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https://www.readbyqxmd.com/read/29794818/rilpivirine-long-acting-for-the-prevention-and-treatment-of-hiv-infection
#1
Francesca Ferretti, Marta Boffito
PURPOSE OF REVIEW: Rilpivirine is a non-nucleoside reverse transcriptase inhibitor approved for the treatment of HIV in combination with other antiretrovirals (ARV). The development of the long-acting formulation of rilpivirine (RPV-LA) and its use in clinical settings is the subject of this review. RECENT FINDINGS: In 2017, the results of the phase IIb study LATTE2 have been published. This study demonstrated that the combination of RPV-LA with a second long-acting agent (cabotegravir) administered intramuscularly every 4--8 weeks was similar in virologic suppression rates to standard of care ARV treatment...
May 22, 2018: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/29769116/efficacies-of-cabotegravir-and-bictegravir-against-drug-resistant-hiv-1-integrase-mutants
#2
Steven J Smith, Xue Zhi Zhao, Terrence R Burke, Stephen H Hughes
BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are the class of antiretroviral (ARV) drugs most recently approved by the FDA for the treatment of HIV-1 infections. INSTIs block the strand transfer reaction catalyzed by HIV-1 integrase (IN) and have been shown to potently inhibit infection by wild-type HIV-1. Of the three current FDA-approved INSTIs, Dolutegravir (DTG), has been the most effective, in part because treatment does not readily select for resistant mutants. However, recent studies showed that when INSTI-experienced patients are put on a DTG-salvage therapy, they have reduced response rates...
May 16, 2018: Retrovirology
https://www.readbyqxmd.com/read/29756689/7-step-flow-synthesis-of-the-hiv-integrase-inhibitor-dolutegravir
#3
Robert E Ziegler, Bimbisar K Desai, Jo-Ann Jee, B Frank Gupton, Thomas D Roper, Timothy F Jamison
Dolutegravir (DTG), an important active pharmaceutical ingredient (API) used in combination therapy for the treatment of HIV, has been synthesized in continuous flow. By adapting the reported GlaxoSmithKline process chemistry batch route for Cabotegravir, DTG was produced in 4.5 h in sequential flow operations from commercially available materials. Key features of the synthesis include rapid manufacturing time for pyridone formation, one-step direct amidation of a functionalized pyridone, and telescoping of multiple steps to avoid isolation of intermediates and enable for greater throughput...
June 11, 2018: Angewandte Chemie
https://www.readbyqxmd.com/read/29746267/cabotegravir-its-potential-for-antiretroviral-therapy-and-preexposure-prophylaxis
#4
Hans-Jürgen Stellbrink, Christian Hoffmann
PURPOSE OF REVIEW: Analyzing the evidence for the strand transfer integrase inhibitor cabotegravir (CAB; GSK744, GSK1265744), its properties and differences from other compounds in the class, as well as reviewing the preclinical and clinical evidence for its potential in antretroviral therapy and medical HIV prevention. RECENT FINDINGS: CAB has been investigated both as an oral and an injectable compound. Recent results show that it has promising properties with regards to its potential for parenteral maintenance therapy in combination with other compounds in HIV-infected patients currently suppressed on oral agents, as well as in preexposure prophylaxis...
May 8, 2018: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/29689540/investigational-antiretroviral-drugs-what-is-coming-down-the-pipeline
#5
Roy M Gulick
Over the past 30 years, antiretroviral drug regimens for treating HIV infection have become more effective, safer, and more convenient. Despite 31 currently approved drugs, the pipeline of investigational HIV drugs remains full. Investigational antiretroviral drugs include the nucleoside analogue reverse transcriptase translocation inhibitor (NRTTI) MK-8591, a long-acting compound that could be dosed once weekly. Investigational nonnucleoside analogue reverse transcriptase inhibitors (NNRTIs) include doravirine, which is active in vitro against NNRTI-resistant HIV and was potent and well-tolerated when used in combination with a dual-nucleoside analogue RTI (nRTI) backbone in treatment-naive individuals...
