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Information on the extent of drug exposure to mothers and infants during pregnancy and lactation normally becomes available years after regulatory approval of a drug. Clinicians face knowledge gaps on drug selection and dosing in pregnancy and infant exposure during breastfeeding. Physiological changes during pregnancy often result in lower drug exposures of antiretrovirals, and in some cases a risk of reduced virologic efficacy. The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) network and the World Health Organization (WHO)-convened Pediatric Antiretrovirals Working Group collaboratively organized a workshop of key stakeholders in June 2019 to define key standards to generate pharmacology data for antiretrovirals to be used among pregnant and lactating women; review the antiretroviral product pipeline; describe key gaps for use in low-income and middle-income countries; and identify opportunities to undertake optimal studies allowing for rapid implementation in the clinical field. We discussed ethical and regulatory principles, systemic approaches to obtaining data for pregnancy pharmacokinetic/pharmacodynamic (PK/PD) studies, control groups, optimal sampling times during pregnancy, and pharmacokinetic parameters to be considered as primary end points in pregnancy PK/PD studies. For lactation studies, the type of milk to collect, ascertainment of maternal adherence, and optimal PK methods to estimate exposure were discussed. Participants strongly recommended completion of preclinical reproductive toxicology studies prior to phase III, to allow study protocols to include pregnant women or to allow women who become pregnant after enrolment to continue in the trial. The meeting concluded by developing an algorithm for design and interpretation of results and noted that recruitment of pregnant and lactating women into clinical trials is critical.

Recognizing the importance of timely guidance regarding the rapidly evolving field of hepatitis C management, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) developed a web-based process for the expeditious formulation and dissemination of evidence-based recommendations. Launched in 2014, the hepatitis C virus (HCV) guidance website undergoes periodic updates as necessitated by availability of new therapeutic agents and/or research data. A major update was released electronically in September 2017, prompted primarily by approval of new direct-acting antiviral agents and expansion of the guidance's scope. This update summarizes the latest release of the HCV guidance and focuses on new or amended recommendations since the previous September 2015 print publication. The recommendations herein were developed by volunteer hepatology and infectious disease experts representing AASLD and IDSA and have been peer reviewed and approved by each society's governing board.

BackgroundConcentrations of tenofovir (TFV) in hair and tenofovir diphosphate (TFV-DP) in dried blood spots (DBSs) as measures of cumulative exposure have been primarily studied in younger, HIV-uninfected individuals taking preexposure HIV prophylaxis. Data on these measures among older HIV-infected individuals are limited.MethodsWe evaluated longitudinal TFV and TFV-DP concentrations in hair and DBS, respectively, from HIV-infected adults. Multivariable model variables included age group (18-35 and 60 years and older), creatinine clearance (CrCl), hematocrit (TFV-DP), and gray hair color (TFV).ResultsBaseline hair TFV and DBS TFV-DP were moderately correlated [r = 0.5 (0.2 to 0.7); P = 0.001] across both age groups [younger (N = 23) and older (N = 22)]. In adjusted models, CrCl was associated with increases of 15.9% (7.4% to 25.0%); P = 0.0006, and 5.7% (-0.2% to 11.9%); P = 0.057 for TFV in hair and TFV-DP in DBS, respectively, for every 20-mL/min CrCl decrease. Although older age (versus younger age) was univariately associated with increased TFV hair levels, older age was not significantly associated with higher concentrations in hair [-1.4% (-26.7% to 32.7%); P = 0.93] or DBS [4.0% (-14.1% to 25.9%); P = 0.68] after adjustment. Similarly, gray color was not significantly associated with higher TFV levels in hair [27.6% (-11.1% to 83.0%; P = 0.18)] in adjusted models. In both adjusted and unadjusted models of TFV-DP levels in DBS, a 1% hematocrit increase was associated with a 3.3% (0.2% to 6.5%) TFV-DP increase (P = 0.04).ConclusionsCumulative drug exposure measures (hair and DBS) were comparable in younger and older HIV-infected individuals on TFV-based therapy after adjustment for renal function.

