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 One participant in the standard of care group was withdrawn at the 6-month visit due to HIV seroconversion.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
OBJECTIVE: HIV prevention service delivery models that offer product choices, and the option to change preferences over time, may increase prevention coverage. Outpatient departments in sub-Saharan Africa diagnose a high proportion of new HIV infections, but are an understudied entry point to biomedical prevention. DESIGN: Individually randomized trial of dynamic choice HIV prevention (DCP) intervention vs. standard-of-care (SOC) among individuals with current/anticipated HIV exposure risk at outpatient departments in rural Kenya and Uganda (SEARCH; NCT04810650). METHODS: Our DCP intervention included 1) product choice (oral preexposure prophylaxis [PrEP] or postexposure prophylaxis [PEP]) with an option to switch over time, 2) HIV provider- or self-testing, 3) service location choice (community vs. clinic-based), and 4) provider training on patient-centered care. Primary outcome was proportion of follow-up covered by PrEP/PEP over 48âweeks assessed via self-report. RESULTS: We enrolled 403 participants (61% women; median 27âyears, IQR 22-37). In the DCP arm, 86% ever chose PrEP, 15% ever chose PEP over 48âweeks; selection of HIV self-testing increased from 26 to 51% and of out-of-facility visits from 8 to 52%. Among 376 of 403 (93%) with outcomes ascertained, time covered by PrEP/PEP was higher in DCP (47.5%) vs. SOC (18.3%); differenceâ=â29.2% (95% confidence interval: 22.7-35.7; P â<â0.001). Effects were similar among women and men (28.2 and 31.0% higher coverage in DCP, respectively) and larger during periods of self-reported HIV risk (DCP 64.9% vs. SOC 26.3%; differenceâ=â38.6%; 95% confidence interval: 31.0-46.2; P â<â0.001). CONCLUSION: A dynamic choice HIV prevention intervention resulted in two-fold greater time covered by biomedical prevention products compared to SOC in general outpatient departments in eastern Africa.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Femenino , Humanos , Masculino , Instituciones de Atención Ambulatoria , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Kenia , Pacientes Ambulatorios , Profilaxis Pre-Exposición/métodos , UgandaRESUMEN
We found that urine tenofovir (TFV) levels >1500 ng/mL strongly predict virologic suppression among people with human immunodeficiency virus taking tenofovir alafenamide (odds ratio, 5.66; 95% confidence interval, 1.59-20.14; P = .007). This suggests an existing point-of-care assay developed for tenofovir disoproxil fumarate will support adherence monitoring for patients on all TFV-based antiretrovirals.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Humanos , Tenofovir/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Alanina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Adenina/uso terapéuticoRESUMEN
Background: Tenofovir-diphosphate (TFV-DP) measured in dried blood spots (DBS) and tenofovir (TFV) measured in urine/plasma have been used to measure TFV-based oral pre-exposure prophylaxis (PrEP) adherence. However, there are limited data comparing these 3 metrics and their appropriate use for PrEP adherence monitoring. Methods: We collected DBS, urine, and plasma samples from HIV-negative adults randomized to a low (2 doses/week), moderate (4 doses/week), or perfect (7 doses/week) adherence group (via directly observed therapy) of tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for 6 weeks, followed by a 4-week washout phase. Drug concentrations were measured using liquid chromatography tandem mass spectrometry. Linear mixed-effects modeling was used to examine associations between drug concentrations and dosing time. Results: Among 28 participants, the median age was 33 years, and 12 (43%) were female. At steady state, 25th percentile TFV-DP concentrations were 466, 779, and 1375 fmol/3â mm punch in the low, moderate, and perfect adherence group, respectively. Correlation was stronger between quantifiable TFV-DP and plasma TFV (r = 0.65; P < .01) than between TFV-DP and urine TFV (r = 0.50; P < .01). Among all participants, each additional week of cumulative dosing on average led to a mean increase of 158 fmol/3â mm punch (P < .001) in TFV-DP during the dosing phase. Each additional day after the last dose was associated with 43 fmol/3â mm punch lower TFV-DP (P = .07). Conclusions: TFV-DP levels in DBS provide valuable insight into both dosing recency and cumulative doses from variable adherence patterns. Our observed benchmark TFV-DP concentrations were slightly higher than prior predicted estimates based on convenience samples.
