CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

967 MZC Gel Inhibits Ex Vivo HIV-1 and HSV-2 Infection in Human Cervical Mucosa Guillermo Villegas ; Giulia Calenda; Patrick Barnable; Keith Levendosky; Michael Cooney; José Fernández-Romero;Thomas Zydowsky; NataliaTeleshova Population Council, New York, NY, US

Background: The transmission of HIV-1 is increased in the presence of other STIs. Of all ulcerative STIs, HSV-2 most strongly impacts sexual transmission and acquisition of HIV. Microbicide products that protect women against HIV and HSV-2 would make a major contribution to public health globally. The Population Council’s leading microbicide gel (MZC) containing 50 m MMIV-150 (M), 14mM Zinc acetate and Carrageenan (CG) protects against SHIV-RT infection vaginally for up to 8h and rectally for 1h. This study aimed to test activity of MZC against HIV-1/HSV-2 co-infection in human cervical explants. Methods: HIV-1 BaL stock was prepared in the presence of 10 m M retinoic acid and 20U/ml of IL-2 in human PBMCs (RA HIV-1 BaL ). Non-stimulated human ectocervical explants were challenged with 500 TCID 50 RA HIV-1 BaL or co-challenged with 500 TCID 50 RA HIV-1 BaL and 10 6 pfu HSV-2 per explant for ~18h. The viral challenge was performed in the presence of 1:100 and 1:300 diluted MZC (vs. untreated medium, diluted CG and 3TC/Acyclovir controls). The tissues were washed after the ~18h incubation and cultured for 14d. Infections were monitored by one step HIV gag RT-qPCR and HSV-2 pol q PCR on culture supernatants. SOFT and CUM endpoint analyses were performed. Tissue viability post exposure to diluted gels was tested using MTT assay. Log-normal generalized linear mixed models were used for data analysis. Results: Tissue challenge with RA HIV-1 BaL and HSV-2 resulted in robust infection of non-stimulated tissue with both viruses (single RA HIV-1 Bal challenge and co-challenge). MZC (1:100 and 1:300 dilutions) significantly inhibited RA HIV-1 BaL infection (vs. medium control) in the single challenge and in the co-challenge models (p<0.0001 and p<0.001, respectively). RA HIV-1 BaL infection level decreased in CG treated tissues (vs. medium control) probably due to a barrier effect (only single challenge; p<0.001 for 1:100 dilution only). Both MZC and CG gels (1:100) strongly inhibited HSV-2. The gel formulations did not decrease tissue viability. Conclusions: MZC is active against RA HIV-1 BaL in the single challenge model and under stringent conditions of co-challenge with HSV-2 in human ectocervical mucosa. MZC provides CG-mediated activity against high dose HSV-2 challenge. These results highlight the promise for further development of MZC as a microbicide and support the ongoing Phase 1 testing of vaginal MZC. 968 GRFT/Carrageenan Gel Inhibits SHIV-RT and HSV-2 Infection in Macaque Vaginal Mucosa Giulia Calenda 1 ; Patrick Barnable 1 ; Keith Levendosky 1 ; Kyle Kleinbeck 1 ; Agegnehu Gettie 2 ; James Blanchard 4 ; José Fernández-Romero 1 ; Barry O’Keefe 3 ;Thomas Zydowsky 1 ; NataliaTeleshova 1 1 Population Council, New York, NY, US; 2 Aaron Diamond AIDS Research Center, New York, NY, US; 3 National Cancer Institute (NCI), Fredrick, MD, US; 4 Tulane University, Covington, LA, US Background: Griffithsin (GRFT) is a lectin with broad antiviral activity, including anti-HIV and anti-HSV-2 activities. The antiviral properties and excellent safety profile have favored GRFT for development as a potential microbicide to prevent HIV/HSV-2 acquisition. Here we tested the safety and antiviral activity of GRFT against ex vivo cell-free SHIV-RT, SHIV-RT/HSV-2 co-challenge and cell-associated SHIV-RT in macaque vaginal mucosa. Methods: Unformulated GRFT and 0.1% G RFT formulated in C arrageenan ( GC ) were tested (vs. medium and carrageenan (C) alone) in macaque vaginal explants. PHA/IL-2 stimulated explants were co-challenged with 10 4 TCID 50 SHIV-RT and 10 6 pfu HSV-2 or SHIV-RT only for ~18h in the presence GC diluted 1:100-1:300 (3.93-1.31 m M GRFT) or unformulated GRFT (0.0001-10 μ M) or tissues were challenged up to 4d post gel/API washout. Alternatively, SHIV-RT-infected PBMCs (10 3 cells/explant) were used as virus inoculum in a cell-associated challenge model. The tissues were washed, cultured for 14d and infections were monitored by SIV gag one step RT-qPCR and HSV-2 pol PCR. SOFT and CUM endpoint analyses were performed. Tissue viability post exposure to unformulated GRFT and neat/diluted gels was tested (MTT). Tissue integrity was examined post neat gel exposure (H&E staining). Log-normal linear generalized mixed models were used for analysis. Results: 0.1-10 m M and 1-10 m M GRFT inhibited SHIV-RT when present at the time of single SHIV-RT challenge and 24h post API washout (p<0.01). GC (up to 1:300 dilution) present at the time of co-challenge inhibited SHIV-RT (p<0.0001 vs. medium control and CG). GC (1:100) inhibited SHIV-RT when tissues were co-challenged up to 4d post gel exposure (p<0.01). GC and C (1:100) present at the time of viral co-challenge (but not post wash out) inhibited HSV-2 (p<0.01). 0.1-10 m M GRFT and GC (1:300) present at the time of challenge strongly inhibited cell-associated SHIV-RT infection. The unformulated and formulated GRFT were equally effective against SHIV-RT. No histopathological changes and no decreased tissue viability were detected post gel/API exposure. Conclusions: GRFT and GC are highly effective against SHIV-RT and provide post washout activity for 24h and up to 4d, respectively. GRFT and GC are highly effective against cell-associated SHIV-RT. Anti-HSV-2 activity of GC was mediated by the carrageenan component. Our data support the notion that GRFT is a strong microbicide candidate for further advancement. 2:30 pm– 4:00 pm PrEP: Uptake 969 Sustained PrEP Use Among High-Risk African HIV Serodiscordant Couples Participating in a PrEP Demonstration Project Renee Heffron 1 ; Kenneth Ngure 2 ; Nulu Bulya Semiyaga 3 ; Josephine Odoyo 4 ; EdnaTindimwebwa 5 ; Jennifer Morton 1 ; Lara Kidoguchi 1 ; Mark A. Marzinke 6 ; Connie Celum 1 ; Jared Baeten 1 Partners Demonstration ProjectTeam 1 University of Washington, Seattle, WA, US; 2 Jomo Kenyatta University of Agriculture and Technology, Nairobi, Kenya; 3 Makerere University College of Health Sciences, Kampala, Uganda; 4 Kenya Medical Research Institute, Nairobi, Kenya; 5 Kabwohe Clinic Research Center, Kabwohe, Uganda; 6 Johns Hopkins University School of Medicine, Baltimore, MD, US Background: Pre-exposure prophylaxis (PrEP) demonstrated high efficacy for HIV prevention in a clinical trial among heterosexual African HIV serodiscordant couples. Assessing uptake and sustained use of PrEP outside of clinical trial settings is an important next step for PrEP implementation. Methods: Between November 2012 and August 2014, high-risk HIV serodiscordant couples were enrolled into an open-label study delivering PrEP and antiretroviral therapy (ART) for HIV prevention in Kenya and Uganda, the Partners Demonstration Project. Quarterly follow up for up to 2 years is ongoing. PrEP is offered to all couples prior to and during the first 6 months after ART initiation by the HIV infected partner, at which time PrEP discontinuation is recommended. Pharmacy refill data and, in a subset, detection of tenofovir in plasma were used to quantify continued use of PrEP. Results: Two-thirds of couples have HIV-uninfected male partners, the median age of HIV-uninfected partners is 30 years (interquartile range: 26-36), and 65% of couples reported unprotected sex in the month prior to enrollment. Overall, 95% initiated PrEP at enrollment and 97% of those attended their first follow-up visit one month after enrolling and continued to use PrEP. For those still in follow-up at 6 and 12 months after enrollment, and for whom the HIV-infected partner had not initiated ART, 91% and 84% TUESDAY, FEBRUARY 24, 2015 Session P-V3 Poster Session Poster Hall

Poster Abstracts

574

CROI 2015