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We demonstrate proof-of-concept for point-of-care assessment of long-term alcohol consumption by measuring phosphatidylethanol in blood/dried blood spots with nano-electrospray ionization and MS/MS using a miniature mass spectrometer. ‘Abstinence’, ‘moderate’, and ‘chronic’ consumption could be distinguished rapidly for both sample types, and quantitative performance was obtained with blood (LoQ-100 ng mL(−1)).

ObjectivesTo determine factors associated with interindividual variability in tenofovir diphosphate (TFV-DP) concentrations in dried blood spots (DBSs) among persons living with HIV (PLWH).MethodsPLWH who were at least 18 years old and taking tenofovir disoproxil fumarate-containing ART were prospectively recruited and enrolled from a clinical cohort and followed longitudinally (up to three visits over 48 weeks). With log-transformed TFV-DP concentrations in DBSs as the outcome, mixed-model regression analyses were used to assess associations between self-reported 3 month ART adherence, race and other clinical covariates (gender, age, BMI, CD4+ T cell count, estimated glomerular filtration rate, haematocrit, duration on current ART and anchor drug class) on TFV-DP in DBSs.ResultsFive hundred and twenty-seven participants (1150 person-visits) were analysed. Adjusting for race and other clinical covariates, every 10% increase in self-reported 3 month ART adherence was associated with an average TFV-DP concentration increase in DBSs of 28% (95% CI: 24%–32%; P ConclusionsIndividual patient characteristics were predictive of TFV-DP concentration in DBSs in PLWH receiving tenofovir disoproxil fumarate-based ART. Future research to incorporate these predictors into the interpretation of this ART adherence biomarker, and to establish whether these associations extend to PLWH taking tenofovir alafenamide-containing ART, is needed.

OBJECTIVE The objective of this study was to determine the magnitude of drug interactions between the hepatitis C virus (HCV) protease inhibitor boceprevir (BOC) and antiretroviral (ARV) agents in persons with HIV/HCV co-infection. METHODS Participants taking two nucleos(t)ide analogs with either efavirenz, raltegravir, or ritonavir-boosted atazanavir, darunavir, or lopinavir underwent intensive pharmacokinetic (PK) sampling for ARV 2 weeks before (week 2) and 2 weeks after initiating BOC (week 6) and for BOC at week 6. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were used to compare ARV PK at weeks 2 and 6 and BOC PK at week 6 to historical data (HD) in healthy volunteers and HCV mono-infected patients. RESULTS ARV PK was available for 55 participants. BOC reduced atazanavir and darunavir exposures by 30 and 42%, respectively. BOC increased raltegravir maximum concentration (C max) by 71%. BOC did not alter efavirenz PK. BOC PK was available for 53 participants. BOC exposures were similar in these HIV/HCV co-infected participants compared with HD in healthy volunteers, but BOC minimum concentrations (C min) were lower with all ARV agents (by 34-73%) compared with HD in HCV mono-infected patients. CONCLUSIONS Effects of BOC on ARV PK in these HIV/HCV co-infected individuals were similar to prior studies in healthy volunteers. However, some differences in the effects of ARV on BOC PK were observed, indicating the magnitude of interactions may differ in HCV-infected individuals versus healthy volunteers. Findings highlight the need to conduct interaction studies with HCV therapies in the population likely to receive the combination.

