RESUMEN
BACKGROUND: Adherence challenges with oral tenofovir-based pre-exposure prophylaxis (PrEP) are common. We developed a point-of-care assay to objectively assess tenofovir in urine and conducted a pilot trial examining the impact of counselling informed by use of this urine assay on long-term PrEP adherence. METHODS: This randomised trial enrolled women not in serodiscordant partnerships 3 months after PrEP initiation at the Kenya Medical Research Institute to compare standard-of-care adherence counselling versus counselling informed by the urine assay (urine-test counselling group) every 3 months for 12 months. In the standard of care group, urine samples were stored and tested at study end without participant feedback. Here we report the adherence primary outcome of hair concentrations of tenofovir at 12 months as a long-term metric (undetectable levels defined long-term non-adherence), as well as urine concentrations of tenofovir at each visit as a short-term adherence metric and acceptability of the assay assessed by quantitative surveys. Data were analysed by randomisation group. This completed trial was registered with ClinicalTrials.gov (NCT03935464). FINDINGS: From March 17, 2021 to Jan 18, 2022 we enrolled 49 women in the urine-test counselling group and 51 in the standard of care group; retention was 86 (86%) of 100. Nine (21%) of 42 in the urine-test counselling group had hair samples at 12 months with tenofovir concentrations below the limit of quantification compared with 15 (37%) of 41 in the standard of care group. The relative odds of long-term non-adherence in the standard of care group compared with urine-test counselling were 3·53 (95% CI 1·03-12·03; p=0·044). Pre-intervention, urine tenofovir was detectable in 65% in the urine-test counselling group and 71% in the standard of care group (p=0·68). At 12 months, 31 (72%) of 43 in the intervention group had detectable urine tenofovir compared with 19 (45%) of 42 in the standard of care group (p=0·0015). 40 (93%) of 43 participants liked the test very much and only one disliked the test. One participant in the standard of care group was withdrawn at the 6-month visit due to HIV seroconversion. INTERPRETATION: A low-cost urine tenofovir assay to inform PrEP counselling resulted in improvement in both short-term and long-term metrics of adherence. This urine tenofovir assay could help to improve long-term PrEP adherence. FUNDING: National Institute of Allergy and Infectious Diseases and National Institutes of Health.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Cumplimiento de la Medicación , Profilaxis Pre-Exposición , Tenofovir , Humanos , Femenino , Tenofovir/orina , Tenofovir/uso terapéutico , Tenofovir/administración & dosificación , Profilaxis Pre-Exposición/métodos , Infecciones por VIH/prevención & control , Kenia , Proyectos Piloto , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Cumplimiento de la Medicación/estadística & datos numéricos , Sistemas de Atención de Punto , Consejo/métodos , Cabello/química , Adulto Joven , Pruebas en el Punto de AtenciónRESUMEN
BACKGROUND: Young men who have sex with men and transgender women (YMSM/TGW) have disproportionately high HIV incidence and lower preexposure prophylaxis (PrEP) adherence. Point-of-care (POC) urine tenofovir (TFV) rapid assay (UTRA) testing permits real-time monitoring for nonadherence within clinical settings. We performed UTRA testing among PrEP users to examine the relationship between low PrEP adherence and future PrEP discontinuation, and the accuracy of POC testing compared to gold-standard liquid chromatography tandem mass spectrometry (LC/MS/MS). METHODS: YMSM/TGW participants ( n â=â100) were recruited during a daily PrEP visit. Logistic regression models analyzed the relationship between the primary predictor of urine POC assay results (cutoff 1,500âng/ml) and the primary outcome of PrEP discontinuation, defined as no PrEP follow-up or prescription within 120âdays. RESULTS: Overall, 19% of participants had low urine TFV and 21% discontinued PrEP, while 11% of participants self-reported low PrEP adherence (<4 pills per week), which was only 43% sensitive/84% specific in predicting low TFV levels and was not associated with PrEP discontinuation. Low urine TFV level predicted PrEP discontinuation [adjusted odds ratio (AOR) 6.1; 95% confidence interval (CI): 1.4-11; P â=â0.005] and was 71% sensitive/90% specific for discontinuation after 120âdays. Compared to LC/MS/MS, UTRA testing had a 98% positive and 100% negative predictive value. CONCLUSIONS: In a sample of YMSM/TGW on daily PrEP, POC UTRA testing predicted PrEP discontinuation more accurately than self-reported adherence, with high predictive values compared to LC/MS/MS. UTRA testing may be a clinical tool for directing preventive interventions towards those likelier to discontinue PrEP despite ongoing HIV vulnerability.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Cumplimiento de la Medicación , Profilaxis Pre-Exposición , Espectrometría de Masas en Tándem , Tenofovir , Humanos , Profilaxis Pre-Exposición/métodos , Infecciones por VIH/prevención & control , Tenofovir/orina , Tenofovir/uso terapéutico , Tenofovir/administración & dosificación , Masculino , Adulto Joven , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/administración & dosificación , Femenino , Cromatografía Liquida , Adulto , Adolescente , Pruebas en el Punto de Atención , Sistemas de Atención de PuntoRESUMEN
