RESUMEN
BACKGROUND: On-demand topical products could be an important tool for human immunodeficiency virus (HIV) prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG, 20â mg/16â mg) insert administered rectally. METHODS: MTN-039 was a phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid, and rectal tissue were collected over 72â hours following rectal administration of 1 and 2 TAF/EVG inserts for each participant. RESULTS: TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4â ng/mL and TFV 4.4â ng/mL. Rectal tissue EVG peaked at 2 hours (median, 2 inserts = 9â ng/mg) but declined to below limit of quantification in the majority of samples at 24 hours, whereas tenofovir diphosphate (TFV-DP) remained high >2000â fmol/million cells for 72 hours with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each time point for both 1 and 2 inserts (P < .065 and P < .039, respectively). DISCUSSION: Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72â hours. Clinical Trials Registration . NCT04047420.
Asunto(s)
Adenina , Administración Rectal , Alanina , Fármacos Anti-VIH , Infecciones por VIH , Quinolonas , Tenofovir , Humanos , Tenofovir/farmacocinética , Tenofovir/administración & dosificación , Tenofovir/análogos & derivados , Infecciones por VIH/prevención & control , Infecciones por VIH/tratamiento farmacológico , Masculino , Quinolonas/farmacocinética , Quinolonas/administración & dosificación , Quinolonas/efectos adversos , Adulto , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Femenino , Alanina/farmacocinética , Alanina/administración & dosificación , Persona de Mediana Edad , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/administración & dosificación , Adenina/efectos adversos , Recto/virología , Adulto Joven , VIH-1/efectos de los fármacos , Combinación de MedicamentosRESUMEN
Intravaginal rings (IVR) containing antiretroviral drugs are a promising method for HIV prevention. We triangulated quantitative and qualitative assessments to evaluate the acceptability of four IVRs used continuously for 28 days as part of a Phase I trial (N = 48 HIV-negative women; ages 18-45). Adherence was high throughout the trial, yet 30% of participants reported involuntary IVR expulsions followed by re-insertion. Most participants (93.6%) felt comfortable with the IVR being inside their body. Participants reported liking the IVR more (36.2%) or the same amount (55.3%) since starting the study. When given the option of choosing between the IVR and/or a male condom for HIV-prevention, most reported preferring the IVR (n = 29, 63.0%), and over a quarter of the sample reported liking them equally (n = 12, 26.1%). We observed no differences in IVR acceptability across the study arms. High adherence and acceptability underscores the promise of an IVR as a female-controlled, sustained mechanism for HIV prevention.
Asunto(s)
Antiinfecciosos/administración & dosificación , Antirretrovirales/administración & dosificación , Infecciones por VIH/prevención & control , Cumplimiento de la Medicación , Aceptación de la Atención de Salud , Cremas, Espumas y Geles Vaginales/uso terapéutico , Administración Intravaginal , Adolescente , Adulto , Femenino , Humanos , Entrevistas como Asunto , Persona de Mediana Edad , Investigación Cualitativa , Conducta Sexual , Estados Unidos , Adulto JovenRESUMEN
BACKGROUND: Vaginal rings (VR) containing antiretroviral (ARV) drugs can be utilized for prevention of human immunodeficiency virus (HIV) with potential for improved adherence compared to daily pills. Combination ARV VRs could improve efficacy. METHODS: MTN-027, a single-blind, randomized, placebo-controlled trial in 48 women, evaluated VRs containing MK-2048 (30 mg) and vicriviroc (VCV, 182 mg), alone or in combination, and placebo used continuously for 28 days. Safety was assessed by recording adverse events. Drug concentrations were quantified in plasma, vaginal fluid, cervical tissue, and rectal fluid. Cervical tissue was utilized for ex vivo HIV inhibition analysis. RESULTS: There was no difference in related genitourinary adverse events between treatment arms compared to placebo. VCV and MK-2048 released from single or combination VRs both achieved peak concentrations in vaginal fluids, which were substantially higher compared to plasma (200× for VCV, 30× for MK-2048) and rectal fluid. In an ex vivo challenge assay, the antiviral activity of VCV and/or MK-2048 was not correlated with tissue-associated drug concentrations. Most women (77%) were fully adherent to 28 days of continuous VR use and found the VR acceptable. CONCLUSIONS: VCV and/or MK-2048 containing VRs were safe and acceptable. Both VCV and MK-2048 were quantifiable in all matrixes tested with peak compartmental drug concentrations similar for single and combination drug VRs. Tissue-associated VCV and/or MK-2048 did not correlate with inhibition of HIV infection. These data highlight the need to assess adequacy of drug dosing in the VR and measuring genital tissue drug concentrations to develop more precise concentration-response relationships.