{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:33:22Z","timestamp":1791304402787,"version":"4.3.1"},"reference-count":74,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases of the National Institutes of Health","doi-asserted-by":"publisher","award":["U19AI113048"],"award-info":[{"award-number":["U19AI113048"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"award":["U19AI113048"],"award-info":[{"award-number":["U19AI113048"]}],"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: The prevention of sexual HIV-1 acquisition in women and girls in sub-Saharan Africa remains an important public health priority. Expanding the existing biomedical product portfolio to include long-acting vaginal products, such as intravaginal rings (IVRs), is expected to appeal to end users and drive adoption. Methods: We formulated two different triple-combination antiretroviral IVRs, both delivering the acid salt tenofovir (TFV), disoproxil fumarate (TDF), and the free base emtricitabine (FTC), with one delivering elvitegravir (EVG) as the free acid and the other as the sodium salt. The devices were evaluated for pharmacokinetics and local safety in two established preclinical models, sheep and pig-tailed macaques. Results: The IVRs were safe and maintained cervicovaginal fluid (CVF) drug concentrations that were above our efficacy targets derived from prior humanized mouse studies. All three agents were uniformly distributed vaginally, as evidenced by CVF and vaginal tissue measurements. Elevated drug concentrations were observed in macaque vaginal tissue samples collected three days after IVR removal, suggesting a possible forgiveness window. TFV and FTC concentrations in rectal tissue and fluid suggested potential for dual-compartment HIV-1 protection, although the vaginal-to-rectal drug transport mechanism appeared to differ across both species. The humanized mouse vaginal HIV-1 efficacy model was used to empirically compare combination effects when TDF, FTC, and EVG were co-administered, and TDF-EVG was identified as a promising combination to be developed further for IVR delivery in parallel with the triple combination.<\/jats:p>","DOI":"10.3390\/pharmaceutics18070829","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T13:19:31Z","timestamp":1783430371000},"page":"829","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Preclinical Pharmacokinetics of a Triple-Combination Intravaginal Ring for HIV Prevention"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8091-3245","authenticated-orcid":false,"given":"John A.","family":"Moss","sequence":"first","affiliation":[{"name":"Department of Chemistry, Oak Crest Institute of Science, Monrovia, CA 91016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priya","family":"Srinivasan","sequence":"additional","affiliation":[{"name":"Laboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, Sexually Transmitted Diseases, and Tuberculosis Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Butkyavichene","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Oak Crest Institute of Science, Monrovia, CA 91016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3137-8669","authenticated-orcid":false,"given":"Manjula","family":"Gunawardana","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Oak Crest Institute of Science, Monrovia, CA 91016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6358-1784","authenticated-orcid":false,"given":"Amalia E.","family":"Castonguay","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Oak Crest Institute of Science, Monrovia, CA 91016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"John M.","family":"Cortez","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Oak Crest Institute of Science, Monrovia, CA 91016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Galvan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Oak Crest Institute of Science, Monrovia, CA 91016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Rivera","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Oak Crest Institute of Science, Monrovia, CA 91016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jining","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, Sexually Transmitted Diseases, and Tuberculosis Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1749-4401","authenticated-orcid":false,"given":"Chuong","family":"Dinh","sequence":"additional","affiliation":[{"name":"Laboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, Sexually Transmitted Diseases, and