BACKGROUND: Poor adherence to ART and pre-exposure prophylaxis (PrEP) can impact patient and public health. Point-of-care testing (POCT) may aid monitoring and adherence interventions. OBJECTIVES: We report the pharmacokinetics of tenofovir [dosed as tenofovir disoproxil (TDF) and tenofovir alafenamide (TAF)], emtricitabine (FTC), lamivudine (3TC) and dolutegravir (DTG) in plasma and urine following drug cessation to evaluate adherence targets in urine for POCT. METHODS: Subjects were randomized (1:1) to receive DTG/FTC/TAF or DTG/3TC/TDF for 15â days. Plasma and spot urine were collected on Day 15 (0-336â h post final dose). Drug concentrations were quantified using LC-MS, and non-linear mixed-effects models applied to determine drug disposition between matrices and relationship with relevant plasma [dolutegravir protein-adjusted 90% inhibitory concentration (PA-IC90â=â64â ng/mL) and minimum effective concentration (MECâ=â324â ng/mL)] and urinary thresholds [tenofovir disoproxil fumarate 1500â ng/mL]. RESULTS: Of 30 individuals enrolled, 29 were included (72% female at birth, 90% Caucasian). Median (range) predicted time to plasma dolutegravir PA-IC90 and MEC were 83.5 (41.0-152) and 49.0â h (23.7-78.9), corresponding to geometric mean (90%) urine concentrations of 5.42 (4.37-6.46) and 27.4â ng/mL (22.1-32.7). Tenofovir in urine reached 1500â ng/mL by 101â h (58.6-205) with an equivalent plasma concentration of 6.20â ng/mL (4.21-8.18). CONCLUSIONS: These data support use of a urinary tenofovir threshold of <1500â ng/mL (tenofovir disoproxil fumarate-based regimens) as a marker of three or more missed doses for a POCT platform. However, due to low dolutegravir concentrations in urine, POCT would be limited to a readout of recent dolutegravir intake (one missed dose).
Asunto(s)
Fármacos Anti-VIH , Emtricitabina , Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Lamivudine , Oxazinas , Piperazinas , Pruebas en el Punto de Atención , Piridonas , Tenofovir , Humanos , Piridonas/orina , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/orina , Compuestos Heterocíclicos con 3 Anillos/sangre , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Masculino , Emtricitabina/orina , Emtricitabina/farmacocinética , Emtricitabina/uso terapéutico , Emtricitabina/sangre , Adulto , Piperazinas/orina , Piperazinas/sangre , Lamivudine/orina , Lamivudine/farmacocinética , Lamivudine/sangre , Femenino , Infecciones por VIH/tratamiento farmacológico , Tenofovir/orina , Tenofovir/farmacocinética , Tenofovir/uso terapéutico , Tenofovir/sangre , Fármacos Anti-VIH/orina , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/uso terapéutico , Persona de Mediana Edad , Profilaxis Pre-Exposición/métodos , Adulto Joven , Plasma/química , Cumplimiento de la MedicaciónRESUMEN
INTRODUCTION: Adherence counselling with point-of-care (POC) drug-level feedback using a novel tenofovir assay may support pre-exposure prophylaxis (PrEP) adherence; however, perceptions of urine testing and its impact on adherence are not well studied. We qualitatively examined how POC tenofovir testing was experienced by transgender women (TGW) in Uganda. METHODS: Within a cluster randomized trial of peer-delivered HIV self-testing, self-sampling for sexually transmitted infections and PrEP among HIV-negative TGW showing overall low PrEP prevention-effective adherence (NCT04328025), we conducted a nested qualitative sub-study of the urine POC assay among a random sample of 30 TGW (August 2021-February 2022). TGW interviews explored: (1) experiences with POC urine tenofovir testing and (2) perceptions of PrEP adherence counselling with drug-level feedback. We used an inductive content analytic approach for analysis. RESULTS: Median age was 21 years (interquartile range 20-24), and 70% engaged in sex work. Four content categories describe how TGW experienced POC urine tenofovir testing: (1) Urine tenofovir testing was initially met with scepticism: Testing urine to detect PrEP initially induced anxiety, with some perceptions of being intrusive and unwarranted. With counselling, however, participants found POC testing acceptable and beneficial. (2) Alignment of urine test results and adherence behaviours: Drug-level feedback aligned with what TGW knew about their adherence. Concurrence between pill taking and tenofovir detection in urine reinforced confidence in test accuracy. (3) Interpretation of urine tenofovir results: TGW familiar with the interpretation of oral-fluid HIV self-tests knew that two lines on the test device signified positivity (presence of HIV). However, two lines on the urine test strip indicated a positive result for non-adherence (absence of tenofovir), causing confusion. Research nurses explained the difference in test interpretation to participants' satisfaction. (4) White coat dosing: Some TGW deliberately chose not to attend scheduled clinic appointments to avoid detecting their PrEP non-adherence during urine testing. They restarted PrEP before returning to clinic, a behaviour called "white coat dosing." CONCLUSIONS: Incorporating POC urine testing into routine PrEP adherence counselling was acceptable and potentially beneficial for TGW but required attention to context. Additional research is needed to identify effective strategies for optimizing adherence monitoring and counselling for this population.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Cumplimiento de la Medicación , Profilaxis Pre-Exposición , Tenofovir , Personas Transgénero , Humanos , Tenofovir/orina , Tenofovir/uso terapéutico , Uganda , Profilaxis Pre-Exposición/métodos , Femenino , Infecciones por VIH/prevención & control , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/orina , Personas Transgénero/psicología , Adulto Joven , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/orina , Masculino , Investigación Cualitativa , Adulto , Consejo/métodosRESUMEN
