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In 2019, more than 4 years after the widespread availability of safe, oral, curative treatments, an estimated 58 million people were living with hepatitis C virus infections (PLWHC). Additional tools may enable those not yet reached to be treated. One such tool could be long-acting parenteral formulations of HCV treatments, which may allow PLWHC to be diagnosed and cured in a single encounter. Although existing highly effective oral medications might be formulated as long-acting parenteral treatments, pharmacological, regulatory, patent, and medical challenges have to be overcome; this requires the concerted efforts of PLWHC, researchers, funding agencies, industry, the World Health Organization, and other stakeholders.

There are an estimated 257 million persons living with chronic hepatitis B for whom there are multiple potential applications of long-acting antiviral compounds. Current efforts include both injection and implant approaches to formulating derivates of existing anti-HBV compounds such as tenofovir or entecavir. Substantial progress has already occurred especially as aligned with the development of long-acting tenofovir-based medications with dual activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). Nonetheless, substantial challenges will need to be overcome before these agents are available.

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)).

OBJECTIVE Tenofovir alafenamide (TAF) preferentially loads peripheral blood mononuclear cells (PBMC), resulting in higher PBMC tenofovir-diphosphate (TFV-DP) vs. tenofovir disoproxil fumarate (TDF). No studies have yet compared TFV-DP in PBMC from lower than daily dosing between prodrugs, which has potential implications for event-driven pre-exposure prophylaxis and pharmacologic forgiveness. DESIGN Two separate randomized, directly observed therapy (DOT) crossover studies (DOT-DBS and TAF-DBS) were conducted to mimic low, medium, and high adherence. METHODS HIV-negative adults were randomized to two 12-week DOT regimens of 33%, 67%, or 100% of daily dosing with emtricitabine (F)/TAF 200 mg/25 mg (TAF-DBS) or F/TDF 200 mg/300 mg (DOT-DBS), separated by a 12-week washout. PBMC steady-state concentrations (Css) of TFV-DP and FTC-TP were estimated using nonlinear mixed models and compared between F/TAF and F/TDF. RESULTS Thirty-five participants contributed to 33% (n = 23), 67% (n = 23), and 100% (n = 23) of daily F/TAF regimens. Forty-four contributed to 33% (n = 15), 67% (n = 16), and 100% (n = 32) of daily F/TDF regimens. PBMC TFV-DP Css were 7.3- (95% CI: 6.4-8.2), 7.1- (5.9-8.2), and 6.7- (4.4-8.9) fold higher (p

The potency of modern antiretroviral therapy (ART) allows for greater forgiveness to missed doses while still achieving, and maintaining, viral suppression. However, imperfect ART adherence, even if sufficient to maintain viral suppression, has been associated with adverse clinical outcomes. ART adherence can be objectively quantified using tenofovir diphosphate (TFV-DP) in dried blood spots (DBS), a biomarker of cumulative adherence that is predictive of future viremia-even among persons with HIV (PWH) with an undetectable HIV viral load (VL). Within a prospective cohort of PWH on tenofovir disoproxil fumarate-including ART, mismatch between drug concentration and HIV VL (i.e., low concentrations of TFV-DP in DBS in the setting of viral suppression with subsequent viremia at the following visit) was observed more frequently in PWH who were Black (36% vs. 15%

Tenofovir diphosphate (TFV-DP) concentrations measured with dried blood spots (DBS) can be used to classify adherence to emtricitabine/tenofovir disoproxil fumarate (F/TDF) for HIV pre-exposure prophylaxis (PrEP). A TFV-DP of 700 fmol/punch was previously associated with high PrEP efficacy, and was estimated to represent ≥4 doses/week on average. However, interindividual variability in TFV-DP concentrations may lead to adherence misclassification and decrease the precision of adherence–efficacy relationships. The purpose of this analysis was to evaluate sources of TFV-DP variability to improve the precision of TFV-DP for adherence assessments by incorporating individual characteristics. Data and samples from a 36-week study of TFV-DP in DBS, collected biweekly, among 48 HIV-negative volunteers (25 Females/26 Caucasian/10 African American/14 Hispanic) receiving F/TDF at 33%, 67%, and 100% of daily dosing under directly observed therapy were used for analysis. The simplest pharmacokinetic model to describe TFV-DP accumulation with acceptable performance was a one-compartment constant input model. Covariates, including laboratory values and demographics were ranked in importance of their association with post hoc pharmacokinetic (PK) parameters using random forest analyses. Weight and platelet count were included in the final model and simulations were conducted to generate benchmarks for 110 kg) doses/week, amounting to a much lower rate of misspecification (17% vs. 30%) with this individualized model versus previous interpretations. Incorporating body weight and platelet count improved the precision of TFV-DP concentrations for adherence assessments. Previous benchmarks were conservative, indicating that the pharmacological forgiveness of F/TDF may be higher than currently recognized and supports continued investigation of intermittent PrEP dosing regimens. Clinical Trial Registration number, NCT02022657.

Ambiguous adherence data adversely effects the statistical analyses, study conclusions, and generalizability of research findings for clinical trials. Fortunately, technology-based measures of drug dosing provide more objective measures of medication adherence. While adherence data obtained through monitoring technology avoids the well documented shortcomings of self-reported adherence data, there are important limitations and nuances with use of these technologies that should be considered at study inception, conduct, and analysis. This article describes considerations for data collection and management with use of electronic adherence monitoring, specifically mobile-phone video applications or electronic pillbox devices. The overall aim of this communique is to provide research teams the ability to collect more accurate adherence data and ultimately improve the quality and outcome of their research.

STUDY OBJECTIVE To assess the association between tenofovir diphosphate (TFV-DP) in dried blood spots (DBS), a measure of cumulative tenofovir-based antiretroviral (ART) adherence, with medication regimen complexity in persons with human immunodeficiency virus (PWH). DESIGN Prospective clinical cohort (up to three visits over 48 weeks). SETTING Academic-based HIV clinic. PATIENTS PWH receiving tenofovir disoproxil fumarate (TDF)-based ART. MEASUREMENTS DBS for TFV-DP were collected at every study visit. Baseline patient-level medication regimen complexity index (pMRCI) scores were calculated and categorized into three sub-scores (disease-specific [ART], non-ART, and over-the-counter [OTC]). The pMRCI scores were evaluated to assess the association with TFV-DP in DBS

Contains fulltext : 235789.pdf (Publisher’s version ) (Open Access) 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.

