Urine Tenofovir Concentrations Correlate With Plasma and Relate to Tenofovir Disoproxil Fumarate Adherence: A Randomized, Directly Observed Pharmacokinetic Trial (TARGET Study).

BACKGROUND: Direct measurement of tenofovir (TFV) in urine could be an objective measure to monitor adherence to preexposure prophylaxis (PrEP) or TFV-based antiretroviral therapy (ART). METHODS: We conducted a 3-arm randomized, pharmacokinetic study of tenofovir disoproxil fumarate (TDF) 300 mg/emtricitabine (FTC) 200 mg among adults living with human immunodeficiency virus. Participants were randomized to receive controlled TDF/FTC dosing as (1) "perfect" adherence (daily); (2) "moderate" adherence (4 doses/week); or (3) "low" adherence (2 doses/week). We obtained trough spot urine and plasma samples during a 6-week directly observed therapy period and a 4-week washout period. TFV concentrations were compared between adherence arms using 1-way analysis of variance. RESULTS: Among 28 participants, the median age was 33 years and 16 (57%) were male. Correlation between TFV plasma and urine concentrations was strong (ρ = 0.78; P < .0001). Median (interquartile range) steady-state trough TFV concentrations (ng/mL) for perfect, moderate, and low TDF adherence were 41 (26-52), 16 (14-19), and 4 (3-5) in plasma; and 6480 (3940-14 300), 3405 (2210-5020), and 448 (228-675) in urine. Trough TFV concentrations at steady state were significantly different between the 3 adherence arms for plasma (P < .0001) and urine (P = .0002). Following drug cessation, TFV concentrations persisted longer in urine than plasma samples. Washout urine TFV concentrations and time to undetectable concentrations did not differ between the 3 randomized adherence groups. CONCLUSIONS: Urine TFV concentrations can inform interpretation of novel point-of-care urine-based TFV assays to assess recent TDF adherence. CLINICAL TRIALS REGISTRATION: NCT03012607

A randomized clinical pharmacokinetic trial of Tenofovir in blood, plasma and urine in adults with perfect, moderate and low PrEP adherence: the TARGET study.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is key component of pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) for HIV, but existing tools to monitor drug adherence are often inaccurate. Detection of tenofovir (TFV) in accessible biological samples, such as fingerprick blood, urine or oral fluid samples could be a novel objective measure of recent TDF adherence. To measure TFV concentrations associated with different levels of TDF adherence, we designed a randomized clinical trial to assess the blood, urine and oral fluid concentrations of TFV in adults with perfect, moderate and low drug adherence. METHODS/DESIGN: A randomized, open-label, clinical pharmacokinetic study of tenofovir in healthy adult volunteers without HIV or Hepatitis B infection in Thailand. Consenting, eligible participants are randomized (1:1:1) among three groups to receive a controlled number of TDF (300 mg) doses in a combination pill with emtricitabine (FTC, 200 mg) for six weeks. Participants in Group 1 receive a single TDF/FTC tablet once daily (Perfect adherence); Group 2 receive a single TDF/FTC tablet 4 times/week (Moderate adherence); and Group 3 receive a single TDF/FTC tablet 2 times/week (Low adherence). Blood, plasma, urine and oral fluid samples are collected for drug measurement during three study phases: (i) initial 6-week treatment phase; (ii) intensive 24-h blood sampling phase after 6 weeks; (iii) 4-week washout phase. Thirty adults with evaluable pharmacokinetic samples (10 per group) will be enrolled [based on ensuring 25% precision in pharmacokinetic parameter estimates]. Pre-dose drug concentrations during the treatment phase will be descriptive and comparisons between groups performed using a Kruskal-Wallis test. A non-compartmental pharmacokinetic analysis will be performed on the intensive sampling data at Week 7 and the time course of TFV washout in the difference biological matrices will be reported based on the detected concentrations following drug cessation. DISCUSSION: The results of this randomized trial will define the target concentration thresholds of TFV in blood, urine and oral fluid that can distinguish between different levels of TDF adherence. Such adherence 'benchmarks' can be applied to real-time drug testing and novel point-of-care tests to identify individuals with poor PrEP or ART adherence. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03012607 .

Plasma and Intracellular Pharmacokinetics of Tenofovir Disoproxil Fumarate 300 mg Every 48 Hours vs 150 mg Once Daily in HIV-Infected Adults With Moderate Renal Function Impairment.

