Pharmacokinetics and tolerability of cabotegravir and rilpivirine long-acting intramuscular injections to the vastus lateralis (lateral thigh) muscles of healthy adult participants.

Cabotegravir + rilpivirine administered via intramuscular gluteal injections is the first complete long-acting (LA) regimen approved for maintaining HIV-1 virologic suppression. The vastus lateralis (lateral) thigh muscle could be a potential alternative site of administration in circumstances such as injection site fatigue, intolerability, or contraindication for gluteal administration. Cabotegravir and rilpivirine pharmacokinetics and participant tolerability were evaluated following single intramuscular injections to the lateral thigh. Healthy adult participants received 4 weeks of daily oral cabotegravir (30 mg) and rilpivirine (25 mg), followed by a 10- to 14-day washout and single 3 mL intramuscular injections of cabotegravir LA 600 mg and rilpivirine LA 900 mg to the lateral thigh. Safety, tolerability, and pharmacokinetics were evaluated through 52 weeks post injection. Pharmacokinetic parameters were estimated using non-compartmental analysis. Fifteen participants (female at birth, n = 6) enrolled. Median age was 33 years. Median weight was 93.6 kg. Median body mass index was 31.4 kg/m2. One participant withdrew due to pregnancy after oral dosing before receiving an injection. Plasma concentrations at Weeks 4 and 8 were 15.4- and 5.3-fold above the protein-adjusted 90% inhibitory concentration for cabotegravir and 4.7- and 2.4-fold for rilpivirine, respectively. The most common injection site reactions were pain [28/28 (100%)], induration [15/28 (54%)], and swelling [12/28 (42%)]; 94% were Grade 1 or 2. Cabotegravir and rilpivirine plasma pharmacokinetic profiles observed in this study support further evaluation of thigh administration in target populations of people living with HIV-1. Tolerability of cabotegravir + rilpivirine LA intramuscular lateral thigh injections was similar to gluteal administration.

Expanded Multivariable Models to Assist Patient Selection for Long-Acting Cabotegravir + Rilpivirine Treatment: Clinical Utility of a Combination of Patient, Drug Concentration, and Viral Factors Associated With Virologic Failure.

BACKGROUND: Previously reported post hoc multivariable analyses exploring predictors of confirmed virologic failure (CVF) with cabotegravir + rilpivirine long-acting (CAB + RPV LA) were expanded to include data beyond week 48, additional covariates, and additional participants. METHODS: Pooled data from 1651 participants were used to explore dosing regimen (every 4 or every 8 weeks), demographic, viral, and pharmacokinetic covariates as potential predictors of CVF. Prior dosing regimen experience was accounted for using 2 populations. Two models were conducted in each population-baseline factor analyses exploring factors known at baseline and multivariable analyses exploring baseline factors plus postbaseline model-predicted CAB/RPV trough concentrations (4 and 44 weeks postinjection). Retained factors were evaluated to understand their contribution to CVF (alone or in combination). RESULTS: Overall, 1.4% (n = 23/1651) of participants had CVF through 152 weeks. The presence of RPV resistance-associated mutations, human immunodeficiency virus-1 subtype A6/A1, and body mass index ≥30 kg/m2 were associated with an increased risk of CVF (P < .05 adjusted incidence rate ratio), with participants with ≥2 of these baseline factors having a higher risk of CVF. Lower model-predicted CAB/RPV troughs were additional factors retained for multivariable analyses. CONCLUSIONS: The presence of ≥2 baseline factors (RPV resistance-associated mutations, A6/A1 subtype, and/or body mass index ≥30 kg/m2) was associated with increased CVF risk, consistent with prior analyses. Inclusion of initial model-predicted CAB/RPV trough concentrations (≤first quartile) did not improve the prediction of CVF beyond the presence of a combination of ≥2 baseline factors, reinforcing the clinical utility of the baseline factors in the appropriate use of CAB + RPV LA.

Impact of Reduced Preincision Antibiotic Infusion Time on Surgical Site Infection Rates: A Retrospective Cohort Study.

