bluuebunny/crossref_metadata_2025_split huggingface dataset:
2501. CCR5 Targeted ARV Loaded Nanoparticle: Dual Protection for HIV Functional Cure
Authors: Destache Christopher J , Prathipati Pavan , Velagaputi Manasa , Mandal Subhra 
Published: October 2019

Abstract

Background
One of the NIH high-priority HIV/AIDS research objectives is to discover novel therapeutics aimed at developing safe, tolerable, strategies that targets cellular protein to induce long-term antiviral suppression. This current research aims at designing a novel targeted nano-formulation combining cell targeting and antiretroviral therapy to provide double protection against HIV-1.

Methods
CCR5 targeted combination antiretroviral drugs (cARV) loaded nanoparticles (NPs) were synthesized based on water-in-oil-in-water (W-O-W) emulsion methodology. For targeting CCR5+ T cells, a modified high affinity CCR5 monoclonal Ab (XFCCR5 mAb), was isolated from XF-CCR5 hybridoma cells. The XFCCR5 mAbs were covalently conjugated through their C-terminus by replacing the NHS group on FTC+DTG NPs with covalent amide bond. The CCR5 mAb binding was evaluated by SDS–PAGE methods. The CCR5-specific binding affinity of XFCCR5-FTC+DTG NP in compared with XFCCR5 monoclonal antibody (mAb) was evaluated by flow cytometry using CD4+CCR5+ TZM-bl cell line and PBMCs. The intracellular pharmacokinetic (PK) profile in TZMbl cells was evaluated by LC-MS/MS analysis, whereas in vitro efficacy was evaluated based on Steady-Glo® Luciferase Assay System using TZM-bl cells.

Results
XFCCR5-FTC+DTG NPs obtained averaged 173 ± 23 nm (mean ± SEM, n = 3) with 2.2 ± 0.47 mg XFCCR5 mAb bound per mg cARV NP. The formulation % entrapment efficiency of DTG and FTC respectively, to be 55 ± 1.6% and 42.6 ± 5.6%. The specific binding affinity (Km) of XFCCR5-FTC+DTG NP and XFCCR5 mAb were estimated to be 0.0057 and 0.0377, higher compared with wild-type anti-CCR5 mAb with higher Km value 0.303. Finally, the 4-day HIV-infection protection study result illustrates IC50 in case of XFCCR5-FTC+DTG NP and XFCCR5 NP to be as low as 0.0069 and 0.0031 µg/mL, respectively, compared with 1.771 µg/mL for XFCCR5 mAb (Figure 1, TZM-bl and Figure 2, PBMCs).

Conclusion
This nano-formulation aimed at duel protection by preventing HIV binding to CCR5+CD4+T cell due to CCR5 receptor blocking. These result support protection against HIV and maintenance of cARV drug levels. This novel formulation could be supportive of immune-alternative to achieve functional-cure against HIV.

Disclosures
All authors: No reported disclosures.
2508. Virologic Suppression in Patients Switched to BIC/TAF/FTC with Baseline NRTI and/or INSTI Resistance
Authors: Natali Kayla M , Tilani Rahul , Slim Jihad 
Published: October 2019

Abstract

Background
BIC/TAF/FTC is the first fixed-dose combination tablet to contain both a second-generation INSTI and TAF and has therefore become a popular treatment option for HIV. Historically, patients with NRTI mutations were placed on four-drug, NRTI-retaining regimens or two-drug, NRTI-sparing regimens. Recently, data have emerged supporting the use of second-generation INSTIs with tenofovir/FTC in the setting of the M184V mutation alone. There is a paucity of data, however, evaluating the use of BIC/TAF/FTC in the setting of NRTI and/or INSTI mutations. This study assessed the role of BIC/TAF/FTC in patients with baseline NRTI and/or INSTI mutations.

Methods
This was an observational retrospective study conducted at an inner city HIV clinic. Patients were eligible if they were switched to BIC/TAF/FTC with confirmed adherence and had either the M184V mutation alone, M184V plus another NRTI mutation(s), an INSTI mutation alone, or both NRTI and INSTI mutation(s) at the time of ART switch. We evaluated virologic response (HIV RNA < 200 copies/mL) and duration of BIC/TAF/FTC therapy.

