Target Population For Treatment Research Articles

1244. Inpatient vs. outpatient initiation of Hepatitis C treatment among hospitalized patients who inject drugs: Lessons from a quality improvement project

Abstract Background Hepatitis C (HCV) diagnoses are rising, driven by infections in people who inject drugs (PWID). PWID are identified as a target population for treatment, but access to care is a barrier. At our institution, Addiction Medicine (AM) and Infectious Diseases (ID) routinely screen hospitalized PWID for HCV. Our novel quality improvement project assessed feasibility of starting HCV care processes for PWID inpatient. This included: (1) inpatient e-consults, (2) inpatient treatment initiation with direct acting antivirals (DAAs) when possible, and (3) post-discharge telehealth care. Methods The project was implemented at an academic hospital in the Southeast in August 2021, with results observed through April 2022. Patients seen by AM consultants with detectable HCV RNA and interest in treatment were eligible. AM recommended ID e-consults focused on HCV care, which began care coordination, including inpatient treatment initiation in select cases (based primarily on length of stay) (Fig 1). The primary outcome was “likely cure,” defined as treatment completion or SVR-4 (chosen due to concerns for loss to follow up). Cascades of care were constructed including: (1) completed HCV e-consult; (2) linkage to care (defined as telehealth visit for those not initiating inpatient); (3) treatment initiation; and (4) likely cure. Figure 1:Workflow Results Twenty patients had detectable HCV RNA and all were interested in treatment. Enrolled patients had a mean age of 33 years; 9/20 (45%) were female; and 17/20 (85%) were White. Of 20 patients (Fig 2), 16 (80%) were linked to care with 13 (81%, 65% overall) started on HCV treatment, of which 9 were started inpatient. Likely cure was achieved for 7, and 6 were still on treatment at the time of this report (Fig 2). Likely cure has so far been achieved in 66% of inpatient initiators (6 of 9), compared with 18% of others (2 of 11) (Figs 3 and 4). 6 patients were lost to follow-up. None of those initiating DAAs inpatient were lost. Conclusion Inpatient initiation of HCV treatment for PWID was feasible for patients with prolonged hospitalizations and may be effective at facilitating HCV treatment and cure among a vulnerable population with substantial barriers to care. Future steps should address inpatient barriers to DAAs, and examine models of HCV telehealth. Disclosures Asher J. Schranz, MD, MPH, UnitedHealthCare: Honoraria.

A lung targeted miR-29 mimic as a therapy for pulmonary fibrosis.

SummaryBackgroundMicroRNAs are non-coding RNAs that negatively regulate gene networks. Previously, we reported that systemically delivered miR-29 mimic MRG-201 reduced fibrosis in animal models, supporting the consideration of miR-29-based therapies for idiopathic pulmonary fibrosis (IPF).MethodsWe generated MRG-229, a next-generation miR-29 mimic based on MRG-201 with improved chemical stability due to additional sugar modifications and conjugation with the internalization moiety BiPPB (PDGFbetaR-specific bicyclic peptide)1. We investigated the anti-fibrotic efficacy of MRG-229 on TGF-β1 treated human lung fibroblasts (NHLFs), human precision cut lung slices (hPCLS), and in vivo bleomycin studies; toxicology was assessed in two animal models, rats, and non-human primates. Finally, we examined miR-29b levels in a cohort of 46 and 213 patients with IPF diagnosis recruited from Yale and Nottingham Universities (Profile Cohort), respectively.FindingsThe peptide-conjugated MRG-229 mimic decreased expression of pro-fibrotic genes and reduced collagen production in each model. In bleomycin-treated mice, the peptide-conjugated MRG-229 mimic downregulated profibrotic gene programs at doses more than ten-fold lower than the original compound. In rats and non-human primates, the peptide-conjugated MRG-229 mimic was well tolerated at clinically relevant doses with no adverse findings observed. In human peripheral blood from IPF patients decreased miR-29 concentrations were associated with increased mortality in two cohorts potentially identified as a target population for treatment.InterpretationCollectively, our results provide support for the development of the peptide-conjugated MRG-229 mimic as a potential therapy in humans with IPF.FundingThis work was supported by NIH NHLBI grants UH3HL123886, R01HL127349, R01HL141852, U01HL145567.