April 2018: Topics in Antiviral Medicine
https://www.readbyqxmd.com/read/29595351/treatment-and-prevention-of-hiv-infection-with-long-acting-antiretrovirals
#6
REVIEW
Laura Benítez-Gutiérrez, Vicente Soriano, Silvia Requena, Ana Arias, Pablo Barreiro, Carmen de Mendoza
Current antiretroviral therapy allows to achieve and sustain maximal suppression of HIV replication in most treated patients. As result, the life expectancy of HIV-infected persons has improved dramatically and is nowadays similar to that of the HIV-negative population. However, oral antiretrovirals have to be taken daily and indefinitely to avoid resumption of HIV replication and selection of drug resistance. Unfortunately, drug adherence is often suboptimal and tends to decline over time. Areas covered: New drugs, formulations and delivery systems are being developed for extended-release of antiretrovirals...
May 2018: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/29553879/optimizing-the-preparation-and-stability-of-decorated-antiretroviral-drug-nanocrystals
#7
Tian Zhou, Zhiyi Lin, Pavan Puligujja, Diana Palandri, James Hilaire, Mariluz Araínga, Nathan Smith, Nagsen Gautam, JoEllyn McMillan, Yazen Alnouti, Xinming Liu, Benson Edagwa, Howard E Gendelman
AIM: While the  therapeutic potential for current long-acting (LA) antiretroviral therapy (ART) is undeniable, ligand-decorated nanoformulated LA-ART could optimize drug delivery to viral reservoirs. The development of decorated ART hinges, however, on formulation processes and manufacture efficiencies. To this end, we compared manufacture and purification techniques for ligand-decorated antiretroviral drug nanocrystals. MATERIALS & METHODS: Ligand-decorated nanoparticle manufacturing was tested using folic acid (FA) nanoformulated cabotegravir...
April 2018: Nanomedicine
https://www.readbyqxmd.com/read/29410019/novel-secondary-mutations-c56s-and-g149a-confer-resistance-to-hiv-1-integrase-strand-transfer-inhibitors
#8
Tomokazu Yoshinaga, Takahiro Seki, Shigeru Miki, Tadashi Miyamoto, Akemi Suyama-Kagitani, Shinobu Kawauchi-Miki, Masanori Kobayashi, Akihiko Sato, Eugene Stewart, Mark Underwood, Tamio Fujiwara
Cabotegravir (CAB, S/GSK1265744) is an investigational second-generation integrase strand transfer inhibitor (INSTI) with a chemical structure similar to dolutegravir. CAB is under development as a long-acting injectable formulation for treatment of HIV-1 infection and for pre-exposure prophylaxis. We conducted an in vitro passage study of raltegravir- or elvitegravir-resistant signature mutants in the presence of CAB to characterize the resistance profile of this drug. During passage with Q148H virus, G140S arose by day 14, followed by G149A and C56S...
April 2018: Antiviral Research
https://www.readbyqxmd.com/read/29317618/development-of-an-oral-once-weekly-drug-delivery-system-for-hiv-antiretroviral-therapy
#9
Ameya R Kirtane, Omar Abouzid, Daniel Minahan, Taylor Bensel, Alison L Hill, Christian Selinger, Anna Bershteyn, Morgan Craig, Shirley S Mo, Hormoz Mazdiyasni, Cody Cleveland, Jaimie Rogner, Young-Ah Lucy Lee, Lucas Booth, Farhad Javid, Sarah J Wu, Tyler Grant, Andrew M Bellinger, Boris Nikolic, Alison Hayward, Lowell Wood, Philip A Eckhoff, Martin A Nowak, Robert Langer, Giovanni Traverso
The efficacy of antiretroviral therapy is significantly compromised by medication non-adherence. Long-acting enteral systems that can ease the burden of daily adherence have not yet been developed. Here we describe an oral dosage form composed of distinct drug-polymer matrices which achieved week-long systemic drug levels of the antiretrovirals dolutegravir, rilpivirine and cabotegravir in a pig. Simulations of viral dynamics and patient adherence patterns indicate that such systems would significantly reduce therapeutic failures and epidemiological modelling suggests that using such an intervention prophylactically could avert hundreds of thousands of new HIV cases...
