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Vicente Soriano,1 Victor Moreno-Torres,1,2 Ana Treviño,1 Octavio Corral,1 Carmen de Mendoza2 1Health Sciences School & Medical Center, Universidad Internacional La Rioja (UNIR), Madrid, Spain; 2Puerta de Hierro University Hospital & Research Institute, Madrid, SpainCorrespondence: Vicente Soriano, UNIR Health Sciences School & Medical Center, Calle García Martín 21, Pozuelo de Alarcón 28224, Madrid, Spain, Tel +34 659687981, Email vicente.soriano@unir.netAbstract: It has been ten years since the identification of NTCP as the cell surface receptor for HBV and HDV entry into hepatocytes. The search for molecules interfering with the binding of NTCP and HBV/HDV led to design bulevirtide (BLV). This large polypeptide mimics a region of the pre-S1 HBsAg and blocks viral entry by inhibitory competition. BLV was initially tested in cell cultures, animal models and more recently in Phase I–III human trials (called ‘MYRS’). As monotherapy or in combination with peginterferon, BLV is well tolerated and exhibits potent antiviral activity. Plasma viremia significantly declines and/or becomes undetectable in more than 75% of patients treated for > 24 weeks. However, serum HBsAg concentrations remain unchanged. No selection of BLV resistance in HBV/HDV has been reported in vivo to date. BLV is administered subcutaneously once daily at doses between 2 and 10 mg. BLV received conditional approval in Europe in 2020 to treat chronic hepatitis delta. The advent of peginterferon lambda or new specific anti-HDV antivirals (lonafarnib, etc.) will open the door for combination therapies with BLV. Since there is no stable reservoir for HDV-RNA within infected hepatocytes, viral clearance might be achieved using antivirals for a minimum timeframe. This is what happens in hepatitis C combining several antivirals, curing nearly all patients treated for 3 months. Clearance of HDV-RNA genomes may occur despite HBV persistence as cccDNA or chromosome integrated HBV-DNA within hepatocytes. This is supported by cases of HDV elimination using BLV despite persistence of serum HBsAg. Another path for HDV cure will derive from achieving HBsAg clearance, the goal of new promising anti-HBV gene therapies (bepirovirsen, etc.). In summary, the advent of BLV has triggered a renovated interest for antiviral therapy in hepatitis delta. We envision combination therapies that will lead to HDV cure in the near future.Keywords: hepatitis delta, bulevirtide, lonafarnib, tenofovir, peginterferon lambda, hepatitis B functional cure, MYR trials

Background Underlying immunodeficiency is associated with severe COVID-19, but the prognosis of persons with human immunodeficiency virus (HIV) (PWH) with COVID-19 is under debate. Aim: assessment of the mortality rate and major determinants of death in HIV-infected patients hospitalized with COVID-19 in Spain before vaccine availability. Design: Retrospective nationwide public database analysis. Methods Nationwide, retrospective, observational analysis of all hospitalizations with COVID-19 during year 2020 in Spain. Stratification was made according to HIV status. The National Registry of Hospital Discharges was used with the ICD-10 coding list. Results A total of 117 694 adults were hospitalized with COVID-19 during 2020. Only 234 (0.2%) were HIV-positives. More than 95% were on antiretroviral therapy. Compared to HIV-negatives, PWH were younger (mean age 53.2 vs. 66.5 years old; P <0.001) and more frequently male (74.8% vs. 56.6%; P <0.001). Most co-morbidities predisposing to severe COVID-19 (diabetes, hypertension, dementia and cardiovascular disease) were more frequent in HIV-negatives. In contrast, the rate of baseline liver disease was over 6-fold higher in PWH (27.4% vs. 4.4%; P <0.001). In-hospital mortality was lower in PWH (9.4% vs. 16%; P =0.004). In multivariate analysis, older age, dementia and especially advanced liver disease (relative risk (RR): 7.6) were the major determinants of death in PWH hospitalized with COVID-19. Conclusion HIV-infected patients hospitalized in Spain with COVID-19 during 2020 had better survival than HIV-negatives, most likely explained by younger age and lower rate of co-morbidities. However, advanced liver disease was a major predictor of death in PWH hospitalized with COVID-19. [ABSTRACT FROM AUTHOR]

A 58-year-old male underwent a surgical procedure called a cephalic duodenopancreatectomy (Whipple procedure) to treat pancreatic adenocarcinoma. One year after the surgery, he experienced abdominal pain and a computed tomography scan revealed partial necrosis of the afferent jejunal loop. A gastroscopy was performed and a foreign body, identified as a fragment of the jejunum wall, was found. Biopsies confirmed the presence of necrohemorrhagic debris, indicating ischemic necrosis of the afferent loop. The foreign body was subsequently removed. [Extracted from the article]

Click here for the corresponding questions to this CME article. [ABSTRACT FROM AUTHOR]

We appreciate the thoughtful comments provided by Lee I et al. i , regarding our conclusions about the impact of HIV infection and advanced liver disease on COVID-19 outcomes in HIV-positive adults. The changing epidemiology of liver disease in HIV patients. In our study, we identified advanced liver disease as a strong prognostic factor of COVID-19 in-hospital mortality in HIV-positive patients. [Extracted from the article]

