Long acting systemic HIV pre-exposure prophylaxis: an examination of the field

  • William R. Lykins
  • Ellen Luecke
  • Daniel Johengen
  • Ariane van der Straten
  • Tejal A. Desai
Review Article


Oral pre-exposure prophylaxis for the prevention of HIV-1 transmission (HIV PrEP) has been widely successful as demonstrated by a number of clinical trials. However, studies have also demonstrated the need for patients to tightly adhere to oral dosing regimens in order to maintain protective plasma and tissue concentrations. This is especially true for women, who experience less forgiveness from dose skipping than men in clinical trials of HIV PrEP. There is increasing interest in long-acting (LA), user-independent forms of HIV PrEP that could overcome this adherence challenge. These technologies have taken multiple forms including LA injectables and implantables. Phase III efficacy trials are ongoing for a LA injectable candidate for HIV PrEP. This review will focus on the design considerations for both LA injectable and implantable platforms for HIV PrEP. Additionally, we have summarized the existing LA technologies currently in clinical and pre-clinical studies for HIV PrEP as well as other technologies that have been applied to HIV PrEP and contraceptives. Our discussion will focus on the potential application of these technologies in low resource areas, and their use in global women’s health.


HIV prevention Pre-exposure prophylaxis Antiretroviral Chemo prophylaxis Long acting 


  1. 1.
    UNAIDS, AIDS By the Numbers, Geneva, Switzerland, 2016.Google Scholar
  2. 2.
    Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012;367(5):399–410. doi:10.1056/NEJMoa1108524.
  3. 3.
    Thigpen MC, Kebaabetswe PM, Paxton LA, Smith DK, Rose CE, Segolodi TM, et al. Antiretroviral Preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367:423–34. doi:10.1056/NEJMoa1110711.PubMedGoogle Scholar
  4. 4.
    Choopanya K, Martin M, Suntharasamai P, Sangkum U, Mock PA, Leethochawalit M, et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2013;381:2083–90. doi:10.1016/S0140-6736(13)61127-7.PubMedGoogle Scholar
  5. 5.
    Marrazzo JM, Ramjee G, Richardson BA, Gomez K, Mgodi N, Nair G, et al. Tenofovir-based Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2015;372:509–18. doi:10.1056/NEJMoa1402269.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363:2587–99. doi:10.1056/NEJMoa1011205.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Cottrell ML, Yang KH, Prince HMA, Sykes C, White N, Malone S, et al. A translational pharmacology approach to predicting outcomes of Preexposure prophylaxis against HIV in men and women using Tenofovir Disoproxil fumarate with or without Emtricitabine. J Infect Dis. 2016;214:55–64. doi:10.1093/infdis/jiw077.PubMedGoogle Scholar
  8. 8.
    Dezzutti CS, Hendrix CW, Marrazzo JM, Pan Z, Wang L, Louissaint N, et al. Performance of swabs, lavage, and diluents to quantify biomarkers of female genital tract soluble mucosal mediators. PLoS One. 2011;6 doi:10.1371/journal.pone.0023136.
  9. 9.
    Van Damme L, Corneli A, Ahmed K, Agot K, Lombaard J, Kapiga S, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367:411–22. doi:10.1056/NEJMoa1202614.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Hickey MB, Merisko-Liversidge E, Remenar JF, Namchuk M. Delivery of long-acting injectable antivirals. Curr Opin Infect Dis. 2015;28:1. doi:10.1097/QCO.0000000000000214.Google Scholar
  11. 11.
    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;103:144–56. doi:10.1016/j.addr.2016.02.003.PubMedGoogle Scholar
  12. 12.
    Boffito M, Jackson A, Owen A, Becker S. New approaches to antiretroviral drug delivery: challenges and opportunities associated with the use of long-acting injectable agents. Drugs. 2014;74:7–13. doi:10.1007/s40265-013-0163-7.PubMedGoogle Scholar
  13. 13.
    Krakower DS, Mayer KH. Pre-exposure prophylaxis to prevent HIV infection: current status, future opportunities and challenges. Drugs. 2015;75:243–51. doi:10.1007/s40265-015-0355-4.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Myers JE, Ellman TM, Westhoff C. Injectable agents for pre-exposure prophylaxis: lessons learned from contraception to inform HIV prevention. Curr Opin HIV AIDS. 2015;10:271–7. doi:10.1097/COH.0000000000000166.PubMedGoogle Scholar
  15. 15.
    Nelson AG, Zhang X, Ganapathi U, Szekely Z, Flexner CW, Owen A, et al. Drug delivery strategies and systems for HIV/AIDS pre-exposure prophylaxis and treatment. J Control Release. 2015;219:669–80. doi:10.1016/j.jconrel.2015.08.042.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Spreen WR, Margolis DA, Pottage JC. Long-acting injectable antiretrovirals for HIV treatment and prevention. Curr Opin HIV AIDS. 2013;8:565–71. doi:10.1097/COH.0000000000000002.PubMedPubMedCentralGoogle Scholar
  17. 17.
    McGowan I. Injectable and implantable antiretroviral strategies for HIV prevention. Future Virol. 2015;10:1163–76. doi:10.2217/fvl.15.83.Google Scholar
  18. 18.
