Sciences Inc Research Articles

Hospital-Associated Transmission of Candida auris from Adult to Pediatric Patient

Background: Candida auris, an emerging multidrug-resistant fungus, is often difficult to control in hospital outbreaks. We report the hospital investigation and findings of a transmission of C. auris from patients hospitalized in an adult unit to a pediatric unit, the first in Maryland. Methods: Between June and September 2023, C. auris was recovered from two patients admitted to an adult Neuroscience Intensive Care Unit (ICU) and a patient admitted to a pediatric ICU. Infection control initiated an investigation involving staff interviews, observations and chart reviews. Cases were defined as any patient with clinical or surveillance cultures growing C. auris. Point prevalence surveillance was conducted by collecting nares and composite axilla/groin swabs from patients on the affected units. Environmental cultures collected using moistened E-Swabs (Copan, Murrieta, CA) from shared supplies were plated on CHROMagar Candida (BD, Sparks, MD). C. auris isolates from patients hospitalized at the facility between February 2022 and October 2023 were analyzed by WGS for relatedness. WGS was performed using Illumina NextSeq 300 bp paired-end sequencing (Illumina, San Diego, CA). Single nucleotide polymorphism (SNP) analysis was performed by comparing raw reads to the reference C. auris B8441 genome for subsequent clustering analysis (Ares Genetics, Vienna, Austria). Results: WGS demonstrated isolates from two adults and one pediatric patient were less than three SNPs different, suggesting a shared isolate. One additional pediatric case was identified from surveillance cultures collected from 27 patients. Investigation into possible transmission routes revealed healthcare personnel serving both units, specifically clinical teams and continuous electroencephalography (cEEG) technologists. Additionally, cEEG equipment was used on both adult and pediatric patients and twelve equipment surface swabs and three samples each of measuring tape and gel were collected. C. auris was not isolated, however sensitivity of environmental sampling is unclear and suspicion for possible fomite/environmental transmission persisted. Other possible transmission routes included gaps in hand hygiene, isolation, disinfection of shared equipment, and reuse of single-use items. Interventions included improving and monitoring infection prevention practices, educating multi-disciplinary personnel and heightened environmental cleaning. Conclusion: This case highlights the feasibility of transmission of C. auris between patients admitted to a geographically distant unit. Our investigation revealed multiple possible routes of transmission including direct contact (from healthcare personnel or equipment) or indirect environmental sources. Prevention of hospital-associated C. auris transmission likely necessitates meticulous adherence to hand hygiene, contact precautions, and careful cleaning and disinfection of patient environments and equipment used by all disciplines.Disclosure: Patricia Simner: Research Contracts: BD Diagnostics, OpGen Inc., Qiagen Sciences Inc, T2 Diagnostics, Accelerate Diagnostics; Research Collaborators:Ares Genetics, CosmosID, IDbyDNA, Illumina; Consulting: OpGen Inc., BD Diagnostics, Shionogi Inc., GeneCapture, Qiagen Sciences Inc, Entasis, Day Zero Diagnostics, Next Gen Diagnostics

Evaluation of Vulnerabilities for the Spread of Carbapenem Resistant Organisms at Five Hospitals in India

Background: The 2022 WHO global survey on infection prevention and control (IPC) exposes significant gaps in IPC in the WHO Southeast Asia region. A better understanding of IPC vulnerabilities will inform improvement initiatives. We describe an evaluation of IPC practices known to prevent and contain carbapenem-resistant organisms (CROs) at hospitals participating in the United States Centers for Disease Control Global Action in Healthcare Network –Antimicrobial Resistance in India. Prior hospital evaluations suggest resistance to carbapenems among gram-negative isolates is up to 45%. Methods: We conducted a mixed methods evaluation including cross-sectional surveys, semi-structured interviews, and site observations at five hospitals (one government, two private tertiary care, and two private teaching) located in three cities. The number of hospital beds ranged from 362 to 2,011. Hospital and IPC program characteristics, and CRO prevention and containment activities were examined virtually. Site observations focused on hand hygiene, environmental cleaning, personal protective equipment (PPE), CRO containment practices and use of water for patient care. Results: All sites had IPC programs with established policies and qualified IPC staff. The IPC nurse-to-bed ratio ranged from 1:73 to 1:432 (mean, 1:209). Due to the integral role of microbiology staff in IPC at these hospitals, the two departments had strong communication channels associated with CRO identification. Screening for CRO colonization, if done, targeted patients from outside hospitals. Three of the five hospitals routinely implemented contact precautions for patients with identified CROs, displayed isolation signage at the bedside, and provided adequate PPE at point-of-use; however, all sites reported barriers to effective isolation and/or cohorting patients with CROs. Timely communication of CROs to clinical staff varied and no sites effectively relayed CRO status upon patient discharge to another facility. IPC teams identified gaps in environmental cleaning procedures and practices related to medical devices and equipment. All sites used alternatives to tap water for clinical care and sink etiquette was evident. Each IPC team performed audits of patient isolation and hand hygiene practices. Despite the considerable proportion of IPC resources dedicated to daily education and feedback in clinical areas, the IPC teams reported that improvement was often difficult to achieve. Conclusion: Given the high burden of CROs and limited IPC resources, detailed knowledge of IPC opportunities for improvement will help hospitals target novel interventions for CRO prevention and containment. Further investigation of colonization rates and effective performance improvement methods in these settings is needed.Disclosure: Patricia Simner: Research Contracts: BD Diagnostics, OpGen Inc., Qiagen Sciences Inc, T2 Diagnostics, Accelerate Diagnostics; Research Collaborators:Ares Genetics, CosmosID, IDbyDNA, Illumina; Consulting: OpGen Inc., BD Diagnostics, Shionogi Inc., GeneCapture, Qiagen Sciences Inc, Entasis, Day Zero Diagnostics, Next Gen Diagnostics

