Search

Background: About 80% of breast cancer (BC) cases express estrogen receptor (ER), which has been correlated with good prognosis and response to estrogen deprivation Aim: To characterize ER positive advanced BC (ABC) patients treated at our institution assessing the impact of clinical pre-sentation (stage IV, de novo disease at diagnosis versus systemic recurrence) and BC subtype on survival rates. Material and Methods: We evaluated 211 ER+ advanced BC (ABC) patients, treated between 1997 and 2017. Results: The median overall survival (OS) was 37 months. Median OS for the period 1997/2006 and 2007/2017 were 33 and 42 months, respectively (p = 0.47). Luminal A, ABC stage IV disease at diagnosis displayed better OS rates than Luminal B stage IV tumors (100 and 32 months respectively, p < 0.01). Conclusions: Clinical presentation (stage IV vs. systemic recurrence) and tumor subtype are key determinants of OS in ABC.

Background Checkpoint inhibitors (CPIs) such as Pembrolizumab have recently become the standard treatment for Non-Small Cell Lung Cancers (NSCLC) in patients without Epidermal Growth Factor (EGFR) gene alterations. Previous reports suggest no significant benefit from CPI treatments among EGFR mutant NSCLC patients and recommend the use of Tyrosine Kinase Inhibitors such as Afatinib. Case presentation: Herein, we report a rare case of a 39-year old, light-smoker woman with a metastatic EGFR mutant NSCLC (exon-19 deletion) that exhibited rapid progression and an unusual clinical response to Afatinib without changes in tumor histology. Tumor was negative for PDL1. Biopsy analyses by NGS prior and after Afatinib treatment indicated an increase in focal somatic copy number alterations (fSCNAs) but no T790M or c-MET amplification, and a low Tumor Mutational Burden (TMB). Given her rapid progression and deterioration, and despite its PDL1- status and her low TMB patient started treatment with Pembrolizumab plus chemotherapy. Surprisingly, patient displayed a complete response after just 4 cycles and is soon to complete a year in remission. Conclusions We speculate intratumoral heterogeneity, the combination of radiotherapy plus immunotherapy or the concomitant use of chemotherapy plus immunotherapy could explain the observed response in this patient. Also, based in our data we suggest the SBRT/CPI combination could be an option for Tyrosine Kinase Inhibitor-refractory EGFR mutant NSCLC patients or as a second-line treatment.

Objective: Clinical guidelines recommend the use of endocrine therapy (ET) in advanced hormone receptor positive (HR+) human epidermal growth factor receptor type 2 negative (HER2-) breast cancer (...

Neuroendocrine Tumors (NETs) encompass a wide variety of tumors arising from neuroendocrine cells, which produce bioactive substances. The incidence of NETs increased significantly lately, becoming one of the most common tumors of the digestive tract. Their clinical presentation is as diverse as their capacity for hormone production. Carcinoid syndrome is the most common hormonal syndrome produced by NETs and is characterized by diarrhea, flushing and cardiac valvular lesions. New research brought multiple changes in the classification of these neoplasms and a new understanding about their diagnosis and treatment, promoting a multidisciplinary approach. Somatostatin analogues, radiation, biological, and cytotoxic drugs have improved the prognosis of these patients, which entails a great challenge for healthcare providers.

Background: Lung cancer (LC) is the second leading cause of cancer death in Chile, causing >3,000 deaths every year. Epidemiological LC data in Chile is scarce and scattered. Here, we aimed to quantify the prevalence of Epidermal Growth Factor Receptor (EGFR) gene mutations in a Chilean cancer center. These data may identify individuals that could benefit from targeted therapies such as Tyrosine Kinase Inhibitors (TKIs). Methods: A total of 1,405 Biopsies from 1,381 LC patients were retrospectively analyzed retrieving clinical data from EGFR mutants including age, gender, histological type, smoking habits and type of EGFR mutation. We also analyzed overall survival (OS) rates. Results: From all patients 21.7% had clinically relevant EGFR mutations, and a median age at diagnosis of 65 years. Most were female (64%), classified as adenocarcinomas (94.5%), and non-smokers/light smokers (93.1%). The most prevalent mutation was exon-19 deletions (50.6%) followed by Leucine-to Arginine 858; OS was 15 months. Clinical follow-up information was available for 83 patients. The use of TKIs in these patients significantly improved OS. Conclusion: The prevalence of EGFR mutations in the studied population was 21.7%, comparable to other countries in Latin America. The most frequent EGFR mutation was exon-19 deletion, OS in this group was 15 months, and TKIs significantly improved OS.

Objective: Tumor response to neoadjuvant chemotherapy (NAC) in breast cancer (BC) patients is a predictor for overall survival. The aim of our study was to determine a relationship between the neutrophil to lymphocyte ratio (NLR) prior to NAC, BC subtypes and the probability of a pathologic complete response (pCR). Materials and Methods: Medical records were collected retrospectively from Centro de Cancer at Red Salud UC-Christus. Clinical data collected included peripheral blood cell counts, BC subtype at diagnosis and the pathology report of surgery after chemotherapy. Results: A total of 88 patients were analyzed. Approximately, a 25% had a pCR, and displayed a significant correlation between BC subtype and pCR (p= 0.0138 Chi2); this was more frequent in epidermal growth factor receptor type 2 (HER2) enriched subtype patients (54%). Luminal B BC patients with a pCR had significantly lower NLR levels (t test, p= 0.0181). Conclusions: HER2-enriched tumors had a higher probability of pCR. In Luminal B tumors, NLR had a statistically significant relationship with the probability of pCR. In this subtype, NLR could be a useful biomarker to predict tumor response to NAC. Further studies including other clinical parameters for systemic inflammation such as platelet counts, intratumoral NLR or body mass index could help identify patients that would get the most benefit from NAC.

Introduction and objectives Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive fibrofatty replacement of predominantly right ventricular myocardium . This cardiomyopathy is a frequent cause of sudden cardiac death in young people and athletes. The aim of our study was to determine the incidence of pathological or likely pathological desmosomal mutations in patients with high-risk definite ARVC. Methods This was an observational, retrospective cohort study , which included 36 patients diagnosed with high-risk ARVC in our hospital between January 1998 and January 2015. Genetic analysis was performed using next-generation sequencing . Results Most patients were male (28 patients, 78%) with a mean age at diagnosis of 45 ± 18 years. A pathogenic or probably pathogenic desmosomal mutation was detected in 26 of the 35 index cases (74%): 5 nonsense, 14 frameshift, 1 splice, and 6 missense. Novel mutations were found in 15 patients (71%). The presence or absence of desmosomal mutations causing the disease and the type of mutation were not associated with specific electrocardiographic, clinical, arrhythmic, anatomic, or prognostic characteristics. Conclusions The incidence of pathological or likely pathological desmosomal mutations in ARVC is very high, with most mutations causing truncation. The presence of desmosomal mutations was not associated with prognosis.