OBJECTIVE: Our objective was to determine the impact of total preincision infusion time on surgical site infections (SSIs) and establish an optimal time threshold for subsequent prospective study. BACKGROUND: SSIs remain a major cause of morbidity. Although regulated, the total time of infusion of preincision antibiotics varies widely. Impact of infusion time on SSI risk is poorly understood. METHODS: All consecutive patients (n = 46,791) undergoing inpatient surgical intervention were retrospectively enrolled (2014-2015) and monitored for 1 year. Primary outcomes: the presence of SSI infection as predicted by reduced preoperative antibiotic infusion time. SECONDARY OUTCOMES: preintervention compliance, the impact of a quality improvement algorithm to optimize infusion time compliance. Multivariate logistic regression of the retrospective cohort demonstrated predictors of infection. Receiver-operating characteristic analysis demonstrated the timing threshold predictive of infection. Cost impact of avoidable infections was analyzed. RESULTS: Only 36.1% of patients received preincision infusion of vancomycin in compliance with national and institutional standards (60-120 min). Cephalosporin infusion times were 53 times more likely to be compliant [odds ratio (OR) 53.33, P < 0.001]. Vancomycin infusion times that were not compliant with national standards (less than standard 60-120 min) did not predict infection. However, significantly noncompliant, reduced preincision infusion time, significantly predicted SSI (<24.6 min infusion, AUC = 0.762). Vancomycin infusion, initiated too close to surgical incision, predicted increased SSI (OR = 4.281, P < 0.001). Implementation of an algorithm to improve infusion time, but not powered to demonstrate infection /reduction, improved vancomycin infusion start time (257% improvement, P < 0.001) and eliminated high-risk infusions (sub-24.6 min). CONCLUSIONS: Initially, vancomycin infusion rarely met national guidelines; however, minimal compliance breach was not associated with SSI implications. The retrospective data here suggest a critical infusion time for infection reduction (24.6 min before incision). Prospective implementation of an algorithm led to 100% compliance. These data suggest that vancomycin administration timing should be studied prospectively.

Validity of the PAI interpersonal scales for measuring the dimensions of the interpersonal circumplex.

Two studies evaluated the validity of the interpersonal scales, Dominance (DOM) and Warmth (WRM), from the Personality Assessment Inventory (PAI; Morey, 1991, 2007) to measure the 2 dimensions of the interpersonal circumplex (IPC). In Study 1, 114 college freshmen completed the PAI and the Interpersonal Adjectives Scale (IAS; Wiggins, 1995). In Study 2, 170 college students completed the PAI and the Inventory of Interpersonal Problems-Short Circumplex (IIP-SC; Soldz, Budman, Demby, & Merry, 1995). The results of both studies supported the convergent validity of DOM and WRM, although discriminant validity was stronger using the IIP-SC as the criterion. Circumplex projections placed DOM and WRM in the appropriate segments of both the IAS and IIP-SC. These findings provide additional support for the validity of the PAI interpersonal scales as measures of the primary dimensions of the IPC.

Initiation of long-acting cabotegravir plus rilpivirine as direct-to-injection or with an oral lead-in in adults with HIV-1 infection: week 124 results of the open-label phase 3 FLAIR study.