January 9, 2018: Nature Communications
https://www.readbyqxmd.com/read/29304154/experiences-with-long-acting-injectable-art-a-qualitative-study-among-plhiv-participating-in-a-phase-ii-study-of-cabotegravir-rilpivirine-latte-2-in-the-united-states-and-spain
#10
Deanna Kerrigan, Andrea Mantsios, Miguel Gorgolas, Maria-Luisa Montes, Federico Pulido, Cynthia Brinson, Jerome deVente, Gary J Richmond, Sarah W Beckham, Paige Hammond, David Margolis, Miranda Murray
Challenges with adherence to daily oral antiretroviral therapy (ART) among people living with HIV (PLHIV) have stimulated development of injectable long-acting (LA) regimens. We conducted 39 in-depth interviews with participants and providers in a Phase IIb study (LATTE-2) evaluating an injectable LA regimen in the U.S. and Spain. Interviews exploring participant and provider attitudes and experiences with LA versus oral ART were audiotaped, transcribed and analyzed using thematic content analysis. Participants described the convenience of LA injections versus daily pills and emotional benefits such as minimized potential for HIV disclosure and eliminating the "daily reminder of living with HIV...
2018: PloS One
https://www.readbyqxmd.com/read/29290075/expanding-the-menu-of-hiv-prevention-options-a-qualitative-study-of-experiences-with-long-acting-injectable-cabotegravir-as-prep-in-the-context-of-a-phase-ii-trial-in-the-united-states
#11
D Kerrigan, A Mantsios, R Grant, M Markowitz, P Defechereux, M La Mar, S W Beckham, P Hammond, D Margolis, M Murray
Adherence challenges with oral pre-exposure prophylaxis have stimulated interest in alternate modes of administration including long-acting injections. We conducted 30 in-depth interviews with 26 male trial participants and 4 clinical providers in a Phase IIa study (ÉCLAIR) evaluating the use of long-acting cabotegravir (CAB-LA) injections in New York and San Francisco. Interviews exploring attitudes and experiences with CAB-LA were audiotaped, transcribed, and analyzed using thematic content analysis. Despite a high frequency of some level of side effects, almost all participants reported being interested in continuing with CAB-LA, versus a daily oral, due to its convenience and the perceived advantage of not worrying about adhering to pills...
December 30, 2017: AIDS and Behavior
https://www.readbyqxmd.com/read/29239896/ex-vivo-antiretroviral-potency-of-newer-integrase-strand-transfer-inhibitors-cabotegravir-and-bictegravir-in-hiv-type-1-non-b-subtypes
#12
Ujjwal Neogi, Kamalendra Singh, Shambhu G Aralaguppe, Leonard C Rogers, Duncan T Njenda, Stefan G Sarafianos, Bo Hejdeman, Anders Sönnerborg
OBJECTIVE: To determine the antiretroviral activity of the integrase strand transfer inhibitors (INSTIs), raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), cabotegravir (CAB) and bictegravir (BIC), against different subtypes as well as primary and acquired drug resistance mutations (DRMs) in a patient-cohort infected with diverse subtypes. DESIGN: Biochemical and virological drug sensitivity analyses using patient-derived HIV type 1 (HIV-1) genes and cross-sectional/longitudinal clinical study...
