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Injectable Antiretroviral Drugs: Back to the Future

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Injectable Antiretroviral Drugs: Back to the Future viruses Review Injectable Antiretroviral Drugs: Back to the Future Marco Berruti 1 , Niccolò Riccardi 2, Diana Canetti 3,4 , Sergio Lo Caputo 5 , Lucia Taramasso 6 and Antonio Di Biagio 1,6,* 1 Infectious Diseases Unit, Department of Health Sciences (DISSAL), University of Genoa, 16132 Genoa, Italy; [email protected] 2 Department of Infectious-Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, 37024 Verona, Italy; [email protected] 3 Clinic of Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20097 Milan, Italy; [email protected] 4 School of Medicine, Vita-Salute San Raffaele University, 20097 Milan, Italy 5 Clinic of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy; [email protected] 6 Infectious Diseases Unit, Department of Internal Medicine, Ospedale Policlinico San Martino IRCCS, 16132 Genoa, Italy; [email protected] * Correspondence: [email protected] Abstract: Current HIV treatment regimens provide sustained virologic suppression, at least partially restore the immune system and have limited side effects; however, they do not allow viral eradication and they are burdened by daily pill intake with a life-long commitment for the people living with HIV (PHIV). Injectable agents might represent a turning point in the care of PHIV, allowing less frequent administration of antiretroviral treatment (ART), more widespread use of pre-exposure prophylaxis (PrEP) and more stable drug levels in the blood, thus increasing the odds to get closer to end the HIV pandemic. The aim of this manuscript is to give a comprehensive review of injectable antiretrovirals that have been used in the past, which are available now, will be available in the future, and their role in the treatment of HIV infection Citation: Berruti, M.; Riccardi, N.; Canetti, D.; Lo Caputo, S.; Taramasso, Keywords: ART; injectable; HIV; antiretroviral; treatment; PrEP L.; Di Biagio, A. Injectable Antiretroviral Drugs: Back to the Future. Viruses 2021, 13, 228. https://doi.org/10.3390/v13020228 1. Introduction Academic Editor: Julien Van About 40 years have passed since the first cases of Acquired Immune Deficiency Grevenynghe Syndrome (AIDS) were observed, and the HIV pandemic is still responsible for roughly Received: 24 November 2020 38 million people living with the virus and 1.7 million new infections every year [1,2]. Accepted: 25 January 2021 Current treatments provide successful virological suppression, at least partially restore Published: 2 February 2021 immune system and have limited side effects; however, they do not allow viral eradication and they are burdened by daily pill intake with a life-long commitment for the patients [3]. Publisher’s Note: MDPI stays neutral Moreover, in some countries with high HIV prevalence, like in Sub-Saharan Africa, dif- with regard to jurisdictional claims in ficulties in anti-retroviral treatment (ART) delivery and poor adherence pose a constant published maps and institutional affil- threat to achieve the 90-90-90 World Health Organization (WHO) strategy goals [4,5]. iations. Furthermore, the emergence of multi-drug resistant (MDR) strains can favor virological failure, disease progression, and transmission [6]. Even if only an efficacious and free vaccine may be the answer for HIV eradication, long-acting injectable antiretrovirals may constitute a turning point for better infection control in difficult settings and decrease the Copyright: © 2021 by the authors. emergence of resistance [7,8]. In fact, long-acting ART may improve adherence to therapy Licensee MDPI, Basel, Switzerland. and extend prophylactic interventions as pre-exposure prophylaxis (PrEP) to vulnerable This article is an open access article populations [9]. The aim of this manuscript is to give a comprehensive review of injectable distributed under the terms and antiretrovirals that have been used in the past, which are available now, will be available in conditions of the Creative Commons the future, and their role in the treatment of HIV infection. Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Viruses 2021, 13, 228. https://doi.org/10.3390/v13020228 https://www.mdpi.com/journal/viruses Viruses 2021, 13, x FOR PEER REVIEW 2 of 12 Viruses 2021, 13, 228 2 of 12 2. Methods 2. Methods We performed a MEDLINE/PubMed search on 03/03/2019 and the complete search string wasWe as performed follows: a(((injectable) MEDLINE/PubMed AND antiretroviral) search on 03/03/2019 AND HIV) and AND the (Clinical complete trial) search ANDstring (“01/01/1990” was as follows: (Date-Publication): (((injectable) AND“03/03/2019” antiretroviral) (Date-Publication)). AND HIV) AND The (Clinicalstring was trial) thenAND updated (“01/01/1990” on the 30 June, (Date-Publication): 2020 to enclose “03/03/2019” more recent papers (Date-Publication)). The string was thenOf the updated 361 papers on the identified, 30 June 2020 299 towere enclose exclud moreed by recent title and papers abstract screening as they were notOf pertinent the 361 papersto our narrative identified, review. 