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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

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.

Pre-exposure prophylaxis (PrEP) containing antiretrovirals tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) can reduce the risk of acquiring HIV. Concentrations of intracellular tenofovir-diphosphate (TFV-DP) measured in dried blood spots (DBS) have been used to quantify PrEP adherence; although even under directly observed dosing, unexplained between-subject variation remains. Here, we wish to identify patient-specific factors associated with TFV-DP levels. Data from the iPrEX Open Label Extension (OLE) study were used to compare multiple covariate selection methods for determining demographic and clinical covariates most important for drug concentration estimation. To allow for the possibility of non-linear relationships between drug concentration and explanatory variables, the component selection and smoothing operator (COSSO) was implemented. We compared COSSO to LASSO, a commonly used machine learning approach, and traditional forward and backward selection. Training (N = 387) and test (N = 166) datasets were utilized to compare prediction accuracy across methods. LASSO and COSSO had the best predictive ability for the test data. Both predicted increased drug concentration with increases in age and self-reported adherence, the latter with a steeper trajectory among Asians. TFV-DP reductions were associated with increasing eGFR, hemoglobin and transgender status. COSSO also predicted lower TFV-DP with increasing weight and South American countries. COSSO identified non-linear relationships between log(TFV-DP) and adherence, weight and eGFR, with differing trajectories for some races. COSSO identified non-linear log(TFV-DP) trajectories with a subset of covariates, which may better explain variation and enhance prediction. Future research is needed to examine differences identified in trajectories by race and country.

IntroductionEvent-driven pre-exposure prophylaxis (edPrEP) with oral tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) is highly effective for preventing HIV acquisition in men who have sex with men (MSM) and is preferred over daily PrEP by some MSM. However, it is largely unknown how well MSM adhere to edPrEP. We then aimed to assess PrEP protection during CAS among MSM using edPrEP and participating in the Amsterdam PrEP demonstration project (AMPrEP).MethodsWe analysed data from participants enrolled in AMPrEP who were taking edPrEP. We measured adherence through (1) a mobile application in which sexual behaviour and PrEP-use were recorded daily, (2) three-monthly self-completed questionnaires and (3) dried blood spot (DBS) samples collected around six, twelve and twenty-four months after PrEP initiation. We assessed the proportion of days with condomless anal sex (CAS) acts that were protected by PrEP, per partner type (i.e. steady partners, known casual partners, unknown casual partners), and the proportion of three-month periods during which PrEP was correctly used. Intracellular TFV-diphosphate (TFV-DP) concentrations were determined from DBS. Good adherence was defined as at least one tablet before and one tablet within 48 hours after a CAS act.ResultsBetween 11 September 2015 and 6 October 2019, 182 of 376 MSM (48.4%) used edPrEP for at least one three-month period. Of the 8224 CAS days that were reported in the app during edPrEP-use, we observed good protection for most CAS days involving steady partners (n = 1625/2455, 66.9%), known casual partners (n = 3216/3472, 92.6%) and unknown casual partners (n = 2074/2297, 90.3%). Men reported consistently correct PrEP-use in 851 (81.4%) of the 1046 three-month periods of edPrEP-use. The median TFV-DP concentration was 591 fmol/sample (interquartile range = 270 to 896).ConclusionsAdherence to edPrEP was high as determined from the online app and questionnaire. DBS measurements were consistent with two to three tablets per week on average.

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

Background Adherence is critical to achieve the benefits of antiretroviral therapy. A smart-pill bottle service that transmits real-time adherence data via cellular networks to a central service and prompts nonadherent patients with phone or text messages may improve adherence. Methods Adults with HIV taking a tenofovir-containing regimen with suboptimal adherence were randomized to adherence counseling ± a smart-pill bottle service for 12 weeks. Tenofovir diphosphate (TFV-DP) levels by dried blood spot, HIV RNA levels, CD4 cell counts, and self-reported adherence were collected. Results Sixty-three participants (22% women; 48% black, 25% Latino) were randomized: 30 to the smart-pill bottle (2 of whom were lost to follow-up before the baseline visit), and 33 to control arms. At baseline, 49% of participants had HIV RNA ≤20 copies/mL and 61% reported 100% adherence with ART over 4 days. From baseline to week 12, median TFV-DP levels were +252 and -41 fmol/punch in the bottle and control arms, respectively (P = 0.10). Exploratory exclusion of 3 participants with known or suspected drug-drug interactions found median TFV-DP levels of +278 and -38 fmol/punch, respectively (P = 0.04). There were no differences in study discontinuations, HIV RNA suppression, CD4 cell counts, or self-reported adherence at week 12. Conclusions In a diverse group of participants with suboptimal adherence to ART, the smart-pill bottle service was associated with higher TFV-DP levels.

Background Intracellular tenofovir diphosphate (TFV-DP) concentration in dried blood spots (DBSs) is used to monitor cumulative pre-exposure prophylaxis (PrEP) adherence. We evaluated TFV-DP in DBSs following daily oral PrEP (emtricitabine 200 mg/tenofovir diphosphate 300 mg) among pregnant and postpartum adolescent girls and young women (AGYW). Methods Directly observed PrEP was administered for 12 weeks in a pregnancy (14–24 weeks’ gestation, n = 20) and postpartum (6–12 weeks postpartum, n = 20) group of AGYW aged 16–24 years in sub-Saharan Africa. Weekly DBS TFV-DP was measured by validated liquid chromatography–tandem mass spectrometry assay. Week 12 TFV-DP distributions were compared between groups with Wilcoxon test. Population pharmacokinetic models were fit to estimate steady-state concentrations and create benchmarks for adherence categories. Baseline correlates of TFV-DP were evaluated. Results Median age was 20 (IQR, 19–22) years. Of 3360 doses, 3352 (>99%) were directly observed. TFV-DP median (IQR) half-life was 10 (7–12) days in pregnancy and 17 (14–21) days postpartum, with steady state achieved by 5 and 8 weeks, respectively. Observed median (IQR) steady-state TFV-DP was 965 fmol/punch (691–1166) in pregnancy versus 1406 fmol/punch (1053–1859) postpartum (P = .006). Modeled median steady-state TFV-DP was 881 fmol/punch (667–1105) in pregnancy versus 1438 fmol/punch (1178–1919) postpartum. In pooled analysis, baseline creatinine clearance was associated with observed TFV-DP concentrations. Conclusions TFV-DP in African AGYW was approximately one-third lower in pregnancy than postpartum. These Population-specific benchmarks can be used to guide PrEP adherence support in pregnant/postpartum African women. Clinical Trials Registration NCT03386578, Concentrations of tenofovir diphosphate in dried blood spots were approximately one-third lower during pregnancy than postpartum after 12 weeks of directly observed dosing among African adolescent girls and young women on daily pre-exposure prophylaxis. We recommend population-specific benchmarks for adherence support.

