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Review

Long-acting approaches for delivery of antiretroviral drugs for prevention and treatment of HIV: a review of recent research

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Pages 1227-1238 | Received 16 Apr 2020, Accepted 12 Jun 2020, Published online: 06 Jul 2020

References

  • Cohen MS. Successful treatment of HIV eliminates sexual transmission. Lancet. 2019 June 15;393(10189):2366–2367.
  • Fonner VA, Dalglish SL, Kennedy CE, et al. Effectiveness and safety of oral HIV preexposure prophylaxis for all populations. Aids. 2016 July 31;30(12):1973–1983.
  • Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010 Dec 30;363(27):2587–2599.
  • Karim SS, Karim QA. Antiretroviral prophylaxis: a defining moment in HIV control. Lancet. 2011 Dec 17;378(9809):e23–5.
  • Koenig LJ, Lyles C, Smith DK. Adherence to antiretroviral medications for HIV pre-exposure prophylaxis: lessons learned from trials and treatment studies. Am J Prev Med. 2013 Jan;44(1 Suppl 2):S91–8.
  • McMahon JM, Myers JE, Kurth AE, et al. Oral pre-exposure prophylaxis (PrEP) for prevention of HIV in serodiscordant heterosexual couples in the United States: opportunities and challenges. AIDS Patient Care STDS. 2014 Sept;28(9):462–474.
  • Gulick RM, Flexner C. Long-acting HIV drugs for treatment and prevention. Annu Rev Med. 2019 Jan 27;70:137–150.
  • Gendelman HE, McMillan J, Bade AN, et al. The promise of long-acting antiretroviral therapies: from need to manufacture. Trends Microbiol. 2019 July;27(7):593–606.
  • Nachman S, Townsend CL, Abrams EJ, et al. Long-acting or extended-release antiretroviral products for HIV treatment and prevention in infants, children, adolescents, and pregnant and breastfeeding women: knowledge gaps and research priorities. Lancet HIV. 2019 Aug;6(8):e552–e58.
  • Owen A, Rannard S. Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: insights for applications in HIV therapy. Adv Drug Deliv Rev. 2016 Aug 1;103:144–156.
  • Nachega JB, Parienti JJ, Uthman OA, et al. Lower pill burden and once-daily antiretroviral treatment regimens for HIV infection: a meta-analysis of randomized controlled trials. Clin Infect Dis. 2014 May;58(9):1297–1307.
  • Taddeo D, Egedy M, Frappier JY. Adherence to treatment in adolescents. Paediatr Child Health. 2008 Jan;13(1):19–24.
  • Chen J, Flexner C, Liberman RG, et al. Biphasic elimination of tenofovir diphosphate and nonlinear pharmacokinetics of zidovudine triphosphate in a microdosing study. J Acquir Immune Defic Syndr. 2012 Dec 15;61(5):593–599.
  • Trezza C, Ford SL, Spreen W, et al. Formulation and pharmacology of long-acting cabotegravir. Curr Opin HIV AIDS. 2015 July;10(4):239–245.
  • Jacobson JM, Flexner CW. Universal antiretroviral regimens: thinking beyond one-pill-once-a-day. Curr Opin HIV AIDS. 2017 July;12(4):343–350.
  • Iglay K, Cao X, Mavros P, et al. Systematic literature review and meta-analysis of medication adherence with once-weekly versus once-daily therapy. Clin Ther. 2015 Aug;37(8):1813–21 e1.
  • Kruk ME, Schwalbe N. The relation between intermittent dosing and adherence: preliminary insights. Clin Ther. 2006 Dec;28(12):1989–1995.
  • Stoddart CA, Galkina SA, Joshi P, et al. Oral administration of the nucleoside EFdA (4ʹ-ethynyl-2-fluoro-2ʹ-deoxyadenosine) provides rapid suppression of HIV viremia in humanized mice and favorable pharmacokinetic properties in mice and the rhesus macaque. Antimicrob Agents Chemother. 2015 July;59(7):4190–4198.
  • Schurmann 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 Mar; 7(3):e164–e172.
