A high oral dose of biotin seems generally well tolerated but a few important safety concerns were identified: 1) teratogenicity in one species and 2) interference with some biotin-based laboratory immunoassays. The animal toxicity data are limited at such high doses. Further preclinical studies would be useful to address the mechanism of action of MD1003. Assessment of clinical benefit duration in responders will be also very important to set. Results of randomized, placebo-controlled trial are reassuring and provide hope for the treatment of progressive MS.

Background:The aim of the study was to analyse efficacy, safety, and health-related quality of life (HRQoL) for sorafenib treatment in patients with metastatic uveal melanoma.Methods:A multicentre, single-arm phase II trial was conducted. The primary objective was to determine the non-progression rate (RECIST) at 24 weeks for patients receiving sorafenib at a dose of 800 mg per day. Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and HRQoL.Results:Thirty-two patients were included. Ten patients showed non-progression at 24 weeks (31.2%) without objective tumour responses. The estimated 24-week PFS was 31.2% (95% CI: 14.8%–47.6%) and the estimated 24-week OS was 62.5% (95% CI: 45.4%–79.6%). Ten patients (34.3%) had at least one grade 3 or 4 adverse reaction and 12 patients (41.4%) required dose modifications due to toxicity. At 24 weeks, no patient had an improvement in global HRQoL and 87.5% experienced a permanent increase in physical fatigue.Conclusions:Sorafenib demonstrated non-progression at 24 weeks in 31.2% of patients. However, 41.4% of patients required dose modifications due to toxicity and no improvement in HRQoL was demonstrated.

Background We aimed to describe the frequency, risk factors, and costs attributable to drug–drug interactions (DDIs) among an aging French HIV population. Methods We conducted a retrospective cohort study using French nationwide health care e-records: the SNIIRAM database. People living with HIV (PLWH) aged >65 years and receiving combined antiretroviral treatment (cART) during 2016 were included. A DDI was defined as “These drugs should not be co-administered,” represented by a red symbol on the University of Liverpool website. Attributable DDIs’ cost was defined as the difference between individuals with and without DDIs regarding all reimbursed health care acts. Results Overall, 9076 PLWH met the study criteria. Their baseline characteristics were: mean age, 71.3 ± 4.9 years; 25% female; median HIV duration (interquartile range [IQR]), 16.2 (9.5–20.3) years; median comorbidities (IQR), 2 (1–3). During 2016, they received a median (IQR) of 14 (9–21) comedications (non-cART), and 1529 individuals had at least 1 DDI (16.8%; 95% confidence interval [CI], 16.1–17.6). In multivariate analysis, raltegravir or dolutegravir plus 2 nucleoside reverse-transcriptase inhibitors (NRTIs) significantly and independently reduced the risk of DDIs (adjusted odds ratio [aOR], 0.02; 95% CI, 0.005–0.050; P < .0001) compared with non-nucleoside reverse-transcriptase inhibitor plus 2 NRTIs, whereas cART with boosted agents (protease inhibitors or elvitegravir) significantly increased the risk (aOR, 4.12; 95% CI, 3.34–5.10; P < .0001). Compared with propensity score–matched PLWH without DDIs, the presence of DDIs was associated with a $2693 additional cost per year (P < .0001). Conclusions The presence of DDIs is frequent and significantly increases health care costs in the aging population of PLWH.

Background Tenofovir and emtricitabine interfere with the SARS CoV-2 ribonucleic acid (RNA)-dependent RNA polymerase (RdRp). Several cohorts reported that people treated by tenofovir disoproxil fumarate and emtricitabine are less likely to develop SARS CoV-2 infection and related severe COVID-19. Methods We conducted a pilot randomized, open-label, controlled, phase 2 trial at two hospitals in France. Eligible patients were consecutive outpatients (aged ≥18 years) with RT-PCR-confirmed SARS-CoV-2 infection and an interval from symptom onset to enrolment of 7 days or less. Patients were randomly assigned in a 1:1 ratio to receive oral tenofovir disoproxil fumarate and emtricitabine (2 pills on day 1 followed by 1 pill per day on days 2–7) or the standard of care. The primary and secondary endpoints were SARS-CoV-2 viral clearance from baseline assessed by cycle threshold (Ct) RT-PCR on nasopharyngeal swab collected at day 4 and day 7, respectively. A higher Ct corresponds to a lower SARS CoV-2 viral burden. Other endpoints were the time to recovery and the number of adverse events. This trial is registered with ClinicalTrials.gov, NCT04685512. Findings From November, 20 th 2020 to March, 19 th 2021, 60 patients were enrolled and randomly assigned to a treatment group (30 to tenofovir disoproxil fumarate and emtricitabine and 30 to standard of care). The median number of days from symptom onset to inclusion was 4 days (IQR 3–5) in both groups. Amongst patients who received tenofovir disoproxil fumarate, the difference from standard of care in the increase in Ct RT-PCR from baseline was 2.3 (95% confidence interval [-0.6 to 5.2], p = 0.13) at day 4 and 2.9 (95% CI [0.1 to 5.2], p = 0.044) at day 7. At day 7, 6/30 in the tenofovir disoproxil fumarate and emtricitabine group and 3/30 in the standard of care group reported no COVID-related symptoms. Adverse events included 11 cases of gastrointestinal side effects (grade ≤ 2), three of which leaded to drug discontinuation. Three patients had COVID-19 related hospitalisation, no participant died. Interpretation In this pilot study of outpatients adult with recent non-severe COVID-19, tenofovir disoproxil fumarate plus emtricitabine appeared to accelerate the natural clearance of nasopharyngeal SARS-CoV-2 viral burden. These findings support the conduct of larger trials of tenofovir-based therapies for the prevention and early treatment of COVID-19. Funding No external funding.

Objectives To explore the frequent interaction between antiretroviral-boosting agents and corticosteroids causing Cushing’s syndrome (CS) in the French Pharmacovigilance Database (FPVD). Methods We conducted a retrospective case–control study describing CS recorded in the FPVD between 1996 and 2018. Case was defined as CS occurring in people living with HIV (PLWH) and control was defined as CS in uninfected individuals. Drug–drug interaction (DDI) was defined as an interaction between corticosteroids and CYP3A4 inhibitors. Data concerning the DDI, corticosteroids involved, route of administration and seriousness of the CS were described. Results Among the 139 instances of CS identified, 34/35 cases (97%) had DDIs (31 with ritonavir and 3 with cobicistat) and 7/104 controls (7%) had DDIs (6 with itraconazole and 1 with verapamil). The main corticosteroid involved was inhaled fluticasone (28/35, 80%) among the cases and oral prednisone (38/104, 37%) among the controls. More CS cases (30/35, 86%) than CS controls (62/104, 60%) were serious (OR = 4.0, 95% CI = 1.4–14.4; P = 0.007). Conclusions Antiretroviral-boosting agents were responsible for one out of four iatrogenic CS cases in a French national database. Prescribers should be aware of the risk of potentially serious DDIs between antiretroviral-boosting agents and corticosteroids, including single-tablet regimens containing cobicistat.