RESUMEN
BACKGROUND: We examined change in antiretroviral treatment (ART) adherence after breastfeeding (BF) cessation using hair tenofovir (TFV) concentrations as an objective metric of medication consumption. METHODS: A subset of postpartum women in Zimbabwe randomized in IMPAACT PROMISE to take ART while BF and post-BF cessation had hair TFV measured longitudinally. Using linear mixed-effect models, we estimated differences in hair TFV levels after BF cessation, accounting for trends in levels over time regardless of BF status and change in slope after breastfeeding cessation. We also estimated the relative risk of viremia (>50 copies/mL) per doubling of hair TFV concentration. RESULTS: Among 55 women (median age 26, interquartile range 24-29 years), hair TFV levels (n = 305) were available for a median of 9 visits per woman between 3 and 29 months postpartum. Hair TFV levels ranged from undetected to 0.25 ng/mg (median 0.04 ng/mg). Controlling for trends since delivery [decline of 2.2% per month, 95% confidence interval (CI): -5.3 to 1.0], TFV levels averaged 24.4% higher (95% CI: -5.1 to 63.1) post-BF cessation than during BF, with no change in slope (0.0% per month, 95% CI: -3.8 to 3.9). Postpartum, 42% of women were ever viremic. Higher TFV levels were strongly protective; relative risk of viremia per doubling of TFV was 0.52 (95% CI: 0.43 to 0.63; P < 0.0001). CONCLUSIONS: Leveraging an objective metric of ART use, we observed modestly declining adherence across the postpartum period, but no additional decline associated with breastfeeding cessation. High viremia frequency and varying postpartum TFV levels observed highlight the importance of enhanced adherence support with viral load monitoring among postpartum women.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Adulto , Femenino , Humanos , Adulto Joven , Fármacos Anti-VIH/uso terapéutico , Antirretrovirales/uso terapéutico , Cabello , Infecciones por VIH/tratamiento farmacológico , Cumplimiento de la Medicación , Tenofovir/uso terapéutico , Viremia/tratamiento farmacológicoRESUMEN
BACKGROUND: Strategies to support adherence are constrained by the lack of tools to objectively monitor medication intake in low-resource settings. Pharmacologic measures are objective, but pharmacy refill data is more accessible and cost-efficient. This study compared short-term and long-term efavirenz (EFV) drug levels with pharmacy refill adherence data (PRA) and evaluated their ability to predict viral suppression among people living with HIV in Nigeria. METHODS: Paired hair and dried blood spot (DBS) samples were obtained from 91 adults living with HIV receiving 600 mg EFV-based antiretroviral therapy (ART) and EFV concentrations were measured via validated methods using liquid-chromatography-mass-spectrometry. PRA was estimated from pharmacy records, based on the number of days a patient collected medication before or after the scheduled pick-up date. PRA was categorized into ≤ 74%, 75-94% and ≥ 95%, defined as poor, medium and high adherence, respectively. HIV viral loads closest to the hair sampling time (within 6 months) were also abstracted. Receiver Operating Characteristics (ROC) curve analyses compared the ability of adherence metrics to predict viral suppression. RESULTS: Based on PRA, 81% of participants had high adherence while 11% and 8% had medium and poor adherence, respectively. The median (IQR) EFV concentrations were 6.85 ng/mg (4.56-10.93) for hair and 1495.6 ng/ml (1050.7-2365.8) for DBS. Of the three measures of adherence, hair EFV concentration had the highest Area Under Curve (AUC) to predict viral suppression. Correlations between EFV concentrations in DBS and hair with PRA were positive (r = 0.12, P = 0.27 and r = 0.21, P = 0.05, respectively) but not strong. CONCLUSIONS: EFV concentrations in hair were the strongest predictor of viral suppression and only weakly correlated with pharmacy refill adherence data in Nigeria. This study suggests that resource-limited settings may benefit from objective adherence metrics to monitor and support adherence.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Farmacia , Adulto , Alquinos , Fármacos Anti-VIH/análisis , Fármacos Anti-VIH/uso terapéutico , Benzoxazinas , Ciclopropanos , Infecciones por VIH/tratamiento farmacológico , Cabello/química , Humanos , NigeriaRESUMEN