Results
There were 16 patients eligible for analysis. Among the patients, 69% were male and 31% were female. The majority of patients were Black (81%). The mean age was 63 years (SD ± 8.6). Thirteen patients were virologically suppressed (HIV RNA < 200 copies/mL) at baseline. The mean CD4 count at baseline was 630.4 cells/mm3 (SD ± 297.1). Mutations at baseline were as follows: M184V alone (25%), M184V plus another NRTI mutation(s) (56.25%), INSTI mutation alone (12.5%), NRTI and INSTI mutation(s) (6.25%). BIC/TAF/FTC mean duration of therapy was 10.5 months (range 6–14 months). The mean CD4 count of the patients switched to BIC/TAF/FTC was 687 cells/mm3 (SD ± 20.7). All patients switched to BIC/TAF/FTC achieved or maintained virologic suppression (HIV RNA < 200 copies/mL) with a mean HIV RNA of 26.25 copies/mL (SD ± 14.1). Fifteen of those switched to BIC/TAF/FTC had an undetectable HIV RNA level (HIV RNA < 50 copies/mL).

Conclusion
While a larger cohort and longer follow-up period is needed, BIC/TAF/FTC may maintain virologic suppression in patients with select baseline NRTI and/or INSTI mutations.

Disclosures
All authors: No reported disclosures.
2509. Pooled Resistance Analyses of Darunavir (DRV) Once Daily (QD) Regimens and Formulations Across 10 Clinical Studies of Treatment-Naïve (TN) and Treatment-Experienced (TE) Patients with Human Immunodeficiency Virus (HIV)-1 Infection
Authors: Lathouwers Erkki , Seyedkazemi Sareh , Luo Donghan , Brown Kimberley , De Meyer Sandra , Wong Eric Y 
Published: October 2019

Abstract

Background
DRV has demonstrated high efficacy and barrier to resistance development across diverse populations, from TN to heavily TE patients. We evaluated resistance data from 10 clinical studies of different DRV 800 mg QD–based antiretroviral regimens and formulations.

Methods
The analysis included patients from 10 phase 2/3 studies (48–192 weeks in duration) of ritonavir- and cobicistat-boosted DRV 800 mg QD–based regimens in TN and virologically failing or suppressed TE patients with HIV-1 (table). Three were phase 3 studies of the DRV/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg single-tablet regimen (STR). Post-baseline resistance was evaluated in patients experiencing protocol-defined virologic failure (PDVF); definitions and criteria for resistance testing varied slightly among studies. Resistance-associated mutations (RAMs) were based on respective International Antiviral Society–USA mutation lists over time.

Results
Of the 3,635 patients evaluated, 250 met PDVF criteria and 205 had post-baseline genotypes/phenotypes. Overall, 4 (0.1%) patients developed (or had identified [switch studies]) ≥1 DRV and/or primary protease inhibitor (PI) RAM (table), and only 1 (< 0.1%, ODIN) patient lost DRV phenotypic susceptibility; this TE patient had prior VF with lopinavir. Among those who used a nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone (mostly emtricitabine [FTC] + tenofovir [TFV]), 12 (0.4%) patients had ≥1 NRTI RAM, including 10 with M184I/V associated with FTC resistance. No TFV RAMs were observed. Among patients receiving D/C/F/TAF (n = 1,949), none had post-baseline DRV, primary PI, or TFV RAMs; only 2 (0.1%) patients developed an FTC RAM.

Conclusion
Across a large, diverse population using DRV 800 mg QD–based regimens and formulations, resistance development remains rare; 0.1% of patients had ≥1 DRV and/or primary PI RAM post-baseline. Among 3 trials of the D/C/F/TAF STR, no patients developed a DRV or primary PI RAM. After > 10 years of investigating DRV 800 mg QD–based regimens in clinical trials, loss of phenotypic susceptibility to DRV has never been observed in TN or TE virologically suppressed patients and was only once observed in a TE patient with prior VF on multiple antiretrovirals, including a PI.

Disclosures
All authors: No reported disclosures.
2515. Clinical Relevance of Immune Non-Response Among Virally Suppressed Adults Living with HIV in Africa and the United States
Authors: Noiman Adi , Wang Xun , Esber Allahna L , Crowell Trevor A , Ganesan Anuradha , Polyak Christina , Ake Julie A , Agan Brian 
Published: October 2019

Abstract

Background
Immune non-response (INR) for people living with HIV (PLWH) is the inability to regain healthy CD4 counts despite viral suppression (VS) on antiretroviral therapy (ART). We identified factors associated with INR in two methodologically similar but demographically diverse cohorts with open access to care and assessed the relationship between INR and incident serious non-AIDS event (SNAE).