OBJECTIVE People living with HIV (PLWH) are living longer and developing more non-AIDS comorbidities, which negatively impact antiretroviral therapy (ART) adherence. Tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is a novel pharmacologic measure of cumulative ART adherence that is predictive of viral suppression and future viremia. However, the relationship between non-AIDS comorbidities and this adherence measure is unknown. We aimed to evaluate the association between 3 non-AIDS comorbidities (diabetes mellitus (DM), hypertension, and hyperlipidemia) and TFV-DP in DBS in PLWH. METHODS Blood for TFV-DP in DBS and HIV viral load was prospectively collected from PLWH on tenofovir disoproxil fumarate for up to 3 times over 48 weeks. Non-AIDS comorbidities were recorded. Mixed effect multivariable linear regression models were used to estimate the changes in TFV-DP concentrations in DBS according to the presence of comorbidities and to estimate the percent differences in TFV-DP concentrations between these groups. RESULTS A total of 1144 person-visits derived from 523 participants with available concentrations of TFV-DP in DBS were included in this analysis. In univariate analysis, no significant association between non-AIDS comorbidities (categorized as having 0, 1, 2, or 3 comorbidities) and the concentrations of TFV-DP in DBS was observed (P = 0.40). Participants who had DM had 25% lower (95% confidence interval: -36% to -12%; P < 0.001) TFV-DP in DBS than participants without DM after adjusting for age, gender, race, body mass index, estimated glomerular filtration rate, CD4 T-cell count, hematocrit, ART class, patient-level medication regimen complexity index, and 3-month self-reported adherence. CONCLUSIONS Diabetic PLWH have lower concentrations of TFV-DP in DBS compared with those without DM. Further research is required to identify the clinical implications and biological mechanisms underlying these findings.

BACKGROUND Tenofovir alafenamide (TAF), in combination with FTC, was recently approved for PrEP in the United States. The objective of this study was to assess the relationship between tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in dried blood spots (DBS) with adherence to TAF/FTC. METHODS TAF-DBS was a randomized, crossover clinical study of TFV-DP in DBS, following directly observed dosing of 33%, 67%, or 100% of daily TAF (25 mg)/FTC (200 mg). Healthy volunteers were randomized to 2 different, 12-week dosing regimens, separated by a 12-week washout. DBS were collected weekly. TFV-DP and FTC-TP were extracted from two 7-mm punches and assayed with LC-MS/MS. RESULTS Thirty-seven participants (17 female, 7 African American, and 6 Hispanic) were included. TFV-DP exhibited a mean half-life of 20.8 days (95% confidence interval: 19.3 to 21.3). The slope for TFV-DP versus dosing arm was 1.14 (90% confidence interval: 1.07 to 1.21). The mean (SD) TFV-DP after 12 weeks was 657 (186), 1451 (501), and 2381 (601) fmol/2 7-mm punches for the 33%, 67%, and 100% arms. The following adherence interpretations are proposed

We assessed cumulative antiretroviral exposure-using tenofovir diphosphate (TFV-DP) in dried blood spots (DBS)-in persons with HIV (PWH) receiving tenofovir disoproxil fumarate (TDF)-based antiretroviral therapy (ART) as single-tablet regimens (STR) or multiple-tablet regimens (MTR).Blood for DBS was prospectively collected in PWH on TDF during 1144 person visits (n = 523). Linear mixed-effects models, adjusted for baseline characteristics, were used to compare TFV-DP in STR versus MTR. Models adjusted for ART regimen using either anchor drug class, pharmacokinetic booster status (unboosted [u/] or boosted [b/]), or a combined STR/MTR and booster categorical variable.In the anchor class-adjusted model, STR had 19% (95% confidence interval [CI]: 3%-37%; p = 0.02) higher TFV-DP concentrations than MTR. However, in the booster-adjusted model, STR was not significantly higher than MTR (estimate 5%, 95% CI: -9% to 21%; p = 0.48), although PWH on b/ART had 35% (95% CI: 16%-58%; p = 0.0001) higher TFV-DP than u/ART. In the STR/MTR-boosted variable model, when compared to u/MTR, b/STR, b/MTR, and u/STR had 25% (95% CI: 7%-47%; p = 0.005), 37% (95% CI: 17%-59%; p 0.0001), and 7% (95% CI: -7% to 24%; p = 0.34) higher TFV-DP, respectively. Compared with b/MTR, b/STR had 9% (95% CI: -31% to 10%; p = 0.37) lower TFV-DP. In a sensitivity analysis of PWH with HIV viral load20 copies/ml at all visits, b/STR and b/MTR had 34% (95% CI: 16%-55%; p 0.0001) and 12% (95% CI: -2% to 27%; p = 0.09) higher TFV-DP, respectively, compared with u/MTR, while u/STR had 4% (95% CI: -15% to 8%; p = 0.50) lower TFV-DP. Compared with b/MTR, b/STR had 17% (95% CI: 2%-30%; p = 0.03) higher TFV-DP.Persons with HIV on b/TDF-based ART had higher TFV-DP than u/ART, regardless of STR or MTR use. No significant differences in TFV-DP between regimens of the same boosting status (i.e., b/STR vs. b/MTR; u/STR vs. u/MTR) were observed in the full cohort. Future research should examine the clinical utility of these findings in patient-tailored ART selection.

