Preliminary Results of an Evaluation of Ledipasvir/Sofosbuvir in Patients with Chronic HCV or HCV/HIV Co-Infection Konstantin Zhdanov 1, Viacheslav Morozov 2, Elena A Orlova-Morozova 3, Riina Salupere 4, Galina Kozhevnikova 5, Svetlana Romanova 6, Vladimir Chulanov 7, Natalia Geyvandova 8, Larisa Gogova 9, Tatiana Shimonova 10, Igor Bakulin 11, Eduard Burnevich 12, Evgenii Chesnokov 13, Elena Nurmukhametova 14, Sergey Zhuravel 15, Djamal Abdurakhmanov 16, Elena Bessonova 17, Vladimir Ivashkin 18, Kathryn Kersey 19, Deyuan Jiang 19, Anupma Roy 19, Anu Osinusi 19, Diana M Brainard 19, Kai Zilmer 20, Natalia Gankina 21, Vasily Isakov 22 1. Military Medical Academy, St Petersburg; 2. Medical Company Hepatolog, LLC, Samara; 3. Moscow Regional Center for Prevention and Control of AIDS and Infectious Diseases, Moscow; 4. Tartu University Hospital, Tartu; Estonia; 5. Central Research Institute of Epidemiology, Moscow; 6.Center for Prevention and Control of AIDS and Infectious Diseases, St Petersburg; 7. Central Research Institute of Epidemiology, Moscow; 8. Stavropol Regional Clinical Center of Special Medical Care, Stavropol,; 9. Central Clinical Hospital of the Russian Academy of Sciences, Moscow; 10. State Healthcare Institution Infectious Clinical Hospital #2 of Moscow City, Moscow; 11. Moscow Central Scientific Institute of Gastroenterology, Moscow 12. Sverdlovsk Regional Clinical Hospital 1, Ekaterinburg; 13. Consultation and Diagnostic Centre, Tymen; 14. Infectious Clinical Hospital 1 of Moscow Healthcare Department, Moscow; 15. Scientific Research Institute of Emergency Care n.a. N.V. Sclifosovskiy of Healthcare Department of Moscow, Moscow; 16. I.M.Sechenov First Moscow State Medical University, Moscow; 17. Sverdlovsk Regional Clinical Hospital 1, Ekaterinburg; 18. First Moscow State Medical University n.a. I.M. Sechenov., Moscow; 19. Gilead Sciences, Inc. Foster City, USA; 20. West Tallinn Central Hospital, Tallinn, Estonia; 21. Krasnoyarsk Regional Center for Prevention and Control of AIDS and Infectious Diseases, Krasnoyarsk; 22. Institute of Nutrition of Russian Academy of Medical Sciences, Moscow. White Nights 2016, St. Petersburg
Disclosures Konstantin Zhdanov is An investigator for Gilead, AbbVie, BMS, Biocad, Janssen, MSD, Novartis, Roche, R-Pharm A speaker for Gilead, AbbVie, Abbott, Biocad, Janssen, MSD, Novartis, Roche, R-Pharm An advisor for Gilead, AbbVie, Abbott, Biocad, Janssen, MSD, Novartis, Roche, R-Pharm 2
Sofosbuvir and Ledipasvir Sofosbuvir Once-daily, oral, 400-mg NS5B inhibitor SOF nucleotide polymerase inhibitor Ledipasvir Once-daily, oral, 90-mg NS5A inhibitor LDV NS5A inhibitor Ledipasvir/Sofosbuvir FDC Once-daily, oral, FDC (90/400 mg) tablet Single-tablet regimen for hepatitis C FDC, fixed-dose combination. LDV NS5A inhibitor LDV NS5A inhibitor SOF SOF SOF nucleotide nucleotide polymerase SOF polymerase inhibitor nucleotide inhibitor polymerase inhibitor
Background and Objectives Ledipasvir/sofosbuvir (LDV/SOF) for 8 weeks resulted in 94% SVR12 rate in treatment-naïve (TN) patients without cirrhosis with HCV genotype (GT) 1 in the phase 3 study ION-3 1 LDV/SOF for 12 weeks resulted in 96% (321/335) SVR12 rate in patients with HCV/HIV coinfection with HCV GT 1 or 4 2 LDV/SOF + ribavirin (RBV) for 12 weeks resulted in 98% (44/45) SVR12 rate in patients with GT 1 HCV who had failed treatment with SOF + RBV ± pegylated interferon 3 The objectives of the current study were to evaluate the safety and efficacy of 8 weeks of LDV/SOF in treatment naïve (TN) patients 12 weeks LDV/SOF + RBV in patients with virologic failure following treatment with SOF + RBV 1. Kowdley, et al. NEJM 2014;370:18790-88; 2. Naggie et al. NEJM 2015; 373:705-13; 3. Wyles, et al. Hepatology 2015 ; 61:1793-97. 4
Study Design GS-US-337-1463 Wk 0 Wk 8 Wk 12 Wk 20 Wk 24 Group 1 TN HCV Monoinfection n=67 LDV/SOF SVR12 Group 2 Group 3 TN HCV/HIV Coinfection n=59 TE* HCV Monoinfection n=27 LDV/SOF LDV/SOF + RBV SVR12 Phase 3b, non-randomized, open-label, multi-center study Conducted at 18 sites in the Russian Federation and 2 sites in Estonia *Patients who previously failed SOF + RBV treatment. TN, treatment-naïve; TE, treatment-experienced. 5
