CROI 2018 Abstract eBook

Abstract eBook

Oral Abstracts

Methods: During phase A (10/1/2015-5/31/2016) we systematically tested all MSM in the SHCS by HCV-RNA PCR. During phase B (6/1/2016-2/28/2017) HCV treatment with the DAA grazoprevir/elbasvir ± ribavirin was offered to all MSM with GT 1 or 4 with the goal to reduce the pool of potential transmitters. Individuals with GT 2 or 3 and individuals not eligible for phase B were treated externally with standard of care DAAs. MSM reporting unprotected sex with occasional partners were asked for participation in a behavioral intervention program during phase B to reduce sexual risk behavior to prevent re-infection. During phase C (3/1/-11/30/2017), we re-tested all MSM in the SHCS by HCV-RNA PCR. Results: During phase A we screened 3’722 out of 4’257 active MSM from the SHCS database (87%) and identified 177 (4.8%) with a replicating HCV infection. Of these 177 infections 31 (18%) were incident (Figure 1A). During phase B we treated 122 out of these 177 replicating infections (69%) within the Swiss HCVree Trial and achieved a SVR12 of 99%. 39 infections (22%) were treated externally using standard of care DAAs (SVR 12 100%). Re-screening of 3’723 MSM during phase C identified 28 infections (0.8%), of them 16 were incident. The remaining 12 infections were chronic infections not treated during phase A. Of the 28 infections identified during phase C, 22 patients (79%) started DAA before end of period C. Overall, we identified and treated 183 out of 206 replicating infections (89%) during phase A and C within and outside the Swiss HCVree Trial (Figure 1B). Of 68 MSM eligible for the behavioral intervention program, 51 (75%) agreed to participate and 46 (68%) completed the program. Conclusion: A systematic, population based HCV RNA screening approach among HIV+MSM from the SHCS identified a high number of potential HCV spreaders. Treatment initiation in 89% of individuals with replicating HCV reduced incident HCV infections by 50% during the study. A systematic population based screening followed by prompt treatment of identified infections combined with a strong behavioral intervention can serve as a model to reach WHO elimination targets by 2030 in HIV/HCV co-infected MSM.

