bluuebunny/crossref_metadata_2025 huggingface dataset:
39. Anti-Spike Monoclonal Antibody Therapy for Kidney Transplant Recipients with COVID-19
Authors: Hardesty Anna , Klein Elizabeth , Vieira Kendra , Farmakiotis Dimitrios
Published: December 2021

Background

Organ transplant recipients may not mount an adequate immune response to COVID-19 infection, and therefore may benefit greatly from passive immunization with anti-spike monoclonal antibodies (mAb), which have been shown to decrease hospitalization rates in the general outpatient population. We evaluated the efficacy of mAb therapy in decreasing hospitalizations or emergency room (ER) visits among kidney transplant recipients (KTR) with COVID-19.

Methods

We identified KTR with COVID-19 between 3/1/2020 and 4/30/2021. Patients were excluded if they had multiorgan transplant or hospital-acquired COVID-19. Data were analyzed by Cox regression with mAb administration as time-dependent variable, and the day of symptom onset as baseline.

Results

We studied 95 KTR; 20 received mAb. Comorbidities and immunosuppression were balanced between the two groups. mAb administration was associated with a significant decrease in hospitalizations or ER visits (15 vs. 76%, P< 0.001). This association remained significant after adjustment for confounders and by analyzing mAb administration as a time-dependent variable (Table: adj. HR 0.2, P=0.04). No KTR who received mAb died or required mechanical ventilation. Black or Hispanic KTR were less likely to receive mAb and more likely to be admitted to the hospital or visit the ER (Table).

Table

Factors significantly associated with hospitalization or ER visit.

Conclusion

In our KTR population, mAb therapy for COVID-19 may have helped decrease hospitalizations and ER visits. Healthcare inequities, including access to investigational treatments, were exacerbated by the COVID-19 pandemic. Acknowledging the nonconcurrent control group as a limitation, we found a strong signal for benefit from mAb treatment. Antiviral mAb are a promising therapeutic modality for immunosuppressed patients.

Disclosures

Dimitrios Farmakiotis, M.D., Astellas (Grant/Research Support)Merck (Grant/Research Support)Viracor (Grant/Research Support)
43. SARS-CoV-2 Cycle threshold (Ct) values predict future COVID-19 cases
Authors: Phillips Matthew , Quintero David , Butler-Wu Susan
Published: December 2021

Background

The threat of surging COVID-19 cases prompted many hospitals in the United States to preemptively suspend elective procedures throughout the pandemic. Utilizing samples from a large hospital in Los Angeles, we sought to determine if temporal trends in SARS-CoV-2 Cycle threshold (Ct) values (proxy for viral RNA loads) were predictive for the number of future COVID-19 cases.

Methods

Nasopharyngeal specimens on symptomatic patients and asymptomatic admissions were tested using the Xpert Xpress SARS-CoV-2 and SARS-CoV-2/Flu/RSV assays (Cepheid). Ct values for all SARS-CoV-2 detections between October 2020 to March 2021 were compiled for analysis.

Results

A total of 2,114 SARS-CoV-2-positive samples were included. The number of tests performed per week increased dramatically in December peaking the first week of January before returning to pre-surge numbers by Mid-February. Ct values fell during this same period with values in December and January (25.6±7.8 and 27±7.9, respectively) significantly lower than those of the other months (30±9.3 to 37.7±6.3). Average weekly Ct values for all patients were significantly, negatively correlated with the number of tests run the following week (R= -0.71, P< 0.001) and two weeks later (R= -0.75, P< 0.0001). Ct values for patients who were asymptomatic at the time of testing most strongly correlated with total number of tests performed one month later (R= -0.86, P< 0.0001).

Average weekly Ct values and number of test run

As cases (light grey) increased during December and January, there was a significant decrease in Ct values (dark grey) during that same time period.

Average Ct values are a leading indicator of cases

Average weekly Ct values for all patients (light grey) were significantly, negatively correlated with the number of tests run the following week (R= -0.71, P<0.001) and two weeks later (R= -0.75, P<0.0001). Ct values for patients who were asymptomatic at the time of testing (dark grey) most strongly correlated with total number of tests performed one month later (R= -0.86, P<0.0001).

Conclusion

Lower Ct values, representing higher levels of viral RNA, have been associated with risk of intubation and infectivity. During the winter surge, we observed significantly lower Ct values suggesting that the increased transmission and morbidity of COVID-19 was temporarily associated with higher viral loads. Interestingly, Ct values for asymptomatic patients were most strongly associated with number of cases observed 1 months in the future, suggesting that asymptomatic viral load may be a leading indicator for forthcoming outbreaks. Given this association, Ct values may be a useful tool for predicting regional outbreaks of COVID-19 and more judicious cessation of elective procedures.

Disclosures

All Authors: No reported disclosures
48. Time Between Viral Loads for Suppressed and Non-Suppressed People with HIV During the COVID-19 Pandemic Compared to Pre-Pandemic
Authors: El-Nahal Walid , Shen Nicola , Lesko Catherine , Fojo Anthony , Lau Bryan , Keruly Jeanne , Manabe Yukari C , Jones Joyce , Moore Richard , Gebo Kelly , Chander Geetanjali
Published: December 2021

Background

During the COVID-19 pandemic, patients at the John G. Bartlett Specialty practice experienced disruptions in viral load (VL) monitoring due to 1) conversion to telemedicine visits and 2) closure of the onsite lab from March 16-July 13, 2021. We described the impact of the pandemic on VL monitoring.