697. Characteristics of Hospitalized Patients Colonized with Clostridioides difficile at an Academic Medical Center

Abstract Background Clinical spectrum of C. difficile can range from colonization to fulminant colitis. Patients with toxin antigen negative, C. difficile nucleic acid amplification (NAAT)-positive diarrhea are frequently only colonized and do not suffer consequences of C. difficile associated disease (CDAD) but receive treatment for CDAD due to the perceived low risk of oral vancomycin vs. the risk of developing CDAD. Methods We performed a retrospective cohort study of hospitalized adult patients with positive C. difficile NAAT and negative toxin antigen results at University of Iowa Health Care between 9/1/2021 and 9/30/2022. Chart review was conducted to obtain patient age, immunocompromised state, involvement of infectious disease (ID) consultant, prior C. difficile test status and treatment course. Results Of the 295 NAAT-positive C. difficile results, 210 (71%) were toxin antigen negative. Patient characteristics and frequency of common risk factors are shown in Table 1. C. difficile colonization was detected ≥4 days after admission in 111 (53%), with internal medicine and stem cell transplant (SCT)/hematologic malignancies (HM) services having the most patients with colonization (31% and 18%, respectively). Antibiotic use in the prior 30 days was reported in 154 (73%). Of 134 (64%) patients on systemic antibiotics at time of C. difficile testing, antibiotics were discontinued in 29 (22%). Only 43 patients (20%) did not receive any treatment for C. difficile. Median treatment duration was 10 days with 133 (80%) being treated for 10-14 days (Table 2). ID consult was obtained in 48 (23%) and recommended no treatment initially in 11 (23%), 4 of whom were started on treatment in subsequent days. Oral twice a day vancomycin for prophylaxis was given to 28 (13%) patients, 19 (68%) of whom were immunocompromised (16 SCT/HM and 3 solid organ transplant). Conclusion Patients with C. difficile colonization have similar risk factors as patients with CDAD. Understanding treatment patterns for C. difficile colonization can guide educational activities. Most colonized patients received C. difficile treatment and/or prophylaxis, likely due to ongoing systemic antibiotic use and immunosuppression. Benefit of treatment and prophylaxis in colonized patients remains an unresolved issue. Disclosures Kelly M. Percival, PharmD, Gilead Sciences Inc: Advisor/Consultant

Overview of alopecia areata for managed care and payer stakeholders in the United States.

Alopecia areata (AA) is an autoimmune disease with a complex pathophysiology resulting in nonscarring hair loss in genetically susceptible individuals. We aim to provide health care decision makers an overview of the pathophysiology of AA, its causes and diagnosis, disease burden, costs, comorbidities, and information on current and emerging treatment options to help inform payer benefit design and prior authorization decisions. Literature searches for AA were conducted using PubMed between 2016 and 2022 inclusive, using search terms covering the causes and diagnosis of AA, pathophysiology, comorbidities, disease management, costs, and impact on quality of life (QoL). AA is a polygenic autoimmune disease that significantly impacts QoL. Patients with AA face economic burden and an increased prevalence of psychiatric disease, as well as numerous systemic comorbidities. AA is predominantly treated using corticosteroids, systemic immunosuppressants, and topical immunotherapy. Currently, there are limited data to reliably inform effective treatment decisions, particularly for patients with extensive disease. However, several novel therapies that specifically target the immunopathology of AA have emerged, including Janus kinase (JAK) 1/2 inhibitors such as baricitinib and deuruxolitinib, and the JAK3/tyrosine kinase expressed in hepatocellular carcinoma (TEC) family kinase inhibitor ritlecitinib. To support disease management, a disease severity classification tool, the Alopecia Areata Severity Scale, was recently developed that evaluates patients with AA holistically (extent of hair loss and other factors). AA is an autoimmune disease often associated with comorbidities and poor QoL, which poses a significant economic burden for payers and patients. Better treatments are needed for patients, and JAK inhibitors, among other approaches, may address this tremendous unmet medical need. DISCLOSURES: Dr King reports seats on advisory boards for and/or is a consultant and/or clinical trial investigator for AbbVie, Aclaris Therapeutics Inc, AltruBio Inc, Almirall, Arena Pharmaceuticals, Bioniz Therapeutics, Bristol Meyers Squibb, Concert Pharmaceuticals Inc, Dermavant Sciences Inc, Eli Lilly and Company, Equillium, Incyte Corp, Janssen Pharmaceuticals, LEO Pharma, Otsuka/Visterra Inc, Pfizer, Regeneron, Sanofi Genzyme, TWi Biotechnology Inc, and Viela Bio; and speakers bureaus for AbbVie, Incyte, LEO Pharma, Pfizer, Regeneron, and Sanofi Genzyme. Pezalla is a paid consultant to Pfizer for market access and payer strategy concerns; Fung, Tran, Bourret, Takiya, Peeples-Lamirande, and Napatalung are employees of Pfizer and hold stock in Pfizer. This article was funded by Pfizer.

