Pharmacokinetics evaluation of nimotuzumab in combination with doxorubicin and cyclophosphamide in patients with advanced breast cancer

EGFr (Epidermal growth factor receptor) overexpression has been detected in many tumors of epithelial origin, specifically in breast cancer and it is often associated with tumor growth advantages and poor prognosis. The nimotuzumab is a genetically engineered humanized MAb (monoclonal antibody) that recognizes an epitope located in the extracellular domain of human EGFr. The aim of this study was to assess the pharmacokinetics of nimotuzumab in patients with locally advanced breast cancer who are receiving neoadyuvant therapy combined with the AC chemotherapy regimen (i.e., 60 mg/m2 of Doxorubicin and 600 mg/m2 of Cyclophosphamide in 4 cycles every 21 days). A single center, non-controlled, open Phase I clinical trial, with histopathological diagnosis of locally advanced stage III breast cancer, was conducted in 12 female patients. Three patients were enrolled at each of the following fixed dose levels: 50, 100, 200 and 400 mg/week. Multiple intermittent short-term intravenous infusions of nimotuzumab were administered weekly, except on weeks 1 and 10, when blood samples were drawn for pharmacokinetic assessments. Nimotuzumab showed dose-dependent kinetics. No anti-idiotypic response against nimotuzumab was detected in blood samples of participants. There was not interaction between the administration of nimotuzumab and chemotherapy at the dose levels studied. The optimal biological doses ranging were estimated to be 200 mg/weekly to 400 mg/weekly

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p < 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

Pharmacokinetics evaluation of nimotuzumab in combination with doxorubicin and cyclophosphamide in patients with advanced breast cancer

EGFr (Epidermal growth factor receptor) overexpression has been detected in many tumors of epithelial origin, specifically in breast cancer and it is often associated with tumor growth advantages and poor prognosis. The nimotuzumab is a genetically engineered humanized MAb (monoclonal antibody) that recognizes an epitope located in the extracellular domain of human EGFr. The aim of this study was to assess the pharmacokinetics of nimotuzumab in patients with locally advanced breast cancer who are receiving neoadyuvant therapy combined with the AC chemotherapy regimen (i.e., 60 mg/m2 of Doxorubicin and 600 mg/m2 of Cyclophosphamide in 4 cycles every 21 days). A single center, non-controlled, open Phase I clinical trial, with histopathological diagnosis of locally advanced stage III breast cancer, was conducted in 12 female patients. Three patients were enrolled at each of the following fixed dose levels: 50, 100, 200 and 400 mg/week. Multiple intermittent short-term intravenous infusions of nimotuzumab were administered weekly, except on weeks 1 and 10, when blood samples were drawn for pharmacokinetic assessments. Nimotuzumab showed dose-dependent kinetics. No anti-idiotypic response against nimotuzumab was detected in blood samples of participants. There was not interaction between the administration of nimotuzumab and chemotherapy at the dose levels studied. The optimal biological doses ranging were estimated to be 200 mg/weekly to 400 mg/weekly

Rat hepatitis E virus (Rocahepevirus ratti) in people living with HIV

ABSTRACTRat hepatitis E virus (ratHEV; species Rocahepevirus ratti) is considered a newly emerging cause of acute hepatitis of zoonotic origin. ratHEV infection of people living with HIV (PLWH) might portend a worse, as with hepatitis E virus (HEV; species Paslahepevirus balayani), and consequently this group may constitute a high-risk population. We aimed to evaluate the prevalence of ratHEV by measuring viral RNA and specific IgG antibodies in a large Spanish cohort of PLWH. Multicentre study conducted in Spain evaluating PLWHIV included in the Spanish AIDS Research Network (CoRIS). Patients were evaluated for ratHEV infection using PCR at baseline and anti-ratHEV IgG by dot blot analysis to evaluate exposure to ratHEV strains. Patients with detectable ratHEV RNA were followed-up to evaluate persistence of viremia and IgG seroconversion. Eight-hundred and forty-two individuals were tested. A total of 9 individuals showed specific IgG antibodies against ratHEV, supposing a prevalence of 1.1 (95% CI; 0.5%−2.1%). Of these, only one was reactive to HEV IgG antibodies by ELISA. One sample was positive for ratHEV RNA (prevalence of infection: 0.1%; 95% CI: 0.08%−0.7%). The case was a man who had sex with men exhibiting a slightly increased alanine transaminase level (49 IU/L) as only biochemical alteration. In the follow-up, the patients showed undetectable ratHEV RNA and seroconversion to specific ratHEV IgG antibodies. Our study shows that ratHEV is geographical broadly distributed in Spain, representing a potential zoonotic threat