    Nyaku AN, Kelly SG, Taiwo BO. Long-acting Antiretrovirals: where are we now? Curr HIV/AIDS Rep. 2017; doi:10.1007/s11904-017-0353-0.
  19. 19.
    Parsons JT, Rendina HJ, Whitfield THF, Grov C. Familiarity with and preferences for oral and long-acting injectable HIV pre-exposure prophylaxis (PrEP) in a National Sample of gay and bisexual men in the U.S. AIDS Behav. 2016;20:1390–9. doi:10.1007/s10461-016-1370-5.PubMedGoogle Scholar
  20. 20.
    Luecke EH, Cheng H, Woeber K, Nakyanzi T, Mudekunye-Mahaka IC, van der Straten A. Stated product formulation preferences for HIV pre-exposure prophylaxis among women in the VOICE-D (MTN-003D) study. J Int AIDS Soc. 2016;19:1–9. doi:10.7448/IAS.19.1.20875.Google Scholar
  21. 21.
    Eisingerich AB, Wheelock A, Gomez GB, Garnett GP, Dybul MR, Piot PK. Attitudes and acceptance of oral and parenteral HIV preexposure prophylaxis among potential user groups: a multinational study. PLoS One. 2012;7(1):1–11. doi:10.1371/journal.pone.0028238.
  22. 22.
    Spreen W, Williams P, Margolis D, Ford SL, Crauwels H, Lou Y, et al. Pharmacokinetics, safety, and tolerability with repeat doses of GSK1265744 and Rilpivirine (TMC278) long-acting Nanosuspensions in healthy adults. J Acquir Immune Defic Syndr. 2014;67:487–92. doi:10.1097/QAI.0000000000000365.PubMedGoogle Scholar
  23. 23.
    Cortez JM, Quintero R, Moss JA, Beliveau M, Smith TJ, Baum MM. Pharmacokinetics of injectable, long-acting nevirapine for HIV prophylaxis in breastfeeding infants. Antimicrob Agents Chemother. 2015;59:59–66. doi:10.1128/AAC.03906-14.PubMedGoogle Scholar
  24. 24.
    Kalepu S, Nekkanti V. Improved delivery of poorly soluble compounds using nanoparticle technology : a review. Drug Deliv Transl Res. 2016:319–32. doi:10.1007/s13346-016-0283-1.
  25. 25.
    Rabinow BE. Nanosuspensions in drug delivery. Nat Rev Drug Discov. 2004;3:785–96. doi:10.1038/nrd1494.PubMedGoogle Scholar
  26. 26.
    Na GC, Stevens HJ, Yuan BO, Rajagopalan N. Physical stability of ethyl diatrizoate nanocrystalline suspension in steam sterilization. Pharm Res. 1999;16:569–74. doi:10.1023/A:1018883431970.PubMedGoogle Scholar
  27. 27.
    Yadollahi R, Vasilev K, Simovic S. Nanosuspension Technologies for Delivery of poorly soluble drugs. J Nanomater. 2015;2015:1–13. doi:10.1155/2015/216375.Google Scholar
  28. 28.
    Merisko-Liversidge EM, Liversidge GG. Drug nanoparticles: formulating poorly water-soluble compounds. Toxicol Pathol. 2008;36:43–8. doi:10.1177/0192623307310946.PubMedGoogle Scholar
  29. 29.
    Merisko-Liversidge E, Liversidge GG, Cooper ER. Nanosizing: a formulation approach for poorly-water-soluble compounds. Eur J Pharm Sci. 2003;18:113–20. doi:10.1016/S0928-0987(02)00251-8.PubMedGoogle Scholar
  30. 30.
    Ziller K, Rupprecht H. Control of crystal-growth in drug suspensions .2. Influence of polymers on dissolution and crystallization during temperature cycling. Pharm Ind. 1990;52:1017–22.Google Scholar
  31. 31.
    Keck CM, Müller RH. Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. Eur J Pharm Biopharm. 2006;62:3–16. doi:10.1016/j.ejpb.2005.05.009.PubMedGoogle Scholar
  32. 32.
    Gao L, Zhang D, Chen M. Drug nanocrystals for the formulation of poorly soluble drugs and its application as a potential drug delivery system. J Nanopart Res. 2008;10:845–62. doi:10.1007/s11051-008-9357-4.Google Scholar
  33. 33.
    Zuidema J, Pieters FAJM, Duchateau GSMJE. Release and absorption rate aspects of intramuscularly injected pharmaceuticals. Int J Pharm. 1988;47:1–12. doi:10.1016/0378-5173(88)90209-8.Google Scholar
  34. 34.
    Stout PJM, Khoury N, Howard SA, Mauger JW. Dissolution performance related to particle size distribution for cohpiercially available prednisolone acetate suspensions. Drug Dev Ind Pharm. 1992;18(4):395–408. doi:10.3109/03639049209043860.
  35. 35.
    Theis JG, Liau-Chu M, Chan HS, Doyle J, Greenberg ML, Koren G. Anaphylactoid reactions in children receiving high-dose intravenous cyclosporine for reversal of tumor resistance: the causative role of improper dissolution of Cremophor EL. J Clin Oncol. 1995;13:2508–16. doi:10.1200/JCO.1995.13.10.2508.PubMedGoogle Scholar
  36. 36.
