Tenofovir-Diphosphate and Emtricitabine-Triphosphate Adherence Benchmarks in Dried Blood Spots for Persons with HIV Receiving Tenofovir Alafenamide and Emtricitabine-based Antiretroviral Therapy (QUANTI-TAF).

BACKGROUND: QUANTI-TAF aimed to establish tenofovir-diphosphate/emtricitabine-triphosphate (TFV-DP/FTC-TP) adherence benchmarks in dried blood spots (DBS) for persons with HIV (PWH) receiving tenofovir alafenamide/emtricitabine (TAF/FTC)-based antiretroviral therapy (ART). METHODS: During a 16-week pharmacokinetic study, PWH received TAF/FTC-based ART co-encapsulated with an ingestible sensor to directly measure cumulative (enrollment to final visit) and 10-day adherence. At monthly visits, intraerythrocytic concentrations of TAF/FTC anabolites (TFV-DP/FTC-TP) in DBS were quantified by LC-MS/MS and summarized at steady-state (week 12 or 16) as median (IQR). Linear mixed-effects models evaluated factors associated with TFV-DP/FTC-TP. RESULTS: 84 participants (86% male, 11% female, and 4% transgender), predominantly receiving bictegravir/TAF/FTC (73%) enrolled. 92% completed week 12 or 16 (94% receiving unboosted ART). TFV-DP for <85% (7/72), ≥85%-<95% (9/72), and ≥95% (56/72) cumulative adherence was 2696 (2039-4108), 3117 (2332-3339), and 3344 (2605-4293) fmol/punches. All participants with ≥85% cumulative adherence had TFV-DP ≥1800 fmol/punches. Adjusting for cumulative adherence, TFV-DP was higher with boosted ART, lower BMI, and in non-Blacks. FTC-TP for <85% (14/77), ≥85%-<95% (6/77), and ≥95% (57/77) 10-day adherence was 3.52 (2.64-4.48), 4.58 (4.39-5.06), and 4.96 (4.21-6.26) pmol/punches. All participants with ≥85% 10-day adherence had FTC-TP ≥2.5 pmol/punches. Low-level viremia (HIV-1 RNA ≥20-<200 copies/mL) occurred at 60/335 (18%) visits in 33/84 (39%) participants (range: 20-149 copies/mL), with similar TFV-DP (3177 [2494-4149] fmol/punches) compared with HIV-1 RNA <20 copies/mL visits (3279 [2580-4407] fmol/punches). CONCLUSIONS: We propose PK-based TFV-DP (≥1800 fmol/punches)/FTC-TP (≥2.5 pmol/punches) benchmarks in DBS for PWH receiving unboosted TAF/FTC-based ART with ≥85% adherence. In the setting of high adherence, low-level viremia was common.

Energy balance and body composition after switch between integrase strand transfer inhibitors and doravirine among people with HIV.

BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are associated with excessive weight gain among a subset of persons with HIV (PWH), due to unclear mechanisms. We assessed energy intake (EI) and expenditure (EE) following switch off and onto INSTIs. METHODS: PWH with >10% weight gain on an INSTI-based regimen switched INSTI to doravirine for 12 weeks, then back to INSTI for 12 weeks while keeping their remaining regimen stable. Twenty-four-hour EE, EI and weight were measured on INSTI, following switch to doravirine, and upon INSTI restart. Mixed models analysed changes over time. RESULTS: Among 18 participants, unadjusted 24 h EE decreased by 83 (95% CI -181 to 14) kcal following switch to doravirine, and by 2 (-105 to 100) kcal after INSTI restart; energy balance (EE-EI) increased by 266 (-126 to 658) kcal from Week 0 to Week 12, and decreased by 3 (-429 to 423) kcal from Week 12 to Week 24. Trends toward weight loss occurred following switch to doravirine [mean -1.25 (-3.18 to 0.69) kg] and when back on INSTI [-0.47 (-2.45 to 1.52) kg]. Trunk fat decreased on doravirine [-474 (-1398 to 449) g], with some regain following INSTI restart [199 (-747 to 1145) g]. Fat-free mass decreased on doravirine [-491 (-1399 to 417) g] and increased slightly after INSTI restart [178 (-753 to 1108) g]. CONCLUSIONS: Among PWH with >10% weight gain on an INSTI, switch to doravirine was associated with a trend towards decreases in 24 h EE, weight, trunk fat mass and fat-free mass. Observed changes were not significant, but suggest a mild weight-suppressive effect of doravirine among PWH.