ImportanceAdolescents represent a key population for implementing preexposure prophylaxis (PrEP) interventions worldwide, yet tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for PrEP is only licensed for adults.ObjectiveTo examine the safety of and adherence to PrEP along with changes in sexual risk behavior among adolescent men who have sex with men (MSM).Design, setting, and participantsAdolescent Medicine Trials Network for HIV/AIDS Interventions 113 (Project PrEPare) was a PrEP demonstration project that evaluated the safety, tolerability, and acceptability of TDF/FTC and patterns of use, rates of adherence, and patterns of sexual risk behavior among healthy young MSM aged 15 to 17 years. Participants were recruited from adolescent medicine clinics and their community partners in 6 US cities, had negative test results for human immunodeficiency virus (HIV) but were at high risk for acquiring an infection, and were willing to participate in a behavioral intervention and accept TDF/FTC as PrEP.ExposuresAll participants completed an individualized evidence-based behavioral intervention and were provided with daily TDF/FTC as PrEP for 48 weeks.Main outcomes and measuresThe main objectives were to: (1) provide additional safety data regarding TDF/FTC use among young MSM who had negative test results for HIV; (2) examine the acceptability, patterns of use, rates of adherence, and measured levels of tenofovir diphosphate in dried blood spots; and (3) examine patterns of risk behavior when young MSM were provided with a behavioral intervention in conjunction with open-label TDF/FTC.ResultsAmong 2864 individuals screened (from August 2013 to September 2014), 260 were eligible and 78 were enrolled (mean [SD] age, 16.5 [0.73] years), of whom 2 (3%) were Asian/Pacific Islander, 23 (29%) were black/African American, 11 (14%) were white, 16 (21%) were white Hispanic, and 26 (33%) were other/mixed race/ethnicity. Over 48 weeks of PrEP use, 23 sexually transmitted infections were diagnosed in 12 participants. The HIV seroconversion rate was 6.4 (95% CI: 1.3-18.7) per 100 person-years. Tenofovir diphosphate levels consistent with a high degree of anti-HIV protection (>700 fmol/punch) were found in 42 (54%), 37 (47%), 38 (49%), 22 (28%), 13 (17%), and 17 (22%) participants at weeks 4, 8, 12, 24, 36, and 48, respectively.Conclusions and relevanceAdolescent Medicine Trials Network for HIV/AIDS Interventions 113 enrolled a diverse sample of adolescent MSM at risk for HIV who consented to study participation. Approximately half achieved protective drug levels during the monthly visits, but adherence decreased with quarterly visits. Youth may need additional contact with clinical staff members to maintain high adherence.Trial registrationclinicaltrials.gov Identifier: NCT01769456.

Background QUANTI-TAF aimed to establish tenofovir-diphosphate (TFV-DP)/emtricitabine-triphosphate (FTC-TP) adherence benchmarks in dried blood spots (DBS) for persons with human immunodeficiency virus (PWH) receiving tenofovir alafenamide/emtricitabine (TAF/FTC)–based antiretroviral therapy (ART). Methods For 16 weeks, PWH received TAF/FTC-based ART co-encapsulated with an ingestible sensor to directly measure cumulative (enrollment to final visit) and 10-day adherence. At monthly visits, intraerythrocytic concentrations of TFV-DP and FTC-TP in DBS were quantified and summarized at steady-state (week 12 or 16) as median (interquartile range). Linear mixed-effects models evaluated factors associated with TFV-DP/FTC-TP. Results Eighty-four participants (11% female, 4% transgender) predominantly receiving bictegravir/TAF/FTC (73%) were enrolled. Ninety-two percent completed week 12 or 16 (94% unboosted ART). TFV-DP for <85% (7/72), 85%–<95% (9/72), and ≥95% (56/72) cumulative adherence was 2696 (2039–4108), 3117 (2332–3339), and 3344 (2605–4293) fmol/punches. Adjusting for cumulative adherence, TFV-DP was higher with boosted ART, lower body mass index, and in non-Black participants. FTC-TP for <85% (14/77), 85%–<95% (6/77), and ≥95% (57/77) 10-day adherence was 3.52 (2.64–4.48), 4.58 (4.39–5.06), and 4.96 (4.21–6.26) pmol/punches. All participants with ≥85% cumulative and 10-day adherence had TFV-DP ≥1800 fmol/punches and FTC-TP ≥2.5 pmol/punches, respectively. Low-level viremia (HIV-1 RNA 20–199 copies/mL) occurred at 18% of visits in 39% of participants with similar TFV-DP (3177 [2494–4149] fmol/punches) compared with suppressed visits (3279 [2580–4407] fmol/punches). Conclusions TFV-DP ≥1800 fmol/punches and FTC-TP ≥2.5 pmol/punches represent DBS benchmarks for ≥85% adherence to unboosted TAF/FTC-based ART. Among PWH with high adherence, low-level viremia was common. Clinical Trials Registration NCT04065347. [ABSTRACT FROM AUTHOR]