    Boedeker BH, Lojeski EW, Kline MD, Haynes DH. Ultra-long-duration local anesthesia produced by injection of lecithin-coated Tetracaine microcrystals. J Clin Pharmacol. 1994;34:699–702. doi:10.1002/j.1552-4604.1994.tb02026.x.PubMedGoogle Scholar
  37. 37.
    Rajoli RKR, Back DJ, Rannard S, Freel Meyers CL, Flexner C, Owen A, et al. Physiologically based pharmacokinetic modelling to inform development of intramuscular long-acting Nanoformulations for HIV. Clin Pharmacokinet. 2015;54:639–50. doi:10.1007/s40262-014-0227-1.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Williams PE, Crauwels HM, Basstanie ED. Formulation and pharmacology of long-acting rilpivirine. Curr Opin HIV AIDS. 2015;10:233–8. doi:10.1097/COH.0000000000000164.PubMedGoogle Scholar
  39. 39.
    van’t Klooster G, Hoeben E, Borghys H, Looszova A, Bouche MP, van Velsen F, et al. Pharmacokinetics and disposition of Rilpivirine (TMC278) Nanosuspension as a long-acting injectable antiretroviral formulation, Antimicrob. Agents Chemother. 2010;54:2042–50. doi:10.1128/AAC.01529-09.Google Scholar
  40. 40.
    McGowan I, Dezzutti CS, Siegel A, Engstrom J, Nikiforov A, Duffill K, et al. Long-acting rilpivirine as potential pre-exposure prophylaxis for HIV-1 prevention (the MWRI-01 study): an open-label, phase 1, compartmental, pharmacokinetic and pharmacodynamic assessment. Lancet HIV. 2016;3018:1–10. doi:10.1016/S2352-3018(16)30113-8.Google Scholar
  41. 41.
    Spreen W, Min S, Ford SL, Chen S, Lou Y, Bomar M, et al. Pharmacokinetics, safety, and monotherapy antiviral activity of GSK1265744, an HIV integrase strand transfer inhibitor. HIV Clin Trials. 2014;14:192–203. doi:10.1310/hct1405-192.Google Scholar
  42. 42.
    Spreen W, Ford SL, Chen S, Wilfret D, Margolis D, Gould E, et al. GSK1265744 pharmacokinetics in plasma and tissue after single-dose long-acting injectable Administration in Healthy Subjects. JAIDS J Acquir Immune Defic Syndr. 2014;67:481–6. doi:10.1097/QAI.0000000000000301.PubMedGoogle Scholar
  43. 43.
    Margolis DA, Boffito M. Long-acting antiviral agents for HIV treatment. Curr Opin HIV AIDS. 2015;10:246–52. doi:10.1097/COH.0000000000000169.PubMedGoogle Scholar
  44. 44.
    Andrews CD, Heneine W. Cabotegravir long-acting for HIV-1 prevention. Curr Opin HIV AIDS. 2015;10:258–63. doi:10.1097/COH.0000000000000161.PubMedGoogle Scholar
  45. 45.
    Kovarova M, Swanson MD, Sanchez RI, Baker CE, Steve J, Spagnuolo RA, et al. A long-acting formulation of the integrase inhibitor raltegravir protects humanized BLT mice from repeated high-dose vaginal HIV challenges. J Antimicrob Chemother. 2016:1–11. doi:10.1093/jac/dkw042.
  46. 46.
    Yoshinaga T, Kobayashi M, Seki T, Miki S, Wakasa-Morimoto C, Suyama-Kagitani A, et al. Antiviral characteristics of GSK1265744, an HIV integrase inhibitor dosed orally or by long-acting injection. Antimicrob Agents Chemother. 2015;59:397–406. doi:10.1128/AAC.03909-14.PubMedGoogle Scholar
  47. 47.
    Mordant C, Schmitt B, Pasquier E, Demestre C, Queguiner L, Masungi C, et al. Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains. Eur J Med Chem. 2007;42:567–79. doi:10.1016/j.ejmech.2006.11.014.PubMedGoogle Scholar
  48. 48.
    Goebel F, Yakovlev A, Pozniak AL, Vinogradova E, Boogaerts G, Hoetelmans R, et al. Short-term antiviral activity of TMC278 - a novel NNRTI - in treatment-naive HIV-1-infected subjects. AIDS. 2006;20:1721–6. doi:10.1097/01.aids.0000242818.65215.bd.PubMedGoogle Scholar
  49. 49.
    Baert L. G. Van ‘t Klooster, W. Dries, M. François, A. Wouters, E. Basstanie, et al., development of a long-acting injectable formulation with nanoparticles of rilpivirine (TMC278) for HIV treatment. Eur J Pharm Biopharm. 2009;72:502–8. doi:10.1016/j.ejpb.2009.03.006.PubMedGoogle Scholar
  50. 50.
    Jackson A, McGowan I. Long-acting rilpivirine for HIV prevention. Curr Opin HIV AIDS. 2015;10:253–7. doi:10.1097/COH.0000000000000160.PubMedGoogle Scholar
  51. 51.
