroenterol. Hepatol.

23 Increasing Potency is Possible Infection Target cell Virions DAA Infected hepatocyte Host Immunity Death Clearance Death/loss

24 AL Study SVR (%) Gane EJ et al. AASLD 2017 Genotype 1 Genotype 3

25 Potent Non Nucleoside Analog HCV RNA viral load decline of 3 logs by 48 hours After the NNI treatment, the viral load levels were slowly increased Drug resistance analysis ongoing HCV RNA IU/mL (log 10) Viral Load Change From Baseline (400 mg QD or 200 mg BID x 7 days) NNI, QD or BID Day No NNI Sub #1 qd Sub #2 qd Sub #4 qd Sub# 5 qd Sub #6 bid Sub #7 bid Sub #8 bid 400 mg QD 200 mg BID Lee S et al. APASL

26 People Who Inject Drugs Increasing incidence of HCV among young adults (USA) MMWR Morb Mortal Wkly Rep. 2015;64:453-8.

27 People Who Inject Drugs Overhus A. et al. AASLD 2016

28 Incarceration 1.9 million HCV + incarcerated persons are reservoir for new infections (USA) Rich JD et al. N Engl J Med

29 Conclusions Shortening HCV therapy beyond 4 weeks in targeted population is possible and should be further explored Factors influencing high SVR with short duration combination DAA therapy include low baseline HCV VL, absence of RAVs, Genotype 1b, being female, and having IL28B CC haplotype For treatment of all patients, newer DAAs that may be more potent and/or have longer half life need to be studied in the future Co-ordinated global strategy to explore short duration therapy for hepatitis C is warranted

30 Acknowledgments Institute of Human Virology Eleanor Wlson MD Lydia Tang MD Amy Nelson RN Jennifer Hoffmann CRNP Shikha Shrivastava Ph.D NIH DC-Program for AIDS Progress Sarah Kattakuzhy MD Elana Rosenthal MD Poonam Mathur DO, MPH Institute for Liver Health, Phoenix NIH Anita Kohli MD Henry Masur MD Dalhousie University, Canada Lisa Barrett MD, Ph.D Humanities and Health Medical Group George Lau MD Vanessa Wu CoCrystal Pharmaceuticals Sam Lee Ph.D Luz Pascual Emory University Raymond Schinazi Ph.D Gilead Sciences Inc. Anu Osinusi MD Patients