Methods

We measured time from all index VLs collected during 3 periods: January 1, 2019 to March 15, 2020 (pre-pandemic); March 16 to July 12, 2020 (pandemic, closed onsite lab); and July 13 to December 31, 2020 (pandemic, open onsite lab) until a subsequent VL, 1 year after the index VL, or administrative censoring on December 31, 2020, whichever came first. We classified follow-up time according to these periods (treating period as a time-varying variable). We report hazard ratios (HRs) and 95% Confidence Intervals (CI) from a Cox proportional hazards model comparing the hazard of a VL during the pandemic periods to the pre-pandemic period, stratified by whether the index VL was suppressed (≤200 copies/mL). We tested for interactions between patient characteristics (age, sex at birth, race, ethnicity, and recent substance use) and period, to investigate differential effects of the pandemic on delayed VL.

Results

After 7,760 suppressed VL measurements, median times to subsequent VL during the pre-pandemic, pandemic (closed lab) and pandemic (open lab) periods, were 4.6 (HR=1.0), 8.9 (HR=0.34, CI:0.30, 0.37), and 5.8 (HR=0.73, CI:0.68,0.78) months respectively. After 1,025 non-suppressed VL measurements, median times to subsequent VL were 2.0 (HR=1.0), 3.9 (HR=0.57, CI:0.42,0.79), and 2.1 (HR=0.92, CI:0.76,1.10) months respectively. Time to subsequent VL after an index suppressed VL was less affected by the pandemic for patients who are white; had private insurance; or had no recent cocaine or heroin use. The effect of the pandemic on time to subsequent VL after a non-suppressed index VL did not significantly differ across patient characteristics.

Conclusion

Onsite lab closure disrupted VL collection for all groups. Once the onsite lab opened, the pandemic period was still associated with a delay among suppressed patients, but not non-suppressed patients. Further studies are needed to investigate if these delays are associated with lapses in viral suppression.

Disclosures

All Authors: No reported disclosures
51. Patient Reported Outcomes Collection: A Mixed Methods Study at an urban HIV Clinic associated with a Historically Black Medical College in the Southern United States
Authors: Parisot Paul , Wheeler Facerlyn , Bonnet Kemberlee , Rebeiro Peter F , McCainster Korlu , Cooper Robert , Berthaud Vladimir , Schlundt David , Pettit April
Published: December 2021

Background

Black Americans, particularly in the South, are disproportionately affected by the US HIV epidemic. We piloted the use of an electronic tablet to collect patient reported outcomes (PRO) data on social and behavioral determinants of health among people with HIV (PWH) at the Meharry Community Wellness Center (MCWC), an HIV clinic affiliated with a Historically Black Medical College in Nashville, Tennessee. Studies have shown PRO collection can improve patient outcomes and provide oft-overlooked data on mental health, substance use, and patient adherence to ART.

Methods

We enrolled 100 PWH in care at the MCWC consecutively to complete validated PRO tools (Table 1) using the Research Electronic Data Capture (REDCap) platform on a hand-held tablet. Using a purposive sampling strategy, we enrolled 20 of the 100 participants in an in-depth interview (IDI). Interview guide development was grounded in the Cognitive Behavioral Model in which thoughts, feelings, and behaviors are inter-related. IDIs were audio recorded, transcribed, de-identified, and formatted for coding. A hierarchical coding system was developed and refined using an inductive-deductive approach.

Results

Among 100 PWH enrolled, median age was 50 years, 89% were Black, 60% were male, and 82% were living below 100% of the Federal Poverty Level. IDI participants felt the tablet was easy to use and the question content was meaningful. Question content related to trauma, sexual and drug use behaviors, mental health, stigma, and discrimination elicited uncomfortable or distressing feelings in some participants. Patients expressed a strong desire to be truthful and most would complete these surveys without compensation at future visits if offered.

Conclusion

The use of an electronic tablet to complete PRO data collection was feasible and well received by this cohort of vulnerable persons in HIV care in the US South. Despite some discomfort, our cohort overwhelmingly believed this was a valuable part of their medical experience. Real-time PRO data collection allows providers to screen for and act on social and behavioral determinants of health. Future research will focus on scaling up the implementation and evaluation of PRO data collection in a contextually appropriate manner.

Disclosures

Peter F. Rebeiro, PhD, MHS, Gilead (Other Financial or Material Support, Single Honorarium for an Expert Panel)
52. PrEP Adherence and Discontinuation at a Pharmacy-Supported PrEP Program in Atlanta, GA
Authors: Yacout Hiba , Smith Bradley L , Foster Shelbie , Lora Meredith , Niles-Carnes Laris , Zheng Ziduo , Kundu Suprateek , Gruen Judah K , Cantos Valeria D
Published: December 2021

Background

Pre-exposure prophylaxis (PrEP) is a highly effective biomedical strategy to decrease Human Immunodeficiency Virus (HIV) acquisition. Effectiveness of oral PrEP is linked to medication adherence. In 2018, Grady Health System (GHS) launched a PrEP program to increase PrEP access among un- and underinsured individuals living in metro Atlanta, Georgia. The purpose of this study is to determine PrEP medication adherence, PrEP discontinuation rates, and associated individual factors of patients enrolled during the first 18 months of the program’s implementation.

Methods

A single-center, retrospective chart review was conducted on patients enrolled in the GHS PrEP program between June 1, 2018 and February 29, 2020 who received more than one monthly PrEP prescription. Adherence was estimated using the medication possession ratio (MPR). The primary outcome was mean adherence to PrEP. Secondary outcomes include rate of high percent adherence (MPR > 80%), median time of engagement in care, PrEP discontinuation rates, rates of PrEP re-engagement, and individual factors associated with PrEP discontinuation and low adherence.

Results

This study included 154 patients, 70.8% of them were Black, 62.3% were cisgender men, 59.1% were uninsured, and the mean age was 34. The majority of patients identified as men who have sex with men (51.9%). Mean PrEP adherence was 89.2%; 77.3% of patients demonstrated a high rate of adherence. No individual or social factors were associated with low adherence, but younger age was associated with higher rates of PrEP discontinuation (p< 0.0061). At the end of the follow up period on October 30, 2020, 53.8% of patients were active in the program and 12.7% of those who discontinued had re-engaged with the program. The average length of program engagement was 9.8 months.