Methods
The US Military HIV Natural History Study (NHS) and the African Cohort Study (AFRICOS) are multisite, open cohort studies enrolling PLWH. Participants with 2 years of VS < 400 copies/mL on ART were evaluated for INR, defined as CD4 < 350 cells/µL at 2 years VS. Logistic regression was used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for factors associated with INR. Cox proportional hazards regression produced adjusted hazard ratios (aHR) and 95% CIs for factors associated with incident SNAE (first non-AIDS cancer, cardiovascular, gastrointestinal, genitourinary, liver, musculoskeletal or respiratory event) after 2 years of VS.

Results
10.8% of the 1,784 NHS and 25.8% of the 984 AFRICOS subjects had INR. The AFRICOS cohort was older and had a higher proportion of females. In both cohorts, immune non-responders were significantly older and had a significantly lower CD4 at ART initiation. Those with INR also took longer to reach 2 years of VS since starting ART. Odds of INR decreased by over 60% for every 100 cell increase in baseline CD4 in both cohorts (NHS aOR = 0.31 [95% CI 0.26, 0.37]; AFRICOS aOR = 0.36 [95% CI 0.21, 0.86]). In the NHS, hazard of incident SNAE was 61% higher for those with INR (aHR = 1.61 [95% CI 1.12, 2.33]). Probability of SNAE-free survival at 15 years since 2 years of VS was approximately 20% lower comparing those with and without INR; nearly equal to the differences observed by 15-year age groups.

Conclusion
INR was common in two diverse cohorts with open access to care and treatment. The association with SNAEs suggests early identification of and interventions to prevent or reverse INR may improve clinical outcomes, but further study is needed. The clinical relevance of INR highlights the value of early HIV identification and treatment, and suggests CD4 monitoring at ART initiation and post-VS is important in settings where INR is prevalent.

Disclosures
All authors: No reported disclosures.
2531. Using Peer-to-Peer Education to Increase Awareness and Uptake of HPV Vaccine Among Chinese International Students
Authors: Esaggoff Aaron , Cohen, Samuel , Chang Guoxuan , Equils Ozlem , Orman Sarah Van , Burnett Alicia 
Published: October 2019

Abstract

Background
There are more than one million international college students in the United States. The University of Southern California hosts about 5,000 Chinese International Students (CIS). HPV-related cancers are common in China and the HPV vaccine was only recently introduced to the Chinese population. CIS in the United States have low HPV vaccination rates upon arrival. Once these students become aware of the affordability and the accessibility of the vaccine, they often contact a provider to start the vaccination series. The HPV vaccine is available to all eligible students at the USC student health center and is free of charge to students with Aetna Student Health Insurance. We examined the impact of a peer-to-peer education program about HPV disease and vaccination amongst CIS and assessed the impact of the program via an analysis of HPV immunization rates amongst CIS.

Methods
The study was IRB approved. Mandarin-speaking USC students volunteered to serve as peer educators in response to an inquiry from academic advisors. 18 CIS were trained by MiOra as Immunization Community Health Educators (ICHE) on HPV disease and vaccination as well as sexually transmitted infections and prevention. CIS educated peers at tables set up throughout USC.

Results
Initial data from 100 CIS students who were surveyed and educated in April 2019 were analyzed. 59 out of 99 (59.6%) students reported that they have either received or are in the process of receiving the HPV vaccine. 93 out of 99 (93.9%) indicated “no knowledge” or “some knowledge” about HPV and HPV vaccine while only 6 students (6.1%) reported “a great deal of knowledge.” 56 out of 99 (56.6%) thought that it is “unlikely” or “impossible” for them to acquire HPV. 92 out of 97 (94.9%) said they would be interested in getting vaccinated if it were free.

Conclusion
Many CIS have limited understanding of HPV risk factors and HPV vaccine; however, when informed, the majority of students indicated they would likely vaccinate if it was covered by insurance. Peer-to-peer education was very effective. Of the first 400 students educated, 80 visited the student health center. This is an ongoing project. We will continue to collect and report data on the impact of the peer-to-peer education and factors influencing.