OBJECTIVE: We examined whether human mobility was associated with antiretroviral treatment adherence, measured via antiretroviral hair concentrations. DESIGN: This is a cross-sectional analysis of adults on antiretroviral treatment in East Africa at baseline in an observational cohort study. METHODS: Participants reported recent mobility (overnight travel) and histories of migration (changes of residence), including reasons, frequency/duration, and locations. Hair antiretroviral concentrations were analyzed using validated methods. We estimated associations between mobility and antiretroviral concentrations via linear regression adjusted for age, sex, region, years on treatment. RESULTS: Among 383 participants, half were women and the median age was 40. Among men, 25% reported recent work-related mobility, 30% nonwork mobility, and 11% migrated in the past year (mostly across district boundaries); among women, 6 and 57% reported work-related and nonwork mobility, respectively, and 8% recently migrated (mostly within district). Those reporting work-related trips 2 nights or less had 72% higher hair antiretroviral levels (Pâ=â0.02) than those who did not travel for work; in contrast, nonwork mobility (any duration, vs. none) was associated with 24% lower levels (Pâ=â0.06). Intra-district migrations were associated with 59% lower antiretroviral levels than nonmigrants (Pâ=â0.003) while inter-district migrations were not (27% higher, Pâ=â0.40). CONCLUSION: We found that localized/intra-district migration and nonwork travel-more common among women-were associated with lower adherence, potentially reflecting care interruptions or staying with family/friends unaware of the participants' status. In contrast, short work-related trips-more common among men-were associated with higher adherence, perhaps reflecting higher income. Adherence interventions may require tailoring by sex and forms of mobility.
Asunto(s)
Infecciones por VIH , Adulto , África Oriental , Antirretrovirales , Estudios Transversales , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Cumplimiento y Adherencia al TratamientoRESUMEN
BACKGROUND: HIV-uninfected persons being evaluated for sexually transmitted infections (STIs) may be good HIV pre-exposure prophylaxis (PrEP) candidates. We measured PrEP use in a sentinel STI patient population. DESIGN: Cross-sectional study, New York City Sexual Health Clinics (January 2019-June 2019). METHODS: Remnant serum samples from 644 HIV-uninfected men who have sex with men (MSM) and 97 women diagnosed with chlamydia, gonorrhea, and/or early syphilis were assayed for tenofovir and emtricitabine levels using a validated liquid chromatography-mass spectrometry assay. Using paired test results and medical records, we assessed (1) prevalence and (2) correlates of PrEP use on the day of STI diagnosis (adjusted prevalence ratios [aPRs]). RESULTS: PrEP use among 741 patients was 32.7% [95% confidence interval (CI): 29.3 to 36.0]; 37.3% for MSM and 2.1% for women. PrEP use was high among White MSM (46.8%) and lowest among women. Among MSM with rectal chlamydia/gonorrhea or early syphilis, PrEP use was associated with age [aPR = 1.7 (95% CI: 1.2 to 2.4) for ages 25-34 years and aPR = 2.0 (1.4 to 2.9) for ages 35-44 years, vs. 15 to 24 years]; number of recent sex partners [aPR = 1.4 (1.0 to 2.0) for 3-5 partners, aPR = 2.1 (1.5 to 3.0) for 6-10 partners, aPR = 2.2 (1.6 to 3.1) for >10 partners, vs. ≤2 partners]; having sex/needle-sharing partners with HIV [aPR = 1.4 (1.1-1.7)]; and inconsistent condom use [aPR = 3.3 (1.8-6.1)]. Race/ethnicity, past-year STI diagnosis, and postexposure prophylaxis use were not associated. CONCLUSIONS: One in 3 people with newly diagnosed STIs had detectable serum PrEP, and PrEP use was exceedingly rare among women. Routinely collected remnant samples can be used to measure PrEP use in populations at high risk of HIV acquisition.