Tuberculosis Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Holder","sequence":"additional","affiliation":[{"name":"Laboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, Sexually Transmitted Diseases, and Tuberculosis Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8066-8988","authenticated-orcid":false,"given":"Dawn","family":"Little","sequence":"additional","affiliation":[{"name":"Katmai Government Services, Anchorage, AK 99515, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5999-8774","authenticated-orcid":false,"given":"Shanon","family":"Bachman","sequence":"additional","affiliation":[{"name":"Libra Management Group, Decatur, GA 30030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4307-3301","authenticated-orcid":false,"given":"Kristen","family":"Kelley","sequence":"additional","affiliation":[{"name":"The DESA Group, Columbia, SC 29223, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina M.","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, UCLA Fielding School of Public Health, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe A.","family":"Gallay","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen L.","family":"Vincent","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Smith","sequence":"additional","affiliation":[{"name":"Laboratory Branch, Division of HIV Prevention, 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Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1016\/S0140-6736(22)00538-4","article-title":"Cabotegravir for the Prevention of HIV-1 in Women: Results from HPTN 084, a Phase 3, Randomised Clinical Trial","volume":"399","author":"Hughes","year":"2022","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1056\/NEJMoa2407001","article-title":"Twice-yearly Lenacapavir or Daily F\/TAF for HIV Prevention in Cisgender Women","volume":"391","author":"Bekker","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_4","unstructured":"Han, K., D\u2019Amico, R., Sievers, J., Brimhall, D., Spears, B., Taylor, D., Dorey, D., Benn, P., Morgan, L., and Hareedy, R. (2024, January 3\u20136). Phase I Study of Cabotegravir Long-acting Injectable Formulations Supports \u22654-Monthly Dose Interval. Proceedings of the 2024 Conference on Retroviruses and Opportunistic Infections (CROI), Denver, CO, USA. Abstract Number 130."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/S0140-6736(25)00405-2","article-title":"Pharmacokinetics and Safety of Once-yearly Lenacapavir: A Phase 1, Open-label Study","volume":"405","author":"Jogiraju","year":"2025","journal-title":"Lancet"},{"key":"ref_6","unstructured":"UNAIDS (2025, November 13). Fact Sheet 2025\u2014Global HIV Satistics. Available online: https:\/\/www.unaids.org\/sites\/default\/files\/2025-07\/2025_Global_HIV_Factsheet_en.pdf."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"97","DOI":"10.2147\/IJWH.S185712","article-title":"\u201cWe Are Not the Same\u201d: African Women\u2019s View of Multipurpose Prevention Products in the TRIO Clinical Study","volume":"11","author":"Manenzhe","year":"2019","journal-title":"Int. J. Womens Health"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e26498","DOI":"10.1002\/jia2.26498","article-title":"Seizing the Moment: The Potential of PrEP Choice and Innovation to Transform HIV Prevention","volume":"28","author":"Schmidt","year":"2025","journal-title":"J. Int. AIDS Soc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1089\/apc.2017.0075","article-title":"Favoring \u201cPeace of Mind\u201d: A Qualitative Study of African Women\u2019s HIV Prevention Product Formulation Preferences from the MTN-020\/ASPIRE Trial","volume":"31","author":"Reddy","year":"2017","journal-title":"AIDS Patient Care STDS"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.contraception.2021.10.001","article-title":"Vaginal Rng Acceptability: A Systematic Review and Meta-analysis of Vaginal Ring Experiences from around the World","volume":"106","author":"Ridgeway","year":"2022","journal-title":"Contraception"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1097\/QAI.0000000000003756","article-title":"Higher Acceptability of the Monthly Dapivirine Ring Versus Daily Oral Pre-Exposure Prophylaxis Among Adolescent Girls and Young Women in Sub-Saharan Africa in the REACH Trial","volume":"100","author":"Friedland","year":"2025","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"das Neves, J., and Sarmento, B. (2014). Microbicide Vaginal Rings. Drug Delivery and Development of Anti-HIV Microbicides, Pan Stanford