Ledipasvir/Sofosbuvir for 12 Weeks in Patients Coinfected With HCV and HIV-1: ION-4

Transcription

1 Ledipasvir/Sofosbuvir for 12 Weeks in Patients Coinfected With HCV and HIV-1: IN-4 Stefan Mauss 8, Curtis Cooper 1, Susanna Naggie 2,Michael Saag 3, Luisa M. Stamm 4, Jenny C. Yang 4, Ewa Siewaszewicz 7, Kamil Lipski 7, Phillip S. Pang 4, John G. McHutchison 4, Douglas Dieterich 5, Mark Sulkowski 6 8 Center for HIV and Hepatogastroenterology, Duesseldorf, Germany; 1 University of ttawa, The ttawa Hospital, ttawa, N, 2 Duke Clinical Research Institute, Durham, NC; 3 University of Alabama at Birmingham, Birmingham, AL, 4 Gilead Sciences, Inc., Foster City, CA; 5 Icahn School of Medicine at Mount Sinai, New York, NY; 6 Johns Hopkins University School of Medicine, Baltimore, MD, Gilead Sciences Poland 7 1st Central Eastern European Meeting on Viral Hepatitis and Co-Infection with HIV Warsaw, Poland

2 Disclosures Dr. Mauss received honoraria as a consultant, for educational activities or as a speaker from AbbVie, BMS, Boehringer Ingelheim, Gilead, Janssen, MSD, Roche, ViiV 2

3 Background Ledipasvir nce-daily, oral, 90-mg NS5A inhibitor LDV NS5A inhibitor H N N N N H F F H N H N N N H Sofosbuvir nce-daily, oral, 400-mg NS5B inhibitor Ledipasvir/Sofosbuvir FDC nce-daily, oral, fixed-dose (90/400 mg) combination tablet Single-tablet regimen for hepatitis C FDC, fixed-dose combination. H 3 C H 3 C CH 3 HN P H LDV NS5A inhibitor LDV NS5A inhibitor N NH CH 3 F SF nucleotide polymerase inhibitor SF SF SF nucleotide nucleotide nucleotide SF polymerase polymerase polymerase nucleotide inhibitor inhibitor polymerase inhibitor 3

4 Background and Aims Liver-related complications remain a leading cause of death among HIV/HCV-coinfected patients 1 Safe and effective oral treatments compatible with multiple antiretrovirals are needed for the eradication of HCV in HIV/HCV-coinfected patients Aim of this study was to evaluate the efficacy and safety of LDV/SF for the treatment of HCV in patients coinfected with HIV-1, currently on antiretroviral therapy 1 Smith, CJ et al. Lancet 2014; 384:

5 Study Design ) Wk 0 Wk 12 Wk 24 N=335 LDV/SF SVR12 Phase 3, multicenter, open-label study (NCT ) HCV GT 1 or 4 patients in US, Canada, and New Zealand Broad inclusion criteria HCV treatment-naïve or treatment-experienced 20% with compensated cirrhosis Platelets 50,000/mm 3 ; hemoglobin 10 mg/dl, CrCl 60 ml/min HIV-1 positive, HIV RNA <50 copies/ml; CD4 cell count >100 cells/mm 3 ART regimens included emtricitabine and tenofovir disoproxil fumarate plus efavirenz, raltegravir, or rilpivirine 5

6 Endpoints Primary efficacy endpoint: SVR12 HCV RNA <LLQ at post-treatment Week 12 Safety HCV RNA analyzed by CBAS TaqMan HCV Test v2.0 HPS, with LLQ of 25 IU/mL Adverse events and discontinuations Maintenance of HIV-1 RNA <50 copies/ml Serum creatinine 6

7 Results: Demographics and Baseline Characteristics LDV/SF 12 weeks N=335 Mean age, y (range) 52 (26-72) Male, n (%) 276 (82) Black, n (%) 115 (34) Hispanic or Latino, n (%) 56 (17) Mean BMI, kg/m 2 (range) 27 (18-66) IL28B CC, n (%) 81 (24) GT (98) HCV treatment experienced, n (%) 185 (55) Cirrhosis, n (%) 67 (20) Mean HCV RNA, log 10 IU/mL ± SD 6.7 ± 0.6 Median CD4 cell count, cells/µl (range) 628 ( ) HIV ARV Regimen Efavirenz + FTC + TDF 160 (48) Raltegravir + FTC + TDF 146 (44) Rilpivirine + FTC + TDF 29 (9) 7

8 Results: SVR12 verall Naïve vs Experienced Cirrhosis Status SVR12 (%) / / / /268 63/67 LDV/SF 12 Weeks Naïve Experienced No Cirrhosis Cirrhosis Error bars represent 95% confidence intervals. 8

9 Results: SVR12 verall Naïve vs Experienced Cirrhosis Status SVR12 (%) / / / /268 63/67 LDV/SF 12 Weeks 10 relapses 2 on-treatment failures (noncompliance, per investigators) 1 lost to follow-up 1 death (IVDU-related endocarditis/sepsis) Naïve Experienced No Cirrhosis Cirrhosis Error bars represent 95% confidence intervals. 9

10 Results: SVR12 by Prior Treatment Experience verall Naïve vs Experienced Cirrhosis Status SVR12 (%) / / / /268 63/67 LDV/SF 12 Weeks Naïve Experienced No Cirrhosis Cirrhosis Error bars represent 95% confidence intervals. 10

11 Results: SVR12 by Prior Treatment Experience and Cirrhosis Status verall Naïve vs Experienced Cirrhosis Status SVR12 (%) / / / /268 63/67 LDV/SF 12 Weeks Naïve Experienced No Cirrhosis Cirrhosis Error bars represent 95% confidence intervals. 11