Background: The relationship between systemic lupus erythematosus (SLE) and low-grade metabolic inflammation (MI) with the microbiota is crucial for understanding the pathogenesis of these diseases and developing effective therapeutic interventions. In this context, it has been observed that the gut microbiota plays a key role in the immune regulation and inflammation contributing to the exacerbation through inflammatory mediators. This research aimed to describe similarities/differences in anthropometric, biochemical, inflammatory, and hepatic markers as well as to examine the putative role of gut microbiota concerning two inflammatory conditions: SLE and MI., Methods: Data were obtained from a cohort comprising adults with SLE and MI. Faecal samples were determined by 16S technique. Statistical analyses compared anthropometric and clinical variables, and LEfSe and MetagenomeSeq were used for metagenomic data. An interaction analysis was fitted to investigate associations of microbiota with fatty liver index (FLI) depending on the inflammatory condition., Results: Participants with low-grade MI showed worse values in anthropometry and biochemicals compared with patients with SLE. The liver profile of patients with MI was unhealthier, while no relevant differences were found in most of the inflammatory markers between groups. LEfSe analysis revealed an overrepresentation of Bifidobacteriaceae family in SLE group. An interactive association between gut Bifidobacterium abundance and type of disease was identified for FLI values, suggesting an effect modification of the gut microbiota concerning liver markers depending on the inflammatory condition., Conclusion: This study found phenotypical and microbial similarities and disparities between these two inflammatory conditions, evidenced in clinical and hepatic markers, and showed the interactive interplay between gut Bifidobacterium and liver health (measured by FLI) that occur in a different manner depending on the type of inflammatory disease. These results underscore the importance of personalized approaches and individual microbiota in the screening of different inflammatory situations, considering unique hepatic and microbiota profiles., (© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Background/Objectives : Prolonged remission on low-dose glucocorticoids (GC) is a main goal in patients with systemic lupus erythematosus (SLE). The aim of this study is to assess whether GC ≤ 5 mg/d increases the risk of damage accrual in patients with SLE in prolonged remission. Methods : Observational study of routine clinical care data of the inception Lupus Cruces-Bordeaux cohort. Only patients in DORIS remission during five consecutive yearly visits were included. The endpoint was damage accrual during the 5-year follow-up, either global or specific damage: GC-induced, cardiovascular (CV), lupus and other. Patients no longer on GC therapy by year 5 (GC5-Off) were compared with those who continued GC therapy (GC5-On). Comparisons were made by Cox and Poisson regressions, which were adjusted with propensity score (PE) in order to control for confounding by indication. Results : 132 patients were included, 56 in the GC5-On and 76 in the GC5-Off groups. All patients were on GC ≤ 5 mg/d for the whole follow-up, the mean prednisone dose in the GC5-On group being 2.96 mg/d during the whole study period and 2.6 mg/d during the 5th year. Fourteen patients (10.6%) accrued damage. More patients in the GC5-On group accrued global damage, 16% vs. 7% in the GC5-Off group, p = 0.08, mainly at CV domains (7% vs. 1%, respectively, p = 0.16). In the PS-adjusted Cox and Poisson regressions, the GC5-On group was not significantly associated with global ( p = 0.39) or CV damage accrual ( p = 0.62), nor with the absolute ( p = 0.40) or CV-restricted final SDI scores ( p = 0.63). The C-index of the propensity score model was 0.79. Conclusions : Maintaining doses of prednisone < 5 mg/d in lupus patients in prolonged remission is not associated with an increased risk of damage accrual.

Competing Interests: We declare no competing interests.

Objectives: Listeria monocytogenes (LM) is a health threat worldwide given its high mortality and the growing of high-risk susceptible populations., Methods: All hospitalizations with a diagnosis of LM in the National Registry of Hospital Discharges were examined in Spain from 2000 to 2021., Results: A total of 8152 hospital admissions with LM were identified. The mean age was 59.5 years and 48% were immunosuppressed (IS). The rate of LM hospitalizations increased from 5 per 1 million population in 2000 to 8.9 in 2021 (p < 0.001). A foodborne outbreak in Andalusia determined a sharp increase in admissions with LM during 2019. The COVID-19 pandemic and lockdowns were associated with a decrease in LM admissions. The overall in-hospital mortality was 16.7%. The number of deaths in patients hospitalized with LM rose from 7.8 per 100,000 deceased in 2000 to 18 in 2021 (p < 0.001). After adjustment, age >65 years (odds ratio [OR] = 2.16), sepsis (OR = 2.60), meningoencephalitis (OR = 1.72), endocarditis (OR = 2.0), neonatal listeriosis (OR = 2.10) and IS (OR = 2.09) were associated with mortality., Conclusions: The number of patients hospitalized with LM in Spain has increased significantly from 2000 to 2021. The increase in the rate of admissions and deaths was largely driven by the growing proportion of elderly and IS patients., Competing Interests: Declaration of competing interests None declared., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: The objective of this study was to analyze the effect of methylprednisolone pulses (MP), given during the first year after the diagnosis of systemic lupus erythematosus (SLE), in achieving prolonged remission according to the degree of lupus activity at presentation., Methods: We conducted an observational study of routine clinical care data from the Lupus-Cruces-Bordeaux cohort. The end point was prolonged remission (ie, during five consecutive yearly visits). The effect of MP on remission during the first year was analyzed in the whole cohort and according to the baseline Systemic Lupus Erythematosus Disease Activity Index 2000 score: <6, 6 to 12, and >12, reflecting mild, moderate, and severe activity, respectively. For adjustment, logistic regression with propensity score (PS) and other therapeutic covariates was performed., Results: Two hundred thirty-three patients were included. Prolonged remission was achieved by 132 patients (57%). MP were associated with prolonged remission (PS-adjusted odds ratio [OR] 2.50, 95% confidence interval [CI] 1.04-623, P = 0.042). A strong clinical effect was seen among patients with moderate (adjusted OR 5.28, 95% CI 1.27-21.97, P = 0.022) and moderate-severe SLE activity (adjusted OR 4.07, 95% CI 1.11-14.82, P = 0.033). The administration of MP resulted in reduced average dosages of prednisone during the first year among patient with moderate (mean 6.6 vs 10.2 mg/day, P = 0.017) and severe activity (mean 14 vs 28 mg/day, P = 0.015). The odds of prolonged remission were increased by longer-term use of hydroxychloroquine (HCQ) and decreased by higher initial doses of prednisone., Conclusion: This study supports the use of MP to induce prolonged remission in patients with SLE, particularly in those with moderate and severe activity. The extended use of HCQ also contributes to achieve prolonged remission., (© 2024 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Patients with COVID-19 may develop a hypercoagulable state due to tissue and endothelial injury, produced by an unbalanced immune response. Therefore, an increased number of thromboembolic events has been reported in these patients. The aim of this study is to investigate the presence of antiphospholipid antibodies (aPL) in COVID-19 patients, their role in the development of thrombosis and their relationship with the severity of the disease. In this retrospective study, serum samples from 159 COVID-19 patients and 80 healthy donors were analysed for the presence of aPL. A total of 29 patients (18.2%) and 14 healthy donors (17.5%) were positive for aPL. Nineteen COVID-19 patients (12%) but no healthy donor presented a positive percentage of the IgA isotype aPL. IgA anti-β2-glycoprotein I antibodies (anti-β2GPI) were the most frequent type (6.3%) in patients but was not detected in any healthy donor. The positivity of this antibody was found to be significantly elevated in patients with thromboembolic events (25% vs. 5%, p = 0.029); in fact, patients with positive IgA anti-β2GPI had an incidence of thrombosis over six times higher than those who had normal antibody concentrations [OR (CI 95%) of 6.67 (1.5-30.2), p = 0.014]. Additionally, patients with moderate-severe disease presented a higher aPL positivity than patients with mild disease according to the Brescia ( p = 0.029) and CURB-65 ( p = 0.011) severity scales. A multivariate analysis showed that positivity for IgA anti-β2GPI is significantly associated with disease severity measured by CURB-65 [OR (CI 95%) 17.8 (1.7-187), p = 0.0016]. In conclusion, COVID-19 patients have a significantly higher positive percentage of the IgA isotype aPL than healthy donors. IgA anti-β2GPI antibodies were the most frequently detected aPL in COVID-19 patients and were associated with thrombosis and severe COVID-19 and are thus proposed as a possible marker to identify high-risk patients.