Background Sofosbuvir is converted to its active form, 007 triphosphate (007-TP), within cells. To date, the association between treatment adherence and 007-TP in dried blood spots (DBS) and factors that influence this relationship remain unknown. Objectives To examine relationships between adherence and 007-TP concentrations in DBS and identify factors that influence 007-TP in DBS. Methods Persons with HCV or HIV/HCV coinfection and self-reported drug and/or alcohol use were randomized to one of two technology-based approaches for monitoring 12 week adherence to once-daily ledipasvir/sofosbuvir. Convenience blood samples were collected every 2 weeks during treatment. 007-TP in DBS was quantified using LC/MS and analysed using mixed-effects models. Results A total of 337 observations were available from 58 participants (78% male; 21% black; 22% Hispanic/Latino; 26% cirrhotic; 78% HIV-coinfected). The mean half-life of 007-TP in DBS was 142 h (95% CI 127–156) and concentrations increased by 7.3% (95% CI 2.2–12.6) for every 10% increase in between-visit adherence. Geometric mean (95% CI) 007-TP concentrations in DBS were 301 (247–368), 544 (462–639) and 647 (571–723) fmol/punch by adherence categories of ≤50%, >50 to ≤80%, and >80%. Adherence, time on therapy, increasing age and decreased estimated glomerular filtration rate were associated with higher 007-TP, whereas increased time since last dose, male sex, black race and higher BMI were associated with lower 007-TP. Conclusions 007-TP has an extended half-life in DBS and concentrations increased with adherence. Further research is needed to examine additional factors that affect 007-TP and the clinical utility of this measure.

Background In the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial, tenofovir disoproxil fumarate (TDF) use was associated with moderate or severe adverse pregnancy/neonatal outcomes. This study characterized tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations in dried blood spots (DBS) and assessed association between severe adverse pregnancy/neonatal outcomes and TFV-DP concentration. Methods Retrospective case-control study of PROMISE trial arm-C women randomized to receive TDF, FTC, and ritonavir-boosted lopinavir (LPV/r), who took at least 1 dose of TDF + FTC and had week-4 postrandomization DBS drawn before delivery. Cases, defined as severe adverse pregnancy/neonatal outcomes (very preterm delivery before 34 weeks of gestation, stillbirth ≥20 weeks of gestation, or infant death before 14 days-of-age), were matched to controls (1:2 ratio) by site and gestational age at entry. Week 4 and week 8 DBS samples were assayed for TFV-DP and FTC-TP by liquid chromatography and tandem mass spectrometry. Associations were tested using Wilcoxon rank test and conditional logistic regression. Results Of 447 PROMISE arm-C women, 33 met case definitions, and overall, 22 cases and 44 controls were analyzed. Median (interquartile range) concentrations of TFV-DP at weeks 4 and 8 were 706 (375-1023) fmol/punch and 806 (414-1265) fmol/punch, respectively. Odds ratio (95% confidence interval) for severe adverse pregnancy/neonatal outcome with natural log of TFV-DP concentrations as the predictor were 1.27 (0.74 to 2.18) and 1.74 (0.66 to 4.60) at weeks 4 and 8, respectively. Median (interquartile range) concentrations of FTC-TP at weeks 4 and 8 were 0.27 (0.05-0.36) pmol/punch and 0.29 (0.05-0.40) pmol/punch, respectively. Conclusions TFV-DP concentrations in DBS appeared not to be associated with severe adverse pregnancy/neonatal outcomes, although sample size was limited.

BackgroundTenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is associated with viral suppression in persons living with HIV (PLWH) taking tenofovir disoproxil fumarate (TDF). However, its value as a predictor of future viremia remained unknown.MethodsBlood for plasma viral load (VL) and TFV-DP in DBS were collected (up to 3 visits within 48 weeks) in PLWH on TDF. TFV-DP cut points were selected using logistic prediction models maximizing the area under the receiver operation characteristic curve, and estimated adjusted odds ratio (aOR) of future viremia (≥20 copies/mL) were compared to the highest TFV-DP category.ResultsAmong all 451 participants in the analysis, aOR of future viremia for participants with TFV-DP ConclusionsTFV-DP in DBS predicts future viremia in PLWH on TDF, even in those who are virologically suppressed. This highlights the utility of this biomarker to inform about adherence beyond VL.Clinical Trials Registration. NCT02012621.

The drivers of low-level viremia (LLV) between 20 and 200 copies/mL remain unclear. In 1042 person-visits from 497 persons with HIV on tenofovir disoproxil fumarate–containing antiretroviral therapy (ART), the association between LLV and cumulative antiretroviral adherence (quantified using tenofovir diphosphate [TFV-DP] in dried blood spots) was assessed. Lower TFV-DP levels were associated with higher odds of LLV. As TFV-DP (fmol/punch) categories decreased from >1650 to 800–1650; 800–1650 to 1650 to

OBJECTIVE Emtricitabine triphosphate (FTC-TP) in dried blood spots (DBS), a measure of short-term antiretroviral therapy (ART) adherence, is associated with viral suppression in persons with HIV (PWH). However, its ability to predict future viremia remains unknown. DESIGN Prospective, observational cohort (up to three visits in 48 weeks). METHODS PWH receiving TDF/FTC-based ART had DBS and HIV viral load obtained at routine clinical visits. FTC-TP in DBS was dichotomized into quantifiable vs. below the limit of quantification (BLQ). The adjusted odds ratio (aOR) of future viremia (≥20 copies/ml at next study visit) was estimated according to FTC-TP at the current visit. To assess for possible interactions, additional models adjusted for tenofovir diphosphate (TFV-DP) in DBS and 3-day self-reported adherence. RESULTS Data from 433 PWH (677 paired DBS/HIV viral load samples) were analyzed. The aOR [95% confidence interval (CI)] for future viremia for BLQ vs. quantifiable FTC-TP was 3.4 (1.8--6.5; P = 0.0002). This diminished after adjusting for TFV-DP [aOR 1.9 (0.9--4.1); P = 0.090]. Among PWH reporting 100% 3-day adherence, the odds of future viremia were 6.0 times higher [(1.8--20.3); P = 0.001] when FTC-TP was BLQ vs. quantifiable. Among participants (n = 75) reporting less than 100% adherence, BLQ FTC-TP in DBS was not predictive of future viremia [aOR 1.3 (0.4--4.6); P = 0.96]. CONCLUSION Nonquantifiable FTC-TP in DBS predicts future viremia and is particularly informative in PWH reporting perfect adherence. As point-of-care adherence measures become available, mismatches between objective and subjective measures, such as FTC-TP in DBS and self-report, could help clinicians identify individuals at an increased risk of future viremia.