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.

Summary Background Tenofovir alafenamide shows high antiviral efficacy and improved renal and bone safety compared with tenofovir disoproxil fumarate when used for HIV treatment. Here, we report primary results from a blinded phase 3 study evaluating the efficacy and safety of pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir alafenamide versus emtricitabine and tenofovir disoproxil fumarate for HIV prevention. Methods This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in regions of Europe and North America, where there is a high incidence of HIV or prevalence of people living with HIV, or both. We enrolled adult cisgender men who have sex with men and transgender women who have sex with men, both with a high risk of acquiring HIV on the basis of their self-reported sexual behaviour in the past 12 weeks or their recent history (within 24 weeks of enrolment) of bacterial sexually transmitted infections. Participants with current or previous use of PrEP with emtricitabine and tenofovir disoproxil fumarate were not excluded. We used a computer-generated random allocation sequence to randomly assign (1:1) participants to receive either emtricitabine (200 mg) and tenofovir alafenamide (25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine (200 mg) and tenofovir disoproxil fumarate (300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). As such, all participants were given two tablets. The trial sponsor, investigators, participants, and the study staff who provided the study drugs, assessed the outcomes, and collected the data were masked to group assignment. The primary efficacy outcome was incident HIV infection, which was assessed when all participants had completed 48 weeks of follow-up and half of all participants had completed 96 weeks of follow-up. This full analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug and had at least one post-baseline HIV test. Non-inferiority of emtricitabine and tenofovir alafenamide to emtricitabine and tenofovir disoproxil fumarate was established if the upper bound of the 95·003% CI of the HIV incidence rate ratio (IRR) was less than the prespecified non-inferiority margin of 1·62. We prespecified six secondary bone mineral density and renal biomarker safety endpoints to evaluate using the safety analysis set. This analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug. This trial is registered with ClinicalTrials.gov , NCT02842086 , and is no longer recruiting. Findings Between Sept 13, 2016, and June 30, 2017, 5387 (92%) of 5857 participants were randomly assigned and received emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693). At the time of the primary efficacy analysis (ie, when all participants had completed 48 weeks and 50% had completed 96 weeks) emtricitabine and tenofovir alafenamide was non-inferior to emtricitabine and tenofovir disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the IRR, was less than the prespecified non-inferiority margin of 1·62 (IRR 0·47 [95% CI 0·19–1·15]). After 8756 person-years of follow-up, 22 participants were diagnosed with HIV, seven participants in the emtricitabine and tenofovir alafenamide group (0·16 infections per 100 person-years [95% CI 0·06–0·33]), and 15 participants in the emtricitabine and tenofovir disoproxil fumarate group (0·34 infections per 100 person-years [0·19–0·56]). Both regimens were well tolerated, with a low number of participants reporting adverse events that led to discontinuation of the study drug (36 [1%] of 2694 participants in the emtricitabine and tenofovir alafenamide group vs 49 [2%] of 2693 participants in the emtricitabine and tenofovir disoproxil fumarate group). Emtricitabine and tenofovir alafenamide was superior to emtricitabine and tenofovir disoproxil fumarate in all six prespecified bone mineral density and renal biomarker safety endpoints. Interpretation Daily emtricitabine and tenofovir alafenamide shows non-inferior efficacy to daily emtricitabine and tenofovir disoproxil fumarate for HIV prevention, and the number of adverse events for both regimens was low. Emtricitabine and tenofovir alafenamide had more favourable effects on bone mineral density and biomarkers of renal safety than emtricitabine and tenofovir disoproxil fumarate. Funding Gilead Sciences.

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

PURPOSE OF REVIEW: Traditional methods to assess antiretroviral adherence, such as self-report, pill counts, and pharmacy refill data, may be inaccurate in determining actual pill-taking to both antiretroviral therapy (ART) or pre-exposure prophylaxis (PrEP). HIV viral loads serve as surrogates of adherence on ART, but loss of virologic control may occur well after decreases in adherence and viral loads are not relevant to PrEP RECENT FINDINGS: Pharmacologic measures of adherence, electronic adherence monitors, and ingestible electronic pills all serve as more objective metrics of adherence, surpassing self-report in predicting outcomes. Pharmacologic metrics can identify either recent adherence or cumulative adherence. Recent dosing measures include antiretroviral levels in plasma or urine, as well as emtricitabine-triphosphate in dried blood spots (DBS) for those on tenofovir-emtricitabine-based therapy, A urine tenofovir test has recently been developed into a point-of-care test for bedside adherence monitoring. Cumulative adherence metrics assess adherence over weeks to months and include measurement of tenofovir-diphosphate in peripheral blood mononuclear cells or DBS, as well as ART levels in hair. Electronic adherence monitors and ingestible electronic pills can track pill bottle openings or medication ingestion, respectively. SUMMARY: New and objective approaches in adherence monitoring can be used to detect nonadherence prior to loss of prevention efficacy or virologic control with PrEP or ART, respectively.

Transgender persons are at increased risk of HIV infection and would benefit from pre-exposure prophylaxis (PrEP) use. However, barriers to healthcare and a lack of data regarding PrEP efficacy among transgender persons limits use. A related issue is whether a drug-drug interaction (DDI) exists between gender affirming hormone therapy (GAHT) and PrEP. Recently, small pharmacokinetic studies were conducted to assess this interaction.This review will assess the pharmacology of PrEP agents, existing data regarding potential DDIs between GAHT and PrEP, and hypothetical mechanisms for these DDIs. A summary will be provided on implications for PrEP use among transgender persons.Theoretically, DDIs are not expected between GAHT and PrEP. However, among transgender women (TGW) on GAHT, small studies identified a minor DDI between GAHT and tenofovir/emtricitabine (TFV/FTC), with TFV/FTC exposures ~12-27% lower among TGW vs. cisgender men. The mechanism of DDIs is unclear and requires further study. For perspective, median TFV/FTC concentrations were still within the range of median concentrations reported across controlled pharmacokinetic studies. TFV-disphosphate/FTC-triphosphate concentrations were similar between TGW and cisgender men. In summary, TDF/FTC likely reaches protective concentrations and should continue to be offered as PrEP for transgender persons.