Despite the advances in genetic marker identification associated with severe COVID-19, the full genetic characterisation of the disease remains elusive. This study explores imputation in low-coverage whole genome sequencing for a severe COVID-19 patient cohort. We generated a dataset of 79 imputed variant call format files using the GLIMPSE1 tool, each containing an average of 9.5 million single nucleotide variants. Validation revealed a high imputation accuracy (squared Pearson correlation ≍0.97) across sequencing platforms, showcasing GLIMPSE1's ability to confidently impute variants with minor allele frequencies as low as 2% in individuals with Spanish ancestry. We carried out a comprehensive analysis of the patient cohort, examining hospitalisation and intensive care utilisation, sex and age-based differences, and clinical phenotypes using a standardised set of medical terms developed to characterise severe COVID-19 symptoms. The methods and findings presented here can be leveraged for future genomic projects to gain vital insights into health challenges like COVID-19., Competing Interests: MC is associated with Cambridge Precision Medicine Ltd. The other authors declare that they have no competing interests., (© The Author(s) 2024.)

Background: Few population-based studies have evaluated the epidemiology of infective endocarditis (IE). Changes in population demographics and guidelines on IE may have affected both the incidence and outcomes of IE. Therefore, the aim of our study is to provide contemporary population-based epidemiological data of IE in Spain., Methods: Retrospective nationwide observational study using data from the Spanish National Health System Discharge Database. We included all patients hospitalized with IE from January 2000 to December 2019., Results: A total of 64,550 IE episodes were included. The incidence of IE rose from 5.25 cases/100,000 person-year in 2000 to 7.21 in 2019, with a 2% annual percentage change (95% CI 1.3-2.6). IE incidence was higher among those aged 85 or older (43.5 cases/100.000 person-years). Trends across the study period varied with sex and age. Patients with IE were progressively older (63.9 years in 2000-2004 to 70.0 in 2015-2019, p < 0.001) and had more frequent comorbidities and predispositions, including, previous valvular prosthesis (12.1% vs 20.9%, p < 0.001). After adjustment, a progressive reduction in mortality was noted including in 2015-2019 compared to 2010-2014 (adjusted odds ratio 0.93, 95% confident interval 0.88-0.99, p = 0.023)., which was associated with more frequent cardiac surgery in recent years (15.1% in 2010-2014 vs 19.9% in 2015-2019)., Conclusions: In Spain, the incidence of IE has increased during the XXI century, with a more pronounced increase in elderly individuals. Adjusted-mortality decreased over the years, which could be related to a higher percentage of surgery. Our results highlight the changing epidemiology of IE., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Several studies suggest that women with Crohn disease (CD) have reduced fertility due to decreased ovarian reserve, among other causes. On the other hand, male CD patients could have difficulties conceiving. The present study aimed to test the effect of CD on both male and female fertility potential, Sertoli cell function and ovarian reserve, assessed by inhibin-B (IB) plus IB:FSH ratio (IFR) and antiMüllerian hormone (AMH), respectively. Sexual dysfunction (SD) was studied as secondary endpoint., Methods: We performed a cross-sectional, case-control study. Serum IB levels plus IFR were measured in 58 men with CD and compared to 25 age-matched healthy controls (HC). Serum AMH levels were measured in 50 women with CD and in 30 HC matched by age. SD was assessed by means of the International Index of Erectile Function (IIFE-15) in males and the Index of Female Sexual Function (IFSF) in women., Results: A total of 108 CD patients and 55 HC were included. IB serum levels were significantly lower in CD men than in HC (177 ± 58 vs. 234 ± 75 pg./mL, p  = 0.001). IFR was also decreased in CD patients compared to HC (58.27 ± 59.5 vs. 91.35 ± 60.04, p  = 0.014). Women with CD > 30 years had lower serum AMH levels compared to HC (1.15 ± 0.74 vs . 2.14 ± 1.68 ng/mL, p  = 0.033). In addition, CD women >30 years presented a serum AMH < 2 ng/mL more frequently than HC (90% vs . 40%, p  = 0.004). The prevalence of SD was significantly higher among both male and female CD patients compared to HC, without association to fertility potential. Age was the only predictor of low ovarian reserve., Conclusion: Testicular Sertoli cell function assessed through serum IB levels and IFR is decreased in CD male patients compared to HC, regardless of age. Age > 30 years is the single independent predictor of reduced ovarian reserve in women with CD. These results should be confirmed in further studies in order to properly counsel patients with CD and desire for offspring., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gutiérrez, Muñoz-Pérez, Zapater, Mira, Rodríguez, Sempere-Robles, Torregrosa, Alfayate, Moreno-Torres, Bernal, Belén-Galipienso, Cameo, Sirera, Herreros, Bernabeu, Moreno-Pérez and Madero-Velázquez.)