Background: Thymic epithelial tumors are rare and highly heterogeneous. Reports from the United States suggest an overall incidence of 0.15 per 100,000/year. In contrast, the incidence of these tumors in Latin America is largely unknown and reports are scarce, somewhat limited to case reports.Methods: Herein, we report a series of 38 thymic tumors from a single institution, retrospectively incorporated into this study. Patient characteristics and outcomes including age, sex, stage, paraneoplastic syndromes, treatment regimens and the date of decease were obtained from medical records.Results: Most cases in our series were females and young age (

Background Breast cancer (BC) is the leading cause of cancer death for Chilean women. About 11% of cases are triple-negative (TN) BC. These are characterised by poor prognosis, higher risk of early recurrence and visceral dissemination versus other BC subtypes. Current standard treatment for early-stage non-metastatic TNBC patients consists of neoadjuvant chemotherapy (NACT) followed by surgery and radiotherapy. Pathological complete response (pCR) to NACT is associated with an increase in survival rates. In general, NACT and adjuvant regimens involve similar cytotoxic drugs. Recent studies have postulated that the use of platinum compounds in TNBC would increase response rates. However, their effects on patient survival remain uncertain. Materials and methods We retrieved and analysed medical records from a total of 156 Chilean stage I-III TNBC female patients that received NACT and compared survival rates using carboplatin (Cb)-containing versus non-Cb-containing regimens at two health cancer centres. Results Median age was 51 years (range: 24-81); 13.5% (n = 21) received Cb-containing regimens, 80.1% (n = 125) received sequential anthracyclines plus taxanes; 29.5% (n = 46) of the total group achieved pCR, 28% for the standard treatment and 35% (n = 8) for the Cb-containing group (p = 0.59). We confirmed pCR was associated with prolonged overall survival, invasive and distant disease-free survival (Log-rank p = 0.0236). But the addition of Cb was not associated with differences in survival measures (Log-rank p = 0.5216). Conclusions To the best of authors' knowledge, this is the first report on real-world data in the Chilean population assessing the effect of Cb-containing NACT in TNBC. The authors' results suggest no survival benefit by the addition of Cb to standard NACT. However, we confirm an increase in survival associated to pCR regardless of treatment.

Leishmaniasis is a neglected tropical disease caused by intracellular parasites from the genus Leishmania. This neglected tropical disease is responsible for significant morbidity and mortality worldwide. One of the most important challenges for the treatment of leishmaniasis is the oral administration of drugs. Such need combined to the predicted high bioavailability of miltefosine prompted its validation. Its antileishmanial activity was better than that of the intravenous sodium stibogluconate. In 2002, it was approved as the first oral drug against leishmaniasis. Miltefosine is being an attractive drug for leishmaniasis due to its cost-effective and oral administration. On the other hand, nanocarriers drug delivery systems used to enhance activity and reduce side effects of antileishmanial drugs. This chapter reviews the most common nanocarriers used for miltefosine, focusing on polymeric micelles, characterized for their core-shell structure. Micelles formed with PEO-PPO block copolymers (Pluronics and Tetronics) and TPGS (PEGylated derivative of vitamin E) are described, as well as their composition, biological activity, and interaction with miltefosine. Promising systems, based on this drug, are reported by the combination of several copolymers, forming polymeric mixed micelles, and the further organization of some PEO-PPO block copolymers micelles into hydrogels.

Introduction There is extensive evidence associating the response to neoadjuvant chemotherapy (NeoCT) with breast cancer (BC) survival. However, to the author's knowledge, there is no published data in Chile. The objective of the study is to evaluate whether achieving pathological complete response (pCR) after NeoCT is associated with greater survival and lower risk of recurrence in a Chilean Public Health Service. Methods Retrospective analysis of a database. Patients with a diagnosis of Stages I-III BC who received NeoCT between 2009 and 2019 were included. Clinical and pathological information were extracted from the clinical records. BC subtypes were defined using hormone receptor (HR) information (HR: oestrogen and/or progesterone) and epidermal growth factor type 2 (HER2), being divided into four groups: HR+/HER2-, HR+/HER2+, HR-/HER2+, HR-/HER2-. pCR was defined as the absence of invasive cancer in the breast and axilla (ypT0/is N0) after NeoCT. Results Of 3,092 patients, 17.2% received NeoCT. Of these, 40.2% corresponded to HR+/HER2-, 20.9% HR+/HER2+, 18.2% HR-/HER2+ and 20.7% HR-/HER2-. Overall, 24.8% achieved pCR, being the lowest for HR+/HER2- (10.3%) and the highest for HR-/HER2+ (53.2%). In the multivariable analysis, family history, HER2+ and type of chemotherapy were associated with a greater probability of pCR. With a median follow-up of 40 months, the overall survival and metastasis-free survival (MFS) at 3 years were greater for the group with pCR compared to that which did not achieve it (90.5% versus 76.7%, p = 0.03 and 88.5% versus 71.4%, p = 0.003, respectively). The multivariable analysis confirmed this finding. Brain MFS was similar in both groups. Conclusion NeoCT is associated with greater pCR in aggressive BC subtypes. In those, achieving pCR was associated with better survival in our study. To the author's knowledge, this is the first study which evaluates the relation between pCR and BC subtypes in a Chilean public hospital.

Breast cancer (BC) is the most common malignancy in women. We retrieved medical records from >2,000 Chilean BC patients over the 1997–2018 period. The objective was to assess changes in clinical presentation or prognosis of our patients throughout these 20 years of practice. Although most variables did not display significant variations, we observed a progressive increase in stage IV BC over this period. Our data showed that tumour stage III/IV or HER2-enriched subtype tumours were associated with poorer prognosis. In contrast, we found that patients diagnosed by mammography had better overall survival. We speculate that better screenings and more sensitive imaging could explain the unexpected rise in stage IV cases. Our results support mammography screenings as an effective measure to reduce BC-related mortality.

Gastric cancer (GC) is a heterogeneous disease. This heterogeneity applies not only to morphological and phenotypic features but also to geographical variations in incidence and mortality rates. As Chile has one of the highest mortality rates within South America, we sought to define a molecular profile of Chilean GCs (ClinicalTrials.gov identifier: NCT03158571/(FORCE1)). Solid tumor samples and clinical data were obtained from 224 patients, with subsets analyzed by tissue microarray (TMA, n = 90) and next generation sequencing (NGS, n = 101). Most demographic and clinical data were in line with previous reports. TMA data indicated that 60% of patients displayed potentially actionable alterations. Furthermore, 20.5% were categorized as having a high tumor mutational burden, and 13% possessed micro-satellite instability (MSI). Results also confirmed previous studies reporting high Epstein-Barr virus (EBV) positivity (13%) in Chilean-derived GC samples suggesting a high proportion of patients could benefit from immunotherapy. As expected, TP53 and PIK3CA were the most frequently altered genes. However, NGS demonstrated the presence of TP53, NRAS, and BRAF variants previously unreported in current GC databases. Finally, using the Kendall method, we report a significant correlation between EBV+ status and programmed death ligand-1 (PDL1)+ and an inverse correlation between p53 mutational status and MSI. Our results suggest that in this Chilean cohort, a high proportion of patients are potential candidates for immunotherapy treatment. To the best of our knowledge, this study is the first in South America to assess the prevalence of actionable targets and to examine a molecular profile of GC patients.

