P549 Changing Lanes: Switching Therapies in Inflammatory Bowel Disease, An Observational Study

Background Switching between therapies in inflammatory bowel disease (IBD) is common and a paucity of data exists regarding the optimal switching strategy. A number of new drug therapies have recently emerged for the treatment of IBD. Failure of biologic and small molecule therapies occur regularly, prompting the need for a treatment switch. Our aim is to review trends amongst our patients who switched biologic/small molecule therapy to identify high risk characteristics and to look for predictor variables which may reduce the need to switch in the future. Methods This is a 4 year retrospective observational study of IBD patients who underwent a therapy switch. Patients were identified from a prospectively maintained IBD database of 141 patients. Patient demographics, treatment history, disease history, biomarkers (within 3 months of switch) and endoscopy results were reviewed. Minitab17 was used for statistical analysis. Results Switching of biologic therapy was observed in 39 patients (28%); 21 (54%) were male; mean age was 42.8Y. Of these, 21 (53.9%) had Crohn’s disease (CD), 17 (44%) had ulcerative colitis (UC) and 1 patient had indeterminate colitis. Mean disease duration at time of switch was 78 months. 82% (n=14/17) of UC patients had pancolitis. 43% (n=9/21) of CD patients had a previous intestinal resection. The most common initial therapy was Adalimumab 46% (n=18) (Fig1) with the most common switch to IFX 36% (n=14) (Fig2). Primary LOR occurred in 28% (n=11) and secondary LOR in 44% (n=17), the remainder switched due to infusion reaction/adverse effects (n=10) and clinical remission (n=1). Mean CRP was 13.68 (95% CI: 7.28, 20.09), mean FCP was 874 (95% CI: 418, 1329), mean mayo score was 1.88 (95% CI: 1.37, 2.39), mean SES CD score was 5.79 (95% CI: 3.24, 8.33). Median IFX level was 0.8ug/ml (IQR 0.4, 9.7), 37.5% (n=6/16) of the patients on IFX developed ADAs to IFX. Median Adalimumab level was 5.2ug/ml (IQR 1.4, 13.5) and 11% (n=2/18) developed ADAs to Adalimumab. A significant negative correlation was found between FCP and IFX level using Spearman rank correlation -0.822, p = 0.01. 39% (n=15) were on an immunomodulator, no significant association was found between immunomodulator therapy and primary/secondary LOR, p= 0.67 and p= 0.63. 28% (n=11) were admitted with an IBD flare in the 1st year post switch and 13% (n=5) underwent intestinal resection. 8 (21%) subsequently switched to a 3rd biologic agent. Conclusion The most common therapy switch was within Anti-TNF drug class, mean CRP and FCP were raised at the time of switch and a significant number of patients were admitted in the year post switch with an IBD flare. Pancolitis in UC and previous intestinal surgery in CD were common characteristics of those who switched.

Acquired HIV-1 Protease Conformational Flexibility Associated with Lopinavir Failure May Shape the Outcome of Darunavir Therapy after Antiretroviral Therapy Switch

Understanding the underlying molecular interaction during a therapy switch from lopinavir (LPV) to darunavir (DRV) is essential to achieve long-term virological suppression. We investigated the kinetic and structural characteristics of multidrug-resistant South African HIV-1 subtype C protease (HIV-1 PR) during therapy switch from LPV to DRV using enzyme activity and inhibition assay, fluorescence spectroscopy, and molecular dynamic simulation. The HIV-1 protease variants were from clinical isolates with a combination of drug resistance mutations; MUT-1 (M46I, I54V, V82A, and L10F), MUT-2 (M46I, I54V, L76V, V82A, L10F, and L33F), and MUT-3 (M46I, I54V, L76V, V82A, L90M, and F53L). Enzyme kinetics analysis shows an association between increased relative resistance to LPV and DRV with the progressive decrease in the mutant HIV-1 PR variants’ catalytic efficiency. A direct relationship between high-level resistance to LPV and intermediate resistance to DRV with intrinsic changes in the three-dimensional structure of the mutant HIV-1 PR as a function of the multidrug-resistance mutation was observed. In silico analysis attributed these structural adjustments to the multidrug-resistance mutations affecting the LPV and DRV binding landscape. Though DRV showed superiority to LPV, as a lower concentration was needed to inhibit the HIV-1 PR variants, the inherent structural changes resulting from mutations selected during LPV therapy may dynamically shape the DRV treatment outcome after the therapy switch.

