Long‐acting and extended‐release implant and nanoformulations with a synergistic antiretroviral two‐drug combination controls HIV‐1 infection in a humanized mouse model. Issue 1 (26th June 2021)

• Record Type: Journal Article
• Authors: Beloor, Jagadish; Kudalkar, Shalley N.; Buzzelli, Gina; Yang, Fan; Mandl, Hanna K.; Rajashekar, Jyothi K.; Spasov, Krasimir A.; Jorgensen, William L.; Saltzman, W. Mark; Anderson, Karen S.; Kumar, Priti
• Is Part Of: Bioengineering & translational medicine. Volume 7:Issue 1(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-06-26
• Subjects: Compound I -- drug synergy -- EFdA -- HIV -- humanized mice -- implants -- long‐acting formulations -- nanoformulations -- pharmacokinetics; Bioengineering -- Periodicals; Drug development -- Periodicals; Drugs -- Testing -- Periodicals; 660.6
• DOI: 10.1002/btm2.10237
• Languages: English
• ISSNs: 2380-6761

Abstract

Abstract: The HIV pandemic has affected over 38 million people worldwide with close to 26 million currently accessing antiretroviral therapy (ART). A major challenge in the long‐term treatment of HIV‐1 infection is nonadherence to ART. Long‐acting antiretroviral (LA‐ARV) formulations, that reduce dosing frequency to less than once a day, are an urgent need that could tackle the adherence issue. Here, we have developed two LA‐ART interventions, one an injectable nanoformulation, and the other, a removable implant, for the delivery of a synergistic two‐drug ARV combination comprising a pre‐clinical nonnucleoside reverse transcriptase inhibitor (NNRTI), Compound I, and the nucleoside reverse transcriptase inhibitor (NRTI), 4′‐ethynyl‐2‐fluoro‐2′‐deoxyadenosine. The nanoformulation is poly(lactide‐ co ‐glycolide)‐based and the implant is a copolymer of ω‐pentadecalactone and p‐ dioxanone, poly(PDL‐ co ‐DO), a novel class of biocompatible, biodegradable materials. Both the interventions, packaged independently with each ARV, released sustained levels of the drugs, maintaining plasma therapeutic indices for over a month, and suppressed viremia in HIV‐1‐infected humanized mice for up to 42 days with maintenance of CD4 + T cells. These data suggest promise in the use of these new drugs as LA‐ART formulations in subdermal implant and injectable mode.