Fetuin-A, inter-α-trypsin inhibitor, glutamic acid and ChoE (18:0) are key biomarkers in a panel distinguishing mild from critical coronavirus disease 2019 outcomes

The mechanistic pathways leading to immune dysregulation and complications driven by uncontrolled severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection remain major challenges.1, 2 Hence, a detailed analysis of the proteome, metabolome and lipidome profile of coronavirus disease 2019 (COVID-19) patients showing different severity grades might shed light on the disease pathophysiology and unveil new predictive biomarkers to promptly ascertain patient's outcomes. Our COVID-19 study cohort included 273 SARS-CoV-2 infected individuals recruited during the first wave (March–April 2020) in three different hospitals and grouped by the disease severity following the medical inclusion criteria3 in mild, severe or critical (Figure 1A), from whom demographic, preexisting clinical conditions and COVID-19 treatments are summarized in Table S1. The greatest significant differences were observed between mild and critically ill patients. These findings indicated that older individuals with comorbidities such as hypertension, obesity, diabetes and cardiovascular disorders, mostly presenting dyspnea (Figure 1B), may be at higher risk of suffering from severe respiratory distress with subsequent oxygen and drug requirements and, eventually, died. Similarly, the serum biochemical composition analysis revealed a well-differentiated blood pattern previously defined for critically ill patients (Figure S1).This work has been developed in the framework of the COVIDOMICS’ project supported by Direcció General de Recerca i Innovació en Salut (DGRIS), Departament de Salut, Generalitat de Catalunya (PoC-6-17 and PoC1-5). The research has also been funded by the Programa de Suport als Grups de Recerca AGAUR (2017SGR948), the SPANISH AIDS Research Network [RD16/0025/0006, RD16/0025/0007 and RD16/0025/0020]-ISCIII-FEDER (Spain), the Centro de Investigación Biomédica en Red de Enfermedades Infecciosas-ISCIII [CB21/13/00020], Madrid, Spain and Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades Junta de Andalucía (research Project CV20-85418). Elena Yeregui was supported by the Instituto de Salud Carlos III (ISCIII) under grant agreement “FI20/00118″ through the programme “Contratos Predoctorales de Formación en Investigación en Salud”. Laia Revertéwas supported by the Instituto de Salud Carlos III (ISCIII) under grant agreement “CD20/00105″ through the programme “Contratos Sara Borrell”. Francesc Vidal was supported by grants from the Programa de Intensificación de Investigadores (INT20/00031)-ISCIII and by “Premi a la Trajectòria Investigadora dels Hospitals de l’ICS 2018″. Anna Rull was supported by a grant from IISPV through the project “2019/IISPV/05″ (Boosting Young Talent), by GeSIDA through the “III Premio para Jóvenes Investigadores 2019″ and by the Instituto de Salud Carlos III (ISCIII) under grant agreement “CP19/00146″ through the Miguel Servet Program. Maria José Buzón was supported by the Miguel Servet Program (CP17/00179). Ezequiel Ruiz- Mateos was supported by the Spanish Research Council (CSIC). Alicia Gutiérrez-Valencia was supported by the Instituto de Salud Carlos III, cofinanced by the European Development Regional Fund (“A way to achieve Europe”), Subprograma Miguel Servet (grant CP19/00159). This project was also funded by a donation from the city Council of Perafort (to Teresa Auguet).Peer reviewe