Disclosures
All authors: No reported disclosures.
2544. An Exploratory Study of Resource Utilization by Practitioners when Managing Infections
Authors: Abdoler Emily , Gruenberg Katherine , Schwartz Brian , Schwartz Brian , MacDougall Conan 
Published: October 2019

Abstract

Background
Antimicrobial prescribing mistakes are common and adherence to guidelines for treatment of infections is poor. Effective use of clinical resources could help ameliorate these issues, but little is known about the use of such resources by physicians and pharmacists. We thus aimed to explore how practitioners utilize clinical resources in the management of infections.

Methods
We conducted individual interviews with a purposeful sample of eight Hospitalists, eight ID attendings, four ID pharmacists, and six non-ID pharmacists. As part of a larger, semi-structured interview exploring ID practice patterns, we asked respondents how they utilize resources when managing infections. We describe the resources mentioned by the different practitioners, as well as the frequency of their reported use.

Results
All respondents reported using at least one resource to help manage infections, with a mean of 5.6 resources each. The majority of respondents use resources daily, although some ID practitioners use resources more frequently and some general practitioners less frequently (Figure 1). The types of resources utilized by respondents fell into six main categories: local ID resources, outside ID resources, primary literature, guidelines, colleagues, and pharmacy resources (Figure 2). In general, local resources are utilized more frequently by non-ID practitioners, while guidelines and the primary literature are utilized more frequently by ID practitioners. ID physicians use pharmacy resources more frequently than non-ID physicians. Six respondents spontaneously reported being motivated to review resources for their own interest or learning. Several also commented that accessibility was important in choosing resources.

Conclusion
Providers report use of resources to manage infections, although the type of resource and frequency of use varies. ID practitioners utilize more detailed resources than nonspecialists. Accessibility seems to influence resource utilization, which may explain the popularity of local ID resources. As such, efforts to make local ID resources as accessible and clear as possible may have an impact on appropriate antibiotic use. Future quantitative studies could help illuminate rates and perceived advantages of specific resource utilization.

Disclosures
All authors: No reported disclosures.
2547. Prioritizing Antimicrobial Resistance Learning Objectives Through a Modified, Two-Round, One-Day Delphi at a Multidisciplinary Conference
Authors: Budak Jehan , Kpokiri Eneyi E , Abdoler Emily , Tucker Joseph , Schwartz Brian , Schwartz Brian 
Published: October 2019

Abstract

Background
Antimicrobial resistance (AMR) is a global public health problem, but the learning needs of the medical profession on this topic are not well understood. The World Health Organization has called for better educational resources on AMR. Thus, we aimed to identify AMR learning objectives for physicians and medical trainees.

Methods
We designed a modified, two-round Delphi process to build consensus around these objectives, recruiting attendees at a one-day, multidisciplinary, international AMR symposium. Through review of the literature and discussion with experts in AMR, we generated an initial list of 17 objectives. We asked participants to rate the importance of including each objective in an AMR curriculum for physicians on a 5-point Likert scale, which ranged from “do not include” (1) to “very important to include” (5). Consensus for inclusion was predefined as ≥ 80% of participants rating the objective ≥ 4.

Results
The first round was completed by 30 participants, and the second by 21. Nobody declined to participate, but several people had to leave between rounds. Participants included physicians, researchers, graduate students, and a pharmacist, foundation manager, patient advocate, leader of an international financial institution, health administrator, and biomedical scientist. After the first round, 16 objectives met the consensus criteria, and participants suggested five additional topics. After the second round, 12 objectives met the consensus criteria (see Table 1). Objectives related to treatment of AMR most frequently met consensus criteria. Specific objectives with the highest consensus ratings were related to identifying infections not requiring antibiotics and recognizing the importance of using the narrowest spectrum antibiotic for the shortest period of time.

Conclusion
We successfully employed a modified, one-day Delphi process at an international, multidisciplinary AMR symposium to build consensus among experts and stakeholders regarding key learning objectives for AMR. This technique may be useful for guideline committees and other taskforces in the Infectious Diseases community. Our generated list may be useful for those developing AMR training materials for medical students and physicians.

Disclosures
All authors: No reported disclosures.
2550. A Meeting of the Minds Over Matters of the Heart: Using Interdisciplinary Education to Build Consensus in Managing Cardiac Implantable Electronic Device (CIED) Infections
Authors: Azim Ahmed Abdul , Zimetbaum Peter , Kramer Daniel B , Karchmer Adolf W , Stead Wendy 
Published: October 2019

Abstract

Background
CIED infections carry significant morbidity and mortality. Guidelines differ in management recommendations for CIED infections, which can result in a lack of consensus amongst Infectious Disease (ID) and Cardiology providers caring for these patients. We sought to identify areas of disagreement and consensus in the care of CIED infections amongst ID and Cardiology providers at an academic medical center. We used these data as a needs assessment to develop an interdisciplinary educational intervention focused on standardizing our institutional approach toward CIED infections, to create an internal guideline and to develop a new multidisciplinary team (MDT) for assistance managing complex patients hospitalized with CIED infections.