BACKGROUND: Preexposure prophylaxis (PrEP) significantly reduces HIV infection risk but is dependent on adherence. Available approaches to measuring adherence have limitations related to accuracy, cost, practicality, and timeliness. This study compared the performance of two methods implementable in clinics and research studies [interview and urine point of care (POC) assay] to the gold-standard for measuring recent and longer term adherence in dried blood spots (DBS). METHODS: Participants were recruited from RADAR, a cohort study of young MSM, or via online advertisements. At 3 monthly visits, an interviewer administered 7-day timeline follow-back (TLFB) questionnaire, DBS samples were tested for tenofovir-diphosphate (TFV-DP) to estimate average dosing over the prior month and emtricitabine-triphosphate (FTC-TP) to assess recent dosing (past 2-3âdays), and a urine POC TFV test to qualitatively assess recent adherence (past 4âdays). RESULTS: Eighty-three PrEP users contributed 163 observations. At visit 1, self-reported adherence was 86% (4+ doses in last 7âdays), versus urine TFV (74%), DBS FTC-TP (76%), and DBS TFV-DP (69%). The objective measures of short-term adherence performed similarly well in predicting longer term adherence. In multivariable logistic regression analyses, the urine assay was a significant predictor of DBS TFV-DP (adjusted ORâ=â19.4, P â<â0.0001); self-report did not add significantly. CONCLUSION: The urine POC TFV assay had excellent predictive values for adherence and self-report did not add significantly to prediction. The POC assay provides results in several minutes to enable same-visit counseling, requires no specialized training, and is projected to be low-cost.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH , Infecciones por VIH , Organofosfatos , Profilaxis Pre-Exposición , Minorías Sexuales y de Género , Masculino , Humanos , Tenofovir/uso terapéutico , Tenofovir/orina , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Fármacos Anti-VIH/uso terapéutico , Homosexualidad Masculina , Sistemas de Atención de Punto , Estudios de Cohortes , Cumplimiento de la Medicación , Emtricitabina/uso terapéuticoRESUMEN
OBJECTIVE: We sought to evaluate the utility of a point-of-care (POC) urine tenofovir (TFV) assay, developed to objectively assess adherence, to predict HIV drug resistance (HIVDR) in people failing first-line antiretroviral therapy (ART). DESIGN: We retrospectively analyzed TFV levels as a biomarker of adherence in urine specimens collected during a clinical trial that enrolled adults with virologic failure on first-line ART in Uganda and South Africa. METHODS: Urine specimens were analyzed from participants on TFV-containing regimens who had a viral load >1000âcopies/ml and paired genotypic resistance test (GRT) results. We assessed recent ART TFV adherence with a qualitative POC lateral flow urine assay with a cut-off value of 1500âng/ml. We then calculated performance characteristics of the POC urine TFV assay to predict HIVDR, defined as intermediate or high-level resistance to any component of the current ART regimen. RESULTS: Urine specimens with paired plasma GRT results were available from 283 participants. The most common ART regimen during study conduct was emtricitabine, tenofovir disoproxil fumarate, and efavirenz. The overall prevalence of HIVDR was 86% ( n = 243/283). Of those with TFV detected on the POC assay, 91% ( n â=â204/224) had HIVDR, vs. only 66% ( n â=â39/59) among those with no TFV detected ( P- value < 0.001). Positive and negative predictive values of the assay to predict HIVDR were 91% and 34%, respectively. CONCLUSIONS: In populations with a high prevalence of HIVDR, the POC urine TFV assay can provide a low-cost, rapid method to guide requirements for confirmatory resistance testing and inform the need for regimen change.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Adulto , Humanos , Tenofovir/uso terapéutico , Tenofovir/orina , Infecciones por VIH/tratamiento farmacológico , Sistemas de Atención de Punto , Estudios Retrospectivos , Antirretrovirales/uso terapéutico , VIH-1/genéticaRESUMEN
BACKGROUND: The detection of tenofovir (TFV) metabolites by point-of-care (POC) urine lateral flow immunoassays (LFIA) indicates adherence to tenofovir-containing HIV pre-exposure prophylaxis. However, the association between urine TFV metabolites as detected by LFIA and HIV viral load suppression in people receiving TFV-based antiretroviral therapy (ART) is unknown as is patient and clinician acceptability of POC urine LFIA testing in clinical practice in low- and middle-income country settings. METHODS: We enrolled 409 people living with HIV from two HIV clinics in Lesotho and investigated the performance of POC urine LFIA TFV testing in predicting viral suppression. We interviewed 12 study participants and conducted a focus-group discussion with 5 clinicians to gather opinions on POC urine TFV testing. RESULTS: Using a viral load threshold of 1000 copies/mL, 398 (98%) participants