  • Michailidis E, Huber AD, Ryan EM, et al. 4ʹ-Ethynyl-2-fluoro-2ʹ-deoxyadenosine (EFdA) inhibits HIV-1 reverse transcriptase with multiple mechanisms. J Biol Chem. 2014 Aug 29;289(35):24533–24548.
  • Salie ZL, Kirby KA, Michailidis E, et al. Structural basis of HIV inhibition by translocation-defective RT inhibitor 4ʹ-ethynyl-2-fluoro-2ʹ-deoxyadenosine (EFdA). Proc Natl Acad Sci U S A. 2016 Aug 16;113(33):9274–9279.
  • Kirby KA, Michailidis E, Fetterly TL, et al. Effects of substitutions at the 4ʹ and 2 positions on the bioactivity of 4ʹ-ethynyl-2-fluoro-2ʹ-deoxyadenosine. Antimicrob Agents Chemother. 2013 Dec;57(12):6254–6264.
  • Markowitz M, Sarafianos SG. 4ʹ-Ethynyl-2-fluoro-2ʹ-deoxyadenosine, MK-8591: a novel HIV-1 reverse transcriptase translocation inhibitor. Curr Opin HIV AIDS. 2018 July;13(4):294–299.
  • Gunaydin H, Altman MD, Ellis JM, et al. Strategy for extending half-life in drug design and its significance. ACS Med Chem Lett. 2018 June 14;9(6):528–533.
  • Smith DA, Beaumont K, Maurer TS, et al. Relevance of half-life in drug design. J Med Chem. 2018 May 24;61(10):4273–4282.
  • Hocqueloux L, Raffi F, Prazuck T, et al. Dolutegravir monotherapy versus dolutegravir/abacavir/lamivudine for virologically suppressed people living with chronic human immunodeficiency virus infection: the randomized noninferiority monotherapy of TiviCAY trial. Clin Infect Dis. 2019 Oct 15;69(9):1498–1505.
  • Pawar VK, Kansal S, Garg G, et al. Gastroretentive dosage forms: a review with special emphasis on floating drug delivery systems. Drug Deliv. 2011 Feb;18(2):97–110.
  • Prinderre P, Sauzet C, Fuxen C. Advances in gastro retentive drug-delivery systems. Expert Opin Drug Deliv. 2011 Sept;8(9):1189–1203.
  • Kirtane AR, Abouzid O, Minahan D, et al. Development of an oral once-weekly drug delivery system for HIV antiretroviral therapy. Nat Commun. 2018 Jan 9;9(1):2.
  • Savage AC, Tatham LM, Siccardi M, et al. Improving maraviroc oral bioavailability by formation of solid drug nanoparticles. Eur J Pharm Biopharm. 2019 May;138:30–36.
  • Giardiello M, Liptrott NJ, McDonald TO, et al. Accelerated oral nanomedicine discovery from miniaturized screening to clinical production exemplified by paediatric HIV nanotherapies. Nat Commun. 2016 Oct 21;7:13184.
  • McDonald TO, Giardiello M, Martin P, et al. Antiretroviral solid drug nanoparticles with enhanced oral bioavailability: production, characterization, and in vitro-in vivo correlation. Adv Healthc Mater. 2014 Mar;3(3):400–411.
  • Augustine R, Ashkenazi DL, Arzi RS, et al. Nanoparticle-in-microparticle oral drug delivery system of a clinically relevant darunavir/ritonavir antiretroviral combination. Acta Biomater. 2018 July 1;74:344–359.
  • Garg B, Beg S, Kaur R, et al. Long-chain triglycerides-based self-nanoemulsifying oily formulations (SNEOFs) of darunavir with improved lymphatic targeting potential. J Drug Target. 2018 Mar;26(3):252–266.
  • Negi LM, Tariq M, Talegaonkar S. Nano scale self-emulsifying oil based carrier system for improved oral bioavailability of camptothecin derivative by P-Glycoprotein modulation. Colloids Surf B Biointerfaces. 2013 Nov;1(111):346–353.
  • Hobson JJ, Edwards S, Slater RA, et al. Branched copolymer-stabilised nanoemulsions as new candidate oral drug delivery systems. RSC Adv. 2018;8:12984–12991.
  • Landovitz RJ, Kofron R, McCauley M. The promise and pitfalls of long-acting injectable agents for HIV prevention. Curr Opin HIV AIDS. 2016 Jan;11(1):122–128.