901. Evaluation of Azithromycin Usage Following a Pharmacist Discontinuation Protocol

Abstract Background Azithromycin usage along with a beta-lactam is common in hospitalized patients with community-acquired pneumonia (CAP). The total recommended dosage is 1500mg as either 500mg on day one followed by 250mg daily for 4 days or 500mg daily for 3 days. It was observed that total doses of >1500mg were frequently administered at our institution. Institutional empiric treatment guidelines for CAP were updated and educational sessions were given for medicine providers in November 2019 to emphasize a total dose of 1500mg. This was further followed in April 2020 by the creation of a pharmacist collaborative practice agreement (CPA) to allow any unit-based clinical pharmacist to discontinue azithromycin for CAP after administration of a sum total of 1500mg. Methods A retrospective quasi experimental study was performed to evaluate the impact of implementing a pharmacist CPA for discontinuation of azithromycin for CAP. The primary objective was to compare the proportion of patients receiving greater than 1500mg of azithromycin during the pre-implementation period of April 2018-March 2020 to the post-implementation period of April 2020-March 2022. Pre- and post-implementation period rates were compared using a Chi-square test. Secondarily, utilization of CPA as the discontinuation method was evaluated. Results A total of 8,373 patients were included (5123 pre and 3250 post) in the analysis. The proportion of patients receiving >1500mg of azithromycin decreased from 29.32% pre-implementation to 20.22% post-implementation (P< 0.001). There was a decrease seen immediately after implementation that has been maintained over time, as shown in figure 1. The CPA was utilized for discontinuation in a minority of patients during the post-implementation period and the majority discontinued by pharmacists were per verbal order. Percentage of Patients Receiving >1500mg Azithromycin Conclusion Implementation of a pharmacist driven CPA for discontinuation of azithromycin for CAP reduced excessive azithromycin usage with minimal time burden for the AMS team. To further meet the goal of decreasing excessive azithromycin usage additional interventions are needed, and low utilization of the CPA should be further evaluated. Disclosures Kelly M. Percival, PharmD, Gilead Sciences Inc: Advisor/Consultant Patrick M. Kinn, PharmD, MPH, Gilead Sciences: Advisor/Consultant Dilek Ince, MD, Evergreen: Member of data monitoring board|Gilead Sciences: Grant/Research Support|Leidos: Grant/Research Support|Moderna: Grant/Research Support.

1755. Interactive Provider Dashboards for Comparison of Outpatient Antimicrobial Prescribing for Respiratory and Otic Conditions in Urgent and Quick Care Clinics

Abstract Background Due to antibiotic overutilization, development of antimicrobial stewardship (AMS) in the outpatient setting has become a necessary focus for AMS programs. The cornerstone of AMS is utilization of antimicrobial prescribing data to provide feedback to individual providers and compare providers to each other in order to promote improved prescribing practices. Respiratory infections, especially conditions that never require antimicrobials, are a common target for this feedback. We aimed to create interactive data visualization dashboards of end-users prescribing for these respiratory and otic conditions in order for AMS and urgent/quick care program staff to identify potential areas of intervention. Methods A multidisciplinary work group consisting of data analysts, infectious diseases physicians, urgent/quick care physicians, and infectious diseases pharmacists determined dashboard content, layout, and comparison charts. Graph types were tested to determine optimal visual output. Using the electronic medical record ICD10 and antimicrobial prescription data was extracted for the encounter with focus on ICD10 codes for respiratory and otic conditions which never require antimicrobials. Rates were calculated as number of antimicrobial prescriptions over total number of visits for these conditions. Results A multi-faceted dashboard was developed in Tableau® to view antimicrobial prescribing rates. Dashboard capabilities include the option to view individual provider prescribing rates compared to other de-identified providers, overall clinic prescribing rate, or individual rate compared to clinic rate. This allows for quick direct comparison of antimicrobial prescribing on the same graph by clinic to identify outliers (Figure 1) and allows visualization of trends in prescribing rates by clinics and providers over time (Figures 2,3). Never Antimicrobial Prescribing Rate Comparison Scatter plot comparing individual prescribers rate of prescribing for never antimicrobial events Clinic Antimicrobial Prescribing Rate Trend Clinic prescribing rate trend over time for never antimicrobial events Prescriber and Clinic Antimicrobial Prescribing Rate Trend Individual prescriber rate compared to clinic rate over time for never antimicrobial events Conclusion We developed an interactive outpatient AMS dashboard to visualize prescribing of antimicrobials for never respiratory and otic conditions. These dashboards can be used by providers along with AMS and clinic leadership to determine areas of intervention in the urgent/quick care setting. Disclosures Kelly M. Percival, PharmD, Gilead Sciences Inc: Advisor/Consultant Patrick M. Kinn, PharmD, MPH, Gilead Sciences: Advisor/Consultant Dilek Ince, MD, Evergreen: Member of data monitoring board|Gilead Sciences: Grant/Research Support|Leidos: Grant/Research Support|Moderna: Grant/Research Support.