BACKGROUND: The approved tenofovir disoproxil fumarate (TDF) dose of 300 mg every 48 hours for adults with moderate renal impairment is often confusing and inconvenient. Using a new TDF formulation, we compared the pharmacokinetics of the standard dose with a dose of 150 mg once daily in HIV-infected adults. METHODS: This was an open-label pharmacokinetic study. Virologically suppressed HIV-infected adults with a creatinine clearance 30 to <50 mL/minute receiving TDF 300 mg every 48 hours as part of a nonnucleoside reverse transcriptase inhibitor (NNRTI)- or lopinavir/ritonavir (LPV/r)-based regimen were enrolled. Intensive 48-hour blood sampling for pharmacokinetic assessment was performed at enrollment, after which the TDF dose was changed to 150 mg once daily. Two weeks later, 24-hour blood sampling was performed; subjects then returned to the standard dose. Tenofovir (TFV) pharmacokinetic parameters were calculated using a noncompartmental analysis. RESULTS: Forty adults (55% female) were enrolled: 20 receiving NNRTI-based and 20 receiving LPV/r-based treatment. Median age was 56 years (range, 44-65 years), weight 51 kg (range, 38-80 kg), and creatinine clearance 43.9 mL/minute (range, 30.9-49.7 mL/minute). The TFV geometric mean ratio of the area under the curve (AUC0-48 h) for every 24 hours vs every 48 hours was 1.09 (90% confidence interval [CI], .98-1.22) and 1.00 (90% CI, .92-1.09) for patients receiving NNRTI- and LPV/r-based treatment, respectively. Concomitant LPV/r use markedly increased TFV plasma concentrations, and AUC0-48 h was 67% higher with the standard dose, whereas no differences in intracellular TFV diphosphate concentrations were observed. All subjects remained virologically suppressed, and no drug-related adverse events were reported. CONCLUSIONS: TDF 150 mg every 24 hours provides comparable systemic exposure to the standard dose of 300 mg every 48 hours in patients with moderate renal impairment. CLINICAL TRIALS REGISTRATION: NCT01671982.

Molnupiravir versus favipiravir in at-risk outpatients with COVID-19: A randomized controlled trial in Thailand.

OBJECTIVES: Evaluate and compare the efficacy and safety of molnupiravir and favipiravir in outpatients with mild to moderate COVID-19 and at risk of severe COVID-19. METHODS: In an open-label, parallel-group, multicenter trial in Thailand, participants with moderate COVID-19 and at least one factor associated with severe COVID-19 were randomly assigned 1:1 to receive oral molnupiravir or oral favipiravir (standard of care). Phone calls for remote symptom assessment were made on Days 6, 15, and 29. Participants with worsening symptoms were instructed to return to the hospital. The primary endpoint was pulmonary involvement by Day 29, as evidenced by ≥2 of the following: dyspnea, oxygen saturation <92% or imaging. RESULTS: Nine hundred seventy-seven participants (487 molnupiravir, 490 favipiravir) were enrolled from 8 July 2022 to 19 January 2023. 98% had received ≥1 dose of COVID-19 vaccine and 83% ≥3 doses. By Day 29, pulmonary involvement occurred in 0% (0/483) in molnupiravir arm versus 1% (5/482) in favipiravir arm (-1.0%; Newcombe 95.2% CI: -2.4% to -0.0%; P = 0.021); all-cause death in 0% (0/483) and <1% (1/482); COVID-19 related hospitalization in <1% (1/483) and 1% (3/482); treatment-related adverse event in 1% (5/483) and 1% (4/486); and serious adverse event in 1% (4/483) and 1% (4/486). CONCLUSIONS: Favipiravir and molnupiravir had a similar efficacy and safety profile. Whether either of the two reduced the risk of complications during the omicron era in this population with a low risk of pulmonary involvement and a high vaccine coverage remains unclear. There were no differences in any of the safety endpoints. THAI CLINICAL TRIALS REGISTRY ID: TCTR20230111009.

Challenges in the Implementation of the NeoOBS Study, a Global Pragmatic Observational Cohort Study, to Investigate the Aetiology and Management of Neonatal Sepsis in the Hospital Setting.

Neonatal sepsis is a significant cause of mortality and morbidity in low- and middle-income countries. To deliver high-quality data studies and inform future trials, it is crucial to understand the challenges encountered when managing global multi-centre research studies and to identify solutions that can feasibly be implemented in these settings. This paper provides an overview of the complexities faced by diverse research teams in different countries and regions, together with actions implemented to achieve pragmatic study management of a large multi-centre observational study of neonatal sepsis. We discuss specific considerations for enrolling sites with different approval processes and varied research experience, structures, and training. Implementing a flexible recruitment strategy and providing ongoing training were necessary to overcome these challenges. We emphasize the attention that must be given to designing the database and monitoring plans. Extensive data collection tools, complex databases, tight timelines, and stringent monitoring arrangements can be problematic and might put the study at risk. Finally, we discuss the complexities added when collecting and shipping isolates and the importance of having a robust central management team and interdisciplinary collaborators able to adapt easily and make swift decisions to deliver the study on time and to target. With pragmatic approaches, appropriate training, and good communication, these challenges can be overcome to deliver high-quality data from a complex study in challenging settings through a collaborative research network.