Pulmonary Function and Quality of Life in Aging Men With and Without HIV from the Multicenter AIDS Cohort Study.

People living with HIV have greater pulmonary function impairments and decreased health-related quality of life (HRQoL) compared to uninfected peers. We examined whether pulmonary impairment was associated with HRQoL or respiratory health status. Using Multicenter AIDS Cohort Study data (2017-2019), associations between outcomes [HRQoL (36-Item Short Form Survey) and respiratory health status (St. George's Respiratory Questionnaire)] with pulmonary impairment [diffusing capacity for carbon monoxide (DLCO) and forced expiratory volume in 1 s (FEV1), defined as <80% predicted for both] were examined. Adjusted analyses utilized linear and zero-inflated beta regression, the latter summarized by odds ratio (OR) and quotient ratios (QRs). We also considered whether the subset of adjustment variables age, HIV serostatus, or smoking modified the relationships examined. Of 1048 men, 55% had HIV, with median age 57 [interquartile range (IQR) = 48, 64] years and 1.2 (IQR = 0, 18.1) smoking pack-years. Impaired DLCO, but not impaired FEV1, was significantly associated with lower physical HRQoL [-2.71 (-4.09, -1.33); -1.46 (-3.45, 0.54), respectively]. Pulmonary impairment was associated with higher odds of any St. George's Respiratory Questionnaire (SGRQ) (total score) limitation [DLCO OR = 1.53 (1.15, 2.04); FEV1 OR = 2.48 (1.16, 5.30)] and was elevated in individuals with more severe SGRQ limitations [DLCO QR = 1.13 (0.94, 1.36); FEV1 QR = 1.27 (0.98, 1.64)]. HIV did not modify any associations examined. Age modified the DLCO and any respiratory limitation (SGRQ symptom score) association for every 10 mL CO/min/mmHg decrease in DLCO [age 30 OR = 1.03 (0.51, 2.08); age 50 OR = 1.85 (1.27, 3.85); and age 70 OR = 3.45 (2.00, 5.88)]. Similarly, age modified the DLCO and any respiratory limitation (SGRQ total score) association. FEV1 associations with SGRQ and HRQoL scores were similar across all ages. Impaired pulmonary function was associated with lower HRQoL and greater respiratory impairments. Future studies can determine if interventions aimed at preserving pulmonary function are effective in improving HRQoL and respiratory health among aging men with and without HIV.

Beyond Undetectable: Modeling the Clinical Benefit of Improved Antiretroviral Adherence in Persons With Human Immunodeficiency Virus With Virologic Suppression.

Background: Incomplete antiretroviral therapy (ART) adherence has been linked to deleterious immunologic, inflammatory, and clinical consequences, even among virally suppressed (<50 copies/mL) persons with human immunodeficiency virus (PWH). The impact of improving adherence in the risk of severe non-AIDS events (SNAEs) and death in this population is unknown. Methods: We estimated the reduction in the risk of SNAEs or death resulting from an increase in ART adherence by (1) applying existing data on the association between adherence with high residual inflammation/coagulopathy in virally suppressed PWH, and (2) using a Cox proportional hazards model derived from changes in plasma interleukin 6 (IL-6) and D-dimer from 3 randomized clinical trials. Comparatively, assuming 100% ART adherence in a PWH who achieves viral suppression, we estimated the number of persons in whom a decrease in adherence to <100% would need to be observed for an additional SNAE or death event to occur during 3- and 5-year follow-up. Results: Increasing ART adherence to 100% in PWH who are suppressed on ART despite imperfect adherence translated into a 6%-37% reduction in the risk of SNAEs or death. Comparatively, based on an anticipated 12% increase in IL-6, 254 and 165 PWH would need to decrease their adherence from 100% to <100% for an additional event to occur over 3- and 5-year follow-up, respectively. Conclusions: Modest gains in ART adherence could have clinical benefits beyond virologic suppression. Increasing ART adherence (eg, via an intervention or switch to long-acting ART) in PWH who remain virally suppressed despite incomplete adherence should be evaluated.

