CROI 2018 Abstract eBook

Abstract eBook

Oral Abstracts

84 GRIFFITHSIN/CARRAGEENAN INSERTS PREVENT SHIV, HSV-2, AND HPV INFECTIONS IN VIVO Nina Derby 1 , Manjari Lal 2 , Meropi Aravantinou 1 , Larisa Kizima 1 , Patrick Barnable 1 , Aixa Rodriguez 1 , Manshun Lai 2 , Asa Wesenberg 1 , Shweta Ugaonkar 1 , Brooke Grasperge 3 , James Blanchard 3 , Agegnehu Gettie 4 , Natalia Teleshova 1 , Jose A. Fernandez-Romero 5 , Thomas M. Zydowsky 1 1 Population Council, New York, NY, USA, 2 PATH, Seattle, WA, USA, 3 Tulane National Primate Research Center, Covington, LA, USA, 4 Aaron Diamond AIDS Research Center, New York, NY, USA, 5 Borough of Manhattan Community College, New York, NY, USA Background: Griffithsin (GRFT) is a potent HIV entry inhibitor (EC 50 = 1.6 ng/ ml in vitro). We have demonstrated that the GRFT/carrageenan (CG) combination provides synergistic antiviral activity against herpes simplex virus (HSV) and inhibits human papillomavirus (HPV). Methods: The pharmacokinetics (PK) and antiviral efficacy of GRFT/CG fast dissolving inserts (FDIs) were examined in mice (PK and efficacy against HSV-2 and HPV) and rhesus macaques (RMs, for PK and efficacy against SHIV). Mouse-sized (0.1 mg GRFT, 0.3 mg CG) and RM-sized (1 mg GRFT, 3 mg CG) FDIs were inserted vaginally in depot medroxyprogesterone acetate (DMPA)-treated animals. In PK studies, vaginal fluid (VF, frommice and RMs) and plasma (from RMs) were collected at baseline and different time-points following FDI insertion. GRFT was quantified by ELISA. For efficacy testing, the same formulations in addition to placebo controls (hydroxyethyl cellulose or CG only) were evaluated in highly stringent vaginal models (SHIV-SF162P3 in RMs, HSV-2 and HPV16 PsV in mice). Formulations were applied vaginally 4 hours before virus challenge in each model. Statistical significance was assessed by Fisher’s exact test (SHIV and HSV-2) and Mann Whitney U test (HPV). Results: The GRFT/CG FDIs significantly protected RMs against SHIV-SF162P3 infection: 8/10 uninfected RMs in the GRFT/CG group vs. 0/10 uninfected in the CG group, 80% protection, p=0.0003 vs. CG. Similarly, the GRFT/CG FDIs protected mice (6 mice per formulation) against HSV-2 (60-73% uninfected in the GRFT/CG FDI group, p <0.0052 vs. placebo) and HPV PsV (100% uninfected in the GRFT/CG FDI group, p<0.0001 vs. placebo). GRFT was not detected in RM plasma. GRFT concentrations above 2 μg/mL (270x the EC 90 ) were found in both mouse and RM VF 4 hours after FDI insertion. Conclusion: GRFT/CG FDIs showed potent and broad spectrum in vivo activity against three incurable viral pathogens. The FDIs significantly protected RMs from SHIV-SF162P3 and mice from HSV-2 and HPV16 PsV infections, showing excellent safety profiles at 4 hours post dosing. These data support the further preclinical and clinical development of GRFT/CG FDIs. 85 ORAL FTC/TAF COMBINATION PREVENTS VAGINAL SHIV INFECTION IN PIGTAIL MACAQUES Ivana Massud 1 , Mian-er Cong 1 , Susan Ruone 1 , James Mitchell 1 , Frank Deyounks 1 , Angela Holder 1 , Chuong Dinh 1 , James F. Rooney 2 , Darius Babusis 2 , Yeojin Park 2 , Scott McCallister 2 , Christian Callebaut 2 , Walid Heneine 1 , Gerardo Garcia-Lerma 1 1 CDC, Atlanta, GA, USA, 2 Gilead Sciences, Inc, Foster City, CA, USA Background: Tenofovir alafenamide (TAF) is a novel tenofovir prodrug with improved properties relative to tenofovir disoproxil fumarate (TDF) that makes it an attractive candidate for PrEP. We recently showed that the combination of TAF and emtricitabine (FTC) was highly effective in preventing rectal simian HIV (SHIV) infection in rhesus macaques. Here we investigated the efficacy of FTC/ TAF against vaginal SHIV infection Methods: The pharmacokinetic profile of TAF was studied at first dose. Tenofovir (TFV) was measured in plasma and vaginal and rectal secretions. Intracellular tenofovir di-phosphate (TFV-DP) and FTC-triphosphate (FTC-TP) were measured in PBMCs and/or rectal and vaginal biopsies. The efficacy of FTC/ TAF in preventing vaginal infection was investigated using an established model of vaginal SHIV exposure consisting of up to 16 once-weekly virus challenges with 50 TCID50 of SHIV162p3. Six macaques received FTC/TAF (20 and 1.5 mg/ kg, respectively) orally 24h before and 2h after each weekly virus exposure and 5 received placebo. Infection was monitored by serology and RT-PCR. Results: As observed in humans, plasma TFV levels with 1.5 mg/kg of TAF were low (Cmax = 17 [5-42] ng/ml). In PBMCs, TFV-DP concentrations peaked at 5-24 hr (median = 154 [34-295] fmol/106cells) and gradually declined with a half-life of 38 (33-122) hr. TFV exposure in vaginal fluids (AUC0-24h = 2,001 [216-11,569] ng*h/mL) was lower than in rectal fluids (17,205 [216-313,122] ng*h/mL) although the difference was not statistically significant (p = 0.38). 24h after dosing, TFV-DP levels in vaginal and rectal tissues were similar (9 [6-10] and