Asunto(s)
Gonorrea , Infecciones por VIH , Profilaxis Pre-Exposición , Enfermedades del Recto , Minorías Sexuales y de Género , Enfermedades de Transmisión Sexual , Sífilis , Adulto , Estudios Transversales , Femenino , Gonorrea/epidemiología , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Homosexualidad Masculina , Humanos , Masculino , Profilaxis Pre-Exposición/métodos , Enfermedades de Transmisión Sexual/epidemiología , Enfermedades de Transmisión Sexual/prevención & control , Sífilis/epidemiologíaRESUMEN
ABSTRACT: In New York City, 91% of sexually transmitted infection clinic patients reported preexposure prophylaxis (PrEP) use that matched the detection of PrEP in their serum. Self-report had 80% sensitivity and 96% specificity ( κ = 0.79) compared with measured PrEP. Our findings suggest that self-report may be a valid indicator of PrEP uptake.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Salud Sexual , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Homosexualidad Masculina , Humanos , Masculino , Ciudad de Nueva York/epidemiología , AutoinformeRESUMEN
From directly observed therapy studies, urine tenofovir (TFV) levels were 74% lower when taking tenofovir alafenamide (TAF) vs tenofovir disoproxil fumarate. Urine TFV remains quantifiable across a range of TAF adherence patterns, but a separate point-of-care lateral flow immunoassay with a lower TFV threshold will be needed to support TAF adherence monitoring.
RESUMEN
OBJECTIVE: Efavirenz (EFV) use is associated with neuropsychiatric side effects, which may include poor neurocognitive performance. We evaluated single nucleotide polymorphisms in genes that contribute to EFV pharmacokinetics and examined them in association with EFV concentrations in plasma and hair, as well as neurocognitive performance. DESIGN: Cross-sectional study in which adults with HIV receiving 600-mg EFV for at least 2 months were recruited and paired hair and dried blood spots (DBS) samples collected. METHODS: Participants (Nâ=â93, 70.3% female) were genotyped for seven single nucleotide polymorphisms in CYP2B6, NRII3 and ABCB1 using DBS. EFV was quantified in DBS and hair using validated liquid-chromatography-tandem-mass-spectrometry methods, with plasma EFV concentrations derived from DBS levels. Participants were also administered a neurocognitive battery of 10 tests (seven domains) that assessed total neurocognitive functioning. RESULTS: Strong correlation (râ=â0.66, Pâ<â0.001) was observed between plasma and hair EFV concentrations. The median (interquartile range) hair EFV concentration was 6.85âng/mg (4.56-10.93). CYP2B6 516G>T, (Pâ<â0.001) and CYP2B6 983T>C (Pâ=â0.001) were each associated with hair EFV concentrations. Similarly, 516G>T (Pâ<â0.001) and 983T>C (Pâ=â0.009) were significantly associated with plasma EFV concentration. No other genetic associations were observed. Contrary to other studies, total neurocognitive performance was significantly associated with plasma EFV concentrations (râ=â0.23, Pâ=â0.043) and 983T>C genotype (râ=â0.38, Pâ<â0.0005). CONCLUSION: This study demonstrated approximately three-fold and two-fold higher EFV plasma and hair concentrations, respectively, among CYP2B6 516TT compared with 516GG. Higher EFV concentrations were associated with better neurocognitive performance, requiring further study to elucidate the relationships between adherence, adverse effects and outcomes.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Adulto , Alquinos , Fármacos Anti-VIH/uso terapéutico , Benzoxazinas/efectos adversos , Estudios Transversales , Ciclopropanos/uso terapéutico , Citocromo P-450 CYP2B6/genética , Femenino , Genotipo , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Nigeria , Farmacogenética , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Suboptimal adherence to antiretroviral therapy (ART) is responsible for most virologic failure among adolescents with HIV. Methods for objectively measuring adherence to ART are limited. This study assessed the association between ritonavir concentrations in hair and self-reported adherence and modified directly administered ART on virologic outcomes among HIV-infected adolescents who were virologically failing second-line ART in Harare, Zimbabwe. METHODS: HIV-infected