Background Hepatitis C virus treatment in persons who use drugs (PWUD) is often withheld due to adherence and reinfection concerns. In this study, we report treatment outcomes, technology-based adherence data, and adherence predictors in PWUD and/or alcohol. Methods INCLUD was a prospective, open-label study of ledipasvir/sofosbuvir for 12 weeks in PWUD aged 18–70 years. Participants were randomized to wireless (wirelessly observed therapy) or video-based directly observed therapy (vDOT). Drug use was assessed every 2 weeks. Sustained virologic response (SVR) was examined by intention-to-treat and as-treated. Factors associated with missing ≥1 dose(s) between visits were examined using generalized linear models. Results Sixty participants received ≥1 ledipasvir/sofosbuvir dose (47 human immunodeficiency virus [HIV]/hepatitis C virus [HCV], 13 HCV only; 78% male; 22% black; 25% cirrhotic). Substance use occurred at 94% of person-visits: 60% marijuana, 56% alcohol, 37% methamphetamine, 22% opioids, 17% cocaine, and 20% injection drug use. The SVR by intention-to-treat was 86.7% (52 of 60) and as-treated was 94.5% (52 of 55). Confirmed failures included 1 relapse, 1 reinfection, and 1 unknown (suspected reinfection). Median total adherence was 96% (interquartile range [IQR], 85%–100%; range, 30%–101%), and between-visit adherence was 100% (IQR, 86%–100%; range, 0%–107%). The odds of missing ≥1 dose between visits increased with HIV coinfection (2.94; 95% confidence interval [CI], 1.37–6.32; P = .006), black race (4.09; 95% CI, 1.42–11.74; P = .009), methamphetamine use (2.51; 95% CI, 1.44–4.37; P = .0.001), and cocaine use (2.12; 95% CI, 1.08–4.18; P = .03) and decreased with marijuana use (0.34; 95% CI, 0.17–0.70; P = .003) and vDOT (0.43; 95% CI, 0.21–0.87; P = .02). Conclusions Persons who use drugs achieved high SVR rates with high, but variable, ledipasvir/sofosbuvir adherence using technology-based methods. These findings support efforts to expand HCV treatment in PWUD., Persons with HCV and active drug/alcohol use demonstrated high, but variable, adherence to ledipasvir/sofosbuvir using wireless pillboxes and video-based directly observed therapy. High SVR rates were achieved, supporting efforts to expand HCV treatment in this population.

Respiratory syncytial virus (RSV) is responsible for significant morbidity and mortality in the lung transplant population. Oral and aerosolized ribavirin may improve outcomes in lung transplant patients with RSV; however, data relating ribavirin concentrations in plasma and intracellular ribavirin triphosphate (iRTP) concentrations in blood and bronchoalveolar lavage (BAL) fluid cells with efficacy and safety are lacking. We describe ribavirin and iRTP concentrations within various compartments in two adult lung transplant recipients with RSV who were sampled throughout successful treatment courses with oral and inhaled ribavirin. In patient one, iRTP BAL concentrations decreased by 45% over three days after changing inhaled ribavirin to oral (6.32 to 3.43 pmol/106 cells). In patient two, iRTP BAL concentrations were 103 pmol/106 cells after five days of oral followed by five days of inhaled ribavirin. Further study is needed to describe ribavirin pharmacokinetics in the respiratory compartment to inform clinical use of ribavirin for respiratory viruses.

Tenofovir alafenamide (TAF), in combination with FTC, was recently approved for PrEP in the United States. The objective of this study was to assess the relationship between tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in dried blood spots (DBS) with adherence to TAF/FTC.TAF-DBS was a randomized, crossover clinical study of TFV-DP in DBS, following directly observed dosing of 33%, 67%, or 100% of daily TAF (25 mg)/FTC (200 mg). Healthy volunteers were randomized to 2 different, 12-week dosing regimens, separated by a 12-week washout. DBS were collected weekly. TFV-DP and FTC-TP were extracted from two 7-mm punches and assayed with LC-MS/MS.Thirty-seven participants (17 female, 7 African American, and 6 Hispanic) were included. TFV-DP exhibited a mean half-life of 20.8 days (95% confidence interval: 19.3 to 21.3). The slope for TFV-DP versus dosing arm was 1.14 (90% confidence interval: 1.07 to 1.21). The mean (SD) TFV-DP after 12 weeks was 657 (186), 1451 (501), and 2381 (601) fmol/2 7-mm punches for the 33%, 67%, and 100% arms. The following adherence interpretations are proposed:450 fmol/punches,2 doses/wk; 450-949 fmol/punches, 2-3 doses/wk; 950-1799 fmol/punches, 4-6 doses/wk; and ≥1800 fmol/punches, 7 doses/wk. FTC-TP was quantifiable for 1 week after drug cessation in 50%, 92%, and 100% of participants in the 33%, 67%, and 100% arms, respectively.TFV-DP in DBS after TAF/FTC exhibited a long half-life and was linearly associated with dosing, similar to its predecessor tenofovir disoproxil fumarate. FTC-TP was quantifiable for up to 1 week after drug cessation. Together, these moieties provide complementary measures of cumulative adherence and recent dosing for TAF/FTC.

BACKGROUND: Emtricitabine triphosphate (FTC-TP), the phosphorylated anabolite of emtricitabine, can be quantified in dried blood spots (DBS). We evaluated FTC-TP in DBS as a predictor of viral suppression and evaluated self-reported adherence as a predictor of FTC-TP. METHODS: Persons living with HIV (PLWH) on an FTC-containing regimen were prospectively recruited. A DBS and HIV viral load were obtained during routine clinical visits. Self-reported adherence for 3 days, 30 days and 3 months was captured. Generalized estimating equations were used to estimate the adjusted odds ratio (aOR) of viral suppression for quantifiable FTC-TP versus below the limit of quantification (BLQ). The utility of self-reported adherence to predict quantifiable FTC-TP was assessed by calculating the area under receiver operating characteristic (ROC) curve. RESULTS: One thousand one hundred and fifty-four person-visits from 514 participants who had DBS assayed for FTC-TP were included in the analysis. After adjusting for age, gender, race, BMI, ART class, ART duration, estimated glomerular filtration rate and CD4+ T cell count, the aOR (95% CI) for viral suppression for quantifiable FTC-TP versus BLQ was 7.2 (4.3–12.0; P