Inadequate adherence to chronic medications is a far-reaching problem with financial and human health consequences. By a wide margin, non-adherence is the leading cause of therapeutic failures of HIV pre-exposure chemoprophylaxis (PrEP) and antiretroviral therapy (ART). It has been proven that HIV infection can be prevented by daily dosing of emtricitabine and tenofovir disoproxil fumarate. Measurement of intracellular tenofovir diphosphate in red blood cells has been established as an effective way to assess cumulative adherence, however, the LC-MS-based analytical method developed for the purpose is both complicated and expensive. Here, we report a simple method for adherence monitoring based on direct MS quantification of intracellular tenofovir diphosphate in human whole blood. The method requires only microliters of whole blood, employs special membranes to perform plasma separation and concomitant desalting during blood collection, and uses nanoelectrospray on a triple quadrupole instrument. Quantitative performance in this proof-of-concept study includes RSDs of

Background Sex hormone and preexposure prophylaxis (PrEP) drug interactions among transgender women (TGW), transgender men (TGM), and cisgender men (CGM) are not fully understood. Methods TGM and TGW on at least 6 months of stable sex hormone therapy containing testosterone or estradiol (respectively) were enrolled in a 4-week study of directly observed dosing of daily oral coformulated emtricitabine and tenofovir disoproxil fumarate (FTC/TDF). TFV-DP in dried blood spots and sex hormones in serum were measured at weekly intervals. TFV-DP was compared with 2- and 4-week samples from Directly Observed Therapy Dried Blood Spots (DOT-DBS) Study (NCT02022657). Results From May 2017 to June 2018, 24 TGM and 24 TGW were enrolled. Testosterone (total and free) and estradiol concentrations were comparable before and after 4 weeks of PrEP use in TGM and TGW, respectively. Historical controls included 17 cisgender women (CGW) and 15 CGM. TFV-DP concentrations at week 4 were comparable between TGW and TGM (mean difference, −6%; 95% confidence interval [CI], −21% to 12%; P = .47), comparable between TGW and CGM (mean difference, −12%; 95% CI, −27% to 7%; P = .21) and were lower among TGM compared with CGW (mean difference, −23%; 95% CI, −36% to −7%; P = .007). All persons in all groups were projected to reach the TFV-DP threshold that has been associated with high protection from human immunodeficiency virus. Conclusions CGM, TGM, and TGW had comparable TFV-DP concentrations in dried blood spots after 4 weeks of directly observed daily FTC/TDF PrEP use. Serum hormone concentrations were not affected by FTC/TDF PrEP use. Clinical Trials Registration NCT04050371.

Background Daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) is effective for reducing human immunodeficiency virus (HIV) acquisition among cisgender women. We report results from the first US observational open-label demonstration project of pre-exposure prophylaxis (PrEP) among at-risk cisgender women. Methods Adherence Enhancement Guided by Individualized Texting and Drug Levels was a 48-week, single-arm, open-label demonstration study of daily oral TDF/FTC in cisgender women ≥18 years old at risk for HIV. Adherence was supported using 2-way text messaging and titrated adherence counseling based on rapid-turnaround tenofovir diphosphate concentrations from dried blood spots. Study visits occurred at baseline, weeks 4 and 12, and quarterly through week 48. Outcomes included TDF/FTC adherence, retention, and persistence. Results From June 2016 to October 2018, 136 cisgender women enrolled (mean age, 40 years (standard deviation, 11); 38% non-Hispanic Black and 19% Latina). At 48 weeks, 84 (62%) participants were retained and 62 (46%) remained on PrEP. More than one-third (12/31) of those on study but off PrEP throughout the study discontinued TDF/FTC because of side effects, and 1 adverse event led to study discontinuation. Of 120 participants with drug concentrations measured, 67 (56%) had at least 1 concentration consistent with 6 doses/week; 22 (18%) had consistent ≥6 doses/week across all study visits attended. There were no incident HIV infections and 4 incident bacterial sexually transmitted infections. Conclusion Adequate PrEP adherence for protective drug concentrations was not achieved for most study participants. More work needs to be done to fully explicate the reasons for nonadherence and low retention in cisgender women.

Objective: Improving adherence to preexposure prophylaxis (PrEP) by providing automated feedback on self-reported PrEP use via a mobile application (app).Design: Randomized clinical trial among MSM participating in the Amsterdam PrEP demonstration project (AMPrEP).Methods: Eligible participants were randomized 1 : 1 to the control or intervention app. Both allowed daily reporting of sexual behaviour and medication intake; the intervention app also provided visual feedback. Dried blood spots collected at 12 and 24 months yielded intracellular tenofovir diphosphate concentrations (TFV-DP). We assessed proportions of participants with poor (TFV-DP Results: We randomized 229 participants, 118 to the intervention and 111 to the control arm. The primary, per-protocol, analysis included 83 participants per arm. In total, 22/166 (13%) of participants adhered poorly, 144/166 (87%) good and 66/166 (40%) excellently. App feedback did not result in a lower proportion of participants with poor adherence [control: 9 of 83 (11%); intervention: 13 of 83 (16%); P = 0.36]. App feedback did result in a larger proportion of participants with excellent adherence [control: 26/83 (31%); intervention: 40/83 (48%); P = 0.026].Conclusion: In this highly adherent population, app feedback did not improve the proportion of participants with poor adherence to PrEP.

Background Tenofovir diphosphate (TFV-DP) concentration in dried blood spots (DBSs) is a reliable pharmacokinetics biomarker of adherence to tenofovir disoproxil fumarate (TDF). We aimed to use DBSs to estimate pill intake among participants using on-demand pre-exposure prophylaxis (PrEP) and to identify predictive factors associated with higher TFV-DP concentrations. Methods DBSs were collected at the last study visit of the open-label phase of the ANRS IPERGAY study, assessing on-demand oral TDF/emtricitabine for PrEP among MSM and transgender female participants. We quantified TFV-DP in DBSs centrally. We assessed correlation between pill count and TFV-DP concentration by Spearman correlation and explored associations between participant demographics, sexual behaviour and PrEP use during sexual intercourse (SI) with TFV-DP concentrations by univariate and multivariate logistic regression models. Results The median age of the 245 participants included in this study was 40 years, with a median body weight of 73 kg. Median (IQR) TFV-DP concentration reached 517 (128–868) fmol/punch, corresponding to an estimated intake of 8–12 tablets per month (2–3 doses per week). Only 39% of participants had a TFV-DP concentration above 700 fmol/punch. TFV-DP concentrations were moderately correlated with pill count (r: 0.59; P This is a pre-copyedited, author-produced PDF of an article accepted for publication in Journal of Antimicrobial Chemotherapy following peer review. The version of record [Estimated pill intake with on-demand PrEP with oral TDF/FTC using TFV-DP concentration in dried blood spots in the ANRS IPERGAY trial. Journal of Antimicrobial Chemotherapy (2021)] is available online at: https://doi.org/10.1093/jac/dkab253. Deposited by shareyourpaper.org and openaccessbutton.org. We've taken reasonable steps to ensure this content doesn't violate copyright. However, if you think it does you can request a takedown by emailing help@openaccessbutton.org.