Gallbladder cancer is the most common malignancy of the biliary tract. Given the lack of therapeutic alternatives for advanced stage patients studies have suggested that palliative chemotherapy could benefit these patients.We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis, and generated a summary of findings table using the GRADE approach.We identified two systematic reviews including two studies overall, of which one was a randomized trial. We concluded that palliative chemotherapy may increase survival in advanced gallbladder cancer patients. However, palliative chemotherapy probably increases adverse effects. In addition, it is essential to carry out a new systematic review, since methodological errors were identified in the analysis and there is new evidence that has not been included in the previous reviews.El cáncer de vesícula es el cáncer más frecuente de la vía biliar. Debido a la escasez de alternativas terapéuticas para pacientes con etapas avanzadas de la enfermedad, se ha planteado que quimioterapia paliativa puede ser beneficiosa para estos pacientes.Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE.Identificamos dos revisiones sistemáticas que en conjunto incluyeron dos estudios primarios, de los cuales, uno corresponde a un ensayo aleatorizado. Concluimos que la quimioterapia paliativa podría aumentar la sobrevida en cáncer de vesícula biliar avanzado. Sin embargo, probablemente aumenta los efectos adversos. Además, es imprescindible realizar una nueva revisión sistemática, ya que se identificaron errores metodológicos importantes en el análisis realizado y existe nueva evidencia que no ha sido incluida en revisiones previas.

Conventional chemotherapy against leishmaniasis includes agents exhibiting considerable toxicity. In addition, reports of drug resistance are not uncommon. Thus, safe and effective therapies are urgently needed. Isoselenocyanate compounds have recently been identified with potential antitumor activity. It is well known that some antitumor agents demonstrate effects against Leishmania. In this study, the in vitro leishmanicidal activities of several organo-selenium and organo-sulfur compounds were tested against Leishmania major and Leishmania amazonensis parasites, using promastigotes and intracellular amastigote forms. The cytotoxicity of these agents was measured in murine peritoneal macrophages and their selectivity indexes were calculated. One of the tested compounds, the isoselenocyanate derivative NISC-6, showed selectivity indexes 2- and 10-fold higher than those of the reference drug amphotericin B when evaluated in L. amazonensis and L. major, respectively. The American strain (L. amazonensis) was less sensitive to NISC-6 than L. major, showing a trend similar to that observed previously for amphotericin B. In addition, we also observed that NISC-6 significantly reduced the number of amastigotes per infected macrophage. On the other hand, we showed that NISC-6 decreases expression levels of Leishmania genes involved in the cell cycle, such as topoisomerase-2 (TOP-2), PCNA, and MCM4, therefore contributing to its leishmanicidal activity. The effect of this compound on cell cycle progression was confirmed by flow cytometry. We observed a significant increase of cells in the G(1) phase and a dramatic reduction of cells in the S phase compared to untreated cells. Altogether, our data suggest that the isoselenocyanate NISC-6 may be a promising candidate for new drug development against leishmaniasis.

Our aim was to analyze the influence of HLA-B haplotypes on liver fibrosis progression in HIV/hepatitis C virus (HCV) co-infected patients. Retrospective longitudinal study including HIV/HCV, non-cirrhotic and HCV treatment-naive patients. The main outcome variable was liver fibrosis progression of at least one stage. One hundred and four patients constituted the study population (F0-F1: 62 (59.6%); F2: 22 (21.2%); F3: 20 (19.2%)). During a median follow-up of 54.5 months (IQR: 26.2-77), 45 patients (43.3%) showed an increase in the stage of liver fibrosis (time to event: 29 (IQR: 14-49.5) months). HLA-B18pos patients more frequently had a higher and faster fibrosis progression rate (73.3%; 24 (IQR: 8-29) months) than HLA-B18neg patients (38.2%; 34.5 (IQR: 14.7-51.2) months). This association was also observed in the development of F3-F4 fibrosis among F0-F2 patients (HLA-B18pos: 69.2%; 18 (6.5-37) months vs HLA-B18neg: 28.2%; 37 (IQR: 19-52) months). These results could impact the timing of HCV therapy in F0-F2 patients.

Hepatitis delta virus (HDV) infection is a neglected disease despite causing the most severe form of viral hepatitis. Over 15 million people are infected worldwide. IFN-α is largely inefficient and poorly tolerated. The discovery of sodium taurocholate cotransporting polypeptide as the cell receptor for HBV (and consequently for HDV) has allowed development of viral entry inhibitors (i.e., myrcludex-B). More recently, prenylation inhibitors (i.e., lonafarnib) that disrupt virion assembly are being tested. At this time, sustained suppression of HDV replication is the primary goal of hepatitis delta treatment, being associated with normalization of liver enzymes and histological improvement. The lack of persistent forms of HDV-RNA could provide unique opportunities for hepatitis delta cure using specific antivirals, even in the face of persistent HBV cccDNA.

Purpose Trastuzumab (TZM) improves survival and the risk of recurrence among patients with early-stage HER2+ breast cancer (BC). TZM treatment can be given intravenously (IV-TZM) or subcutaneously (SC-TZM). Although both methods have similar efficacy and safety, they differ in dosage and administration. Previous studies of cost minimization determined that SC-TZM is associated with lower costs than IV-TZM; however, those studies did not include the costs associated with body weight-based dosage and the treatment of adverse drug reactions (ADRs). Methods/Patients We performed a model-based cost-minimization analysis. The analysis included direct and indirect medical costs associated with TZM preparation (adjusted by body weight) and administration and also costs due to severe ADRs and non-medical costs that occurred during the total treatment course (18 cycles). We performed a sensitivity analysis to test the robustness of the results across various TZM costs and patient body weights. Results The overall cost (in USD) of IV-TZM treatment was $83,309.1 per patient compared with $77,067.7 per patient for SC-TZM. Thus, one year of SC-TZM treatment cost $6,241.4 less per patient than one year of IV-TZM treatment. The sensitivity analysis revealed that the results were mainly driven by the price of each TZM vial and body weight. Conclusion SC-TZM is a cost-saving therapy for Chilean patients with early-stage HER2+ BC. Given their similar efficacy and safety, we suggest the use of SC formulations rather than IV formulations. The use of SC-TZM instead of IV-TZM may have a significant economic impact on public/private healthcare systems.