AIM To quantify drug-drug-interactions (DDIs) encountered in patients prescribed hepatitis C virus (HCV) treatment, the interventions made, and the time spent in this process. METHODS As standard of care, a clinical pharmacist screened for DDIs in patients prescribed direct acting antiviral (DAA) HCV treatment between November 2013 and July 2015 at the University of Colorado Hepatology Clinic. HCV regimens prescribed included ledipasvir/sofosbuvir (LDV/SOF), paritaprevir/ritonavir/ombitasvir/dasabuvir (OBV/PTV/r + DSV), simeprevir/sofosbuvir (SIM/SOF), and sofosbuvir/ribavirin (SOF/RBV). This retrospective analysis reviewed the work completed by the clinical pharmacist in order to measure the aims identified for the study. The number and type of DDIs identified were summarized with descriptive statistics. RESULTS Six hundred and sixty four patients (83.4% Caucasian, 57% male, average 56.7 years old) were identified; 369 for LDV/SOF, 48 for OBV/PTV/r + DSV, 114 for SIM/SOF, and 133 for SOF/RBV. Fifty-one point five per cent of patients were cirrhotic. Overall, 5217 medications were reviewed (7.86 medications per patient) and 781 interactions identified (1.18 interactions per patient). The number of interactions were fewest for SOF/RBV (0.17 interactions per patient) and highest for OBV/PTV/r + DSV (2.48 interactions per patient). LDV/SOF and SIM/SOF had similar number of interactions (1.28 and 1.48 interactions per patient, respectively). Gastric acid modifiers and vitamin/herbal supplements commonly caused interactions with LDV/SOF. Hypertensive agents, analgesics, and psychiatric medications frequently caused interactions with OBV/PTV/r + DSV and SIM/SOF. To manage these interactions, the pharmacists most often recommended discontinuing the medication (28.9%), increasing monitoring for toxicities (24.1%), or separating administration times (18.2%). The pharmacist chart review for each patient usually took approximately 30 min, with additional time for more complex patients. CONCLUSION DDIs are common with HCV medications and management can require medication adjustments and increased monitoring. An interdisciplinary team including a clinical pharmacist can optimize patient care.

BackgroundCurrent guidelines for the management of hepatitis C virus (HCV) infections provide varying recommendations for the optimal treatment of acute HCV infections. There are limited data from small cohort studies to provide guidance on the best approach to treatment of this important patient population.MethodsSofosbuvir-Containing Regimens Without Interferon for Treatment of Acute HCV in HIV-1 Infected Individuals is an open-label, 2-cohort, Phase 1 clinical trial in which the second cohort assessed the safety and efficacy of 8 weeks of ledipasvir/sofosbuvir for the treatment of acute HCV infections in participants with chronic human immunodeficiency virus (HIV)-1 infections. This final analysis of the second cohort had a planned accrual of 27 participants, based on non-inferiority criteria, compared to the study-defined, historical, sustained virologic response (SVR) of 60% with pegylated-interferon/ribavirin.ResultsWe enrolled 27 men (9 Hispanic; 11 White, non-Hispanic; 5 Black, non-Hispanic; 2 Asian or Pacific Islander; median age 46 years). Most (96%) had HCV genotype-1 infection and 59% had the favorable interleukin 28B CC genotype. The median baseline HCV RNA load was 6.17 log10 IU/mL (interquartile range 4.51 – 6.55). All participants (100%) achieved the primary outcome of a sustained virologic response 12 weeks after the date of the last dose of study treatment (90% confidence interval 90–100%), achieving non-inferiority versus the 60% historic benchmark. No treatment discontinuations occurred.ConclusionsThis multicenter clinical trial, investigating 8 weeks of ledipasvir/sofosbuvir for acute HCV infections in men with HIV infections, reports a 100% SVR. This study provides the rationale for larger studies of shortened courses of direct-acting antiviral therapies in persons with HIV infections, including those with high baseline HCV RNA loads.Clinical Trials RegistrationNCT02128217.

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.