adolescents on atazanavir-based or ritonavir-based second-line treatment for >6 months with viral load ≥1000 copies/mL were randomized to either modified directly administered ART (mDAART) plus standard of care (intervention) or standard of care alone (control). Questionnaires were administered; viral load and hair samples were collected at baseline and after 90 days. Virological suppression was defned as <1000 copies/mL after follow-up. RESULTS: Fifty adolescents (13-19 years) were enrolled in the study, and 42 adolescents had ritonavir concentrations measured in hair at baseline and at 90 days. Twenty-three participants (46%) were randomized to mDAART. Viral load suppression at follow-up [regression coefficient (standard error): -0.3 (0.1); 95% confidence interval (CI): -0.5 to -0.06; P = 0.01], self-reported adherence at follow-up [regression coefficient (standard error): 0.01 (0.005); 95% CI: 0.004 to 0.02; P = 0.006], and being male sex [regression coefficient (standard error): 0.3 (0.1); 95% CI: 0.08 to 0.5; P = 0.008] were associated with ritonavir concentrations in hair. The intervention, mDAART, was not associated with ritonavir concentrations [regression coefficient (standard error) 0.2 (0.1); 95% CI: -0.07 to 0.4; P = 0.2]. CONCLUSIONS: Ritonavir concentrations in hair predicted virological suppression and were associated with self-reported adherence and being male in this cohort of adolescents with treatment failure to atazanavir-based or ritonavir-based second-line ART. Measuring ritonavir concentrations in hair in adolescents on protease inhibitor-based regimens could assess adherence in this vulnerable group to avert subsequent virologic failure.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Sulfato de Atazanavir/uso terapéutico , Cabello/química , Ritonavir/metabolismo , Carga Viral/efectos de los fármacos , Adolescente , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Ritonavir/uso terapéutico , Insuficiencia del Tratamiento , Resultado del Tratamiento , ZimbabweRESUMEN
Three-dimensional (3D) microphysiological systems (MPSs) mimicking human organ function in vitro are an emerging alternative to conventional monolayer cell culture and animal models for drug development. Human induced pluripotent stem cells (hiPSCs) have the potential to capture the diversity of human genetics and provide an unlimited supply of cells. Combining hiPSCs with microfluidics technology in MPSs offers new perspectives for drug development. Here, the integration of a newly developed liver MPS with a cardiac MPS-both created with the same hiPSC line-to study drug-drug interaction (DDI) is reported. As a prominent example of clinically relevant DDI, the interaction of the arrhythmogenic gastroprokinetic cisapride with the fungicide ketoconazole was investigated. As seen in patients, metabolic conversion of cisapride to non-arrhythmogenic norcisapride in the liver MPS by the cytochrome P450 enzyme CYP3A4 was inhibited by ketoconazole, leading to arrhythmia in the cardiac MPS. These results establish integration of hiPSC-based liver and cardiac MPSs to facilitate screening for DDI, and thus drug efficacy and toxicity, isogenic in the same genetic background.
RESUMEN
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
The objective of this study was to determine the effects of the OATP inhibitor rifampin on pharmacokinetic of Biopharmaceutics Drug Disposition Classification System Class 1 compound fluvastatin. A crossover study was carried out in 10 healthy subjects who were randomized to 2 phases to receive fluvastatin 20 mg orally alone and following a 30-minute 600 mg i.v. infusion of rifampin. The results demonstrated that i.v. rifampin increased the mean area under the plasma fluvastatin concentration-time curve (AUC0-∞ ) by 255%, mean peak plasma concentration (Cmax ) by 254%, decreased oral volume of distribution by 71%, whereas the mean elimination terminal half-life (T1/2 ), mean absorption time (MAT), and time to peak concentration (Tpeak ) of fluvastatin did not significantly change. The study demonstrated that rifampin exhibited a significant drug interaction with fluvastatin. The mechanism of the increased plasma concentrations is likely due to inhibition of OATP transporters in hepatocytes.