  • Kennedy J, Larraneta E, McCrudden MTC, et al. In vivo studies investigating biodistribution of nanoparticle-encapsulated rhodamine B delivered via dissolving microneedles. J Control Release. 2017 Nov 10;265:57–65.
  • Pastore MN, Kalia YN, Horstmann M, et al. Transdermal patches: history, development and pharmacology. Br J Pharmacol. 2015 May;172(9):2179–2209.
  • 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 Apr 9;11(4):173.
  • Mc Crudden MTC, Larraneta E, Clark A, et al. Design, formulation and evaluation of novel dissolving microarray patches containing a long-acting rilpivirine nanosuspension. J Control Release. 2018 Dec 28;292:119–129.
  • Rein-Weston A, Tekko I, Zehrung D. LB8. Microarray patch delivery of long-acting HIV PrEP and contraception. Open Forum Infect Dis. 2019;6:S996.
  • RTHO EVRA® (norelgestromin/ethinyl estradiol TRANSDERMAL SYSTEM). 2010 [cited 2020 June]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021180s035lbl.pdf
  • Sharma S, Hatware K, Bhadane P, et al. Recent advances in microneedle composites for biomedical applications: advanced drug delivery technologies. Mater Sci Eng C Mater Biol Appl. 2019 Oct;103:109717.
  • Human factors studies and related clinical study considerations in combination product design and development: draft guidance for industry and FDA staff. US Department of Health and Human Services In: FDA, ed. 2016.
  • Draft guidance on principles of premarket pathways for combination products: guidance for industry and FDA staff. In: US Department of Health and Human Services FDA CfDEaRC, ed. 2019 ed 2019.
  • UNAIDS. Update on the access components of the UNAIDS 2016–2021 strategy: removing access barriers to health technologies for HIV and its co-infections and co-morbidities in low- and middle-income countries. 2018.
  • Shisana O, Risher K, Celentano DD, et al. Does marital status matter in an HIV hyperendemic country? Findings from the 2012 South African National HIV prevalence, incidence and behaviour survey. AIDS Care. 2016;28(2):234–241.
  • Kashuba AD, Gengiah TN, Werner L, et al. Genital tenofovir concentrations correlate with protection against HIV infection in the CAPRISA 004 trial: importance of adherence for microbicide effectiveness. J Acquir Immune Defic Syndr. 2015 July 1;69(3):264–269.
  • Baeten JM, Palanee-Phillips T, Brown ER, et al. Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. N Engl J Med. 2016 Dec 1;375(22):2121–2132.
  • Nel A, van Niekerk N, Kapiga S, et al. Safety and efficacy of a dapivirine vaginal ring for HIV prevention in women. N Engl J Med. 2016 Dec 1;375(22):2133–2143.
  • Thurman AR, Schwartz JL, Brache V, et al. Randomized, placebo controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of tenofovir and tenofovir plus levonorgestrel vaginal rings in women. PLoS One. 2018;13(6):e0199778.
  • Chen BA, Panther L, Marzinke MA, et al. Phase 1 safety, pharmacokinetics, and pharmacodynamics of dapivirine and maraviroc vaginal rings: a double-blind randomized trial. J Acquir Immune Defic Syndr. 2015 Nov 1;70(3):242–249.
  • HIGHLIGHTS OF PRESCRIBING INFORMATION. These highlights do not include all the information needed to useANNOVERA™safely and effectively. See Full Prescribing Information for ANNOVERA™.ANNOVERA™ (segesterone acetate and ethinyl estradiol vaginal system). 2018 [cited 2020 June]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209627s000lbl.pdf
  • Klatt NR, Cheu R, Birse K, et al. Vaginal bacteria modify HIV tenofovir microbicide efficacy in African women. Science. 2017 June 2;356(6341):938–945.
  • Duby Z, Katz AWK, Browne EN, et al. Hygiene, blood flow, and vaginal overload: why women removed an HIV prevention vaginal ring during menstruation in Malawi, South Africa, Uganda and Zimbabwe. AIDS Behav. 2020 Feb;24(2):617–628.
