Viral Kinetics and Resistance Development in Children Treated with Neuraminidase Inhibitors: The Influenza Resistance Information Study (IRIS).

BACKGROUND: We studied the effect of age, baseline viral load, vaccination status, antiviral therapy, and emergence of drug resistance on viral shedding in children infected with influenza A or B virus. METHODS: Samples from children (aged ≤13 years) enrolled during the 7 years of the prospective Influenza Resistance Information Study were analyzed using polymerase chain reaction to determine the influenza virus (sub-)type, viral load, and resistance mutations. Disease severity was assessed; clinical symptoms were recorded. The association of age with viral load and viral clearance was examined by determining the area under the curve for viral RNA shedding using logistic regression and Kaplan-Meier analyses. RESULTS: A total of 2131 children infected with influenza (683, A/H1N1pdm09; 825, A/H3N2; 623, influenza B) were investigated. Age did not affect the mean baseline viral load. Children aged 1-5 years had prolonged viral RNA shedding (±1-2 days) compared with older children and up to 1.2-fold higher total viral burden. Besides, in older age (odds ratio [OR], 1.08; confidence interval [CI], 1.05-1.12), prior vaccination status (OR, 1.72; CI, 1.22-2.43) and antiviral treatment (OR, 1.74; CI, 1.43-2.12) increased the rate of viral clearance. Resistance mutations were detected in 49 children infected with influenza A virus (34, A/H1N1pdm09; 15, A/H3N2) treated with oseltamivir, most of whom were aged <5 years (n = 39). CONCLUSIONS: Children aged 1-5 years had a higher total viral burden with prolonged virus shedding and had an increased risk of acquiring resistance mutations following antiviral treatment. CLINICAL TRIALS REGISTRATION: NCT00884117.

Oseltamivir in pregnancy and birth outcomes.

BACKGROUND: Prenatal exposure to influenza or fever is associated with risk of congenital malformations. Oseltamivir is used to treat influenza and to provide post-exposure prophylaxis. We examined the association between oseltamivir use during pregnancy and birth outcomes. METHODS: This was a nationwide registry-based prevalence study with individual level data linkage, in a setting of universal health care access. We included all recorded pregnancies in Denmark in 2002-2013, and used data from population registries to examine associations between dispensings for oseltamivir during pregnancy (first trimester, second/third trimester, none) and congenital malformations, foetal death, preterm birth, foetal growth, and low 5-min Apgar score. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using propensity score matching. RESULTS: The study included 946,176 pregnancies. Of these, 449 had first-trimester exposure and 1449 had second/third-trimester exposure to oseltamivir. Adjusted ORs following first-trimester exposure were 0.94 (95% CI 0.49 to 1.83) for any major congenital malformation and 1.75 (95% CI 0.51 to 5.98) for congenital heart defects, based on 7 exposed cases. The association with congenital heart defects was present for etiologically implausible exposure periods and for known safe exposures. There was no evidence of an association between prenatal exposure to oseltamivir and any of the other birth outcomes assessed. CONCLUSIONS: The study does not provide evidence of risk associated with oseltamivir treatment additional to that associated with influenza infection.

18F-Fluciclovine PET/CT performance in biochemical recurrence of prostate cancer: a systematic review.

BACKGROUND: A systematic literature review of the performance of 18Fluorine-fluciclovine PET/CT for imaging of men with recurrent prostate cancer was performed. METHODS: Scientific literature databases (MEDLINE, ScienceDirect and Cochrane Libraries) were searched systematically during Oct 2020 using PRISMA criteria. No limit was put on the date of publication. Prospective studies reporting a patient-level 18F-fluciclovine detection rate (DR) from ≥25 patients with recurrent prostate cancer were sought. Proceedings of relevant meetings held from 2018 through Oct 2020 were searched for abstracts meeting criteria. RESULTS: Searches identified 321 unique articles. In total, nine articles (six papers and three conference abstracts), comprising a total of 850 patients met inclusion criteria. Most studies (n = 6) relied on ASTRO-Phoenix Criteria, EAU-ESTRO-SIOG, and/or ASTRO-AUA guidelines to identify patients with biochemical recurrence. Patients' PSA levels ranged from 0.02-301.7 ng/mL (median level per study, 0.34-4.10 ng/mL [n = 8]). Approximately 64% of patients had undergone prostatectomy, but three studies focused solely on post-prostatectomy patients. Adherence to imaging protocol guidelines was heterogeneous, with variance seen in administered activity, uptake and scan times. Overall patient-level DR varied between studies from 26% to 83%, with 78% of studies reporting a DR > 50%. DR was proportional to PSA, but even at PSA < 0.5 ng/mL DR of up to 53% were reported. Prostate/bed DR (n = 7) ranged from 18% to 78% and extra-prostatic rates (n = 6) from 8% to 72%. Pelvic node and bone lesion DR ranged from 8% to 47% and 0% to 26%, respectively (n = 5). 18F-Fluciclovine PET/CT was shown to impact patient management and outcomes. Two studies reported 59-63% of patients to have a management change post-scan. A further study showed significant increase in failure-free survival following 18F-fluciclovine-guided compared with conventional imaging-guided radiotherapy planning. CONCLUSIONS: 18F-Fluciclovine PET/CT shows good performance in patients with recurrent prostate cancer leading to measurable clinical benefits. Careful adherence to recommended imaging protocols may help optimize DR.

IL-6 receptor inhibition positively modulates bone balance in rheumatoid arthritis patients with an inadequate response to anti-tumor necrosis factor therapy: biochemical marker analysis of bone metabolism in the tocilizumab RADIATE study (NCT00106522).

OBJECTIVE: To evaluate changes in biochemical markers of bone metabolism in response to tocilizumab in patients with anti-tumor necrosis factor-refractory rheumatoid arthritis (RA). METHODS: RADIATE was a randomized, double-blind, placebo-controlled, parallel-group phase 3 trial. C-reactive protein, osteocalcin (OC), C-terminal telopeptides of type-I collagen (C-terminal telopeptides of type-1 collagen (CTX-I) and type-I collagen degradation product), and matrix metalloproteinase-3 (MMP-3) serum levels were analyzed from 299 RA patients. Patients were randomly assigned to either tocilizumab (4 or 8 mg/kg) or placebo intravenously every 4 weeks, along with concomitant stable methotrexate (10 to 25 mg weekly) in all treatment arms. The change in biochemical markers CTX-I and OC in combination was evaluated as a measure of net bone balance, a reflection of the change in equilibrium between resorption and formation. RESULTS: Both tocilizumab doses decreased C-reactive protein levels and significantly inhibited cathepsin K-mediated bone resorption in RADIATE subjects, as measured by a decrease in CTX-I. There was a significant overall improvement in net bone balance at week 16 as measured by a decrease in the CTX-I:OC ratio (-25%, P < 0.01). Furthermore, a significant reduction in MMP-3 (43%, P < 0.001) and type-I collagen degradation product levels (18%, P < 0.001) were observed following treatment, both consistent with decreased MMP-mediated type-I collagen catabolism in joint tissue. CONCLUSIONS: In anti-tumor necrosis factor-refractory patients, tocilizumab significantly reduced the levels of biochemical markers of cathepsin K-mediated bone resorption and MMP-mediated tissue degradation and remodeling. These observations suggest that tocilizumab has a positive effect on bone balance, which could in part explain the retardation of progressive structural damage observed with tocilizumab. Clinical trial registry number: NCT00106522.