    Gautam R, Nishimura Y, Pegu A, Nason MC, Klein F, Gazumyan A, et al. A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. Nature. 2016;533:105–9. doi:10.1038/nature17677.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Saunders KO, Pegu A, Georgiev IS, Zeng M, Joyce MG, Yang Z-Y, et al. Sustained delivery of a broadly neutralizing antibody in nonhuman primates confers long-term protection against simian/human immunodeficiency virus infection. J Virol. 2015;89:5895–903. doi:10.1128/JVI.00210-15.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Sun M, Li Y, Yuan Z, Lu W, Kang G, Fan W, et al. VRC01 antibody protects against vaginal and rectal transmission of human immunodeficiency virus 1 in hu-BLT mice. Arch Virol. 2016;161:2449–55. doi:10.1007/s00705-016-2942-4.PubMedGoogle Scholar
  54. 54.
    Ledgerwood JE, Coates EE, Yamshchikov G, Saunders JG, Holman L, Enama ME, et al. Safety, pharmacokinetics and neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults. Clin Exp Immunol. 2015;182:289–301. doi:10.1111/cei.12692.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Whaley KJ, Zeitlin L. Antibody-based concepts for multipurpose prevention technologies. Antivir Res. 2013;100:S48–53. doi:10.1016/j.antiviral.2013.09.027.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Cheeseman HM, Olejniczak NJ, Rogers PM, King DFL, Ziprin P, Liao H-X, et al. Broadly Neutralising Antibodies Display Superior Potential Over Non- 1 Neutralising Antibodies in Preventing HIV-1 infection of Mucosal Tissue 2 3 Running Title: Mucosal HIV-1 Antibody Inhibition 4 5 2016. doi:10.1128/JVI.01762-16.
  57. 57.
    Zalevsky J, Chamberlain AK, Horton HM, Karki S, Leung IWL, Sproule TJ, et al. Enhanced antibody half-life improves in vivo activity. Nat Biotechnol. 2010;28:157–9. doi:10.1038/nbt.1601.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Dall’Acqua WF, Kiener PA, Wu H. Properties of human IgG1s engineered for enhanced binding to the neonatal fc receptor (FcRn). J Biol Chem. 2006;281:23514–24. doi:10.1074/jbc.M604292200.PubMedGoogle Scholar
  59. 59.
    Warne NW. Development of high concentration protein biopharmaceuticals: the use of platform approaches in formulation development. Eur J Pharm Biopharm. 2011;78:208–12. doi:10.1016/j.ejpb.2011.03.004.PubMedGoogle Scholar
  60. 60.
    Hoffman AS. The origins and evolution of “controlled” drug delivery systems. J Control Release. 2008;132:153–63. doi:10.1016/j.jconrel.2008.08.012.PubMedGoogle Scholar
  61. 61.
    Brambilla D, Luciani P, Leroux JC. Breakthrough discoveries in drug delivery technologies: the next 30 years. J Control Release. 2014;190:9–14. doi:10.1016/j.jconrel.2014.03.056.PubMedGoogle Scholar
  62. 62.
    Stevenson CL, Santini JT, Langer R. Reservoir-based drug delivery systems utilizing microtechnology. Adv Drug Deliv Rev. 2012;64:1590–602. doi:10.1016/j.addr.2012.02.005.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Anselmo AC, Mitragotri S. An overview of clinical and commercial impact of drug delivery systems. J Control Release. 2014;190:15–28. doi:10.1016/j.jconrel.2014.03.053.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Park K. Controlled drug delivery systems: past forward and future back. J Control Release. 2014;190:3–8. doi:10.1016/j.jconrel.2014.03.054.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Solorio L, Carlson A, Zhou H, Exner AA. Implantable Drug Delivery Systems. In: Eng. Polym. Syst. Improv. Drug Deliv., John Wiley & Sons, Inc., Hoboken, NJ, USA, 2014. pp. 189–225. doi:10.1002/9781118747896.ch7.
  66. 66.
    Rajgor N, Bhaskar V, Patel M. Implantable drug delivery systems: an overview. Syst Rev Pharm. 2011;2:91. doi:10.4103/0975-8453.86297.Google Scholar
  67. 67.
    Lewis KA, Goldyn AK, West KW, Eugster EA. A single histrelin implant is effective for 2 years for treatment of central precocious puberty. J Pediatr. 2013;163:1214–6. doi:10.1016/j.jpeds.2013.05.033.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Wenzl R, Van Beek A, Schnabel P, Huber J. Pharmacokinetics of etonogestrel released from the contraceptive implant Implanon®. Contraception. 1998;58:283–8. doi:10.1016/S0010-7824(98)00110-3.PubMedGoogle Scholar
  69. 69.
    Palomba S, Falbo A, Di Cello A, Materazzo C, Zullo F. Nexplanon: the new implant for long-term contraception. A comprehensive descriptive review. Gynecol Endocrinol. 2012;28:710–21. doi:10.3109/09513590.2011.652247.PubMedGoogle Scholar
  70. 70.
    Ritger PL, Peppas NA. A simple equation for description of solute release I. Fickian and non-fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs. J Control Release. 1987;5:23–36. doi:10.1016/0168-3659(87)90034-4.Google Scholar
  71. 71.