BACKGROUND: The nucleotide analogues tenofovir and sofosbuvir are considered to have low potential for drug interactions. OBJECTIVES: To determine the effect of sofosbuvir-based HCV treatment on plasma concentrations of tenofovir and cellular concentrations of tenofovir diphosphate. METHODS: HIV-infected participants with acute HCV were treated for 12 weeks with sofosbuvir + ribavirin in Cohort 1 or 8 weeks with ledipasvir/sofosbuvir in Cohort 2 of AIDS Clinical Trials Group study 5327. Only participants taking tenofovir disoproxil fumarate were included in this analysis. Tenofovir in plasma, tenofovir diphosphate in dried blood spots and tenofovir diphosphate in PBMCs were measured pre-HCV therapy and longitudinally during the study using validated LC/MS-MS. RESULTS: Fifteen and 22 men completed Cohorts 1 and 2, respectively. In Cohort 1, tenofovir diphosphate was 4.3-fold higher (95% CI geometric mean ratio 2.46–7.67; P = 0.0001) in dried blood spots and 2.3-fold higher (95% CI 1.09–4.92; P = 0.03) in PBMCs following 12 weeks of sofosbuvir + ribavirin versus study entry. Tenofovir in the plasma was unchanged. In Cohort 2, tenofovir diphosphate was 17.8-fold higher (95% CI 12.77–24.86; P

The coformulation of the nucleos(t)ide analogs (NA) tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC) is approved for HIV-infection treatment and prevention. Plasma TFV and FTC undergo complicated hybrid processes to form, accumulate, and retain as their active intracellular anabolites: TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP). Such complexities manifest in nonlinear intracellular pharmacokinetics (PK). In target cells, TFV-DP/FTC-TP compete with endogenous deoxynucleoside triphosphates (dNTP) at the active site of HIV reverse transcriptase, underscoring the importance of analog:dNTP ratios for antiviral efficacy. However, NA such as TFV and FTC have the potential to disturb the dNTP pool, which could augment or reduce their efficacies. We conducted a pharmacokinetics-pharmacodynamics (PKPD) study among forty subjects receiving daily TDF/FTC (300 mg/200 mg) from the first-dose to pharmacological intracellular steady-state (30 days). TFV/FTC in plasma, TFV-DP/FTC-TP and dNTPs in peripheral blood mononuclear cells (PBMC) were quantified using validated LC/MS/MS methodologies. Concentration-time data were analyzed using nonlinear mixed effects modeling (NONMEM). Formations and the accumulation of intracellular TFV-DP/FTC-TP was driven by plasma TFV/FTC, which was described by a hybrid of first-order formation and saturation. An indirect response link model described the interplay between TFV-DP/FTC-TP and the dNTP pool change. The EC50 (interindividual variability, (%CV)) of TFV-DP and FTC-TP on the inhibition of deoxyadenosine triphosphate (dATP) and deoxycytidine triphosphate (dCTP) production were 1020 fmol/106 cells (130%) and 44.4 pmol/106 cells (82.5%), resulting in (90% prediction interval) 11% (0.45%, 53%) and 14% (2.6%, 35%) reductions. Model simulations of analog:dNTP molar ratios using IPERGAY dosing suggested that FTC significantly contributes to the protective effect of preexposure prophylaxis (PrEP). Simulation-based intracellular operational multiple dosing half-lives of TFV-DP and FTC-TP were 6.7 days and 33 hours. This model described the formation of intracellular TFV-DP/FTC-TP and the interaction with dNTPs, and can be used to simulate analog:dNTP time course for various dosing strategies.

To develop and validate a method for the simultaneous measurement of adenosine, guanosine, and inosine derived from mono (MP) and triphosphate (TP) forms in peripheral blood mononuclear cells (PBMCs), red blood cells (RBCs) and dried blood spots (DBS).Solid phase extraction of cell lysates followed by dephosphorylation to molar equivalent nucleoside and LC-MS/MS quantification.The assay was linear for each of the three quantification ranges: 10-2000, 1.0-200 and 0.25-50 pmol/sample for adenosine, guanosine, and inosine, respectively. Intraassay (n = 6) and interassay (n = 18) precision (%CV) were within 1.7 to 16% while accuracy (%deviation) was within -11.5 to 14.7% for all three analytes. Nucleotide monophosphates were less concentrated than triphosphates (except for inosine) and levels in PBMCs were higher than RBCs for all three nucleotides (10, 55, and 5.6 fold for ATP, GTP and ITP, respectively). DBS samples had an average (SD) of -26% (22.6%) lower TP and 184% (173%) higher MP levels compared to paired RBC lysates, suggesting hydrolysis of the TP in DBS.This method was accurate and precise for physiologically relevant concentrations of adenosine, guanosine and inosine nucleotides in mono- and triphosphate forms, providing a bioanalytical tool for quantitation of nucleotides for clinical studies.