11 [7-19]) fmol/mg, respectively, p = 0.25). All 5 untreated controls exposed vaginally to SHIV were infected after a median of 5 [2-14] exposures. In contrast, 5 of the 6 animals that received FTC/TAF remained uninfected after 16 virus challenges (p = 0.012 log-rank test). All the protected animals had detectable TFV-DP and FTC-TP in PBMCs (median = 237 [123-829] and 1837 [1256-2653] fmols/106 cells, respectively) at the time of virus exposure. In contrast, the PrEP breakthrough animal only had detectable FTC-TP (median=1499 fmols/106 cells). Conclusion: A clinically equivalent dose of FTC/TAF administered orally to macaques 24h before and 2h after vaginal SHIV exposure prevented infection to a degree similar to that previously observed with FTC/TDF. These results support the evaluation of FTC/TAF for PrEP against vaginal HIV infection. 86 BY RACE/ETHNICITY, BLACKS HAVE HIGHEST NUMBER NEEDING PrEP IN THE UNITED STATES, 2015 Dawn K. Smith , Michelle Van Handel, Jeremy A. Grey CDC, Atlanta, GA, USA Background: To effectively measure progress in delivering PrEP, it is necessary to have national and subnational estimates of the number of persons with indications for its use that account for racial/ethnic disparities and differences in HIV infection rates by transmission risk group (risk group). Methods: We used data on new HIV diagnoses and population-based estimates of risk group size to derive estimated numbers of persons with indications by jurisdiction. For each jurisdiction, we multiplied the estimated number of men who have sex with men (MSM) by the proportion of MSM with indications to calculate the number of MSM with indications. For heterosexually active adults (HET) and persons who inject drugs (PWID), we calculated ratios of the numbers of HIV diagnoses in 2015 attributed to HET or PWID to the number attributed to MSM. The ratios were multiplied by the number of MSM with indications to calculate the numbers of HET and PWID with indications. Proportions of HIV diagnoses in 2015 by race/ethnicity or sex (HET only) were multiplied by estimates for each risk group to calculate numbers with indications by risk group, race/ethnicity and sex. We summed subnational estimates to produce national estimates. Results: Nationally, an estimated 1.1 million persons had indications in 2015, of whom 500,340 were black (44%), 303,230 were white, 282,260 were Hispanic/ Latino (Latino), and 58,720 were of other race/ethnicities (Table). Of 813,970 MSM (71% of total) with indications, 38%were black, 29%were white, and 27%were Latino. Of 258,080 HET with indications, 64%were black, 18%were Latino, and 14%were white; while 68% (176,670) were female and 32%were male. Among 72,510 PWID with indications, 39%were white, 37%were black, and 21%were Latino. States in the South and DC had the highest proportions of blacks with indications. Conclusion: Blacks comprised the highest number of persons with PrEP indications overall and among MSM and HET. In light of other studies showing that PrEP use is low in black persons, these findings strongly support the highest priority for increasing awareness of, access to, and utilization of PrEP by this group. All MSM, and especially black MSM, must remain a high priority for PrEP delivery because of their high numbers compared to other risk groups. Use of these estimates as denominators will allow for the assessment of PrEP coverage and impact on HIV incidence by race/ethnicity and risk group over time at subnational levels.

Oral Abstracts

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CROI 2018