Login Register Cart 0
Generic placeholder image

Current HIV Research

Editor-in-Chief

ISSN (Print): 1570-162X
ISSN (Online): 1873-4251

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Mini-Review Article

Emerging Trends in the Long-Acting Antiretroviral Therapy: Current Status and Therapeutic Challenges

Author(s): Rajpushpa Labh and Rachna Gupta*

Volume 19, Issue 1, 2021

Published on: 24 August, 2020

Page: [4 - 13] Pages: 10

DOI: 10.2174/1570162X18666200824104140

Price: $65

Abstract

Antiretroviral drug therapy has significantly improved the prognosis and life expectancy of people living with HIV over the years. But this progress comes with an important caveat that antiretroviral regimens generally require adherence to life-long, daily dosing, to keep viral multiplication under check. Non-adherence to such dosing leads to decreased efficacy and increased drug resistance against antiretroviral drugs. Besides, poor drug penetration to certain tissues like CNS and lymph nodes leads to the build-up of viral reservoirs in these sites. To combat some of these challenges and improve patient compliance, long-acting antiretroviral drugs, are a new weapon in the arsenal, in the fight against HIV. Few long-acting preparations have been approved, and several others are in various clinical and preclinical stages of development. However, long-acting formulations also have their share of clinical issues like limited drug distribution, long term adverse drug reactions, drug-drug interactions, and gradual development of drug resistance. Modern technological premises are being tested to mitigate some of these problems. One such promising approach involves nanotechnological methods, which are being used to develop ultra-long acting formulations and drug delivery systems, targeting tissues with residual HIV concentration. Long-Acting Slow Effective Release Antiretroviral Therapy aka LASER ART, also builds on nanotechnology and prodrug modifications to design preparations with tailor-made favorable pharmacokinetics and wider drug distribution. These recent advances are fueling the progression of antiretroviral therapy towards eliminating the disease.

Keywords: HIV/AIDS, anti retroviral therapy, long acting, implant, nanotechnology, laser art.