Establishing baseline framework for hepatitis B virus micro-elimination in Ho Chi Minh City, Vietnam – a community-based seroprevalence study

We conducted a community-based seroprevalence study using three HBV seromarkers (HBsAg, anti-HBs, anti-HBc) in Ho Chi Minh City (HCMC), Vietnam, to (1) determine the prevalence of HBV serologic profiles; (2) document factors associated with HBV infection or susceptibility; and (3) propose strategies toward HBV elimination by2030. During 2019-2020, we deployed a multistage cluster design with probability proportionate to size, to recruit 20,000 adults for an HBV screening and linkage to care program citywide. Screening results with interpretation, recommendations, and health education materials were returned to participants. Post-study surveys were conducted within three months to identify gaps in linkage to care. Of the 17,600 adults invited, 15,275 (86.7%) participated in the study, 14,674 (96.1%) completing all data for final analyses. The prevalence of HBsAg (+) and HBV-naïve were 7.5% and 37.7%, respectively. HBV vaccination rates were 18.7% and about 50% of HCMC population had been exposed to HBV. Of the persons with HBsAg (+), 27.1% linked to care (76% used health insurance). There were wide variations in HBsAg (+) and HBV vaccination rates between districts, risk factors, and socio-economic statuses. The significant disease burden of and gaps in the continuum of care highlight the need and urgency to address the HBV public health problem in Vietnam. Using three screening seromarkers that tailor interventions to the needs of HBV micro-populations could be an effective strategy to pursue HBV elimination goals. Gilead Sciences Inc; Roche Diagnostic International Ltd; Roche Diagnostics-Vietnam; Abbott Diagnostics-Vietnam; Hepatitis B Foundation; Medic MedicalCenter, Vietnam; Center of Excellence for Liver Disease in Vietnam, Johns Hopkins University School of Medicine.

EXERCISE THERAPY TO COMBAT THE POSTACUTE SEQUELAE OF COVID-19: A CASE SERIES

EXERCISE THERAPY TO COMBAT THE POSTACUTE SEQUELAE OF COVID-19: A CASE SERIES

NO RELATIONSHIP BETWEEN PULMONARY FUNCTION AND EXERCISE CAPACITY IN PEOPLE WITH POSTACUTE SEQUELAE OF SARS-COV-2 INFECTION

NO RELATIONSHIP BETWEEN PULMONARY FUNCTION AND EXERCISE CAPACITY IN PEOPLE WITH POSTACUTE SEQUELAE OF SARS-COV-2 INFECTION

Lenacapavir: First Approval.

Lenacapavir (Sunlenca®) is a long-acting capsid inhibitor of human immunodeficiency virus type1 (HIV-1) being developed by Gilead Sciences Inc. It is available as an oral tablet and injectable solution, with the latter being a slow-release formulation to allow bi-annual subcutaneous administration. In August 2022, lenacapavir received its first approval in the EU for use in combination with other antiretroviral(s) in adults with multi-drug resistant HIV infection, for whom it is otherwise not possible to construct a suppressive anti-viral regimen. This article summarizes the milestones in the development of lenacapavir leading to this first approval for the treatment of HIV-1 infection.