Tenofovir-Diphosphate in Dried Blood Spots vs Tenofovir in Urine/Plasma for Oral Preexposure Prophylaxis Adherence Monitoring.

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/3 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/3 mm punch (P < .001) in TFV-DP during the dosing phase. Each additional day after the last dose was associated with 43 fmol/3 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.

Plasma pharmacokinetics and urinary excretion of tenofovir following cessation in adults with controlled levels of adherence to tenofovir disoproxil fumarate.

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.

Assessment of Nevirapine Prophylactic and Therapeutic Dosing Regimens for Neonates.

BACKGROUND: Nevirapine (NVP) is a key component of antiretroviral prophylaxis and treatment for neonates. We evaluated current World Health Organization (WHO) weight-band NVP prophylactic dosing recommendations and investigated optimal therapeutic NVP dosing for neonates. METHODS: The PHPT-5 study in Thailand assessed the efficacy of "Perinatal Antiretroviral Intensification" to prevent mother-to-child transmission of HIV in women with <8 weeks of antiretroviral treatment before delivery (NCT01511237). Infants received a 2-week course of zidovudine/lamivudine/NVP (NVP syrup/once daily: 2 mg/kg for 7 days; then 4 mg/kg for 7 days). Infant samples were assessed during the first 2 weeks of life. NVP population pharmacokinetics (PK) parameters were estimated using nonlinear mixed-effects models. Simulations were performed to estimate the probability of achieving target NVP trough concentrations for prophylaxis (>0.10 mg/L) and for therapeutic efficacy (>3.0 mg/L) using different infant dosing strategies. RESULTS: Sixty infants (55% male) were included. At birth, median (range) weight was 2.9 (2.3-3.6) kg. NVP concentrations were best described by a 1-compartment PK model. Infant weight and postnatal age influenced NVP PK parameters. Based on simulations for a 3-kg infant, ≥92% would have an NVP trough >0.1 mg/L after 48 hours through 2 weeks using the PHPT-5 and WHO-dosing regimens. For NVP-based therapy, a 6-mg/kg twice daily dose produced a trough >3.0 mg/L in 87% of infants at 48 hours and 80% at 2 weeks. CONCLUSION: WHO weight-band prophylactic guidelines achieved target concentrations. Starting NVP 6 mg/kg twice daily from birth is expected to achieve therapeutic concentrations during the first 2 weeks of life.

Low-doses of indinavir boosted with ritonavir in HIV-infected Thai patients: pharmacokinetics, efficacy and tolerability.

OBJECTIVES: To assess the steady-state pharmacokinetics of two reduced doses of indinavir boosted with ritonavir (indinavir/ritonavir) in HIV-infected Thai patients. PATIENTS AND METHODS: Thirteen immunocompromised antiretroviral-naive patients (6 males, 7 females) initiated 600/100 mg indinavir/ritonavir, zidovudine and lamivudine, every 12 h. After 1 month, blood samples were taken at pre-dose, and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 h after drug intake. Indinavir dosing was then reduced to 400 mg (twice daily) and 1 week later an identical series of samples were drawn. Patients then resumed 600 mg of indinavir. HIV-1 RNA viral load was determined at 8, 24 and 48 weeks. Indinavir plasma levels were determined by HPLC and pharmacokinetic parameters by non-compartmental analysis. RESULTS: Median (range) weight was 58 kg (51-73) for men and 53 kg (46-59) for women. On 600 mg of indinavir, median indinavir AUC, C(max), and C(min) were 39.3 mg.h/L (20.6-50.5), 6.2 mg/L (3.7-9.0) and 0.41 mg/L (0.12-0.77), respectively, and on indinavir 400 mg, 18.3 mg.h/L (11.1-33.0), 3.8 mg/L (2.2-7.8) and 0.17 mg/L (0.10-0.39), respectively. No renal complications were observed. At 48 weeks, 6/13 (46%) patients had stopped 600 mg of indinavir due to intolerability (gastrointestinal and cutaneous), and 5/7 (71%) patients had a HIV-1 viral load <50 copies/mL. CONCLUSIONS: Reduced doses of indinavir/ritonavir maintained adequate indinavir plasma levels compared to current guidelines suggesting that these doses are efficacious in this setting. Considering the poor tolerability of 600 mg of indinavir, the 400 mg of indinavir may be preferred due to its lower exposure indices but long-term efficacy data are needed.