**12. Intravaginal rings**

PrEP using intravaginal rings (IVR) with antiretroviral drugs, is emerging as a promising strategy for the prevention of sexual HIV-1 infection [274]. The use of IVR as controlled release strategy of antiretroviral drugs may improve adherence to PrEP, and provide sustained mucosal levels independent of coitus and daily dosing [275]. The delivery of two or more antiretroviral drugs from conventional IVR designs involves significant technological and manufacturing challenges [276]. Recently, an IVR was developed which allows the release of multiple agents over a wide range of target delivery rates and aqueous solubilities [277-279]. Researchers have evaluated the pharmacokinetics of IVR containing five drugs as a proof-ofconcept, described as advanced multipurpose prevention technology, which combines three antiretroviral drugs from different mechanistic classes (tenofovir, nevirapine, and saquinavir) with a proven estrogen-progestogen contraceptive for prevention of HIV-1 infection and unintended pregnancy [280, 281]. Studies with IVR delivering TDF and emtricitabine, as well as a triple-combination IVR delivering TDF, emtricitabine, and selzentry are in progress for safety and pharmacokinetics evaluation. Preliminary results show that no adverse events were observed, although certain toxicological findings were observed. Mild-to-moderate increases in inflammatory infiltrates were observed in the vaginal tissues of some animals in both the presence and absence of IVR [277-281]. New perspectives and challenges are open for the development of IVR delivering multiple drugs, to ensure the safety and efficacy for the prevention of HIV-1 infection [279-281].
