Intracellular Tenofovir-Diphosphate and Emtricitabine-Triphosphate in Dried Blood Spots following Directly Observed Therapy

ABSTRACT Studies of daily emtricitabine-tenofovir disoproxil fumarate (FTC-TDF) for HIV preexposure prophylaxis (PrEP) in men who have sex with men (MSM) modeled intracellular tenofovir-diphosphate (TFV-DP) in dried blood spots (DBS) to assess adherence and corresponding PrEP outcomes. We conducted a prospective, randomized, crossover pharmacokinetic study of TFV-DP in DBS during 33%, 67%, or 100% of daily dosing under directly observed therapy (DOT). Participants were assigned to two 12-week dosing regimens, separated by a 12-week washout. Forty-eight adults (25 women) from Denver and San Francisco were included. TFV-DP exhibited a median half-life of 17 days, reaching steady state in 8 weeks. TFV-DP was dose proportional with mean (SD) steady-state concentrations of 530 (159), 997 (267), and 1,605 (405) fmol/punch for the 33%, 67%, and 100% arms, respectively. Prior work in MSM demonstrated clinically meaningful TFV-DP thresholds of 350, 700, and 1,250 fmol/punch, which were estimated 25th percentiles for 2, 4, and 7 doses/week. In the present study, corresponding TFV-DP was within 3% of the prior estimates, and subgroups by site, race, and sex were within 14% of prior estimates, although males had 17.6% (95% confidence intervals [CIs], 6.5, 27.4%) lower TFV-DP than females. The thresholds of 350, 700, and 1,250 fmol/punch were achieved by 75% of men taking ≥1.2, 3.2, and 6 doses/week and 75% of women taking ≥0.6, 2.0, and 5.3 doses/week, indicating that lower dosing reached these thresholds for both sexes. In conclusion, TFV-DP arising from DOT was similar to previous estimates and is useful for interpreting PrEP adherence and study outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT02022657.)

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Emtricitabine-Triphosphate in Dried Blood Spots as a Marker of Recent Dosing

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01017-16 ◽

2016 ◽

Vol 60 (11) ◽

pp. 6692-6697 ◽

Cited By ~ 30

Author(s):

Jose Castillo-Mancilla ◽

Sharon Seifert ◽

Kayla Campbell ◽

Stacey Coleman ◽

Kevin McAllister ◽

...

Keyword(s):

Half Life ◽

Dried Blood Spots ◽

Directly Observed Therapy ◽

Open Label ◽

Limit Of Quantification ◽

Antiretroviral Adherence ◽

Blood Spots ◽

Preexposure Prophylaxis ◽

The Mean ◽

Hiv Negative

ABSTRACTNew objective measures of antiretroviral adherence are needed. We determined if emtricitabine triphosphate (FTC-TP) in dried blood spots (DBS) can be used as a marker of recent dosing with tenofovir disoproxil fumarate-emtricitabine (TDF-FTC). The half-life of FTC-TP was estimated in DBS samples obtained from an intensive pharmacokinetic (PK) study of coformulated TDF-FTC in HIV-negative and HIV-infected participants. The concordance of quantifiable FTC-TP in DBS with tenofovir (TFV)/FTC in plasma was evaluated by utilizing paired plasma-DBS samples from participants enrolled in 2 large preexposure prophylaxis (PrEP) open-label trials. The time to FTC-TP nondetectability after TDF-FTC dosing was evaluated utilizing DBS from HIV-negative participants enrolled in a directly observed therapy study of variable adherence to TDF-FTC. The mean (95% confidence interval [CI]) terminal half-life of FTC-TP in the PK study was 35 (23 to 47) h. A total of 143/163 (88%) samples obtained 0 to 48 h post-TDF-FTC dose had quantifiable FTC-TP in DBS, compared with 2/93 (2%) and 0/87 (0%) obtained >48 and >96 h postdose. In 746 paired plasma-DBS samples from 445 participants enrolled in PrEP trials, when both TFV/FTC in plasma were below the limit of quantification, FTC-TP was as well in 98.9% of the samples, and when either TFV or FTC in plasma was quantifiable, FTC-TP was as well in 90.5% of the samples. The half-life of FTC-TP in DBS is short relative to that of TFV-diphosphate (TFV-DP), making it a surrogate for TFV-FTC detection in plasma. FTC-TP can be quantified in DBS simultaneously with TFV-DP, which quantifies cumulative adherence to TDF-FTC. (The clinical trials discussed in this article have been registered at ClinicalTrials.gov under identifiers NCT01040091, NCT02022657, NCT00458393, NCT01772823, and NCT02012621.)

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Sex Hormone Therapy and Tenofovir Diphosphate Concentration in Dried Blood Spots: Primary Results of the Interactions Between Antiretrovirals And Transgender Hormones Study

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1160 ◽

2020 ◽

Author(s):

Robert M Grant ◽

Marion Pellegrini ◽

Patricia A Defechereux ◽

Peter L Anderson ◽

Michelle Yu ◽

...