Table 1. Baseline socio-demographic characteristics (N=154)

Table 2. PrEP Adherence and Discontinuation at the GHS PrEP Program from 2018 to 2020 (N=154)

Table 4. Multivariate analysis of individual factors associated with PrEP discontinuation and low adherence

Conclusion

Mean PrEP adherence at a safety net PrEP program in Atlanta was high and PrEP discontinuation rates were comparable to other PrEP clinics nationwide. We found no association with individual factors previously linked to lower adherence, including Black race, younger age, and insurance status. Program-related factors that may have impacted these findings need to be investigated. Other future areas of research include strategies to optimize engagement in care in younger patients.

Disclosures

Bradley L. Smith, Pharm.D., AAHIVP, Gilead Sciences, Inc (Advisor or Review Panel member)
54. Self-Perception of Risk for HIV Acquisition and Calculated Risk for HIV Acquisition Among Active Duty Air Force Members with Newly Diagnosed HIV Infection
Authors: Schmid Audie B , Okulicz Jason , Hakre Shilpa , Yabes Joseph , Mika Walter V
Published: December 2021

Background

Persons may underestimate their risk of HIV infection despite presence of risk factors. Accurate appraisal of HIV risk may assist both patients and providers in preventing HIV acquisition. We evaluated self-perceived risk (SPR) versus calculated risk (CR) of HIV infection in active duty US Air Force (USAF) members with incident HIV infection.

Methods

USAF members with new HIV diagnosis evaluated at a specialty care military medical center between January 2015-March 2020 with available case report forms were included (n=142). Chart reviews were performed and demographic, social, and clinical characteristics were collected from initial Infectious Disease specialty encounters and case report forms. SPR was characterized as Low or High and compared to CR derived by the Denver HIV Risk Score (DHRS) by points based on patient demographic and risk exposure characteristics.

Results

Overall, patients were predominantly male (98%), with a median age of 26 years (IQR 22-30), and the majority (85%) reported same-sex partners (Table 1). Patients more commonly characterized themselves as Low SPR (n=78; 55%) than High SPR (n=64; 45%). Demographic characteristics were similar except a higher proportion of Low SPR patients (29%) were married or partnered compared to High SPR patients (14%; p=0.04). There was no difference in self-reported condom use (≥50% of the time) between Low (63%) and High (72%) SPR patients (p=0.28) and documented history of sexually transmitted infections was similarly high in both groups ( >70%; p=0.85). Previous HIV pre-exposure prophylaxis (PrEP) use was uncommon in both Low SPR (8%) and High SPR (6%) groups. For the evaluation of CR by DHRS (Table 2), both Low and High SPR groups had median scores in the very high risk category (≥50 points) with similar results by test component.

Conclusion

USAF members with incident HIV infection more commonly identified with low SPR despite similar risk behaviors and CRs as high SPR patients. The development of patient education programs and promotion of HIV prevention services including PrEP are needed to reduce incident HIV cases in the USAF. Validated HIV risk calculators like the DHRS may also assist medical providers in identifying candidates for HIV prevention services.

Disclosures

All Authors: No reported disclosures
55. Infective Endocarditis After Surgical or Transcatheter Aortic Valve Replacement
Authors: Papamanoli Aikaterini , Muncan Brandon , Parikh Puja , Skopicki Hal A , Kalogeropoulos Andreas
Published: December 2021

Background

Infective endocarditis (IE) can complicate both surgical aortic valve replacement (SAVR) and transcatheter aortic valve implantation (TAVI) with significant morbidity and mortality despite differing pathogenesis. In the presence of limited data from direct comparison studies and recent expansion of TAVI to younger and lower- risk patients, we compared the incidence and timing of IE in TAVI versus SAVR.

Methods

Using data from the TriNetX electronic health records network, we identified (1) a cohort of patients who underwent TAVI between January 2016 and December 2020 (CPT procedure code 1021150) and (2) a propensity score-matched cohort of patients who underwent SAVR (CPT procedure codes 1035167 or 1029693, without any associated transcatheter procedure). We examined the incidence of IE (captured with ICD-10 codes I33, I38, or I39) over a 5-year follow up period and matched the cohorts for demographic data and clinically relevant background history. We used Kaplan-Meier estimates and Cox proportional hazards models to compare incidence between matched cohorts.

Results

We identified 6,302 patients with TAVI and 6,302 matched patients with SAVR. The baseline characteristics of the cohorts were well balanced, Table 1. All standardized mean differences were < 0.05, indicating adequate matching between cohorts. The Kaplan-Meier mortality at 5 years was 38.0% in the TAVI vs. 22.0% in the SAVR cohort (log-rank P < 0.001). There were 290 cases with IE in the TAVI and 604 cases in the SAVR cohort. The corresponding 5-year event rates were 10.0% vs. 16.9% (log-rank P < 0.001), respectively, Figure 1. The risk ratio of TAVI vs. SAVR related IE over the entire 5-year period was 0.48 (95%CI 0.42 — 0.55; P < 0.001). However, the relative risk for IE was non-proportional between groups over the 5-year period, with an early pronounced incidence among SAVR relative to TAVI patients and gradual convergence of the hazard rates over time, Figure 2.

