title: The nonnucleoside reverse transcription inhibitor MIV-160 delivered from an intravaginal ring, but not from a carrageenan gel, protects against simian/human immunodeficiency virus-RT Infection.
abstract: We previously showed that a carrageenan (CG) gel containing 50 μM MIV-150 (MIV-150/CG) reduced vaginal simian/human immunodeficiency virus (SHIV)-RT infection of macaques (56%, p>0.05) when administered daily for 2 weeks with the last dose given 8 h before challenge. Additionally, when 100 mg of MIV-150 was loaded into an intravaginal ring (IVR) inserted 24 h before challenge and removed 2 weeks after challenge, >80% protection was observed (p<0.03). MIV-160 is a related NNRTI with a similar IC(50), greater aqueous solubility, and a shorter synthesis. To objectively compare MIV-160 with MIV-150, herein we evaluated the antiviral effects of unformulated MIV-160 in vitro as well as the in vivo protection afforded by MIV-160 delivered in CG (MIV-160/CG gel) and in an IVR under regimens used with MIV-150 in earlier studies. Like MIV-150, MIV-160 exhibited potent antiviral activity against SHIV-RT in macaque vaginal explants. However, formulated MIV-160 exhibited divergent effects in vivo. The MIV-160/CG gel offered no protection compared to CG alone, whereas the MIV-160 IVRs protected significantly. Importantly, the results of in vitro release studies of the MIV-160/CG gel and the MIV-160 IVR suggested that in vivo efficacy paralleled the amount of MIV-160 released in vitro. Hundreds of micrograms of MIV-160 were released daily from IVRs while undetectable amounts of MIV-160 were released from the CG gel. Our findings highlight the importance of testing different modalities of microbicide delivery to identify the optimal formulation for efficacy in vivo.
authors: Population Council, New York, New York, USA.
authors: Meropi
authors: M
authors: Aravantinou
authors: Rachel
authors: R
authors: Singer
authors: Nina
authors: N
authors: Derby
authors: Giulia
authors: G
authors: Calenda
authors: Paul
authors: P
authors: Mawson
authors: Ciby J
authors: CJ
authors: Abraham
authors: Radhika
authors: R
authors: Menon
authors: Samantha
authors: S
authors: Seidor
authors: Daniel
authors: D
authors: Goldman
authors: Jessica
authors: J
authors: Kenney
authors: Guillermo
authors: G
authors: Villegas
authors: Agegnehu
authors: A
authors: Gettie
authors: James
authors: J
authors: Blanchard
authors: Jeffrey D
authors: JD
authors: Lifson
authors: Michael
authors: M
authors: Piatak
authors: José A
authors: JA
authors: Fernández-Romero
authors: Thomas M
authors: TM
authors: Zydowsky
authors: Natalia
authors: N
authors: Teleshova
authors: Melissa
authors: M
authors: Robbiani
mesh_terms: D000282:Administration, Intravaginal; D000285:Administration, Rectal; D000818:Animals; D002351:Carrageenan / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D006801:Humans; D008253:Macaca mulatta; D011725:Pyridines / Q000494:pharmacology; D012007:Rectum / Q000187:drug effects* / Q000473:pathology / Q000821:virology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D016896:Treatment Outcome; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D014621:Vagina / Q000187:drug effects* / Q000473:pathology / Q000821:virology
chemical_list: D004791:Enzyme Inhibitors; C510296:MIV 150; C580640:MIV-160; D011725:Pyridines; D013844:Thiazoles; D014508:Urea; D002351:Carrageenan; D054303:HIV Reverse Transcriptase; D013890:Thiourea