439TiP A phase II (ph2), randomized study of magrolimab with bevacizumab and FOLFIRI in previously treated patients with advanced inoperable metastatic colorectal cancer (mCRC)

For patients (pts) with mCRC who are ineligible/unable to derive benefit from novel targeted therapies or immunotherapies, standard of care (SOC) doublet or triplet chemotherapy-based regimens associated with toxicity and limited responses are the only available treatment options. Magrolimab is an antibody blocking CD47, a “don’t eat me” signal on cancer cells, resulting in tumor phagocytosis by macrophages and nonclinical activity in hematologic and solid tumor malignancies. Chemotherapeutic agents can enhance prophagocytic signals on tumor cells, leading to the potential for synergistic antitumor activity with magrolimab. This study is evaluating the safety, tolerability, and efficacy of magrolimab with bevacizumab + FOLFIRI in advanced inoperable mCRC. This ph2, randomized, open-label study consists of safety run-in and ph2 cohorts. Eligible pts (≥18 y) progressed on or after 1 prior systemic therapy with chemotherapy based on 5-FU with oxaliplatin and bevacizumab. Magrolimab is administered intravenously with an initial 1-mg/kg priming dose to mitigate on-target anemia, followed by a 30-mg/kg dose during cycle 1 (28-day cycles) in the safety run-in to determine a recommended ph2 dose (RP2D) and evaluate pharmacokinetics and immunogenicity. In ph2, pts will be randomized 2:1 to magrolimab in combination with bevacizumab + FOLFIRI vs bevacizumab + FOLFIRI. After the magrolimab priming dose on day (D)1, the RP2D will be administered weekly starting on D8 for the next 6 doses, followed by every other week. Bevacizumab is administered at 5 mg/kg on D1 and D15 each cycle. FOLFIRI is administered per SOC on D1, D2, D15, and D16 of each cycle. Pts may continue treatment until unacceptable toxicity, progressive disease by RECIST 1.1, or pt/investigator choice. Primary endpoints include incidence of dose-limiting toxicities and adverse events (safety run-in) and PFS by investigator (ph2). Secondary endpoints include magrolimab concentration vs time, antidrug antibodies (safety run-in), objective response rate, PFS by independent central review, duration of response, and overall survival (ph2). NCT05330429. Gilead Sciences Inc.

Short-Term Efficacy of Combined ab Interno Canaloplasty and Trabeculotomy in Pseudophakic Eyes with Open-Angle Glaucoma.

PurposeTo evaluate short-term outcomes of combined ab interno canaloplasty and trabeculotomy in pseudophakic eyes with open-angle glaucoma.Patients and MethodsSeries included all pseudophakic eyes with open-angle glaucoma treated with up to 360° ab interno canaloplasty and up to 360° ab interno trabeculotomy using a purpose-engineered device (OMNI, Sight Sciences Inc). Data collected prior to surgery and out to 6-months postoperative. Surgical success defined as a 20% reduction in intraocular pressure (IOP) without increase in glaucoma medication, or discontinuation of at least one glaucoma medication without increase in IOP. Other primary endpoints included mean IOP and number of glaucoma medications.ResultsThe study included 67 eyes of 52 patients with a mean age of 76.5 ± 8.9 years. Preoperative mean IOP was 22.1±8.0 mmHg on 2.3±1.4 glaucoma medications. Pressure lowering effects were sustained out to 6 months postoperative with a mean IOP of 15.2±4.9 mmHg (p < 0.001) and mean medication reduction of 0.7±1.4 (p < 0.001). Surgical success rate was 69.8% (30 eyes) and correlated with preoperative IOP. Two patients required a secondary surgical intervention.ConclusionCombined ab interno canaloplasty and trabeculotomy as a standalone procedure is an effective means of reducing IOP and medication burden in pseudophakic eyes with open-angle glaucoma.

Maintenance, withdrawal, and re-treatment with ritlecitinib and brepocitinib in patients with alopecia areata in a single-blind extension of a phase 2a randomized clinical trial

Maintenance, withdrawal, and re-treatment with ritlecitinib and brepocitinib in patients with alopecia areata in a single-blind extension of a phase 2a randomized clinical trial

