Treatment with protease inhibitors and coinfection with hepatitis C virus are independent predictors of preterm delivery in HIV-infected pregnant women.

In a recent study, Cotter et al. [1] analyzed a cohort of HIV-infected pregnant women followed at a single site, to examine the risk of preterm delivery and other pregnancy outcomes. Their results indicated that combination therapy with protease inhibitors (PIs), compared with monotherapy and combination therapy without a PI, is independently associated with preterm delivery. Such results are in accordance with those reported in a common analysis of 2 European cohorts [2], but a previous US study found no association between combination therapy and preterm delivery [3]. The role played by PIs in preterm delivery remains uncertain, because none of the studies controlled for indication for antiretroviral therapy, thereby not ruling out the possibility that treatment with PIs represents a marker for more-advanced disease [4]. We analyzed data from the largest surveillance study currently being conducted in Italy of the use of antiretroviral drugs in pregnancy [5], to establish the role played by PIs in preterm delivery after controlling for important prognostic cofactors. For the purpose of this analysis, we considered all pregnancies that resulted in the delivery of a live newborn (n=417) or in neonatal death (n=2) from all the HIV-positive women enrolled in our observational study between December 2001 (the date of the start of the study) and March 2006. Nonsingleton pregnancies and pregnancies that ended in spontaneous or voluntary abortion or in intrauterine death were excluded. Information and measurements were collected at routine visits performed during the 3 trimesters of pregnancy (with no restrictions in gestational age at entry into prenatal care). Gestational age at birth was determined on the basis of the last menstrual period, ultrasound biometry, or both. Preterm delivery was defined as delivery before 37 completed weeks of gestation. Unadjusted and adjusted odds ratios and 95% confidence intervals were used to estimate in univariate and multivariate logistic regression models the association of different variables with preterm delivery. All the analyses were performed using SPSS software (version 13.0.1; SPSS). Preterm delivery occurred in 96 (22.9%) of 419 women. Antiretroviral therapy (combination therapy in all cases) was present in 309 women at second trimester (81.1%) and in 366 women (91.3%) at third trimester. PI use occurred in 31.3% and 39.8% at second and third trimester, respectively. Sixty-five percent of the women had an indication for antiretroviral treatment for their own health. In univariate analysis, the following baseline variables were significantly associated with preterm delivery: (1) higher age at conception (P=.023); (2) hepatitis C virus (HCV) coinfection (P<.001); and (3) prior pregnancies (P=.017). No association was found for hepatitis B virus coinfection, a prior AIDS diagnosis, sexually transmitted infections, alcohol or substance abuse, and cigarette smoking (P≥.10, for all). The multivariate logistic regression models included the 3 significantly related variables (1–3) indicated above plus the following: (4) indication for antiretroviral treatment during pregnancy (maternal health or only for prophylaxis of vertical transmission); (5) prior preterm delivery; (6) treatment with PIs; (7) HIV RNA load (log10 transformed); (8) CD4 cell count; and (9) any antiretroviral treatment. The status with respect to variables 6–9 was defined separately at second and third trimester, and 2 separate logistic models were designed using the same baseline data (variables 1–5) plus data from the relevant trimester for variables 6–9. The results of the multivariate analysis are shown in table 1. Use of PI and HCV coinfection remained consistently associated with preterm delivery after age, prior pregnancies, prior preterm deliveries, any antiretroviral treatment, indication for antiretroviral treatment, HIV RNA load, and CD4 cell count were controlled for. View larger version: In this page In a new window Download as PowerPoint Slide Table 1. Association between preterm delivery and prognostic factors in a multivariate analysis. Our study provides important new information: first, we were able to confirm the effect of PIs on preterm delivery after controlling for several potential confounding variables, including indication for antiretroviral treatment. The observed rate of preterm delivery among women receiving PIs at second trimester was 32.2%, compared with 18.2% in women not receiving PIs. These figures and the observed size of the effect—a 2-fold adjusted increase in risk attributable to PI use—confirms the results reported by others. Our study, however, has the additional advantage of being entirely based on women enrolled in recent years, with combination therapy as standard treatment and a high proportion of women receiving PIs. The risk assessment, therefore, is based on current standards of care. We also describe an independent role for HCV coinfection in preterm delivery. Rates of preterm delivery in women with and without HCV coinfection were 38.6% and 17.1%, respectively, with a 2-fold increase in risk. Further studies should explore the mechanisms responsible for such an association

Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials

Data sharing: We will follow the common controlled access principles outlined by the Medical Research Council Clinical Trials Unit. According to those principles, we will acknowledge that data with long-term value be preserved, and usable for future research. We do, however, want to ensure that there are legal, ethical, and commercial constraints maintained on the release of research data according to the following code. Research teams are entitled to receive appropriate recognition for their efforts in collecting and analysing data and should be given at least a limited period of sole access to use and publish the data, before key trial data are open for use by other researchers. If such requests are made to access the data, resources need to be available to process the request and prepare the data in a timely manner, if possible. Because of these demands, there must be an important scientific objective behind each request. Especially in the case of our international project, The ONE Study, any request must comply with regulations set by the competent authorities in the relevant countries that govern data security policies.Supplementary material is available online at: https://www.sciencedirect.com/science/article/pii/S0140673620301677#sec1 .Background: Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment. Methods: The ONE Study consisted of seven investigator-led, single-arm trials done internationally at eight hospitals in France, Germany, Italy, the UK, and the USA (60 week follow-up). Included patients were living-donor kidney transplant recipients aged 18 years and older. The reference group trial (RGT) was a standard-of-care group given basiliximab, tapered steroids, mycophenolate mofetil, and tacrolimus. Six non-randomised phase 1/2A cell therapy group (CTG) trials were pooled and analysed, in which patients received one of six CBMPs containing regulatory T cells, dendritic cells, or macrophages; patient selection and immunosuppression mirrored the RGT, except basiliximab induction was substituted with CBMPs and mycophenolate mofetil tapering was allowed. None of the trials were randomised and none of the individuals involved were masked. The primary endpoint was biopsy-confirmed acute rejection (BCAR) within 60 weeks after transplantation; adverse event coding was centralised. The RTG and CTG trials are registered with ClinicalTrials.gov, NCT01656135, NCT02252055, NCT02085629, NCT02244801, NCT02371434, NCT02129881, and NCT02091232. Findings: The seven trials took place between Dec 11, 2012, and Nov 14, 2018. Of 782 patients assessed for eligibility, 130 (17%) patients were enrolled and 104 were treated and included in the analysis. The 66 patients who were treated in the RGT were 73% male and had a median age of 47 years. The 38 patients who were treated across six CTG trials were 71% male and had a median age of 45 years. Standard-of-care immunosuppression in the recipients in the RGT resulted in a 12% BCAR rate (expected range 3·2–18·0). The overall BCAR rate for the six parallel CTG trials was 16%. 15 (40%) patients given CBMPs were successfully weaned from mycophenolate mofetil and maintained on tacrolimus monotherapy. Combined adverse event data and BCAR episodes from all six CTG trials revealed no safety concerns when compared with the RGT. Fewer episodes of infections were registered in CTG trials versus the RGT. Interpretation: Regulatory cell therapy is achievable and safe in living-donor kidney transplant recipients, and is associated with fewer infectious complications, but similar rejection rates in the first year. Therefore, immune cell therapy is a potentially useful therapeutic approach in recipients of kidney transplant to minimise the burden of general immunosuppression. Funding: The 7th EU Framework Programme.The 7th EU Framework Programme. This work was also supported by funds from IHU-CESTI (Investissement d'Avenir ANR-10-IBHU-005, Région Pays de la Loire and Nantes Métropole), the Labex IGO project (ANR-11-LABX-0016-01), and a donation from John Lang and Nancy Merrell. We also thank the Cell and Gene Therapy Manufacturing facility from Centre Hospitalier Universitaire de Nantes for the ATDC production. In addition, we thank apceth Biopharma (Munich, Germany) for Mreg production in the study. We thank the nurses, physicians, and patients who contributed to the study. The research leading to these results has received funding from the EU Seventh Framework Programme (FP7) under grant agreement number 260687. This research was funded and supported in part by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London and the NIHR Clinical Research Facility.

Surveillance of hospital-acquired infections in Liguria, Italy: results from a regional prevalence study in adult and paediatric acute-care hospitals.

A multi-hospital prevalence study of hospital-acquired infections (HAIs) was carried out between 19 March and 6 April 2007 in Liguria, Italy, being the first to be performed in this region. Of the 29 existing public acute hospitals, 25 took part in the investigation (86.2%). In total, 3176 patients were enrolled in the study, representing a regional average bed-occupancy rate of nearly 70%. Three-hundred and ten HAIs were diagnosed from 283 patients, with an overall prevalence of infections and cases of 9.8% and 8.9%, respectively. Prevalence varied considerably between hospitals, ranging from 0 to 24.4% [95% confidence interval (CI): 15.53-33.27]. Urinary tract infections (UTIs) (30.0%) and respiratory tract infections (RTIs) (26.1%) presented the highest relative frequency, followed by bloodstream infections (BSIs) (14.8%), surgical site infections (11.6%) and gastrointestinal infections (6.5%). Intensive care units (ICUs) and haemato-oncological units showed the highest specific prevalence of HAI, respectively 42.5% (95% CI: 34.48-50.52) and 13.3% (6.28-20.32), with RTI and BSI as the predominant infections. Spinal units (33.3%; 13.14-53.46) and functional-rehabilitation units (18.9%; 17.75-24.06) demonstrated a high rate of urinary tract infections. Uni- and multivariate analyses were performed to assess the main risk factors and conditions associated with HAI, both overall and by site. Our study provides an overall picture of the epidemiology of HAI in Liguria, which may be usefully employed as a starting point to plan and organise future surveillance and control programmes