Discovering HIV related information by means of association rules and machine learning

Acquired immunodeficiency syndrome (AIDS) is still one of the main health problems worldwide. It is therefore essential to keep making progress in improving the prognosis and quality of life of affected patients. One way to advance along this pathway is to uncover connections between other disorders associated with HIV/AIDS-so that they can be anticipated and possibly mitigated. We propose to achieve this by using Association Rules (ARs). They allow us to represent the dependencies between a number of diseases and other specific diseases. However, classical techniques systematically generate every AR meeting some minimal conditions on data frequency, hence generating a vast amount of uninteresting ARs, which need to be filtered out. The lack of manually annotated ARs has favored unsupervised filtering, even though they produce limited results. In this paper, we propose a semi-supervised system, able to identify relevant ARs among HIV-related diseases with a minimal amount of annotated training data. Our system has been able to extract a good number of relationships between HIV-related diseases that have been previously detected in the literature but are scattered and are often little known. Furthermore, a number of plausible new relationships have shown up which deserve further investigation by qualified medical experts

COVID-19 in hospitalized HIV-positive and HIV-negative patients : A matched study

CatedresObjectives: We compared the characteristics and clinical outcomes of hospitalized individuals with COVID-19 with [people with HIV (PWH)] and without (non-PWH) HIV co-infection in Spain during the first wave of the pandemic. Methods: This was a retrospective matched cohort study. People with HIV were identified by reviewing clinical records and laboratory registries of 10 922 patients in active-follow-up within the Spanish HIV Research Network (CoRIS) up to 30 June 2020. Each hospitalized PWH was matched with five non-PWH of the same age and sex randomly selected from COVID-19@Spain, a multicentre cohort of 4035 patients hospitalized with confirmed COVID-19. The main outcome was all-cause in-hospital mortality. Results: Forty-five PWH with PCR-confirmed COVID-19 were identified in CoRIS, 21 of whom were hospitalized. A total of 105 age/sex-matched controls were selected from the COVID-19@Spain cohort. The median age in both groups was 53 (Q1-Q3, 46-56) years, and 90.5% were men. In PWH, 19.1% were injecting drug users, 95.2% were on antiretroviral therapy, 94.4% had HIV-RNA < 50 copies/mL, and the median (Q1-Q3) CD4 count was 595 (349-798) cells/μL. No statistically significant differences were found between PWH and non-PWH in number of comorbidities, presenting signs and symptoms, laboratory parameters, radiology findings and severity scores on admission. Corticosteroids were administered to 33.3% and 27.4% of PWH and non-PWH, respectively (P = 0.580). Deaths during admission were documented in two (9.5%) PWH and 12 (11.4%) non-PWH (P = 0.800). Conclusions: Our findings suggest that well-controlled HIV infection does not modify the clinical presentation or worsen clinical outcomes of COVID-19 hospitalization

Impact of late presentation of HIV infection on short-, mid- and long-term mortality and causes of death in a multicenter national cohort : 2004-2013

To analyze the impact of late presentation (LP) on overall mortality and causes of death and describe LP trends and risk factors (2004-2013). Cox models and logistic regression were used to analyze data from a nation-wide cohort in Spain. LP is defined as being diagnosed when CD4 < 350 cells/ml or AIDS. Of 7165 new HIV diagnoses, 46.9% (CI:45.7-48.0) were LP, 240 patients died.First-year mortality was the highest (aHR = 10.3[CI:5.5-19.3]); between 1 and 4 years post-diagnosis, aHR = 1.9(1.2-3.0); an

Prediction of long-term outcomes of HIV-infected patients developing non-AIDS events using a multistate approach