Objective: To evaluate the impact of the different types of neoplasms and lineages on mortality of patients with SLE., Methods: Retrospective and observational comparison of the neoplasm-related deaths in patients with SLE and the general Spanish population reported in the Spanish Hospital Discharge Database. To determine the impact of SLE on the risk of dying from each neoplasm lineage, a binary logistic regression considering age, female sex, tobacco and alcohol consumption, was performed., Results: During 2016-2019, 139 531 in-hospital deaths from neoplasms were certified in Spain (91 in patients with SLE). Patients with SLE presented a lower mortality rate from solid organ neoplasms, (80.2% vs 91.1%, OR 0.393), linked to their lower risk of colorectal carcinoma (1.1% vs 10.8%, OR 0.110). By contrast, gynaecological neoplasms presented a higher risk (8.8% vs 3%, OR 3.039) in the deceased patients with SLE, associated with the higher frequency of vulvar neoplasms (2% vs 0.2%, OR 14.767) and cervical carcinomas (3.3% vs 0.5%, OR 3.809). Haematological neoplasm-related deaths were also more prevalent in patients with SLE (19.8% vs 8.9%, OR 2.546), mostly attributable to the higher proportion of deaths due to non-Hodgkin's lymphoma (11% vs 2.9%, OR 4.060) of B cell lineage (9.9% vs 2.5%, OR 4.133)., Conclusions: Patients with SLE present a higher risk of death from vulvar neoplasms, cervical carcinomas and B-cell non-Hodgkin's lymphoma in comparison with the general Spanish population. In addition to developing strategies that might help to attenuate their occurrence and impact, such as decreasing the immunosuppressive burden, specific early detection programmes for these conditions should be investigated and considered carefully., Competing Interests: Competing interests: AH is in advisory board of AstraZenecea, Otsuka and Vifor and receives funding for talks and educational activities from GSK, AstraZeneca, Otsuka and Vifor., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Infection with the hepatitis B virus (HBV) is highly prevalent globally. Over 250 million people suffer from chronic hepatitis B, and more than 800,000 patients die each year due to hepatitis B complications, including liver cancer. Although protective HBV vaccines are recommended for all newborns, global coverage is suboptimal. In adults, sexual transmission is by far the most frequent route of contagion. The WHO estimates that 1.5 million new HBV infections occur annually. Oral nucleos(t)ide analogues entecavir and tenofovir are the most frequent antivirals prescribed as HBV therapy. Almost all patients adherent to the medication achieve undetectable plasma viremia beyond 6 months of monotherapy. However, less than 5% achieve anti-HBs seroconversion, and viral rebound occurs following drug discontinuation. Therefore, nucleos(t)ide analogues need to be lifelong. New long-acting formulations of tenofovir and entecavir are being developed that will maximize treatment benefit and overcome adherence barriers. Furthermore, new antiviral agents are in development, including entry inhibitors, capside assembly modulators, and RNA interference molecules. The use of combination therapy pursues a functional HBV cure, meaning it is negative for both circulating HBV-DNA and HBsAg. Even when this goal is achieved, the cccDNA reservoir within infected hepatocytes remains a signal of past infection, and HBV can reactivate under immune suppression. Therefore, new gene therapies, including gene editing, are eagerly being pursued to silence or definitively disrupt HBV genomes within infected hepatocytes and, in this way, ultimately cure hepatitis B. At this time, three actions can be taken to push HBV eradication globally: (1) expand universal newborn HBV vaccination; (2) perform once-in-life testing of all adults to identify susceptible HBV persons that could be vaccinated (or re-vaccinated) and unveil asymptomatic carriers that could benefit from treatment; and (3) provide earlier antiviral therapy to chronic HBV carriers, as being aviremic reduces the risk of both clinical progression and transmission.