« Previous Next »
Graphical Abstract

[1]
World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. World Health Organization 2016.
[2]
Palella FJ Jr, Baker RK, Moorman AC, et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr 2006; 43(1): 27-34.
[http://dx.doi.org/10.1097/01.qai.0000233310.90484.16] [PMID: 16878047]
[3]
Wandeler G, Johnson LF, Egger M. Trends in life expectancy of HIV-positive adults on ART across the globe: comparisons with general population. Curr Opin HIV AIDS 2016; 11(5): 492.
[http://dx.doi.org/10.1097/COH.0000000000000298] [PMID: 27254748]
[4]
Roul H, Mary-Krause M, Ghosn J, et al. FHDH-ANRS CO4. CD4+ cell count recovery after combined antiretroviral therapy in the modern combined antiretroviral therapy era. AIDS 2018; 32(17): 2605-14.
[http://dx.doi.org/10.1097/QAD.0000000000002010] [PMID: 30289817]
[5]
Wayengera M. Targeting persistent HIV infection: where and how, if possible? HIV AIDS Rev 2011; 10(1): 1-8.
[http://dx.doi.org/10.1016/j.hivar.2011.01.002]
[6]
Calin R, Hamimi C, Lambert-Niclot S, et al. Treatment interruption in chronically HIV-infected patients with an ultralow HIV reservoir. AIDS 2016; 30(5): 761-9.
[http://dx.doi.org/10.1097/QAD.0000000000000987] [PMID: 26730568]
[7]
Chun TW, Davey RT Jr, Engel D, Lane HC, Fauci AS. Re-emergence of HIV after stopping therapy. Nature 1999; 401(6756): 874-5.
[http://dx.doi.org/10.1038/44755] [PMID: 10553903]
[8]
Iacob SA, Iacob DG, Jugulete G. Improving the adherence to antiretroviral therapy, a difficult but essential task for a successful hiv treatment—clinical points of view and practical considerations. Front Pharmacol 2017; 8: 831.
[http://dx.doi.org/10.3389/fphar.2017.00831] [PMID: 29218008]
[9]
Heffernan JM, Wahl LM. Treatment interruptions and resistance: a review. Deterministic and Stochastic Models of AIDS and HIV with Intervention. 2005 Jul 7; 423-56.
[10]
Claborn KR, Meier E, Miller MB, Leffingwell TR. A systematic review of treatment fatigue among HIV-infected patients prescribed antiretroviral therapy. Psychol Health Med 2015; 20(3): 255-65.
[http://dx.doi.org/10.1080/13548506.2014.945601] [PMID: 25110152]
[11]
Gulick RM, Flexner C. Long-acting HIV drugs for treatment and prevention. Annu Rev Med 2019; 70: 137-50.
[http://dx.doi.org/10.1146/annurev-med-041217-013717] [PMID: 30355266]
[12]
Gao Y, Kraft JC, Yu D, Ho RJ. Recent developments of nanotherapeutics for targeted and long-acting, combination HIV chemotherapy. Eur J Pharm Biopharm 2018; 138: 75-91.
[PMID: 29678735]
[13]
Beccari MV, Mogle BT, Sidman EF, Mastro KA, Asiago-Reddy E, Kufel WD. Ibalizumab, a novel monoclonal antibody for the management of multidrug-resistant HIV-1 infection. Antimicrob Agents Chemother 2019; 63(6): e00110-9.
[http://dx.doi.org/10.1128/AAC.00110-19] [PMID: 30885900]
[14]
FDA approves new HIV treatment for patients who have limited treatment options 2018. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm599657.htm
[15]
Markham A. Ibalizumab: first global approval. Drugs 2018; 78(7): 781-5.
[http://dx.doi.org/10.1007/s40265-018-0907-5] [PMID: 29675744]
[16]
Iacob SA, Iacob DG. Ibalizumab targeting CD4 receptors, an emerging molecule in HIV therapy. Front Microbiol 2017; 8: 2323.
[http://dx.doi.org/10.3389/fmicb.2017.02323] [PMID: 29230203]
[17]
Song R, Franco D, Kao CY, Yu F, Huang Y, Ho DD. Epitope mapping of ibalizumab, a humanized anti-CD4 monoclonal antibody with anti-HIV-1 activity in infected patients. J Virol 2010; 84(14): 6935-42.
