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.
Highlights
The annual number of new HIV infections continues to decline, the global HIV-1 pandemic remains an unprecedented public health problem, with 2.1 million new infections in 2013 and an estimated 35 million people already infected [1]
pre-exposure prophylaxis (PrEP) has been shown to reduce the risk of HIV infection by up to 92% in people who are at high risk
We combined the highly efficient encapsulation of antiretroviral drugs into nanoparticles with a thermosensitive gel that remains liquid at room temperature and solidifies at body temperature
Summary
The annual number of new HIV infections continues to decline, the global HIV-1 pandemic remains an unprecedented public health problem, with 2.1 million new infections in 2013 and an estimated 35 million people already infected [1]. This highlights the urgent need for effective and safe prevention strategies for HIV infection. To improve adherence and PrEP efficacy, several strategies are being considered These include effective antiretrovirals, administered in single topical or systemic dose pericoitally, and long-acting ARV formulations that release drugs over many weeks systemically, requiring infrequent parenteral administration [6,7,8]
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