Using Wearable Technology to Quantify Physical Activity Recovery: Secondary Report From the AFTER (App-Facilitated Tele-Rehabilitation) Program for COVID-19 Survivors Randomized Study.

BACKGROUND: Knowledge on physical activity recovery after COVID-19 survival is limited. The AFTER (App-Facilitated Tele-Rehabilitation) program for COVID-19 survivors randomized participants, following hospital discharge, to either education and unstructured physical activity or a telerehabilitation program. Step count data were collected as a secondary outcome, and we found no significant differences in total step count trajectories between groups at 6 weeks. Further step count data were not analyzed. OBJECTIVE: The purpose of this analysis was to examine step count trajectories and correlates among all participants (combined into a single group) across the 12-week study period. METHODS: Linear mixed models with random effects were used to model daily steps over the number of study days. Models with 0, 1, and 2 inflection points were considered, and the final model was selected based on the highest log-likelihood value. RESULTS: Participants included 44 adults (41 with available Fitbit [Fitbit LLC] data). Initially, step counts increased by an average of 930 (95% CI 547-1312; P<.001) steps per week, culminating in an average daily step count of 7658 (95% CI 6257-9059; P<.001) at the end of week 3. During the remaining 9 weeks of the study, weekly step counts increased by an average of 67 (95% CI -30 to 163; P<.001) steps per week, resulting in a final estimate of 8258 (95% CI 6933-9584; P<.001) steps. CONCLUSIONS: Participants showed a marked improvement in daily step counts during the first 3 weeks of the study, followed by more gradual improvement in the remaining 9 weeks. Physical activity data and step count recovery trajectories may be considered surrogates for physiological recovery, although further research is needed to examine this relationship. TRIAL REGISTRATION: ClinicalTrials.gov NCT04663945; https://tinyurl.com/2p969ced.

Improving the accuracy of adherence data collected using medication monitoring technology in clinical research.

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

Demographic and Clinical Characteristics of Persons with HIV with Viral Load:Adherence Mismatch Who Are at Risk of Future Viremia.

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%; p = .04), had body mass index >30 kg/m2 (40% vs. 13%; p = .01), and reported <100% 3 months (68% vs. 50%; p = .005) and 30 days (56% vs. 31%; p = .001) adherence, compared with PWH without mismatch. Identifying PWH at risk for future viremia could help clinicians implement targeted timely interventions before episodes of breakthrough viremia.

Pulmonary and physical function limitations in aging men with and without HIV from the Multicenter AIDS Cohort Study (MACS).

PURPOSE: We examined the associations between pulmonary impairments and physical function and whether age, HIV serostatus, or smoking modified these relationships. METHODS: Using Multicenter AIDS Cohort Study data, we examined associations between pulmonary function (diffusing capacity for carbon monoxide [DLCO], one-second forced expiratory volume [FEV1]) and subsequent physical outcomes (gait speed, grip strength, frailty [non-frail, pre-frail, frail]) using mixed models. RESULTS: Of 1,048 men, 55% were living with HIV, median age was 57(IQR=48,64) and median cumulative pack-years was 1.2(IQR = 0,18.1); 33% and 13% had impaired DLCO and FEV1(<80% predicted), respectively. Participants with impaired DLCO had 3.5 kg (95%CI: -4.6, -2.4) weaker grip strength, 0.04 m/sec (95%CI: -0.06, -0.02) slower gait speed and 4.44-fold (95%CI: 1.81, 10.93) greater odds of frailty compared to participants with normal DLCO. Participants with impaired FEV1 had 3.1 kg (95%CI: -4.8, -1.4) weaker grip strength, similar gait speed (-0.001 m/sec [95%CI: -0.04, 0.03]) and 5.72-fold (95%CI: 1.90, 17.19) greater odds of frailty compared to participants with normal FEV1. Age, but not smoking or HIV, significantly modified the DLCO effect on gait speed and grip strength. CONCLUSIONS: Pulmonary impairment and decreased physical function were associated. Preserving pulmonary function may help preserve physical function in aging men with and without HIV.