Neuroendocrine tumors (NETs) are relatively rare and highly heterogeneous neoplasms. Despite this, recent studies from North America and Central Europe have suggested an increase in incidence. In Latin America, NET data are scarce and scattered with only a few studies reporting registries. Our goal was to establish a NET registry in Chile. Here, we report the establishment and our first 166 NET patients. We observed a slight preponderance of males, a median age at diagnosis of 53 years and a median overall survival of 110 months. As anticipated, most tumors were gastroenteropancreatic (GEP). Survival analyses demonstrated that non-GEP or stage IV tumors presented significantly lower overall survival (OS). Similarly, patients with surgery classified as R0 had better OS compared to R1, R2, or no surgery. Furthermore, patients with elevated chromogranin A (CgA) or high Ki67 showed a trend to poorer OS; however, these differences did not reach statistical significance (log-rank test p = 0.07). To the best of our knowledge, this is the first report of a NET registry in Chile. Median OS in our registry (110 months) is in line with other registries from Argentina and Spain. Other variables including age at diagnosis and gender were similar to previous studies; however, our data indicate a high proportion of small-bowel NETs compared to other cohorts, reflecting the need for NET regional registries. Indeed, these registries may explain regional discrepancies in incidence and distribution, adding to our knowledge on this seemingly rare, highly heterogeneous disease. Electronic supplementary material The online version of this article (10.1007/s12672-018-0354-5) contains supplementary material, which is available to authorized users.

Baseline serum HCV-RNA predicts sustained virological response in chronic hepatitis C patients treated with antiviral therapy. A threshold at 6 million IU/mL has been proposed to best discriminate treatment outcomes on sofosbuvir-based regimens. In comparison with the general population, immunosuppressed individuals exhibit greater viral load values.To estimate the rate and predictors of serum HCV-RNA above 6 millionIU/mL in chronic hepatitis C patients on care outside clinical trials.Serum HCV-RNA values recorded from all chronic hepatitis C patients consecutively attended at our clinic during the last decade were analyzed. Testing had been performed using the COBAS TaqMan HCV test v2.0.A total of 816 individuals with detectable serum HCV-RNA were identified. The main characteristics of this population were as follows: mean age 48.6 years-old; 73.4% males; mean ALT 82.6IU/L; mean HCV-RNA 6.02logIU/mL; 80.6% HCV genotypes 1 or 4; 34.9% advanced liver fibrosis; 35.4% IL28B-CC alleles. HIV coinfection in 78.7%, of whom 91% were on antiretroviral therapy. Overall, 127 (15.6%) had serum HCV-RNA values6 millionIU/mL. This high viremia was found in 18.2% of HIV-positive versus 5.7% of HIV-negative subjects (p0.001). In multivariate analysis, serum HCV-RNA6 millionIU/mL was only significantly associated with HIV coinfection (OR: 4.03; 95% CI: 1.98-8.19, p0.01) and HCV genotypes 1 or 4 (OR: 1.88; 95% CI: 1.05-3.37, p=0.03).Serum HCV-RNA6 millionIU/mL is roughly seen in 6% of chronic hepatitis C monoinfected patients, and increases up to 18% in HIV coinfection.

Roughly 10 % of HIV-positive individuals worldwide have concomitant chronic hepatitis B virus (HBV) infection, with large differences between geographical regions and/or risk groups. Hepatitis B is a preventable infection with vaccines. However, it cannot be eradicated once acquired, resembling HIV and in contrast with HCV. In developed countries, hepatitis B exhibits particular features in the HIV population. First, HBV infection is less frequently misdiagnosed than in the general population. Second, nucleos(t)ide analogs active against HBV are widely used as part of antiretroviral combinations and are taken by most HIV patients. Lastly, as the HIV population ages given the success of antiretroviral therapy, non-AIDS co-morbidities are becoming a major cause of disease, for which specific drugs are required, increasing the risk of interactions and hepatotoxicity. Furthermore, concern on HBV reactivation is rising as immunosuppressive drug therapies are increasingly been used for cancers and other non-malignant conditions. In this scenario, new challenges are emerging in the management of hepatitis B in HIV-positive individuals. Among them, major interest is focused on failures to suppress HBV replication, HBV breakthroughs and reactivations, the meaning of isolated anti-HBc, screening for liver cancer, and the complexity arising when hepatitis viruses C and/or D are additionally present. This review will focus on these challenges and the major advances in HBV coinfection in HIV.

Aims Hypertrophic cardiomyopathy is one of the main causes of sudden death in young people. Recent clinical practice guidelines include a risk prediction model for sudden death (HCM Risk-SCD), which facilitates the decision of whether to implant a defibrillator. The aim of our study was to ascertain the percentage of events in our series of primary prevention implantable cardioverter-defibrillator recipients with hypertrophic cardiomyopathy and whether HCM Risk-SCD predicts the onset of arrhythmic events. Methods and results This was an observational, retrospective cohort study, which included 48 primary prevention defibrillator recipient patients with HCM. We compiled their demographic and clinical characteristics, estimated 5-year risk using HCM Risk-SCD, and collected the documentation on arrhythmias during follow-up. The majority was male (66.7%) and mean age at implantation was 44.44 ± 14.46 years. Non-sustained ventricular tachycardia was the most prevalent risk factor (66.67%), followed by a family history of sudden death (47.92%). Mean HCM Risk-SCD was 6.15 ± 5.01%. HCM Risk-SCD was the only factor independently associated with the onset of ventricular tachyarrhythmia, above any other classic risk factor or association [odds ratio = 1.46 (95% confidence interval 1.051–2.013); P = 0.02]. None of the 11 patients estimated as low risk using HCM Risk-SCD suffered any appropriate events ( P < 0.05). Conclusions During an average follow-up of 4 years, 16.67% presented appropriate events (4.16%/year). HCM Risk-SCD predicted the onset of events more suitably than classic risk factors.

The fixed-dose combination of three direct-acting antivirals (DAA), namely sofosbuvir, velpatasvir and voxilaprevir is the first pangenotypic, single tablet regimen developed for the treatment of HCV infection. Areas covered: The pharmacokinetics, pharmacodynamics, efficacy and safety of the co-formulation are reviewed. Information on drug absorption, distribution, metabolism and excretion of each of the three antivirals is evaluated. Finally, antiviral activity, safety and potential for drug interactions in phase II/III clinical trials in distinct patient populations are discussed. Expert opinion: The triple co-formulation of sofosbuvir-velpatasvir-voxilaprevir represents a major step towards HCV eradication. It depicts high efficacy even in patients infected with viruses harboring resistance-associated substitutions (RAS), including those selected after DAA failures. Likewise, very high success rates and good tolerance are seen in special patient populations, including decompensated cirrhotics, HIV coinfection, organ transplantation or renal insufficiency. A pill once daily for 8 weeks gives SVR rates above 95%. In prior DAA failures, extending treatment to 12 weeks maximizes SVR rates.

