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Background: Itraconazole is the treatment of choice for many fungal infections, including histoplasmosis. While the tolerability of itraconazole has been described in short-term trial settings, there are few studies on side effects during long-term therapy. Fluconazole, which is usually thought to be less toxic, is associated with 52% toxicity in long-term treatment., Objectives: To determine the frequency, types, and timing of side effects from itraconazole therapy, the resulting changes to treatment plans, and associations between patient characteristics and itraconazole serum levels with side effect status., Methods: We conducted a single-centre, retrospective study of adult patients with histoplasmosis receiving itraconazole therapy for at least 28 days from 2002 to 2021. Reported side effects were characterized, and propensity score matching was used to compare itraconazole serum levels between patients with and without side effects., Results: Sixty-three out of 227 (27.8%) patients experienced at least one side effect, the most common of which were hepatotoxicity (7.0%), nausea/vomiting (6.6%), and diarrhoea (6.2%). 12 (19.0%) patients with side effects underwent an itraconazole dose reduction and 29 (46.0%) had itraconazole discontinued. The median time to side effect was 45 days. Median itraconazole serum levels were significantly higher among patients with side effects than in a propensity score-matched population without side effects (2.9 versus 1.8 mcg/mL, P = 0.009)., Conclusions: Side effects were experienced by approximately one-quarter of patients with histoplasmosis receiving long-term itraconazole therapy. About two-thirds of these patients had a therapeutic intervention. Itraconazole resulted in a lower frequency of side effects than fluconazole, as measured in other studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Histoplasmosis is an important infection among transplant recipients. Few studies have described its epidemiology and outcomes in the modern era., Methods: We conducted a retrospective analysis using medical records from a single center in the United States. We included patients 18 years or older with histoplasmosis. We divided the cohort into transplant recipients and immunocompetent groups to assess the outcomes in both groups. We utilized Cox hazard models to assess 90-day all-cause mortality., Results: The study included 137 patients; with 28 (20%) transplant recipients. After the first year post-transplant, patients with lung transplant (30%) had a diagnosis of histoplasmosis. Transplant recipients exhibited a significantly higher incidence of disseminated histoplasmosis than immunocompetent patients (64% vs. 34%, p = 0.001), higher admission to ICU (39% vs. 16%; p = 0.01) and higher but not significant 90-day crude all-cause mortality (14% vs. 11%, p = 0.71). Patients with transplants had a higher, but not significant hazard of all-cause mortality at 90 days (hazard ratio: 1.5; 95% confidence interval: 0.4-3.9) when compared to immunocompetent patients., Conclusion: Transplant recipients were more commonly diagnosed with histoplasmosis after the first year post-transplantation, and although they exhibited a higher hazard for death at 90 days, this increase was not statistically significant., (© 2024 Wiley Periodicals LLC.)

Human immunodeficiency virus 1 (HIV-1) reservoir cells persist lifelong despite antiretroviral treatment 1,2 but may be vulnerable to host immune responses that could be exploited in strategies to cure HIV-1. Here we used a single-cell, next-generation sequencing approach for the direct ex vivo phenotypic profiling of individual HIV-1-infected memory CD4 + T cells from peripheral blood and lymph nodes of people living with HIV-1 and receiving antiretroviral treatment for approximately 10 years. We demonstrate that in peripheral blood, cells harbouring genome-intact proviruses and large clones of virally infected cells frequently express ensemble signatures of surface markers conferring increased resistance to immune-mediated killing by cytotoxic T and natural killer cells, paired with elevated levels of expression of immune checkpoint markers likely to limit proviral gene transcription; this phenotypic profile might reduce HIV-1 reservoir cell exposure to and killing by cellular host immune responses. Viral reservoir cells harbouring intact HIV-1 from lymph nodes exhibited a phenotypic signature primarily characterized by upregulation of surface markers promoting cell survival, including CD44, CD28, CD127 and the IL-21 receptor. Together, these results suggest compartmentalized phenotypic signatures of immune selection in HIV-1 reservoir cells, implying that only small subsets of infected cells with optimal adaptation to their anatomical immune microenvironment are able to survive during long-term antiretroviral treatment. The identification of phenotypic markers distinguishing viral reservoir cells may inform future approaches for strategies to cure and eradicate HIV-1., (© 2023. The Author(s).)

HIV-1 establishes a life-long reservoir of virally infected cells which cannot be eliminated by antiretroviral therapy (ART). Here, we demonstrate a markedly altered viral reservoir profile of long-term ART-treated individuals, characterized by large clones of intact proviruses preferentially integrated in heterochromatin locations, most prominently in centromeric satellite/micro-satellite DNA. Longitudinal evaluations suggested that this specific reservoir configuration results from selection processes that promote the persistence of intact proviruses in repressive chromatin positions, while proviruses in permissive chromosomal locations are more likely to be eliminated. A bias toward chromosomal integration sites in heterochromatin locations was also observed for intact proviruses in study participants who maintained viral control after discontinuation of antiretroviral therapy. Together, these results raise the possibility that antiviral selection mechanisms during long-term ART may induce an HIV-1 reservoir structure with features of deep latency and, possibly, more limited abilities to drive rebound viremia upon treatment interruptions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

HIV-1-infected cells that persist despite antiretroviral therapy (ART) are frequently considered "transcriptionally silent," but active viral gene expression may occur in some cells, challenging the concept of viral latency. Applying an assay for profiling the transcriptional activity and the chromosomal locations of individual proviruses, we describe a global genomic and epigenetic map of transcriptionally active and silent proviral species and evaluate their longitudinal evolution in persons receiving suppressive ART. Using genome-wide epigenetic reference data, we show that proviral transcriptional activity is associated with activating epigenetic chromatin features in linear proximity of integration sites and in their inter- and intrachromosomal contact regions. Transcriptionally active proviruses were actively selected against during prolonged ART; however, this pattern was violated by large clones of virally infected cells that may outcompete negative selection forces through elevated intrinsic proliferative activity. Our results suggest that transcriptionally active proviruses are dynamically evolving under selection pressure by host factors., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: The objective of this study was to evaluate possible nonlinear lamotrigine (LTG) pharmacokinetics at elevated concentration. LTG is reported to have linear kinetics, so that elimination rate is linearly proportional to blood concentration and a change in dose is accompanied by a proportionate change in serum concentration. We encountered patients in whom LTG serum concentration increased dramatically in response to minor or no change in LTG dose. We studied this phenomenon in patients with LTG toxicity in one clinic., Materials and Methods: Using electronic medical records from 1997 to 2014, we identified patients who developed clinical LTG toxicity with LTG serum concentrations >20 mg/l, after tolerating lamotrigine at lower serum concentrations. We reviewed LTG dose change and other changes that preceded the episode of toxicity., Results: Twenty-two patients had at least one episode of LTG toxicity with levels higher than 20 mg/l (of 922 patients with available levels). The peak serum concentration varied from 21.1 to 40.3 mg/l (mean 28.7). The increase in level was explained in three patients (post-delivery in one, addition of valproate in two). In the 18 others, the increase was not explained or it was disproportionate to an increase in LTG dose., Conclusions: Spikes in LTG levels and associated clinical toxicity may occur unexpectedly, suggesting that elimination kinetics may be nonlinear in some individuals at serum concentrations in the upper range. Measurement and close monitoring of LTG levels is warranted for new symptoms that could be consistent with lamotrigine toxicity, particularly when the baseline serum concentration has been >10 mg/l., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)