Background Ledipasvir/sofosbuvir increases tenofovir plasma exposures by up to 98% with tenofovir disoproxil fumarate (TDF), and exposures are highest with boosted PIs. There are currently no data on the combined use of the newer tenofovir prodrug, tenofovir alafenamide (TAF), boosted PIs and ledipasvir/sofosbuvir. Objectives To compare the plasma and intracellular pharmacokinetics and renal safety of TAF with ledipasvir/sofosbuvir when co-administered with boosted PIs. Methods Persons with HIV between 18 and 70 years and on a boosted PI with TDF were eligible. The study was comprised of four phases: (1) TDF 300 mg with boosted PI; (2) TAF 25 mg with boosted PI; (3) TAF 25 mg with boosted PI and ledipasvir/sofosbuvir; and (4) TAF 25 mg with boosted PI. Pharmacokinetic sampling, urine biomarker collection [urine protein (UPCR), retinol binding protein (RBP) and β2 microglobulin (β2M) normalized to creatinine] and safety assessments occurred at the end of each phase. Plasma, PBMCs and dried blood spots were collected at each visit. Results Ten participants were enrolled. Plasma tenofovir exposures were 76% lower and tenofovir-diphosphate (TFV-DP) concentrations in PBMCs increased 9.9-fold following the switch to TAF. Neither of these measures significantly increased with ledipasvir/sofosbuvir co-administration, nor did TAF plasma concentrations. No significant changes in estimated glomerular filtration rate or UPCR occurred, but RBP:creatinine and β2M:creatinine improved following the switch to TAF. Conclusions Ledipasvir/sofosbuvir did not significantly increase plasma tenofovir or intracellular TFV-DP in PBMCs with TAF. These findings provide reassurance that the combination of TAF, boosted PIs and ledipasvir/sofosbuvir is safe in HIV/HCV-coinfected populations.

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.

BackgroundAlthough tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is a predictor of adherence and pre-exposure prophylaxis efficacy, its utility in human immunodeficiency virus (HIV) treatment remains unknown.MethodsDBS for TFV-DP were collected up to 3 times over 48 weeks in persons living with HIV (PLWH) who were receiving TFV disoproxil fumarate (TDF)-based therapy. Log-transformed baseline TFV-DP was compared using t-tests or analyses of variance; generalized estimating equations were used to estimate the adjusted odds ratio (aOR) of viral suppression (ResultsWe analyzed 1199 DBS from 532 participants (76 female; 101 Black, 101 Hispanic). Among the virologically-suppressed participants at baseline (n = 347), TFV-DP was lower in Blacks (geometric mean 1453, 95% confidence interval [CI] 1291–1635) vs Whites (1793, 95% CI 1678–1916; P = .002) and Hispanics (1760, 95% CI 1563–1982; P = .025); in non-boosted (1610, 95% CI 1505–1723) vs. boosted (1888, 95% CI 1749–2037; P = .002) regimens; and in non-nucleoside reverse transcription inhibitor–based (1563, 95% CI 1432–1707) vs. boosted protease inhibitor–based (1890, 95% CI 1704–2095; P = .006) and multiclass-based (1927, 95% CI 1650–2252; P = .022) regimens. The aOR of virologic suppression, after adjusting for age, gender, race, body mass index, estimated glomerular filtration rate, CD4+ T-cell count, antiretroviral drug class and duration of therapy, was 73.5 (95% CI 25.7–210.5; P < .0001) for a TFV-DP concentration ≥1850 fmol/punch compared to ConclusionsTFV-DP in DBS is strongly associated with virologic suppression in PLWH on TDF-based therapy and is associated with certain participant characteristics. Further research is required to evaluate this drug adherence and exposure measure in clinical practice.Clinical Trials RegistrationNCT02012621.

Direct-acting antivirals (DAAs) achieve high hepatitis C virus (HCV) cure rates and are forgiving to missed doses, but adherence–efficacy relationships have not been well defined. Traditional adherence measures (e.g. pill counts, self-report and pharmacy refills) over-estimate medication adherence. Newer technology-based tools have been used to provide more objective adherence data. Herein, electronic medication diaries (e-diaries), medication events monitoring system (MEMS®) caps, electronic blister packs, electronic pill boxes, video-based directly observed therapy (vDOT), artificial intelligence platforms (AIPs), and ingestible sensor systems are described, and compared based on existing studies using DAA. Percent adherence, predictors of adherence, and HCV cure rates utilizing these technologies are included. DAA adherence with e-diaries was 95–96%, MEMS® caps and ingestible biosensors were between 95% and 97%, blister pack weekly dosing ranged 73–98%, and daily dosing 73–94%, whereas electronic pill boxes ranged between 39% and 89%, vDOT was 98% and AIP 91–96%. Despite a wide range of adherence, high sustained virologic response (SVR) rates (86–100%) were observed across all studies utilizing these different technology-based tools. Current data support the forgiveness of DAA therapies to missed doses using tools that provide more quantitative adherence measures compared with self-report and provide insight on adherence–efficacy relationships for contemporary DAA.

Background Dolutegravir, an HIV integrase strand-transfer inhibitor, and simeprevir, an HCV NS3/4A PI, have the potential to interact as dolutegravir is a P-glycoprotein, uridine glucuronosyl transferase 1A1 and cytochrome P4503A substrate and simeprevir has been shown to mildly inhibit these. Objectives To compare dolutegravir and simeprevir pharmacokinetics (PK) when given separately versus in combination. Methods Healthy volunteers received: (i) 150 mg of simeprevir once daily for 7 days; (ii) 50 mg of dolutegravir once daily for 7 days; and (iii) 150 mg of simeprevir once daily plus 50 mg of dolutegravir once daily for 7 days, with randomization to treatment sequence. Twenty-four hour intensive PK sampling was performed on day 7 of each sequence following observed dosing and a standardized meal. PK parameters were determined using non-compartmental methods and compared using paired t-tests. Bioequivalence for area under the curve (AUCtau) and maximum concentration (Cmax) were also assessed. NCT02404805. Results Twenty-four subjects completed all three sequences. Dolutegravir trough was increased 24% (P = 0.0003) with simeprevir. Dolutegravir AUCtau was increased 15% (P = 0.002), but was deemed bioequivalent as the 90% CI for the geometric mean ratio was 107%-123%. Dolutegravir Cmax was bioequivalent. Simeprevir PK was unaffected by dolutegravir. There were no discontinuations due to adverse events and all adverse events were mild to moderate in severity. Conclusions Dolutegravir trough was increased slightly with simeprevir, but AUCtau was bioequivalent. Despite the increase in trough, dolutegravir concentrations were well within the range with established safety data. Suggesting that simeprevir and dolutegravir can be safely co-administered.

