HIV

Predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis across three phase 3 studies

Date: 
3/18/21
Citation: 

Cutrell AG, Schapiro JM, Perno CF, Kuritzkes DR, Quercia R, Patel P, Polli JW, Dorey D, Wang Y, Wu S, van Eygen V, Crauwels H, Ford SL, Baker M, Talarico CL, Clair MST, Jeffrey J, White CT, Vanveggel S, Vandermeulen K, Margolis DA, Aboud M, Spreen WR, van Lunzen J. Predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis across three phase 3 studies. AIDS. 2021 Mar 16. doi: 10.1097/QAD.0000000000002883. Epub ahead of print. PMID: 33730748.

Efficacy and safety of long-acting (LA) cabotegravir (CAB) and rilpivirine (RPV) dosed intramuscularly every 4 or 8 weeks has been demonstrated in three Phase 3 trials. Here, factors associated with virologic failure at Week 48 were evaluated post hoc.

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Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study

Date: 
12/9/20
Citation: 

Overton ET, Richmond G, Rizzardini G, Jaeger H, Orrell C, Nagimova F, Bredeek F, Deltoro MG, Swindells S, Andrade-Villanueva JF, Wong A, Khuong-Josses M, Solingen-Ristea RV, Eygen VV, Crauwels H, Ford S, Talarico C, Benn P, Wang Y, Hudson KJ, Chounta V, Cutrell A, Patel P, Shaefer M, Margolis DA, Smith KY, Vanveggel S, Spreen W. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study, The Lancet, 2020, ISSN 0140-6736.

Phase 3 clinical studies showed non-inferiority of long-acting intramuscular cabotegravir and rilpivirine dosed every 4 weeks to oral antiretroviral therapy. Important phase 2 results of every 8 weeks dosing, and supportive modelling, underpin further evaluation of every 8 weeks dosing in this trial, which has the potential to offer greater convenience. Our objective was to compare the week 48 antiviral efficacy of cabotegravir plus rilpivirine long-acting dosed every 8 weeks with that of every 4 weeks dosing. 

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Long-Acting Drugs and Formulations for the Treatment and Prevention of HIV

Date: 
11/6/20
Citation: 

Flexner C, Owen A, Siccardi M, Swindells S. Long-Acting Drugs and Formulations for the Treatment and Prevention of HIV,
International Journal of Antimicrobial Agents,2020, 106220,ISSN 0924-8579.

Long acting and extended-release formulations represent one of the most important approaches to improving the treatment and prevention of chronic HIV infection. Long acting small molecules and monoclonal antibodies have demonstrated potent anti-HIV activity in early and late stage clinical trials. Strategies to manage toxicities and falling drug concentrations after missed doses, as well as primary and secondary resistance to current drugs and monoclonal antibodies are important considerations.

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Exploration into the opinions of patients with HIV, healthcare professionals and the lay public of the use of microneedles in clinical practice: highlighting the translational potential for their role in HIV infection

Date: 
9/18/20
Citation: 

Moffatt K, Quinn C, McCague PJ, Donnelly RF. Exploration into the opinions of patients with HIV, healthcare professionals and the lay public of the use of microneedles in clinical practice: highlighting the translational potential for their role in HIV infection. Drug Deliv Transl Res. 2020 Sep 18. doi: 10.1007/s13346-020-00848-8. Epub ahead of print. PMID: 32946042.

Poor adherence to oral antiretroviral therapy (ART) remains an important challenge in the treatment of HIV. Microneedles (MN) potentially could offer a non-invasive long-acting (LA) delivery approach, avoiding the need for daily dosing of ART. However, this claim has yet to be explored amongst its potential end-users. The aim of this mixed methods study was to investigate the perspectives from various end-users surrounding the translation of MN technology to general clinical practice, with a particular focus on delivery of ART. Quantitative postal questionnaires were distributed amongst healthcare professionals (HCPs) and the lay public (LP). A total of 208 responses were obtained (HCP, 69; LP, 139), with a completion rate of 34.7%. The consensus on MN technology was positive from both demographics (HCP, 97.1%; LP, 98.6%), with further strong support of postulated MN use within HIV (HCP, 97.1%; LP, 98.6%). 