997. RLS-0071 Improves Survival in a Rat Model of Intestinal Necrosis

BackgroundIntestinal necrosis and perforation are potentially life-threatening medical conditions that can lead to bacterial sepsis and systemic inflammatory response syndrome. Various etiologies can compromise the intestinal wall causing leakage of luminal contents including enteric bacteria and precipitate aggressive immunological responses including the complement system and neutrophils. RLS-0071 is a peptide inhibitor of the classical and lectin pathways and known modulator of various neutrophil mediated effectors including myeloperoxidase activity and NETosis.MethodsIn this study we evaluated the extent to which immunomodulation via inhibition of the complement system and neutrophil effectors would alter survival in the setting of intestinal necrosis. Adolescent male Long-Evans rats were subject to cecal ligation and puncture (CLP) with one cohort receiving 40 mg/kg of RLS-0071 thirty minutes after surgery while the control group received no treatment. Survival of the rats was then assessed up to 5 days after surgery. ResultsAnimals treated with RLS-0071 demonstrated nearly 1.5-fold increase in survival compared to the untreated group. In order to further elucidate the increase in survival we explored inflammatory responses as assessed by markers of NETosis i.e., free DNA in plasma, and the pro-inflammatory cytokine, IL-6. A reduction in blood levels of free DNA and the inflammatory cytokine IL-6 were observed for animals treated with RLS-0071.RLS-0071 increases survival of rats after cecal ligation Kaplan-Meier survival curve assessment. The red line indicates the outcome after 75% CLP in animals not receiving treatment (n=13), whereas red curves represent the outcome after animals received a single dose of 40 mg/kg RLS-0071 (n=11).RLS-0071 reduces free DNA levels in the blood Plasma was isolated before surgery (pre-bleed) (n=7) and from animals subject to CLP with (n=4) and without (n=3) RLS-0071 administration 24 hours post-surgery. Plasma samples were incubated with PicoGreen. Fluorescence was read at an excitation wavelength of 485 nm and an emission wavelength of 520nm in a microplate reader. Data are means and standard error of the meansRLS-0071 reduces IL-6 levels in the blood Plasma was isolated before surgery (pre-bleed) (n=8) and from animals subject to CLP with (n=3) and without (n=5) RLS-0071 administration 24 hours post-surgery. Plasma samples were analyzed in an IL-6 ELISA according to the manufacturer’s instructions. Data are means and standard error of the means.ConclusionThe results of these experiments demonstrate that RLS-0071 can increase survival after intestinal perforation by multi-pronged modulation of complement activation, neutrophil immune mechanisms and cytokine mediated inflammatory responses.Disclosures Kenji Cunnion, MD, MPH, ReAlta Life Sciences Inc (Board Member, Employee, Shareholder) Parvathi Kumar, MBBS, ReAlta Life Sciences Inc (Employee) Brittany Lassiter, BS, ReAlta Life Sciences Inc (Employee) Katherine LaValle, DVM, ReAlta Life Sciences Inc (Employee) Neel Krishna, PhD, ReAlta Life Sciences Inc (Employee, Shareholder)

855. Persistence on F/TAF versus F/TDF for HIV Pre-Exposure Prophylaxis: A Real-World Evidence Analysis in the United States

BackgroundPersistence to preexposure prophylaxis (PrEP) is an important determinant of its efficacy, but evidence on real-world persistence is lacking. This study assesses adherence to F/TDF and F/TAF for PrEP both in terms of discontinuation and re-initiation patterns. MethodsWe identified HIV-negative individuals in the United States who initiated F/TDF or F/TAF for PrEP between October 2019 and December 2020 from a de-identified prescription claims database; users taking generic F/TDF were excluded. Non-persistence was defined as a prescription fill gap of >30 days; discontinuation included switch from F/TDF to F/TAF or F/TAF to F/TDF. We used survival analyses to estimate persistence, Cox regressions to compare the hazard ratios (HR) of discontinuation, and logistic regression to compare the odds ratios of re-initiation after discontinuation.ResultsAmong F/TAF users (N=82,402) median age at PrEP initiation was 35 years (interquartile range [IQR] 28−47) and median PrEP persistence was 4 months (IQR 1.8-8.9), compared to 31 years (IQR 25−40) and 2 months (IQR 1.0-3.8) for F/TDF users (N=48,501). PrEP persistence at 60 and 90 days was higher among F/TAF users than F/TDF users (Figure). F/TDF users were 2.5 times more likely to discontinue than F/TAF users, with more marked differences in older users than that in younger users (p for interaction between discontinuation and age group < 0.01, Table). We also observed a higher rate of discontinuation of F/TDF versus F/TAF if PrEP was prescribed by internal medicine or infectious disease physicians than by family medicine physicians (data not shown). After discontinuation, F/TAF users were 1.7 times more likely than F/TDF users to re-initiate PrEP; the association was not different by age.Persistence rates of F/TAF and F/TDF for PrEP by time of PrEP initiation Hazard ratios (HR) and corresponding 95% confidence intervals (CI) of non-persistence and odds ratios (OR) of re-initiation after discontinuation for users of F/TAF and F/TDF for PrEP in the US, Oct 2019 – Dec 2020 ConclusionIn this real-world analysis, the F/TAF for PrEP regimen was associated with higher persistence and re-initiation than F/TDF for PrEP. These findings underscore the dynamic nature of PrEP utilization in the real-world and the importance of interventions aimed at improving PrEP persistence and re-initiation in people who would benefit from PrEP. Disclosures Li Tao, MD, PhD, Gilead Sciences Inc (Employee, Shareholder) Valentina Shvachko, MS, Gilead Sciences Inc (Employee, Shareholder) Moupali Das, MD, Gilead Sciences Inc. (Employee, Shareholder) Christoph C. Carter, MD, Gilead Sciences Inc. (Employee, Shareholder) Jared Baeten, MD, PHD, Gilead Sciences Inc. (Employee, Shareholder) David Magnuson, PharmD, Gilead Sciences Inc (Employee, Shareholder)

911. Rapid Hepatitis C Treatment Initiation in Young People Who Inject Drugs: Final Results from the HCV-Seek, Test and Rapid Treatment (HCV-ST&amp;RT) Randomized Pilot Clinical Trial