Figure 1. Cumulative 5-Year Incidence (Kaplan-Meier Estimates) of Infective Endocarditis Among Matched Transcatheter Aortic Valve Implantation (TAVI) vs. Surgical Aortic Valve Replacement (SAVR) Recipients

Figure 2. Risk of Infective Endocarditis in SAVR vs. TAVI Recipients Over Time

Conclusion

In this comparative study, the risk for IE was lower among TAVI vs. SAVR recipients, primarily due to the higher risk of IE during the early post-SAVR period. With increasing uptake of TAVI procedures, a better understanding of the temporal occurrence and pathophysiology of IE and application of effective treatment strategies in these patients is required.

Disclosures

All Authors: No reported disclosures
56. Long-Term Cardiovascular Outcomes After Drug-Related vs Non-Drug-Related Infective Endocarditis
Authors: Muncan Brandon , Papamanoli Aikaterini , Skopicki Hal A , Kalogeropoulos Andreas
Published: December 2021

Background

Drug use-related infective endocarditis (IE) has nearly doubled in the past two decades in the United States, largely due to the current opioid crisis. Although there are robust data on surgical outcomes for people who use drugs (PWUD) vs. non-PWUD patients after an initial encounter for IE, long-term comparative data on post-IE outcomes are relatively sparse.

Methods

Using data from the TriNetX electronic health records network, we identified (1) a cohort of patients 16 to 64 years old who had a first encounter for IE (captured with ICD-10 codes I33, I38, or I39) and history of drug use (captured with ICD-10 codes F11, F13-F16, F18, F19, O99.32, or T40) preceding the IE episode and (2) a propensity score-matched cohort of patients age 16-64 who had a first episode of IE and no documented drug use. We compared the post-IE incidence of (1) mortality; (2) ischemic stroke; (3) intracranial hemorrhage; (4) myocardial infarction; (5) heart failure; and (6) sudden cardiac death (cardiac arrest or ventricular fibrillation or tachycardia) between the 2 cohorts over a 5-year follow up period. We matched the cohorts for demographic data and clinically relevant medical history. We used Kaplan-Meier estimates and Cox models to compare incidence.

Results

We identified 6,578 PWUD patients and 6,578 matched non-PWUD patients 16-64 years old with a first episode of IE. The baseline characteristics are summarized in Table 1. Standardized mean differences of characteristics were generally < 0.1, indicating adequate matching. The 5-year Kaplan-Meier rates of outcomes of interest are summarized in Table 2. Mortality did not differ between cohorts. However, the incidence of ischemic stroke and intracranial hemorrhage was consistently higher among PWUD throughout the 5-year follow-up. Rates of myocardial infarction were also higher among PWUD; however, the difference was more pronounced later during follow-up. Rates of heart failure and sudden cardiac death did not differ.

Conclusion

Cardiovascular events after IE were common among both PWUD and non-PWUD patients over a 5-year follow-up period. However, rates of ischemic and hemorrhagic stroke were consistently higher among PWUD. Further investigation is needed to elucidate the sources of elevated stroke risk among PWUD and identify targets for intervention.

Disclosures

All Authors: No reported disclosures
57. Evaluation of the 2019 European Heart Rhythm Association International Consensus Document in Patients with Cardiovascular Implantable Electronic Devices Who Develop Staphylococcus aureus Bacteremia
Authors: Chesdachai Supavit , Baddour Larry M , Sohail Muhammad R , Palraj Raj , Madhavan Malini , Tabaja Hussam , Fida Madiha , DeSimone Daniel
Published: December 2021

Background

Cardiovascular implantable electronic device (CIED) implantation has markedly increased over the past two decades. Staphylococcus aureus bacteremia (SAB) occurs in patients with CIED and determination of device infection among patients without clinical findings of pocket site infection is often difficult. Our study examines the characteristics, management, and outcomes of SAB in patients living with CIED using 2019 international criteria to define CIED infection.

Methods

We conducted a retrospective study of patients with CIED who were hospitalized at Mayo Clinic, Rochester, with SAB from January 1, 2012 to December 31, 2019. Patients who met CIED infection criteria following SAB based on the 2019 European Heart Rhythm Association International Concensus Document were identified. A time-to-event analysis was used to determine the impact, if any, of complete device extraction on outcomes.

Results

Overall, 110 patients with CIED developed SAB and 92 (83.6%) of them underwent transesophageal echocardiogram (TEE). Eighty-eight (80%) had CIED infection with 57 (51.8%) and 31 (28.2%) patients meeeting criteria for definite and possible CIED infections, respectively. Forty-three (75.4%) patients with definite CIED infection underwent complete device extraction. For possible and rejected CIED infection, the rates of complete device extraction were 35.5% and 27.3%, respectively (p< .001 for each). The primary endpoint of a composite of one-year mortality and SAB relapse had a rate that was significantly lower in patients with CIED infection who underwent complete device extraction as compared to that of patients who did not undergo device extraction (25.9% vs. 76.5%, p< .001). No significant difference in outcomes was seen in the rejected CIED infection group (33.3% vs. 62.5%, p =.27).

Conclusion

The rate of CIED infections following SAB was higher than that reported previously. Increased use of TEE and a novel case definition with broader diagnostic criteria were likely operative, in part, in accounting for the the higher rate of CIED infections complicating SAB. Complete device removal is critical in patients with either definite or possible CIED infection as defined by the 2019 consensus document to improve one-year mortality and SAB relapse rates.

Disclosures

Larry M. Baddour, MD, Boston Scientific (Individual(s) Involved: Self): Consultant; Botanix Pharmaceuticals (Individual(s) Involved: Self): Consultant; Roivant Sciences (Individual(s) Involved: Self): Consultant Muhammad R. Sohail, MD, Medtronic (Consultant)Philips (Consultant)
61. Short- versus prolonged-courses of antimicrobial therapy for patients with uncomplicated Pseudomonas aeruginosa bloodstream infection
Authors: Bae Moonsuk , Jeong Yun-Seo , Bae Seongman , Kim Min Jae , Chong Yong Pil , Kim Sung-Han , Lee Sang-Oh , Choi Sang-Ho , Kim Yang Soo , Jung Jiwon
Published: December 2021

Background

The optimal duration of antimicrobial therapy for uncomplicated Pseudomonas aeruginosa bloodstream infection (BSI) is unknown. We compared the outcomes of short and prolonged courses of antimicrobial therapy in adults with uncomplicated pseudomonal BSI.