The introduction of direct-acting antivirals (DAA) has revolutionized the hepatitis C field. Most hepatitis C patients can now be cured, including those coinfected with HIV. However, drug-drug interactions (DDI) between DAA and antiretrovirals (ARV) should be known to prevent either toxicity due to drug overexposure or treatment failures due to low drug concentrations. Areas covered: Clinically significant DDI may be classified as major (when co-administration should be contraindicated) or minor (when they require close monitoring, changes in drug dosage or in timing). Strategies for preventing and managing DDI influence response rates in HIV/HCV-coinfected patients. Pharmacokinetic evidence of interactions from clinical trials and reports from real-world experience are discussed. Expert opinion: The most frequent DDI between DAA and ARV affect drug metabolism by CYP450 induction/inhibition, leading to abnormal drug exposures. Throughout this mechanism interact HCV and HIV boosted protease inhibitors, and most non-nucleoside HCV and HIV polymerase inhibitors. In contrast, HIV and HCV nucleos(t)ide analogue polymerase inhibitors, most HCV NS5A inhibitors and HIV integrase inhibitors (e.g., dolutegravir), do not or only marginally affect CYP450, and therefore are relatively free of DDI. Exposure to some HIV and HCV nucleos(t)ide analogues (e.g., tenofovir and sofosbuvir, respectively) is subject to induction/inhibition of drug transporters (e.g., P-glycoprotein) and requires special attention in patients with renal insufficiency.

The advent of oral direct-acting antivirals (DAA) has revolutionized the hepatitis C virus (HCV) therapeutic landscape providing cure rates over 90%. However, a subset of patients remains at higher risk for treatment failure, including those infected with: i) genotype 3 and cirrhosis; ii) resistance-associated substitutions (RAS) occurring either as natural polymorphisms or selected after prior DAA failure; and iii) poor drug adherence associated with social disabilities (homeless, psychiatric illnesses, injection drug use, alcoholism, etc.). Whereas discovery of new DAA with increased antiviral activity across all genotypes and over RAS may enhance efficacy, development of fixed dose combinations (FDC) may be the best way to improve drug adherence in difficult-to-treat HCV populations. Areas covered: Three FDC regimens are in the last steps of clinical development for treating hepatitis C. Two distinct nucleotide analogues that inhibit the HCV polymerase, sofosbuvir and uprifosbuvir, are part of the FDC from Gilead and Merck, respectively. The AbbVie dual FDC does not include a polymerase inhibitor. All three new FDC include second-generation NS3 protease inhibitors and NS5A inhibitors active across all HCV genotypes and over common RAS. Expert opinion: Hepatitis C cure rates over 95% are expected with all three next-coming DAA, even in the most difficult-to-treat and/or cure patient populations. These regimens would be particularly needed for the growing number of prior DAA failures. Co-formulations and 8-week shorter treatment lengths will help to overcome drug adherence challenges in certain populations.

Current treatment with oral nucleos(t)ides entecavir or tenofovir provide sustained suppression of HBV replication and clinical benefit in most chronic hepatitis B virus (HBV) infected persons. However, HBV rebound generally occurs upon drug discontinuation due to persistence of genomic HBV reservoirs as episomic cccDNA and chromosomic integrated HBV-DNA. There is renewed enthusiasm on HBV drug discovery following recent successes with antivirals for hepatitis C and immunotherapies for some cancers. Areas covered: New drugs that target distinct steps of the HBV life cycle are been developed, including inhibitors of viral entry, new polymerase inhibitors, capsid and assembly inhibitors, virus release blockers, and disruptors of cccDNA formation and transcription. Alongside these antivirals, agents that enhance anti-HBV specific immune responses are being tested, including TLR agonists, checkpoint inhibitors and therapeutic vaccines. Expert opinion: The achievement of a 'functional cure' for chronic HBV infection, with sustained HBsAg clearance and undetectable viremia once medications are stopped, represents the next step in the pace towards HBV elimination. Hopefully, the combination of new drugs that eliminate or functionally inactivate the genomic HBV reservoirs (cccDNA and integrated HBV-DNA) along with agents that enhance or activate immune responses against HBV will lead to a 'definitive cure' for chronic HBV infection.

Background Roughly 15 million people worldwide have hepatitis delta, the most severe form of chronic viral hepatitis that often leads to cirrhosis and liver cancer. Injection drug users (IDUs) are the largest HDV reservoir. Their resurgence in North America and Europe may represent a new opportunity for HDV to spread more widely. Methods We examined all consecutive active IDUs seen for the first time and enrolled in detoxification programmes at two clinics in Spain during two periods (1993–1996 and 2011–2014, respectively). Serum markers of HIV, HBV and HDV infection were tested. Results A total of 209 IDUs were examined in the first period. Mean age was 27-years-old. All had markers of past or current HBV infection. The rate of HIV-antibody (Ab), hepatitis B surface antigen (HBsAg) and HDV-Ab was as follows: 122 (58.4%), 73 (34.9%) and 62 (29.7%), respectively. Serum HDV-Ab was recognized in 53.4% of HBsAg+ and 16.9% of HBsAg- patients ( PConclusions Acute HBV–HDV coinfections and self-limited HDV infections were frequent in the 1990s among IDUs in Spain, especially in HIV+ individuals. In contrast, circulation of HDV has dramatically declined among active IDUs in Spain and is currently very rare, being concentrated in foreign immigrants. It may refect the benefit of universal HBV vaccination as well as the success of needle exchange programmes in Spain.

Patients with chronic kidney disease have an increased cardiovascular risk. Several non-traditional factors have been showed to be associated with this risk, including hyperhomocysteinemia. The effects of reducing homocysteine levels with folic acid supplementation have been studied in a number of randomized trials, with mixed results. In this article we critically appraise two systematic reviews providing disparate conclusions about this question and we summarize their main findings using the GRADE methodology. We conclude that there are methodological differences that may explain the mixed results in both systematic reviews. Folic acid supplementation does not reduce cardiovascular morbidity or mortality in patients with chronic kidney disease at any stage.

Mutations in the gene encoding glypican (GPC) 3 appear to be responsible for most cases of Simpson-Golabi-Behmel syndrome type 1. Duplication of the GPC4 gene has also been associated to this syndrome; however, no duplications involving GPC3 have been related. We describe a family that harbors a novel exon 2-4 duplication event leading to a truncating germline mutation of the GPC3 gene that, to our knowledge, has not been previously reported. GPC3 transcripts that carry this duplication bear non-functional proteins making its pathogenic role highly probable. The absence of a functional GPC3 may alter the normal differentiation of embryonal mesodermal tissues predisposing to the development of embryonal tumors, as the index case studied who developed a hepatoblastoma at age 9 months.