  • McLellan JS, Pancera M, Carrico C, et al. Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature. 2011 Nov 23;480(7377):336–343.
  • Walker LM, Huber M, Doores KJ, et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature. 2011 Sept 22;477(7365):466–470.
  • Huang J, Kang BH, Pancera M, et al. Broad and potent HIV-1 neutralization by a human antibody that binds the gp41-gp120 interface. Nature. 2014 Nov 6;515(7525):138–142.
  • Kong R, Xu K, Zhou T, et al. Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody. Science. 2016 May 13;352(6287):828–833.
  • van Gils MJ, van den Kerkhof TL, Ozorowski G, et al. An HIV-1 antibody from an elite neutralizer implicates the fusion peptide as a site of vulnerability. Nat Microbiol. 2016 Nov 14;2:16199.
  • Scheid JF, Mouquet H, Ueberheide B, et al. Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science. 2011 Sept 16;333(6049):1633–1637.
  • Zhou T, Zheng A, Baxa U, et al. A neutralizing antibody recognizing primarily N-linked glycan targets the silent face of the HIV envelope. Immunity. 2018 Mar 20;48(3):500–13 e6.
  • Schoofs T, Barnes CO, Suh-Toma N, et al. Broad and potent neutralizing antibodies recognize the silent face of the HIV envelope. Immunity. 2019 June 18;50(6):1513–29 e9.
  • Gruell H, Klein F. Antibody-mediated prevention and treatment of HIV-1 infection. Retrovirology. 2018 Nov 16;15(1):73.
  • Wang Q, Zhang L. Broadly neutralizing antibodies and vaccine design against HIV-1 infection. Front Med. 2020 Feb;14(1):30–42.
  • Caskey M, Klein F, Lorenzi JC, et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature. 2015 June 25;522(7557):487–491.
  • Gaudinski MR, Coates EE, Houser KV, et al. Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: a phase 1 open-label clinical trial in healthy adults. PLoS Med. 2018 Jan;15(1):e1002493.
  • Bar KJ, Sneller MC, Harrison LJ, et al. Effect of HIV antibody VRC01 on viral rebound after treatment interruption. N Engl J Med. 2016 Nov 24;375(21):2037–2050.
  • Scheid JF, Horwitz JA, Bar-On Y, et al. HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature. 2016 July 28;535(7613):556–560.
  • Bar-On Y, Gruell H, Schoofs T, et al. Safety and antiviral activity of combination HIV-1 broadly neutralizing antibodies in viremic individuals. Nat Med. 2018 Nov;24(11):1701–1707.
  • Mendoza P, Gruell H, Nogueira L, et al. Combination therapy with anti-HIV-1 antibodies maintains viral suppression. Nature. 2018 Sept;561(7724):479–484.
  • Lynch RM, Boritz E, Coates EE, et al. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Sci Transl Med. 2015 Dec 23;7(319):319ra206.
  • Gautam R, Nishimura Y, Gaughan N, et al. A single injection of crystallizable fragment domain-modified antibodies elicits durable protection from SHIV infection. Nat Med. 2018 May;24(5):610–616.
  • Liu Q, Lai YT, Zhang P, et al. Improvement of antibody functionality by structure-guided paratope engraftment. Nat Commun. 2019 Feb 13;10(1):721.
  • Nyaku AN, Kelly SG, Taiwo BO. Long-acting antiretrovirals: where are we now? Curr HIV/AIDS Rep. 2017 Apr;14(2):63–71.
  • Flexner C. Antiretroviral implants for treatment and prevention of HIV infection. Curr Opin HIV AIDS. 2018 July;13(4):374–380.
  • Malcolm RK, Fetherston SM, McCoy CF, et al. Vaginal rings for delivery of HIV microbicides. Int J Womens Health. 2012;4:595–605.
  • Chen J, Walters K, Ashton P. Correlation of in vitro-in vivo release rates for sustained release nevirapine implants in rats. J Control Release. 2005 Jan 3;101(1–3):357–358.
  • Devlin B, Nuttall J, Wilder S, et al. Development of dapivirine vaginal ring for HIV prevention. Antiviral Res. 2013 Dec;100(Suppl):S3–8.