Methods

All patients with uncomplicated P. aeruginosa BSI admitted at a tertiary-care hospital from May 2016 to September 2020 were included. We compared the rate of recurrent P. aeruginosa infection and 30-day mortality among patients who underwent short (7‒11 days) and prolonged (12‒21 days) courses of antimicrobial therapy using propensity score analysis with the inverse probability of treatment weighting (IPTW) method.

Results

We evaluated 1,477 patients with uncomplicated P. aeruginosa BSI; of them, 290 met the eligibility criteria, including 97 (33%) who underwent short-course therapy (9 [interquartile range (IQR), 8‒11] days) and 193 (67%) who underwent prolonged-course therapy (15 [IQR, 14‒18] days). We found no significant difference in the risk of recurrence or 30-day mortality between the prolonged-course and short-course groups (n=10, 11% vs. n=32, 16%; IPTW-adjusted hazard ratio (HR) 0.61; 95% confidence interval (CI) 0.30−1.24; p=0.17). The recurrence of P. aeruginosa infection at any site within 180 days of completing therapy occurred significantly more in the prolonged-course group (n=10, 10% vs. n=38, 20%; IPTW-adjusted HR 0.48; 95% CI 0.24−0.96, p=0.04). The resistance acquisition in subsequent P. aeruginosa isolates was more frequent in the prolonged-course group, although the difference was not statistically significant (n=2, 20% vs. n=12, 32%; p=0.70).

Conclusion

Short-course antimicrobial therapy could be as effective as prolonged-course therapy for uncomplicated P. aeruginosa bloodstream infection.

Disclosures

All Authors: No reported disclosures
64. Novel Biomarkers Improve Estimation of Vancomycin Clearance in Critically Ill Children
Authors: Downes Kevin J , Zuppa Athena F , Sharova Anna , Gianchetti Lauren , Duffey Emily , Goldstein Stuart L , Neely Michael
Published: December 2021

Background

There are a paucity of robust population PK (popPK) models to inform vancomycin (VAN) dosing in critically ill children. The majority of published models incorporate peak/trough data and rely on flawed estimates of renal function. We sought to develop a popPK model for IV VAN in critically ill children utilizing novel plasma and urinary biomarkers.

Methods

We conducted a prospective observational study of critically ill children prescribed VAN for a suspected infection in the CHOP pediatric ICU. Children < 1 year of age and those receiving ECMO or CRRT were excluded. Five VAN samples were collected from a single dosing interval for each subject. Plasma biomarkers (creatinine [Cr], cystatin C [CysC], NGAL) and urinary biomarkers (CysC, NGAL, KIM-1, osteopontin) were collected the morning of PK sampling; urinary biomarkers were corrected for urine creatinine. Nonparametric popPK modeling was performed using Pmetrics. The impact of renal function (GFR) on VAN clearance (CL) was estimated first, comparing model performance with each biomarker (Cr and plasma CysC). The influence of age, sex, additional biomarkers, PIM3 score, and receipt of vasopressors as covariates was then assessed for relevant PK parameters.

Results

30 subjects completed the study. Median age was 10 years (range 1-17); 76% were male. The majority (90%) of children received VAN for suspected sepsis. PK sampling occurred at a median of 37.7 hours (range 24.6-94.8) into VAN treatment; 136 VAN samples were included. A 2-compartment model with fixed allometric scaling of 0.75 on clearances and 1 on volumes best described the data. CysC-based GFR as a covariate on VAN CL using the HOEK formula (GFR = -4.32 + (80.35/CysC)) resulted in the best model fit. Age and plasma NGAL were also informative on VAN CL in the final model (Figure 1). During model building, urinary NGAL was also associated with VAN CL (comparable to plasma NGAL) and outperformed Cr, although it was not retained in the final model.

Figure 1. Final population PK model and parameter estimates.

Conclusion

Plasma CysC is a better renal function estimate than Cr to inform VAN clearance in critically ill children. Urinary and plasma NGAL also improved estimation of VAN CL during popPK modeling. Novel biomarkers can better describe VAN exposures in critically ill children than reliance on Cr alone.

Disclosures

Kevin J. Downes, MD, Merck (Individual(s) Involved: Self): Grant/Research Support Stuart L. Goldstein, MD, Bioporto (Consultant, Grant/Research Support)
65. In Vivo Efficacy of Human Simulated Minocycline (MIN) against Stenotrophomonas maltophilia (STM)
Authors: Fratoni Andrew J , Nicolau David P , Kuti Joseph L
Published: December 2021

Background

The current susceptibility breakpoint for MIN against STM is 4mg/L, yielding >99% of isolates susceptible. Unfortunately, there are limited pre-clinical and clinical data to support this breakpoint for STM. The purpose of this study was to evaluate the efficacy of a MIN human simulated regimen (HSR) against STM across a wide range of MICs in the murine neutropenic thigh model.

Methods

Clinical STM with modal MIN MICS of 0.25-8mg/L were included. Confirmatory pharmacokinetic (PK) studies were performed in infected neutropenic mice to develop a MIN HSR providing an area under the curve (AUC) and maximum concentration (Cmax) exposure similar to MIN 100mg intravenous (IV) q12h at steady-state based on PK parameters from critically ill adult patients. The murine neutropenic thigh infection model was utilized to examine the antibacterial effects of the confirmed MIN HSR against 17 STM. Both thighs of neutropenic ICR mice were inoculated with bacterial suspensions of 107 colony forming units (CFU)/mL. Two hours after inoculation, the MIN HSR was administered subcutaneously (SC) over 24h. Control mice received normal saline. Efficacy was measured as the change in log10CFU/thigh at 24h compared with 0h controls.

