Hepatitis C virus (HCV) infection is associated with lymphoproliferative disorders and B-cell non-Hodgkin lymphomas (B-NHLs). Evaluation of the efficacy and safety profiles of different antiviral ...therapies in HCV patients with B-NHL is warranted.
First, we evaluated the sustained virologic response (SVR) and safety of Peg-interferon-alpha (Peg-IFN) + ribavirin +/- first protease inhibitors (PI1s) therapy in 61 HCV patients with B-NHL enrolled in a nationwide observational survey compared with 94 matched HCV-infected controls without B-NHL. In a second series, interferon-free regimens using a newly optimal combination therapy with direct-acting antiviral drugs (DAAs) were evaluated in 10 patients with HCV and B-NHL.
The main lymphoma type was diffuse large B-cell lymphoma (38%) followed by marginal zone lymphoma (31%). In the multivariate analysis, patients with B-NHL treated by Peg-IFN-based therapy exhibited a greater SVR rate compared with controls, 50.8% vs 30.8%, respectively, p<0.01, odds ratio (OR) = 11.2 2.3, 52.8. B-NHL response was better (p = 0.02) in patients with SVR (69%) than in patients without SVR (31%). Premature discontinuation of Peg-IFN-based therapy was significantly more frequent in the B-NHL group (19.6%) compared with the control group (6.3%), p<0.02. Overall, survival was significantly enhanced in the controls than in the B-NHL group (hazard ratio = 34.4 3.9, 304.2, p< 0.01). Using DAAs, SVR was achieved in 9/10 patients (90%). DAAs were both well tolerated and markedly efficient.
The virologic response of HCV-associated B-NHL is high. Our study provides a comprehensive evaluation of different strategies for the antiviral treatment of B-NHL associated with HCV infection.
Data on the SARS-CoV-2 infection among primary health care workers (PHCWs) are scarce but essential to reflect on policy regarding prevention and control measures. We assessed the prevalence of PHCWs ...who have been infected by SARS-CoV-2 in comparison with modeling from the general population in metropolitan France, and associated factors. A cross-sectional study was conducted among general practitioners (GPs), pediatricians, dental and pharmacy workers in primary care between May and August 2021. Participants volunteered to provide a dried-blood spot for SARS-CoV-2 antibody assessment and completed a questionnaire. The primary outcome was defined as the detection of infection-induced antibodies (anti-nucleocapsid IgG, and for non-vaccinees: anti-Spike IgG and neutralizing antibodies) or previous self-reported infection (positive RT-qPCR or antigenic test, or positive ELISA test before vaccination). Estimates were adjusted using weights for representativeness and compared with prediction from the general population. Poisson regressions were used to quantify associated factors. The analysis included 1612 PHCWs. Weighted prevalences were: 31.7% (95% CI 27.5-36.0) for GPs, 28.7% (95% CI 24.4-33.0) for pediatricians, 25.2% (95% CI 20.6-31.0) for dentists, and 25.5% (95% CI 18.2-34.0) for pharmacists. Estimates were compatible with model predictions for the general population. PHCWs more likely to be infected were: GPs compared to pharmacist assistants (adjusted prevalence ratio aPR = 2.26; CI 95% 1.01-5.07), those living in Île-de-France (aPR = 1.53; CI 95% 1.14-2.05), South-East (aPR = 1.57; CI 95% 1.19-2.08), North-East (aPR = 1.81; CI 95% 1.38-2.37), and those having an unprotected contact with a COVID-19 case within the household (aPR = 1.48; CI 95% 1.22-1.80). Occupational factors were not associated with infection. In conclusion, the risk of SARS-CoV-2 exposure for PHCWs was more likely to have occurred in the community rather than at their workplace.
Direct antiviral agents (DAAs) became available in France in 2014 for the treatment of chronic hepatitis C (CHC) in patients with severe fibrosis (prioritized access); in 2017, DAAs became available ...to all CHC patients (universal access). We evaluated the impact of extending DAA availability on CHC patient care, especially on screening and time to treatment.