Cutaneous melanoma is a highly aggressive tumor developing from melanocytes, its incidence is increasing, and prognosis in advanced stages is daunting. New therapies have been approved during the recent years with unprecedented results, including inhibitors of MAPK/ERK pathway and immune checkpoint blockade (anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) as ipilimumab, anti-programmed cell death protein 1 (PD-L1) as pembrolizumab and anti-programmed cell death protein 1 ligand (PD-L1), among many others). The aim of this paper is to review currently available metastatic melanoma therapies focusing mainly on new therapies that have demonstrated effectiveness, after several decades of little progress in the treatment of this disease.

Here, we present the draft genome sequence of Burkholderia pseudomallei PHLS 6, a virulent clinical strain isolated from a melioidosis patient in Bangladesh in 1960. The draft genome consists of 39 contigs and is 7,322,181 bp long.

Background Cure rates above 90% have been reported in most Phase III clinical trials using distinct all-oral direct-acting antivirals (DAAs) in chronic hepatitis C patients. Preliminary results in real-world patients have confirmed this, although efficacy tends to be lower. Methods All consecutive chronic hepatitis C patients treated with all-oral DAA regimens at three hepatitis clinics in Spain were retrospectively examined. Host and viral factors were tested as predictors of treatment failure. Results A total of 363 chronic hepatitis C patients had completed a course of all-oral DAA therapy outside clinical trials up to the end of 2015. All but 14 (4%) patients achieved sustained virological response. There were 10 failures that occurred after 12 weeks of sofosbuvir-ledipasvir, despite 5 of them being on ribavirin. All failures but one were relapses. The only patient with viral breakthrough selected NS5B L159F and NS5A Y93H. In multivariate analyses, only advanced liver fibrosis (Metavir F3–F4) and HIV coinfection were significantly associated with treatment failure. A trend towards lower response was seen for HCV genotype 4. Conclusions Treatment failures outside clinical trials are roughly seen in 4% of chronic hepatitis C patients who complete a course of all-oral DAA therapy, resembling what is seen in registration trials. In our series, outcomes were not significantly influenced by ribavirin addition, IL28B polymorphisms, HCV genotype, high baseline HCV RNA or prior interferon failure. However, advanced liver fibrosis and HIV coinfection were significantly associated with treatment failure. Our findings support that there is still room for individualization of current DAA therapy.

A diagnosis of drowning is a challenge in legal medicine as there is generally a lack of pathognomonic findings indicative of drowning. This article investigates whether the skeletal muscle undergoes structural changes during death by drowning. Eighteen Wistar rats were divided into 3 equal groups according to the cause of death: drowning, exsanguination, and cervical dislocation. Immediately after death, samples of the masseter, sternohyoid, diaphragm, anterior tibial, soleus, and extensor digitorum longus muscles were obtained and examined by light and electron microscopy.In the drowning group, all muscles except the masseter displayed scattered evidence of fiber degeneration, and modified Gomori trichrome staining revealed structural changes in the form of abnormal clumps of red material and ragged red fibers. Under the electron microscope, there was myofibrillar disruption and large masses of abnormal mitochondria. In the exsanguination group, modified Gomori trichrome staining disclosed structural changes and mitochondrial abnormalities were apparent under light microscopy; however, there was no evidence of degeneration. No alterations were observed in the cervical dislocation group.As far as we know, this is the first time that these histological findings are described in death by drowning and are consistent with rhabdomyolysis and intense anoxia of skeletal muscle.

Background Baseline serum HCV RNA predicts treatment success in chronic hepatitis C patients. Thresholds at 0.8, 2, 4 and 6 million IU/ml discriminate treatment outcomes using distinct antiviral regimens. Compared to the general population, immunosuppressed individuals exhibit greater viral load values. This has been confirmed in HIV– HCV-coinfected patients, although little is known about the influence of antiretroviral therapy. Methods Serum HCV RNA results recorded from all chronic hepatitis C patients who consecutively attended at our clinic were analysed. Results A total of 813 patients with detectable HCV RNA were identified. HIV coinfection was present in 78.7%, of whom 91% were on antiretroviral therapy. Overall, 467 (57%), 273 (34%), 170 (21%) and 127 (16%) had HCV RNA >0.8, >2, >4 and >6 million IU/ml, respectively. These high viral load values were found in 60%/36%/23%/18% of HIV-positive versus 47%/25%/11%/6% of HIV-negative individuals ( P≤0.01), respectively. In multivariate analysis, the greatest HCV RNA values were only significantly associated with HIV coinfection and HCV genotypes-1 or -4. Greater HCV RNA values were paradoxically found in HIV patients on than off antiretroviral therapy. Conclusions Serum HCV RNA values above 0.8, 2, 4 and 6 million IU/ml are roughly seen in 47%, 25%, 11% and 6% of chronic hepatitis C monoinfected patients, respectively. Despite being on antiretroviral therapy, the corresponding figures are 1.3- to 3.0-fold greater in HIV–HCV-coinfected patients, who may benefit less frequently from shorter oral HCV treatment lengths.

OBJECTIVE To determine prevalence and risk factors for hypertension and isolated office hypertension diagnosed by ambulatory blood pressure monitoring in HIV-infected patients. METHODS Cross-sectional study of 310 patients. A 24-hour ambulatory blood pressure monitoring procedure was performed on the nondominant arm in those patients showing office systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg. RESULTS Twenty patients (6.5%) had a prior diagnosis of hypertension. Hypertension was confirmed by ambulatory blood pressure monitoring in 26 patients and isolated office hypertension in 17 patients. Isolated office hypertension and hypertension prevalence were 5.5% (95% confidence interval: 3 to 8) and 14.8% (95% confidence interval; 10.8 to 18.8), respectively. Isolated office hypertension was present in 39% of patients with office hypertension. In the univariate analysis, variables significantly associated with hypertension were age, waist circumference, established cardiovascular disease, family history of hypertension, lipoatrophy, metabolic syndrome, duration of infection, CD4 nadir, HIV RNA

The immunomodulatory receptor CD300a is expressed on human B cells. Naive B cells express very low levels of this receptor, whereas memory B cells and plasmablasts/cells express variable levels of CD300a. Germinal center B cells are negative for CD300a expression. Stimulation of naive B cells via B-cell receptor (BCR) and Toll-like receptor 9, along with T-cell help, failed to up-regulate CD300a cell surface expression despite the increased expression of the memory marker CD27 and the down-regulation of CD305. However, Toll-like receptor 9 stimulation alone significantly increased CD300a expression on memory B cells, whereas interleukin-4 and transforming growth factor-β1 act as negative regulators of CD300a expression on memory B cells. Coligation of BCR and CD300a inhibits Ca2+ mobilization and nuclear factor of activated T cell transcriptional activity evoked by BCR ligation alone. Suppression of CD300a expression in primary B cells with siRNA resulted in increased BCR-mediated proliferation, thereby confirming the inhibitory capacity of CD300a. Finally, we show that CD300a expression levels are significantly down-regulated in the circulating B cells of HIV-infected patients. Altogether, these data demonstrate a novel mechanism for suppressing the activity of B cells and suggest a potential role for CD300a in the B-cell dysfunction observed in HIV-induced immunodeficiency.

