CROI 2016 Abstract eBook

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Oral Abstracts

152 Broadly Neutralizing Antibodies Avert HCV ReInfection or Subsequent Chronic Infection Sabrina J. Merat 1 ; Richard Molenkamp 2 ; Dorien van de Berg 1 ; Camille Bru 1 ; Sylvie M. Koekkoek 2 ; Neeltje A. Kootstra 2 ; Maria Prins 3 ; Arjen Q. Bakker 1 ;Tim Beaumont 1 ; Janke Schinkel 2 1 AIMM Therapeutics, Amsterdam, Netherlands; 2 Academic Med Cntr, Amsterdam, Netherlands; 3 PH Service of Amsterdam, Amsterdam, Netherlands Background: Understanding of protective immunity against hepatitis C virus (HCV) chronic infection is needed for designing an effective vaccine. Development of a broad neutralizing antibody response against the HCV E1E2 glycoproteins early in infection has been associated with clearance of infection. However, little is known about the characteristics of protective antibodies. Methods: Therefore, we analyzed the antibody repertoire of twelve participants from the Amsterdam Cohort Study among drug users with median follow-up of 16.8 years. Five subjects became chronically infected; 3 following primary infection, and 2 cleared a primary infection but became chronically infected following reinfection. Seven subjects never became chronically infected following spontaneous clearance, although 4 out of 7 subjects had documented reinfections. From each subject CD27+IgG+memory B cells, collected 1 year after initial HCV infection, were immortalized by transduction with BCL6 and BCL-XL. To characterize the breadth of the antibody repertoire, 10,000 B cells were analyzed for binding to E1E2 from genotype 1 to 6 using a multiplex flow cytometry-based assay. Results: In 10 of 12 subjects, E1E2 specific B cell cultures were detected with a median frequency of 0.14 %. Interestingly, in subjects who had prolonged risk behavior but never became chronically infected, the antibody repertoire was broader compared to subjects who became chronically infected. In 5 of 7 subjects who never became chronically infected, 0.02 to 0.37 % of the B cells recognized at least 5 HCV genotypes, whereas in none of the 5 chronically infected subjects such B cells were detected (p = 0.03). From 3 clearers with B cells recognizing at least 5 genotypes, 75 cultures were selected to identify the epitope of these antibodies. All selected cultures recognized to a non-linear epitope. Using alanine mutagenesis scanning, we determined that the major epitope targeted by these antibodies was an epitope combining epitope II and domain B. In addition, 14 cultures from 2 of these 3 clearers bound to the AR4 epitope. Since these epitopes are the targets of broadly neutralizing antibodies, B cell clones were isolated to confirm the neutralization capacity of these antibodies. Conclusions: These data strongly suggest that broadly neutralizing antibodies protect against primary and subsequent HCV chronic infections. 153 High Response Rate in HCV-Genotype 4 Patients TreatedWith Ravidasvir and Sofosbuvir Gamal Esmat 1 ; Maissa El Raziky 2 ; Asmaa Gomaa 3 ;Tamer Elbaz 4 ; Mahmoud Abouelkhair 2 ; Alyaa Sabry 3 ; Hadeel Gamal Eldeen 4 ; Mohammed Karim 2 ; Mohammed Abdel-Hamid 5 ; Ola Nada 5 ; Sherine Helmy 6 ; Hanaa Abdel-Maguid 6 ; Richard Colonno 7 ; Nathaniel Brown 7 ; Eric Ruby 7 ; PamelaVig 7 ; ImamWaked 3 1 Cairo Univ, Cairo, Egypt; 2 Cairo Fatemic Hosp, Cairo, Egypt; 3 Natl Liver Inst, Shebeen El Kom, Egypt; 4 Kasr Alaini Viral Hepatitis Cntr, Cairo, Egypt; 5 MyLab Lab, Cairo, Egypt; 6 European Egyptian Pharmaceutical Industries, Alexandria, Egypt; 7 Presidio Pharmaceuticals, San Francisco, CA, USA Background: Egypt has the highest prevalence of hepatitis C infection in the world, of which 90% is due to HCV genotype-4 (gt-4). Increasing HCV-related morbidity in Egypt presents an urgent need for highly curative, safe and affordable therapies. We report results from a Phase 3 registrational trial in Egyptian HCV gt-4 patients, assessing the combination of ravidasvir (RDV), a pan-genotypic HCV NS5A inhibitor, and sofosbuvir (SOF), a nucleotide HCV NS5B polymerase inhibitor, with or without ribavirin (RBV). Methods: Key inclusion criteria were age 18-65 yr, HCV gt-4 infection, serum HCV RNA >4 log10 IU/mL, and absence of decompensated cirrhosis or other causes of liver disease. Patients were enrolled into 3 groups: treatment-naïve non-cirrhotic and cirrhotic, by Fibroscan & FIB-4 score (Group 1); interferon (IFN)-experienced non-cirrhotic (Group 2); and IFN-experienced cirrhotic (Group 3). Groups 1 and 2 were treated with RDV 200 mg QD + SOF 400 mg QD for 12 wk, randomized 1:1 to additional RBV (weight-based) or no RBV. Group 3 patients all received RDV+SOF+RBV and were randomized 1:1 to 12 wk vs.16 wk of treatment. The primary endpoint is sustained virologic response (SVR), defined as serum HCV RNA below the lower limit of detection (LLD <12 IU/mL by the Abbott Real-Time™ PCR assay) at 12 wk post-treatment (SVR12). Results: This study is fully enrolled with 300 patients (150 in Group 1, 80 in Group 2, and 70 in Group 3); 284 patients had completed treatment at the time of this abstract. Study treatment has been generally well tolerated, with one serious adverse event possibly attributed to study drug (transient episode of symptomatic bradycardia). The most common adverse events are headache and fatigue. HCV RNA decreased by ~6 logs in all groups by Wk 1, with 94% of patients HCV RNA undetectable by Wk 4. Of the 265 patients who have reached 4 wk post-treatment, 262 (99%) had RNA Conclusions: To our knowledge, this is the largest IFN-free clinical trial in HCV gt-4 patients. Treatment with RDV+SOF±RBV has been well-tolerated and shows high sustained response rates in a large population of Egyptian patients, regardless of previous treatment status or underlying cirrhosis.

Oral Abstracts

58

CROI 2016