Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression suggesting diverse host immune responses. We performed an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. A unique phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-β and low IFN-α production and activity), associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor NF-κB and characterized by increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production and signaling. These data suggest that type-I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.

Results-A total of 2522 prescriptions were administered to 989 patients; 844 (33%) were used either in an unlicensed (4%) or an oV label (29%) manner. A total of 550 (56%) paediatric patients received one or more oV label prescriptions. Conclusions-OV label prescriptions (that is, outside the terms of the Summary of Product Characteristics) are widespread in oYce based paediatric practice, while unlicensed drug use is rare in our study. New regulations in the licensing process in Europe are needed to allow children to receive drugs that have been fully evaluated in their specific age group. (Arch Dis Child 2000;83:502-505)

According to the European AIDS Clinical Society, tenofovir disoproxil fumarate can be used in HIV-infected pregnant women if started prior to pregnancy, although no data are available on the pharmacokinetics of tenofovir (TFV) during pregnancy. The aim of this study was to describe TFV pharmacokinetics in HIV-infected women and to evaluate the effect of pregnancy on TFV disposition. Samples were collected according to a therapeutic drug monitoring in 186 women, including 46 pregnant women treated with TFV and retrospectively analyzed by a population approach. TFV pharmacokinetics were ascribed to an open two-compartment model with linear absorption and elimination. The mean population parameter estimates (between-subject variability) were as follows: absorption rate constant, 0.56 h ؊1 ; elimination clearance, 59.9 liters h ؊1 (0.436); central volume of distribution, 552 liters (1.96); intercompartmental clearance, 172 liters/h; and peripheral volume of distribution, 1,390 liters. Pregnant women had a 39% higher apparent clearance compared to nonpregnant women. Apparent clearance significantly decreased with age. In order to obtain an exposure similar to the known exposure in adults and guarantee similar trough concentrations (C min ) as observed in adults, an increase in the TFV dose should be considered for women from the second trimester to delivery. Because of the lack of data on the use of tenofovir disoproxil fumarate (TDF) in pregnancy and concerns over possible bone toxicity, U.S. guidelines recommend that TDF-based highly active antiretroviral therapy (HAART) should be used only after careful considerations of alternatives (8). However, for women who were already treated by TDF prior to pregnancy, European AIDS Clinical Society guidelines recommend to continue the TDF treatment during pregnancy. Thus, in these therapeutic drug monitoring data, some women were taking TDF during their pregnancy in the first, second, and third trimester.TDF is already taken during pregnancy at the same dose as in adults although physiological changes associated with pregnancy can lead to significant variations in pharmacokinetics (modified absorption, distribution, and elimination). No pharmacokinetic data on the use of TDF before the 38th week of pregnancy are available. Two studies restricted to late pregnancy and labor suggest that tenofovir (TFV) exposure is lower than nonpregnant adult exposure (9, 16).We performed here a population pharmacokinetic study of women during pregnancy, at delivery, and out of pregnancy in order to investigate TFV pharmacokinetics throughout pregnancy. MATERIALS AND METHODSPatients and treatments. The population included nonpregnant women, pregnant women, and women on the day of delivery receiving oral TFV for treatment of HIV infection and whose antiretroviral drug plasma concentrations were monitored on a routine basis. TFV was administered chronically using a 300-mg once-daily regimen. For each woman, the time elapsed between administration and sampling times, the time of dosing, the bod...