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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.

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.

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

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.

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.

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.

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.)

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

Objectives. Compare the Plan B levonorgestrel (LNG) area under the concentration- time curve (AUC12) prior to and with efavirenz (EFV).Design. Prospective, open-label, single-arm, equivalence study.Methods. Healthy HIV-negative subjects underwent 12 hr intensive pharmacokinetic (PK) sampling following single dose LNG alone and after 14 days of EFV. Geometric means, Geometric Mean Ratios, and 90% confidence intervals (CI) are reported for PK Parameters.T-tests were utilized. Clinical parameters and liver function tests (LFTs) were assessed.Results. 24 women enrolled and 21 completed the study. With EFV, LNG AUC12was reduced 56% (95% CI: 49%, 62%) from 42.9 to 17.8 ng*hr/mL, and maximum concentration (Cmax⁡) was reduced 41% (95% CI: 33%, 50%) from 8.4 to 4.6 ng/mL. LNG was well tolerated with no grade 3 or 4 treatment-related toxicities.Conclusions. EFV significantly reduced LNG exposures. Higher LNG doses may be required with EFV. These results reinforce the importance of effective contraception in women taking EFV.

A key factor to the successful treatment of HIV is good adherence to antiretroviral therapy (ART). We developed a pharmacist-managed adherence clinic and designed a study to assess the impact of the adherence interventions by measuring the proportion of patients with 95% or greater adherence to ART before and after referral to the program. HIV providers referred patients with adherence problems to a pharmacist-managed adherence clinic. Interventions included scheduled clinic visits with the HIV Clinical Pharmacist and monthly refill reminders from pharmacy staff members over a 6-month period. Those aged 18-75, prescribed an ART regimen for a minimum of 3 months, and who filled their medications exclusively at the clinic pharmacy were eligible for study participation. The Proportion of Days Covered (PDC) served as a surrogate marker of overall adherence. A total of 34 patients were referred to the pharmacy clinic for adherence counseling, of whom 28 enrolled in the study. The proportion of participants with 95% or greater adherence to their ART regimen increased from 7% at baseline to 32% postintervention (p = 0.01). A subanalysis of the PDC revealed an overall increase from a baseline adherence mean of 60% to 81% postintervention (p 0.0001). There was a notable trend toward an increase in the proportion of participants with an undetectable HIV-1 viral load (58-73%, baseline and postintervention, respectively, p = 0.10), but no statistically significant improvement in CD4 cell count. Clinical pharmacy interventions improved overall adherence to ART regimens in these patients with HIV.

Sir, Patients with end-stage liver disease (ESLD) have lower rates of sustained virological response to hepatitis C virus (HCV) treatment compared with those without significant hepatic impairment.1 There may be pathophysiological alterations associated with ESLD, which may alter drug penetration or drug activation in the liver.2 Comparing the concentrations of antiviral drugs in liver versus blood may inform drug selection in ESLD. The objective of this work was to quantify antiviral drugs in liver tissue and the active, phosphorylated forms of nucleos(t)ide analogues (NAs) in hepatocytes obtained from a fresh liver explant and to compare these values with drug concentrations in paired plasma and PBMCs. A 50-year-old male with HIV/HCV coinfection on the liver transplant list was transferred to our hospital with acute kidney injury (serum creatinine 4.11 mg/dL) with a Model for ESLD score of 40. In the year prior to hospitalization, the patient's antiretroviral regimen included 300 mg of tenofovir disoproxil fumarate once daily plus 200 mg of emtricitabine once daily, 800 mg of darunavir once daily, 100 mg of ritonavir once daily and 400 mg of raltegravir twice daily. The patient had an HIV-1 RNA of