[http://dx.doi.org/10.1128/JVI.00453-10] [PMID: 20463063]
[18]
US FDA. TROGARZO™ (ibalizumab-uiyk): US prescribing Information. 2018. www.access data.fda.gov/drugsatfda_docs/label/2018/761065lbl.pdf [Accessed 18 Feb 2020]
[19]
Dhody K, Kazempour K, Pourhassan N, Maddon PJ. Primary efficacy results of PRO 140 SC in a pivotal phase 2b/3 study in heavily treatment-experienced HIV-1 patients Proceedings of the ASM Microbe 2018; 7-11.
[20]
CytoDyn. https://www.cytodyn.com/newsroom/press-releases/detail/327/cytodyns-monotherapy-trial-with-leronlimab-pro-140 Accessed 18 Feb 2020
[21]
Grobben M, Stuart RA, van Gils MJ. The potential of engineered antibodies for HIV-1 therapy and cure. Curr Opin Virol 2019; 38: 70-80.
[http://dx.doi.org/10.1016/j.coviro.2019.07.007] [PMID: 31421319]
[22]
Cohen YZ, Caskey M. Broadly neutralizing antibodies for treatment and prevention of HIV-1 infection. Curr Opin HIV AIDS 2018; 13(4): 366-73.
[http://dx.doi.org/10.1097/COH.0000000000000475] [PMID: 29697469]
[23]
Gama L, Koup RA. New-generation high-potency and designer antibodies: role in HIV treatment. Annu Rev Med 2018; 69: 409-19.
[http://dx.doi.org/10.1146/annurev-med-061016-041032] [PMID: 29029583]
[24]
Wensel D, Sun Y, Li Z, et al. Discovery and characterization of a novel CD4-binding adnectin with potent anti-HIV activity. Antimicrob Agents Chemother 2017; 61(8): e00508-17.
[http://dx.doi.org/10.1128/AAC.00508-17] [PMID: 28584151]
[25]
Wensel D, Sun Y, Davis J, et al. A novel gp41-binding adnectin with potent anti-HIV activity is highly synergistic when linked to a CD4-binding adnectin. J Virol 2018; 92(14): e00421-18.
[http://dx.doi.org/10.1128/JVI.00421-18] [PMID: 29743355]
[26]
Zheng J, Yant SR, Ahmadyar S, et al. 539. GS-CA2: a novel, potent, and selective first-in-class inhibitor of HIV-1 capsid function displays nonclinical pharmacokinetics supporting long-acting potential in humans. Open Forum Infect Dis 2018; 5(1): s199-200.
[27]
Singh K, Gallazzi F, Hill KJ, et al. GS-CA compounds: first-in- class HIV-1 capsid inhibitors covering multiple grounds. Front Microbiol 2019; 10: 1227.
[http://dx.doi.org/10.3389/fmicb.2019.01227] [PMID: 31312185]
[28]
Cevik M, Orkin C. Insights into HIV-1 capsid inhibitors in preclinical and early clinical development as antiretroviral agents. Expert Opin Investig Drugs 2019; 28(12): 1021-4.
[http://dx.doi.org/10.1080/13543784.2019.1692811] [PMID: 31738620]
[29]
Margolis DA, Brinson CC, Smith GHR, et al. LAI116482 Study Team. Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial. Lancet Infect Dis 2015; 15(10): 1145-55.
[http://dx.doi.org/10.1016/S1473-3099(15)00152-8] [PMID: 26201299]
[30]
Landovitz RJ, Li S, Grinsztejn B, et al. Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals: HPTN 077, a phase 2a randomized controlled trial. PLoS Med 2018; 15(11): e1002690.
[http://dx.doi.org/10.1371/journal.pmed.1002690] [PMID: 30408115]
[31]
Verloes R, Deleu S, Niemeijer N, Crauwels H, Meyvisch P, Williams P. Safety, tolerability and pharmacokinetics of rilpivirine following administration of a long-acting formulation in healthy volunteers. HIV Med 2015; 16(8): 477-84.
[http://dx.doi.org/10.1111/hiv.12247] [PMID: 25988676]
[32]
Williams PE, Crauwels HM, Basstanie ED. Formulation and pharmacology of long-acting rilpivirine. Curr Opin HIV AIDS 2015; 10(4): 233-8.