299 were We excluded ultimately by selected title and 36 abstract papers: screening the full texts as they andwere pertinent not pertinent references to our were narrative then retrie review.ved We and ultimately collectively selected discussed. 36 papers: The thedecision full texts aboutand inclusion pertinent in references the present were narrative then retrieved review andwas collectivelyultimately made discussed. according The decision to the sub- about jectiveinclusion impression in the of present the auth narrativeors. Eventually, review was the ultimately review was made organized according for each to the drug subjective an- alyzedimpression in the following of the authors. paragraphs: Eventually, (i) “Molec the reviewular characteristics”; was organized for(ii) each“Available drug analyzed formu- in the following paragraphs: (i) “Molecular characteristics”; (ii) “Available formulations”; (iii) lations”; (iii) “Recommended doses”; and (iv) “Place in therapy”. Finally, a discussion “Recommended doses”; and (iv) “Place in therapy”. Finally, a discussion about the future about the future applications of the reviewed drugs is given. applications of the reviewed drugs is given. 3. Zidovudine3. Zidovudine (AZT) (AZT) 3.1.3.1. Molecular Molecular Characteristics Characteristics ZidovudineZidovudine (AZT) (AZT) (3’-azido-2’3’-dideoxythymidine) (30-azido-2030-dideoxythymidine) was was the thefirst first antiretroviral antiretroviral drug drug availableavailable in the in the1980s. 1980s. Initially Initially studied studied as an as antineoplastic an antineoplastic drug, drug, it subsequently it subsequently showed showed in vitroin vitro andand in invivo vivo activityactivity against against HIV-1 HIV-1 virus virus and, and, in in a a lesser extent,extent, againstagainstHTLV-1 HTLV-1 and andHIV-2. HIV-2. AZT AZT is is a thymidinea thymidine analogue analogue which which intracellularly intracellularly is phosphorylatedis phosphorylated to itsto activeits active50-triphosphate 5′-triphosphate metabolite, metabolite, zidovudine zidovudine triphosphate triphosphate (ZDV-TP). (ZDV-TP). The The principalprincipal mode of of actionaction of ZDV-TP isis thethe inhibitioninhibition of of reverse reverse transcriptase transcriptase (RT) (RT) via via DNA DNA chain chain termination termi- nationafter after incorporation incorporation of the of nucleotidethe nucleotide analogue. analogue. ZDV-TP ZDV-TP is a weakis a weak inhibitor inhibitor of the of cellular the cellularDNA DNA polymerases polymerasesα and αγ andand γ hasandbeen has been reported reported to be to incorporated be incorporated into theinto DNA the DNA of cells of cellsin culture in culture [10,11 [10,11]] (Figure (Figure1). 1). FigureFigure 1. Zidovudine. 1. Zidovudine. 3.2. Available Formulations 3.2. Available Formulations AZT is available in both oral and parenteral formulation and, by a pharmacokinetic AZT is available in both oral and parenteral formulation and, by a pharmacokinetic point of view, it shows good oral bioavailability (64%) with serum concentration peak 30 pointto 90of view, min after it shows administration good oral bioavailability [12]. The AZT (64%) serum with half-life serum is concentration 1 h but the intracellular peak 30 to 90half-life min after is about administration 3 h and is eliminated [12]. The with AZT urine serum after half-life undergoing is 1 h glucuronidation but the intracellular through half-lifethe liver. is about Of note, 3 h AZT and goodis eliminated distribution with volume urine allowsafter undergoing good penetration glucuronidation in the central throughnervous the systemliver. Of (CNS) note,and AZT through good distributi the placentaon volume [12]. allows good penetration in the central nervous system (CNS) and through the placenta [12]. Viruses 2021, 13, x FOR PEER REVIEW 3 of 12 3.3. Recommended Doses Viruses 2021, 13, 228 3 of 12 AZT is recommended at the dosage of 300 mg every 12 h in oral formulation and 1 mg/kg/dose every 4 h in the prevention of perinatal transmission of HIV (2 mg/kg loading dose followed by continuous infusion of 1 mg/kg until delivery). 3.3. Recommended Doses 3.4. Place in Therapy AZT is recommended at the dosage of 300 mg every 12 h in oral formulation and AZT use is no1 longer mg/kg/dose recommended every 4 h in in the the prevention treatment of perinatalof HIV infection; transmission
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