Impact of a pilot multimodal intervention to decrease antibiotic use for respiratory infections in a geriatric clinic.

Background: More than 80% of antibiotics are prescribed in the outpatient setting, of which 30% are inappropriate. The National Action Plan for Combating Antimicrobial Resistance called for a 50% decrease in outpatient antibiotic use by 2020. Inappropriate antibiotics are associated with adverse reactions and Clostridioides difficile infection, especially among older adults. Study design: Before and after study. Methods: We performed a quality improvement initiative at the University of Colorado Seniors Clinic. Providers received education on antibiotic guidelines, electronic antibiotic order sets were introduced with standardized stop dates. Antibiotic use data were collected for 6 months before and 6 months after the intervention, from December to May to avoid seasonal variation. Descriptive statistics and linear mixed-effects regression models were used for this comparison. Results: Total antibiotic prescriptions for acute respiratory conditions decreased from 137 prescriptions before the intervention (December 1, 2017, to May 31, 2018) to 112 prescriptions after the intervention (December 1, 2018, to May 31, 2019), driven primarily by decreases in antibiotic prescriptions for pneumonia, sinusitis, and bronchitis. Prescriptions for broad-spectrum antibiotics declined following the intervention including decreases in levofloxacin from 12 (9%) to 3 (3%) and amoxicillin-clavulanate from 15 (12%) to 7 (7%). We detected significant reductions in prescribed antibiotic durations (days) after the intervention for sinusitis (estimate, -2.0; 95% CI, -3.1 to -1.0; P = .0003), pharyngitis (estimate, -2.5; 95% CI, -4.6 to -0.5; P = .018), and otitis (-3.2; 95% CI, -5.2 to -1.3; P = .008). Conclusions: Low-cost interventions were initially successful in changing patterns of antibiotic use and decreasing overall antibiotic prescribing among older patients in the outpatient setting. Long-term follow-up studies are needed to determine the sustainability and clinical impact of these interventions.

Evaluation of a training intervention to improve cancer care in Zimbabwe: Strategies to Improve Kaposi Sarcoma Outcomes (SIKO), a prospective community-based stepped-wedge cluster randomized trial.

INTRODUCTION: Most Zimbabweans access medical care through tiered health systems. In 2013, HIV care was decentralized to primary care clinics; while oncology care remained centralized. Most persons in Zimbabwe with Kaposi sarcoma (KS) are diagnosed late in their disease, and the prognosis is poor. Little is known about whether educational interventions could improve KS outcomes in these settings. METHODS: Interventions to improve KS detection and management were evaluated at eight Zimbabwe primary care sites (four rural/four urban) that provided HIV care. Interventions included a standardized KS clinical evaluation tool, palliative care integration, standardized treatment and improved consultative services. Interventions were implemented between February 2013 and January 2016 using a randomized stepped-wedge cluster design. Sites were monitored for KS diagnosis rates and KS outcomes, including early diagnosis (T0 vs. T1 tumour stage), participant retention and mortality. Analyses controlled for within-clinic correlations. RESULTS: A total of 1102 persons with suspected KS (96% HIV positive) were enrolled: 47% incident (new diagnosis), 20% prevalent (previous diagnosis) and 33% determined as not KS. Early (T0) diagnosis increased post-intervention, though not significant statistically (adjusted odds ratio [aOR] = 1.48 [95% confidence interval (95% CI): 0.66-3.79], p = 0.37). New KS diagnosis rates increased 103% (95% CI: 11-273%), p = 0.02) post-intervention; although paired with an increased odds of incorrectly diagnosing KS (aOR = 2.08 [95% CI: 0.33-3.24], p = 0.001). Post-intervention, non-significant decreases in 90-day return rates (adjusted hazard ratio [aHR] = 0.69 [95% CI: 0.38-1.45], p = 0.21) and survival (aHR = 1.36 [95% CI: 0.85-2.20], p = 0.20) were estimated. CONCLUSIONS: KS training interventions at urban and rural Zimbabwe decentralized primary care clinics significantly increased overall and incorrect KS diagnosis rates, but not early KS diagnosis rates, 90-day return rates or survival.