Adult patients affiliated with the national health insurance system (SNDS) who were screened or treated for CHC between 2015 and 2019 were included. Algorithms were developed to identify at-risk subpopulations.
The proportion of screened patients increased by 1% between 2015 and 2019, from 4·6% to 5·6%. The main nonexclusive risk factors for CHC were psychiatric conditions (27%), drug use (21%) and HIV positivity (11%); more than 50% of psychiatric patients had additional risk factors, mainly drug use with a 38% to 52% overlap.
The median interval between the last screening test and treatment initiation decreased from 64 days in 2015 to 37 days in 2019.
During the study period, 71,466 patients began CHC treatment (median age 55 48-62; 59% male), including 46% of “at-risk” patients with an increase in treatment initiation by 44% between 2015 and 2017 and a decrease of 46% between 2017 and 2019. Only 2,212 (3%) patients were treated at least twice.
Among treated patients, the proportion of HIV+ patients decreased from 19% to 8% (prioritization consequence), while the proportions increased in the other at-risk subpopulations.
we showed that policies extending DAA availability are associated with a screening increase and a decrease in the time to treatment initiation, while universal access led to a surge in treatment initiations in 2017. This study may also contribute to improving the cascade of care in the at-risk subpopulations. For instance, by pointing out their relative importance, especially for the psychiatric subpopulation, it highlights the importance to address them with tailored policies.
This study was funded by Gilead Sciences.
We aimed to investigate the immunoglobulin G response and neutralizing activity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) among primary health care workers (PHCW) in France ...and assess the association between the neutralizing activity and several factors, including the coronavirus disease 2019 (COVID-19) vaccination scheme. A cross-sectional survey was conducted between 10 May 2021 and 31 August 2021. Participants underwent capillary blood sampling and completed a questionnaire. Sera were tested for the presence of antibodies against the nucleocapsid (N) protein and the S-1 portion of the spike (S) protein and neutralizing antibodies. In total, 1612 PHCW were included. The overall seroprevalences were: 23.6% (95% confidence interval (CI) 21.6-25.7%) for antibodies against the N protein, 94.7% (93.6-95.7%) for antibodies against the S protein, and 81.3% (79.4-83.2%) for neutralizing antibodies. Multivariate regression analyses showed that detection of neutralizing antibodies was significantly more likely in PHCW with previous SARS-CoV-2 infection than in those with no such history among the unvaccinated (odds ratio (OR) 16.57, 95% CI 5.96-59.36) and those vaccinated with one vaccine dose (OR 41.66, 95% CI 16.05-120.78). Among PHCW vaccinated with two vaccine doses, the detection of neutralizing antibodies was not significantly associated with previous SARS-CoV-2 infection (OR 1.31, 95% CI 0.86-2.07), but was more likely in those that received their second vaccine dose within the three months before study entry than in those vaccinated more than three months earlier (OR 5.28, 95% CI 3.51-8.23). This study highlights that previous SARS-CoV-2 infection and the time since vaccination should be considered when planning booster doses and the design of COVID-19 vaccine strategies.
The protocol study will focus on the seroprevalence of IgG antibodies to SARS-CoV-2 achieved by vaccination and/or natural protection as well as the history, symptoms, and risk factors for SARS-CoV-2 ...in four primary health-care workers (PHCWs) and their household contacts in metropolitan France.
Here, we propose a protocol for a nationwide survey to determine the seroprevalence of IgG antibodies to SARS-CoV-2 achieved by vaccination and/or natural protection in four PHCW populations (general practitioners, pediatricians, pharmacists and assistants, and dentists and assistants) and their household contacts. Participants will be included from June to July 2021 (Phase 1) among PHCW populations located throughout metropolitan France. They will be asked to provide a range of demographic and behavioral information since the first SARS-CoV-2 wave and a self-sampled dried blood spot. Phase 1 will involve also a questionnaire and serological study of PHCWs' household contacts. Seroprevalence will be estimated using two ELISAs designed to detect specific IgG antibodies to SARS-CoV-2 in humoral fluid, and these results will be confirmed using a virus neutralization test. This study will be repeated from November to December 2021 (Phase 2) to evaluate the evolution of immune status achieved by vaccination and/or natural protection of PHCWs and to describe the history of exposure to SARS-CoV-2.