    Hsieh DS, Rhine WD, Langer R. Zero-order controlled-release polymer matrices for micro- and macromolecules. J Pharm Sci. 1983;72:17–22. doi:10.1002/jps.2600720105.PubMedGoogle Scholar
  72. 72.
    Del Valle EMM, Galán MA, Carbonell RG. Drug delivery technologies: the way forward in the new decade. Ind Eng Chem Res. 2009;48:2475–86. doi:10.1021/ie800886m.Google Scholar
  73. 73.
    Au JS, Jang SH, Zheng J, Chen CT, Song S, Hu L, et al. Determinants of drug delivery and transport to solid tumors. J Control Release. 2001;74:31–46. doi:10.1016/S0168-3659(01)00308-X.PubMedGoogle Scholar
  74. 74.
    Vidin E, Garbin O, Rodriguez B, Favre R, Bettahar-Lebugle K. Removal of etonogestrel contraceptive implants in the operating theater: report on 28 cases. Contraception. 2007;76:35–9. doi:10.1016/j.contraception.2007.03.012.PubMedGoogle Scholar
  75. 75.
    Mascarenhas L. Insertion and removal of Implanon®. Contraception. 1998;58:79S–83S. doi:10.1016/S0010-7824(98)00121-8.PubMedGoogle Scholar
  76. 76.
    Williams DF. Biocompatibility pathways; biomaterials-induced sterile inflammation, Mechanotransduction and principles of biocompatibility control. ACS Biomater Sci Eng. 2016; doi:10.1021/acsbiomaterials.6b00607.
  77. 77.
    Klopfleisch K, Jung F. The pathology of the foreign body reaction against biomaterials. J Biomed Mater Res Part A. 2017;105(3):927–940. doi:10.1002/jbm.a.35958.
  78. 78.
    Sheikh Z, Brooks PJ, Barzilay O, Fine N, Glogauer M. Macrophages, foreign body giant cells and their response to implantable biomaterials. Materials (Basel). 2015;8:5671–701. doi:10.3390/ma8095269.Google Scholar
  79. 79.
    Benagiano G, Gabelnick H, Farris M. Contraceptive devices: subcutaneous delivery systems. Expert Rev Med Devices. 2008;5:623–37. doi:10.1586/17434440.5.5.623.PubMedGoogle Scholar
  80. 80.
    Holt J, Brimer A, Fetherston S, Boyd P, Devlin B, Malcolm K. Matrix vaginal ring formulations that maintain target in vitro release rates of Dapivirine and Levonorgestrel (alone or in combination) over 90 days. AIDS Res Hum Retrovir. 2014;30:A138–9. doi:10.1089/aid.2014.5276.abstract.Google Scholar
  81. 81.
    Schlesinger E, Ciaccio N, Desai TA. Polycaprolactone thin-film drug delivery systems: empirical and predictive models for device design. Mater Sci Eng C. 2015;57:232–9. doi:10.1016/j.msec.2015.07.027.Google Scholar
  82. 82.
    Ratner BD. The biocompatibility manifesto: biocompatibility for the twenty-first century. J Cardiovasc Transl Res. 2011;4:523–7. doi:10.1007/s12265-011-9287-x.PubMedGoogle Scholar
  83. 83.
    Burada PS, Hänggi P, Marchesoni F, Schmid G, Talkner P. Diffusion in confined geometries. ChemPhysChem. 2009;10:45–54. doi:10.1002/cphc.200800526.PubMedGoogle Scholar
  84. 84.
    Bernards DA, Lance KD, Ciaccio NA, Desai TA. Nanostructured thin film polymer devices for constant-rate protein delivery. Nano Lett. 2012;12:5355–61. doi:10.1021/nl302747y.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Ferrati S, Fine D, You J, De Rosa E, Hudson L, Zabre E, et al. Leveraging nanochannels for universal, zero-order drug delivery in vivo. J Control Release. 2013;172:1011–9. doi:10.1016/j.jconrel.2013.09.028.PubMedGoogle Scholar
  86. 86.
    Gunawardana M, Remedios-Chan M, Miller CS, Fanter R, Yang F, Marzinke MA, et al. Pharmacokinetics of long-acting tenofovir alafenamide (GS-7340) subdermal implant for HIV prophylaxis. Antimicrob Agents Chemother. 2015;59:3913–9. doi:10.1128/AAC.00656-15.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Ma G, Song C, Sun H, Yang J, Leng X. A biodegradable levonorgestrel-releasing implant made of PCL/F68 compound as tested in rats and dogs. Contraception. 2006;74:141–7. doi:10.1016/j.contraception.2006.02.013.PubMedGoogle Scholar
  88. 88.
    Ray AS, Fordyce MW, Hitchcock MJM. Tenofovir alafenamide: a novel prodrug of tenofovir for the treatment of human immunodeficiency virus. Antivir Res. 2016;125:63–70. doi:10.1016/j.antiviral.2015.11.009.PubMedGoogle Scholar
  89. 89.
    Margot NA, Liu Y, Miller MD, Callebaut C. High resistance barrier to tenofovir alafenamide is driven by higher loading of tenofovir diphosphate into target cells compared to tenofovir disoproxil fumarate. Antivir Res. 2016; doi:10.1016/j.antiviral.2016.05.012.
  90. 90.