We studied the effects of transcranial magnetic stimulation (TMS, 60 Hz and 0.7 mT for 4 h/day for 14 days) on oxidative and cell damage caused by olfactory bulbectomy (OBX) in Wistar rats. The levels of lipid peroxidation products and caspase-3 were enhanced by OBX, whereas it prompted a reduction in reduced glutathione (GSH) content and antioxidative enzymes activities. The treatment with TMS reverted towards normality the biomarkers indicative of oxidative stress and apoptosis. In conclusion, our data show that TMS induced a protection against cell and oxidative damage induced by OBX, as well as they support the hypothesis that oxidative stress may play an important role in depression.

Although changes in atrioventricular conduction frequently occur after percutaneous implantation of an aortic valve prosthesis, little is known about the mechanisms involved or how these changes progress. We investigated ECG abnormalities and predictors of pacemaker need after percutaneous implantation of the CoreValve® aortic valve prosthesis.Between April 2008 and October 2009, 65 patients with symptomatic severe aortic stenosis received a CoreValve® prosthesis. Clinical and ECG parameters were recorded and predictors of pacemaker need due to advanced atrioventricular block were investigated. The analysis excluded three patients because they had pacemakers and a fourth who died during the procedure.The patients' mean age was 79 ± 7.8 years and their logistic EuroSCORE was 20 ± 14%. Implantation was successful in 98.4%. After implantation, 47.5% had left bundle branch block and 21 patients (34.4%) required a permanent pacemaker. The need for a pacemaker was associated with a greater depth of prosthesis implantation in the left ventricular outflow tract (LVOT): 13 ± 2.5 mm vs. 8.8 ± 2.8 mm (P.001). Moreover, depth was the only predictor: odds ratio 1.9, 95% confidence interval 1.19-3.05 (P.007). A cutpoint of 11.1 mm for the prosthesis depth in the LVOT had a sensitivity of 81% and a specificity of 84.6% for predicting the need for a pacemaker.After CoreValve® aortic valve prosthesis implantation, a high percentage of patients needed a permanent pacemaker for advanced atrioventricular block. The only independent predictor was the depth of the prosthesis in the LVOT, which could serve as an early indicator of pacemaker need.

Aims Cardiac resynchronization therapy (CRT) improves survival and quality of life in advanced heart failure (HF). Although mitral regurgitation (MR) reduction has been reported, its presence has been associated with non-response to CRT. This study was undertaken to assess the potential role of significant mitral regurgitation (SMR) persistence after CRT on clinical outcome, major arrhythmic events, and echocardiographic response in the mid-long term. Methods and results Seventy-six patients (28.9% women, 63 ± 11 years) with dilated cardiomyopathy in advanced HF were included. SMR, defined as regurgitant orifice area ≥0.20 cm2, was assessed at baseline and its evolution 6 months after CRT. Clinical outcome (cardiovascular death/HF readmission), major arrhythmic events, and echocardiographic response (reverse remodelling) were recorded on follow-up. Thirty-two patients (42.1%) presented baseline SMR, becoming non-significant in 11 of the 32 patients (34.3%) 6 months after CRT. Its persistence was associated with higher rates of clinical events (46.4 vs. 18.7%, P = 0.011), arrhythmic events (35.7 vs. 14.5%, P = 0.034), and less reverse remodelling (28.5 vs. 83.3%, P < 0.001). Conclusion CRT can reduce moderate or severe baseline MR to non-significant in one-third of patients. However, its persistence was associated with worse clinical evolution, greater incidence of arrhythmic events, and less reverse remodelling.

We report a new case of the unusual myeloproliferative syndrome chronic neutrophilic leukemia (CNL) that met all the criteria generally required for the diagnosis of this entity. The patient presented abnormalities in platelet function not previously reported that may explain the bleeding tendency observed in these patients. The study of neutrophil function suggested also defective mobility and intracellular bactericidal activity. The chromosomal study revealed original abnormalities consisting of multiple chromosomal ruptures and figures. The disease was controlled with busulfan. After 20 months, the patient died of sepsis. An autopsy was performed confirming the diagnosis and ruling out the existence of a cause of a leukemoid reaction, such as cancer or granulomatous disease.

The aim of this study was to compare the effects of cardiac resynchronization therapy on left ventricular function and reverse remodeling in patients in sinus rhythm with the effects in patients with atrial fibrillation who have not undergone atrioventricular node ablation. Echocardiographic and clinical parameters were evaluated at baseline and after 6 months of cardiac resynchronization therapy in 55 patients: 15 had atrial fibrillation and 40 were in sinus rhythm. Device programming was similar in the 2 groups, as were the reductions in QRS interval and echocardiographic measures of asynchrony observed after implantation. However, although significant improvements in end-systolic volume and ejection fraction were seen in both groups, reverse remodeling was greater in patients in sinus rhythm (reduction in end-systolic volume 30.9%+/-24.6% vs 12.5%+/-18.6%; P=.024), as was the relative increase in ejection fraction (15.4%+/-12.6% vs 5.0%+/-7.2%; P=.010). Cardiac resynchronization therapy in patients with atrial fibrillation who had not undergone atrioventricular node ablation resulted in significant improvements in ejection fraction and reverse remodeling, but these were less than those observed in patients in sinus rhythm.

Aims Cardiac resynchronization therapy (CRT) reduces the degree of functional mitral regurgitation (FMR). However, FMR has also been associated with a lack of clinical response to CRT. We undertook this study to determine whether the presence of FMR influences the reverse remodelling induced by CRT. Methods and results We used Doppler echocardiography to assess 20 patients with dilated cardiomyopathy before and 6 months after undergoing CRT. We evaluated the effect of reverse remodelling (reduction ≥ 10% in end-systolic volume) according to the presence or absence of important FMR, defined as a regurgitant orifice area (ROA) of ≥ 0.20 cm2. Of the 20 patients (mean age, 64.7 ± 8.2 years, eight women), 9 had marked FMR (ROA 0.40 ± 0.12 cm2), 6 mild FMR (ROA 0.15 ± 0.02 cm2), and 5 had trivial or no FMR. CRT reduced the presence of mitral regurgitation by 33.3% and induced reverse remodelling in 60% of the patients. A ROA ≥ 0.20 cm2 was associated with a lack of reverse remodelling, despite presenting similar baseline characteristics and a reduction in asynchrony to the other patients. Reverse remodelling was produced in all the other patients, with a significant reduction in end-systolic volume (41.7 ± 21%; P = 0.003), accompanied by improvement in the ejection fraction ( P = 0.003) and myocardial performance index ( P = 0.027). Conclusion CRT improved FMR, although the baseline presence of important mitral regurgitation, with a ROA ≥ 0.20 cm2, in patients undergoing CRT was associated with a lack of response in reverse remodelling.

