Recent Publications - HIV

Predicting pharmacokinetics of a tenofovir alafenamide subcutaneous implant using PBPK modelling

Date: 
5/18/20
Citation: 

Rajoli RKR, Demkovich ZR, Flexner C, Owen A, Siccardi M. Predicting pharmacokinetics of a tenofovir alafenamide subcutaneous implant using PBPK modelling. Antimicrob Agents Chemother. 2020 May 18:AAC.00155-20. doi: 10.1128/AAC.00155-20. PMID: 32423957.

Long-acting (LA) administration using a subcutaneous (SC) implant presents opportunities to simplify administration of antiretroviral drugs, improve pharmacological (PK) profile and overcome sub-optimal adherence associated with daily oral formulations. Tenofovir alafenamide (TAF) is a highly potent nucleoside reverse transcriptase inhibitor (NRTI) and an attractive agent for LA delivery, with a high potency and long intracellular half-life. The aim of this study was to predict minimum TAF doses required to achieve concentrations effective for HIV pre-exposure prophylaxis (PrEP). Daily drug-release requirements were then ascertained by averaging across the dosing interval.

Integration of Computational and Experimental Approaches to Elucidate Mechanisms of First-Pass Lymphatic Drug Sequestration and Long-Acting Pharmacokinetics of the Injectable Triple-HIV Drug Combination TLC-ART 101

Date: 
5/15/20
Citation: 

Perazzolo S, Shireman LM, McConnachie LA, Koehn J, Kinman L, Lee W, Lane S, Collier AC, Shen DD, Ho RJY. Integration of Computational and Experimental Approaches to Elucidate Mechanisms of First-Pass Lymphatic Drug Sequestration and Long-Acting Pharmacokinetics of the Injectable Triple-HIV Drug Combination TLC-ART 101. J Pharm Sci. 2020 May;109(5):1789-1801. doi: 10.1016/j.xphs.2020.01.016. Epub 2020 Jan 29. PMID: 32006525.

TLC-ART101 is a long-acting triple-HIV drug combination of lopinavir-ritonavir-tenofovir in one nanosuspension intended for subcutaneous injection. After a single TLC-ART 101 administration in nonhuman primates, drug concentrations in both plasma and HIV-target lymph node mononuclear cells were sustained for 2 weeks. Nevertheless, the mechanisms leading to the targeted long-acting pharmacokinetics remain elusive. Therefore, an intravenous study of TLC-ART 101 in nonhuman primates was conducted to elucidate the degree of association of drugs in vivo, estimate subcutaneous bioavailability, and refine a mechanism-based pharmacokinetic (MBPK2) model. The MBPK2 model considers TLC-ART 101 systemic drug clearances, nanoparticle-associated/dissociated species, more detailed mechanisms of lymphatic first-pass retention of associated-drugs after subcutaneous administrations, and the prediction of drug concentration time-courses in lymph node mononuclear cells. 

Health Topics: 

A Conjoint Analysis of the Acceptability of Targeted Long-Acting Injectable Antiretroviral Therapy Among Persons Living with HIV in the U.S

Date: 
4/15/20
Citation: 

Simoni JM, Tapia K, Lee SJ, Graham SM, Beima-Sofie K, Mohamed ZH, Christodoulou J, Ho R, Collier AC. A Conjoint Analysis of the Acceptability of Targeted Long-Acting Injectable Antiretroviral Therapy Among Persons Living with HIV in the U.S. AIDS Behav. 2020 Apr;24(4):1226-1236. doi: 10.1007/s10461-019-02701-7. PMID: 31655915; PMCID: PMC7085450.

With long-acting injectable antiretroviral therapy likely to be a treatment option for people living with HIV (PLWH), it is critical to assess its acceptability among potential end-users. Based on formative qualitative work and our own ongoing development of targeted long-acting products in nanosuspension formulations, we created eight hypothetical medication scenarios varying along six dichotomous attributes: administration location (home versus [vs.] clinic), dosing frequency (every 2 weeks vs. 1 week), injections per dose (one vs. two), injection pain (mild vs. moderate), injection site reaction (mild vs. moderate), and effectiveness (better vs. same as pills). PLWH from three outpatient care clinics in Seattle, WA and Riverside, CA rated acceptability (i.e., willingness to try each hypothetical medication) from 0 (very unlikely) to 100 (very likely). In conjoint analyses, we examined level and correlates of acceptability, the impact of each attribute on overall acceptability, and moderators of this effect. 

Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection

Date: 
3/19/20
Citation: 

C. Orkin, K. Arasteh, M. Górgolas Hernández‑Mora, V. Pokrovsky, E.T. Overton, P.‑M. Girard, S. Oka, S. Walmsley, C. Bettacchi, C. Brinson, P. Philibert, J. Lombaard, M. St. Clair, H. Crauwels, S.L. Ford, P. Patel, V. Chounta, R. D’Amico, S. Vanveggel, D. Dorey, A. Cutrell, S. Griffith, D.A. Margolis, P.E. Williams, W. Parys, K.Y. Smith, and W.R. Spreen. Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection. N Engl J Med 2020;382:1124-35.DOI: 10.1056/NEJMoa1909512

This study assessed whether switching to monthly injections of long-acting cabotegravir plus rilpivirine would be noninferior to continuing oral therapy in patients with HIV type 1 (HIV-1) who had viral suppression in response to oral induction therapy.

Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression

Date: 
3/4/20
Citation: 

Swindells, J.-F. Andrade-Villanueva, G.J. Richmond, G. Rizzardini, A. Baumgarten, M. Masiá, G. Latiff, V. Pokrovsky, F. Bredeek, G. Smith, P. Cahn, Y.-S. Kim, S.L. Ford, C.L. Talarico, P. Patel, V. Chounta, H. Crauwels, W. Parys, S. Vanveggel, J. Mrus, J. Huang, C.M. Harrington, K.J. Hudson, D.A. Margolis, K.Y. Smith, P.E. Williams, and W.R. Spreen. Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 SuppressionS. N Engl J Med 2020;382:1112-23.DOI: 10.1056/NEJMoa1904398

Simplified regimens for the treatment of human immunodeficiency virus type 1 (HIV-1) infection may increase patient satisfaction and facilitate adherence.

A multi-site study of women living with HIV's perceived barriers to, and interest in, long-acting injectable anti-retroviral therapy.

Date: 
3/2/20
Citation: 

Philbin MM, Parish C, Kinnard EN, Reed SE, Kerrigan D, Alcaide M, Cohen MH, Sosanya O, Sheth AN, Adimora AA, Cocohoba J, Goparaju L, Golub ET, Fischl M, Metsch LR. A multi-site study of women living with HIV's perceived barriers to, and interest in, long-acting injectable anti-retroviral therapy. J Acquir Immune Defic Syndr. 2020 Mar 2. doi: 10.1097/QAI.0000000000002337. PMID: 32141961

Adherence to antiretroviral therapy (ART) is imperative for viral suppression and reducing HIV transmission, but many people living with HIV report difficultly sustaining long-term adherence. Long-acting injectable (LAI) ART has the potential to transform HIV treatment and prevention. However, little LAI ART-related behavioral research has occurred among women, particularly outside of clinical trials.

Long-acting rilpivirine (RPV LA) pre-exposure prophylaxis does not inhibit vaginal transmission of RPV-resistant HIV-1 nor select for high frequency drug resistance in humanized mice.

Date: 
1/22/20
Citation: 

Melody K, Roy CN, Kline C, Cottrell ML, Evans D, Shutt K, Pennings PS, Keele BF, Bility M, Kashuba ADM, Ambrose Z. Long-acting rilpivirine (RPV LA) pre-exposure prophylaxis does not inhibit vaginal transmission of RPV-resistant HIV-1 or select for high frequency drug resistance in humanized mice. J Virol. 2020 Mar 31;94(8):e01912-19. doi: 10.1128/JVI.01912-19. Print 2020 Mar 31. PMID: 31969438; PMCID: PMC7108851.

As a long-acting formulation of the non-nucleoside reverse transcriptase inhibitor rilpivirine (RPV LA) has been proposed for use as pre-exposure prophylaxis (PrEP) and the prevalence of transmitted RPV-resistant viruses can be relatively high, we evaluated the efficacy of RPV LA to inhibit vaginal transmission of RPV-resistant HIV-1 in humanized mice. 

Addressing the global burden of hepatitis B virus while developing long-acting injectables for the prevention and treatment of HIV

Date: 
12/20/19
Citation: 

Bollinger RC, Thio CL, Sulkowski MS, McKenzie-White J, Thomas DL, Flexner C. Addressing the global burden of hepatitis B virus while developing long-acting injectables for the prevention and treatment of HIV. Lancet HIV. 2020;7(6):e443-e448. doi:10.1016/S2352-3018(19)30342-X. PMID: 31870675; PMCID: PMC7376366.

The first long-acting formulations of HIV drugs are undergoing regulatory review for use in maintenance of viral suppression in people with HIV.

Modelling the intradermal delivery of microneedle array patches for long-acting antiretrovirals using PBPK

Date: 
12/6/19
Citation: 

Rajoli RKR, Flexner C, Chiong J, Owen A, Donnelly RF, Larraneta E, Siccardi M. Modelling the intradermal delivery of microneedle array patches for long-acting antiretrovirals using PBPK. Eur J Pharm Biopharm. 2019 Nov;144:101-109.  doi: 10.1016/j.ejpb.2019.09.011. Epub 2019 Sep 13. PMID: 31525446; PMCID: PMC6917207.

Existing HIV therapy using oral antiretrovirals (ARVs) can result in pill fatigue and sub-optimal adherence. Microneedle array patches (MAPs) offer non-invasive, blood-free and painless drug delivery, and may improve patient adherence.

Long-acting implants to treat and prevent HIV infection

Date: 
12/6/19
Citation: 

Weld ED, Flexner C. Long-acting implants to treat and prevent HIV infection. Curr Opin HIV AIDS. 2020 Jan;15(1):33-41. doi: 10.1097/COH.0000000000000591. PMID: 31764198; PMCID: PMC7050620.

Subcutaneous implants are a promising technology to enable long-acting parenteral delivery of antiretroviral drugs (ARV) because they may be able to provide protective drugs concentrations for a year or longer following a single implant. The present review covers the current status of preclinical and clinical development of antiretroviral implants.

Pages