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.

Contains fulltext : 218239.pdf (Publisher’s version ) (Closed access) BACKGROUND: Treatment of hepatitis B virus (HBV) infection with current therapy suppresses HBV DNA, but loss of hepatitis B surface antigen (HBsAg; functional cure), is rare. Multiple compounds are under investigation. AIMS: To describe the pharmacology, including drug interactions, efficacy, safety and mechanisms of action of investigational compounds for HBV infection. METHODS: Descriptive review using PubMed and Google to identify literature/conference papers on investigational compounds (>/=Phase 2) with data on efficacy and safety in HBV-infected patients. RESULTS: Bulevirtide, JNJ-56136379, ABI-H0731, REP-2139, and inarigivir decrease HBV DNA/RNA, with greater potency than current nucleos(t)ide analogues. REP-2139 (25%-75% of patients, 20-48 weeks treatment) and inarigivir (26% of patients, 12-24 weeks treatment) induce HBsAg loss. ARO-HBV reduced (>1.5 log10 UI/mL) HBsAg in 85% of patients (12 weeks treatment). There are some safety concerns with investigational agents (e.g., increased bile acids with bulevirtide, and liver enzyme flares with REP-2139) which will require a risk benefit assessment compared with current therapies. Single and multidose pharmacokinetic data are available for bulevirtide, JNJ-56136379, ABI-H0731; no such data are available for REP-2139, ARO-HBV, inarigivir. Initial drug interaction assessments have been performed with bulevirtide and inarigivir (only in vitro). CONCLUSIONS: There are promising investigational therapies for HBV infection. Increasing the potential for HBsAg loss may result in more patients achieving functional cure. However, many knowledge gaps remain such as pharmacokinetics in those with HBV, cirrhosis and renal impairment but also the interaction potential between investigational therapies, risk-benefit profiles, and potential for drug interactions with medications used to treat comorbidities associated with aging.

Variable adherence to antiretroviral therapy (ART) can maintain HIV viral suppression, but our understanding of the ART adherence continuum remains limited. In a clinical cohort of adult persons living with HIV treated with a tenofovir (TFV) disoproxil fumarate/emtricitabine (TDF/FTC)-based regimen, data on 3-month self-reported adherence and dried blood spots (DBS) for TFV diphosphate (TFV-DP) and FTC triphosphate (FTC-TP) were collected. Among 521 participants in whom DBS were available upon enrollment, 333 were virologically suppressed (

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.

Background Historically, acute hepatitis C virus (HCV) infection was treated with shorter durations of interferon-containing therapies. In the era of direct-acting antivirals (DAAs), it is unclear whether the efficacy of treatment achieved in chronic infection can be maintained with abbreviated courses of therapy during the acute phase. Methods The sofosbuvir-containing regimens without interferon for treatment of acute HCV in HIV-1 infected individuals (SWIFT-C) is an open-label, 2-cohort clinical trial in which the first cohort assessed for the safety and efficacy of 12 weeks of sofosbuvir plus ribavirin for the treatment of acute HCV infection in participants with chronic human immunodeficiency virus type 1 (HIV-1) infection. This is a preplanned analysis of the first cohort, which had a planned accrual of 17 participants. Results Seventeen men (11 Hispanic, 6 white, median age 45 years) were enrolled. Most (88%) had HCV genotype-1 infection and few (24%) had the favorable IL28B CC genotype. Median baseline HCV RNA was 2 280 000 IU/mL (interquartile range, 272 000-4 230 000). Ten participants (59%) achieved the primary outcome of SVR12 (90% confidence interval, 36%-78%), failing to establish noninferiority. All treatment failures were due to viral relapse (41%). There were no premature treatment discontinuations. The only factor that differed between participants who achieved SVR vs those who relapsed was ribavirin concentration at the end of treatment. Conclusion Sofosbuvir-ribavirin for 12 weeks for the treatment of acute HCV genotype-1 infection in HIV-1-infected persons results in a high relapse rate. Preliminary studies of DAA combination therapies suggest improved response rates, although the adequate duration of therapy remains unclear. Clinical trials registration NCT02128217.

The pharmacokinetics (PK) of tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP), the active anabolites of tenofovir disoproxil fumarate (TDF), and emtricitabine (FTC) in blood, genital, and rectal compartments was determined in HIV-positive and seronegative adults who undertook a 60-day intensive PK study of daily TDF/FTC (plus efavirenz in HIV positives). Lymphocyte cell sorting, genital, and rectal sampling occurred once per subject, at staggered visits. Among 19 HIV-positive (3 female) and 21 seronegative (10 female) adults, TFV-DP in peripheral blood mononuclear cells (PBMC) accumulated 8.6-fold [95% confidence interval (CI): 7.2–10] from first-dose to steady-state concentration (Css) versus 1.7-fold (95% CI: 1.5–1.9) for FTC-TP. Css was reached in ∼11 and 3 days, respectively. Css values were similar between HIV-negative and HIV-positive individuals. Css TFV-DP in rectal mononuclear cells (1,450 fmol/106 cells, 898–2,340) was achieved in 5 days and was >10 times higher than PBMC (95 fmol/106 cells, 85–106), seminal cells (22 fmol/106 cells, 6–79), and cervical cells (111 fmol/106 cells, 64–194). FTC-TP Css was highest in PBMC (5.7 pmol/106 cells, 5.2–6.1) and cervical cells (7 pmol/106 cells, 2–19) versus rectal (0.8 pmol/106 cells, 0.6–1.1) and seminal cells (0.3 pmol/106 cells, 0.2–0.5). Genital drug concentrations on days 1–7 overlapped with estimated Css, but accumulation characteristics were based on limited data. TFV-DP and FTC-TP in cell sorted samples were highest and achieved most rapidly in CD14+ compared with CD4+, CD8+, and CD19+ cells. Together, these findings demonstrate cell-type and tissue-dependent cellular pharmacology, preferential accumulation of TFV-DP in rectal mononuclear cells, and rapid distribution into rectal and genital compartments.