were virologically suppressed, and 8 were viremic. Tenofovir was detected in the urine of 405 (99%) participants. The sensitivity of the POC urine LFIA test in detecting TFV in participants with viral suppression was 99.3% (95% CI: 97.8-99.8); the specificity was 12.5% (95% CI: 0.3-52.6). The positive and negative predictive values were 98.3% and 25%, respectively. Point-of-care urine TFV testing was viewed favorably by both participants and clinicians. However, clinicians stated that the 2-3-days detection window of the assay studied limits adherence categorization. CONCLUSIONS: In our study cohort, urine POC TFV testing demonstrated high sensitivity in predicting viral suppression, but low specificity and negative predictive value. Urine POC TFV testing was highly acceptable to participants and clinicians; however, clinicians expressed concern about its clinical utility because of its limitations. While further research is needed to assess performance in less adherent populations, this test may support adherence counseling in some clinical settings.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Humanos , Sistemas de Atención de Punto , Pruebas en el Punto de Atención , ARN , Tenofovir/uso terapéutico , Tenofovir/orinaRESUMEN
BACKGROUND: Tenofovir alafenamide (TAF) is increasingly used in HIV treatment, with or without agents that require pharmacologic boosters such as ritonavir/cobicistat. Boosters increase TAF levels, so the TAF dose is lowered in single-pill combinations. We hypothesized that individuals on dose-adjusted boosted TAF would have similar urine tenofovir (TFV) concentrations to those on unboosted TAF. SETTING/METHODS: We collected urine samples from patients with HIV on TAF, with evidence of virologic suppression and high self-reported adherence at 2 San Francisco clinics from June 2019 to January 2020. We measured urine TFV levels by liquid chromatography/tandem mass spectrometry and used linear regression to compare natural log-transformed urine TFV levels for patients on boosted versus unboosted TAF. RESULTS: Our analysis included 30 patients on unboosted TAF (25 mg daily TAF) and 15 on boosted TAF (12 on 10 mg daily TAF and 3 on 25 mg daily TAF). Patients on unboosted vs. boosted TAF had similar baseline age, weight, sex, and creatinine. In unadjusted univariate linear regression, there were no significant differences in urine TFV levels based on presence/absence of boosting after TAF dose reduction to 10 mg (geometric mean ratio 1.07; 95% confidence interval: 0.53 to 2.16). This finding was unchanged in adjusted analysis. CONCLUSIONS: No significant differences in urine TFV levels were seen for patients on unboosted vs. boosted dose-reduced TAF. These results have important implications for our forthcoming point-of-care urine immunoassay for TAF, implying that separate adherence cutoffs will not be necessary for patients on boosters and dose-reduced TAF. A single POC TAF immunoassay will, thus, support monitoring on most TAF-based antiretroviral therapy.
Asunto(s)
Alanina/orina , Antivirales/orina , Infecciones por VIH/tratamiento farmacológico , Cumplimiento de la Medicación , Tenofovir/análogos & derivados , Tenofovir/orina , Adenina/farmacocinética , Adenina/uso terapéutico , Adenina/orina , Alanina/farmacocinética , Alanina/uso terapéutico , Terapia Antirretroviral Altamente Activa , Antivirales/farmacocinética , Antivirales/uso terapéutico , Cromatografía Liquida , Femenino , Infecciones por VIH/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Sistemas de Atención de Punto , San Francisco/epidemiología , Espectrometría de Masas en Tándem , Tenofovir/farmacocinética , Tenofovir/uso terapéuticoRESUMEN
Approximately 32 million people have died of HIV infection since the beginning of the outbreak, and 38 million are currently infected. Among strategies adopted by the Joint United Nations Programme on HIV/AIDS to end the AIDS global epidemic, the treatment, diagnosis, and viral suppression of the infected subjects are considered crucial for HIV prevention and transmission. Although several antiretroviral (ARV) drugs are successfully used to manage HIV infection, their efficacy strictly relies on perfect adherence to the therapy, which is seldom achieved. Patient supervision, especially in HIV-endemic, low-resource settings, requires rapid, easy-to-use, and affordable analytical tools, such as the enzyme-linked immunosorbent assay (ELISA) and especially the lateral flow immunoassay (LFIA). In this work, high-affinity monoclonal antibodies were generated to develop ELISA and LFIA prototypes for monitoring tenofovir (TFV), an ARV drug present in several HIV treatments. TFV was functionalized by inserting a carboxylated C5-linker at the phosphonic group of the molecule, and the synthetic derivative was conjugated to proteins for mice immunization. Through a rigorous screening strategy of hybridoma supernatants, a panel of monoclonal antibodies strongly binding to TFV was obtained. Following antibody characterization for affinity and selectivity by competitive ELISA, a LFIA prototype was developed and tentatively applied to determine TFV in simulated urine. The point-of-care test showed ultra-high detectability (the visual limit of detection was 2.5 nM, 1.4 ng mL-1), excellent selectivity, and limited proneness to matrix interference, thus potentially making this rapid method a valuable tool for the on-site assessment of patient adherence to ARV therapy.