Asunto(s)
Antibacterianos/efectos adversos , Fluvastatina/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Rifampin/efectos adversos , Administración Oral , Adulto , Antibacterianos/administración & dosificación , Área Bajo la Curva , Estudios Cruzados , Interacciones Farmacológicas , Femenino , Fluvastatina/administración & dosificación , Semivida , Voluntarios Sanos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Infusiones Intravenosas , Absorción Intestinal , Masculino , Persona de Mediana Edad , Transportadores de Anión Orgánico , Estudios Prospectivos , Rifampin/administración & dosificaciónRESUMEN
Tenofovir disoproxil fumarate (TDF) in combination with emtricitabine (FTC) is the backbone for both human immunodeficiency virus (HIV) treatment and pre-exposure prophylaxis (PrEP) worldwide. Tenofovir alafenamide (TAF) with FTC is increasingly used in HIV treatment and was recently approved for PrEP among men-who-have-sex-with-men. TDF and TAF are both metabolized into tenofovir (TFV). Antiretrovirals in plasma are taken up into hair over time, with hair levels providing a long-term measure of adherence. Here, we report a simple, robust, highly sensitive, and validated high-performance liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS)-based analytical method for analyzing TFV and FTC from individuals on either TDF/FTC or TAF/FTC in small hair samples. TFV/FTC are extracted from ~5 mg hair and separated on a column using a gradient elution. The lower quantification limits are 0.00200 (TFV) and 0.0200 (FTC) ng/mg hair; the assay is linear up to 0.400 (TFV) and 4.00 (FTC) ng/mg hair. The intra-day and inter-day coefficients of variance (CVs) are 5.39-12.6% and 6.40-13.5% for TFV and 0.571-2.45% and 2.45-5.16% for FTC. TFV concentrations from participants on TDF/FTC-based regimens with undetectable plasma HIV RNA were 0.0525 ± 0.0295 ng/mg, whereas those from individuals on TAF/FTC-based regimens were 0.0426 ± 0.0246 ng/mg. Despite the dose of TFV in TDF being 10 times that of TAF, hair concentrations of TFV were not significantly different for those on TDF versus TAF regimens. Pharmacological enhancers (ritonavir and cobicistat) did not boost TFV concentrations in hair. In summary, we developed and validated a sensitive analytical method to analyze TFV and FTC in hair and found that hair concentrations of TFV were essentially equivalent among those on TDF and TAF.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/análisis , Combinación Emtricitabina y Fumarato de Tenofovir Disoproxil/análisis , Emtricitabina/análisis , Cabello/química , Tenofovir/análisis , Adenina/análisis , Adenina/farmacocinética , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Cromatografía Líquida de Alta Presión/métodos , Cobicistat/administración & dosificación , Relación Dosis-Respuesta a Droga , Emtricitabina/farmacocinética , Combinación Emtricitabina y Fumarato de Tenofovir Disoproxil/administración & dosificación , Combinación Emtricitabina y Fumarato de Tenofovir Disoproxil/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Análisis de Cabello , Humanos , Ritonavir/administración & dosificación , Espectrometría de Masas en Tándem/métodos , Tenofovir/farmacocinética , Distribución TisularRESUMEN
BACKGROUND: Oral pre-exposure prophylaxis (PrEP) is highly effective for HIV prevention, but data are limited on HIV incidence among PrEP users in generalized epidemic settings, particularly outside of selected risk groups. We performed a population-based PrEP study in rural Kenya and Uganda and sought to evaluate both changes in HIV incidence and clinical and virologic outcomes following seroconversion on PrEP. METHODS AND FINDINGS: During population-level HIV testing of individuals ≥15 years in 16 communities in the Sustainable East Africa Research in Community Health (SEARCH) study (NCT01864603), we offered universal access to PrEP with enhanced counseling for persons at elevated HIV risk (based on serodifferent partnership, machine learning-based risk score, or self-identified HIV risk). We offered rapid or same-day PrEP initiation and flexible service delivery with follow-up visits at facilities or community-based sites at 4, 12, and every 12 weeks up to week 144. Among participants with incident HIV infection after PrEP initiation, we offered same-day antiretroviral therapy (ART) initiation and analyzed HIV RNA, tenofovir hair concentrations, drug resistance, and viral suppression (<1,000 c/ml based on available assays) after ART start. Using Poisson regression with cluster-robust standard errors, we compared HIV incidence among PrEP initiators to incidence among propensity score-matched recent historical controls (from the year before PrEP availability) in 8 of the 16 communities, adjusted for risk group. Among 74,541 individuals who tested negative for