Transporters are important determinants of drug absorption, distribution, and excretion. The clinical relevance of drug transporters in drug disposition and toxicology depends on their localization in liver, kidney, and brain. There has been growing evidence regarding the importance of disease status on alterations in metabolizing enzymes and transporter proteins. This review focuses on uptake and efflux transporter proteins in liver, kidney, and brain and discusses mechanisms of altered transporter expression and function secondary to disease.

Roughly one-third of individuals living with the human immunodeficiency virus (HIV) are coinfected with the hepatitis C virus (HCV) due to shared routes of transmission. HIV accelerates the progression of HCV disease; thus, coinfected individuals are at high priority for HCV treatment. Several new HCV therapies, called direct-acting antiviral agents (DAAs), are available that achieve cure rates of >90% in many patient populations including individuals with HIV. The primary consideration in treating HCV in HIV-infected persons is the potential for drug interactions. We describe the clinical pharmacology and drug interaction potential of the DAAs, review the interaction data with DAAs and antiretroviral agents, and identify the knowledge gaps in the pharmacologic aspects of treating HCV in individuals with HIV coinfection. This review will focus on DAAs that have received regulatory approval in the United States and Europe and agents in late stages of clinical development.

Mental health (MH) disorders are more prevalent among persons living with HIV (PLWH) compared to the general population, and may contribute to suboptimal adherence to antiretroviral therapy (ART). Tenofovir-diphosphate (TFV-DP), the phosphorylated anabolite of tenofovir (TFV), is a biomarker with a 17-day half-life in red blood cells (RBCs). TFV-DP can be measured in dried blood spots (DBS) using liquid chromatography/tandem mass spectrometry (LC-MS/MS) to assess adherence and cumulative drug exposure to tenofovir disoproxil fumarate (TDF)-based ART. From a larger clinical cohort (N=807), TFV-DP concentrations and a paired HIV viral load (VL) were available from 521 participants at their enrollment visit. We used multivariable linear regression to evaluate the association between TFV-DP in DBS and engagement in MH care. After adjusting for clinical covariates, participants with MH disorders who were engaged in MH care had 40% higher TFV-DP compared to participants with MH disorders who were not engaged in MH care (p

Background Untreated, chronic hepatitis C virus (HCV) infection may lead to progressive liver damage, which can be mitigated by successful treatment. This integrated analysis reports the safety, efficacy, and pharmacokinetics (PK) of the ribavirin-free, direct-acting, antiviral, fixed-dose combination of glecaprevir/pibrentasvir (G/P) in patients with chronic HCV genotype 1–6 infections and compensated liver disease, including patients with chronic kidney disease stages 4 or 5 (CKD 4/5). Methods Data from 9 Phase II and III clinical trials, assessing the efficacy and safety of G/P treatment for 8–16 weeks, were included. The presence of cirrhosis was determined at screening using a liver biopsy, transient elastography, or serum biomarkers. The objectives were to evaluate safety, the rate of sustained virologic response at post-treatment week 12 (SVR12), and steady-state PK by cirrhosis status. Results Among 2369 patients, 308 (13%) were Child-Pugh Class A, including 20 with CKD 4/5. Overall, Glecaprevir/pibrentasvir is a safe and efficacious pangenotypic, direct-acting antiviral regimen for hepatitis C virus patients with Child-Pugh A cirrhosis (including with chronic kidney disease stages 4 or 5), despite a ~2-fold increase in glecaprevir exposures in patients with compensated cirrhosis.

BackgroundIntracellular tenofovir diphosphate concentrations are markedly increased in HIV/HCV coinfected individuals receiving tenofovir disoproxil fumarate (TDF) with sofosbuvir-containing treatment. Sofosbuvir may inhibit the hydrolysis of TDF to tenofovir, resulting in increased concentrations of the disoproxil or monoester forms, which may augment cell loading. We sought to quantify tenofovir disoproxil and monoester concentrations in individuals receiving TDF with and without ledipasvir/sofosbuvir.MethodsHIV/HCV coinfected participants receiving TDF-based therapy were sampled pre-dose and 1 and 4 h post-dose prior to and 4 weeks after initiating ledipasvir/sofosbuvir. Tenofovir disoproxil was not detectable. Tenofovir monoester in plasma and tenofovir diphosphate in PBMC and dried blood spots (DBS) were quantified using LC-MS/MS. Geometric mean ratios (week 4 versus baseline) and 95% CIs were generated for the pharmacokinetic parameters. P values reflect paired t-tests.ResultsTen participants had complete data. At baseline, geometric mean (95% CI) tenofovir monoester plasma concentrations at 1 and 4 h post-dose were 97.4 ng/mL (33.0–287.5) and 0.74 ng/mL (0.27–2.06), respectively. With ledipasvir/sofosbuvir, tenofovir monoester concentrations at 4 h post-dose were 5.02-fold higher (95% CI 1.40–18.05; P = 0.019), but did not significantly differ at 1 h post-dose (1.72-fold higher, 95% CI 0.25–11.78; P = 0.54), possibly due to absorption variability. Tenofovir diphosphate in PBMC and DBS were increased 2.80-fold (95% CI 1.71–4.57; P = 0.001) and 7.31-fold (95% CI 4.47–11.95; P ConclusionsTenofovir monoester concentrations were increased in individuals receiving TDF with ledipasvir/sofosbuvir, consistent with inhibition of TDF hydrolysis. Additional studies are needed to determine the clinical relevance of this interaction.