[http://dx.doi.org/10.1097/COH.0000000000000164] [PMID: 26049947]
[33]
Bekker LG, Li SS, Tolley E, et al. HPTN 076: TMC278 LA safe, tolerable and acceptable for HIV pre-exposure prophylaxis. In: In 24th Conference on Retroviruses and Opportunistic Infections. 2017; pp. pp. 13-16.
[34]
Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, et al. 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. Lancet 2017; 390(10101): 1499-510.
[http://dx.doi.org/10.1016/S0140-6736(17)31917-7] [PMID: 28750935]
[35]
Orkin C, Arasteh K, Hernández-Mora MG. Long-Active Cabotegravir+ Rilpivirine for HIV Maintenance: FLAIR Week 48 Results 2019.
[36]
Margolis DA, Swindells S, Andrade-Villanueva JF. Long-acting cabotegravir plus rilpivirine as maintenance therapy: ATLAS week-48 results. HIV Med 2019; 20: 20-1.
[37]
Vii V. Healthcare. Study evaluating the efficacy, safety, and tolerability of switching to long-acting cabotegravir plus long-acting rilpivirine from current antiretroviral regimen in virologically suppressed HIV-1-infected adults. ClinicalTrials.gov. Available from: https://clinicaltrials.gov/ct2/show/NCT02951052 Accessed 18 Feb 2020
[38]
Chong H, Yao X, Zhang C, et al. Biophysical property and broad anti-HIV activity of albuvirtide, a 3-maleimimidopropionic acid- modified peptide fusion inhibitor. PLoS One 2012; 7(3): e32599.
[http://dx.doi.org/10.1371/journal.pone.0032599] [PMID: 22403678]
[39]
Xie D. 2016. Efficacy and safety of long-acting HIV fusion inhibitor albuvirtide in antiretroviral-experienced adults with HIV-1: interim 48-week results from the randomized, controlled, phase 3, non-inferiority TALENT study, abstr O355. International Congress on Drug Therapy in HIV Infection (HIV Glasgow), Glasgow, Scotland.
[40]
Das K, Clark AD Jr, Lewi PJ, et al. Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. J Med Chem 2004; 47(10): 2550-60.
[http://dx.doi.org/10.1021/jm030558s] [PMID: 15115397]
[41]
Nel A, van Niekerk N, Kapiga S, et al. Ring Study Team. Safety and efficacy of a dapivirine vaginal ring for HIV prevention in women. N Engl J Med 2016; 375(22): 2133-43.
[http://dx.doi.org/10.1056/NEJMoa1602046] [PMID: 27959766]
[42]
Baeten JM, Palanee-Phillips T, Brown ER, et al. MTN-020–ASPIRE Study Team. Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. N Engl J Med 2016; 375(22): 2121-32.
[http://dx.doi.org/10.1056/NEJMoa1506110] [PMID: 26900902]
[43]
Riddler SA, Balkus JE, Parikh UM, et al. MTN-015 and MTN-020/ASPIRE Study Teams. Clinical and virologic outcomes following initiation of antiretroviral therapy among seroconverters in the Microbicide Trials Network-020 phase III trial of the dapivirine vaginal ring. Clin Infect Dis 2019; 69(3): 523-9.
[http://dx.doi.org/10.1093/cid/ciy909] [PMID: 30346511]
[44]
Montgomery ET, van der Straten A, Chitukuta M, et al. MTN-020/ASPIRE Study. Acceptability and use of a dapivirine vaginal ring in a phase III trial. AIDS 2017; 31(8): 1159-67.
[http://dx.doi.org/10.1097/QAD.0000000000001452] [PMID: 28441175]
[45]
Wang Y, De Clercq E, Li G. Current and emerging non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV-1 treatment. Expert Opin Drug Metab Toxicol 2019; 15(10): 813-29.
[http://dx.doi.org/10.1080/17425255.2019.1673367] [PMID: 31556749]
[46]
Al-Salama ZT. Elsulfavirine: first global approval. Drugs 2017; 77(16): 1811-6.
[http://dx.doi.org/10.1007/s40265-017-0820-3] [PMID: 28940154]
[47]