Results

MIN 22, 10, 14, and 10mg/kg dosed SC at 0, 6, 12, and 18h best recapitulated the human Cmax and AUC profile. Mean ± standard deviation bacterial burden at 0h across all isolates was 6.03±0.32 log10CFU/thigh. Bacterial growth was 1.35±0.68 log10CFU/thigh in 24h controls. Six of 7 isolates (86%) with MIC ≤ 0.5mg/L achieved 1-log kill with MIN HSR (-1.44±1.37 log10CFU/thigh). All STM with MIC ≥ 1mg/L experienced bacterial growth (1.18±0.79 log10CFU/thigh) (Figure).

Figure. Efficacy of a minocycline human simulated exposure of 100mg intravenous Q12h in the murine neutropenic thigh model against 17 clinical Stenotrophomonas maltophilia isolates

Conclusion

These data describe the in vivo efficacy of a MIN HSR with exposures similar to MIN 100mg IV q12h in critically ill adults. Lack of antibacterial activity against STM with MICs ≥ 1mg/L justifies a reassessment of the current susceptibility breakpoint.

The study was funded under FDA Contract 75F40120C00171.

Disclosures

David P. Nicolau, PharmD, Abbvie, Cepheid, Merck, Paratek, Pfizer, Wockhardt, Shionogi, Tetraphase (Other Financial or Material Support, I have been a consultant, speakers bureau member, or have received research funding from the above listed companies.) Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)BioMérieux (Consultant, Research Grant or Support, Speaker’s Bureau)Contrafect (Scientific Research Study Investigator)GSK (Consultant)Merck (Research Grant or Support)Paratek (Speaker’s Bureau)Roche Diagnostics (Research Grant or Support)Shionogi (Research Grant or Support)Summit (Scientific Research Study Investigator)
67. Agreement Among Bayesian Dosing Software for Calculating Vancomycin Area Under the Curve
Authors: Pineda Ross , Kanatani Meganne , Davis Matthew R , Sim Myung-Shin , Deville Jaime , Pham Christine
Published: December 2021

This abstract has been withdrawn.
72. Massive Weight Gain in People with HIV (PWH) Starting Initial Antiretroviral Therapy (ART): Risk Factors and Predictive Ability of Early Weight Gain
Authors: Phupitakphol Tanit , McEwen Dean , Hawkins Kellie , Gardner Edward
Published: December 2021

Background

Using a clinic cohort of ART naïve PWH, we sought to understand factors associated with massive weight gain as well as to assess if early weight gain could help predict massive weight gain at two years.

Methods

This was a retrospective cohort study of PWH from a large, urban clinic initiating first ART from January 2005 through March 2019, who had 21 – 27 months follow-up without ART changes, and were suppressed (HIV-RNA < 200 cps/ml) during that time. We defined massive weight gain as the top 20% of weight gainers at two years measured by percent (%) gain compared to baseline. Using bivariate and multivariate logistic regression (including factors in bivariate analysis with p< 0.20), we assessed the association of demographics, ART regimen, baseline CD4 count, HIV viral load, and body mass index (BMI) with weight gain at 2 years. We also assessed early weight gain (between 4 and 12 wks) and its association with massive weight gain at two years.

Results

Of 266 PWH included (table1), the median age was 36 years (IQR 29 - 45), 9% were women, 14% black, and 43% Latino. Overall, median % weight gain at 2 years was 4% (-1.1 – 11.6) In bivariate analyses, baseline factors significantly associated with massive weight gain included lower CD4 count, higher viral load, and lower baseline BMI. In multivariate analysis the odds of having massive weight gain were higher with lower CD4 count, adjusted odds ratio (aOR) 0.8 (95% CI 0.6 – 0.9) per 100 cells/ul increase and higher viral load, aOR 2.6 (95% CI 1.4 – 4.6) per 1 log increase. Early weights were available for 217 individuals at a median of 56 days (IQR 44 – 63) after ART initiation. Early weight gain correlated with % weight gain at 2 years (R=0.58). Individuals with ≤ 3% early weight gain represented 66% of the population and had a 10% risk (14 of 144) of having massive weight gain at 2 years. In contrast, 43 individuals had > 5% early weight gain and their risk of massive weight gain at 2 years was 56% (24 of 43).

Conclusion

In this real-world dataset, drug class or specific NRTI use was not associated with massive weight gain which was primarily dependent on baseline CD4 count and HIV viral load. There was a moderate correlation between early weight gain and massive weight gain at 2 years which can help with patient counseling and interventions aimed at slowing weight gain in this population.

Disclosures

All Authors: No reported disclosures
73. Interim Resistance Analysis of Long-Acting Lenacapavir in Treatment-Naïve People with HIV at 28 Weeks
Authors: VanderVeen Laurie , Margot Nicolas , Naik Vidula , Chang Silvia , Martin Ross , Dvory-Sobol Hadas , Rhee Martin , Callebaut Christian
Published: December 2021

Background

Lenacapavir (LEN) is a first-in-class HIV-1 capsid (CA) inhibitor in clinical development for treatment and prevention of HIV-1 infection. CALIBRATE is an ongoing, phase 2 clinical study evaluating subcutaneous (SC) or oral LEN, in combination with other antiretrovirals, in treatment-naïve people with HIV-1. High rates of virologic success (HIV-1 RNA < 50 copies/mL) were achieved with LEN-based regimens by FDA Snapshot analysis at Week 28. Here, we present interim resistance analyses through Week 28.