Keyword(s):

Hormone Therapy ◽

Dried Blood Spots ◽

Sex Hormone ◽

Mean Difference ◽

Directly Observed Therapy ◽

Blood Spots ◽

Preexposure Prophylaxis ◽

Immunodeficiency Virus ◽

Before And After ◽

Serum Hormone

Abstract Background Sex hormone and preexposure prophylaxis (PrEP) drug interactions among transgender women (TGW), transgender men (TGM), and cisgender men (CGM) are not fully understood. Methods TGM and TGW on at least 6 months of stable sex hormone therapy containing testosterone or estradiol (respectively) were enrolled in a 4-week study of directly observed dosing of daily oral coformulated emtricitabine and tenofovir disoproxil fumarate (FTC/TDF). TFV-DP in dried blood spots and sex hormones in serum were measured at weekly intervals. TFV-DP was compared with 2- and 4-week samples from Directly Observed Therapy Dried Blood Spots (DOT-DBS) Study (NCT02022657). Results From May 2017 to June 2018, 24 TGM and 24 TGW were enrolled. Testosterone (total and free) and estradiol concentrations were comparable before and after 4 weeks of PrEP use in TGM and TGW, respectively. Historical controls included 17 cisgender women (CGW) and 15 CGM. TFV-DP concentrations at week 4 were comparable between TGW and TGM (mean difference, −6%; 95% confidence interval [CI], −21% to 12%; P = .47), comparable between TGW and CGM (mean difference, −12%; 95% CI, −27% to 7%; P = .21) and were lower among TGM compared with CGW (mean difference, −23%; 95% CI, −36% to −7%; P = .007). All persons in all groups were projected to reach the TFV-DP threshold that has been associated with high protection from human immunodeficiency virus. Conclusions CGM, TGM, and TGW had comparable TFV-DP concentrations in dried blood spots after 4 weeks of directly observed daily FTC/TDF PrEP use. Serum hormone concentrations were not affected by FTC/TDF PrEP use. Clinical Trials Registration NCT04050371.

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Tenofovir diphosphate concentrations in dried blood spots from pregnant and postpartum adolescent and young women receiving daily observed pre-exposure prophylaxis in sub-Saharan Africa

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1872 ◽

2020 ◽

Author(s):

Lynda Stranix-Chibanda ◽

Peter L Anderson ◽

Deborah Kacanek ◽

Sybil Hosek ◽

Sharon Huang ◽

...

Keyword(s):

Steady State ◽

Young Women ◽

Dried Blood Spots ◽

Wilcoxon Test ◽

Sub Saharan Africa ◽

Blood Spots ◽

Sub Saharan ◽

Exposure Prophylaxis ◽

Tenofovir Diphosphate ◽

In Pregnancy

Abstract Background Intracellular tenofovir diphosphate (TFV-DP) concentration measured in dried blood spots (DBS) is used to monitor cumulative adherence to pre-exposure prophylaxis (PrEP). We evaluated TFV-DP in DBS following daily oral PrEP (emtricitabine 200mg/tenofovir diphosphate 300mg) among pregnant and postpartum adolescent girls and young women (AGYW). Methods Directly observed PrEP was administered for 12 weeks in a pregnancy group (14-24 weeks gestation, n=20) and a postpartum group (6-12 weeks postpartum, n=20) of AGYW aged 16-24 years in sub-Saharan Africa. Weekly DBS TFV-DP was measured by validated liquid chromatography-tandem mass spectrometry assay. Week 12 TFV-DP distributions were compared between groups with the Wilcoxon test. Population pharmacokinetic models were fit to estimate steady-state concentrations and create benchmarks for adherence categories. Baseline correlates of TFV-DP were evaluated. Results Participant median age was 20 years (IQR:19,22). Of 3360 doses, 3352 (>99%) were directly observed. TFV-DP median half-life was ten days (IQR:7, 12) in pregnancy and 17 days (IQR:14, 21) postpartum, with steady-state achieved by five and eight weeks, respectively. Observed median steady-state TFV-DP was 965 fmol/punch (IQR:691, 1166) in pregnancy vs 1406 fmol/punch (IQR:1053, 1859) postpartum (p=0.006). Modelled median steady-state TFV-DP was 881 fmol/punch (IQR: 667,1105) in pregnancy vs 1438 fmol/punch (IQR: 1178,1919) postpartum. In pooled analysis, baseline creatinine clearance was associated with observed TFV-DP concentrations. Conclusion TFV-DP in African AGYW was approximately one-third lower in pregnancy than postpartum. Population-specific benchmarks provided by this study can be used to guide PrEP adherence support in pregnant/postpartum African women.

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Associations Between Tenofovir Diphosphate in Dried Blood Spots, Impaired Physical Function, and Fracture Risk

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa577 ◽

2020 ◽

Vol 8 (1) ◽

Author(s):

Mona Abdo ◽

Ryan P Coyle ◽

Sharon M Seifert ◽

Jose R Castillo-Mancilla ◽

Catherine M Jankowski ◽

...