OBJECTIVES The objective of this study was to evaluate the effects of abacavir on intracellular ribavirin triphosphate and plasma ribavirin trough concentrations. METHODS Hepatitis C virus-infected subjects who had been cured or failed prior treatment were randomized to 8 weeks of ribavirin alone (N = 14; weight-based dosing) or weight-based ribavirin + abacavir (N = 14; 300 mg orally every 12 h). Ribavirin trough concentrations were measured on days 14, 28, 42 and 56; PBMCs for ribavirin triphosphate determination were sampled on days 28 and 56, pre-dose and at 6 and 12 h post-dose. ClinicalTrials.gov: NCT01052701. RESULTS Twenty-six subjects completed the study (24 males, 17 Caucasians, median age 52 years); 2 were excluded for missed pharmacokinetic visits. Fourteen subjects received ribavirin + abacavir and 12 received ribavirin alone. Mean ± SD plasma ribavirin trough concentrations (μg/mL) on days 14, 28, 42 and 56, respectively, were not significantly different with coadministration of abacavir (1.54 ± 0.60, 1.93 ± 0.54, 2.14 ± 0.73 and 2.54 ± 1.05) compared with ribavirin alone (1.48 ± 0.32, 2.08 ± 0.41, 2.32 ± 0.47 and 2.60 ± 0.62) (P > 0.40). Mean ribavirin triphosphate intracellular concentrations (pmol/10(6) cells) on days 28 and 56, respectively, did not differ statistically between abacavir users (11.98 ± 9.86 and 15.87 ± 12.52) and non-users (15.91 ± 15.58 and 15.93 ± 12.69) (P > 0.4). Adverse events were mild or moderate, except for three grade 3 occurrences of transaminitis, cholecystitis and low absolute neutrophil count that resolved and were judged not attributable to study medications. CONCLUSIONS Abacavir did not significantly alter ribavirin or ribavirin triphosphate concentrations.

Objectives Ribavirin concentrations may impact hepatitis C virus (HCV) treatment outcome. We modelled ribavirin serum and intracellular ribavirin monophosphate (RBV-MP) and ribavirin triphosphate (RBV-TP) pharmacokinetics in red blood cells (RBC) using samples collected during the NIAID SPARE trial to explore associations with treatment outcome and the development of anaemia. Patients and methods Individuals infected with HCV genotype 1 (GT1) received 400 mg of sofosbuvir and either low-dose or weight-based ribavirin as part of the NIAID SPARE trial. Concentrations were modelled using NONMEM and associated with treatment outcomes using unpaired t-tests or Pearson's rho correlations. Results Average day 14 RBV-MP concentrations were higher in subjects with haemoglobin nadir Conclusions RBV-MP concentrations in RBC at day 14 were related to anaemia and SVR. A therapeutic range was identified for RBV-MP in persons with HCV GT1 disease receiving 24 weeks of sofosbuvir plus ribavirin, suggesting a potential pharmacological basis for individualized ribavirin dosing in IFN-free regimens.

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. IMPORTANCE (The clinical trial registration number for this study is NCT00490412 and is available online at http://clinicaltrials.gov/ct2/show/NCT00490412 .)

A 44 year-old Caucasian male presented to the emergency department with a three day history of priapism requiring a surgically performed distal penile shunt. A drug-drug interaction is the suspected cause whereby CYP3A4 inhibition by boceprevir led to increased exposures of doxazosin, tamsulosin and/or quetiapine, resulting in additional α-adrenergic blockade.