Abstract PD2-10: Predicting sensitivity to CDK4/6 inhibition in ER+/HER2- breast cancer cell lines

Abstract Background: For treatment of metastatic or advanced ER+/HER2- breast cancer, CDK4/6 inhibition (CDKi), including CDK4/6 inhibitors palbociclib, ribociclib and abemaciclib, is now the standard of care. Approximately 25% of patients however will not respond or demonstrate progression within 6 months. The successful clinical implementation of these agents will require understanding which patient subgroups are more likely to benefit from targeted therapies. The goal of this study was to identify molecular alterations contributing to the intrinsic and acquired resistance to CDK4/6 inhibition. Methods/Results: A panel of fifteen ER+/HER2- cell lines was characterized using a NanoString PAM50-like assay as well as next generation sequencing. Cell lines were screened with three CDK4/6 inhibitors: palbociclib, ribociclib and abemaciclib. Growth rate (GR) inhibition metrics, which control for different doubling times of the cell lines, were used to generate normalized GR inhibition values. A range of sensitivities to palbociclib was observed based on molecular alterations, varying from 75 to 200nM in sensitive cell lines to 800nM to >5000nM in resistant cell lines. In response to 24h treatment with 1µM palbociclib, cell lines downregulated expression of E2F-target genes involved in cell cycle progression, and increased growth factor receptor signaling. Following treatment with 1µM palbociclib, resistant cell lines had increased expression of genes involved in DNA repair, replication and cell cycle checkpoints, as well as downregulation of genes involved in the regulation of cellular response to growth factor stimulation. Downregulated genes included several members of the DUSP family of phosphatases that are responsible for negative regulation of MAPK signaling, and infers a possible target population for treatment with palbociclib. To determine whether the same pathways driving intrinsic resistance to palbociclib are also driving acquired resistance, two in-vitro models of acquired resistance to CDKi were developed by treating MCF7 and T47D cell lines with increasing concentrations of palbociclib or abemaciclib. Loss of RB1 was observed in MCF7 CDKi-resistant cell lines, as well as copy number gains of EGFR, BRCA1 and SMO. In the MCF7 CDKi-resistant cell lines, increased activity of EGFR and MAPK signaling pathways as well as increased expression of cyclin E1 was observed. Conclusions: These results suggest that alterations in cell cycle and MAPK signaling pathways contribute to both intrinsic and acquired resistance to CDKi in ER+/HER2- breast cancer cell lines. Citation Format: Lauren Bathurst, Linda Liao, Cheryl Crozier, Jane Bayani, John Bartlett, Melanie Spears. Predicting sensitivity to CDK4/6 inhibition in ER+/HER2- breast cancer cell lines [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD2-10.

Determining Accuracy of oAb as a Mechanistic Biomarker for Alzheimer's Disease in Human Plasma

Alzheimer's disease (AD) is a fatal neurodegenerative disease that is the 6th leading cause of death in the United States with no cure and few palliative treatments. Currently, there is no preventative treatment, and even if such a therapeutic could be identified, without a predictive biomarker, a target population for treatment could not be determined. Although the mechanism remains unclear, AD is caused by increased levels of the amyloid‐b peptide (Ab), which aggregates to form both amyloid plaques and soluble oligomeric Ab (oAb), the latter considered a proximal neurotoxin. We believe that levels of oAb in human plasma are a prognostic biomarker, and have developed and licensed a method for their detection (LOD <5pMol). While age is the greatest risk factor for AD, APOE4 is the greatest genetic risk factor, increasing risk up to 15‐fold compared to the more common APOE3. Importantly, female (♀) APOE4 carriers have an increased risk for AD compared to male (♂) APOE4 carriers. Key to the success of this project has been the stratification of both control and AD subjects by sex within APOE genotype, with the results that plasma oAb levels are: ♀APOE4> ♂APOE4> ♀APOE3> ♂APOE3. This response was observed in two large human post‐mortem cohorts. However, stratification, the principle of personalized medicine, is simply not applied to AD populations. We now seek to threshold oAb levels using longitudinal and human AD trial data to establish prognostic potential, with the goal of partnering with the private sector for commercialization.Support or Funding InformationLaDu lab funding includes an Anonymous Donor, the University of Illinois College of Medicine, and UIC Honors College Grant.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Operational lessons from 20 years of the Mectizan Donation Program for the control of onchocerciasis

The donation of ivermectin (Mectizan, Merck & Co., Inc.) to control onchocerciasis (river blindness) was established in 1987 and has since gradually expanded to provide for >570 million treatments cumulatively over the past 20 years. The Mectizan Donation Program (MDP) operates within a broad partnership in 33 endemic countries in need of mass treatment. Particular operational methods and tools are applied to facilitate ivermectin mass treatment. Drug management has been streamlined, including dosing, tablet size and packaging, and monitoring for adverse events. Much of the experience gained in the development of ivermectin mass treatment can be usefully applied in the recent broader perspective of control of neglected tropical diseases. The most important operational lessons of the MDP include: (i) the need to easily define the target population for treatment using rapid, non-invasive techniques; (ii) the value of a broad partnership; (iii) the great potential of working through community-directed treatment; (iv) the need to streamline all drug management aspects and (v) the importance of operations research to tackle new challenges.