Use and Effectiveness of Infection Prophylaxis Strategies in a National Cohort of Patients with ANCA Vasculitis

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PROJECT SUMMARY/ABSTRACT Reducing infection risk is a priority in patients with antineutrophil cytoplasmic autoantibody (ANCA) – associated vasculitis (AAV), a group of rare, life-threatening autoimmune diseases that cause inflammation and necrosis of blood vessels in multiple organs, most commonly the kidneys. The availability of effective, aggressive immunosuppressive medications transformed AAV from a rapidly fatal condition to a chronic, relapsing-remitting disease, but comes with a high burden of severe infections, which are now the leading cause of morbidity and mortality in AAV. To prevent opportunistic infection with Pneumocystis jirovecii pneumonia (PJP), treatment guidelines recommend prophylaxis with trimethoprim/sulfamethoxazole (TMP/SMX). However, PJP occurs very rarely in AAV, even in those not receiving prophylaxis. Other severe infections are common and may be effectively prevented by alternative prophylactic antimicrobials (e.g., fluoroquinolones, doxycycline, amoxicillin, antifungals) recommended for non-AAV immunosuppressed populations. Limited available data suggests under-utilization and widespread variation in use of recommended and alternative prophylaxis strategies, but generalizable information about drivers of this variation is lacking. In addition, we lack evidence from randomized trials or rigorous observational studies designed to assess causal effects of recommended and alternative prophylaxis on key outcomes in AAV, including severe infections and mortality. The long-term goal of this research is to reduce infection-related morbidity and mortality in AAV, through improved understanding of the determinants of patients’ use of prophylaxis and evidence regarding effectiveness of recommended vs. alternative prophylaxis. The proposed retrospective cohort study will use medical claims and prescription drug data for a national cohort of Medicare beneficiaries with AAV who initiate a new course of immunosuppressive therapy in 2016-2017. Specific aims are to (1) identify predisposing, enabling, and medical need (i.e., clinical) factors associated with use of TMP/SMX prophylaxis, alternative prophylaxis strategies, or no prophylaxis; and (2) assess the effectiveness of antimicrobial prophylaxis strategies in reducing risk of severe infections and mortality. Aim 1 analyses will use regression analyses to identify factors associated with use of guideline-recommended TMP/SMX prophylaxis or alternative prophylaxis strategies, versus no prophylaxis. Aim 2 will use powerful pharmacoepidemiologic methods to reduce potential for selection bias and confounding, including an active-comparator, new-user design and advanced covariate balancing methods (i.e., entropy balancing), to compare severe infection and mortality risk in those receiving TMP/SMX vs. alternative prophylaxis. This study will identify patients most at-risk for not receiving recommended prophylaxis, improve the evidence base to inform decision-making about prophylaxis in AAV, and build a foundation for future comparative effectiveness trials comparing promising alternative prophylaxis strategies to the current standard of care in this understudied population.