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

IntroductionHIV transmission within serodifferent heterosexual couples plays a key role in sustaining the global HIV pandemic. In the USA, transmission within established mixed-status couples accounts for up to half of all new HIV infections among heterosexuals. Oral HIV pre-exposure prophylaxis (PrEP) is a highly effective prevention method, although underutilised among serodifferent couples. Moreover, there is a dearth of research on US HIV-serodifferent couples’ perspectives and use of PrEP, alone or in combination with other prevention methods. In this paper, we describe the study protocol for the Magnetic Couples Study, designed to fill critical knowledge gaps regarding HIV-serodifferent heterosexual couples’ perspectives, experiences and utilisation of PrEP.Methods and analysisThe Magnetic Couples Study is a mixed methods prospective cohort study designed to describe temporal patterns and identify determinants at multiple levels (individual, couple, HCF) of PrEP outcomes along the care continuum (PrEP awareness, linkage, uptake, retention and medication adherence) among HIV-serodifferent heterosexual couples residing in New York City. The study will also examine clinical management of PrEP, side effects and changes in sexual-related and substance use–related behaviour. A prospective cohort of 230 mixed-status couples already on oral PrEP was recruited, with quarterly assessments over 18 months; in addition, a cross-sectional sample of 150 mixed-status couples not currently on PrEP was recruited. In-depth semistructured qualitative interviews were conducted with a subsample of 25 couples. Actor-partner interdependence modelling using multilevel analysis will be employed for the analysis of longitudinal dyadic data. Framework analysis will be used to analyse qualitative data. A parallel convergent design will be used for mixed methods integration.Ethics and disseminationThe study was approved by the University of Rochester Institutional Review Board (RSRB00052766). Study findings will be disseminated to community members and providers and to researchers and policy makers.

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 Pre-exposure prophylaxis (PrEP) is highly effective and an important prevention tool for African adolescent girls and young women (AGYW), but adherence and persistence are challenging. PrEP adherence support strategies for African AGYW were studied in an implementation study. Methods and findings HIV Prevention Trials Network (HPTN) 082 was conducted in Cape Town, Johannesburg (South Africa) and Harare (Zimbabwe) from October 2016 to October 2018 to evaluate PrEP uptake, persistence, and the effect of drug level feedback on adherence. Sexually active HIV–negative women ages 16–25 were offered PrEP and followed for 12 months; women who accepted PrEP were randomized to standard adherence support (counseling, 2-way SMS, and adherence clubs) or enhanced adherence support with adherence feedback from intracellular tenofovir-diphosphate (TFV-DP) levels in dried blood spots (DBS). PrEP uptake, persistence through 12 months (no PrEP hold or missed visits), and adherence were assessed. The primary outcome was high adherence (TFV-DP ≥700 fmol/punch) at 6 months, compared by study arm. Of 451 women enrolled, median age was 21 years, and 39% had curable sexually transmitted infections (STIs). Most (95%) started PrEP, of whom 55% had uninterrupted PrEP refills through 12 months. Of those with DBS, 84% had detectable TFV-DP levels at month 3, 57% at month 6, and 31% at month 12. At 6 months, 36/179 (21%) of AGYW in the enhanced arm had high adherence and 40/184 (22%) in the standard adherence support arm (adjusted odds ratio [OR] of 0.92; 95% confidence interval [CI] 0.55, 1.34; p = 0.76). Four women acquired HIV (incidence 1.0/100 person-years), with low or undetectable TFV-DP levels at or prior to seroconversion, and none of whom had tenofovir or emtricitabine resistance mutations. The study had limited power to detect a modest effect of drug level feedback on adherence, and there was limited awareness of PrEP at the time the study was conducted. Conclusions In this study, PrEP initiation was high, over half of study participants persisted with PrEP through month 12, and the majority of young African women had detectable TFV-DP levels through month 6 with one-fifth having high adherence. Drug level feedback in the first 3 months of PrEP use did not increase the proportion with high adherence at month 6. HIV incidence was 1% in this cohort with 39% prevalence of curable STIs and moderate PrEP adherence. Strategies to support PrEP use and less adherence-dependent formulations are needed for this population. Trial registration ClinicalTrials.gov NCT02732730., Connie Celum and co-workers report on use of pre-exposure prophylaxis by young women in Southern Africa., Author summary Why was this study done? HIV incidence remains high (4%) in young African women. Pre-exposure prophylaxis (PrEP) has over 90% efficacy in preventing HIV infection when used consistently and could reduce HIV incidence in young African women. Adherence was low in placebo-controlled efficacy trials of oral PrEP among young African women. Qualitative research among a subset of women at unblinding of the efficacy trials indicated that women thought drug level feedback would support their adherence and foster open discussions with counselors about adherence. Drug level feedback should be evaluated as a strategy to increase PrEP adherence among young African women. What did the researchers do and find? A cohort of 451 young women in South Africa and Zimbabwe who were at risk for HIV were recruited and offered PrEP, among whom 95% initiated PrEP. Half were randomized to receive drug level feedback at months 2 and 3 plus the standard adherence support package (2-way SMS, brief counseling, and optional PrEP adherence clubs), and half received the standard adherence support package without drug level feedback. The majority had detectable intracellular drug levels through the first 6 months, and 21% had high adherence at month 6, defined as intracellular tenofovir-diphosphate (TFV-DP) ≥700 fmol/punch. PrEP adherence did not differ based on whether they were randomized to receive drug level feedback at months 2 and 3 or to standard of care (SOC) PrEP adherence support without drug level feedback. What do these findings mean? Drug level feedback was not associated with improved PrEP adherence among young African women. Additional strategies need to be evaluated for their effectiveness in increasing adherence with oral PrEP for young African women. Longer-acting and less user-dependent PrEP formulations may also overcome adherence challenges with daily oral PrEP.

Pre-exposure prophylaxis (PrEP) using antiretroviral oral drugs is effective at preventing HIV transmission when individuals adhere to the dosing regimen. Tenofovir alafenamide (TAF) is a potent antiretroviral drug, with numerous long-acting (LA) delivery systems under development to improve PrEP adherence. However, none has undergone preventive efficacy assessment. Here we show that LA TAF using a novel subcutaneous nanofluidic implant (nTAF) confers partial protection from HIV transmission. We demonstrate that sustained subcutaneous delivery through nTAF in rhesus macaques maintained tenofovir diphosphate concentration at a median of 390.00 fmol/106 peripheral blood mononuclear cells, 9 times above clinically protective levels. In a non-blinded, placebo-controlled rhesus macaque study with repeated low-dose rectal SHIVSF162P3 challenge, the nTAF cohort had a 62.50% reduction (95% CI: 1.72% to 85.69%; p=0.068) in risk of infection per exposure compared to the control. Our finding mirrors that of tenofovir disoproxil fumarate (TDF) monotherapy, where 60.00% protective efficacy was observed in macaques, and clinically, 67.00% reduction in risk with 86.00% preventive efficacy in individuals with detectable drug in the plasma. Overall, our nanofluidic technology shows potential as a subcutaneous delivery platform for long-term PrEP and provides insights for clinical implementation of LA TAF for HIV prevention.