The emergence of direct-acting antiviral agents (DAAs) for HCV infection represents a major advance in treatment. The NS3 protease inhibitors, boceprevir and telaprevir, were the first DAAs to receive regulatory approval. When combined with PEG-IFN and ribavirin, these agents increase rates of sustained virologic response in HCV genotype 1 to ∼70%. However, this treatment regimen is associated with several toxicities. In addition, both boceprevir and telaprevir are substrates for and inhibitors of the drug transporter P-glycoprotein and the cytochrome P450 enzyme 3A4 and are, therefore, prone to clinically relevant drug interactions. Several new DAAs for HCV are in late stages of clinical development and are likely to be approved in the near future. These include the protease inhibitors, simeprevir and faldaprevir, the NS5A inhibitor, daclatasvir, and the nucleotide polymerase inhibitor, sofosbuvir. Herein, we review the clinical pharmacology and drug interactions of boceprevir, telaprevir and these investigational DAAs. Although boceprevir and telaprevir are involved in many interactions, these interactions are manageable if health-care providers proactively identify and adjust treatments. Emerging DAAs seem to have a reduced potential for drug interactions, which will facilitate their use in the treatment of HCV.

Boceprevir and telaprevir, when added to pegylated interferon and ribavirin for the treatment of chronic hepatitis C virus infection, increase the rates of sustained virologic response in treatment naïve persons to approximately 70%. While these agents represent an important advance in the treatment of chronic hepatitis C virus, they present new treatment challenges to the Hepatology community. Boceprevir and telaprevir are both substrates and inhibitors of the hepatic enzyme cytochrome P450 3A and the drug transporter, P-glycoprotein, which predisposes these agents to many drug interactions. Identification and appropriate management of potential drug interactions with telaprevir and boceprevir is critical for optimizing therapeutic outcomes during hepatitis C treatment. This review highlights the pharmacologic characteristics and drug interaction potential of boceprevir and telaprevir and provides guidance on the management of drug interactions with these agents.

The relationships among the dose of tenofovir disoproxil fumarate (TDF), tenofovir (TFV) plasma concentrations, and intracellular TFV diphosphate (TFV-DP) concentrations are poorly understood. Our objective was to characterize TFV and TFV-DP relationships. Data were pooled from two studies in HIV-infected persons ( n = 55) on stable antiretroviral therapy. TFV and TFV-DP were measured with validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods. Nonlinear mixed effects modeling (NONMEM 7) was used to develop the population model and explore the influence of covariates on TFV. A sequential analysis approach was utilized. A two-compartment model with first-order absorption best described TFV PK (FOCEI). An indirect stimulation of response model best described TFV-DP, where formation of TFV-DP was driven by plasma TFV concentration. Final plasma population estimates were as follows: absorption rate constant, 1.03 h −1 ; apparent clearance (CL/F), 42 liters/h (33.5% interindividual variability [IIV]); intercompartment clearance, 181 liters/h; apparent central distribution volume (Vc/F), 273 liters (64.8% IIV); and apparent peripheral distribution volume (Vp/F), 440 liters (46.5% IIV). Creatinine clearance was the most significant covariate on CL/F and Vc/F. The correlation between CL/F and Vc/F was 0.553. The indirect response model for TFV-DP resulted in estimates of the maximal intracellular concentration ( E max ), the TFV concentration producing 50% of E max (EC 50 ), and the intracellular elimination rate constant ( k out ) of 300 fmol/10 6 cells (82% IIV), 100 ng/ml (106% IIV), and 0.008 h −1 , respectively. The estimated k out gave an 87-h TFV-DP half-life. A predictive check assessment indicated satisfactory model performance. This model links formation of TFV-DP with plasma TFV concentrations and should facilitate more informed investigations of TFV clinical pharmacology.

