Nanoformulations of Rilpivirine for Topical Pericoital and Systemic Coitus-Independent Administration Efficiently Prevent HIV Transmission

Abstract

Vaginal HIV transmission accounts for the majority of new infections worldwide. Currently, multiple efforts to prevent HIV transmission are based on pre-exposure prophylaxis with various antiretroviral drugs. Here, we describe two novel nanoformulations of the reverse transcriptase inhibitor rilpivirine for pericoital and coitus-independent HIV prevention. Topically applied rilpivirine, encapsulated in PLGA nanoparticles, was delivered in a thermosensitive gel, which becomes solid at body temperature. PLGA nanoparticles with encapsulated rilpivirine coated the reproductive tract and offered significant protection to BLT humanized mice from a vaginal high-dose HIV-1 challenge. A different nanosuspension of crystalline rilpivirine (RPV LA), administered intramuscularly, protected BLT mice from a single vaginal high-dose HIV-1 challenge one week after drug administration. Using transmitted/founder viruses, which were previously shown to establish de novo infection in humans, we demonstrated that RPV LA offers significant protection from two consecutive high-dose HIV-1 challenges one and four weeks after drug administration. In this experiment, we also showed that, in certain cases, even in the presence of drug, HIV infection could occur without overt or detectable systemic replication until levels of drug were reduced. We also showed that infection in the presence of drug can result in acquisition of multiple viruses after subsequent exposures. These observations have important implications for the implementation of long-acting antiretroviral formulations for HIV prevention. They provide first evidence that occult infections can occur, despite the presence of sustained levels of antiretroviral drugs. Together, our results demonstrate that topically- or systemically administered rilpivirine offers significant coitus-dependent or coitus-independent protection from HIV infection.

Advancements in nano-enabled therapeutics for neuroHIV management

“…The sustained release of anti-HIV drug significantly reduced the HIV infection level in the GALT, compared to the free drug. 26 Recently, nanomedicine technology has been explored to improve the efficacy of LA Rpv via developing an NF for pericoital and coitus-independent HIV infection therapeutics, demonstrated by Kovarova et al 27 In this research, the authors binded Rpv with poly(lactic-coglycolic acid) nanoparticles and encapsulated them with a thermosensitive gel for delivery purpose. This NF, considered as solid nanosuspension of LA Rpv, was administrated intramuscularly in the bone marrow-liver-thymus mice.…”

“…Thus, implication of LA Rpv for HIV therapeutics is crucial and can be achieved by infecting such developed LA Rpv-based NF. 27 To manage HIV-1 infection in the brain, significant efforts must be made to deliver this NF to the CNS. Numerous reports confirm that navigation across the BBB depends on the properties of NCs and NFs.…”

HIV pre-exposure prophylaxis for women and infants prevents vaginal and oral HIV transmission in a preclinical model of HIV infection

“…All samples were stored at 2808C until analysis. were generated as previously described 25,28 and titred on TZM-bl cells (NIH AIDS Research and Reference Reagent Program) to quantify the number of tissue culture infectious units (TCIU)/mL.…”

A Shot in the Arm for HIV Prevention? Recent Successes and Critical Thresholds

“…32,33 Although this approach has considerable promise, there are drawbacks. First, the release of drugs from the sustained release formulations is asymmetric: initially, too much drug is released and essentially wasted and has the potential for increased adverse effects.…”

“…Two recently published studies highlight this potential problem. 33,39 In one, rhesus macaques appeared to be protected from multiple vaginal high dose viral challenge by an injectable nanoformulation of cabotegravir. However, when systemic levels of the drug dipped below therapeutic levels, systemic infection emerged in one of the animals months after the last viral challenge.…”