BackgroundYoung people who inject drugs (PWID) have higher HCV incidence and lower treatment initiation rates compared to their older peers. Novel, simplified care models need to be developed to engage, treat and cure hard to reach patient populations, such as young PWID.MethodsWe present final data from the randomized pilot clinical trial HCV-Seek Test & Rapid Treatment (HCV-ST&RT) for curing HCV in young PWID. Eligible participants were 18-29 years of age, HCV Ab+, treatment naïve, and had injected drugs in the past 30 days. Participants were randomized 1:1 to the Rapid Treatment or Usual Care arm. Participants randomized to Rapid Treatment received a same-day medical evaluation, confirmatory and baseline lab testing, and 7-day starter pack of sofosbuvir/velpatasvir. Participants in Usual Care received same-day HCV confirmatory testing and, if positive, facilitated referral to local providers. The primary endpoint was sustained virologic response (SVR12) in RNA+ participant within 12 months of enrollment. ResultsAmong 47 eligible participants, 38 were enrolled and randomized. 14/18 in the Rapid Treatment arm and 11/20 in the Usual Care arm were confirmed HCV RNA+ and included in the intention-to-treat analysis. Demographics of the RNA+ participants were similar in the two arms with a mean age of 26 years; 24% women; 36% Hispanic and 4% non-Hispanic black. At baseline 24% were homeless, 52% received medication for opioid use disorder in the prior 90 days, and participants injected a median of 20 of the last 30 days. In the intention-to-treat analysis, 9/14 (64%) of the Rapid Treatment arm and 2/11 (18%) of the Usual Care arm had confirmed SVR12 (p=0.042). Of the 5 participants in the Rapid Treatment arm who did not achieve SVR12, 1 had treatment failure, 1 never started DAA therapy, 1 had an on-treatment response with pending SVR12 confirmation, and 2 were lost to follow-up. ConclusionAmong young HCV RNA+ PWID, significantly higher rates of cure were achieved using the Rapid Treatment model with same day, low-threshold, simplified HCV care compared to facilitated referral. Meeting young PWID where they’re at and initiating HCV treatment ‘in the moment’ without the need for repeat visits appears to be a promising strategy for treating this hard to reach population.Disclosures Benjamin Eckhardt, MD, MS, Gilead Sciences (Grant/Research Support) Shashi Kapadia, MD, Gilead Sciences Inc (Grant/Research Support) Kristen Marks, MD, Gilead Sciences (Grant/Research Support)

917. Accessible HCV Care for People Who Inject Drugs: Randomized Clinical Trial Comparing Low-Threshold Treatment at a Syringe Service Program Versus Facilitated Referral

BackgroundTo achieve hepatitis C virus (HCV) elimination, treatment programs need to be developed to engage, treat, and cure people who inject drugs (PWID).MethodsWe present final data from the Accessible Care Trial for curing HCV in PWID. The randomized clinical trial compared on-site, low-threshold HCV treatment with care-coordination at a NYC syringe service program (Accessible Care) with facilitated referral to local providers through a patient navigation program (Usual Care). Eligible participants were HCV RNA+ and had injected drugs in the past 90 days. Participants were randomized 1:1 to the Accessible Care or Usual Care arm. The primary endpoint was achievement of sustained virologic response (SVR12) within 12 months of enrollment. Secondary endpoints examined rates HCV care cascade step completion from referral to clinician, attending clinical visit, baseline lab testing, treatment initiation, and cure.ResultsAmong the 572 participants screened, 167 met eligibility criteria and were enrolled, with two excluded post-randomization (N=165). Demographics were similar with a median age of 41 years; 22% women; 59% Hispanic and 5% non-Hispanic black. At baseline, 84% of participants had injected drugs in the past 30 days with those averaging 22 injections/month, 70% were receiving either methadone or buprenorphine, 57% were recently homeless, 7% were HIV+, and 11% were HCV treatment experienced. In the intention-to-treat analysis, 55/82 (67.1%) of the Accessible Care arm and 19/83 (22.9%) of the Usual Care arm achieved SVR12 (p< 0.001). The SVR12 rates of those starting therapy were 55/64 (85.9%) and 19/22 (86.3%) in the two arms (p=0.96). Loss to follow-up (12.2% and 16.9%, p=0.51) was similar in the two arms. Significantly more participants in the Accessible Care arm achieved all steps in the care cascade with the greatest attrition in the Usual Care arm seen in referral to clinician and attending clinical visit. ConclusionAmong HCV RNA+ PWID significantly higher rates of cure were achieved using the Accessible Care model focused on low-threshold, destigmatized, flexible HCV care compared to facilitated referral. To achieve HCV elimination, expansion of treatment programs specifically geared toward engaging PWID is paramount. Disclosures Benjamin Eckhardt, MD, MS, Gilead Sciences (Grant/Research Support) Shashi Kapadia, MD, Gilead Sciences Inc (Grant/Research Support) Kristen Marks, MD, Gilead Sciences (Grant/Research Support)