Lymphocyte recovery after fingolimod discontinuation in patients with MS

ObjectiveTo investigate the dynamics of immune cells recovery after treatment discontinuation of fingolimod in real-life clinical practice, we analyzed the course of lymphocyte reconstitution and its potential influencing factors in patients with multiple sclerosis (MS).MethodsWe analyzed leukocyte, lymphocyte, and granulocyte counts of 58 patients at 3, 6, and 12 months after fingolimod cessation and the following parameters as potential risk factors for a prolonged lymphopenia up to 12 months: age; sex; Expanded Disability Status Scale, and disease duration at the time of fingolimod start; type and number of previous immunomodulatory treatments; fingolimod treatment duration; lymphocyte count at baseline before fingolimod, at fingolimod stop, and at the time of therapy switch; time interval between fingolimod cessation and new treatment initiation; type of the follow-up immunomodulatory treatment; and corticosteroid administration after fingolimod cessation.ResultsAll patients showed a drop of the lymphocyte count under fingolimod with no relevant leukopenia or neutropenia. One year after discontinuation, still 22% of the patients were lymphopenic and 54% of them did not reach 80% of the baseline lymphocyte value. Low lymphocyte counts before fingolimod start, under fingolimod, and at therapy switch, successive treatment with rituximab, and pretreatment with mitoxantrone were significantly associated with a prolonged immune cell recovery.ConclusionsProlonged lymphopenia after fingolimod cessation exists in a subgroup of patients with MS and should be considered in clinical practice, particularly when changing treatment regimens.

Comparison of the therapy effect of aflibercept and ranibizumab in patients with neovascular retinal pigment epithelium detachment identified by fluorescence angiography and optical coherence tomography angiography

Background To report on the current methods for choroidal neovascularization (CNV) detection and the clinical outcome of intravitreal therapies in patients with neovascular pigment epithelium detachment (PED). Methods Retrospective, interventional cohort study on 77 eyes of 59 patients. Inclusion criteria were a neovascular PED, identified by fluorescence angiography (FA) or/and optical coherence tomography angiography (OCTA) treated with aflibercept (16 eyes) or ranibizumab monotherapy (36 eyes) or with at least three injections of ranibizumab, with a therapy switch to aflibercept in case of persistent fluid (25 eyes). The therapy regimen was a pro re nata (PRN) scheme with an upload phase of three monthly injections. Outcome measures were sensitivity of CNV detection and evaluation of CNV activity at baseline on FA compared to OCTA, the change in highest retinal prominence (HRP) and PED size, assessed by spectral - domain OCT (SD-OCT), and the change in best-corrected visual acuity (BCVA) three months after therapy initiation in the monotherapy groups or after the switch. Results Sensitivity of CNV detection was slightly superior for FA (0.786) compared to OCTA (0.706), whereas CNV activity evaluation was superior on OCTA. HRP significantly decreased after aflibercept (p<0.001) or ranibizumab monotherapy (p<0.001), and after therapy switch to aflibercept (p<0.001) in ranibizumab refractory patients. Corresponding BCVA improved in these groups, but without statistical significance (p=0.46; p = 0.11; p=0.19). PED size significantly decreased after aflibercept monotherapy (p=0.001) or after therapy switch to aflibercept (p<0.001), but not after ranibizumab. Conclusions The combination of FA and OCTA offers significantly improved visualisation, quantification, and predictability of CNV activity in neovascular PED. Aflibercept and ranibizumab are effective treatment options for neovascular AMD with PED, with a stronger effect of aflibercept on the PED itself. Furthermore, aflibercept appears to be a valuable tool for the management of patients unresponsive to ranibizumab.