Methods

Participants were randomized (2:2:2:1) to treatment groups (TG) (Figure): SC LEN + oral daily emtricitabine/tenofovir alafenamide (F/TAF); at Week 28, participants switch F/TAF to oral TAF (TG-A) or bictegravir (B, BIC) (TG-B); oral daily LEN + F/TAF (TG-C), or oral daily B/F/TAF (TG-D). Genotypic analyses (population sequencing) of HIV-1 reverse transcriptase and integrase, and genotypic (deep sequencing)/phenotypic analyses for CA were performed at screening; genotypic and phenotypic analyses were conducted at confirmed virologic failure.

Figure

CALIBRATE Study Design

Results

182 participants were randomized and dosed in TG-A to D (n=52, 53, 52, 25). Most participants had subtype B HIV-1 (92.9%). Sequence analysis of baseline samples found 65% of amino acid residues were conserved with < 1% variation across CA overall, and 55% of residues were fully conserved. No mutations were detected at 6 positions in CA associated with reduced susceptibility to LEN in vitro; residues were fully conserved at 5 positions (L56, M66, Q67, K70, N74), and < 2% variation was observed at 1 position (T107). Three participants met the criteria for resistance analysis: 2 participants resuppressed to < 50 copies/mL while continuing treatment. One participant on SC LEN + F/TAF developed emergent resistance to LEN (Q67H+K70R) and emtricitabine (M184M/I), followed by resuppression after starting dolutegravir, zidovudine + lamivudine, tenofovir disoproxil fumarate.

Conclusion

Emergent resistance to LEN was uncommon in treatment-naïve participants receiving SC or oral LEN (0.6%, 1/157). These interim resistance findings support the ongoing evaluation of LEN for treatment and prevention of HIV.

Disclosures

Laurie VanderVeen, PhD, Gilead Sciences (Employee, Shareholder) Nicolas Margot, MA, Gilead Sciences (Employee, Shareholder) Vidula Naik, MSc, Gilead Sciences (Employee, Shareholder) Silvia Chang, Masters, Gilead Sciences, Inc (Employee, Shareholder) Ross Martin, PhD, Gilead Sciences, Inc (Employee, Shareholder) Hadas Dvory-Sobol, PhD, Gilead Sciences (Employee, Shareholder) Martin Rhee, MD, Gilead Sciences (Employee, Shareholder) Christian Callebaut, PhD, Gilead Sciences (Employee, Shareholder)
76. Effects of the “Undetectable = Untransmittable” (“U=U”) Educational Campaign on Treatment Outcomes and Perceptions among People Living with HIV in North American Countries
Authors: Spinelli Frank , Richman Bruce , Rios Patricia De Los , Young Benjamin , Muchenje Marvelous , Van de Velde Nicolas , Okoli Chinyere
Published: December 2021

Background

The educational campaign “Undetectable = Untransmittable” (U=U) began in 2016 to improve the well-being of people living with HIV (PLHIV) and recalibrate HIV-related social norms. As medical practice can vary by region, we examined reports from PLHIV in North American countries to identify if the campaign affected healthcare provider (HCP) communication of U=U and if positive health outcomes differed by U=U-informed status or country.

Methods

Data were collected from the 2019 Positive Perspectives survey of PLHIV in Canada (n=120), Mexico (n=63), and the United States (US; n=400) and stratified by country. Outcomes were self-rated mental and sexual health (“Good”/”Very good”), viral suppression, and sharing of HIV status. Treatment perceptions were also assessed.

Results

Whether diagnosis occurred before or after the U=U campaign launch did not significantly affect the proportion of PLHIV who reported receipt of U=U from an HCP in any North American country. Whether an individual was informed of U=U varied significantly by sexual orientation (heterosexual, 62.8%; homosexual, 74.9%; other, 87.8%), sex (men, 64.7%; women, 89.8%; other, 100%), and metropolitan vs non-metropolitan residence (metropolitan, 78.2%; non-metropolitan, 65.2%) in the US (P< 0.01 for all) but not in Canada or Mexico. Prevalence of sharing of HIV status with ≥ 1 person besides an HCP varied among PLHIV (Canada, 87%; Mexico, 95%; US, 84%). Prevalence of other positive outcomes varied by country and whether PLHIV had been informed of U=U (Figure). Whether PLHIV were informed of U=U was also correlated with treatment satisfaction and the perception that treatment needs were being met among PLHIV in the US and Canada (P< 0.01 for all), and with the belief that treatment prevents transmission among PLHIV in the US (P=0.01).

Figure. Prevalence of positive outcomes among PLHIV in Canada (n=120), Mexico (n=63), and the US (n=400). PLHIV, people living with HIV; US, United States; U=U, Undetectable = Untransmittable. *P<0.01 for U=U informed vs uninformed.

Conclusion

Being informed of U=U was associated with higher treatment satisfaction, and higher mental and sexual health outcomes among PLHIV in North America. Receipt of U=U was associated with significantly higher treatment satisfaction among PLHIV in the US and Canada, and significantly more PLHIV with optimal mental and sexual health in the US.

Disclosures

Frank Spinelli, MD, ViiV Healthcare (Employee) Bruce Richman, JD, ViiV Healthcare (Consultant) Patricia De Los Rios, MSc, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Benjamin Young, MD, PhD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Nicolas Van de Velde, PhD, ViiV Healthcare (Employee) Chinyere Okoli, PharmD, MSc, DIP, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee)
78. Non-Invasive Prediction of Invasive Fungal Infection by Plasma-Based Microbial Cell-Free DNA Next-Generation Sequencing (mcfDNA NGS) in Pediatric Patients with Relapsed or Refractory Leukemia
Authors: Wolf Joshua , Wolf Joshua , Maron Gabriela , Goggin Kathryn , Allison Kim J , Merritt Pamela , griffen Amanda , Rubnitz Jeffrey , Duttagupta Radha , Brenner Abigail , Blair Lily , Ahmed Asim A , Morin Cara
Published: December 2021

Background

Diagnosis of invasive fungal infections (IFIs), a life-threatening complication of cancer therapy or hematopoietic cell transplantation (HCT) can be challenging, and IFI has poor outcomes. Prediction or early non-invasive diagnosis of IFI in high-risk hosts before onset of symptoms could reduce morbidity and mortality.