Safety, feasibility and initial efficacy of an app-facilitated telerehabilitation (AFTER) programme for COVID-19 survivors: a pilot randomised study.

OBJECTIVES: Determine the safety, feasibility and initial efficacy of a multicomponent telerehabilitation programme for COVID-19 survivors. DESIGN: Pilot randomised feasibility study. SETTING: In-home telerehabilitation. PARTICIPANTS: 44 participants (21 female, mean age 52 years) discharged home following hospitalisation with COVID-19 (with and without intensive care unit (ICU) stay). INTERVENTIONS: Participants were block randomised 2:1 to receive 12 individual biobehaviourally informed, app-facilitated, multicomponent telerehabilitation sessions with a licenced physical therapist (n=29) or to a control group (n=15) consisting of education on exercise and COVID-19 recovery trajectory, physical activity and vitals monitoring, and weekly check-ins with study staff. Interventions were 100% remote and occurred over 12 weeks. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was feasibility, including safety and session adherence. Secondary outcomes included preliminary efficacy outcomes including tests of function and balance; patient-reported outcome measures; a cognitive assessment; and average daily step count. The 30 s chair stand test was the main secondary (efficacy) outcome. RESULTS: No adverse events (AEs) occurred during testing or in telerehabilitation sessions; 38% (11/29) of the intervention group compared with 60% (9/15) of the control group experienced an AE (p=0.21), most of which were minor, over the course of the 12-week study. 27 of 29 participants (93%; 95% CI 77% to 99%) receiving the intervention attended ≥75% of sessions. Both groups demonstrated clinically meaningful improvement in secondary outcomes with no statistically significant differences between groups. CONCLUSION: Fully remote telerehabilitation was safe, feasible, had high adherence for COVID-19 recovery, and may apply to other medically complex patients including those with barriers to access care. This pilot study was designed to evaluate feasibility; further efficacy evaluation is needed. TRIAL REGISTRATION NUMBER: NCT04663945.

Cumulative tenofovir diphosphate exposure in persons with HIV taking single- vs. multiple-tablet regimens.

BACKGROUND: We assessed cumulative antiretroviral exposure-using tenofovir diphosphate (TFV-DP) in dried blood spots (DBS)-in persons with HIV (PWH) receiving tenofovir disoproxil fumarate (TDF)-based antiretroviral therapy (ART) as single-tablet regimens (STR) or multiple-tablet regimens (MTR). METHODS: Blood for DBS was prospectively collected in PWH on TDF during 1144 person visits (n = 523). Linear mixed-effects models, adjusted for baseline characteristics, were used to compare TFV-DP in STR versus MTR. Models adjusted for ART regimen using either anchor drug class, pharmacokinetic booster status (unboosted [u/] or boosted [b/]), or a combined STR/MTR and booster categorical variable. RESULTS: In the anchor class-adjusted model, STR had 19% (95% confidence interval [CI]: 3%-37%; p = 0.02) higher TFV-DP concentrations than MTR. However, in the booster-adjusted model, STR was not significantly higher than MTR (estimate 5%, 95% CI: -9% to 21%; p = 0.48), although PWH on b/ART had 35% (95% CI: 16%-58%; p = 0.0001) higher TFV-DP than u/ART. In the STR/MTR-boosted variable model, when compared to u/MTR, b/STR, b/MTR, and u/STR had 25% (95% CI: 7%-47%; p = 0.005), 37% (95% CI: 17%-59%; p < 0.0001), and 7% (95% CI: -7% to 24%; p = 0.34) higher TFV-DP, respectively. Compared with b/MTR, b/STR had 9% (95% CI: -31% to 10%; p = 0.37) lower TFV-DP. In a sensitivity analysis of PWH with HIV viral load <20 copies/ml at all visits, b/STR and b/MTR had 34% (95% CI: 16%-55%; p < 0.0001) and 12% (95% CI: -2% to 27%; p = 0.09) higher TFV-DP, respectively, compared with u/MTR, while u/STR had 4% (95% CI: -15% to 8%; p = 0.50) lower TFV-DP. Compared with b/MTR, b/STR had 17% (95% CI: 2%-30%; p = 0.03) higher TFV-DP. CONCLUSIONS: Persons with HIV on b/TDF-based ART had higher TFV-DP than u/ART, regardless of STR or MTR use. No significant differences in TFV-DP between regimens of the same boosting status (i.e., b/STR vs. b/MTR; u/STR vs. u/MTR) were observed in the full cohort. Future research should examine the clinical utility of these findings in patient-tailored ART selection.