Keyword(s):

Fracture Risk ◽

Physical Function ◽

Lean Body Mass ◽

Body Mass ◽

Fat Mass ◽

Dried Blood Spots ◽

Blood Spots ◽

Hip Bmd ◽

Total Fat ◽

Tenofovir Diphosphate

Abstract Background In this study, we evaluate associations between cumulative antiretroviral adherence/exposure, quantified using tenofovir diphosphate (TFV-DP) in dried blood spots (DBS), and human immunodeficiency virus (HIV)-related aging factors. Methods This is a cross-sectional analysis of younger (ages 18–35) and older (ages ≥60) persons with HIV (PWH) taking TFV disoproxil fumarate. Tenofovir diphosphate concentrations were quantified in DBS. Linear and logistic regression models were used to evaluate associations between TFV-DP and bone mineral density (BMD), physical function, frailty, and falls. Results Forty-five PWH were enrolled (23 younger, 22 older). Every 500 fmol/punch (equivalent to an increase in ~2 doses/week) increase in TFV-DP was associated with decreased hip BMD (−0.021 g/cm2; 95% confidence interval [CI], −0.040 to −0.002; P = .03). Adjusting for total fat mass, every 500 fmol/punch increase in TFV-DP was associated with higher odds of Short Physical Performance Battery impairment (score ≤10; adjusted odds ratio [OR], 1.6; 95% CI, 1.0–2.5; P = .04). Every 500 fmol/punch increase in TFV-DP was associated with slower 400-meter walk time (14.8 seconds; 95% CI, 3.8–25.8; P = .01) and remained significant after adjusting for age, lean body mass, body mass index (BMI), and fat mass (all P ≤ .01). Every 500 fmol/punch increase in TFV-DP was associated with higher odds of reporting a fall in the prior 6 months (OR, 1.8; 95% CI, 1.1–2.8; P = .02); this remained significant after adjusting for age, lean body mass, BMI, and total fat mass (all P < .05). Conclusions Higher TFV-DP levels were associated with lower hip BMD, poorer physical function, and greater risk for falls, a concerning combination for increased fracture risk.

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Tenofovir, Emtricitabine, and Tenofovir Diphosphate in Dried Blood Spots for Determining Recent and Cumulative Drug Exposure

AIDS Research and Human Retroviruses ◽

10.1089/aid.2012.0089 ◽

2013 ◽

Vol 29 (2) ◽

pp. 384-390 ◽

Cited By ~ 134

Author(s):

Jose R. Castillo-Mancilla ◽

Jia-Hua Zheng ◽

Joseph E. Rower ◽

Amie Meditz ◽

Edward M. Gardner ◽

...

Keyword(s):

Drug Exposure ◽

Dried Blood Spots ◽

Blood Spots ◽

Tenofovir Diphosphate

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Higher Medication Complexity in Persons with HIV is Associated with Lower Tenofovir Diphosphate in Dried Blood Spots

Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy ◽

10.1002/phar.2490 ◽

2020 ◽

Author(s):

Austin M. Saderup ◽

Mary Morrow ◽

Anne M. Libby ◽

Ryan P. Coyle ◽

Stacey S. Coleman ◽

...

Keyword(s):

Dried Blood Spots ◽

Blood Spots ◽

Medication Complexity ◽

Tenofovir Diphosphate

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Bayesian clinical decision support-guided versus clinician-guided vancomycin dosing in attainment of targeted pharmacokinetic parameters in a paediatric population

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz444 ◽

2019 ◽

Author(s):

David M Hughes ◽

Srijib Goswami ◽

Ron J Keizer ◽

Maria-Stephanie A Hughes ◽

Jonathan D Faldasz

Keyword(s):

Decision Support ◽

Steady State ◽

San Francisco ◽

Clinical Decision Support ◽

Clinical Decision ◽

Paediatric Population ◽

Target Range ◽

Secondary Outcome ◽

Pharmacokinetic Parameters ◽

Dosing Regimens

Abstract Objectives To compare a Bayesian clinical decision support (CDS) dose-optimizing software program with clinician judgement in individualizing vancomycin dosing regimens to achieve vancomycin pharmacokinetic (PK)/pharmacodynamic (PD) targets in a paediatric population. Methods A retrospective review combined with a model-based simulation of vancomycin dosing was performed on children aged 1 year to 18 years at the University of California, San Francisco Benioff Children’s Hospital Mission Bay. Dosing regimens recommended by the clinical pharmacists, ‘clinician-guided’, were compared with alternative ‘CDS-guided’ dosing regimens. The primary outcome was the percentage of occasions predicted to achieve steady-state trough levels within the target range of 10–15 mg/L, with a secondary outcome of predicted attainment of AUC24 ≥400 mg·h/L. Statistical comparison between approaches was performed using a standard t-test. Results A total of n = 144 patient occasions were included. CDS-guided regimens were predicted to achieve vancomycin steady-state troughs in the target range on 70.8% (102/144) of occasions, as compared with 37.5% (54/144) in the clinician-guided arm (P < 0.0001). An AUC24 of ≥400 mg·h/L was achieved on 93% (112/121) of occasions in the CDS-guided arm versus 72% (87/121) of occasions in the clinician-guided arm (P < 0.0001). Conclusions In a simulated analysis, the use of a Bayesian CDS tool was better than clinician judgement in recommending vancomycin dosing regimens in which PK/PD targets would be attained in children.

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