BACKGROUND: Previous work established non-inferiority of switching participants who were virologically suppressed from daily oral standard of care to monthly long-acting intramuscular injections of cabotegravir plus rilpivirine over 96 weeks following a cabotegravir plus rilpivirine oral lead-in. Here, we report an evaluation of switching participants from standard of care oral regimens to long-acting cabotegravir plus rilpivirine via direct-to-injection or oral lead-in pathways. METHODS: This study reports the week 124 results of the FLAIR study, an ongoing phase 3, randomised, open-label, multicentre (11 countries) trial. Antiretroviral therapy (ART)-naive participants who were virologically suppressed (HIV-1 RNA <50 copies per mL) during the 20-week induction phase with standard of care were randomly assigned (1:1) to continue the standard of care oral regimen or switch to long-acting cabotegravir plus rilpivirine (283 per group) in the 100-week maintenance phase. Randomisation was stratified by sex at birth and baseline (pre-induction) HIV-1 RNA (<100 000 or ≥100 000 copies per mL). Participants randomly assigned to long-acting therapy at baseline received a cabotegravir (30 mg) plus rilpivirine (25 mg) once daily oral lead-in for at least 4 weeks before first injection and could choose to continue long-acting cabotegravir (400 mg) plus rilpivirine (600 mg) every 4 weeks from week 100 or withdraw. At week 100, participants in the oral comparator ART group, in discussion with the investigator, could elect to switch to long-acting therapy (extension switch population), either direct-to-injection or with a 4 week oral lead-in (oral lead-in group), or withdraw. Week 124 endpoints included plasma HIV-1 RNA 50 or more copies per mL and less than 50 copies per mL (US Food and Drug Administration [FDA] Snapshot), confirmed virological failure (two consecutive HIV-1 RNA ≥200 copies per mL), and safety and tolerability. The study is registered at ClinicalTrials.gov, NCT02938520. FINDINGS: Screening occurred between Oct 27, 2016, and March 24, 2017. At week 100, 232 (92%) of 253 participants transitioned to long-acting cabotegravir plus rilpivirine in the extension phase (111 [48%] in the direct-to-injection group and 121 [52%] in the oral lead-in group; extension switch population). 243 (86%) of the 283 who were randomly assigned to the long-acting therapy group continued the long-acting regimen into the extension phase. One (<1%) participant in each extension switch group had 50 or more HIV-1 RNA copies per mL; 110 (99%) participants in the direct-to-injection group and 113 (93%) participants in the oral lead-in group remained suppressed (HIV-1 RNA <50 copies per mL) at the week 124 Snapshot. The lower suppression rates in the oral lead-in group were driven by non-virological reasons. For participants in the randomly assigned long-acting group, 227 (80%) of 283 participants remained suppressed; at the week 124 Snapshot, 14 (5%) participants had HIV-1 RNA 50 or more copies per mL, including five additional participants since the week 96 analysis. The remaining 42 (15%) participants in the randomly assigned long-acting group had no virological data. Adverse events leading to withdrawal were infrequent, occurring in three (1%) participants in the extension switch population (one in the direct-to-injection group and two in the oral lead-in group) after 24 weeks of cabotegravir plus rilpivirine therapy, and 15 (5%) participants in the randomly assigned long-acting group up to 124 weeks of therapy. No deaths occurred in the extension phase. Overall, cabotegravir plus rilpivirine adverse event type, severity, and frequency were similar across all groups. Injection site reactions were the most common adverse event, occurring after 914 (21%) of 4442 injections in the extension switch population and 3732 (21%) of 17 392 injections in the randomly assigned long-acting group. Injection site reactions were mostly classified as mild-to-moderate in severity and decreased in incidence over time. Four (2%) of 232 participants in the extension switch population and seven (2%) of 283 in the randomly assigned long-acting group withdrew due to injection-related reasons. INTERPRETATION: After 24 weeks of follow-up, switching to long-acting treatment with or without an oral lead-in phase had similar safety, tolerability, and efficacy, supporting future evaluation of the simpler direct-to-injection approach. The week 124 results for participants randomly assigned originally to the long-acting therapy show long-acting cabotegravir plus rilpivirine remains a durable maintenance therapy with a favourable safety profile. FUNDING: ViiV Healthcare and Janssen Research & Development.

Psychometric characteristics of the Inventory of Interpersonal Problems-Short Circumplex (IIP-SC) with college students.

The Inventory of Interpersonal Problems-Circumplex (IIP-C; Alden, Wiggins, & Pincus, 1990) is a commonly used measure, and the Short Circumplex Version (IIP-SC; Soldz, Budman, Demby, & Merry, 1995) provides a potentially valuable and economical method for personality assessment researchers. However, despite the common use of the IIP-C with college students, the psychometric characteristics of the IIP-SC have not been established in a college student sample. This study provides reliability, structural validity, concurrent validity, and descriptive data for the IIP-SC in two samples of undergraduate students.