Inference following multiple imputation for generalized additive models: an investigation of the median p-value rule with applications to the Pulmonary Hypertension Association Registry and Colorado COVID-19 hospitalization data.

BACKGROUND: Missing data prove troublesome in data analysis; at best they reduce a study's statistical power and at worst they induce bias in parameter estimates. Multiple imputation via chained equations is a popular technique for dealing with missing data. However, techniques for combining and pooling results from fitted generalized additive models (GAMs) after multiple imputation have not been well explored. METHODS: We simulated missing data under MCAR, MAR, and MNAR frameworks and utilized random forest and predictive mean matching imputation to investigate a variety of rules for combining GAMs after multiple imputation with binary and normally distributed outcomes. We compared multiple pooling procedures including the "D2" method, the Cauchy combination test, and the median p-value (MPV) rule. The MPV rule involves simply computing and reporting the median p-value across all imputations. Other ad hoc methods such as a mean p-value rule and a single imputation method are investigated. The viability of these methods in pooling results from B-splines is also examined for normal outcomes. An application of these various pooling techniques is then performed on two case studies, one which examines the effect of elevation on a six-minute walk distance (a normal outcome) for patients with pulmonary arterial hypertension, and the other which examines risk factors for intubation in hospitalized COVID-19 patients (a dichotomous outcome). RESULTS: In comparison to the results from generalized additive models fit on full datasets, the median p-value rule performs as well as if not better than the other methods examined. In situations where the alternative hypothesis is true, the Cauchy combination test appears overpowered and alternative methods appear underpowered, while the median p-value rule yields results similar to those from analyses of complete data. CONCLUSIONS: For pooling results after fitting GAMs to multiply imputed datasets, the median p-value is a simple yet useful approach which balances both power to detect important associations and control of Type I errors.

Lipidome Alterations with Exercise Among People With and Without HIV: An Exploratory Study.

Age-related comorbidities and physical function impairments in aging people with HIV (PWH) can be improved through exercise interventions. The mechanisms underlying these improvements, including lipidomic changes, are unknown. Sedentary adults (50-75 years old) with or without HIV participated in supervised endurance/resistance exercise for 24 weeks. Plasma lipid concentrations (∼1,200 lipid species from 13 lipid classes) at baseline and week 24 were measured by mass spectrometry. Given multiple comparisons, unadjusted and Benjamini-Hochberg corrected p values are reported. Analyses are considered exploratory. Twenty-five PWH and 24 controls had paired samples at baseline and week 24. The change in total triacylglycerol (TAG) concentrations after exercise intervention differed between groups (unadj-p = 0.006, adj-p = 0.078) with concentrations increasing among controls, but not among PWH. Changes in concentrations of TAG species composed of long-chain fatty acids differed between groups (unadj-p < 0.04) with increases among controls, but not among PWH. Changes in total diacylglycerol (DAG) concentration from baseline to week 24 differed between groups (unadj-p = 0.03, adj-p = 0.2) with an increase in PWH and a nonsignificant decrease in controls. Baseline to week 24 changes in DAGs composed of palmitic acid (16:0), palmitoleic acid (16:1), and stearic acid (18:0) differed by serostatus (unadj-p = 0.009-0.03; adj-p 0.10-0.12), with nonsignificant increases and decreases in concentrations in PWH and controls, respectively. Concentrations of individual lysophosphatidylcholine (LPC) and ceramide (CER) species also differed by HIV serostatus (unadj-p < = 0.05). Although exploratory, the effects of exercise on the lipidome may differ among people with and without HIV, potentially due to underlying alterations in lipid processing and fatty acid oxidation in PWH. Clinical Trials NCT02404792.

Predictors of 007 triphosphate concentrations in dried blood spots in persons with hepatitis C and active drug or alcohol use.

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.

The High-Intensity Exercise Study to Attenuate Limitations and Train Habits in Older Adults With HIV (HEALTH): A Research Protocol.