Publishing.","DOI":"10.1201\/b17559"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1007\/BF00314990","article-title":"Dosage Frequency and Drug Compliance Behavior\u2014A Comparative Study on Compliance with a Medication to Be Taken Twice or 4 Times Daily","volume":"41","author":"Kruse","year":"1991","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_14","first-page":"CD001361","article-title":"Depot Haloperidol Decanoate for Schizophrenia","volume":"2","author":"Quraishi","year":"2000","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1016\/S0169-409X(02)00090-X","article-title":"Implantable, Polymeric Systems for Modulated Drug Delivery","volume":"54","author":"Sershen","year":"2002","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"295","DOI":"10.2174\/1568005033481079","article-title":"Is Resistance Futile?","volume":"3","author":"Kutilek","year":"2003","journal-title":"Curr. Drug Targets Infect. Disord."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S0924-977X(03)00109-3","article-title":"A Review of Compliance, Depot Intramuscular Antipsychotics and the New Long-acting Injectable Atypical Antipsychotic Risperidone in Schizophrenia","volume":"14","author":"Bhanji","year":"2004","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3","DOI":"10.2165\/00019053-200523001-00002","article-title":"Pharmacoeconomics of Long-acting Risperidone: Results and Validity of Cost-effectiveness Models","volume":"23","author":"Haycox","year":"2005","journal-title":"Pharmacoeconomics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2705","DOI":"10.1185\/030079907X233403","article-title":"A Review of Compliance to Treatment in Alzheimer\u2019s Disease: Potential Benefits of a Transdermal Patch","volume":"23","author":"Small","year":"2007","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_20","first-page":"728","article-title":"Comparing Adherence and Persistence Across 6 Chronic Medication Classes","volume":"15","author":"Yeaw","year":"2009","journal-title":"J. Manag. Care Pharm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1056\/NEJMoa1506110","article-title":"Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women","volume":"375","author":"Baeten","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1056\/NEJMoa1602046","article-title":"Safety and Efficacy of a Dapivirine Vaginal Ring for HIV Prevention in Women","volume":"375","author":"Nel","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e77","DOI":"10.1016\/S2352-3018(20)30300-3","article-title":"Safety, Adherence, and HIV-1 Seroconversion among Women Using the Dapivirine Vaginal Ring (DREAM): An Open-label, Extension Study","volume":"8","author":"Nel","year":"2021","journal-title":"Lancet HIV"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e779","DOI":"10.1016\/S2352-3018(23)00227-8","article-title":"Adherence, Safety, and Choice of the Monthly Dapivirine Vaginal Ring or Oral Emtricitabine Plus Tenofovir Disoproxil Fumarate for HIV Pre-exposure Prophylaxis among African Adolescent Girls and Young Women: A Randomised, Open-label, Crossover Trial","volume":"10","author":"Nair","year":"2023","journal-title":"Lancet HIV"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e26457","DOI":"10.1002\/jia2.26457","article-title":"PrEP Choice in the Real World: Results of a Prospective Cohort Study Describing Uptake and Use Patterns of Oral PrEP and the Dapivirine Vaginal Ring among Women in sub-Saharan Africa","volume":"28","author":"Fonner","year":"2025","journal-title":"J. Int. AIDS Soc."},{"key":"ref_26","unstructured":"(2025, November 13). The Dapivirine Vaginal Ring. Available online: https:\/\/www.prepwatch.org\/products\/dapivirine-vaginal-ring\/."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.1002\/jps.23208","article-title":"An Intravaginal Ring for the Simultaneous Delivery of Multiple Drugs","volume":"101","author":"Baum","year":"2012","journal-title":"J. Pharm. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Vincent, K.L., Moss, J.A., Marzinke, M.A., Hendrix, C.W., Anton, P.A., Gunawardana, M., Dawson, L., Olive, T.J., Pyles, R.B., and Baum, M.M. (2018). Phase I Trial of Pod-intravaginal Rings Delivering Antiretroviral Agents for HIV-1 Prevention.: Rectal Drug Exposure from Vaginal Dosing with Tenofovir Disoproxil Fumarate, Emtricitabine, and Maraviroc. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0201952"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Vincent, K.L., Moss, J.A., Marzinke, M.A., Hendrix, C.W., Anton, P.A., Pyles, R.B., Guthrie, K.M., Dawson, L., Olive, T.J., and Butkyavichene, I. (2018). Safety and Pharmacokinetics of Single, Dual, and Triple Antiretroviral Drug Formulations Delivered by Pod-intravaginal Rings Designed for HIV-1 Prevention: A Phase I Trial. PLoS Med., 15.","DOI":"10.1371\/journal.pmed.1002655"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1097\/QAD.0b013e3283509abb","article-title":"Tenofovir and Tenofovir Disoproxil Pharmacokinetics from Intravaginal Rings","volume":"26","author":"Moss","year":"2012","journal-title":"AIDS"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5125","DOI":"10.1128\/AAC.02871-14","article-title":"Pharmacokinetics and Preliminary Safety Study of Pod-Intravaginal Rings Delivering Antiretroviral Combinations for HIV Prophylaxis in a Macaque Model","volume":"58","author":"Moss","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.ijpharm.2015.09.028","article-title":"An Intravaginal Ring for the Sustained Delivery of Tenofovir Disoproxil Fumarate","volume":"495","author":"Baum","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3759","DOI":"10.1128\/AAC.00391-16","article-title":"Combination Pod-intravaginal Ring Delivers Antiretroviral Agents for HIV Prophylaxis: Pharmacokinetic Evaluation in an Ovine Model","volume":"60","author":"Moss","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3611","DOI":"10.1002\/jps.24154","article-title":"An Intravaginal Ring for the Sustained Delivery of Antibodies","volume":"103","author":"Gunawardana","year":"2014","journal-title":"J. Pharm. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e02465-16","DOI":"10.1128\/AAC.02465-16","article-title":"Pharmacokinetics and Preliminary Safety of Pod-Intravaginal Rings Delivering the Monoclonal Antibody VRC01-N for HIV Prophylaxis in a Macaque Model","volume":"61","author":"Zhao","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.1128\/AAC.02542-13","article-title":"Sustained Delivery of Commensal Bacteria from Pod-intravaginal Rings","volume":"58","author":"Gunawardana","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Srinivasan, P., Moss, J.A., Gunawardana, M., Churchman, S.A., Yang, F., Dinh, C.T., Mitchell, J.M., Zhang, J., Fanter, R., and Miller, C.S. (2016). Topical Delivery of Tenofovir Disoproxil Fumarate and Emtricitabine from Pod-intravaginal Rings Protect Macaques from Multiple SHIV Exposures. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0157061"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1111\/j.1600-0684.2009.00354.x","article-title":"Development and Evaluation of a Vaginal Ring Device for Sustained Delivery of HIV Microbicides to Non-human Primates","volume":"38","author":"Smith","year":"2009","journal-title":"J. Med. Primatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5952","DOI":"10.1128\/AAC.01198-12","article-title":"Safety and Pharmacokinetics of Intravaginal Rings Delivering Tenofovir in Pig-tailed Macaques","volume":"56","author":"Moss","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1128\/AAC.05662-11","article-title":"Simultaneous Delivery of Tenofovir and Acyclovir via an Intravaginal Ring","volume":"56","author":"Moss","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_41","unstructured":"National Research Council (2011). Guide for the Care and Use of Laboratory Animals, The National Academies Press. [8th ed.]."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Smith, J.M., Moss, J.A., Srinivasan, P., Butkyavichene, I., Gunawardana, M., Fanter, R., Miller, C.S., Sanchez, D., Yang, F., and Ellis, S. (2017). Novel Multipurpose Pod-intravaginal Ring for the Prevention of HIV, HSV, and Unintended Pregnancy: Pharmacokinetic Evaluation in a Macaque Model. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0185946"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1097\/OLQ.0b013e31815abad8","article-title":"Application of Optical Coherence Tomography for Monitoring Changes in Cervicovaginal Epithelial Morphology in Macaques: Potential for Assessment of Microbicide Safety","volume":"35","author":"Vincent","year":"2008","journal-title":"Sex. Transm. Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1097\/OLQ.0b013e31819496e4","article-title":"High Resolution Imaging of Epithelial Injury in the Sheep Cervicovaginal Tract: A Promising Model for Testing Safety of Candidate Microbicides","volume":"36","author":"Vincent","year":"2009","journal-title":"Sex. Transm. Dis."},{"key":"ref_45","unstructured":"US FDA (2001). Guidance for Industry: Bioanalytical Method Validation."