Asunto(s)
Fármacos Anti-VIH/orina , Anticuerpos Monoclonales/inmunología , Monitoreo de Drogas/métodos , Infecciones por VIH/tratamiento farmacológico , Inmunoensayo/métodos , Tenofovir/orina , Animales , Fármacos Anti-VIH/inmunología , Anticuerpos Monoclonales/análisis , Ensayo de Inmunoadsorción Enzimática/métodos , Humanos , Ratones , Pruebas en el Punto de Atención , Tenofovir/inmunologíaRESUMEN
BACKGROUND: Real-time, objective measures of adherence to antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) are needed to better assess adherence levels and to expedite clinical response for those with suboptimal adherence. Point-of-care tenofovir (POC-TFV) testing has been proposed as a solution to facilitate real-time antiretroviral adherence monitoring, but little is known about how health care providers, people living with HIV (PLWH) receiving ART, and people receiving PrEP will perceive POC-TFV testing. METHODS: We conducted an exploratory qualitative study to assess perspectives on the utility and interest in POC-TFV testing from potential end users. We conducted three focus group discussions (FGDs) among 17 PLWH receiving ART and four individuals receiving PrEP, as well as eight in-depth interviews (IDIs) with health care providers in the Seattle area and presented participants with a hypothetical urine-based POC-TFV test. FGDs and IDIs were audio recorded, transcribed, coded, and analyzed to describe emerging themes. RESULTS: Overall, study participants demonstrated divergent opinions about the POC-TFV test. Among study participants, PLWH were most ambivalent about POC-TFV testing, first demonstrating reluctance to TFV-level monitoring and shifting positions during the FGDs. However, all PLWH participants were receptive to POC-TFV testing if requested by their provider. PrEP participants were generally supportive of POC-TFV testing for routine adherence monitoring and emphasized potential value in self-administered testing. Providers' perceptions were equally divided - half suggested POC-TFV testing would be valuable, particularly for people receiving PrEP, while half indicated the test would have little benefit for most individuals receiving ART or PrEP in the U.S. All providers agreed that POC-TFV test results could be beneficial for assessing discrepancies in viral load results and self-reported adherence among PLWH. The study also revealed that a low-cost, non-urine-based POC-TFV test with a long-term limit of detection would be preferred over the hypothetical urine-based test. CONCLUSIONS: Our findings indicate POC-TFV testing may be beneficial for routine, clinic-based adherence monitoring, particularly for individuals receiving PrEP or for PLWH with persistent viremia or following recent ART initiation. These findings should also be used to formulate a target product profile for a POC-TFV test and to guide further developments in tools for objective antiretroviral adherence monitoring.
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Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Cumplimiento de la Medicación/estadística & datos numéricos , Sistemas de Atención de Punto , Profilaxis Pre-Exposición/métodos , Tenofovir/uso terapéutico , Tenofovir/orina , Adulto , Anciano , Terapia Antirretroviral Altamente Activa , Femenino , Grupos Focales , Personal de Salud , Humanos , Límite de Detección , Masculino , Persona de Mediana Edad , Pruebas en el Punto de Atención , Profilaxis Pre-Exposición/estadística & datos numéricos , Investigación Cualitativa , Estados UnidosRESUMEN
OBJECTIVES: The aim was to fully characterize the plasma and urine washout pharmacokinetics of tenofovir (TFV) in adults following 6 weeks of controlled levels of tenofovir disoproxil fumarate (TDF) adherence, in order to inform the utility of clinic-based adherence testing. DESIGN: This was a three-arm, randomized, open-label study in adult volunteers. Participants were randomized to receive TDF 300 mg/emtricitabine (FTC) 200 mg as (1) 7 doses/week (perfect adherence), (2) 4 doses/week (moderate adherence), or (3) 2 doses/week (low adherence). Plasma and urine samples were collected regularly during the 6-week dosing phase and for 4 weeks following drug cessation. RESULTS: Twenty-eight adults were included in this analysis. Median (range) age was 33 (20-49) years. No differences in TFV pharmacokinetic parameters during the washout were observed across the study arms. Small differences in TFV plasma concentrations occurred across arms between 4 and 10 h post-dose. The cumulative amount of TFV excreted in urine was not different at 24 h post-dose, but at 148 h it was 24.8 mg, 21.0 mg, and 17.2 mg for the perfect, moderate, and low adherence arms, respectively (p = 0.043). CONCLUSIONS: Among adults with different TDF adherence patterns, relative differences in plasma concentrations and cumulative urine extraction of TFV were minor following cessation. TFV measurement in plasma or urine is more indicative of last drug ingestion, rather than prior dose patterns.
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Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/psicología , Tenofovir/farmacocinética , Adulto , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/orina , Emtricitabina/administración & dosificación , Emtricitabina/sangre , Emtricitabina/farmacocinética , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/orina , Conductas Relacionadas con la Salud , Humanos , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Plasma/química , Tenofovir/sangre , Tenofovir/uso terapéutico , Tenofovir/orina , Adulto JovenRESUMEN
BACKGROUND: Therapeutic drug monitoring measures antiretroviral adherence more accurately than self-report but has not been available at the point-of-care (POC) until now. We compare a novel POC test for urine tenofovir to laboratory-based enzyme-linked immunosorbent assay (ELISA) testing in diverse patient populations urine pre-exposure prophylaxis (PrEP). SETTING: Urine samples were analyzed using ELISA and the POC lateral flow immunoassay (LFA) test from 2 cohorts of PrEP users taking tenofovir disoproxil fumarate/emtricitabine: the Partners PrEP Study, which recruited Kenyan and Ugandan heterosexual men and women, and the IBrEATHe Study, which recruited US transgender women and men using gender-affirming hormone therapy. METHODS: We calculated the sensitivity, specificity, and accuracy of the POC test compared with ELISA at a cutoff of 1500 ng/mL. RESULTS: Overall, 684 urine samples were tested from 324 participants in the 2 cohorts. In Partners PrEP, 454 samples from 278 participants (41% women) were tested with a median age of 33 years. In IBrEATHe, 231 samples from 46 individuals (50% transwomen) were tested with a median age of 31 years. Comparison of the LFA read-out to ELISA yielded 100% sensitivity [97.5% one-sided confidence interval (CI) = 99.3%], 98.3% specificity (95% CI = 95.2% to 99.7%), and 99.6% accuracy (95% CI = 98.7% to 99.9%). CONCLUSION: The sensitivity, specificity, and accuracy of a novel POC test for urine tenofovir all exceeded 98% when compared with a laboratory-based ELISA method when tested in diverse patient populations. Given the LFA's high accuracy and expected low cost, this POC test is a promising tool to support antiretroviral adherence that could be widely scalable to real-world clinical settings.