    Lee WA, He GX, Eisenberg E, Cihlar T, Swaminathan S, Mulato A, et al. Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue. Antimicrob Agents Chemother. 2005;49:1898–906. doi:10.1128/AAC.49.5.1898-1906.2005.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Zhang W, Parniak MA, Sarafianos SG, Cost MR, Rohan LC. Development of a vaginal delivery film containing EFdA, a novel anti-HIV nucleoside reverse transcriptase inhibitor. Int J Pharm. 2014;461:203–13. doi:10.1016/j.ijpharm.2013.11.056.PubMedGoogle Scholar
  92. 92.
    Michailidis E, Ryan E, Hachiya A, Kirby K, Marchand B, Leslie M, et al. Hypersusceptibility mechanism of Tenofovir-resistant HIV to EFdA. Retrovirology. 2013;10:65. doi:10.1186/1742-4690-10-65.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Langer R. Implantable controlled release systems. Pharmacol Ther. 1983;21:35–51. doi:10.1016/0163-7258(83)90066-9.PubMedGoogle Scholar
  94. 94.
    Cherng JY, Hou TY, Shih MF, Talsma H, Hennink WE. Polyurethane-based drug delivery systems. Int J Pharm. 2013;450:145–62. doi:10.1016/j.ijpharm.2013.04.063.PubMedGoogle Scholar
  95. 95.
    Bolto B, Tran T, Hoang M, Xie Z. Crosslinked poly(vinyl alcohol) membranes. Prog Polym Sci. 2009;34:969–81. doi:10.1016/j.progpolymsci.2009.05.003.Google Scholar
  96. 96.
    Moulay S. Review: poly(vinyl alcohol) Functionalizations and applications. Polym-Plast Technol Eng. 2015;54:1289–319. doi:10.1080/03602559.2015.1021487.Google Scholar
  97. 97.
    Hsu TT, Langer R. Polymers for the controlled release of macromolecules: effect of molecular weight of ethylene-vinyl acetate copolymer. J Biomed Mater Res. 1985;19:445–60. doi:10.1002/jbm.820190409.PubMedGoogle Scholar
  98. 98.
    Robb WL. Thin silicon membranes. Their permeation properties and some applications. Ann N Y Acad Sci. 1968;146:119–37. doi:10.1111/j.1749-6632.1968.tb20277.x.PubMedGoogle Scholar
  99. 99.
    Malcolm K, Woolfson D, Russell J, Tallon P, McAuley L, Craig D. Influence of silicone elastomer solubility and diffusivity on the in vitro release of drugs from intravaginal rings. J Control Release. 2003;90:217–25. doi:10.1016/S0168-3659(03)00178-0.PubMedGoogle Scholar
  100. 100.
    Petrova NV, Evtushenko AM, Chikhacheva IP, Zubov VP, Kubrakova IV. Effect of microwave irradiation on the cross-linking of polyvinyl alcohol. Russ J Appl Chem. 2005;78:1158–61. doi:10.1007/s11167-005-0470-1.Google Scholar
  101. 101.
    Byron PR, Dalby RN. Effects of heat treatment on the permeability of polyvinyl alcohol films to a hydrophilic solute. J Pharm Sci. 1987;76:65–7. doi:10.1002/jps.2600760118.PubMedGoogle Scholar
  102. 102.
    Sun H, Mei L, Song C, Cui X, Wang P. The in vivo degradation, absorption and excretion of PCL-based implant. Biomaterials. 2006;27:1735–40. doi:10.1016/j.biomaterials.2005.09.019.PubMedGoogle Scholar
  103. 103.
    Silva-Cunha A, Fialho SL, Naud MC, Behar-Cohen F. Poly-ε-caprolactone intravitreous devices: an in vivo study. Investig Ophthalmol Vis Sci. 2009;50:2312–8. doi:10.1167/iovs.08-2969.Google Scholar
  104. 104.
    Ali SAM, Zhong S-P, Doherty PJ, Williams DF. Mechanisms of polymer degradation in implantable devices I. Poly(caprolactone). Biomaterials. 1993;14:648–56. doi:10.1016/0142-9612(93)90063-8.PubMedGoogle Scholar
  105. 105.
    Garza-Flores J, Hall PE, Perez-Palacios G. Long-acting hormonal contraceptives for women. J Steroid Biochem Mol Biol. 1991;40:697–704. doi:10.1016/0960-0760(91)90293-E.PubMedGoogle Scholar
  106. 106.
    Schlesinger E, Johengen D, Luecke E, Rothrock G, McGowan I, van der Straten A, 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;33:1649–56. doi:10.1007/s11095-016-1904-6.PubMedGoogle Scholar
  107. 107.
    Jullien V, Tréluyer J-M, Pons G, Rey E. Determination of tenofovir in human plasma by high-performance liquid chromatography with spectrofluorimetric detection. J Chromatogr B. 2003;785:377–81. doi:10.1016/S1570-0232(02)00933-9.Google Scholar
  108. 108.
    Birkus G, Wang R, Liu X, Kutty N, MacArthur H, Cihlar T, et al. Cathepsin a is the major hydrolase catalyzing the intracellular hydrolysis of the antiretroviral nucleotide phosphonoamidate prodrugs GS-7340 and GS-9131. Antimicrob Agents Chemother. 2007;51:543–50. doi:10.1128/AAC.00968-06.PubMedGoogle Scholar
  109. 109.