Introduction: Patients with sarcoidosis have a lower survival rate than the general population, in part due to cardiovascular disease, infections and neoplasms. Our objective was to evaluate the impact of haematological neoplasms (HN) and lymphomas on sarcoidosis patient mortality in a nation-wide analysis conducted in Spain, a country with a population of 47 million., Methods: Retrospective and observational comparison of the HN related deaths in sarcoidosis patients and the general Spanish population reported in the Spanish Hospital Discharge Database. To determine the impact of sarcoidosis on the risk of dying from each HN lineage, a binary logistic regression considering age, female sex, tobacco and alcohol consumption, was performed., Results: In the period 2016 and 2019, 139,531 in-hospital deaths from neoplasms were certified in Spain (77 in patients with sarcoidosis). Patients with sarcoidosis died at younger age than the general Spanish population (72.9 vs 77.6, p<0.001). Sarcoidosis patients presented a higher mortality risk from HN (20.8% vs 8.9%, p=0.001, OR=2.64, 95% CI 1.52-4.59), attributable to the higher proportion of deaths from non-Hodgkin lymphoma (NHL), (9.2% vs 2.9%, p=0.006, OR= 3.33, 95% CI 1.53-7.25) from both B cell (6.6% vs 2.5%, p=0.044, OR= 2.62, 95% 1.06-6.5) and T/NK cell lineages (2.6% vs 0.3%, p=0.024, OR= 7.88, 95% CI 1.92-32.29) as well as HN with uncertain behavior and myeloproliferative disorders (2.6% vs 0.3%, p=0.018, OR= 11.88, 95% CI 2.88-49.02). The mean age of sarcoidosis patients who died from HN (63.6 vs 71.9, p=0.032) and non-Hodgkin lymphoma (56.9 vs 71, p=0.009) was lower than that of the general population., Conclusion: Patients with sarcoidosis present a higher risk of premature death from HN, including NHL from B, T/NK cell lineage and myeloproliferative disorders in comparison with the general Spanish population. In addition to developing strategies that might help to attenuate their occurrence and impact, such as decreasing the immunosuppressive burden, specific early-detection programs for these conditions should be investigated and considered carefully., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Viruses cause a large burden of human infectious diseases. During the past 50 years, antivirals have been developed to treat many pathogenic viruses, including herpesviruses, retroviruses, hepatitis viruses, and influenza. Besides being used as treatment, antivirals have shown efficacy for preventing certain viral infections. Following the success in the HIV field, a renewed interest has emerged on the use of antivirals as prophylaxis for other viruses. The development of formulations with extended half-life has pushed further this consideration in persons at risk for a wide range of viral infections. In this way, long-acting antivirals might behave as "chemovaccines" when classical vaccines do not exist, cannot be recommended, immune responses are suboptimal, escape mutants emerge, and/or immunity wanes. Five main caveats would temper its use, namely, selection of drug resistance, drug interactions, short- and long-term side effects, potential teratogenicity in women of child-bearing age, and high cost. Herein, we discuss the prospects for long-acting antivirals as prophylaxis of human viral infections other than HIV.

Background: Before the advent of COVID-19 vaccines, hospitalizations due to SARS-CoV-2 infection during 2020 collapsed most medical centers worldwide. Disruptions in health care for clinical conditions other than COVID-19 were not uniform. Herein, we report the impact of COVID-19 on hospitalizations due to viral hepatitis in Spain., Methods: Retrospective study of all hospitalizations in Spain during 10 months before (pre-pandemic period) and after (pandemic period) March 1st 2020. Admissions with a diagnosis of hepatitis B, C and/or delta were retrieved and compared using the Spanish National Registry of Hospital Discharges., Results: Nationwide hospitalizations declined 14.6% during the pandemic period, from 3,144,164 to 2,684,845. This reduction was significantly more pronounced for admissions due to viral hepatitis (18.1% drop), falling from 46,521 to 38,115. During the pandemic period, patients admitted with viral hepatitis died significantly more frequently than during the pre-pandemic period (7.2% vs 6.1%; p < 0.001). Liver transplants significantly declined during the pandemic period. COVID-19 was diagnosed in 10.3% of patients hospitalized with viral hepatitis during the pandemic period. This subset of patients was older and died 2.4-fold more frequently than the rest, despite having advanced liver disease less frequently., Conclusion: Hospitalizations due to viral hepatitis significantly declined in Spain during the COVID-19 pandemic. Patients admitted with viral hepatitis experienced a greater mortality during the pandemic period. Deaths were more pronounced when coinfected with SARS-CoV-2 despite having advanced liver disease less frequently., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Mortality from candidemia is higher in elderly population than in younger patients, which may be related to suboptimal management. The aim of the present study is to evaluate adherence to the recommendations for the clinical management of candidemia in a population over 75 years before and after implementing specific training., Patients and Methods: We recorded retrospectively data from candidemia episodes in elderly patients during two periods of time: 2010-2015 years (before training) and 2017-2022 years (after training), as well as adherence to the recommendations of the clinical practice guidelines, mortality and consultation to infectious disease specialists., Results: Forty-five episodes of candidemia were recorded in the first period and 29 episodes in the second period. A better compliance to the recommendations of the clinical practice guidelines was observed in the second period: echocardiogram performance (75.9% vs. 48.9% p = .021), fundoscopy (65.5% vs. 44.4% p = .076), follow-up blood cultures (72.4% vs. 42.2% p = .011), removal of central venous catheter (80% vs. 52.9% p = .080) and adequate antifungal treatment (82.6% vs. 52.6% p = .018). A trend towards lower mortality was observed during the second period (27.6% vs. 44.4% p = .144)., Conclusion: The improvement of knowledge of clinical guidelines on candidemia and the participation of infectious disease specialists may increase the quality of care in elderly patients with candidemia. It would be necessary to enlarge the sample size to evaluate the real impact of this intervention on mortality., (© 2023 The Authors. Mycoses published by Wiley-VCH GmbH.)

