Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial.

BACKGROUND: The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and human Caco-2 cells. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19. METHODS: Due to the initial absence of preclinical models, the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized COVID-19 patients were randomly assigned to standard of care with or without itraconazole. Primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated. FINDINGS: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and because an interim analysis showed no signal for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19) for itraconazole vs standard of care. INTERPRETATION: Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. This prompted the premature termination of the proof-of-concept clinical study. FUNDING: KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates Foundation.

Prevalence and epidemiology of HIV type 1 drug resistance among newly diagnosed therapy-naive patients in Belgium from 2003 to 2006.

This study is the first prospective study to assess the prevalence, epidemiology, and risk factors of HIV-1 drug resistance in newly diagnosed HIV-infected patients in Belgium. In January 2003 it was initiated as part of the pan-European SPREAD program, and continued thereafter for four inclusion rounds until December 2006. Epidemiological, clinical, and behavioral data were collected using a standardized questionnaire and genotypic resistance testing was done on a sample taken within 6 months of diagnosis. Two hundred and eighty-five patients were included. The overall prevalence of transmitted HIV-1 drug resistance in Belgium was 9.5% (27/285, 95% CI: 6.6-13.4). Being infected in Belgium, which largely coincided with harboring a subtype B virus, was found to be significantly associated with transmission of drug resistance. The relatively high rate of baseline resistance might jeopardize the success of first line treatment as more than 1 out of 10 (30/285, 10.5%) viruses did not score as fully susceptible to one of the recommended first-line regimens, i.e., zidovudine, lamivudine, and efavirenz. Our results support the implementation of genotypic resistance testing as a standard of care in all treatment-naive patients in Belgium.

Nonadherence to highly active antiretroviral therapy: clinically relevant patient categorization based on electronic event monitoring.

Adherence to highly active antiretroviral therapy (HAART) is crucial, but which aspects of drug-taking behavior are important remain largely unknown. In a prospective observational study, 43 HIV-1-infected patients taking HAART underwent electronic event monitoring (EEM). Taking adherence was defined as the percentage of doses taken compared with the number prescribed, dosing adherence was defined as the percentage of days on which all doses were taken, and timing adherence was defined as the percentage of doses taken within 1 hr of the time prescribed. Drug holidays were defined as periods of no drug intake for >24 hr. Cluster analysis, including the four EEM parameters, was used and refined to construct an algorithm to discriminate patients. Patients were categorized as nonadherent if they had a taking adherence of <90%, or a dosing adherence of <75% and at least 1 drug holiday, or a timing adherence of <80% and at least 1 drug holiday, or >6 drug holidays per 100 days. All four EEM parameters differed significantly (p < 0.0001) between the two groups. Adherent patients had a better outcome, as shown by a larger drop in viral load (p = 0.011) and rise in CD4+ cell count (p = 0.035), showing that the algorithm-based categorization is clinically relevant.

A combination of poor adherence and a low baseline susceptibility score is highly predictive for HAART failure.

The relationship between adherence, virological response to highly active antiretroviral therapy (HAART) and the presence and development of genotypic resistance was assessed in 41 HIV-infected patients on HAART. Four adherence parameters (drug taking adherence, dosing adherence, timing adherence and drug holidays) were scored prospectively using electronic event monitoring. Genotypic resistance at baseline and after therapy failure was scored retrospectively and a genotype-based susceptibility score was calculated. Overall median adherence rates were high. All adherence parameters were better in virological responders (n=31) compared to non-responders (n=10), drug taking adherence and number of drug holidays being significantly different. Responders had a significantly higher susceptibility score. Stepwise logistic regression showed that the number of drug holidays and a low susceptibility score were highly predictive for therapy failure. Despite the presence of a limited number of baseline resistance mutations, perfectly adherent patients can control virus replication for a prolonged period.

Prevalence and correlates of nonadherence to antiretroviral therapy in a population of HIV patients using Medication Event Monitoring System.

Nonadherence to antiretroviral therapy (ART) jeopardizes good clinical outcome in people living with HIV. In a single-center prospective study, prevalence and correlates of nonadherence were investigated in 43 patients on ART. Nonadherence was assessed using Medication Event Monitoring System (MEMS), self-report and collateral report of treating physicians. Based on MEMS data, median taking adherence, dosing adherence, and timing adherence was 98% (interquartile range [IQR] = 5.3), 91.5% (IQR = 18), and 86% (IQR = 31.5), respectively. The median number of drug holidays per 100 days was 0.8 (IQR = 4.8). The prevalence of nonadherence measured by MEMS was 40%. Self-reported nonadherence and collateral report of nonadherence by physicians varied from 5% to 41% and 24% to 28%, respectively. Patients were categorized as adherent or nonadherent based on a clinically validated algorithm derived from MEMS parameters. Nonadherent patients used significantly more escaping coping strategies (p = 0.003) and planned problem solving strategies (p = 0.049), were prescribed significantly more antiretroviral medications (p = 0.02) and were significantly longer on ART (p = 0.04) than adherent patients. Identified correlates of nonadherence may help clinicians in detecting patients with HIV at risk for nonadherence and can support the development of adherence enhancing interventions.