    Matheson LE, Hunke WA. Mass transport properties of co(polyether) polyurethane membranes I: preparation and characterization. J Pharm Sci. 1981;70:571–3. doi:10.1002/jps.2600700528.PubMedGoogle Scholar
  110. 110.
    Guan J, Sacks MS, Beckman EJ, Wagner WR. Biodegradable poly (ether ester urethane) urea elastomers based on poly (ether ester) triblock copolymers and putrescine: synthesis, characterization and cytocompatibility. Biomaterials. 2004;25:85–96. doi:10.1016/S0142-9612(03)00476-9.PubMedGoogle Scholar
  111. 111.
    Shore N. Introducing Vantas: the first once-yearly Luteinising hormone-releasing hormone agonist. Eur Urol Suppl. 2010;9:701–5. doi:10.1016/j.eursup.2010.08.004.Google Scholar
  112. 112.
    Schlegel PN. Efficacy and safety of histrelin subdermal implant in patients with advanced prostate cancer. J Urol. 2006;175:1353–8. doi:10.1016/S0022-5347(05)00649-X.PubMedGoogle Scholar
  113. 113.
    Schlegel P. A review of the pharmacokinetic and pharmacological properties of a once-yearly administered histrelin acetate implant in the treatment of prostate cancer. BJU Int. 2009;103:7–13. doi:10.1111/j.1464-410X.2009.08383.x.PubMedGoogle Scholar
  114. 114.
    Croxatto HB. Progestin implants. Steroids. 2000;65:681–5. doi:10.1016/S0039-128X(00)00124-0.PubMedGoogle Scholar
  115. 115.
    Ferrati S, Nicolov E, Bansal S, Zabre E, Geninatti T, Ziemys A, et al. Delivering enhanced testosterone replacement therapy through Nanochannels. Adv Healthc Mater. 2015;4:446–51. doi:10.1002/adhm.201400348.PubMedGoogle Scholar
  116. 116.
    Nicolov E, Ferrati S, Goodall R, Hudson L, Hosali S, Crowley M, et al. Mp43-20 nanotechnology-based implant for long term testosterone replacement. J Urol. 2014;191:e485–6. doi:10.1016/j.juro.2014.02.1177.Google Scholar
  117. 117.
    Henry RR, Rosenstock J, Logan D, Alessi T, Luskey K, Baron MA. Continuous subcutaneous delivery of exenatide via ITCA 650 leads to sustained glycemic control and weight loss for 48 weeks in metformin-treated subjects with type 2 diabetes. J Diabetes Complicat. 2014;28:393–8. doi:10.1016/j.jdiacomp.2013.12.009.PubMedGoogle Scholar
  118. 118.
    Rohloff CM, Alessi TR, Yang B, Dahms J, Carr JP, Lautenbach SD. DUROS technology delivers peptides and proteins at consistent rate continuously for 3 to 12 months. J Diabetes Sci Technol. 2008;2:461–7. doi:10.1177/193229680800200316.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Clark MR et al. Long-acting intrauterine system delivers integrase inhibitor throughout the reproductive tract of rabbits and macaques. Poster P07.40. HIV R4P. Chicago, IL. 2016.Google Scholar
  120. 120.
    Romano J, Manning J, Hemmerling A, McGrory E, Young Holt B. Prioritizing multipurpose prevention technology development and investments using a target product profile. Antivir Res. 2013;100:S32–8. doi:10.1016/j.antiviral.2013.09.016.PubMedGoogle Scholar
  121. 121.
    Lucas J, El-Sahn M, Kong K, Kretschmer S. Assessing the potential of MPTs in Uganda, Nigeria, and South Africa. Seattle, WA: Bill and Melinda Gates Foundation; 2014.Google Scholar
  122. 122.
    Meyers K, Rodriguez K, Moeller RW, Gratch I, Markowitz M, Halkitis PN. High interest in a long-acting injectable formulation of pre-exposure prophylaxis for HIV in young men who have sex with men in NYC: a P18 cohort substudy. PLoS One. 2014;9:1–16. doi:10.1371/journal.pone.0114700.Google Scholar
  123. 123.
    Reuter S, Smith A. Implanon: user views in the first year across three family planning services in the Trent region, UK. Eur J Contracept Reprod Health Care. 2003;8:27–36. doi:10.1080/713604396.PubMedGoogle Scholar
  124. 124.
    Guthrie KM, Vargas S, Shaw JG, Rosen RK, Van Den Berg JJ, Kiser PF, et al. The promise of intravaginal rings for prevention: user perceptions of biomechanical properties and implications for prevention product development. PLoS One. 2015;10:1–17. doi:10.1371/journal.pone.0145642.Google Scholar
  125. 125.
    Lin AH, Breger TL, Barnhart M, Kim A, Vangsgaard C, Harris E. Learning from the private sector: towards a keener understanding of the end-user for microbicide introduction planning. J Int AIDS Soc. 2014;17:1–6. doi:10.7448/IAS.17.3.19162.Google Scholar
  126. 126.