Objectives: Underlying immunodeficiency has been associated with worse clinical presentation and increased mortality in patients with COVID-19. We evaluated the mortality of solid organ transplant (SOT) recipients (SOTR) hospitalized in Spain due to COVID-19., Methods: Nationwide, retrospective, observational analysis of all adults hospitalized because of COVID-19 in Spain during 2020. Stratification was made according to SOT status. The National Registry of Hospital Discharges was used, using the International Classification of Diseases, 10th revision coding list., Results: Of the 117,694 adults hospitalized during this period, 491 were SOTR: kidney 390 (79.4%), liver 59 (12%), lung 27 (5.5%), and heart 19 (3.9%). Overall, the mortality of SOTR was 13.8%. After adjustment for baseline characteristics, SOTR was not associated with higher mortality risk (odds ratio [OR] = 0.79, 95% confidence interval [CI] 0.60-1.03). However, lung transplantation was an independent factor related to mortality (OR = 3.26, 95% CI 1.33-7.43), while kidney, liver, and heart transplantation were not. Being a lung transplant recipient was the strongest prognostic factor in SOT patients (OR = 5.12, 95% CI 1.88-13.98)., Conclusion: This nationwide study supports that the COVID-19 mortality rate in SOTR in Spain during 2020 did not differ from the general population, except for lung transplant recipients, who presented worse outcomes. Efforts should be focused on the optimal management of lung transplant recipients with COVID-19., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Characterization of host genetic factors contributing to COVID-19 severity promises advances on drug discovery to fight the disease. Most genetic analyses to date have identified genome-wide significant associations involving loss-of-function variants for immune response pathways. Despite accumulating evidence supporting a role for T cells in COVID-19 severity, no definitive genetic markers have been found to support an involvement of T cell responses. We analyzed 205 whole exomes from both a well-characterized cohort of hospitalized severe COVID-19 patients and controls. Significantly enriched high impact alleles were found for 25 variants within the T cell receptor beta (TRB) locus on chromosome 7. Although most of these alleles were found in heterozygosis, at least three or more in TRBV6-5 , TRBV7-3 , TRBV7-6 , TRBV7-7 , and TRBV10-1 suggested a possible TRB loss of function via compound heterozygosis. This loss-of-function in TRB genes supports suboptimal or dysfunctional T cell responses as a major contributor to severe COVID-19 pathogenesis., Competing Interests: At the time of writing, M.C. is associated with Cambridge Precision Medicine Limited., (© 2023 The Authors.)