February 20, 2018: AIDS
https://www.readbyqxmd.com/read/29059541/creation-of-a-nanoformulated-cabotegravir-prodrug-with-improved-antiretroviral-profiles
#13
Tian Zhou, Hang Su, Prasanta Dash, Zhiyi Lin, Bhagya Laxmi Dyavar Shetty, Ted Kocher, Adam Szlachetka, Benjamin Lamberty, Howard S Fox, Larisa Poluektova, Santhi Gorantla, JoEllyn McMillan, Nagsen Gautam, R Lee Mosley, Yazen Alnouti, Benson Edagwa, Howard E Gendelman
Long-acting parenteral (LAP) antiretroviral drugs have generated considerable interest for treatment and prevention of HIV-1 infection. One new LAP is cabotegravir (CAB), a highly potent integrase inhibitor, with a half-life of up to 54 days, allowing for every other month parenteral administrations. Despite this excellent profile, high volume dosing, injection site reactions and low body fluid drug concentrations affect broad use for virus infected and susceptible people. To improve the drug delivery profile, we created a myristoylated CAB prodrug (MCAB)...
January 2018: Biomaterials
https://www.readbyqxmd.com/read/29042321/multimodal-imaging-approach-to-examine-biodistribution-kinetics-of-cabotegravir-gsk1265744-long-acting-parenteral-formulation-in-rat
#14
Beat M Jucker, Hasan Alsaid, Mary Rambo, Stephen C Lenhard, Bao Hoang, Fang Xie, M Reid Groseclose, Stephen Castellino, Valeriu Damian, Gary Bowers, Manish Gupta
Long-Acting Parenterals (LAPs) have been used in the clinic to provide sustained therapeutic drug levels at a target site, and thereby reducing the frequency of dosing required. In an effort to understand the factors associated with long-acting cabotegravir (GSK1265744 LAP) pharmacokinetic variability, the current study was designed to investigate the temporal relationship between intramuscular (IM) or subcutaneous (SC) drug depot morphology and distribution kinetics with plasma pharmacokinetics. Therefore, a multi-modal molecular imaging (MRI & MALDI IMS) approach was employed to examine the temporal GSK1265744 LAP biodistribution in rat following either IM or SC administration...
December 28, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/29019353/hot-news-ready-for-hiv-dual-therapy-new-data-from-international-hiv-aids-society-2017
#15
George A Yendewa, Robert A Salata
The introduction of combination antiretroviral therapy (ART) in the 1990s has fundamentally transformed the landscape of HIV medicine, greatly improved disease morbidity and mortality, and reduced transmission rates across all demographic groups. Central to this success was the idea that to achieve best disease outcomes and minimize the development of drug resistance, at least three antiretroviral agents should be used for HIV treatment. This therapeutic strategy is a core tenet of HIV medicine, backed by incontrovertible scientific evidence, and made easy to deploy by the high compliance levels with once-daily coformulations, which have generally been well tolerated...
October 2017: AIDS Reviews
https://www.readbyqxmd.com/read/28956664/investigational-hiv-integrase-inhibitors-in-phase-i-and-phase-ii-clinical-trials
#16
REVIEW
Yingshan Han, Thibault Mesplède, Mark A Wainberg
To date, three HIV integrase strand transfer inhibitors (INSTIs), i.e. raltegravir, elvitegravir and dolutegravir, have been approved for clinical use. Recent research has focused on new integrase inhibitors including those targeting non-catalytic sites of HIV integrase. Areas covered: This paper reviews two investigational INSTIs in phase I and II clinical trials, bictegravir (BIC) and cabotegravir (CAB), as well as an investigational noncatalytic integrase inhibitor (NCINI) termed BI 224436. Expert opinion: Data from phase I and II clinical trials demonstrate that CAB has good efficacy and is well-tolerated...
November 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28923862/antiviral-activity-of-bictegravir-and-cabotegravir-against-integrase-inhibitor-resistant-sivmac239-and-hiv-1
#17
Said A Hassounah, Ahmad Alikhani, Maureen Oliveira, Simrat Bharaj, Ruxandra-Ilinca Ibanescu, Nathan Osman, Hong-Tao Xu, Bluma G Brenner, Thibault Mesplède, Mark A Wainberg
Animal models are essential to study novel antiretroviral drugs, resistance-associated mutations (RAMs), and treatment strategies. Bictegravir (BIC) is a novel potent integrase strand transfer inhibitor (INSTI) that has shown promising results against HIV-1 infection in vitro and in vivo and against clinical isolates with resistance against INSTIs. BIC has a higher genetic barrier to the development of resistance than two clinically approved INSTIs, termed raltegravir and elvitegravir. Another clinically approved INSTI, dolutegravir (DTG) also possesses a high genetic barrier to resistance, while a fourth compound, termed cabotegravir (CAB), is currently in late phases of clinical development...
