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CROI 2015, Seattle Ledipasvir/Sofosbuvir for 12 Weeks in Patients Coinfected With HCV and HIV-1: ION-4 Susanna Naggie 1, Curtis Cooper 2, Michael Saag.

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Presentation on theme: "CROI 2015, Seattle Ledipasvir/Sofosbuvir for 12 Weeks in Patients Coinfected With HCV and HIV-1: ION-4 Susanna Naggie 1, Curtis Cooper 2, Michael Saag."— Presentation transcript:

1 CROI 2015, Seattle Ledipasvir/Sofosbuvir for 12 Weeks in Patients Coinfected With HCV and HIV-1: ION-4 Susanna Naggie 1, Curtis Cooper 2, Michael Saag 3, Luisa M. Stamm 4, Jenny C. Yang 4, Phillip S. Pang 4, John G. McHutchison 4, Douglas Dieterich 5, Mark Sulkowski 6 1 Duke Clinical Research Institute, Durham, NC; 2 University of Ottawa, The Ottawa Hospital, Ottawa, ON; 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

2 Background FDC, fixed-dose combination. 2  Ledipasvir –Once-daily, oral, 90-mg NS5A inhibitor  Sofosbuvir ‒ Once-daily, oral, 400-mg NS5B inhibitor  Ledipasvir/Sofosbuvir FDC –Once-daily, oral, fixed-dose (90/400 mg) combination tablet –Single-tablet regimen for hepatitis C SOF nucleotide polymerase inhibitor LDV NS5A inhibitor SOF nucleotide polymerase inhibitor SOF nucleotide polymerase inhibitor LDV NS5A inhibitor SOF nucleotide polymerase inhibitor LDV NS5A inhibitor SOF nucleotide polymerase inhibitor

3 Background and Aims HIV-HCV (ION-4)  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/SOF for the treatment of HCV in patients coinfected with HIV-1, currently on antiretroviral therapy. 1 Smith, CJ et al. Lancet 2014; 384:

4 Study Design HIV-HCV (ION-4)  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 100 cells/mm 3  ART regimens included emtricitabine and tenofovir disoproxil fumarate plus efavirenz, raltegravir, or rilpivirine 4 Wk 0 Wk 12Wk 24 SVR12 LDV/SOF N=335

5 Endpoints HIV-HCV (ION-4)  Primary efficacy endpoint: SVR12 –HCV RNA

6 Results: Demographics and Baseline Characteristics HIV-HCV (ION-4) 6

7 Naïve vs ExperiencedOverallCirrhosis Status LDV/SOF 12 Weeks ExperiencedNaïveNo CirrhosisCirrhosis 321/335142/150179/185 63/67258/268 SVR12 (%) Results: SVR12 HIV-HCV (ION-4) Error bars represent 95% confidence intervals. 7

8 Naïve vs ExperiencedOverallCirrhosis Status LDV/SOF 12 Weeks ExperiencedNaïveNo CirrhosisCirrhosis 321/335142/150179/185 63/67258/268 SVR12 (%) Results: SVR12 HIV-HCV (ION-4) Error bars represent 95% confidence intervals. 10 relapses 2 on-treatment failures (noncompliance, per investigators) 1 lost to follow-up 1 death (IVDU-related endocarditis/sepsis) Overall 8

9 Naïve vs ExperiencedOverallCirrhosis Status LDV/SOF 12 Weeks ExperiencedNaïveNo CirrhosisCirrhosis 321/335142/150179/185 63/67258/268 SVR12 (%) Results: SVR12 by Prior Treatment Experience HIV-HCV (ION-4) Error bars represent 95% confidence intervals. Overall 9

10 Naïve vs ExperiencedOverallCirrhosis Status LDV/SOF 12 Weeks ExperiencedNaïveNo CirrhosisCirrhosis 321/335142/150179/185 63/67258/268 SVR12 (%) Results: SVR12 by Prior Treatment Experience and Cirrhosis Status HIV-HCV (ION-4) Error bars represent 95% confidence intervals. Overall 10

11 11 LDV/SOF 12 Weeks, N=335 Overall Sex Male Female Race Black Non-Black HCV Genotype 1a 1b 4 Baseline HCV RNA (IU/mL) <800,000 ≥800,000 Baseline BMI (kg/m 2) <30 ≥30 IL28B CC CT TT Cirrhosis No Yes Prior HCV Treatment No Yes ARV Regimen EFV + FTC + TDF RAL + FTC + TDF RPV + FTC + TDF Baseline CD4 (cells/μL) <350 ≥350 Results: SVR12 in Subgroups HIV-HCV (ION-4) SVR12, % (95% CI)

12 12 LDV/SOF 12 Weeks, N=335 Overall Sex Male Female Race Black Non-Black HCV Genotype 1a 1b 4 Baseline HCV RNA (IU/mL) <800,000 ≥800,000 Baseline BMI (kg/m 2) <30 ≥30 IL28B CC CT TT Cirrhosis No Yes Prior HCV Treatment No Yes ARV Regimen EFV + FTC + TDF RAL + FTC + TDF RPV + FTC + TDF Baseline CD4 (cells/μL) <350 ≥350 Results: SVR12 in Subgroups HIV-HCV (ION-4) SVR12, % (95% CI) Statistically significant in multivariate analysis

13 PK and Other Exploratory Analyses HIV-HCV (ION-4)  No difference in SVR in HCV mono-infected ION program (12 weeks) for black (89/90, 99%) versus non-black (431/448, 96%) 2  LDV and SOF 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 Oral abstract #237 13

14 Results: HCV Sequence Analysis HIV-HCV (ION-4)  Deep sequencing of NS5A at baseline identified 67 (20%) patients with NS5A variants (RAVs) –63 (94%) 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 14

15 Results: Safety Summary HIV-HCV (ION-4) *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. 15  Stable CD4 counts through treatment and follow-up phase  No patient had confirmed HIV virologic rebound

16 Results: Adverse Events (≥5%) HIV-HCV (ION-4) 16

17 Results: Renal Function HIV-HCV (ION-4) 17 EFV+FTC+TDF (n=160) RAL+FTC+TDF (n=146) RPV+FTC+TDF (n=29) LDV/SOF + Creatinine Clearance (mL/min), mean ± SD Week BL FU-4  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 Conclusions HIV-HCV (ION-4)  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/SOF –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/SOF (SVR12 90%)  LDV/SOF was well tolerated, with no treatment discontinuations due to adverse events and no adverse impact on HIV disease or its treatment 18


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