ABSTRACT: The High-Intensity Exercise Study to Attenuate Limitations and Train Habits in Older Adults With HIV (HEALTH), which incorporates an exercise and biobehavioral coaching intervention, has the following overall goals: (a) to determine whether high-intensity interval training (HIIT) mitigates physical function impairments, fatigue, and impairments in mitochondrial bioenergetics of older people living with HIV (PLWH) to a greater extent than continuous moderate exercise (CME); and (b) to determine whether a biobehavioral coaching and mobile health text messaging intervention after HIIT or CME can promote long-term adherence to physical activity. The HEALTH study is a randomized trial of 100 older PLWH (≥50 years of age) who self-report fatigue and have a sedentary lifestyle. Enrolled participants will be randomized to 16 weeks of supervised HIIT or CME training, followed by a 12-week maintenance phase, involving a mobile health coaching intervention. Outcomes of the HEALTH study will inform the development of scalable, effective exercise recommendations tailored to the unique needs of aging PLWH.

Predicting prognosis in COVID-19 patients using machine learning and readily available clinical data.

RATIONALE: Prognostic tools for aiding in the treatment of hospitalized COVID-19 patients could help improve outcome by identifying patients at higher or lower risk of severe disease. The study objective was to develop models to stratify patients by risk of severe outcomes during COVID-19 hospitalization using readily available information at hospital admission. METHODS: Hierarchical ensemble classification models were trained on a set of 229 patients hospitalized with COVID-19 to predict severe outcomes, including ICU admission, development of acute respiratory distress syndrome, or intubation, using easily attainable attributes including basic patient characteristics, vital signs at admission, and basic lab results collected at time of presentation. Each test stratifies patients into groups of increasing risk. An additional cohort of 330 patients was used for blinded, independent validation. Shapley value analysis evaluated which attributes contributed most to the models' predictions of risk. MAIN RESULTS: Test performance was assessed using precision (positive predictive value) and recall (sensitivity) of the final risk groups. All test cut-offs were fixed prior to blinded validation. In development and validation, the tests achieved precision in the lowest risk groups near or above 0.9. The proportion of patients with severe outcomes significantly increased across increasing risk groups. While the importance of attributes varied by test and patient, C-reactive protein, lactate dehydrogenase, and D-dimer were often found to be important in the assignment of risk. CONCLUSIONS: Risk of severe outcomes for patients hospitalized with COVID-19 infection can be assessed using machine learning-based models based on attributes routinely collected at hospital admission.

Tenofovir-diphosphate in peripheral blood mononuclear cells during low, medium and high adherence to emtricitabine/ tenofovir alafenamide vs. emtricitabine/ tenofovir disoproxil fumarate.

OBJECTIVE: Tenofovir alafenamide (TAF) preferentially loads peripheral blood mononuclear cells (PBMCs), 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 preexposure 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% confidence interval (95% CI): 6.4-8.2], 7.1 (5.9-8.2) and 6.7- (4.4-8.9) fold higher (P < 0.0001) following F/TAF vs. F/TDF; 593 vs. 81.7, 407 vs. 57.4, and 215 vs. 32.3 fmol/106 cells, respectively. TFV-DP was 2.6 (2.1-3.1) fold higher with 33% F/TAF vs. 100% F/TDF. Estimated half-lives (95% CI) of TFV-DP in PBMC were 2.9 (1.5-5.5) days for F/TAF and 2.1 (1.5-2.9) days for F/TDF. FTC-TP was similar in both studies (P = 0.119). CONCLUSION: F/TAF produced 6.7 to 7.3-fold higher TFV-DP in PBMC vs. F/TDF across adherence levels, supporting increased potency and pharmacologic forgiveness with F/TAF in the PBMC compartment.

Low-Level Viremia Is Associated With Cumulative Adherence to Antiretroviral Therapy in Persons With HIV.

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 <800; and >1650 to <800, the adjusted odds ratios for LLV vs HIV VL <20 copies/mL were 2.0 (95% CI, 1.2-3.1), 2.4 (95% CI, 1.1-5.0), and 4.6 (95% CI, 2.2-9.9), respectively. This suggests that adherence could impact LLV.