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EVG, TAF, and FTC in Nanoparticles Control HIV in Humanized Mice
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ICAAC 2016, June 16-20, 2016, Boston
Mark Mascolini
Nanoparticles containing elvitegravir, tenofovir alafenamide (TAF), and emtricitabine (FTC) injected four times over 7 weeks suppressed viremia in mice with a functional human immune system in a study at Creighton University and the University of Nebraska-Lincoln [1]. Viral loads remained undetectable for 3 weeks after dosing stopped.
A long-acting injectable coformulation of the integrase inhibitor cabotegravir and the nonnucleoside rilpivirine is about to begin phase 3 trials in humans. Stribild, an oral coformulation of the integrase inhibitor elvitegravir boosted by cobicistat plus tenofovir/emtricitabine is a recommended first-line once-daily regimen. Independently of Gilead Sciences, Stribild's maker, a Creighton/University of Nebraska team formulated nanoparticles loaded with elvitegravir, TAF, and FTC and tested them in humanized bone marrow, liver, thymus (huBLT) mice, which have a functional human immune system.
The study involved 12 huBLT mice infected with intravaginal doses of two HIV transmission/founder viruses from acutely infected people. The researchers measured plasma viral loads 2 weeks after inoculation, when antiretroviral treatment began, then every 2 weeks. Six mice received subcutaneous injections of nanoparticles containing 200 mg/kg elvitegravir, 200 mg/kg TAF, and 100 mg/kg FTC, and six control mice received injections containing no antiretrovirals. Starting 3 weeks after HIV inoculation, all mice received an injection every 2 weeks for the first three doses then a fourth dose 1 week after the third dose. The researchers measured plasma viral load every other week for 10 weeks. On alternate weeks they measured trough concentrations of elvitegravir, tenofovir, and FTC.
Drug entrapment efficiency in nanoparticles averaged 45% for elvitegravir, 40% for TAF, and 62% for FTC. Pretreatment viral loads averaged 1.2 x 10(4) copies/mL in treated mice and 1.7 x 10(5) copies/mL in control mice. In control animals, viral loads stayed high throughout dosing. In mice injected with antiretroviral-loaded nanoparticles, viral load began to drop after the first injection and continued to fall with subsequent injections. After four doses all antiretroviral-treated mice had an undetectable viral load (below 800 copies/mL), whereas viremia averaged 1.7 x 10(6) copies/mL in control mice (P = 0.03). Viral loads remained undetectable in antiretroviral-treated mice for 3 weeks after the last dose.
In antiretroviral-treated mice, trough concentrations of elvitegravir, tenofovir, and FTC lay around 100 ng/g of tissue or higher in lymph nodes. Elvitegravir and tenofovir trough concentrations lay around 10 ng/g in female reproductive tract tissue. And tenofovir and FTC troughs lay around the same level in liver.
The researchers believe their ability to encapsulate the three antiretrovirals "into a nanoparticle formulation with good entrapment efficiency [allowing] nanoparticle administration for a three-drug regimen in a 500-mg/kg dose is novel."
Reference
1. Mandal S, Kang G, Yuan Z, Lu W, Prathipali PK, Li Q, Destache CJ. Combination antiretroviral (cARV) drug loaded nanoparticles (NPs) are efficacious in humanized (Hu-BLT) mice. ICAAC 2016, June 16-20, 2016, Boston. Abstract Sunday-408.
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