December 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28750935/long-acting-intramuscular-cabotegravir-and-rilpivirine-in-adults-with-hiv-1-infection-latte-2-96-week-results-of-a-randomised-open-label-phase-2b-non-inferiority-trial
#18
David A Margolis, Juan Gonzalez-Garcia, Hans-Jürgen Stellbrink, Joseph J Eron, Yazdan Yazdanpanah, Daniel Podzamczer, Thomas Lutz, Jonathan B Angel, Gary J Richmond, Bonaventura Clotet, Felix Gutierrez, Louis Sloan, Marty St Clair, Miranda Murray, Susan L Ford, Joseph Mrus, Parul Patel, Herta Crauwels, Sandy K Griffith, Kenneth C Sutton, David Dorey, Kimberly Y Smith, Peter E Williams, William R Spreen
BACKGROUND: Cabotegravir and rilpivirine are antiretroviral drugs in development as long-acting injectable formulations. The LATTE-2 study evaluated long-acting cabotegravir plus rilpivirine for maintenance of HIV-1 viral suppression through 96 weeks. METHODS: In this randomised, phase 2b, open-label study, treatment-naive adults infected with HIV-1 initially received oral cabotegravir 30 mg plus abacavir-lamivudine 600-300 mg once daily. The objective of this study was to select an intramuscular dosing regimen based on a comparison of the antiviral activity, tolerability, and safety of the two intramuscular dosing regimens relative to oral cabotegravir plus abacavir-lamivudine...
September 23, 2017: Lancet
https://www.readbyqxmd.com/read/28744666/lessons-for-patient-education-around-long-acting-injectable-prep-findings-from-a-mixed-method-study-of-phase-ii-trial-participants
#19
Kathrine Meyers, Kristina Rodriguez, Atrina L Brill, Yumeng Wu, Melissa La Mar, Debora Dunbar, Beryl Koblin, David Margolis, Magdalena E Sobieszczyk, Hong Van Tieu, Ian Frank, Martin Markowitz, Sarit A Golub
This study aimed to identify patients' physical and psychosocial experiences of an investigational long-acting injectable PrEP product to aid in the development of patient and provider education materials. Twenty-eight participants of a Phase 2 safety, tolerability, and acceptability study of long-acting integrase inhibitor cabotegravir (CAB-LA) were interviewed on their physical and psychosocial experiences of the injections. Five themes emerged through a framework analysis on these interview transcripts: (1) injection-related pain is highly variable across individuals; (2) pain is more impactful after the injections than during; (3) patient anxiety is critical, but does not determine the experience of injections and decreases over time; (4) intimacy and awkwardness of gluteal injections impacts patients' experiences; (5) patient education and care strategies can mitigate the above factors...
April 2018: AIDS and Behavior
https://www.readbyqxmd.com/read/28739783/effect-of-rifampin-on-the-single-dose-pharmacokinetics-of-oral-cabotegravir-in-healthy-subjects
#20
S L Ford, K Sutton, Y Lou, Z Zhang, A Tenorio, C Trezza, P Patel, W Spreen
Drug-drug interactions between antiretroviral medications and rifampin complicate the treatment of HIV and tuberculosis coinfection. This study evaluated the effect of rifampin on the pharmacokinetics of oral cabotegravir, an integrase strand transfer inhibitor being investigated for long-acting treatment and prevention of HIV-1 infection. This was a phase I, single-center, open-label, fixed-sequence crossover study in healthy adults. The objective was to evaluate the effect of steady-state rifampin on the single-dose plasma pharmacokinetics of cabotegravir...
October 2017: Antimicrobial Agents and Chemotherapy
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