Introduction Randomized trials of new agents for HIV pre‐exposure prophylaxis (PrEP) compare against emtricitabine and tenofovir disoproxil fumarate (F/TDF), without a placebo group. We used the well‐characterized adherence‐efficacy relationship for F/TDF to back‐calculate the (non‐PrEP) counterfactual background HIV incidence (bHIV) in a randomized trial of a novel PrEP agent and estimate comparative efficacy (to counterfactual bHIV). Methods The DISCOVER trial (ClinicalTrials.gov: NCT02842086) randomized 5387 men who have sex with men (MSM) and transgender women who have sex with men and demonstrated non‐inferiority of emtricitabine and tenofovir alafenamide (F/TAF) to F/TDF (HIV incidence rate ratio [IRR] 0·47, 95% CI: 0·19 to 1.15). Tenofovir diphosphate (TFV‐DP) levels in dried blood spots (DBS) were assessed for all diagnosed with HIV and in a random 10% of the cohort. We used a Bayesian model with a diffuse prior distribution, derived from established data relating tenofovir diphosphate levels to HIV prevention efficacy. This prior, combined with the F/TDF seroconversion rate and tenofovir diphosphate levels in DISCOVER, yielded Bayesian inferences on the counterfactual bHIV. Results There were six versus 11 postbaseline HIV infections (0.14 vs. 0.25/100 person‐years [PY]) on F/TAF and F/TDF respectively. Of the 11 on F/TDF, 10 had low, none had medium and one had high tenofovir diphosphate levels; among HIV‐negative controls, 5% of the person‐time years had low, 9% had medium and 86% had high TFV‐DP levels. A non‐informative prior distribution for counterfactual bHIV, combined with the prior for TFV‐DP level‐efficacy relationship, yielded a posterior counterfactual bHIV of 3·4 infections/100 PY (0.80 Bayesian credible interval [CrI] 1·9 to 5·9), which suggests a median HIV efficacy of 96% (0.95 CrI [88% to 99%]) for F/TAF and 93% (0.95 CrI [87% to 96%]) for F/TDF compared to bHIV. Conclusions Based on the established connection of drug concentrations to PrEP prevention efficacy, a Bayesian framework can be used to estimate a synthetic non‐PrEP control group in randomized, active‐controlled PrEP trials that include a F/TDF‐comparator group.

Failure of pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine may occur despite perfect adherence, although this is uncommon. Failure results in breakthrough HIV infection. Delayed seroconversion associated with antiretroviral use may complicate the picture, causing uncertainties in interpreting adherence patterns for establishing the true cause of PrEP failure.

Human immunodeficiency virus–seronegative men aged 15–22 years who lost bone mineral density (BMD) during tenofovir disoproxil fumarate/emtricitabine preexposure prophylaxis (PrEP) showed BMD recovery 48 weeks following PrEP discontinuation. Lumbar spine and whole body BMD z-scores remained below baseline 48 weeks off PrEP in participants aged 15–19 years.Clinical Trials Registration. NCT01772823 (ATN 110) and NCT01769456 (ATN 113).

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.

Intravaginal rings (IVR) containing antiretroviral (ARV) drugs are a promising method for HIV prevention. We triangulated quantitative and qualitative assessments to evaluate the acceptability of four IVRs used continuously for 28 days as part of a Phase I trial (N=48 HIV-negative women; ages 18-45). Adherence was high throughout the trial, yet 30% of participants reported involuntary IVR expulsions followed by re-insertion. Most participants (93.6%) felt comfortable with the IVR being inside their body. Participants reported liking the IVR more (36.2%) or the same amount (55.3%) since starting the study. When given the option of choosing between the IVR and/or a male condom for HIV-prevention, most reported preferring the IVR (n=29, 63.0%), and over a quarter of the sample reported liking them equally (n=12, 26.1%). We observed no differences in IVR acceptability across the study arms. High adherence and acceptability underscores the promise of an IVR as a female-controlled, sustained mechanism for HIV prevention.

OBJECTIVE:HIV Prevention Trials Network 069/AIDS Clinical Trials Group A5305 was a study of 48-week oral pre-exposure prophylaxis (PrEP) regimens in MSM and transgender women. A rectal substudy was included to evaluate drug concentrations in rectal compartment vs. blood, gut-associated lymphoid tissue (GALT) responses to four antiretroviral PrEP regimens [maraviroc (MVC), MVC + emtricitabine (FTC), MVC + tenofovir (TFV) disoproxil fumarate, and TFV disoproxil fumarate + FTC], and to determine whether ARV exposure was associated with ex-vivo suppression of HIV infection in colorectal explants. METHODS:C-C chemokine receptor type 5 (CCR5) genotype was characterized using PCR. At baseline and at Weeks 24, 48, and 49, GALT phenotype was characterized by flow cytometry, rectal biopsies were challenged with HIV-1BaL, and tissue and plasma pharmacokinetics were measured via mass spectrometry. RESULTS:Exposure to MVC was not associated with increased expression of CD4+/CCR5+ HIV target T cells. Significant ex-vivo viral suppression compared with baseline was seen at Weeks 24 and 48, ranging from 1.4 to 1.8 log10 for all study regimens except the MVC-alone arm which did not show statistically significant viral suppression at Week 48. Tissue concentrations of TFV, TFV-diphosphate, and FTC were correlated with viral suppression. CONCLUSION:MVC-containing HIV PrEP regimens did not increase GALT CD4+ T-cell activation or the CD4+/CCR5+ phenotype. No virologic suppression was seen with MVC-alone at Week 48 compared with combination regimens, suggesting MVC monotherapy might be less effective than combination antiretroviral PrEP regimens.