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A year-long extended release nanoformulated cabotegravir prodrug

Date: 
8/15/20
Citation: 

Kulkarni TA, Bade AN, Sillman B, et al. A year-long extended release nanoformulated cabotegravir prodrug. Nat Mater. 2020;19(8):910-920. doi:10.1038/s41563-020-0674-z

Long-acting cabotegravir (CAB) extends antiretroviral drug administration from daily to monthly. However, dosing volumes, injection site reactions and health-care oversight are obstacles towards a broad usage. The creation of poloxamer-coated hydrophobic and lipophilic CAB prodrugs with controlled hydrolysis and tissue penetrance can overcome these obstacles. To such ends, fatty acid ester CAB nanocrystal prodrugs with 14, 18 and 22 added carbon chains were encased in biocompatible surfactants named NMCAB, NM2CAB and NM3CAB and tested for drug release, activation, cytotoxicity, antiretroviral activities, pharmacokinetics and biodistribution.

Controlled Solvent Removal from Antiviral Drugs and Excipients in Solution Enables the Formation of Novel Combination Multi-Drug-Motifs in Pharmaceutical Powders Composed of Lopinavir, Ritonavir and Tenofovir

Date: 
8/10/20
Citation: 

Yu J, Yu D, Lane S, McConnachie L, Ho RJY. Controlled Solvent Removal from Antiviral Drugs and Excipients in Solution Enables the Formation of Novel Combination Multi-Drug-Motifs in Pharmaceutical Powders Composed of Lopinavir, Ritonavir and Tenofovir. J Pharm Sci. 2020 Aug 10:S0022-3549(20)30434-2. doi: 10.1016/j.xphs.2020.08.003. Epub ahead of print. PMID: 32791073.

Diverging physicochemical properties of HIV drug combinations are challenging to formulate as a single dosage form. We have found that 2-to-4 hydrophilic and hydrophobic HIV drugs in combination can be stabilized with lipid excipients under a controlled solvent removal process to form a novel pharmaceutical powder distinct from typical amorphous material. This discovery has enabled production of a drug combination nanoparticle (DcNP) powder composed of 3 HIV drugs-water-insoluble lopinavir (LogP = 4.7) and ritonavir (LogP = 5.6) and water-soluble tenofovir (LogP = -1.6). 

Health Topics: 

LEAP Extended for 5 Years

Date: 
7/28/20

Long-Acting/Extended Release Antiretroviral Research Resource Program to add therapy development for tuberculosis and viral hepatitis

July 28, 2020—The Long-Acting/Extended Release Antiretroviral Research Resource Program (LEAP) today announced approval of a new NIH grant that allows for expansion of its charter to promote development of medications that are more manageable for patients. Going forward LEAP will include tuberculosis and viral hepatitis, which are comorbidities that complicate HIV treatment.

Pharmacokinetics, Safety and Tolerability of Long-Acting Parenteral Intramuscular Injection Formulations of Doravirine

Date: 
6/5/20
Citation: 

Yee KL, Mittal S, Fan L, et al. Pharmacokinetics, safety and tolerability of long-acting parenteral intramuscular injection formulations of doravirine [published online ahead of print, 2020 Jun 5]. J Clin Pharm Ther. 2020;10.1111/jcpt.13182. doi:10.1111/jcpt.13182. PMID: 32501541.

Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus (HIV)-1 infection. This phase 1 study in healthy adults investigated the pharmacokinetics, safety and tolerability of long-acting parenteral (LAP) microsuspension formulations of doravirine administered as an intramuscular (IM) injection.

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