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Fármacos Anti-VIH/orina , Monitoreo de Drogas/métodos , Ensayo de Inmunoadsorción Enzimática/métodos , Infecciones por VIH/tratamiento farmacológico , Tenofovir/orina , Adulto , Fármacos Anti-VIH/uso terapéutico , Anticuerpos , Combinación de Medicamentos , Emtricitabina/administración & dosificación , Emtricitabina/uso terapéutico , Femenino , Humanos , Kenia , Laboratorios , Masculino , Cooperación del Paciente , Pruebas en el Punto de Atención , Sensibilidad y Especificidad , Tenofovir/administración & dosificación , Tenofovir/uso terapéutico , UgandaAsunto(s)
Adultos Sobrevivientes de Eventos Adversos Infantiles/estadística & datos numéricos , Fármacos Anti-VIH/administración & dosificación , Ansiedad/epidemiología , Depresión/epidemiología , Infecciones por VIH/prevención & control , Cumplimiento de la Medicación/psicología , Profilaxis Pre-Exposición/métodos , Adolescente , Adulto , Adultos Sobrevivientes de Eventos Adversos Infantiles/psicología , Fármacos Anti-VIH/uso terapéutico , Ansiedad/psicología , Estudios Transversales , Depresión/psicología , Femenino , Humanos , Masculino , Cumplimiento de la Medicación/estadística & datos numéricos , Cuestionario de Salud del Paciente , Prevalencia , Tenofovir/orinaRESUMEN
Tenofovir Disoproxil Fumarate (TDF) and tenofovir Alafenamide (TAF) are prodrugs of tenofovir and have excellent long-term efficacy and tolerability for the treatment of HIV. An objective marker of adherence to tenofovir-based therapy could be clinically useful in supporting adherence to TDF-based HIV pre-Exposure Prophylaxis (PrEP) in populations in whom, self-report has been shown to be unreliable, and could play a role in resource-limited settings to support HIV and hepatitis B treatment adherence. A semi-quantitative high-performance liquid chromatographymass spectrometry method for tenofovir quantification of urine samples was developed. This assay detects tenofovir concentration in log10 levels between 1 and 10,000 ng/mL, and was shown to distinguish between recent adherence and low/non-adherence to both TDF and TAF, with a concentration of >1000 ng/mL, highly predictive of medication ingestion in the last 24-48 hours. This assay was validated relative to other markers of adherence including dried blood spot and selfreport in a highly adherent population of PrEP patients, and tenofovir was shown to be stable at room temperature in urine for at least 14 days. The assay was successfully used in a clinical setting to maintain high PrEP adherence and retention in care of 50 young men who have sex with men (MSM) over 48 weeks, to assess PrEP adherence in youth with mental health conditions, and to monitor drug levels relative to plasma levels in a case study of chewed TDF/FTC (tenofovir/emtricitabine) for PrEP. Further studies are underway to implement the tenofovir urine assay to monitor adherence and pre-exposure prophylaxis, nationally and internationally.
Asunto(s)
Alanina/administración & dosificación , Fármacos Anti-VIH/administración & dosificación , Cumplimiento de la Medicación , Tenofovir/análogos & derivados , Alanina/orina , Fármacos Anti-VIH/orina , Cromatografía Líquida de Alta Presión/métodos , Infecciones por VIH/prevención & control , Humanos , Espectrometría de Masas/métodos , Profilaxis Pre-Exposición/métodos , Tenofovir/administración & dosificación , Tenofovir/orinaRESUMEN
OBJECTIVE: HIV prevention and treatment studies demonstrate that pharmacologic adherence metrics are more accurate than self-report. Currently available metrics use liquid-chromatography/tandem-mass-spectrometry (LC-MS/MS), which is expensive and laboratory-based. We developed a specific and sensitive antibody against tenofovir, the backbone of treatment and prevention, but conversion to a lateral flow assay (LFA) - analogous to a urine pregnancy test - is required for point-of-care testing. We describe the development of the first LFA to measure antiretroviral adherence in real-time. METHODS: Previous work in a directly observed therapy study of providing tenofovir disoproxil fumarate (TDF) to HIV-noninfected volunteers at various simulated adherence patterns defined the appropriate cut-off for the LFA (1500âng tenofovir/ml urine). We developed the LFA using a sample pad for urine; a conjugate pad coated with TFV-specific antibodies conjugated to colloidal gold nanoparticles; a nitrocellulose membrane striped with tenofovir-antigen (test line) and a control line; with an absorbent pad to draw urine across the reaction membrane. RESULTS: We tested 300 urine samples collected from the directly observed therapy study by this LFA and the gold-standard method of LC-MS/MS. The LFA demonstrated 97% specificity (95% CI 93-99%) and 99% sensitivity (94-100%) compared with LC-MS/MS. The LFA accurately classified 98% of patients who took a dose within 24âh as adherent. CONCLUSION: We describe the development and validation of the first point-of-care assay to measure short-term adherence to HIV prevention and treatment in routine settings. The assay is low-cost, easy-to-perform and measures the breakdown product (tenofovir) of both TDF and tenofovir alafenamide (TAF). This assay has the potential to improve HIV and PrEP outcomes worldwide by triggering differentiated service delivery with further study merited.