This case-control study explored cumulative tenofovir exposure among patients with human immunodeficiency virus/hepatis B virus (HIV/HBV) coinfection with HIV viral suppression. Among patients taking tenofovir disoproxil fumarate, median TFV-DP levels in dried blood spots were ∼3-fold lower among patients with incomplete HBV viral suppression (n = 4) compared to those with complete suppression (n = 5) (516 vs 1456 fmol/punch). [ABSTRACT FROM AUTHOR]

BackgroundTenofovir (TDF) is associated with phosphaturia and elevated 1,25 dihydroxy vitamin D (1,25-OH(2)D). Fibroblast growth factor 23 (FGF23) causes phosphaturia and increases in response to elevated 1,25-OH(2)D. Vitamin D-binding protein (VDBP) binds to 1,25-OH(2)D, decreasing its biological activity, and is elevated in individuals with higher plasma tenofovir concentrations. We compared FGF23 and VDBP before and after vitamin D3 (VITD) supplementation in youths treated with combination antiretroviral therapy (cART) containing or not containing TDF.MethodsA randomized controlled trial in HIV-positive youths aged 18-25 years enrolled participants based on cART treatment with TDF (TDF; n=118) or without TDF (no-TDF; n=85), and randomized within those groups to VITD (50,000 IU every 4 weeks) or placebo (PL). We measured FGF23 and VDBP and calculated free 1,25-OH(2)D at baseline and week 12, and compared changes by TDF treatment and VITD randomized group.ResultsAt baseline, serum FGF23 concentration showed a quadratic relationship with 1,25-OH(2)D most pronounced in the TDF group. At week 12, total and free 1,25-OH(2)D increased in the VITD but not PL groups, independent of TDF use. FGF23 increased in the TDF group receiving VITD, but there was no FGF23 change in the no-TDF group receiving VITD or the PL groups. The adjusted mean change in FGF23 from baseline to week 12 was 7.7 pg/ml in the TDF/VITD group, compared with -1.7 (no-TDF/VITD, P=0.010), -1.3 (TDF/PL, P=0.006) and 1.1 (no-TDF/PL, P=0.035).ConclusionsThese results suggest that TDF-containing cART may alter the FGF23 response to vitamin D supplementation in HIV-infected youths. Clinical trials number: NCT00490412.

Tenofovir disoproxil fumarate (TDF) causes bone, endocrine, and renal changes by an unknown mechanism(s). Data are limited on tenofovir pharmacokinetics and these effects. Using baseline data from a multicenter study of HIV-infected youth on stable treatment with regimens containing TDF (n = 118) or lacking TDF (n = 85), we measured cross-sectional associations of TDF use with markers of renal function, vitamin D-calcium-parathyroid hormone balance, phosphate metabolism (tubular reabsorption of phosphate and fibroblast growth factor 23 [FGF23]), and bone turnover. Pharmacokinetic-pharmacodynamic associations with plasma tenofovir and intracellular tenofovir diphosphate concentrations were explored among those receiving TDF. The mean age was 20.9 (standard deviation [SD], 2.0) years; 63% were male; and 52% were African American. Compared to the no-TDF group, the TDF group showed lower mean estimated glomerular filtration rates and tubular reabsorption of phosphate, as well as higher parathyroid hormone and 1,25-dihydroxy vitamin D [1,25-OH(2)D] levels. The highest quintile of plasma tenofovir concentrations was associated with higher vitamin D binding protein, lower free 1,25-OH(2)D, higher 25-OH vitamin D, and higher serum calcium. The highest quintile of intracellular tenofovir diphosphate concentration was associated with lower FGF23. Higher plasma tenofovir concentrations were associated with higher vitamin D binding protein and lower free 1,25-OH(2)D, suggesting a functional vitamin D deficiency explaining TDF-associated increased parathyroid hormone. The finding of lower FGF23 accompanying higher intracellular tenofovir diphosphate suggests that different mechanisms mediate TDF-associated changes in phosphate handling. Separate pharmacokinetic properties may be associated with distinct TDF toxicities: tenofovir with parathyroid hormone and altered calcium balance and tenofovir diphosphate with hypophosphatemia and FGF23 regulation. (The clinical trial registration number for this study is NCT00490412 and is available online at http://clinicaltrials.gov/ct2/show/NCT00490412.).