Viriom Inc. Viriom obtains first market approval of elsulfavirine(ElpidaÒ) for treatment of HIV-1 infection in Russia [mediarelease]. 2017. https://www.viriom.com Accessed 18 Feb 2020
[48]
Markowitz M, Grobler JA. Islatravir for the treatment and prevention of infection with the human immunodeficiency virus type 1. Curr Opin HIV AIDS 2020; 15(1): 27-32.
[http://dx.doi.org/10.1097/COH.0000000000000599] [PMID: 31658118]
[49]
Bernatchez JA, Paul R, Tchesnokov EP, et al. Derivatives of mesoxalic acid block translocation of HIV-1 reverse transcriptase. J Biol Chem 2015; 290(3): 1474-84.
[http://dx.doi.org/10.1074/jbc.M114.614305] [PMID: 25355312]
[50]
Flexner C. Antiretroviral implants for treatment and prevention of HIV infection. Curr Opin HIV AIDS 2018; 13(4): 374-80.
[http://dx.doi.org/10.1097/COH.0000000000000470] [PMID: 29794816]
[51]
Schürmann D, Rudd DJ, Zhang S, et al. Safety, pharmacokinetics, and antiretroviral activity of islatravir (ISL, MK-8591), a novel nucleoside reverse transcriptase translocation inhibitor, following single-dose administration to treatment-naive adults infected with HIV-1: an open-label, phase 1b, consecutive-panel trial. Lancet HIV 2020; 7(3): e164-72.
[http://dx.doi.org/10.1016/S2352-3018(19)30372-8] [PMID: 31911147]
[52]
Ruane PJ, DeJesus E, Berger D, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults. J Acquir Immune Defic Syndr 2013; 63(4): 449-55.
[http://dx.doi.org/10.1097/QAI.0b013e3182965d45] [PMID: 23807155]
[53]
Childs-Kean LM, Egelund EF, Jourjy J. Tenofovir Alafenamide for the Treatment of Chronic Hepatitis B Monoinfection. Pharmacotherapy 2018; 38(10): 1051-7.
[http://dx.doi.org/10.1002/phar.2174] [PMID: 30120841]
[54]
Gunawardana M, Remedios-Chan M, Miller CS, et al. Pharmacokinetics of long-acting tenofovir alafenamide (GS-7340) subdermal implant for HIV prophylaxis. Antimicrob Agents Chemother 2015; 59(7): 3913-9.
[http://dx.doi.org/10.1128/AAC.00656-15] [PMID: 25896688]
[55]
Puri A, Bhattaccharjee SA, Zhang W, et al. Development of a transdermal delivery system for tenofovir alafenamide, a prodrug of tenofovir with potent antiviral activity against HIV and HBV. Pharmaceutics 2019; 11(4): 173.
[http://dx.doi.org/10.3390/pharmaceutics11040173] [PMID: 30970630]
[56]
Schlesinger E, Johengen D, Luecke E, et al. A tunable, biodegradable, thin-film polymer device as a long-acting implant delivering tenofovir alafenamide fumarate for HIV pre-exposure prophylaxis. Pharm Res 2016; 33(7): 1649-56.
[http://dx.doi.org/10.1007/s11095-016-1904-6] [PMID: 26975357]
[57]
O’Neill AM. Perceptual rotations on children’s Rorschachs. J Clin Psychol 1989; 45(5): 809-13.
[http://dx.doi.org/10.1002/1097-4679(198909)45:5<809:AID-JCLP2270450519>3.0.CO;2-9] [PMID: 2808740]
[58]
Ray AS, Vela JE, Boojamra CG, et al. Intracellular metabolism of the nucleotide prodrug GS-9131, a potent anti-human immunodeficiency virus agent. Antimicrob Agents Chemother 2008; 52(2): 648-54.
[http://dx.doi.org/10.1128/AAC.01209-07] [PMID: 18056281]
[59]
White KL, Margot N, Stray K, et al. GS-9131 is a novel NRTI with activity against NRTI-resistant HIV-1. InConference on Retroviruses and Opportunistic Infections 2017; Feb 13.
[60]
Mackman RL, Ray AS, Hui HC, et al. Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148. Bioorg Med Chem 2010; 18(10): 3606-17.
[http://dx.doi.org/10.1016/j.bmc.2010.03.041] [PMID: 20409721]
[61]