Asunto(s)
Fármacos Anti-VIH/orina , Cumplimiento de la Medicación/estadística & datos numéricos , Pruebas en el Punto de Atención , Profilaxis Pre-Exposición/métodos , Tenofovir/orina , Fármacos Anti-VIH/uso terapéutico , Cromatografía Liquida , Oro/orina , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Humanos , Nanopartículas del Metal , Profilaxis Pre-Exposición/estadística & datos numéricos , Espectrometría de Masas en Tándem , Tenofovir/uso terapéuticoRESUMEN
BACKGROUND AND OBJECTIVES: The elderly population receives the majority of prescription drugs but are usually excluded from Phase 1 clinical trials. Alternative approaches to estimate increases in toxicity risk or decreases in efficacy are therefore needed. This study predicted the pharmacokinetics (PK) of three renally excreted antiretroviral drugs in the elderly population and compared them with known exposures in renal impairment, to evaluate the need for dosing adjustments. METHODS: The performance of the physiologically based pharmacokinetic (PBPK) models for tenofovir, lamivudine and emtricitabine were verified using clinical data in young and older subjects. Models were then used to predict PK profiles in a virtual population aged 20 to 49 years (young) and a geriatric population aged 65 to 74 years (elderly). Predicted exposure in the elderly was then compared with exposure reported for different degrees of renal impairment, where doses have been defined. RESULTS: An increase in exposure (AUC) with advancing age was predicted for all drugs. The mean ratio of the increase in exposure were 1.40 for emtricitabine, 1.42 for lamivudine and 1.48 for tenofovir. The majority of virtual patients had exposures that did not require dosage adjustments. About 22% of patients on tenofovir showed exposures similar to that in moderate renal impairment, where dosage reduction may be required. CONCLUSION: Comparison of the exposure in the elderly with exposure observed in patients with different levels of renal impairment, indicated that a dosage adjustment may not be required in elderly patients on lamivudine, emtricitabine and the majority of the patients on tenofovir. Clinical trials to verify these predictions are essential.
Asunto(s)
Envejecimiento/orina , Fármacos Anti-VIH , Enfermedades Renales/orina , Modelos Biológicos , Adulto , Anciano , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/orina , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Emtricitabina/administración & dosificación , Emtricitabina/orina , Humanos , Pruebas de Función Renal , Lamivudine/administración & dosificación , Lamivudine/orina , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Tenofovir/administración & dosificación , Tenofovir/orina , Adulto JovenRESUMEN
BACKGROUND: Urine provides a minimally invasive specimen that may allow for development of rapid tests to detect antiretroviral drugs and provide opportunities to improve individual adherence. This study sought to determine whether urine could provide a biomarker of adherence for currently approved pre-exposure prophylaxis and HIV treatment regimens. METHODS: Urine and blood were collected from 34 HIV-negative men who have sex with men aged 18-49 years, enrolled in a clinical trial comparing 2 antiretroviral regimens. Specimens were collected 4 and 24 hours after a single oral dose of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) (n = 10) or tenofovir alafenamide (TAF)/FTC/cobicistat (COBI)/elvitegravir (EVG) (n = 8), or after 4 and 10 days of daily oral TDF/FTC (n = 9) or TAF/FTC/COBI/EVG (n = 7). Tenofovir (TFV), FTC, and EVG were measured by high-performance liquid chromatography-mass spectrometry. RESULTS: Median urine FTC concentrations at 4 and 24 hours were similar between men receiving TDF/FTC (4 hours 147 µg/mL; 24 hours 10 µg/mL) and men receiving TAF/FTC/COBI/EVG (4 hours 333 µg/mL, P = 0.173; 24 hours 13 µg/mL, P = 0.681). Median urine TFV concentrations were lower among men receiving TAF/FTC/COBI/EVG (4 hours 1.2 µg/mL; 24 hours 0.8 µg/mL) compared with men receiving TDF/FTC (4 hours 17 µg/mL, P < 0.001; 24 hours 7 µg/mL, P = 0.001). Urine TFV concentrations remained reduced among men receiving TAF/FTC/COBI/EVG compared with men receiving TDF/FTC after daily dosing. EVG was not consistently measurable in urine. CONCLUSIONS: High urine FTC and TFV concentrations could provide an indication of adherence to daily oral dosing with TDF or TAF-based regimens used for treatment and prevention.
Asunto(s)
Antirretrovirales/orina , Biomarcadores/orina , Emtricitabina/orina , Infecciones por VIH/tratamiento farmacológico , Homosexualidad Masculina , Minorías Sexuales y de Género , Tenofovir/orina , Adenina/análogos & derivados , Administración Oral , Adolescente , Adulto , Alanina , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/orina , Antirretrovirales/administración & dosificación , Antirretrovirales/uso terapéutico , Cobicistat/uso terapéutico , Emtricitabina/administración & dosificación , Emtricitabina/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Quinolonas , Tenofovir/administración & dosificación , Tenofovir/uso terapéutico , Factores de Tiempo , Adulto JovenRESUMEN
Maximizing the impact of HIV pre-exposure prophylaxis (PrEP) requires optimizing access and adherence for those at risk of contracting HIV. This study examined challenges to the processes of accessing and adhering to PrEP encountered by participants from a large, U.S. urban clinical center and assessed the utility of objectively monitoring PrEP adherence via urine. Most participants (65%) reported starting PrEP within 1-3 months of hearing about it, although 35% of participants encountered a provider unwilling to prescribe PrEP. Self-reported adherence was high among this population, with remembering to take the medication reported as the major barrier to adherence (44%) rather than cost or stigma. Urine tenofovir (TFV) monitoring was highly acceptable to this population, and participants indicated greater willingness to undergo urine monitoring every 3 months compared to finger prick (dried blood spot), phlebotomy, or hair follicle testing. These findings highlight the importance of focusing efforts toward reducing obstacles to PrEP use and support the use of urine TFV adherence monitoring as a marker of PrEP adherence.
Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/orina , Infecciones por VIH/prevención & control , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Cumplimiento de la Medicación/psicología , Profilaxis Pre-Exposición , Tenofovir/administración & dosificación , Adolescente , Adulto , Fármacos Anti-VIH/uso terapéutico , Centros Comunitarios de Salud , Femenino , Humanos , Masculino , Percepción , Philadelphia , Profilaxis Pre-Exposición/métodos , Profilaxis Pre-Exposición/estadística & datos numéricos , Tenofovir/uso terapéutico , Tenofovir/orina , Población Urbana , Adulto JovenRESUMEN
OBJECTIVE: We examined the relationship between urine tenofovir (TFV) levels measured with a novel immunoassay, which permits point-of-care testing, with HIV seroconversion and objective adherence metrics in a large preexposure prophylaxis (PrEP) demonstration project. DESIGN: Secondary analysis of stored specimens from an open-label PrEP cohort study. METHODS: We examined the association between undetectable urine TFV levels and HIV seroconversion in iPrEx open-label extension using generalized estimating equations. We examined rank correlations between levels of TFV and emtricitabine in urine, dried blood spots (DBS), and hair and determined the sensitivity and specificity of undetectable urine TFV for predicting dosing cut-offs in DBS. RESULTS: The median urinary TFV level was 15â000âng/ml in those who remained HIV-negative (nâ=â105; interquartile range: 1000-45â000); 5500 in those who eventually seroconverted (nâ=â11; interquartile range: 1000-12â500); and all were undetectable at seroconversion (nâ=â9; Pâ<â0.001). Decreasing strata of urine TFV levels were associated with future HIV seroconversion (Pâ=â0.03). An undetectable urine TFV was 100% sensitive and 81% specific when compared with an undetectable DBS TFV-diphosphate level and 69% sensitive, but 94% specific when compared with low adherence by DBS (<2 doses/week). CONCLUSION: Urine TFV detection by a novel antibody-based assay was associated with protection from HIV acquisition among individuals on PrEP. Urine TFV levels were correlated with hair and DBS levels and undetectable urine TFV was 100% sensitive in detecting nonadherence. By implementing the immunoassay into a point-of-care strip test, PrEP nonadherence could be detected in real-time, allowing rapid intervention.
Asunto(s)
Fármacos Anti-VIH/orina , Infecciones por VIH/prevención & control , Inmunoensayo/métodos , Profilaxis Pre-Exposición , Seroconversión/efectos de los fármacos , Tenofovir/orina , Urinálisis , Adulto , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Pruebas con Sangre Seca , Femenino , Humanos , Masculino , Cumplimiento de la Medicación , Pruebas en el Punto de Atención , Estudios Prospectivos , Tenofovir/farmacocinética , Tenofovir/uso terapéuticoRESUMEN
BACKGROUND: Current pharmacologic adherence monitoring for antiretrovirals involves expensive, labor-intensive liquid chromatography/tandem mass spectrometry (LC-MS/MS)-based methods. Antibody-based assays can monitor and support adherence in real time. We developed a tenofovir (TFV)-based immunoassay and further validated it in a directly observed therapy (DOT) study. DESIGN: Pharmacologic DOT study of TFV disoproxil fumarate (TDF)/emtricitabine (FTC) administered to HIV-noninfected volunteers. METHODS: The TARGET study provided directly observed TDF 300 mg/FTC 200 mg 7 (high adherence), 4 (moderate), and 2 doses/week (low) to 30 volunteers (10/group) in Thailand, collecting a total of 637 urine samples over 6 weeks of administration and during washout. ELISA measured urine TFV levels by the immunoassay and LC-MS/MS-based concentrations served as the gold standard. A mixed-effects regression model evaluated cutoffs for a point-of-care assay. Performance characteristics of the immunoassay were compared with LC-MS/MS at a chosen cutoff. RESULTS: Median TFV levels were 12,000 ng/mL by the immunoassay 1 day after dosing; 5000 ng/mL 2 days after dosing; 1500 ng/mL 3 days after dosing; and below the lower limit of quantification thereafter (≥4 days). An immunoassay cutoff of 1500 ng/mL accurately classified 98% of patients who took a dose 24 hours ago as adherent. The specificity and sensitivity of the immunoassay compared with LC-MS/MS at the 1500 ng/mL cutoff were 99% and 94%; the correlation between TFV levels by the 2 assays was high (0.92, P < 0.00001). CONCLUSIONS: We have developed a novel TFV immunoassay that is highly specific, sensitive, and correlates strongly with LC-MS/MS measurements in a large DOT study. Adherence benchmarks from this DOT study will guide the development of a low-cost rapid point-of-care test for pre-exposure prophylaxis and antiretroviral treatment adherence monitoring and interventions.