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

Introduction African adolescent girls and young women (AGYW) eligible for HIV pre‐exposure prophylaxis (PrEP) experience high levels of depressive symptoms. Depression can reduce PrEP adherence among adults, although analyses have considered depression as a time‐varying exposure rather than modelling distinct patterns of symptoms. The association between depressive symptoms and PrEP adherence has not been explored for AGYW. To address these gaps, we sought to understand depressive symptom trajectories among African AGYW initiating PrEP and the impact of time‐varying depressive symptoms and symptom trajectories on PrEP adherence. Methods HPTN 082 was an open‐label PrEP study among AGYW (ages 16 to 24) in Zimbabwe and South Africa from 2016 to 2018. Depressive symptoms were measured at enrolment and Weeks 13, 26 and 52, using the 10‐item Center for Epidemiologic Studies scale; a score ≥10 is indicative of elevated depressive symptoms. PrEP adherence was defined as any detectable tenofovir diphosphate (TFV‐DP) levels. Group‐based trajectory modelling was used to model longitudinal patterns of depressive symptoms. We assessed psychosocial and behavioural predictors of depressive symptom trajectory membership (e.g. PrEP stigma, intimate partner violence [IPV], sexual behaviour). We modelled associations between (1) group trajectory membership and PrEP adherence at Week 52 and (2) time‐varying depressive symptoms and PrEP adherence through follow‐up. Results At enrolment, 179 (41.9%) participants had elevated depressive symptoms. Group‐based trajectory models revealed persistent elevated depressive symptoms in 48.5%, declining symptoms in 9.4% and no consistent or mild depressive symptoms in 43.3%. AGYW who engaged in transactional sex, reported IPV, or had traumatic stress symptoms were more likely to be assigned to the persistent elevated symptom group compared with the consistent no/mild symptom group (Wald test p‐value all

Early antiretroviral therapy (ART) initiation after cryptococcal meningitis increases mortality, and those unmasking cryptococcosis after

Author(s): Sekabira, Rogers; McGowan, Ian; Yuhas, Krista; Brand, Rhonda M; Marzinke, Mark A; Manabe, Yukari C; Frank, Ian; Eron, Joseph; Landovitz, Raphael J; Anton, Peter; Cranston, Ross D; Anderson, Peter; Mayer, Kenneth H; Amico, K Rivet; Wilkin, Timothy J; Chege, Wairimu; Kekitiinwa, Adeodata R; McCauley, Marybeth; Gulick, Roy M; Hendrix, Craig W | Abstract: ObjectiveThe objective of this study was to compare HIV-negative cisgender women (CGW) with MSM for mucosal tissue differences in pharmacokinetics, HIV infectivity and cell phenotype.DesignA substudy of HPTN 069/ACTG A5305, 48-week study of three oral candidate preexposure prophylaxis regimens: maraviroc, maraviroc/emtricitabine and maraviroc/tenofovir disoproxil fumarate (TDF) compared with a TDF/emtricitabine control group.MethodsPlasma, peripheral blood mononuclear cells and cervical and colorectal tissue biopsies were collected at Baseline (no drug), Week 24 and 48 (on drug), and Week 49 (1-week postdrug). Drug concentrations were assessed in all matrices. HIV infectivity was assessed using tissue biopsy 'explants' challenged with HIV ex vivo followed by HIV p24 measurement. Flow cytometry evaluated colorectal cell phenotype.ResultsThirty-seven CGW and 54 MSM participated. CGW's colorectal explant p24 was higher than MSM before (0.31 log10, P = 0.046), during (1.01-1.19 log10, P = 0.016) and one week after (0.61 log10, P = 0.011) study drug dosing. Pooling regimens, cervical explant p24 did not differ among visits. CGW had higher plasma maraviroc and colorectal tissue tenofovir diphosphate and lower colorectal tissue emtricitabine (all P l 0.005) compared with MSM. Each study drug's cervical tissue concentrations were more than 10-fold below paired colorectal concentrations (P l 0.001). Cell phenotype sex differences included 4% higher CD38+/CD8+ cells at baseline and 3-7% higher CD69+/CD8+ cells throughout Weeks 24-49 in CGW compared with MSM (P l 0.05).ConclusionColorectal explants in CGW demonstrated greater HIV infectivity than MSM with and without study drugs. Small differences in adherence, drug concentration and colorectal tissue flow cytometry cannot fully explain this difference.

Background The HIV Prevention Trials Network (HPTN) 083 trial demonstrated that long-acting cabotegravir (CAB-LA) was more effective than tenofovir disoproxil fumarate–emtricitabine (TDF/FTC) in preventing human immunodeficiency virus (HIV) in cisgender men and transgender women who have sex with men. We characterized HIV infections that occurred in the blinded phase of HPTN 083. Methods Retrospective testing included HIV testing, viral load testing, quantification of study drugs, and HIV drug resistance testing. Results Fifty-eight infections were evaluated, including 51 incident infections (12 in CAB arm and 39 in TDF/FTC arm). In many cases (5 in CAB arm and 37 in TDF/FTC arm), infection was associated with low or unquantifiable study drug concentrations. In 4 cases, infection occurred with on-time CAB-LA injections and expected plasma CAB concentrations. CAB exposure was associated with prolonged viral suppression and delayed antibody expression. In some cases, delayed HIV diagnosis resulted in CAB provision to participants with undetected infection, delayed antiretroviral therapy, and emergence of drug resistance; most of these infections would have been detected earlier with viral load testing. Conclusions Early detection of HIV infection and prompt antiretroviral therapy initiation could improve clinical outcomes in persons who become infected despite CAB-LA prophylaxis. Further studies are needed to elucidate the correlates of HIV protection in persons receiving CAB-LA.

HIV pre-exposure prophylaxis (PrEP) is effective at preventing sexual acquisition of HIV, and failures in clinical trials are largely attributable to medication nonadherence. We report here a case of infection with a fully susceptible strain of HIV in an individual adherent to PrEP as demonstrated by pharmacy records and intracellular tenofovir diphosphate levels. At diagnosis, the viral load was 90 copies/mL precluding initial genotype testing due to low copy number. While PrEP failure is rare, this case underscores the importance of regular HIV testing for patient on PrEP and prompts discussion regarding the approach to treatment following failure where an initial genotype is not yet available or not possible due to low viral load. Few other case reports of PrEP failure exist in the literature and approaches to treatment varied widely. We suggest the initial viral copy number may guide next steps and discuss the risks and benefits of stopping PrEP, escalating therapy with integrase inhibitors or boosted protease inhibitors, or switching to non-nucleoside antiretroviral treatment regimens.

BACKGROUND Benin has a long-standing history of HIV prevention programs aimed at female sex workers (FSWs). We used data from a national survey among FSWs (2017) to assess the prevention and care cascades in this population. METHODS Female sex workers were recruited through cluster sampling of sex work sites. A questionnaire was administered, and HIV tested. HIV-positive participants were asked to provide dried blood spots and were tested for antiretroviral and viral load. We assessed 2 prevention cascades (HIV testing and safer sex) and the treatment cascade, using a combination of self-reported and biological variables. RESULTS Mean age of the 1086 FSWs was 30 years. Half of them were Beninese, and two-thirds had a primary school education level or less. Almost all FSWs had ever heard of HIV/AIDS. More than half (79.1%) had ever been tested, and 84.1% of the latter had been tested in the last year. In the previous 6 months, 90.1% were exposed to prevention messages. Women exposed to any HIV prevention message reported a higher level of consistent condom use in the last month (69.0%) than those who were not (48.5%, P < 0.0001). HIV prevalence was 7.7%. Among HIV-positive women, 60.6% knew their status; among those, 90.5% were on antiretroviral and 81.8% of them had a suppressed viral load. CONCLUSIONS Despite long-standing HIV prevention programs for FSWs, the prevention indicators were often low. Linkage to care was good, viral suppression was suboptimal, but knowledge of HIV-positive status was low. Exposing women to prevention messages is necessary, as to increase HIV testing.