Hepatitis delta virus (HDV) is a defective agent that only infects individuals with hepatitis B virus (HBV). Around 5-10% of chronic hepatitis B patients worldwide are superinfected with HDV, which means 15-25 million people. Hepatitis delta is the most severe of all chronic viral hepatitis, leading to cirrhosis, liver cancer and/or transplantation in most patients. Despite it, many HDV patients remain undiagnosed. The only treatment available until recently was peginterferon alfa, with poor results and significant side effects. The recent approval of bulevirtide, a lipopeptide that blocks HBV/HDV entry, has revolutionized the field. Another drug, lonafarnib, already approved to treat progeria, is expected to be available soon as HDV therapy. Since there is no cell reservoir for the HDV RNA genome, hypothetically viral clearance could be achieved if complete blocking of viral replication occurs for a minimum time frame. This is what happens in hepatitis C using direct-acting antivirals, with the achievement of cure in nearly all treated patients. We envision the cure of hepatitis delta using combination antiviral therapy. Given that sexual and parenteral transmission routes are the most frequent for the acquisition of HBV and HDV, shared with HIV infection and HBV/HDV and HIV coinfection. The clinical outcome of hepatitis delta is worst in the HIV setting, with more frequent liver complications. Since most persons infected with HIV are on regular health care follow-up, we propose that HIV-HDV patients should be prioritized for moving forward new and potentially curative treatments for hepatitis delta., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To assess the prevalence and impact of cerebrovascular risk factors (CRF) on cerebrovascular events (CVE) in patients with giant cell arteritis (GCA)., Methods: Analysis of the patients diagnosed with GCA identified in the Spanish Hospital Discharge Database between 2016 and 2018., Results: 8,474 hospital admissions from patients diagnosed with GCA were identified. 3.4% of the admissions were motivated by CVE (stroke in 2.8% and transient ischemic attack in 0.6%). When compared with the admissions due to other causes, the patients who suffered from CVE presented a higher rate of male sex (36.2% vs 43.5%, p=0.007), hypertension (66.9% vs 74.4%, p=0.004), diabetes (27.6% vs 33.7%, p=0.016) and atherosclerosis (6.6% vs 10.2%, p=0.0.017). After adjustment, male sex (OR=1.35, 95% CI 1.06-1.72) and mainly hypertension (OR=1.44, 95% CI 1.11-1.90) were associated with a higher risk of CVE., Conclusion: Hypertension, along with male sex, was the strongest risk factor for cerebrovascular events in GCA patients. In these high-risk patients, antiplatelet therapy should be re-considered and evaluated in prospective studies., (Copyright © 2023 The Author(s). Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: SARS-CoV-2 infection and COVID-19 vaccines might have increased the incidence of giant-cell arteritis (GCA) and the risk of associated stroke in Spain., Methods: Retrospective nation-wide observational analysis of all adults hospitalized with GCA in Spain during 5 years (Jan-2016 and Dec-2021). The incidence and proportion of admissions with or because of GCA and GCA-associated stroke were compared between pre-pandemic (2016-2019) and pandemic (2020 and 2021) years. Sensitivity analyses were conducted for the different COVID-19 waves and vaccine timing schedules., Results: A total of 17,268 hospital admissions in patients diagnosed with GCA were identified. During 2020 there were 79.3 and 8.1 per 100,000 admissions of GCA and GCA-associated stroke, respectively. During 2021 these figures were 80.8 and 7.7 per 100,00 admissions, respectively. As comparison, yearly admissions due to GCA and GCA-associated stroke were 72.4 and 5.7 per 100,00, respectively, during the pre-pandemic period (p < 0.05). Coincident with the third wave of COVID-19 (and first vaccine dosing), the rate of GCA-associated stroke admissions increased significantly (from 6.7 to 12%; p < 0.001). Likewise, there was an increase in GCA-associated stroke (6.6% vs 4.1%, p = 0.016) coincident with the third dose vaccination (booster) in patients older than 70 at the end of 2021. In multivariate analysis, only patients admitted during the third COVID-19 wave (and first vaccine dosing) (OR = 1.89, 95% CI 1.22-2.93), and during the third vaccination dosing in patients older than 70 (booster) (OR = 1.66, CI 1.11-2.49), presented a higher GCA-associated stroke risk than the same months of previous years after adjustment by age, sex, classical cardiovascular risk factors and COVID-19 diagnosis., Conclusions: The COVID-19 pandemic led to an increased incidence of GCA during 2020 and 2021. Moreover, the risk of associated stroke significantly risen accompanying times of COVID-19 vaccine dosing, hypothetically linked to an increased thrombotic risk of mRNA-SARS-CoV-2 vaccines. Hence, forthcoming vaccine policies and indications must weigh the risk of severe COVID-19 with the risk of flare or stroke in patients with GCA., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Victor Moreno-Torres reports financial support was provided by Academia Médico-Quirúrgica Española. Guillermo Ruiz-Irastorza reports financial support was provided by Department of Education of the Basque Government., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: We aimed to analyse the efficacy and safety of oral sequential therapy (OST) in uncomplicated Staphylococcus aureus bacteraemia (SAB)., Methods: Single-centre observational cohort at a tertiary hospital in Spain, including all patients with the first SAB episode from January 2015 to December 2020. We excluded patients with complicated SAB and those who died during the first week. Patients were classified into the OST group (patients who received oral therapy after initial intravenous antibiotic therapy [IVT]), and IVT group (patients who received exclusively IVT). We performed a propensity-score matching to balance baseline differences. The primary composite endpoint was 90-day mortality or microbiological failure. Secondary endpoints included 90-day SAB relapse., Results: Out of 407 SAB first episodes, 230 (56.5%) were included. Of these, 112 (n = 48.7%) received OST and 118 (51.3%) IVT exclusively. Transition to oral therapy was performed after 7 days (interquartile range, 4-11). The primary endpoint occurred in 10.7% (11/112) in OST vs. 30.5% (36/118) in IVT (p < 0.001). SAB relapses occurred in 3.6% (4/112) vs. 1.7% (2/118) (p 0.436). None of the deaths in OST were related to SAB or its complications. After propensity-score matching, the primary endpoint was not more frequent in the OST group (relative risk, 0.42; 95% CI, 0.22-0.79). Ninety-day relapses occurred similarly in both groups (relative risk, 1.35; 95% CI, 0.75-2.39)., Discussion: After an initial intravenous antibiotic, patients with uncomplicated SAB can safely be switched to oral antibiotics without apparent adverse outcomes. This strategy could save costs and complications of prolonged hospital stays. Prospective randomized studies are needed., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objective: To compare the efficacy, toxicity and glucocorticoid (GC)-sparing effects of intravenous cyclophosphamide (iv CYC) with other immunosuppressive regimes as the induction treatment for Idiopathic Inflammatory Myopathy-Related Interstitial Lung Disease (IIM-ILD)., Methods: Observational comparative study of patients with IIM-ILD from the EPIMAR and Cruces cohorts. The main efficacy outcome was a 6 to 12-month improvement >10% in the forced vital capacity (FVC) from baseline., Results: Overall, 47 patients were included: 22 (47%) in the CYC group and 25 (53%) in the non-CYC group (32% azathioprine, 28% GC alone, 20% mycophenolate, 16% calcineurin-inhibitors and methotrexate and 4% rituximab). 81% patients were female with a mean age of 50.4 years. FVC improvement was achieved by 64% patients in the CYC group vs. 32% in the non-CYC group (p = 0.03). In the logistic regression model, CYC was identified as the only independent predictor of FVC improvement (OR=3.97, 95% CI 1.07-14.75). Patients in the CYC group received more methyl-prednisolone pulses (MP) (59% vs. 28% in the non-CYC group, p = 0.03), less initial GCs doses >30 mg/d (19% vs. 77%, p = 0.001) and lower 6-month average doses of prednisone (11 mg/d vs. 31.1 mg/d, p = 0.001)., Conclusion: iv CYC showed better functional outcomes than other immunosuppressants in IIM-ILD. The additional use of MP is likely to potentiate the effects of CYC and allows lowering prednisone doses. Therefore, CYC in combination with MP could be considered as the first line induction therapy in IIM-ILD, without limiting its use to rapidly progressive, life-threatening or refractory disease., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Viral infections activate the innate immune response and the secretion of inflammatory cytokines. They also alter oxidative stress markers, which potentially can have an involvement in the pathogenesis of the disease. The aim of this research was to study the role of the oxidative stress process assessed through lactate dehydrogenase (LDH) on the severity of COVID-19 measured by oxygen saturation (SaO 2 ) and the putative interaction with inflammation. The investigation enrolled 1808 patients (mean age of 68 and 60% male) with COVID-19 from the HM Hospitals database. To explore interactions, a regression model and mediation analyses were performed. The patients with lower SaO 2 presented lymphopenia and higher values of neutrophils-to-lymphocytes ratio and on the anisocytosis coefficient. The regression model showed an interaction between LDH and anisocytosis, suggesting that high levels of LDH (>544 U/L) and an anisocytosis coefficient higher than 10% can impact SaO 2 in COVID-19 patients. Moreover, analysis revealed that LDH mediated 41% ( p value = 0.001) of the effect of anisocytosis on SaO 2 in this cohort. This investigation revealed that the oxidative stress marker LDH and the interaction with anisocytosis have an important role in the severity of COVID-19 infection and should be considered for the management and treatment of the oxidative phenomena concerning this within a precision medicine strategy.