  • Nel AM, Coplan P, Smythe SC, et al. Pharmacokinetic assessment of dapivirine vaginal microbicide gel in healthy, HIV-negative women. AIDS Res Hum Retroviruses. 2010 Nov;26(11):1181–1190.
  • Kovarova M, Benhabbour SR, Massud I, et al. Ultra-long-acting removable drug delivery system for HIV treatment and prevention. Nat Commun. 2018 Oct 8;9(1):4156.
  • Benhabbour SR, Kovarova M, Jones C, et al. Ultra-long-acting tunable biodegradable and removable controlled release implants for drug delivery. Nat Commun. 2019 Sept 20;10(1):4324.
  • Barrett SE, Teller RS, Forster SP, et al. Extended-duration MK-8591-eluting implant as a candidate for HIV treatment and prevention. Antimicrob Agents Chemother. 2018 Oct;62(10). DOI:10.1128/AAC.01058-18
  • Matthews RP, Barrett SE, Patel M, et al. First-in-human trial of MK-8591-eluting implants demonstrates concentrations suitable for HIV prophylaxis for at least one year. 10th IAS Conference on HIV Science. Mexico City, Mexico; 2019.
  • Johnson LM, Krovi SA, Li L, et al. Characterization of a reservoir-style implant for sustained release of tenofovir alafenamide (TAF) for HIV pre-exposure prophylaxis (PrEP). Pharmaceutics. 2019 July 4;11(7):315.
  • 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 July;33(7):1649–1656.
  • 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 July;59(7):3913–3919.
  • Chua CYX, Jain P, Ballerini A, et al. Transcutaneously refillable nanofluidic implant achieves sustained level of tenofovir diphosphate for HIV pre-exposure prophylaxis. J Control Release. 2018 Sept 28;286:315–325.
  • Pons-Faudoa FP, Sizovs A, Di Trani N, et al. 2-Hydroxypropyl-beta-cyclodextrin-enhanced pharmacokinetics of cabotegravir from a nanofluidic implant for HIV pre-exposure prophylaxis. J Control Release. 2019 July 28;306:89–96.
  • Su JT, Simpson SM, Sung S, et al. A subcutaneous implant of tenofovir alafenamide fumarate causes local inflammation and tissue necrosis in rabbits and macaques. Antimicrob Agents Chemother. 2020 Feb 21;64(3). DOI:10.1128/AAC.02247-19
  • Pons-Faudoa FP, Ballerini A, Sakamoto J, et al. Advanced implantable drug delivery technologies: transforming the clinical landscape of therapeutics for chronic diseases. Biomed Microdevices. 2019 May 18;21(2):47.
  • Spreen WR, Margolis DA, Pottage JC Jr. Long-acting injectable antiretrovirals for HIV treatment and prevention. Curr Opin HIV AIDS. 2013 Nov;8(6):565–571.
  • Rabinow BE. Nanosuspensions in drug delivery. Nat Rev Drug Discov. 2004 Sept;3(9):785–796.
  • van ‘T Klooster G, Hoeben E, Borghys H, et al. Pharmacokinetics and disposition of rilpivirine (TMC278) nanosuspension as a long-acting injectable antiretroviral formulation. Antimicrob Agents Chemother. 2010 May;54(5):2042–2050.
  • Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med. 2020 Mar 19;382(12):1112–1123.
  • Orkin C, Arasteh K, Gorgolas Hernandez-Mora M, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med. 2020 Mar 19;382(12):1124–1135.
  • 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 Sept 23;390(10101):1499–1510.
  • Markowitz M, Frank I, Grant RM, et al. Safety and tolerability of long-acting cabotegravir injections in HIV-uninfected men (ECLAIR): a multicentre, double-blind, randomised, placebo-controlled, phase 2a trial. Lancet HIV. 2017 Aug;4(8):e331–e40.
  • Zhou T, Su H, Dash P, et al. Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles. Biomaterials. 2018 Jan;151:53–65.