Key Inclusion Criteria Treatment-naïve GT 1 HCV RNA 10 4 IU/mL No cirrhosis With or without HIV coinfection Treatment-experienced GT 1 or 3 Did not achieve SVR12 following 16 or 24 weeks SOF + RBV HCV RNA >LLOQ With or without compensated cirrhosis 6
Key Exclusion Criteria Exclusion Non-HCV liver disease etiology Current or prior hepatic decompensation Current drug or alcohol abuse Treatment-experienced: no prior NS5A inhibitor 7
Additional Criteria: HIV/HCV Coinfection Inclusion criteria ARV-naïve: CD4 T-cell count >500 cells/mm 3 On ARV therapy: CD4 T-cell count >200 cells/mm 3 6 months and maintained HIV RNA <50 copies/ml Stable protocol-approved ARV regimen for 8 weeks (6 months for abacavir-containing regimens) Exclusion criteria Opportunistic infection within 6 months prior to Screening Active, serious infection requiring parenteral antibiotics, antivirals or antifungals within 30 days prior to baseline ARV, antiretroviral. 8
HIV ARV Regimens Emtricitabine/Tenofovir or lamivudine/zidovudine or abacavir/lamivudine plus: Efavirenz; or Rilpivirine; or Raltegravir; or Dolutegravir 9
Study Endpoints Efficacy Primary endpoint is SVR12 (HCV RNA <LLOQ at post-treatment Week 12) Additional endpoints include HCV RNA on treatment, SVR4, SVR24 HCV RNA is analyzed by COBAS TaqMan HCV Test v2.0 for use with the Ampliprep System with LLOQ of 15 IU/mL Safety AEs and discontinuations Laboratory abnormalities 10
Demographics and Baseline Characteristics HCV Monoinfection n=67 Treatment Naïve HIV/HCV Coinfection n=59 Treatment Experienced HCV Monoinfection n=27 Mean age, years (range) 42 (19, 76) 34 (23, 58) 47 (28, 68) Male, n (%) 34 (51) 34 (58) 18 (67) Mean BMI, kg/m 2 (range) 25 (18, 36) 24 (19, 34) 29 (20, 43) Genotype 1, n (%) 67 (100) 59 (100) 21 (78) Cirrhosis, n (%) 0 0 10 (37) IL28B non-cc, n (%) 50 (75) 50 (85) 20 (74) Mean HCV RNA, log 10 IU/mL (range) 5.9 (2.6, 7.0) 6.1 (4.6, 7.0) 6.3 (5.0, 7.5) 11
Median HCV RNA (log 10 IU/mL) Viral Kinetics 7 6 5 TN, HCV-monoinfection (n=67) TN, HCV/HIV coinfection (n=59) TE, HCV-monoinfection (n=27) 4 3 2 EOT LDV/SOF 8 Weeks EOT LDV/SOF + RBV 12 Weeks 1 0 BL 0 1 2 4 6 8 10 12 Week BL, baseline; EOT, end of treatment; TN, treatment-naïve; TE, treatment-experienced. 12
Overall Safety Patients, n (%) TN HCV Monoinfection n=67 LDV/SOF 8 weeks TN HIV/HCV Coinfection n=59 LDV/SOF +RBV 12 weeks TE HCV Monoinfection n=27 Any AE 19 (28) 17 (29) 11 (41) Grade 3/4 AEs* 1 (1) 0 0 Serious AEs 0 0 0 Study drug modification/interruption due to AE 0 0 0 Grade 3-4 laboratory values 5 (7) 4 (7) 5 (19) Hemoglobin <10 g/dl 0 0 1 (4) *1 grade 3 AE of asymptomatic neutropenia, based on an grade 3 neutrophil count; considered unrelated to study treatment. TN, treatment-naïve; TE, treatment-experienced. 13
Overall Safety Patients, n (%) TN HCV Monoinfection n=67 LDV/SOF 8 weeks TN HIV/HCV Coinfection n=59 LDV/SOF +RBV 12 weeks TE HCV Monoinfection n=27 Headache 4 (6) 0 4 (15) Abdominal pain upper 1 (1) 1 (2) 2 (7) Asthenia 1 (1) 0 2 (7) Dyspepsia 0 0 3 (11) Irritability 0 1 (2) 2 (7) Blood bilirubin increased 0 0 2 (7) TN, treatment-naïve; TE, treatment-experienced. 14
Conclusions LDV/SOF ± RBV resulted in rapid suppression of HCV RNA LDV/SOF ± RBV was well tolerated with low rates of adverse events Safety profile when co-administered with RBV is consistent with a ribavirin-containing regimen These data support the regimen of LDV/SOF for 8 weeks in treatment naïve, non-cirrhotic patients with chronic HCV infection including those with HIV coinfection LDV/SOF + RBV for 12 weeks may be a useful option for those who have failed prior HCV treatment with a sofosbuvir-based regimen 15
Acknowledgments We extend our thanks to Study staff at the clinical sites The patients and their families This study was funded by Gilead Sciences, Inc. 16