Because non-invasive plasma mcfDNA NGS can detect invasive fungal infections, and may predict bloodstream infections in immunocompromised patients, we hypothesized that mcfDNA NGS might also predict invasive fungal infection before clinical presentation.

Methods

In a prospective study, serial remnant plasma samples were collected from pediatric patients undergoing treatment for relapsed or refractory leukemia. IFI events were classified according to EORTC criteria by 2 independent experts, and episodes empirically treated for suspected IFI, but not meeting ‘possible’ criteria were classified as ‘suspected’. All samples collected within 30 days before clinical diagnosis of non-fungemic IFI were tested for fungal DNA by mcfDNA NGS using a research-use only assay by Karius, Inc. optimized for fungi; because of overlapping clinical syndromes, non-fungal DNA was not considered in this study.

Results

There were 15 episodes of suspected IFI in 14 participants with ≥1 sample available from either diagnostic (within 1 day of diagnosis) or predictive (2 to 30 days prior to diagnosis) periods (5 “suspected”, and 4 probable and 6 proven by EORTC definitions).

Of 10 probable or proven IFIs, 6 (60%) had a relevant fungal pathogen identified mcfDNA NGS at diagnosis. In each of these cases the fungal DNA was also detectable prior to clinical onset of IFI (Range 2 to 41 days; Figure 1). In an additional case, manual review of sequence data identified the fungal DNA at diagnosis and during the prior month. Of 5 “suspected” IFI episodes, all were determined by expert review as not representing fungal infection; fungal DNA was identified by mcfDNA NGS in 2/54 (3.7%) of samples from these episodes.

Table 1. Characteristics of Invasive Fungal Infections

Conclusion

mcfDNA NGS can identify fungal pathogen DNA before clinical onset of IFI, so might predict IFI in immunocompromised hosts, and may help differentiate fungal infection from other etiologies of lung nodules or infiltrates.

Disclosures

Joshua Wolf, MBBS, PhD, FRACP, Karius Inc. (Research Grant or Support) Joshua Wolf, MBBS, PhD, FRACP, Nothing to disclose Radha Duttagupta, PhD, Karius inc (Employee) Lily Blair, PhD, Karius Inc. (Employee) Asim A. Ahmed, MD, Karius, Inc. (Employee)
81. SARS-CoV-2 RNAemia and Disease Severity in Pediatric Coronavirus Disease 2019 (COVID-19)
Authors: Mertz Cameron , Glowinski Rebecca M , Mertz Sara , Peachey Colin L , Miller Lauren , Sanchez Pablo J , Cohen Shira H , Ye Fang , Wolfe Amber , Pifer Traci , Everhart Kathy , Ramilo Octavio , Mejias Asuncion
Published: December 2021

Background

Children with COVID-19 may develop severe disease. In hospitalized adults, detection of plasma SARS-CoV-2 RNAemia ranges from 19% to 42% and has been associated with worse clinical outcomes. A similar association in children remains unexplored. We determined the frequency of SARS-CoV-2 RNAemia in children hospitalized with COVID-19 and evaluated its potential association with severe disease.

Methods

Single center prospective study that enrolled hospitalized children and adolescents ≤21 years old with COVID-19 from March 2020-April 2021 at Nationwide Children’s Hospital, Columbus, OH. Nasopharyngeal (NP) and blood samples were obtained and SARS-CoV-2 RNA was quantified using a real time PCR assay targeting the N1 gene. Pertinent demographic, clinical, laboratory, and outcome data were evaluated.

Results

We enrolled a convenience sample of 103 hospitalized children (median age, 9 years; range, 3 days-21 years) who had confirmed SARS-CoV-2 infection and both NP and blood samples obtained (Table 1). Overall, 27 (26%) patients with COVID-19 had SARS-CoV-2 RNAemia. Compared with patients who had undetectable RNAemia, those with SARS-CoV-2 RNAemia had significantly higher nasopharyngeal RNA loads (8.1 vs. 4.9 log10 copies/mL; p=0.0006), fever (78 vs 54%; p=0.02), receipt of supplemental oxygen (37% vs 14%; p=0.02), and treatment with anti-COVID-19 medications (30% vs 12%; p=0.04). In addition, patients with SARS-CoV-2 RNAemia were more likely to require intensive care (40%% vs. 20%, p= 0.04) and had longer hospitalization (2.56 vs 2.15 days; p=0.03). There were no COVID-19 related deaths.

Table 1. Demographic, clinical, laboratory and virology characteristics of study patients

Conclusion

The frequency of SARS-CoV-2 RNAemia in pediatric patients was 26% and its finding was associated with worse clinical in-hospital outcomes, similar to that reported in adults. Testing for SARS-CoV-2 RNAemia in children may help identify those who could benefit from more intensive supportive care as well as antiviral and anti-inflammatory medications.

Disclosures

Octavio Ramilo, MD, Adagio (Consultant)Bill & Melinda Gates Foundation (Grant/Research Support)Janssen (Grant/Research Support)Lilly (Consultant)Merck (Consultant, Grant/Research Support)NIH (Grant/Research Support)Pfizer (Consultant)SANOFI (Board Member) Asuncion Mejias, MD, PhD, MsCS, Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Roche (Advisor or Review Panel member)Sanofi (Advisor or Review Panel member)