OBJECTIVES: This open-label, single-arm, pharmacokinetic (PK) study in HIV-seronegative volunteers evaluated the bioequivalence of rosuvastatin and lopinavir/ritonavir when administered alone and in combination. Tolerability and lipid changes were also assessed. METHODS: Subjects took 20 mg of rosuvastatin alone for 7 days, then lopinavir/ritonavir alone for 10 days, and then the combination for 7 days. Intensive PK sampling was performed on days 7, 17, and 24. RESULTS: Twenty subjects enrolled, and PK data were available for 15 subjects. Geometric mean (+/-SD) rosuvastatin area under the concentration time curve (AUC)[0,tau] and maximum concentration (Cmax) were 47.6 ng.h/mL (+/-15.3) and 4.34 ng/mL (+/-1.8), respectively, when given alone versus 98.8 ng.h/mL (+/-65.5) and 20.2 ng/mL (+/-16.9) when combined with lopinavir/ritonavir (P < 0.0001). The geometric mean ratio was 2.1 (90% confidence interval [CI]: 1.7 to 2.6) for rosuvastatin AUC[0,tau] and 4.7 (90% CI: 3.4 to 6.4) for rosuvastatin Cmax with lopinavir/ritonavir versus rosuvastatin alone (P < 0.0001). There was 1 asymptomatic creatine phosphokinase elevation 17 times the upper limit of normal (ULN) and 1 liver function test elevation between 1.1 and 2.5 times the ULN with the combination. CONCLUSIONS: Rosuvastatin low-density lipoprotein reduction was attenuated with lopinavir/ritonavir. Rosuvastatin AUC and Cmax were unexpectedly increased 2.1- and 4.7-fold in combination with lopinavir/ritonavir. Rosuvastatin and lopinavir/ritonavir should be used with caution until the safety, efficacy, and appropriate dosing of this combination have been demonstrated in larger populations.

Background Nucleos(t)ide reverse transcriptase inhibitors (NRTIs), such as tenofovir, require intracellular phosphorylation for pharmacologic activity. Drug transporters may contribute to the intracellular disposition of NRTIs. Objective We characterized intracellular tenofovir diphosphate (TFV-DP) concentrations in HIV-infected patients (n = 30), and investigated associations between TFV-DP concentrations and polymorphisms in the drug transporter genes SLC22A6, ABCC2, and ABCC4. Methods Subjects were genotyped for 6 single-nucleotide polymorphisms: 2 in SLC22A6 (encodes influx transporter, human organic anion transporter 1), 728G>A and 453G>A; 2 in ABCC2 (encodes efflux transporter, multidrug resistance protein [MRP] 2), -24C>T and 1249G>A; and 2 in ABCC4 (encodes efflux transporter, MRP4), 3463A>G and 4131T>G. Results The mean TFV-DP was 76.1 fmol/10(6) cells (range: 16.3 to 212 fmol/10(6) cells). Tenofovir apparent oral and renal clearances were significantly predictive of intracellular TFV-DP concentrations. For every 1-L/h decrease in tenofovir renal clearance, there was, on average, an 8% increase in TFV-DP (P = 0.002). We identified a novel relation between ABCC4 3463A>G genotype and TFV-DP. ABCC4 3463G variants had TFV-DP concentrations 35% higher (29 fmol/10(6) cells) than wild type (P = 0.04). Conclusion This study provides direction for future investigations to elucidate the contribution of clinical characteristics and drug transporter genotype to TFV-DP safety and efficacy.

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.

Therapeutic drug monitoring (TDM) is the process by which a patient's dosing regimen is guided by repeated measures of plasma drug concentrations. An enormous challenge with regard to TDM of antiretroviral drugs (ARV) is that the concentration goals can be moving targets. Well-designed prospective studies demonstrating that prospectively altering ARV doses based on TDM leads to virologic success and increased tolerability are needed. Nevertheless, there are specific clinical instances where this experimental intervention should be considered to potentially reduce toxicity and improve therapeutic outcomes.