Background Tenofovir monoester is a relatively lipophilic intermediate formed during the hydrolysis of tenofovir disoproxil to tenofovir. Its clinical pharmacokinetic profile and influence on the cellular pharmacology of tenofovir diphosphate have not been reported. Methods Plasma, PBMC and dried blood spots (DBS) were obtained from HIV-uninfected adults participating in a randomized, cross-over bioequivalence study of single-dose tenofovir disoproxil fumarate (TDF)/emtricitabine unencapsulated or encapsulated with a Proteus® ingestible sensor. Plasma pharmacokinetics of tenofovir monoester and tenofovir were characterized using non-compartmental methods. Relationships with tenofovir diphosphate in DBS and PBMC were examined using mixed-effects models. Results Samples were available from 24 participants (13 female; 19 white, 3 black, 2 Hispanic). Tenofovir monoester appeared rapidly with a median (range) Tmax of 0.5 h (0.25–2) followed by a rapid monophasic decline with a geometric mean (coefficient of variation) t½ of 26 min (31.0%). Tenofovir monoester Cmax was 131.6 ng/mL (69.8%) and AUC0–4 was 93.3 ng·h/mL (47.9%). The corresponding values for plasma tenofovir were 222.2 ng/mL (37.1%) and 448.1 ng·h/mL (30.0%). Tenofovir monoester AUC0–∞ (but not tenofovir AUC0–∞) was a significant predictor of tenofovir diphosphate in both PBMC (P = 0.015) and DBS (P = 0.005), increasing by 3.8% (95% CI 0.8%–6.8%) and 4.3% (95% CI 1.5%–7.2%), respectively, for every 10 ng·h/mL increase in tenofovir monoester. Conclusions Tenofovir monoester Cmax and AUC0–4 were 59.2% and 20.6% of corresponding plasma tenofovir concentrations. Tenofovir monoester was significantly associated with intracellular tenofovir diphosphate concentrations in PBMC and DBS, whereas tenofovir concentrations were not. Tenofovir monoester likely facilitates cell loading, thereby increasing tenofovir diphosphate exposures in vivo.

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

Sofosbuvir (SOF) is a highly efficacious and well-tolerated uridine nucleotide analog that inhibits the hepatitis C virus (HCV) NS5B polymerase enzyme. SOF is administered as a prodrug, which undergoes intracellular phosphorylation by host enzymes to a monophosphate, diphosphate, and finally a pharmacologically active triphosphate. In order to fully understand the clinical pharmacology of SOF, there is a great need to determine the intracellular phosphate concentrations of the drug. We describe the validation and utilization of a method to characterize SOF's disposition into various in vivo cell types, including hepatocytes, peripheral blood mononuclear cells (PBMC), and red blood cells (RBC). Standard bioanalytical validation criteria were applied to lysed cellular matrices, with a validated linear range of 50 to 50,000 fmol/sample for each phosphate moiety. The assay was utilized to collect the first data demonstrating concentrations of phosphorylated anabolites formed in PBMC, hepatocytes, and RBC in vivo during SOF therapy. Median concentrations in PBMC were 220 (range, 51.5 to 846), 70.2 (range, 25.8 to 275), and 859 (range, 54.5 to 6,756) fmol/10 6 cells in the monophosphate, diphosphate, and triphosphate fractions, respectively. In contrast, RBC triphosphate concentrations were much lower than those of PBMC, as the median concentration was 2.91 (range, 1.14 to 10.4) fmol/10 6 cells. The PBMC triphosphate half-life was estimated at 26 h using noncompartmental approaches, while nonlinear mixed-effect modeling was used to estimate a 69 h half-life for this moiety in RBC. The validated method and the data it generates provide novel insight into the cellular disposition of SOF and its phosphorylated anabolites in vivo .

Ribavirin, a guanosine analog, is a broad-spectrum antiviral agent. Ribavirin has been a fundamental component of the treatment of hepatitis C virus (HCV) infection for decades, but there is a very limited understanding of the clinical pharmacology of this drug. Furthermore, it is associated with a major dose-limiting toxicity, hemolytic anemia. Ribavirin undergoes intracellular phosphorylation by host enzymes to ribavirin monophosphate (RMP), ribavirin diphosphate (RDP), and ribavirin triphosphate (RTP). The intracellular forms have been associated with antiviral and toxic effects in vitro , but the kinetics of these phosphorylated moieties have not been fully elucidated in vivo . We developed a model to characterize the plasma pharmacokinetics of ribavirin and the difference between intracellular phosphorylation kinetics in red cells (nonnucleated) and in peripheral blood mononuclear cells (nucleated). A time-independent two-compartment model with first-order absorption described the plasma data well. The cellular phosphorylation kinetics was described by a one-compartment model for RMP, with the formation rate driven by plasma concentrations and the first-order degradation rate. RDP and RTP rapidly reached equilibrium with RMP. Concomitant telaprevir use, inosine triphosphatase genetics, creatinine clearance, weight, and sex were significant covariates. The terminal ribavirin half-life in plasma and phosphorylated anabolites in cells was approximately 224 h. We found no evidence of time-dependent kinetics. These data provide a foundation for uncovering concentration-effect associations for ribavirin and determining the optimal dose and duration of this drug for use in combination with newer direct-acting HCV agents. (This study has been registered at ClinicalTrials.gov under registration no. NCT01097395.)

The recent epidemic of Zika virus (ZIKV) in the Americas and its association with fetal and neurological complications has shown the need to develop a treatment. Repurposing of drugs that are already FDA approved or in clinical development may shorten drug development timelines in case of emerging viral diseases like ZIKV. Initial studies have shown conflicting results when testing sofosbuvir developed for treatment of infections with another Flaviviridae virus, hepatitis C virus. We hypothesized that the conflicting results could be explained by differences in intracellular processing of the compound. We assessed the antiviral activity of sofosbuvir and mericitabine against ZIKV using Vero, A549, and Huh7 cells and measured the level of the active sofosbuvir metabolite by mass spectrometry. Mericitabine did not show activity, while sofosbuvir inhibited ZIKV with an IC50 of ∼4 μM, but only in Huh7 cells. This correlated with differences in intracellular concentration of the active triphosphate metabolite of sofosbuvir, GS-461203 or 007-TP, which was 11–342 times higher in Huh7 cells compared to Vero and A549 cells. These results show that a careful selection of cell system for repurposing trials of prodrugs is needed for evaluation of antiviral activity. Furthermore, the intracellular levels of 007-TP in tissues and cell types that support ZIKV replication in vivo should be determined to further investigate the potential of sofosbuvir as anti-ZIKV compound.