An Intravaginal Ring That Releases the NNRTI MIV-150 Reduces SHIV Transmission in Macaques

MIV-150 is a potent NNRTI that has been previously demonstrated to provide partial protection against vaginal SHIV-RT transmission in macaques when delivered from a vaginal gel. The addition of zinc acetate to the gel significantly boosted its protective potential to 89%. The current study aimed to develop IVRs as an alternative delivery platform for this promising API combination. Silicone IVRs were formulated with 50 mg of MIV-150 and evaluated for in vitro release. Daily release ranged from 111 to 33 mg/day, averaging 54 mg/day with a day 15 median of 45 mg/day. The cumulative amount of MIV-150 released at 29 days was 1410 mg, or 2.8% of the loading dose. The cumulative percentage of MIV-150 released over time exhibited partition-controlled kinetics. The IC50 value of MIV-150 released into SNaC buffer on day 1 was 2.7 nM, whereas MIV-150 released into aqueous ethanol on day 1 had an IC50 value of 0.60 nM. To characterize in vivo release, MIV-150 was quantified in plasma, vaginal swabs, and vaginal and cervical tissues of Depo-Provera-treated macaques that received silicone IVRs for 4 weeks. MIV-150 was below the limit of detection in the plasma 14 and 28 days after IVR insertion. Similar MIV-150 levels were detected in vaginal swabs 14 days (28.5 ± 8.5 ng/ml, 77.0 nM) and 28 days after insertion (22.9 ± 5.6 ng/ml, 61.8 nM). MIV-150 was detected in cervical (0.027 ± 0.006 ng/mg wet tissue) and vaginal (0.008 ± 0.004 ng/mg) biopsies 14 days after insertion, increasing significantly by 28 days. Silicone IVRs reduced infection frequency to 29% (two of seven; 58% reduction in infection compared to three of five infected in the placebo IVR group). This was not statistically significant due to the small number of animals tested. Virus in both infected macaques peaked 3 weeks after infection before declining to a variable set point. There was no difference in average viremia between infected animals that received placebo or MIV-150 IVRs. Plasma viral RNA from infected animals at peak viremia showed none of the 10 most frequent NNRTI-associated resistance mutations. EVA IVRs loaded with MIV-150 were also evaluated for in vitro release. Daily release for the 50-mg IVRs ranged from 238 to 130 mg/day, averaging 163 mg/day with a day 14 median of 151 mg/day. The cumulative amounts of MIV-150 released at 28 days from the 50- and 100-mg EVA-40 IVRs were 4370 mg, or 8.7% of the loading dose, and 5285 mg, or 5.3% of the loading dose, respectively. The in vitro antiviral activity of MIV-150 released from 100-mg EVA-40 IVRs into SNaC buffer and aqueous ethanol confirmed that IVR processing conditions did not affect MIV-150's activity. Active MIV-150 was released from EVA-40 IVRs in vivo. The IC50 value for MIV-150 released into SNaC buffer was 2.8 and 0.5 nM for release into aqueous ethanol. The results demonstrate that MIV-150-releasing IVRs can protect against immunodeficiency virus challenge and support the development of IVRs that release MIV-150 and zinc acetate to prevent HIV and other STIs.