Coinfection with hepatitis viruses A to E is frequent in persons living with HIV (PLWH) and causes significant morbidity and mortality. Oro-fecal transmissible hepatitis A and E mostly produce acute self-limited episodes in poor income regions and in non-vaccinated travelers. In high-income countries, outbreaks of hepatitis A occur in men having sex with men (MSM) and chronic hepatitis E is occasionally reported among PLWH with severe immunodeficiency. Chronic hepatitis B, C, and D are frequent in PLWH in highly endemic regions and globally in persons who inject drugs (PWID) and MSM. Progression to liver cirrhosis and development of hepatocellular carcinoma (HCC) is major clinical complications in coinfected patients. Current estimates for PLWH are of 38 million worldwide. Roughly 12% have chronic viral hepatitis (5 million). Coinfection figures are of 5-10% for HBV (2-4 million), 4% for HCV (1.5 million), and 15% of HBsAg+ for HDV (0.5 million). Oral direct-acting antivirals (DAA) cure almost all treated patients with hepatitis C. However, given that there is no protective HCV immunity, PLWH with high-risk behaviors may experience HCV reinfection episodes. Tenofovir is the drug of choice in PLWH with chronic hepatitis B, given its dual effect on HIV and HBV. Lifelong oral tenofovir suppresses HBV replication and ameliorate liver damage. However, the risk of HCC persists even in the absence of cirrhosis. Finally, HDV causes the worst of viral hepatitis with faster progression to cirrhosis and HCC. An entry inhibitor, bulevirtide, has recently been approved and another drug, lonafarnib, is completing Phase 3 trials. Combination antiviral therapy for hepatitis D could improve dramatically the poor prognosis of HIV-HDV coinfected patients. The resumption of good medical practices in PLWH after the big disruption caused by COVID-19 will reduce the burden of viral hepatitis coinfections. Renewed efforts on HAV and HBV vaccination of susceptible individuals and earlier and wider prescription of antiviral therapy for HBV, HCV, and/or HDV coinfection should be prioritized in PLWH. The benefits of innovative strategies for viral hepatitis, including pre-exposure prophylaxis or use of long-acting antivirals, warrant further consideration in PLWH., (Copyright: © 2023 Permanyer.)

Introduction: Both HCV and HIV are highly prevalent infections with current estimates of 57 and 38 million people infected worldwide, respectively. Oral antivirals can be curative for HCV and rescue HIV patients from disease progression. Dual therapy in coinfected patients requires expertise., Areas Covered: Four major issues challenge dual HCV and HIV treatment, including overlapping drug-related side effects, hepatitis B reactivation, immune reconstitution inflammatory syndromes (IRIS), and drug-drug interactions (DDI). A search was conducted in PubMed from January 2010 to March 2023., Expert Opinion: The advent of second-generation direct-acting antivirals (DDA) that depict higher antiviral potency, fewer side effects, pangenotypic activity and are co-formulated has expanded the indication of HCV therapy and particularly in HIV-coinfected individuals. Sequential initiation of antiretrovirals (ARV) followed by DAA is generally preferred to start dual treatment concomitantly. Close monitoring of rare episodes of HBV reactivation and IRIS is warranted. The most frequent DDI between DAA and ARV affect drug metabolism by CYP450 induction/inhibition, leading to abnormal drug exposures. Throughout this mechanism interact most HCV and HIV protease inhibitors and non-nucleoside polymerase inhibitors. Exposure to some HIV and HCV nucleos(t)ide analogues (e.g. tenofovir and sofosbuvir, respectively) is subject to induction/inhibition of drug transporters and requires special attention in patients with renal insufficiency.

Around 10% of adults infected with SARS-CoV-2 that survive a first episode of COVID-19 appear to experience long-term clinical manifestations. The signs and symptoms of this post-acute COVID-19 syndrome (PACS) include fatigue, dyspnea, joint pain, myalgia, chest pain, cough, anosmia, dysgeusia, headache, depression, anxiety, memory loss, concentration difficulties, and insomnia. These sequelae remind the constellation of clinical manifestations previously recognized as myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS). This condition has been described following distinct infectious events, mostly acute viral illnesses. In this way, the pathophysiology of PACS might overlap with mechanisms involved in other post-infectious fatigue syndromes. The risk of PACS is more frequent in women than men. Additional host genetic factors could be involved. There is a dysregulation of multiple body organs and systems, involving the immune system, the coagulation cascade, endocrine organs, autonomic nervous system, microbiota-gut-brain axis, hypothalamic-pituitary-adrenal axis, hypothalamic-pituitary-thyroid axis, etc. Hypothetically, an abnormal response to certain infectious agents could trigger the development of postinfectious fatigue syndromes.