  • ViiV Healthcare presents positive 48-week data from phase III study showing every-two-month regimen of investigational long-acting, injectable cabotegravir and rilpivirine has similar efficacy to once-monthly dosing. 2020 [cited 2020 June]. Available from: https://viivhealthcare.com/en-gb/media/press-releases/2020/march/viiv-healthcare-presents-positive–48-week-data-from-phase-iii-s/
  • Global HIV prevention study to stop early after ViiV Healthcare’s long-acting injectable formulation of cabotegravir dosed every two months shows higher efficacy than daily oral PrEP. 2020 [cited 2020 June]. Available from: https://viivhealthcare.com/en-gb/media/press-releases/2020/may/global-hiv-prevention-study-to-stop-early-after-viiv-healthcares/
  • 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.
  • Sager JE, Begley R, Rhee M, et al. Safety and PK of subcutaneous GS-6207, a novel HIV-1 capsid inhibitor. Conference on Retroviruses and Opportunistic Infections. Seattle (WA); 2019.
  • Edagwa B, McMillan J, Sillman B, et al. Long-acting slow effective release antiretroviral therapy. Expert Opin Drug Deliv. 2017 Nov;14(11):1281–1291.
  • Zhou T, Lin Z, Puligujja P, et al. Optimizing the preparation and stability of decorated antiretroviral drug nanocrystals. Nanomedicine (Lond). 2018 Apr;13(8):871–885.
  • Sillman B, Bade AN, Dash PK, et al. Creation of a long-acting nanoformulated dolutegravir. Nat Commun. 2018 Feb 6;9(1):443.
  • Hilaire JR, Bade AN, Sillman B, et al. Creation of a long-acting rilpivirine prodrug nanoformulation. J Control Release. 2019 Oct;311–312:201–211.
  • Smith N, Bade AN, Soni D, et al. A long acting nanoformulated lamivudine ProTide. Biomaterials. 2019 Dec;223:119476.
  • Soni D, Bade AN, Gautam N, et al. Synthesis of a long acting nanoformulated emtricitabine ProTide. Biomaterials. 2019 Nov;222:119441.
  • Ibrahim IM, Bade AN, Lin Z, et al. Synthesis and characterization of a long-acting emtricitabine prodrug nanoformulation. Int J Nanomedicine. 2019;14:6231–6247.
  • Lin Z, Gautam N, Alnouti Y, et al. ProTide generated long-acting abacavir nanoformulations. Chem Commun (Camb). 2018 July 24;54(60):8371–8374.
  • McMillan J, Szlachetka A, Zhou T, et al. Pharmacokinetic testing of a first-generation cabotegravir prodrug in rhesus macaques. AIDS. 2019 Mar 1;33(3):585–588.
  • Rautio J, Meanwell NA, Di L, et al. The expanding role of prodrugs in contemporary drug design and development. Nat Rev Drug Discov. 2018 Aug;17(8):559–587.
  • Huttunen KM, Raunio H, Rautio J. Prodrugs–from serendipity to rational design. Pharmacol Rev. 2011 Sept;63(3):750–771.
  • Rautio J, Kumpulainen H, Heimbach T, et al. Prodrugs: design and clinical applications. Nat Rev Drug Discov. 2008 Mar;7(3):255–270.
  • Dash PK, Kaminski R, Bella R, et al. Sequential LASER ART and CRISPR treatments eliminate HIV-1 in a subset of infected humanized mice. Nat Commun. 2019 July 2;10(1):2753.
  • Gnanadhas DP, Dash PK, Sillman B, et al. Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs. J Clin Invest. 2017 Mar 1;127(3):857–873.
  • Thomas MB, Gnanadhas DP, Dash PK, et al. Modulating cellular autophagy for controlled antiretroviral drug release. Nanomedicine (Lond). 2018 Sept;13(17):2139–2154.
  • Kulkarni TA, Bade AN, Sillman B, et al. A year-long extended release nanoformulated cabotegravir prodrug. Nat Mater. 2020 Apr 27. DOI:10.1038/s41563-020-0674-z
  • Cauchon NS, Oghamian S, Hassanpour S, et al. Innovation in chemistry, manufacturing, and controls-a regulatory perspective from industry. J Pharm Sci. 2019 July;108(7):2207–2237.
  • Moore GL, Stringham RW, Teager DS, et al. Practical synthesis of the bicyclic darunavir side chain: (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol from monopotassium Isocitrate. Org Process Res Dev. 2017 Jan 20;21(1):98–106.

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