Abstract Background and Aims Iron deficiency (ID) is common in patients with chronic kidney disease (CKD) but remains under-diagnosed and its prognosis poorly documented in the absence of anemia. ...Data from CKDopps showed low TSAT levels were associated with increased risk of all-cause mortality and incidence of major cardiovascular events in patients with moderate to advanced CKD, an effect that was not modified by the presence of anemia 1. Additionally, patients with both low TSAT and high ferritin levels displayed the highest risk of all-cause mortality. The aim of the study was to assess the relationship between ID and the risk of major adverse outcomes in patients with CKD in France. Method Using data from the French CKD-REIN cohort which included and followed over 5 years, 3,033 nephrology outpatients with CKD stage 2 to 5 CKD 2, we estimated the prevalence of ID, defined by a ferritin level < 100 mg/L and/or a transferrin saturation (TSAT) < 20%, and associated hazard ratios (HR) of kidney failure with replacement therapy, kidney failure defined by an eGFR < 15 ml/min per 1.73 m2 or initiation of kidney replacement therapy, all-cause mortality, all-cause hospitalization and death or hospitalization for heart failure. The analysis was conducted using a Cox model in which ID was included as a time-dependent variable and adjusted for identified confounders (socio-demographic characteristics, comorbidities, and biological measures) and hemoglobin level. Results A total of 2 914 patients with at least one ferritin or TSAT measurement at baseline or during follow-up were included in the analysis. The majority were men (66%), with a mean age of 67 ± 13 years; 49.6%, 41.2%, and 9.2%, had CKD stage 2/3, 4, and 5, respectively. Baseline prevalence of ID in the cohort was 50% 48-52. Mean hemoglobin was 13 ± 1.7 g/dL, and only 31% of patients with ID also had a hemoglobin < 12 g/dL. Of the 2 914 patients included in the analysis, 627 (22%) required dialysis or transplantation, and 382 (13%) died before kidney replacement therapy. The incidence rate of kidney failure with replacement therapy was 6.76 versus 3.53 per 100 person-years in patients with and without ID. ID was associated with significant increased risk of kidney failure with replacement therapy, with adjusted HRs for confounders and hemoglobin level of 1.51 1.24-1.82 (Fig. 1). A total of 836 patients (29%) progressed to kidney failure during the study period, and 341 (12%) died before this stage. The incidence rate of kidney failure was 8.66 versus 6.43 per 100 person-years in patients with and without ID. ID was associated with significant increased risk of kidney failure, with adjusted HRs for confounders and hemoglobin level of 1.19 1.02-1.38 (Fig. 1). Adjusted HRs for all-cause mortality, for all-cause hospitalization, and for hospitalization or death for heart failure, were 1.31 1.04-1.66, 1.04 0.93-1.15, and 1.38 1.07-1.80, respectively (Fig. 2). Conclusion This study confirms that ID is common in patients with CKD and shows that ID is significantly associated with the risk for kidney failure, all-cause mortality, and heart failure, independent of the presence of anemia. An intervention trial would be needed to assess whether correction of this ID in CKD patients is associated with a reduction in associated risks.