Freeling JP, Koehn J, Shu C, Sun J, Ho RJ. Anti-HIV drug-combination nanoparticles enhance plasma drug exposure duration as well as triple-drug combination levels in cells within lymph nodes and blood in primates. AIDS Res Hum Retroviruses 2015; 31(1): 107-14.
[http://dx.doi.org/10.1089/aid.2014.0210] [PMID: 25402233]
[62]
Gautam N, Roy U, Balkundi S, et al. Preclinical pharmacokinetics and tissue distribution of long-acting nanoformulated antiretroviral therapy. Antimicrob Agents Chemother 2013; 57(7): 3110-20.
[http://dx.doi.org/10.1128/AAC.00267-13] [PMID: 23612193]
[63]
Corsi F, Sorrentino L, Mazzucchelli S, et al. Antiretroviral therapy through barriers: a prominent role for nanotechnology in HIV-1 eradication from sanctuaries.
[64]
Sagar V, Atluri VS, Pilakka-Kanthikeel S, Nair M. Magnetic nanotherapeutics for dysregulated synaptic plasticity during neuroAIDS and drug abuse. Mol Brain 2016; 9(1): 57.
[http://dx.doi.org/10.1186/s13041-016-0236-0] [PMID: 27216740]
[65]
Li T, Gendelman HE, Zhang G, et al. Magnetic resonance imaging of folic acid-coated magnetite nanoparticles reflects tissue biodistribution of long-acting antiretroviral therapy. Int J Nanomedicine 2015; 10: 3779-90.
[PMID: 26082630]
[66]
Gendelman HE, McMillan J, Bade AN, Edagwa B, Kevadiya BD. The promise of long-acting antiretroviral therapies: from need to manufacture. Trends Microbiol 2019; 27(7): 593-606.
[http://dx.doi.org/10.1016/j.tim.2019.02.009] [PMID: 30981593]
[67]
Edagwa B, McMillan J, Sillman B, Gendelman HE. Long-acting slow effective release antiretroviral therapy. Expert Opin Drug Deliv 2017; 14(11): 1281-91.
[http://dx.doi.org/10.1080/17425247.2017.1288212] [PMID: 28128004]
[68]
Danial M, Andersen AH, Zuwala K, et al. Triple activity of lamivudine releasing sulfonated polymers against HIV-1. Mol Pharm 2016; 13(7): 2397-410.
[http://dx.doi.org/10.1021/acs.molpharmaceut.6b00156] [PMID: 27244595]
[69]
Sillman B, Bade AN, Dash PK, et al. Creation of a long-acting nanoformulated dolutegravir. Nat Commun 2018; 9(1): 443.
[http://dx.doi.org/10.1038/s41467-018-02885-x] [PMID: 29402886]
[70]
Zhou T, Su H, Dash P, et al. Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles. Biomaterials 2018; 151: 53-65.
[http://dx.doi.org/10.1016/j.biomaterials.2017.10.023] [PMID: 29059541]
[71]
McMillan J, Szlachetka A, Slack L, et al. Pharmacokinetics of a long-acting nanoformulated dolutegravir prodrug in rhesus macaques. Antimicrob Agents Chemother 2017; 62(1): e01316-7.
[http://dx.doi.org/10.1128/AAC.01316-17] [PMID: 29061742]
[72]
McMillan J, Szlachetka A, Zhou T, et al. Pharmacokinetic testing of a first-generation cabotegravir prodrug in rhesus macaques. AIDS 2019; 33(3): 585-8.
[http://dx.doi.org/10.1097/QAD.0000000000002032] [PMID: 30289818]
[73]
Lin Z, Gautam N, Alnouti Y, et al. ProTide generated long-acting abacavir nanoformulations. Chem Commun (Camb) 2018; 54(60): 8371-4.
[http://dx.doi.org/10.1039/C8CC04708A] [PMID: 29995046]
[74]
Mehellou Y, Rattan HS, Balzarini J. The ProTide Prodrug Technology: From the Concept to the Clinic. J Med Chem 2018; 61(6): 2211-26.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00734] [PMID: 28792763]
[75]
Jacobson JM, Flexner CW. Universal antiretroviral regimens: thinking beyond one-pill-once-a-day. Current Opinion in HIV and AIDS. 2017. Jul; 12(4): 343.

Rights & Permissions Print Cite
Article Metrics
40
© 2024 Bentham Science Publishers | Privacy Policy