HIV, 15,632/74,541 (21%) were assessed to be at elevated HIV risk; 5,447/15,632 (35%) initiated PrEP (49% female; 29% 15-24 years; 19% in serodifferent partnerships), of whom 79% engaged in ≥1 follow-up visit and 61% self-reported PrEP adherence at ≥1 visit. Over 7,150 person-years of follow-up, HIV incidence was 0.35 per 100 person-years (95% confidence interval [CI] 0.22-0.49) among PrEP initiators. Among matched controls, HIV incidence was 0.92 per 100 person-years (95% CI 0.49-1.41), corresponding to 74% lower incidence among PrEP initiators compared to matched controls (adjusted incidence rate ratio [aIRR] 0.26, 95% CI 0.09-0.75; p = 0.013). Among women, HIV incidence was 76% lower among PrEP initiators versus matched controls (aIRR 0.24, 95% CI 0.07-0.79; p = 0.019); among men, HIV incidence was 40% lower, but not significantly so (aIRR 0.60, 95% CI 0.12-3.05; p = 0.54). Of 25 participants with incident HIV infection (68% women), 7/25 (28%) reported taking PrEP ≤30 days before HIV diagnosis, and 24/25 (96%) started ART. Of those with repeat HIV RNA after ART start, 18/19 (95%) had <1,000 c/ml. One participant with viral non-suppression was found to have transmitted viral resistance, as well as emtricitabine resistance possibly related to PrEP use. Limitations include the lack of contemporaneous controls to assess HIV incidence without PrEP and that plasma samples were not archived to assess for baseline acute infection. CONCLUSIONS: Population-level offer of PrEP with rapid start and flexible service delivery was associated with 74% lower HIV incidence among PrEP initiators compared to matched recent controls prior to PrEP availability. HIV infections were significantly lower among women who started PrEP. Universal HIV testing with linkage to treatment and prevention, including PrEP, is a promising approach to accelerate reductions in new infections in generalized epidemic settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT01864603.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/epidemiología , Riesgo , Factores Sexuales , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Infecciones por VIH/tratamiento farmacológico , Homosexualidad Masculina , Humanos , Incidencia , Kenia/epidemiología , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Profilaxis Pre-Exposición/métodos , Tenofovir/administración & dosificación , Tenofovir/uso terapéutico , Uganda/epidemiología , Adulto JovenRESUMEN
We conducted a pilot randomized controlled trial of a social network-based intervention to promote PrEP adherence among transgender women (TW) in Lima, Peru. We enrolled 89 TW from six social networks and cluster-randomized them 1:1 to standard of care (n = 44) or the TransPrEP intervention (n = 45). Core workshops discussed strategies to support PrEP adherence and defined group adherence objectives. Maintenance workshops discussed participants' experiences taking PrEP and collective adherence goals. At 3-month follow-up, we evaluated 40 participants and obtained 29 hair samples for tenofovir level measurements. Though no significant differences were observed, 36.4% (4/11) of participants of TransPrEP participants and 10.0% (1/10) of control participants had tenofovir levels > 0.023 ng/mg, consistent with ≥ 4 doses per week. 81.8% (9/11) of intervention and 40.0% (4/10) of control participants had any detectable tenofovir in their hair. Pilot assessment of our network-based intervention suggested a trend towards improved PrEP adherence, measured objectively, for TW in Peru.
RESUMEN: Realizamos un estudio piloto controlado y aleatorizado de una intervención basada en redes sociales para promover la adherencia al PrEP en mujeres transgénero (MT) de Lima, Perú. Enrolamos a 89 MT de 6 redes sociales y las aleatorizamos por grupos a razón 1:1 al estándar de atención como control (n = 44) o a la intervención TransPrEP (n = 45). En los talleres centrales se discutieron estrategias para respaldar la adherencia al PrEP y se definieron los objetivos de adherencia del grupo. En los talleres de mantenimiento se discutieron las experiencias de los participantes al tomar PrEP y los objetivos de adherencia colectiva. A los 3 meses de seguimiento, evaluamos a 40 participantes y obtuvimos 29 muestras de cabello para medir el nivel de tenofovir. Aunque no se observaron diferencias significativas, el 36.4% (4/11) de los participantes de TransPrEP y el 10.0% (1/10) de los participantes del grupo control tenían niveles de tenofovir> 0.023 ng/mg, congruente con 4 o más dosis por semana. El 81.8% (9/11) del grupo de intervención y el 40.0% (4/10) de los participantes de control tenían tenofovir detectable en el cabello. La evaluación piloto de nuestra intervención basada en redes sugiere una tendencia hacia una mejor adherencia al PrEP, medida objetivamente, para las MT en Perú.