Methods
A pre-intervention survey was delivered to advanced practitioner providers, fellows and faculty of the divisions of Cardiology, Electrophysiology (EP) and ID to assess content knowledge in the diagnosis and management of CIED infections, attitudes toward the formation of a MDT, and perception of the degree of consensus amongst these specialty providers.

Results
The survey was sent to 206 providers, 40 (19.4%) participated. Only 16/40 (40%) agreed that there was consensus within the ID division in managing patients with CIED infections, and only 8/40 (20%) agreed that there was consensus amongst Cardiology and EP providers. 37/40 (92.5%) agreed that a MDT approach would be beneficial. Some survey responses diverged significantly from guideline recommended management strategies, including only 50% of respondents recommending CIED extraction for devices eroding through the skin. For patients with CIED-related endocarditis, 35% recommended delaying reimplantation of a new CIED until completion of a full course of antibiotics, despite guideline recommendations of significantly shorter delays.

Conclusion
Our survey revealed a striking lack of consensus amongst ID and Cardiology providers in the appropriate diagnosis and management of CIED infections, along with divergence from guideline recommendations in key areas. An interdisciplinary educational intervention to update provider content knowledge and unify interspecialty approaches could improve collaborative efforts and, ultimately, care of patients with CIED infections.

Disclosures
All authors: No reported disclosures.
2568. Mechanisms of a Specific Probiotic Comprised of Lactobacillus acidophilus CL1285, L. casei LBC80R and L. rhamnosus CLR2 that Interferes with Clostridioides difficile 20291 Toxin Production
Authors: Gunaratnam Sathursha , Diarra Carine , Paquette Patrick D , Ship Noam , Millette Mathieu , Lacroix Monique 
Published: October 2019

Abstract

Background
Clostridioides difficile infections (CDI) result from antibiotic use and cause severe diarrhea (C. difficile-associated diarrhea, CDAD) which is life-threatening and costly. A specific probiotic containing Lactobacillus acidophilus CL1285, L. casei LBC80R and L. rhamnosus CLR2 (Bio-K+) has demonstrated benefits in preventing CDI and has a strong inhibitory effect on the growth of several nosocomial C. difficile strains in vitro. Many Lactobacilli can inhibit CD growth though lactic acidification. Here, we have investigated novel acid-independent mechanisms by which these strains impair C. difficile virulence.

Methods
The hypervirulent strain C. difficile R20291 was co-cultured anaerobically with Bio-K+ probiotic strains in various media and glucose concentrations (5 g/L, 3 g/L, 0 g/L), for 24 hours at 37°C. Parameters such as Log CFU, pH, Toxin A and B, cell cytotoxicity were measured. Statistical comparisons using ANOVA one-way was performed in order to determine whether the groups were significantly different.

Results
At 5 g/L glucose, no C. difficile toxin was produced and co-culture with these lactobacilli resulted in potent acidification and growth inhibition. At 3 g/L glucose, C. difficile toxin production occurred and acidification by the lactobacilli resulted in growth inhibition as well as >99% reduced Toxin A and B production. In the absence of glucose and a starting pH of 7.0, TY broth, the lactobacilli did not acidify the medium and C. difficile growth was normal yet Toxin A and B production was partially reduced at, 20% and 41% lower. Toxin B from the supernatant of C. difficile grown in TY was cytotoxic to human fibroblast cells, but this was less cytotoxic when co-cultured with the Lactobacilli.

Conclusion
These results suggest that the combination of L. acidophilus CL1285, L. casei LBC80R and L. rhamnosus CLR2 interferes with C. difficile pathogenesis through: 1) inhibition of C. difficile growth (via lactic acid secretion), 2) reduced toxin A/B synthesis and (3) toxin neutralization. These results might explain the strain specificity of Bio-K+ probiotic bacteria in potentially preventing C. difficile-associated diarrhea in antibiotic treated patients.

Disclosures
All authors: No reported disclosures.