Outcomes of people living with HIV (PLWH) developing non-AIDS events (NAEs) remain poorly defined. We aimed to classify NAEs according to severity, and to describe clinical outcomes and prognostic factors after NAE occurrence using data from CoRIS, a large Spanish HIV cohort from 2004 to 2013. Prospective multicenter cohort study. Using a multistate approach we estimated 3 transition probabilities: from alive and NAE-free to alive and NAE-experienced ("NAE development"); from alive and NAE-experienced to death ("Death after NAE"); and from alive and NAE-free to death ("Death without NAE"). We analyzed the effect of different covariates, including demographic, immunologic and virologic data, on death or NAE development, based on estimates of hazard ratios (HR). We focused on the transition "Death after NAE". 8,789 PLWH were followed-up until death, cohort censoring or loss to follow-up. 792 first incident NAEs occurred in 9.01% PLWH (incidence rate 28.76; 95% confidence interval [CI], 26.80-30.84, per 1000 patient-years). 112 (14.14%) NAE-experienced PLWH and 240 (2.73%) NAE-free PLWH died. Adjusted HR for the transition "Death after NAE" was 12.1 (95%CI, 4.90-29.89). There was a graded increase in the adjusted HRs for mortality according to NAE severity category: HR (95%CI), 4.02 (2.45-6.57) for intermediate-severity; and 9.85 (5.45-17.81) for serious NAEs compared to low-severity NAEs. Male sex (HR 2.04; 95% CI, 1.11-3.84), ag

How do women living with HIV experience menopause? Menopausal symptoms, anxiety and depression according to reproductive age in a multicenter cohort

CatedresBackground: To estimate the prevalence and severity of menopausal symptoms and anxiety/depression and to assess the differences according to menopausal status among women living with HIV aged 45-60 years from the cohort of Spanish HIV/AIDS Research Network (CoRIS). Methods: Women were interviewed by phone between September 2017 and December 2018 to determine whether they had experienced menopausal symptoms and anxiety/depression. The Menopause Rating Scale was used to evaluate the prevalence and severity of symptoms related to menopause in three subscales: somatic, psychologic and urogenital; and the 4-item Patient Health Questionnaire was used for anxiety/depression. Logistic regression models were used to estimate odds ratios (ORs) of association between menopausal status, and other potential risk factors, the presence and severity of somatic, psychological and urogenital symptoms and of anxiety/depression. Results: Of 251 women included, 137 (54.6%) were post-, 70 (27.9%) peri- and 44 (17.5%) pre-menopausal, respectively. Median age of onset menopause was 48 years (IQR 45-50). The proportions of pre-, peri- and post-menopausal women who had experienced any menopausal symptoms were 45.5%, 60.0% and 66.4%, respectively. Both peri- and post-menopause were associated with a higher likelihood of having somatic symptoms (aOR 3.01; 95% CI 1.38-6.55 and 2.63; 1.44-4.81, respectively), while post-menopause increased the likelihood of having psychological (2.16; 1.13-4.14) and urogenital symptoms (2.54; 1.42-4.85). By other hand, post-menopausal women had a statistically significant five-fold increase in the likelihood of presenting severe urogenital symptoms than pre-menopausal women (4.90; 1.74-13.84). No significant differences by menopausal status were found for anxiety/depression. Joint/muscle problems, exhaustion and sleeping disorders were the most commonly reported symptoms among all women. Differences in the prevalences of vaginal dryness (p = 0.002), joint/muscle complaints (p = 0.032), and sweating/flush (p = 0.032) were found among the three groups. Conclusions: Women living with HIV experienced a wide variety of menopausal symptoms, some of them initiated before women had any menstrual irregularity. We found a higher likelihood of somatic symptoms in peri- and post-menopausal women, while a higher likelihood of psychological and urogenital symptoms was found in post-menopausal women. Most somatic symptoms were of low or moderate severity, probably due to the good clinical and immunological situation of these women