12 Results: SVR12 in Subgroups verall Sex Race HCV Genotype Baseline HCV RNA (IU/mL) Baseline BMI (kg/m 2) IL28B Cirrhosis Prior HCV Treatment ARV Regimen Baseline CD4 (cells/μl) Male Female Black Non-Black 1a 1b 4 <800, ,000 <30 30 CC CT TT No Yes No Yes EFV + FTC + TDF RAL + FTC + TDF RPV + FTC + TDF < LDV/SF 12 Weeks, N= SVR12, % (95% CI) 12

13 Results: SVR12 in Subgroups verall Sex Race HCV Genotype Baseline HCV RNA (IU/mL) Baseline BMI (kg/m 2) IL28B Cirrhosis Prior HCV Treatment ARV Regimen Baseline CD4 (cells/μl) Male Female Black Non-Black 1a 1b 4 <800, ,000 <30 30 CC CT TT No Yes No Yes EFV + FTC + TDF RAL + FTC + TDF RPV + FTC + TDF < LDV/SF 12 Weeks, N= SVR12, % (95% CI) Statistically significant in multivariate analysis 13

14 PK and ther Exploratory Analyses No difference in SVR in HCV mono-infected IN program (12 weeks) for black (89/90, 99%) versus non-black (431/448, 96%) 2 LDV and SF population PK levels Similar across the different ARV regimens Similar between black and non-black patients Similar between patients who relapsed and those who achieved SVR GWAS and whole genome sequencing analysis underway 2 Lennox et al. AASLD 2014 ral abstract #237 14

15 Results: HCV Sequence Analysis Deep sequencing of NS5A at baseline identified 59 (18%) patients with NS5A variants (RAVs) 55 (93%) of patients with NS5A RAVs achieved SVR12 Post-treatment NS5A RAVs were observed in 10 of the 12 patients with virologic failure No NS5B S282T was observed in any patient at baseline or virologic failure 15

16 Results: Safety Summary Patients, n (%) LDV/SF 12 Weeks N=335 AEs 257 (77) Grade 3 4 AE 14 (4) verall safety Serious AE 8 (2)* Treatment D/C due to AE 0 Death 1 (<1) Grade 3 4 laboratory abnormality 36 (11) Stable CD4 counts through treatment and follow-up phase No patient had confirmed HIV virologic rebound *Serious AEs in >1 patient were hepatocellular carcinoma (n=2) and portal vein thrombosis (n=2) in patients with cirrhosis. Confirmed IV drug user developed Staphylococcus aureus sepsis, endocarditis with associated embolic brain abscesses, and multi-organ system failure. 16

17 Results: Adverse Events ( 5%) Patients, n (%) LDV/SF 12 Weeks N=335 Headache 83 (25) Fatigue 71 (21) Diarrhea 36 (11) Nausea 33 (10) Arthralgia 22 (7) Upper respiratory tract infection 18 (5) 17

18 Results: Renal Function Creatinine Clearance (ml/min), mean ± SD LDV/SF + EFV+FTC+TDF (n=160) RAL+FTC+TDF (n=146) RPV+FTC+TDF (n=29) BL FU-4 Week 4 patients (1%) had change in creatinine 0.4 mg/dl 2 completed treatment with no ART change 1 had dose reduction of TDF, 1 discontinued TDF 18

19 Conclusions In this Phase 3 study of 335 HIV/HCV-coinfected patients, 96% achieved SVR12 after 12 weeks of a once-daily, single-tablet regimen of LDV/SF Prior HCV treatment status or the presence or absence of cirrhosis did not impact outcome In contrast to larger studies among monoinfected patients, a lower response rate was observed among coinfected black patients treated with LDV/SF (SVR12 90%) LDV/SF was well tolerated, with no treatment discontinuations due to adverse events and no adverse impact on HIV disease or its treatment 19

20 Acknowledgments We extend our thanks to: The patients and their families All participating investigators throughout the US, Canada, and New Zealand UNITED STATES: David Asmuth, Rachel Baden, Meena Bansal, Maurizio Bonacini, Norbert Brau, U. Fritz Bredeek, Raymond Chung, Calvin J. Cohen, Eric Daar, Craig Dietz, Robin Henry Dretler, Richard Elion, W.J. Fessel, Jason Flamm, Timonthy Friel, Joel E. Gallant, Joseph C. Gathe, Eliot Godofsky, Philip M. Grant, Federico Hinestrosa, Gregory Huhn, Mamta Jain, Dushyantha Jayaweera, Donald Kotler, Jay Lalezari, Charles Landis, Annie Luetkemeyer, Kristen Marks, Cynthia Mayer, Anthony Mills, Karam Mounzer, Susanna Naggie, Bruce S. Rashbaum, Jorge E. Rodriguez, Peter J. Ruane, Paul Edward Sax, Michael Saag, Kenneth Sherman, Marc Siegel, Richard Sterling, Mark Sulkowski, Karen T. Tashima, Pablo Tebas, Melanie A. Thompson, William J. Towner, Chia Wang, David A. Wheeler, David A. Wohl, Kimberly Workowski, David Wyles, Benjamin Young CANADA: Curtis Cooper, Emmanuelle Huchet, Mark Hull, Marina Klein, David Wong PUERT RIC: Javier. Morales-Ramirez, Jorge L. Santana-Bagur NEW ZEALAND: Edward Gane, Catherine Stedman This study was funded by Gilead Sciences, Inc. 20