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.jchromb.2016.02.033","article-title":"Accurate Measurement of Female Genital Tract Fluid Dilution in Cervicovaginal Lavage Samples","volume":"1017","author":"Churchman","year":"2016","journal-title":"J. Chromatogr. B"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Massud, I., Nishiura, K., Ruone, S., Holder, A., Dinh, C., Lipscomb, J., Mitchell, J., Khalil, G.M., Heneine, W., and Garcia-Lerma, J.G. (2024). Weekly Oral Tenofovir Alafenamide Protects Macaques from Vaginal and Rectal Simian HIV Infection. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16030384"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3659","DOI":"10.1016\/j.jchromb.2009.09.007","article-title":"On-line Coupling of Anion Exchange and Ion-pair Chromatography for Measurement of Intracellular Triphosphate Metabolites of Reverse Transcriptase Inhibitors","volume":"877","author":"Kuklenyik","year":"2009","journal-title":"J. Chromatogr. B"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1182\/blood-2005-11-4388","article-title":"Reconstitution of a Functional Human Immune System in Immunodeficient Mice through Combined Human Fetal Thymus\/Liver and CD34+ Cell Transplantation","volume":"108","author":"Lan","year":"2006","journal-title":"Blood"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1038\/nm1431","article-title":"Humanized Mice Mount Specific Adaptive and Innate Immune Responses to EBV and TSST-1","volume":"12","author":"Melkus","year":"2006","journal-title":"Nat. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1084\/jem.20062411","article-title":"Intrarectal Transmission, Systemic Infection, and CD4(+) T Cell Depletion in Humanized Mice Infected with HIV-1","volume":"204","author":"Sun","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.virol.2011.05.013","article-title":"Superior Human Leukocyte Reconstitution and Susceptibility to Vaginal HIV Transmission in Humanized NOD-scid IL-2R\u03b3(\u2212\/\u2212) (NSG) BLT Mice","volume":"15","author":"Stoddart","year":"2011","journal-title":"Virology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/mi.2012.31","article-title":"IL-2 Receptor Gamma-chain Molecule is Critical for Intestinal T-cell Reconstitution in Humanized Mice","volume":"5","author":"Denton","year":"2012","journal-title":"Mucosal Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Gallay, P.A., Chatterji, U., Kirchhoff, A., Gandarilla, A., Gunawardana, M., Pyles, R.B., Marzinke, M.A., Moss, J.A., and Baum, M.M. (2017). Prevention of Vaginal and Rectal HIV Transmission by Antiretroviral Combinations in Humanized Mice. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0184303"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1371\/journal.pmed.0050016","article-title":"Antiretroviral Pre-exposure Prophylaxis Prevents Vaginal Transmission of HIV-1 in Humanized BLT Mice","volume":"5","author":"Denton","year":"2008","journal-title":"PLoS Med."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Denton, P.W., Krisko, J.F., Powell, D.A., Mathias, M., Kwak, Y.T., Martinez-Torres, F., Zou, W., Payne, D.A., Estes, J.D., and Garcia, J.V. (2010). Systemic Administration of Antiretrovirals Prior to Exposure Prevents Rectal and Intravenous HIV-1 Transmission in Humanized BLT Mice. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0008829"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"7582","DOI":"10.1128\/JVI.00537-11","article-title":"One Percent Tenofovir Applied Topically to Humanized BLT Mice and Used According to the CAPRISA 004 Experimental Design Demonstrates Partial Protection from Vaginal HIV Infection, Validating the BLT Model for Evaluation of New Microbicide Candidates","volume":"85","author":"Denton","year":"2011","journal-title":"J. Virol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Chateau, M.L., Denton, P.W., Swanson, M.D., McGowan, I., and Garcia, J.V. (2013). Rectal Transmission of Transmitted\/Founder HIV-1 Is Efficiently Prevented by Topical 1% Tenofovir in BLT Humanized Mice. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0060024"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/1874357901812010001","article-title":"Protection Efficacy of C5A Against Vaginal and Rectal HIV Challenges in Humanized Mice","volume":"12","author":"Gallay","year":"2018","journal-title":"Open Virol. J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"12995","DOI":"10.1038\/s41598-020-69937-5","article-title":"Highly Synergistic Drug Combination Prevents Vaginal HIV Infection in Humanized Mice","volume":"10","author":"Baum","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4594","DOI":"10.1038\/s41598-023-31695-5","article-title":"Acute Antagonism in Three-drug Combinations for Vaginal HIV Prevention in Humanized Mice","volume":"13","author":"Gallay","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0065-2571(84)90007-4","article-title":"Quantitative Analysis of Dose-effect Relationships: The Combined Effects of Multiple Drugs or Enzyme Inhibitors","volume":"22","author":"Chou","year":"1984","journal-title":"Adv. Enzym. Regul."