This paper evaluates the effects of testosterone (0.5 mg/kg subcutaneously (s.c.) for 8 days) on oxidative stress and cell damage induced by 3-nitropropionic acid (20 mg/kg intraperitoneally (i.p.) for 4 days) in ovariectomized rats. Gonadectomy triggered oxidative damage and cell loss, evaluated by the detection of caspase-3, whereas 3-nitropropionic acid increased the levels of oxidative stress induced by ovariectomy and prompted cell damage characterized by enhanced levels of lactate dehydrogenase. These changes were blocked by testosterone administration. Our results support the following conclusions: i) ovariectomy triggers oxidative and cell damage via caspase-3 in the striatum; ii) 3-nitropropionic acid exacerbates oxidative stress induced by ovariectomy and leads to cell damage characterized by increased levels of lactate dehydrogenase; iii) testosterone administration decreases oxidative stress and cell damage. Additionally, these data support the hypothesis that testosterone might play an important role in the onset and development of neurodegenerative diseases.

Chronic hepatitis C virus (HCV) infection has become a curable disease. More than 90% sustained virologic response rates have been obtained with 8-24 weeks of treatment with distinct combinations of direct-acting antivirals (DAA) in most registration trials. However, outcomes in real-world patients tend to be lower and treatment of special patient populations is often challenging.We address the treatment of chronic hepatitis C with DAA in major special patient populations, such as HIV-positive persons, transplant recipients, patients with advanced cirrhosis, renal insufficiency, hepatitis B or D coinfection, injection drug users (IDUs) and prior DAA failures.Drug interactions between DAA and medications given to persons with HIV infection or transplant recipients can result in treatment failure and adverse events. Severe organ dysfunction as in kidney insufficiency or decompensated cirrhosis may lead to DAA overexposure and toxicities. Dysfunctional social circumstances and behavior are associated to poor drug adherence and increased risk for HCV re-infection in active IDUs. Finally, DAA response might be impaired by viral interference in patients with hepatitis B or D coinfection or drug resistance in HCV either at baseline or after prior DAA failures.

BACKGROUND The causes of HIV-vaccines failure are poorly understood. Therapeutic vaccination with modified vaccinia Ankara (MVA)-B in HIV-1-infected individuals did not control the virus upon analytical treatment interruption (ATI). We investigated whether the functional characteristics of HIV-specific CD8 T-cell responses stimulated by this vaccine, and the level of exhaustion of these cells might explain these results. METHODS Twenty-one HIV-1 chronically infected patients on combination antiretroviral therapy, included in the therapeutic vaccine trial RISVAC03, were studied: 13 immunized and eight controls. Functional characteristics, cytotoxic potential and exhaustion of HIV-specific CD8 T cells, were evaluated by polychromatic flow cytometry. Differences between groups were tested using nonparametric tests. RESULTS MVA-B vaccine induced an increase in HIV-specific CD8 T-cell response, but also increased their levels of exhaustion. At week 18 (following three immunizations) the level of response increased with respect to baseline (P = 0.02). A significant increase at weeks 18 and 24 (ATI) in granzyme B content was also observed. Interestingly, an increase in expression of exhaustion markers was found at weeks 18 (P = 0.006) and 24 (P = 0.01). However, there was no significant change in the functional profile of vaccine-induced CD8 cells. At week 36, in parallel to the rebound of plasma viremia after 12 weeks ATI, a significant increase in the level of CD8 response, in granzyme B content and in exhaustion markers expression, was observed in both groups. CONCLUSION We show that therapeutic vaccination with MVA-B tilts the balance between activation and regulation of the response of HIV-specific CD8 T cells towards regulation, which impacts on the viral rebound after ATI.

Our aim was to evaluate the killer cell immunoglobulin-like receptors (KIRs) as a marker for the development of thrombocytopenia secondary to Peg-interferon (IFN) therapy in a cohort of human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infected patients. Patients were naive to HCV treatment, receiving a first course of Peg-IFN/Ribavirin combination therapy. Total platelet count (cells ml-1) was determined at each visit, determining platelet decline from baseline to weeks 1, 2, 4, 8 and 12 after starting therapy. The end point of the study was development of thrombocytopenia, defined as a platelet count of

Roughly 20% of HIV-positive persons worldwide are coinfected with hepatitis C virus (HCV). The recent advent of direct-acting antivirals (DAA) that cure most hepatitis C patients has attracted much attention. Knowledge on drug interactions between DAA and antiretrovirals (ARV) may allow maximizing antiviral efficacy while minimizing drug-related toxicities.We review the most frequent side effects and clinically significant drug interactions between DAA and ARV. We further discuss how they can be prevented and managed in HIV/HCV-coinfected patients.The safety profile of current DAA and the most recently approved ARV is quite favorable. Interactions between DAA and ARV could be frequent in clinical practice. The most common drug interactions affect drug metabolism by inducing or inhibiting the cytochrome P450 system, leading to abnormal drug exposures. Throughout this mechanism HCV and HIV protease inhibitors interact, especially when co-formulated with ritonavir as a pharmacoenhancer, and non-nucleoside HCV and HIV polymerase inhibitors. In contrast, HIV and HCV nucleos(t)ide polymerase inhibitors, and most HCV NS5A inhibitors (i.e., ledipasvir) and HIV integrase inhibitors (i.e., dolutegravir), do not or only marginally affect CYP450, and therefore are free of significant drug interactions. Exposure to HIV and HCV nucleos(t)ide analogues (i.e., tenofovir and sofosbuvir, respectively) is subject to induction/inhibition of drug transporters (i.e., P-glycoprotein).

This Living FRISBEE (Living FRIendly Summary of the Body of Evidence using Epistemonikos) is an update of the summary published in August 2014, based on two systematic reviews appeared in January and February 2015. There is controversy about the effects of prophylactic antibiotics in acute pancreatitis. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified 18 systematic reviews including 19 randomised studies overall. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded that prophylactic antibiotics may reduce mortality and length of hospitalization in patients with acute pancreatitis, but the certainty of the evidence is low. The probability that future evidence change what we know is high.Este resumen Epistemonikos (Living FRISBEE: Living FRIendly Summary of the Body of Evidence using Epistemonikos) es una actualización del resumen publicado en Agosto de 2014, basado en dos nuevas revisiones sistemáticas aparecidas en Enero y Febrero de 2015. Existe controversia sobre los efectos del uso de antibióticos profilácticos en pacientes con pancreatitis aguda. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en 30 bases de datos, identificamos 18 revisiones sistemáticas que en conjunto incluyen 19 estudios aleatorizados. Los combinamos mediante un metanálisis y generamos tablas de resumen de resultados utilizando el método GRADE. Concluimos que el uso de antibióticos profilácticos podría disminuir la mortalidad y el tiempo de hospitalización en pacientes con pancreatitis aguda, pero la certeza de la evidencia es baja. La probabilidad que la aparición de nueva evidencia cambie lo que sabemos es alta.