Importance Adolescents 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. Objective To 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 Participants Adolescent 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. Exposures All participants completed an individualized evidence-based behavioral intervention and were provided with daily TDF/FTC as PrEP for 48 weeks. Main Outcomes and Measures The 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. Results Among 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 Relevance Adolescent 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 Registration clinicaltrials.gov Identifier:NCT01769456

Atazanavir (ATV) is an attractive option for the treatment of Pediatric HIV infection, based on once-daily dosing and the availability of a formulation appropriate for younger children. Pediatric AIDS Clinical Trials Group 1020A was a phase I/II open label study of ATV (with/without ritonavir [RTV] boosting)-based treatment of HIV-infected children; here we report the long-term safety and virologic and immunologic responses.Antiretroviral-naïve and experienced children, ages 91 days to 21 years, with baseline plasma HIV RNA5000 copies/mL (cpm) were enrolled at sites in the United States and South Africa.Of 195 children enrolled, 142 (73%) subjects received ATV-based regimens at the final protocol recommended dose; 58% were treatment naive. Overall, at week 24, 84/139 subjects (60.4%) and at week 48, 83/142 (58.5%) had HIV RNA ≤ 400 cpm. At week 48, 69.5% of naïve and 43.3% of experienced subjects had HIV RNA ≤ 400 cpm; median CD4 increase was 196.5 cells/mm. The primary adverse event (AE) was increased serum bilirubin; 9% of subjects had levels ≥ 5.1 times upper limit of normal (ULN) and 1.4% noted jaundice. Three percent of subjects experienced grade 2 or 3 prolongation in PR or QTc intervals. At week 48, there was a 15% increase in total cholesterol (TC), with TC199 mg/dL increasing from 1% at baseline to 5.7%.Use of once-daily ATV, with/without RTV, was safe and well tolerated in children, with acceptable levels of viral suppression and CD4 count increase. The primary AE, as expected, was an increase in bilirubin levels.

Approximately 7% of an atazanavir (Reyataz; Bristol–Myers Squibb, Princeton, New Jersey, USA) dose is excreted as unchanged drug in the urine and the solubility of atazanavir increases with acidity [1]. These properties are similar to those of indinavir, which is more soluble in acid solutions and o

Background Tenofovir (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. Methods A 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. Results At 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). Conclusions These 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. 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.

Objective: The primary aim of this study was to determine the bioequivalence of boceprevir, an HCV protease inhibitor and etravirine, an HIV non–nucleoside reverse transcriptase inhibitor; area under the concentration time curve (AUC0,t); maximum concentration (Cmax); and trough concentration (C8 or Cmin) when administered in combination versus alone. Design: Open-label crossover study in healthy volunteers. Methods: Boceprevir, etravirine, and the combination were administered for 11–14 days with intensive sampling between days 11 and 14 of each sequence. Boceprevir and etravirine were quantified using validated liquid chromatography coupled with tandem mass spectrometry and high-performance liquid chromatography/ultraviolet assays, respectively and pharmacokinetics determined using noncompartmental methods. Geometric mean ratios (GMRs) and 90% confidence interval (CI) for the combination versus each drug alone were evaluated using 2 one-sided t tests. The hypothesis of equivalence was rejected if 90% GMR CI was not contained in the interval (0.8–1.25). Results: Twenty subjects completed study. GMRs (90% CI) for etravirine AUCo,t ,C max ,a nd Cmin were 0.77 (0.66 to 0.91), 0.76 (0.68 to 0.85), and 0.71 (0.54 to 0.95), respectively, in combination versus alone. Boceprevir GMRs (90% CI) for AUCo,t ,C max ,a nd C8 were 1.10 (0.94 to 1.28), 1.10 (0.94 to 1.29), and 0.88 (0.66 to 1.17), respectively, in combination versus alone. All adverse events (n = 112) were mild or moderate. Six subjects discontinued: 4 due to rash, 1 due to central nervous system effects, and 1 for a presumed viral illness. Conclusions: Etravirine AUCo,t ,C max ,a nd Cmin decreased 23%, 24%, and 29%, respectively, with boceprevir. Boceprevir AUC0,t and Cmax increased 10% and C8 decreased 12% by etravirine. Additional research is needed to elucidate the mechanism(s) and therapeutic implications of the observed interaction.