Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisition.

BACKGROUND: The phase 2b proof-of-concept Antibody Mediated Prevention (AMP) trials showed that VRC01, an anti-HIV-1 broadly neutralising antibody (bnAb), prevented acquisition of HIV-1 sensitive to VRC01. To inform future study design and dosing regimen selection of candidate bnAbs, we investigated the association of VRC01 serum concentration with HIV-1 acquisition using AMP trial data. METHODS: The case-control sample included 107 VRC01 recipients who acquired HIV-1 and 82 VRC01 recipients who remained without HIV-1 during the study. We measured VRC01 serum concentrations with a qualified pharmacokinetic (PK) Binding Antibody Multiplex Assay. We employed nonlinear mixed effects PK modelling to estimate daily-grid VRC01 concentrations. Cox regression models were used to assess the association of VRC01 concentration at exposure and baseline body weight, with the hazard of HIV-1 acquisition and prevention efficacy as a function of VRC01 concentration. We also compared fixed dosing vs. body weight-based dosing via simulations. FINDINGS: Estimated VRC01 concentrations in VRC01 recipients without HIV-1 were higher than those in VRC01 recipients who acquired HIV-1. Body weight was inversely associated with HIV-1 acquisition among both placebo and VRC01 recipients but did not modify the prevention efficacy of VRC01. VRC01 concentration was inversely correlated with HIV-1 acquisition, and positively correlated with prevention efficacy of VRC01. Simulation studies suggest that fixed dosing may be comparable to weight-based dosing in overall predicted prevention efficacy. INTERPRETATION: These findings suggest that bnAb serum concentration may be a useful marker for dosing regimen selection, and operationally efficient fixed dosing regimens could be considered for future trials of HIV-1 bnAbs. FUNDING: Was provided by the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID) (UM1 AI068614, to the HIV Vaccine Trials Network [HVTN]; UM1 AI068635, to the HVTN Statistical Data and Management Center [SDMC], Fred Hutchinson Cancer Center [FHCC]; 2R37 054165 to the FHCC; UM1 AI068618, to HVTN Laboratory Center, FHCC; UM1 AI068619, to the HPTN Leadership and Operations Center; UM1 AI068613, to the HIV Prevention Trials Network [HPTN] Laboratory Center; UM1 AI068617, to the HPTN SDMC; and P30 AI027757, to the Center for AIDS Research, Duke University (AI P30 AI064518) and University of Washington (P30 AI027757) Centers for AIDS Research; R37AI054165 from NIAID to the FHCC; and OPP1032144 CA-VIMC Bill & Melinda Gates Foundation.

Adherence to Perioperative Antibiotic Prophylaxis Recommendations and Its Impact on Postoperative Surgical Site Infections.

Introduction Surgical site infections (SSIs) are common and carry a significant risk of morbidity and mortality and lead to increased healthcare costs. Perioperative antibiotic prophylaxis decreases the risk of SSIs. There are several guidelines on the use of perioperative antibiotic prophylaxis. The American College of Surgeons (ACS) recommends weight-based antibiotic administration within 60 minutes prior to (two hours for vancomycin/fluoroquinolones) incision and redosing by drug half-life. There are limited data regarding adherence to existing recommendations. Furthermore, there are scarce data on the relationship between adherence to recommendations and the risk of postoperative SSI. Objectives In this study, we aimed to assess the adherence to ACS guidelines for perioperative antimicrobial prophylaxis in the Seattle Children's Hospital (SCH) National Surgical Quality Improvement Program (NSQIP) pediatric cohort and to determine whether adherence to ACS guidelines is associated with a decreased risk of SSI. the secondary objective was to identify risk factors associated with SSI in our patient population. Materials and methods We conducted a secondary analysis of an institutional NSQIP pediatric data cohort between Jan 1, 2012, and Dec 31, 2017. We calculated summary statistics to assess adherence to ACS recommendations and fit a logistic regression model to identify factors associated with the risk of SSI. Patients who did not receive antibiotic prophylaxis were excluded. Results  A total of 6,072 surgeries among 5,532 patients met the inclusion criteria. Adherence was achieved for weight-based dosing in 35% of surgeries, administration prior to the incision in 91%, administration within 60 minutes (two hours for vancomycin/fluoroquinolones) in 86%, correct redosing in 97%, and to all recommendations in 29%. There were no significant associations between any adherence metrics and SSI, although confidence intervals were wide for some metrics. Factors associated with SSI when adherence was met included urgent case status, wound class 2 or 4, the American Society of Anesthesiologists (ASA) class 2-5, and surgery duration. Conclusion There was varying adherence to ACS recommendations on antibiotic prophylaxis in our cohort. More evidence is needed to better understand the effects of adherence to any or all components of the recommendations on SSI. We identified a group of pediatric patients at risk of SSI and a need for further research and targeted interventions.