From directly observed therapy studies, urine tenofovir (TFV) levels were 74% lower when taking tenofovir alafenamide (TAF) vs tenofovir disoproxil fumarate. Urine TFV remains quantifiable across a range of TAF adherence patterns, but a separate point-of-care lateral flow immunoassay with a lower TFV threshold will be needed to support TAF adherence monitoring.

Despite being FDA-approved for COVID-19, the clinical efficacy of remdesivir (Veklury®) remains contentious. We previously pointed out pharmacokinetic, pharmacodynamic and toxicology reasons for why its parent nucleoside GS-441524, is better suited for COVID-19 treatment. Here, we assess the oral bioavailability of GS-441524 in beagle dogs and show that plasma concentrations ∼24-fold higher than the EC50 against SARS-CoV-2 are easily and safely sustained. These data support translation of GS-441524 as an oral agent for COVID-19.

Background Treatment failure of Mycobacterium avium complex (MAC) pulmonary disease occurs in about 30% of people with cystic fibrosis (CF) and may be a result of abnormal drug concentrations. Methods Prospective, cross-over, single-dose PK study of 20 pancreatic insufficient individuals with CF and 10 healthy controls (HC). CF subjects received simultaneous doses of oral azithromycin, ethambutol, and rifampin in the fasting state and with food and pancreatic enzymes, separated by two weeks. HC received fasting doses only. A non-compartmental model was used to estimate PK parameters of drugs and metabolites. Results Azithromycin maximum concentration (Cmax ) was higher and rifampin Cmax was lower in fasting CF subjects compared to HC, while other PK measures, including those for ethambutol, were similar. Addition of food and enzymes did not improve the Cmax of the antimycobacterial drugs. Nineteen of 20 CF subjects had one or more abnormal Cmax z-scores in either the fasting or fed state (or both), when compared to HC. Conclusion PK profiles of azithromycin and ethambutol were similar between CF and HC, except azithromycin Cmax was slightly higher in people with CF after a single dose. Rifampin PK parameters were altered in persons with CF. Addition of food and enzymes in CF subjects did not improve PK parameters. Standard dosing guidelines should be used as a starting point for people with CF initiating MAC therapy and therapeutic drug monitoring should be routinely performed to prevent the possibility of treatment failure due to abnormal drug concentrations. Clinical trial registration ClinicalTrials.gov Identifier: NCT02372383 Prior abstract publication: 1. Martiniano S, Wagner B, Brennan L, Wempe M, Anderson P, Nick J, Sagel S. Pharmacokinetics of oral MAC antibiotics in cystic fibrosis. Am J Resp Crit Care Med A4842-A4842, 2017. 2. Martiniano SL, Wagner BD, Brennan L, Wempe MF, Anderson PL, Nick JA, Sagel SD. Pharmacokinetics of oral MAC antibiotics in cystic fibrosis. J Cyst Fibros 16: S52–53, 2017.

The urgent global public health need presented by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has brought scientists from diverse backgrounds together in an unprecedented international effort to rapidly identify interventions. There is a pressing need to apply clinical pharmacology principles and this has already been recognized by several other groups. However, one area that warrants additional specific consideration relates to plasma and tissue protein binding that broadly influences pharmacokinetics and pharmacodynamics. The principles of free drug theory have been forged and applied across drug development but are not currently being routinely applied for SARS-CoV-2 antiviral drugs. Consideration of protein binding is of critical importance to candidate selection but requires correct interpretation, in a drug-specific manner, to avoid either underinterpretation or overinterpretation of its consequences. This paper represents a consensus from international researchers seeking to apply historical knowledge, which has underpinned highly successful antiviral drug development for other viruses, such as HIV and hepatitis C virus for decades.

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.

HIV-1 is a chronic disease managed by strictly adhering to daily antiretroviral therapy (ART). However, not all people living with HIV-1 have access to ART, and those with access may not adhere to treatment regimens increasing viral load and disease progression. Here, a subcutaneous nanofluidic implant was used as a long-acting (LA) drug delivery platform to address these issues. The device was loaded with tenofovir alafenamide (TAF) and implanted in treatment-na&iuml, ve simian HIV (SHIV)-positive nonhuman primates (NHP) for a month. We monitored intracellular tenofovir-diphosphate (TFV-DP) concentration in the target cells, peripheral blood mononuclear cells (PBMC). The concentrations of TFV-DP were maintained at a median of 391.0 fmol/106 cells (IQR, 243.0 to 509.0 fmol/106 cells) for the duration of the study. Further, we achieved drug penetration into lymphatic tissues, known for persistent HIV-1 replication. Moreover, we observed a first-phase viral load decay of &minus, 1.14 &plusmn, 0.81 log10 copies/mL (95% CI, &minus, 0.30 to &minus, 2.23 log10 copies/mL), similar to &minus, 1.08 log10 copies/mL decay observed in humans. Thus, LA TAF delivered from our nanofluidic implant had similar effects as oral TAF dosing with a lower dose, with potential as a platform for LA ART.

Background In this study, we evaluate associations between cumulative antiretroviral adherence/exposure, quantified using tenofovir diphosphate (TFV-DP) in dried blood spots (DBS), and human immunodeficiency virus (HIV)-related aging factors. Methods This is a cross-sectional analysis of younger (ages 18–35) and older (ages ≥60) persons with HIV (PWH) taking TFV disoproxil fumarate. Tenofovir diphosphate concentrations were quantified in DBS. Linear and logistic regression models were used to evaluate associations between TFV-DP and bone mineral density (BMD), physical function, frailty, and falls. Results Forty-five PWH were enrolled (23 younger, 22 older). Every 500 fmol/punch (equivalent to an increase in ~2 doses/week) increase in TFV-DP was associated with decreased hip BMD (−0.021 g/cm2; 95% confidence interval [CI], −0.040 to −0.002; P = .03). Adjusting for total fat mass, every 500 fmol/punch increase in TFV-DP was associated with higher odds of Short Physical Performance Battery impairment (score ≤10; adjusted odds ratio [OR], 1.6; 95% CI, 1.0–2.5; P = .04). Every 500 fmol/punch increase in TFV-DP was associated with slower 400-meter walk time (14.8 seconds; 95% CI, 3.8–25.8; P = .01) and remained significant after adjusting for age, lean body mass, body mass index (BMI), and fat mass (all P ≤ .01). Every 500 fmol/punch increase in TFV-DP was associated with higher odds of reporting a fall in the prior 6 months (OR, 1.8; 95% CI, 1.1–2.8; P = .02); this remained significant after adjusting for age, lean body mass, BMI, and total fat mass (all P, The associations between tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) and human immunodeficiency virus (HIV)-related aging factors was evaluated. Higher TFV-DP levels were found to be associated with impaired physical function and fracture risk.