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1124\/pr.58.3.10","article-title":"Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies","volume":"58","author":"Chou","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_64","unstructured":"Chou, T.C., and Martin, N. (2005). CompuSyn for Drug Combinations: PC Software and User\u2019s Guide: A Computer Program for Quantitation of Synergism and Antagonism in Drug Combinations, and the Determination of IC50 and ED50 and LD50 Values, ComboSyn Inc."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1097\/OLQ.0b013e3181cbf77d","article-title":"Prevalence and Correlates of Heterosexual Anal Intercourse Among Clients Attending Public Sexually Transmitted Disease Clinics in Los Angeles County","volume":"37","author":"Javanbakht","year":"2010","journal-title":"Sex. Transm. Dis."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1097\/QAI.0000000000000314","article-title":"Order of Orifices: Sequence of Condom Use and Ejaculation by Orifice During Anal Intercourse Among Women: Implications for HIV Transmission","volume":"67","author":"Gorbach","year":"2014","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1007\/s10461-015-0997-y","article-title":"Prevalence and Frequency of Heterosexual Anal Intercourse Among Young People: A Systematic Review and Meta-analysis","volume":"19","author":"Owen","year":"2015","journal-title":"AIDS Behav."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1158\/0008-5472.CAN-09-1947","article-title":"Drug Combination Studies and Their Synergy Quantification Using the Chou-Talalay Method","volume":"70","author":"Chou","year":"2010","journal-title":"Cancer Res."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Peet, M.M., Agrahari, V., Anderson, S.M., Hanif, H., Singh, O.N., Thurman, A.R., Doncel, G.F., and Clark, M.R. (2019). Topical Inserts: A Versatile Delivery Form for HIV Prevention. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11080374"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"104361","DOI":"10.1016\/j.ebiom.2022.104361","article-title":"Single Dose Topical inserts Containing Tenofovir Alafenamide Fumarate and Elvitegravir Provide Pre- and Post-exposure Protection against Vaginal SHIV Infection in Macaques","volume":"86","author":"Dobard","year":"2022","journal-title":"eBioMedicine"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"104338","DOI":"10.1016\/j.ebiom.2022.104338","article-title":"Pharmacokinetics and Efficacy of Topical Inserts Containing Tenofovir Alafenamide Fumarate and Elvitegravir Administered Rectally in Macaques","volume":"86","author":"Makarova","year":"2022","journal-title":"eBioMedicine"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Thurman, A.R., Ouattara, L.A., Yousefieh, N., Anderson, P.L., Bushman, L.R., Fang, X., Hanif, H., Clark, M., Singh, O., and Doncel, G.F. (2023). A Phase I Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of a Vaginal Insert Containing Tenofovir Alafenamide and Elvitegravir. Front. Cell. Infect. Microbiol., 13.","DOI":"10.3389\/fcimb.2023.1130101"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"O\u2019Hanlon, D.E., Come, R.A., and Moench, T.R. (2019). Vaginal pH Measured in Vivo: Lactobacilli Determine pH and Lactic acid Concentration. BMC Microbiol., 19.","DOI":"10.1186\/s12866-019-1388-8"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Miller, E.A., Beasley, D.E., Dunn, R.R., and Archie, E.A. (2016). Lactobacilli Dominance and Vaginal pH: Why Is the Human Vaginal Microbiome Unique?. Front. Microbiol., 7.","DOI":"10.3389\/fmicb.2016.01936"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/7\/829\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T12:59:31Z","timestamp":1783515571000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/7\/829"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,7]]},"references-count":74,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["pharmaceutics18070829"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18070829","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,7]]}}}