Nanoformulations of Rilpivirine for Topical Pericoital and Systemic Coitus-Independent Administration Efficiently Prevent HIV Transmission.
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.
Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, United States of America.
Martina
M
Kovarova
Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, United States of America.
Olivia D
OD
Council
Department of Pharmacy Practice, Creighton University School of Pharmacy and Health Professions, Omaha, Nebraska, United States of America.
Abhijit A
AA
Date
Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, United States of America.
Julie M
JM
Long
Tomonori
T
Nochi
Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, United States of America.
Tomonori
T
Nochii
Department of Pharmacy Practice, Creighton University School of Pharmacy and Health Professions, Omaha, Nebraska, United States of America.
Michael
M
Belshan
Department of Pharmacy Practice, Creighton University School of Pharmacy and Health Professions, Omaha, Nebraska, United States of America.
Annemarie
A
Shibata
Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, United States of America.
Heather
H
Vincent
Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, United States of America.
Caroline E
CE
Baker
Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, United States of America.
William O
WO
Thayer
Janssen Research and Development, Beerse, Belgium.
Guenter
G
Kraus
Janssen Research and Development, Beerse, Belgium.
Sophie
S
Lachaud-Durand
Janssen Research and Development, Beerse, Belgium.
Peter
P
Williams
Department of Pharmacy Practice, Creighton University School of Pharmacy and Health Professions, Omaha, Nebraska, United States of America.
Christopher J
CJ
Destache
Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, United States of America.
J Victor
JV
Garcia
D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D015658:HIV Infections / Q000517:prevention & control* / Q000635:transmission; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage; D000068696:Rilpivirine / Q000008:administration & dosage*; D014622:Vaginal Creams, Foams, and Jellies / Q000494:pharmacology
D019380:Anti-HIV Agents; D014622:Vaginal Creams, Foams, and Jellies; D000068696:Rilpivirine