While HIV infections among men who have sex men (MSM) have started to decline in the United States, Black MSM continue to experience disproportionate rates of HIV infection. The purpose of this secondary analysis is to examine risk perception and its influence on PrEP adherence among Black MSM from HPTN 073. Risk perception was measured using the adapted Perceived Vulnerability to HIV Scale. The associations between risk perception and PrEP adherence were tested using generalized estimation equation model for time-variant repeated measures. Risk perception was not significantly associated with PrEP adherence. These findings suggest an there was no risk compensation among PrEP users, and inconsistency in perceived risk for HIV. Future studies should investigate the rationale for long term adherence to PrEP among Black MSM.

BACKGROUND The Antibody-Mediated Prevention trials (HVTN 704/HPTN 085 and HVTN 703/HPTN 081) are the first efficacy trials to evaluate whether VRC01, a broadly neutralizing monoclonal antibody targeting the CD4-binding site of the HIV envelope protein, prevents sexual transmission of HIV-1. HVTN 704/HPTN 085 enrolled 2701 cisgender men and transgender (TG) individuals who have sex with men at 26 sites in Brazil, Peru, Switzerland, and the United States. METHODS Participants were recruited and retained through early, extensive community engagement. Eligible participants were randomized 1:1:1 to 10 mg/kg or 30 mg/kg of VRC01 or saline placebo. Visits occurred monthly, with intravenous (IV) infusions every 8 weeks over 2 years, for a total of 10 infusions. Participants were followed for 104 weeks after first infusion. RESULTS The median HVTN 704/HPTN 085 participant age was 28 years; 99% were assigned male sex; 90% identified as cisgender men, 5% as TG women and the remaining as other genders. Thirty-two percent were White, 15% Black, and 57% Hispanic/Latinx. Twenty-eight percent had a sexually transmitted infection at enrollment. More than 23,000 infusions were administered with no serious IV administration complications. Overall, retention and adherence to the study schedule exceeded 90%, and the dropout rate was below 10% annually (7.3 per 100 person-years) through week 80, the last visit for the primary end point. CONCLUSIONS HVTN 704/HPTN 085 exceeded accrual and retention expectations. With exceptional safety of IV administration and operational feasibility, it paves the way for future large-scale monoclonal antibody trials for HIV prevention and/or treatment.

Summary Background Pre-exposure prophylaxis (PrEP) is highly effective for preventing HIV acquisition. However, adherence among young women (aged 18–24 years) has been challenging. SMS reminders have been shown to improve adherence to antiretroviral therapy in some contexts, including in combination with real-time adherence monitoring. We aimed to determine the effect of SMS reminders on PrEP adherence among young women in Kenya over a 2-year period. Methods The monitoring PrEP among young adult women (MPYA) study was an open label randomised controlled trial involving young adult women at high risk of HIV in Thika and Kisumu, Kenya. Participants were recruited from colleges, vocational institutions, informal settlements, and community-based organisations supporting young women. Women had to be aged 18–24 years and at high risk of HIV acquisition (defined as a VOICE risk score of 5 or higher, or being in a serodiscordant relationship). Study staff randomly assigned participants (1:1) to receive either SMS reminders (SMS reminder group) or no reminders (no SMS reminder group). Study group assignment was known to trial staff but masked to investigators. Reminders were initially sent daily and participants could switch to as-needed reminders (ie, sent only if they missed opening the monitor as expected) after 1 month. Study visits occurred at 1 month, 3 months, and then quarterly (ie, every 3 months). The primary outcome was PrEP adherence over 24 months measured with a real-time electronic monitor and assessed by negative binomial models adjusted for the study site and quarter among participants who collected PrEP. This trial is registered with ClinicalTrials.gov , NCT02915367 . Findings Of 642 women initially approached, 348 eligible women were enrolled between Dec 21, 2016, and Feb 5, 2018. Participants were randomly assigned to either the SMS reminder group (n=173) or the no SMS reminder group (n=175). The median age was 21 years (IQR 19–22) and 228 (66%) of the 348 participants reported condomless sex in the month before baseline. 24 (14%) of the 173 participants assigned to receive daily SMS reminders later opted for as-needed reminders. 69 291 (97%) of 71 791 SMS reminders were sent as planned. Among participants collecting PrEP (thus potentially suggesting a desire for HIV protection), electronically monitored adherence averaged 26·8% over 24 months and was similar by study group (27·0% with SMS, 26·6% without SMS, adjusted incidence rate ratio 1·16 [95% CI 0·93–1·45], p=0·19). There were no serious adverse events related to trial participation; five social harms occurred in each study group, primarily related to PrEP use. Interpretation SMS reminders were ineffective in promoting PrEP adherence among young Kenyan women. Given the overall low adherence in the trial, additional interventions are needed to support PrEP use in this population. Funding US National Institute of Mental Health.

Practice guidelines on pre-exposure prophylaxis (PrEP) for HIV serodiscordant couples recommend PrEP when the viral load of the partner living with HIV is either detectable or unknown. However, adherence to combination antiretroviral therapy is inconsistent, and research has found that individuals vulnerable to HIV place value on additional protective barriers. We conducted a prospective cohort study to assess the feasibility, perceptions, and adherence associated with periconceptional PrEP use among females without HIV and their male partners living with HIV across four academic medical centers in the United States. We performed descriptive statistics, McNemar's test of marginal homogeneity to assess discordance in female/male survey responses, and Spearman's correlation to determine associations between dried blood spot levels and female self-reported adherence to PrEP. We enrolled 25 women without HIV and 24 men living with HIV (one male partner did not consent to the study). Women took PrEP for a median of 10.9 months (interquartile range 3.8–12.0) and were generally adherent. In total, 87% of women (20/23) had a dried blood spot with >700 fmol/punch or ≥4 doses/week, 4% (1/23) at 350–699 fmol/punch or 2–3 doses/week, and 9% (2/23) at

Cases of seroconversion on pre-exposure prophylaxis (PrEP) should be carefully investigated, given their public health implications and rarity. We report a case of transmitted drug resistance causing seroconversion on PrEP in spite of high adherence, confirmed with dried blood spot and segmental hair drug-level testing and single-genome sequencing.

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.