EBV-induced gene 3 (EBI3) can associate with p28 to form the heterodimeric cytokine IL-27, or with the p35 subunit of IL-12 to form the EBI3/p35 heterodimer, recently named IL-35. In mice, IL-35 has ...been shown to be constitutively expressed by CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg cells) and suggested to contribute to their suppressive activity. In this study, we investigated whether human Treg cells express IL-35. Double-staining analysis of human thymuses showed that neither Foxp3(+) nor CD25(+) cells coexpressed EBI3. Similarly, Foxp3(+) cells present in human lymph nodes, tonsils, spleens, and intestines did not express EBI3. Consistent with these in situ observations, Treg cells purified from blood or tonsils were negative for EBI3 by immunoblotting. Other human T cell subsets, including effector T cells, naive and memory CD4(+) T cells, CD8(+) and gammadelta T cells also did not constitutively express EBI3, which contrasts with IL-35 expression observed in murine CD8(+) and gammadelta T cells. Furthermore, although CD3/CD28 stimulation consistently induced low levels of EBI3 in various CD4(+) T cell subsets, no EBI3 could be detected in CD3/CD28-stimulated Treg cells. RT-PCR analysis showed that, whereas p35 transcripts were detected in both Teff and Treg cells, EBI3 transcripts were detected only in activated Teff cells, but not in resting or activated Treg cells. Thus, in contrast to their murine counterpart, human Treg cells do not express detectable amounts of IL-35.
Human genetic factors influence the outcome of pegylated interferon and ribavirin hepatitis C therapy. We explored the role of IL28B, APOH and ITPA SNPs on the outcomes of triple therapy including ...telaprevir or boceprevir in patients with compensated cirrhosis chronically infected with HCV-1.
A total of 256 HCV-1 Caucasian treatment-experienced patients with compensated cirrhosis from the ANRS CO20-CUPIC cohort were genotyped for a total of 10 candidate SNPs in IL28B (rs12979860 and rs368234815), APOH (rs8178822, rs12944940, rs10048158, rs52797880, rs1801689 and rs1801690) and ITPA (rs1127354 and rs7270101). We tested the association of IL28B and APOH SNPs with sustained virological response and of ITPA SNPs with anemia related phenotypes by means of logistic regression assuming an additive genetic model.
None of the six APOH SNPs were associated with sustained virological response. The favorable alleles of the IL28B SNPs rs12979860 and rs368234815 were associated with sustained virological response (rs12979860: OR = 2.351.50-3.70, P = 2x10(-4)). Refined analysis showed that the effect of IL28B SNPs on sustained virological response was restricted to prior PegIFN/RBV relapse (OR = 3.801.82-8.92, P = 8x10(-4)). We also confirmed the association between ITPA low activity alleles and protection against early hemoglobin decline in triple therapy (P = 2x10(-5)).
Our results suggest that the screening of rs12979860 may remain interesting for decision making in prior relapse HCV-1 Caucasian patients with compensated cirrhosis eligible for a telaprevir- or boceprevir-based therapy.
IL-27 induces stronger proliferation of naive than memory human B cells and CD4+ T cells. In B cells, this differential response is associated with similar levels of IL-27 receptor chains, IL-27Rα ...and gp130, in both subsets and stronger STAT1 and STAT3 activation by IL-27 in naive B cells. Here, we show that the stronger proliferative response of CD3-stimulated naive CD4+ T cells to IL-27 is associated with lower levels of IL-27Rα but higher levels of gp130 compared with memory CD4+ T cells. IL-27 signaling differs between naive and memory CD4+ T cells, as shown by more sustained STAT1, -3, and -5 activation and weaker activation of SHP-2 in naive CD4+ T cells. In the latter, IL-27 increases G0/G1 to S phase transition, cell division and, in some cases, cell survival. IL-27 proliferative effect on naive CD4+ T cells is independent of MAPK, but is dependent on c-Myc and Pim-1 induction by IL-27 and is associated with induction of cyclin D2, cyclin D3, and CDK4 by IL-27 in a c-Myc and Pim-1-dependent manner. In BCR-stimulated naive B cells, IL-27 only increases entry in the S phase and induces the expression of Pim-1 and of cyclins A, D2, and D3. In these cells, inhibition of Pim-1 inhibits IL-27 effect on proliferation and cyclin induction. Altogether, these data indicate that IL-27 mediates proliferation of naive CD4+ T cells and B cells through induction of both common and distinct sets of cell cycle regulators.
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