Long-Term Results of Alliance A041202 Show Continued Advantage of Ibrutinib-Based Regimens Compared with Bendamustine Plus Rituximab (BR) Chemoimmunotherapy

Long-Term Results of Alliance A041202 Show Continued Advantage of Ibrutinib-Based Regimens Compared with Bendamustine Plus Rituximab (BR) Chemoimmunotherapy

Characterization of Residual CLL Following Long-Term Bruton Tyrosine Kinase Inhibitor Therapy

Introduction:The development of Bruton tyrosine kinase inhibitors (BTKi) and their introduction into clinical practice represent a major advance in the treatment of chronic lymphocytic leukemia (CLL). Ibrutinib and other second generation BTKi as monotherapies generally do not produce minimal residual disease negative (MRD-) complete remissions even with extended therapy. The reason for lack of continued elimination of CLL to a MRD- status over time is unknown, and we hypothesized that biological differences in the CLL cells or immune microenvironment might make them resistant to elimination.Methods:Samples were obtained from patients on continuous ibrutinib who hadn't relapsed at time points of 3 years on treatment and 5 years on treatment; and pre-ibrutinib. Isolated CLL cells were subject to B-cell receptor (BCR) sequencing using NEBNext Immune Sequencing Kit by New England Biolabs (NEB, Inc., USA). In a separate cohort, 10X VDJ+5‘-sequencing was performed on peripheral blood mononuclear cells. Flow cytometry and ELISA were used to identify alterations in immune cell subtype and identify immune profiles associated with MRD positive (MRD+) status.Results:To identify the clonal pattern in MRD+, we performed deep sequencing of the BCR repertoire on samples from 13 patients with 3 time points each. We found that dominant clones tended to remain constant, but new clones appeared in later time points (Figure 1). MiXCR (v3.0.5) was used with default parameters to identify preprocessed reads containing CDR3 regions from B-cell heavy, kappa, and lambda chains, generating a list of unique productive and nonproductive CDR3 sequences associated with their relative abundances and specific V(D)J gene usage. Two out of three patients (patients 1 and 3) showed significant change in the clone over time. In patients 1 and 2, we saw that heavy chain clones emerge at later time points. In patient 3 alone, we observed that at 5 years there are two dominant clones. Our findings suggest that each patient shows a diverse repertoire of CLL clones and that the dominant clone does not change significantly across time points.To identify cell populations based on gene expression patterns, we performed 10X VDJ+5‘-seq. Based on the expression of known markers, we identified CLL cells and other immune cell subtypes. We identified differentially expressed genes (DEGs) for CLL cells in each time points. Over time, we observed upregulation of CD79a, LTB, TAGLN2, and LGALS, genes typically associated with leukemic cell survival. Suggesting differential expression of pro-survival genes contribute to continued presence of MRD over time. T cells are known to be dysfunctional in CLL and have not previously been extensively studied in the setting of long term BTKi. We performed flow cytometry to determine the repertoire and function of T cells at 3 and 5 years of ibrutinib therapy. We found that the percentage of CD3+ T cells increases at later time points in all the 8 patients (p<0.05). Although T cell numbers increase, we do see skewing of these cells towards a terminally differentiated phenotype (p<0.05). We also observed significant increases in NK cells across time points (p<0.05), albeit non-functional due to high expression of inhibitory receptor KLRG1 in 7 out of 8 patients (p<0.05). Although overall the number of immune cells increase in long time ibrutinib therapy, they exhibit exhausted or non-functional phenotypes.Conclusion:Extended ibrutinib treatment yields a subset of patients who become MRD- whereas a large majority remain MRD+. Our findings suggest that BCR repertoire in CLL MRD might change in long term ibrutinib therapy and induce necessary genes for its survival in the microenvironment. Although T cells and NK cells are non-functional at later time points, better understanding of these subtypes may lead to new strategies and to improve antitumor function of these cells. Differentiating the biology of why certain patients attain MRD- status on BTK inhibitor is of high interest as it could provide rationale for therapy discontinuation or add on approaches. [Display omitted] DisclosuresRogers: AbbVie Inc.: Consultancy, Research Funding; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy, Research Funding; Innate Pharma: Consultancy; Pharmacyclics LLC: Consultancy; Janssen Pharmaceuticals, Inc: Research Funding; ovartis Pharmaceuticals Corporation: Research Funding. Bhat: Beigene: Consultancy; AstraZeneca: Consultancy; Aptitude Health: Honoraria; Onclive: Honoraria. Kittai: Bristol-Meyers Squibb: Consultancy; Abbvie: Consultancy; Janssen: Consultancy. Blachly: INNATE: Consultancy, Honoraria; KITE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees. Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; Gilead Sciences Inc: Other: Data & Safety.

Pirtobrutinib, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated CLL/SLL: Updated Results from the Phase 1/2 BRUIN Study

Pirtobrutinib, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated CLL/SLL: Updated Results from the Phase 1/2 BRUIN Study