    Murphy PA, Brixner D. Hormonal contraceptive discontinuation patterns according to formulation: investigation of associations in an administrative claims database. Contraception. 2008;77:257–63. doi:10.1016/j.contraception.2008.01.002.PubMedGoogle Scholar
  127. 127.
    Leite IC, Gupta N. Assessing regional differences in contraceptive discontinuation, failure and switching in Brazil. Reprod Health. 2007;4:6. doi:10.1186/1742-4755-4-6.PubMedPubMedCentralGoogle Scholar
  128. 128.
    Jacobstein R, Stanley H. Contraceptive implants: providing better choice to meet growing family planning demand. Glob Heal Sci Pract. 2013;1:11–7. doi:10.9745/GHSP-D-12-00003.Google Scholar
  129. 129.
    Duvall S, Thurston S, Weinberger M, Nuccio O, Fuchs-Montgomery N. Scaling up delivery of contraceptive implants in sub-Saharan Africa: operational experiences of Marie stopes international. Glob Heal Sci Pract. 2014;2:72–92. doi:10.9745/GHSP-D-13-00116.Google Scholar
  130. 130.
    Walensky RP, Jacobsen MM, Bekker L-G, Parker RA, Wood R, Resch SC, et al. Potential clinical and economic value of long-acting Preexposure prophylaxis for South African women at high-risk for HIV infection. J Infect Dis. 2016;213:1523–31. doi:10.1093/infdis/jiv523.PubMedGoogle Scholar
  131. 131.
    Ying R, Sharma M, Heffron R, Celum CL, Baeten JM, Katabira E, et al. Cost-effectiveness of pre-exposure prophylaxis targeted to high-risk serodiscordant couples as a bridge to sustained ART use in Kampala, Uganda. J Int AIDS Soc. 2015;18:1–9. doi:10.7448/IAS.18.4.20013.Google Scholar
  132. 132.
    Chen A, Kosimbei G, Mwai D. Cost of providing oral pre-exposure prophylaxis to prevent Hiv infection among sex workers. Washington, DC: Futures Group; 2014.Google Scholar
  133. 133.
    Pretorius C, Stover J, Bollinger L, Bacaër N, Williams B. Evaluating the cost-effectiveness of pre-exposure prophylaxis (PrEP) and its impact on HIV-1 transmission in South Africa. PLoS One. 2010;5 doi:10.1371/journal.pone.0013646.
  134. 134.
    Kleiner LW, Wright JC, Wang Y. Evolution of implantable and insertable drug delivery systems. J Control Release. 2014;181:1–10. doi:10.1016/j.jconrel.2014.02.006.PubMedGoogle Scholar
  135. 135.
    Brayden DJ. Controlled release technologies for drug delivery. Drug Discov Today. 2003;8:976–8. doi:10.1016/S1359-6446(03)02874-5.PubMedGoogle Scholar
  136. 136.
    Landovitz RJ, Grinsztejn B. Long-acting injectable Preexposure prophylaxis for HIV prevention in South Africa: is there a will and a way? J Infect Dis. 2016;213:1519–20. doi:10.1093/infdis/jiv524.PubMedGoogle Scholar
  137. 137.
    Blaschke TF, Osterberg L, Vrijens B, Urquhart J. Adherence to medications: insights arising from studies on the unreliable link between prescribed and actual drug dosing histories. Annu Rev Pharmacol Toxicol. 2012;52:275–301. doi:10.1146/annurev-pharmtox-011711-113247.PubMedGoogle Scholar
  138. 138.
    van der Straten A, Montgomery ET, Hartmann M, Minnis A. Methodological lessons from clinical trials and the future of microbicide research. Curr HIV/AIDS Rep. 2012;10:89–102. doi:10.1007/s11904-012-0141-9.Google Scholar
  139. 139.
    Jacobstein R. Long-acting and permanent contraception: an international development, service delivery perspective. J Midwifery Women’s Heal. 2007;52:361–7. doi:10.1016/j.jmwh.2007.01.001.Google Scholar
  140. 140.
    Arya V, Au S, Belew Y, Miele P, Struble K. Regulatory challenges in developing long-acting antiretrovirals for treatment and prevention of HIV infection. Curr Opin HIV AIDS. 2015;10:278–81. doi:10.1097/COH.0000000000000163.PubMedGoogle Scholar
  141. 141.
    Wu P, Grainger DW. Drug/device combinations for local drug therapies and infection prophylaxis. Biomaterials. 2006;27:2450–67. doi:10.1016/j.biomaterials.2005.11.031.PubMedGoogle Scholar

Copyright information

© Controlled Release Society 2017

Authors and Affiliations

  • William R. Lykins
    • 1
    • 2
  • Ellen Luecke
    • 3
  • Daniel Johengen
    • 2
  • Ariane van der Straten
    • 2
    • 4
  • Tejal A. Desai
    • 1
    • 2
  1. 1.UC Berkeley-UCSF Graduate Program in BioengineeringSan Francisco and BerkeleyUSA
  2. 2.Department of Bioengineering and Therapeutic SciencesUniversity of California San FranciscoSan FranciscoUSA
  3. 3.Women’s Global Health ImperativeRTI InternationalSan FranciscoUSA
  4. 4.Center for AIDS Prevention Studies, Department of MedicineUniversity of California San FranciscoSan FranciscoUSA

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