Impact of HIV-1 Resistance-Associated Mutations on Susceptibility to Doravirine: Analysis of Real-World Clinical Isolates.

Clinical management of human immunodeficiency virus type-1 (HIV-1) infection may be negatively impacted by either acquired or transmitted drug resistance. Here, we aim to extend our understanding of the impact of resistance-associated mutations (RAMs) on the susceptibility of clinical isolates to the nonnucleoside reverse transcriptase inhibitor (NNRTI) doravirine. Clinical isolates from people living with HIV-1 undergoing routine testing for susceptibility to doravirine and other approved NNRTIs (etravirine, rilpivirine, efavirenz, and nevirapine) were collected from August 2018 to August 2019. Susceptibility in the presence/absence of NNRTI and nucleos(t)ide reverse transcriptase inhibitor (NRTI) mutations was determined using cutoffs for relative fold change in inhibition (ratio of the 50% inhibitory concentration [IC50] of patient virus compared with the IC50 of a wild-type reference strain). Biological cutoffs of 3- to 15-fold change were investigated for doravirine, with preestablished cutoffs used for the other NNRTIs. Of 4,070 clinical isolates, 42.9% had ≥1 NNRTI RAM. More isolates were susceptible to doravirine (92.5-96.7%) than to etravirine (91.5%), rilpivirine (89.5%), efavirenz (81.5%), or nevirapine (77.5%). Based on a 3-fold cutoff, doravirine susceptibility was retained in 44.7-65.8% of isolates resistant to another NNRTI and 28.5% of isolates resistant to all other tested NNRTIs. The presence of NRTI RAMs, including thymidine analog mutations, was associated with doravirine hypersusceptibility in some isolates, particularly in the absence of NNRTI RAMs. These results support the favorable resistance profile of doravirine and are of particular importance given the challenge posed by both acquired and transmitted resistance.

Antiarrhythmic effects of interleukin 1 inhibition after myocardial infarction.

BACKGROUND: Interleukin 1ß (IL-1ß) is a key regulator of the inflammatory response after myocardial infarction (MI) by modulating immune cell recruitment, cytokine production, and extracellular matrix turnover. Elevated levels of IL-1ß are associated with adverse remodeling, and inhibition of IL-1 signaling after MI results in improved contractile function. OBJECTIVE: The goal of this study was to determine whether IL-1 signaling also contributes to post-MI arrhythmogenesis. METHODS: MI was created in 2 murine models of elevated inflammation: atherosclerotic on the Western diet or wild-type with a subseptic dose of lipopolysaccharide. The role of IL-1ß was assessed with the IL-1 receptor antagonist anakinra (10 mg/(kg·d), starting 24 hours post-MI). RESULTS: In vivo and ex vivo molecular imaging showed reduced myocardial inflammation after a 4-day course of anakinra treatment, despite no change in infarct size. At day 5 post-MI, high-speed optical mapping of transmembrane potential and intracellular Ca2+ in isolated hearts revealed that IL-1ß inhibition improved conduction velocity, reduced action potential duration dispersion, improved intracellular Ca2+ handling, decreased transmembrane potential and Ca2+ alternans magnitude, and reduced spontaneous and inducible ventricular arrhythmias. These functional improvements were linked to increased expression of connexin 43 and sarcoplasmic reticulum Ca2+-ATPase. CONCLUSION: This study revealed a novel mechanism for IL-1ß in contributing to defective excitation-contraction coupling and arrhythmogenesis in the post-MI heart. Our results suggest that inhibition of IL-1 signaling post-MI may represent a novel antiarrhythmic therapy.