18th Conference on Retroviruses
and Opportunistic Infections (CROI)
27 February–2 March 2011
"An EVA vaginal ring containing the NNRTI MIV-150 protects against SHIV-RT infection in vivo"
Rachel Singer, Nina Derby, Paul Mawson, Jeffrey Lifson, Michael Piatak Jr.,Jose Fernández-Romero, Thomas M. Zydowsky, Agegnehu Gettie, James Blanchard, Melissa Robbiani
Vaginal rings are a promising delivery vehicle for microbicides because they may improve adherence by eliminating the need for daily application and represent a coitally independent protection method. We previously evaluated the use of a silicone ring containing 50 mg of the NNRTI MIV-150 to prevent vaginal transmission of SHIV-RT in rhesus macaques challenged 2 weeks (2 wks) post-ring insertion (PRI). Although the silicone/MIV-150 ring reduced infection from 60 percent (3/5) in the control to 28.6 percent (2/7) in the test group, the difference was not statistically significant. Ethylene-vinyl acetate (EVA) rings have been shown to release MIV-150 better than silicone. In the current study, we formulated 40 percent EVA rings with 100 mg of MIV-150 and compared protection against SHIV-RT when macaques were challenged either 24 hours (24 h) or 2 wks PRI.
Depo-Provera–treated rhesus macaques (n=18) had either EVA/MIV-150 (n=7 each) or EVA/no drug (n=2 each) rings inserted vaginally before being challenged vaginally either 24 h or 2 wks PRI with 103 TCID50 SHIV-RT (SIVmac239 with HIV-1 RT). Infection was determined from plasma virus RNA and SIV-specific antibody (Ab) responses. MIV-150 levels in plasma at various time points were measured by radioimmunoassay. Statistical significance was determined with Fisher's exact test.
In the test groups, 1/7 animals challenged 24 h PRI and 1/7 animals challenged 2 wks PRI became infected (2/14 total, 14.3%). In the control groups, 2/2 animals challenged 24 h PRI and 1/2 animals challenged 2 wks PRI became infected (3/4 total, 75%). SIV RNA and SIV-specific Abs were detected in the plasma of all infected (but not uninfected) animals. These data indicate that EVA/MIV-150 rings provided significant protection (p<0.044) against vaginal SHIV-RT infection. MIV-150 was not detected in the plasma (lower limit of quantification = 2.7nM) 30 min to 72 h PRI.
EVA vaginal rings releasing MIV-150 blocked SHIV infection in macaques and warrant further development for the prevention of HIV infection. Future studies will determine the optimal dose of MIV-150 and timing of ring insertion relative to virus exposure.
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