plasma viral load assay. Three control macaques were challenged similarly. All study macaques received DMPA (30mg) intramuscularly at 2 weeks before the first SHIV challenge (corresponding to 1 week before bNAb injection in treatment groups), and every 4 weeks thereafter to normalize SHIV susceptibility. Longitudinal plasma samples were assayed to determine bNAb concentrations. Results: Maximum bNAb concentrations were observed in plasma at 1 week post-administration. Mean Cmax for 10-1074 (38.8ug/ml) was ~6 times as high as 3BNC117 (6.5ug/ml; P=0.001, t-test). Estimated plasma half-life of 3BNC117 (t 1/2 = 10.7+/-2.9 days) was similar to 10-1074 (t 1/2 = 8.4+/-1.9 days). Macaques administered 3BNC117 alone exhibited significantly delayed SHIV acquisition (median of 5 challenges to infection vs 2 in untreated controls, P=0.002, Log-rank test). Initial detection of SHIV viremia correlated with plasma 3BNC117 levels ≤0.8ug/ml (mean = 0.5+/-0.2 ug/ml). Animals that received 10-1074 in combination with 3BNC117 exhibited significantly greater protection against SHIV acquisition (median 11.5 challenges) compared to 3BNC117-alone (P=0.0005) or to untreated controls (P=0.002, Log-rank test). In this group, first SHIV acquisition corresponded to a plasma 10-1074 level <0.4ug/ml, at which time 3BNC117 was undetectable in all animals. Conclusion: One subcutaneous administration of 3BNC117 singly, or in combination with 10-1074, conferred significant protection in macaques against repeated vaginal challenges with SHIV. The greater protection observed in the 2-bNAb group appears due to the longer persistence of 10-1074. 1 CDC, Atlanta, GA, USA, 2 ViiV Healthcare, Research Triangle Park, NC, USA Background: Cabotegravir long-acting (CAB LA) is an investigational HIV integrase inhibitor that is currently in clinical development as a PrEP agent. In pre-clinical proof-of-concept studies in macaques, CAB LA was highly effective against rectal, vaginal, and intravenous infection with simian HIV (SHIV). Penile transmission accounts for nearly one-half of all HIV infections globally, and whether CAB LA can also protect against this important route has not been adequately addressed primarily due to the lack of a validated in vivo model of penile transmission. Here we used a novel macaque model of repeated penile SHIV exposures to investigate the efficacy of CAB LA against penile infection. Methods: Rhesus macaques (n=22) were exposed once a week (up to 12 weeks) to low doses of SHIV162p3 administered into the foreskin pouch (200 TCID50) and urethra (16 TCID50). Of these, 6 received CAB LA (50 mg/kg) and 10 received no drug. CAB LA was administered intramuscularly every 4 weeks to sustain plasma drug levels above 4 times the protein-adjusted IC90 (4xPA-IC90) to model plasma concentrations in humans treated with CAB (600 mg) every 8 weeks. For model validation, an additional group of 6 macaques received oral FTC/TDF (20/22 mg/kg) 24h before and 2h after each penile SHIV exposure. Infection was monitored weekly by PCR amplification of SHIV RNA in plasma. Plasma CAB levels were measured weekly by HPLC. Results: All 10 controls were infected after a median of 3 penile SHIV exposures (range=1-12). In contrast, 5 of 6 animals that received CAB LA were SHIV negative during 12 penile challenges and remain aviremic 5 weeks after the last challenge (estimated efficacy of 94%, p=0.0003). Plasma CAB concentrations during the challenge period (median = 2,175 ng/ml, range = 303-5,025) remained above the 4xPA-IC90 (664 ng/ml) in all 5 protected animals. Plasma CAB levels in the breakthrough infection fell below the 4xPA-IC90 at weeks 4, 8, and the week prior to detecting SHIV RNA in plasma (week 12). Consistent with clinical efficacy in men, oral FTC/TDF was highly protective with 5 of 6 animals uninfected after 12 SHIV challenges (estimated efficacy of 94%, p=0.0007). Conclusion: Monthly injections of CAB LA was as effective as oral FTC/ TDF in a macaque model of penile SHIV infection that mimics high-risk HIV exposures in men. The high efficacy by CAB LA was related to high plasma drug concentrations that remained above 4xPA-IC90. These data support advancement of CAB LA as a PrEP candidate for men. Charles Dobard 1 , Natalia Makarova 1 , Kenji Nishiura 1 , Mara Sterling 1 , Chuong Dinh 1 , James Mitchell 1 , David A. Garber 1 , William Spreen 2 , Walid Heneine 1 , Gerardo Garcia-Lerma 1

Oral Abstracts

83 LONG-ACTING CABOTEGRAVIR PROTECTS MACAQUES AGAINST REPEATED PENILE SHIV EXPOSURES

82 PROTECTION AGAINST REPEATED VAGINAL SHIV CHALLENGES BY BNAB 3BNC117 AND 10-1074 David A. Garber 1 , Debra Adams 1 , James Mitchell 1 , Shanon Ellis 1 , Till Schoofs 2 , Michael S. Seaman 3 , Janet McNicholl 1 , Michel Nussenzweig 2 , Walid Heneine 1 1 CDC, Atlanta, GA, USA, 2 The Rockefeller University, New York, NY, USA, 3 Beth Israel Deaconess Medical Center, Boston, MA, USA Background: Passive immunization using highly potent broadly neutralizing antibodies (bNAbs) against HIV is a promising strategy for pre-exposure prophylaxis. In preclinical models, bNAbs 3BNC117 and 10-1074, which target the CD4 binding site and V3 glycan supersite on HIV Env, respectively, have been shown to protect macaques against rectal SHIV challenge. Here we compared the protective efficacy of a single subcutaneous injection of these antibodies against repeated vaginal SHIV challenges in macaques. Methods: Groups of six female rhesus macaques were injected subcutaneously once with either a single bNAb (3BNC117, 10mg/kg) or two bNAbs (3BNC117 and 10-1074, 10mg each/kg) and repeatedly challenged (once weekly) intravaginally with 300 TCID 50 SHIV AD8-EO , until systemic SHIV infection was confirmed via a

30

CROI 2018