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

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

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:

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

Endpoints HIV-HCV (ION-4)  Primary efficacy endpoint: SVR12 –HCV RNA <LLOQ at post-treatment Week 12 HCV RNA analyzed by COBAS TaqMan HCV Test v2.0 HPS, with LLOQ of 25 IU/mL  Safety –Adverse events and discontinuations –Maintenance of HIV-1 RNA <50 copies/mL –Serum creatinine 5

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

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

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

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

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 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 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

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

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

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

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

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

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