To describe the pharmacokinetics of atazanavir (ATV) and ritonavir-boosted ATV (ATV/r) in children aged 91 days to 21 years.A phase I/II, open-label, multicenter study of once-daily ATV and ATV/r as part of combination antiretroviral treatment in HIV-infected treatment-experienced and treatment-naive children.Sites in the United States and South Africa.One hundred and ninety-five children enrolled; 172 had evaluable ATV pharmacokinetics on day 7.Children were entered in age, dose, and formulation (powder or capsule) cohorts. Intensive pharmacokinetic sampling occurred 7 days after starting ATV. ATV doses were increased or decreased if the 24-h area under the concentration time curves (AUC0-24hr) were less than 30 or more than 90 μg × h/ml, respectively.Cohorts satisfied protocol-defined pharmacokinetic criteria if the median ATV AUC0-24hr was 60 μg × h/ml or less, and AUC0-24hr and ATV concentrations 24-h postdose (C24) were more than 30 μg × h/ml and at least 60 ng/ml, respectively, in at least 80% of the children, with no individual AUC0-24hr less than 15 μg × h/ml.Unboosted ATV capsules satisfied pharmacokinetic criteria at a dose of 520 mg/m for those aged more than 2 to 13 years or less and 620 mg/m for those aged more than 13 to 21 years or less. ATV/r capsules satisfied criteria at a dose of 205 mg/m for those aged more than 2 to 21 years or less. ATV/r powder satisfied criteria at a dose of 310 mg/m for those aged more than 2 to 13 years or less, but pharmacokinetics in those aged 2 years or less were highly variable.Body surface area-determined doses of ATV capsules and of ATV/r powder and capsules provide ATV exposures in children of more than 2 years that approximate concentrations in adults receiving ATV/r.

The primary objective of this study was to measure atazanavir-ritonavir and tenofovir pharmacokinetics when the drugs were used in combination in young adults with human immunodeficiency virus (HIV). HIV-infected subjects ≥18 to 0-24), maximum concentration of drug in serum (Cmax), concentration at 24 h postdose (C24), and total apparent oral clearance (CL/F) values were 35,971 ng·hr/ml (30,853 to 41,898), 3,504 ng/ml (2,978 to 4,105), 578 ng/ml (474 to 704), and 8.3 liter/hr (7.2 to 9.7), respectively. The geometric mean (95% CI) tenofovir AUC0-24,Cmax,C24, and CL/Fvalues were 2,762 ng·hr/ml (2,392 to 3,041), 254 ng/ml (221 to 292), 60 ng/ml (52 to 68), and 49.2 liter/hr (43.8 to 55.3), respectively. Body weight was significantly predictive of CL/Ffor all three drugs. For every 10-kg increase in weight, there was a 10%, 14.8%, and 6.8% increase in the atazanavir, ritonavir, and tenofovir CL/F, respectively (P≤ 0.01). Renal function was predictive of tenofovir CL/F. For every 10 ml/min increase in creatinine clearance, there was a 4.6% increase in tenofovir CL/F(P< 0.0001). The geometric mean (95% CI) TFV-DP concentrations at 1, 4, and 24 h postdose were 96.4 (71.5 to 130), 93.3 (68 to 130), and 92.7 (70 to 123) fmol/million cells. There was an association between renal function, tenofovir AUC, and tenofovirCmaxand intracellular TFV-DP concentrations, although none of these associations reached statistical significance. In these HIV-infected young adults treated with atazanavir-ritonavir plus TDF, the atazanavir AUC was similar to those of older adults treated with the combination. Based on data for healthy volunteers, a higher tenofovir AUC may have been expected, but was not seen in these subjects. This might be due to faster tenofovir CL/Fbecause of higher creatinine clearance in this age group. Additional studies of the exposure-response relationships of this regimen in children, adolescents, and adults would advance our knowledge of its pharmacodynamic properties.