Increased incidence and mortality from Listeria monocytogenes infection in Spain.

BACKGROUND: Listeria monocytogenes (LM) is a health treat 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 8,152 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 of admissions with LM during 2019. The COVID-19 pandemic and lockdowns were associated with a fall 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-old (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 risen significantly from 2000 to 2021. The increase in the rate of admissions and deaths was largely driven by the growing proportion of elderly and of immunosuppressed patients.

Prospects for Controlling Hepatitis B Globally.

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.

Pre-exposure prophylaxis of non-HIV viral infections and the role of long-acting antivirals.

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.

Genetic signature detected in T cell receptors from patients with severe COVID-19.

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.

Impact of the COVID-19 pandemic on hospital admissions due to viral hepatitis in Spain.

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.

Safety considerations in the management of hepatitis C and HIV co-infection.

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.

Viral hepatitis in persons living with HIV in the post-COVID era.

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.

Improvement of Akanthomyces lecanii resistance to tebuconazole through UV-C radiation and selective pressure on microbial evolution and growth arenas.

Tebuconazole (TEB) is a fungicide widely used in agriculture; however, its constant application has increased the emergence of resistant plant pathogenic fungal strains and reduced the effectiveness of fungi as biological control agents; for instance, the entomopathogenic and hyperparasitic fungus Akanthomyces lecanii, suitable for simultaneous biological control of insect pest and plant pathogenic fungi, is highly sensitive to fungicides. We carried out the induction of resistance to TEB in two wild type strains of A. lecanii by UV radiation and selective pressure in increasing fungicide gradients using a modified Microbial Evolution and Growth Arena (MEGA), to produce A. lecanii strains that can be used as biological control agent in the presence of tebuconazole. Nine UV-induced and three naturally adapted A. lecanii strains were resistant to TEB at the agriculturally recommended dose, and three irradiated strains were resistant to TEB concentration ten times higher; moreover, growth, sporulation rates, production of hydrolytic enzymes, and virulence against the hemipteran Coccus viridis, a major pest of coffee crops, were not affected in the TEB-resistant strains. These A. lecanii TEB-resistant strains would have a greater opportunity to develop and to establish themselves in fields where the fungicide is present and can be used in a combined biological-chemical strategy to improve insect and plant pathogenic fungal control in agriculture. Also, the selective pressure through modified MEGA plate methodology can be used for the adaptation of entomopathogenic filamentous fungi to withstand other chemical or abiotic stresses that limits its effectiveness for pest control.

Susceptibility to hepatitis B virus infection in adults living in Spain.

BACKGROUND: A protective hepatitis B virus (HBV) vaccine has been available for four decades. Universal HBV vaccination of infants is recommended by the WHO since the 1990s. Furthermore, HBV immunization is advised for all adults with high-risk behaviours and no seroprotection. However, HBV vaccine coverage remains globally suboptimal. The advent of new more efficacious trivalent HBV vaccines has renewed the interest in HBV vaccination. At present, the extent of current HBV susceptibility in adults remains unknown in Spain. METHODS: HBV serological markers were assessed on a large and representative sample of adults in Spain, including blood donors and individuals belonging to high-risk groups. Serum HBsAg, anti-HBc and anti-HBs were tested in specimens collected during the last couple of years. RESULTS: From 13 859 consecutive adults tested at seven cities across the Spanish geography, overall 166 (1.2%) had positive HBsAg. Past HBV infection was recognized in 14% and prior vaccine immunization in 24%. Unexpectedly, 37% of blood donors and 63% of persons belonging to high-risk groups had no serum HBV markers and therefore were potentially HBV susceptible. CONCLUSION: Roughly 60% of adults living in Spain seem to be HBV susceptible. Waning immunity might be more common than expected. Hence, HBV serological testing should be performed at least once in all adults regardless of risk exposures. HBV vaccine full courses or boosters should be administered to all adults lacking serological evidence of HBV protection.

Bulevirtide in the Treatment of Hepatitis Delta: Drug Discovery, Clinical Development and Place in Therapy.

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.

Impact of potent nucleos(t)ide therapy on hepatitis B hospitalisations in Spain.

BACKGROUND: Chronic hepatitis B virus (HBV) infection is a major cause of decompensated cirrhosis and liver cancer worldwide. Newborn HBV vaccination was implemented in Spain two decades ago, and potent oral antivirals entecavir and tenofovir were introduced around 2007. AIM: To assess the clinical benefits of these interventions nationwide. METHODS: Including HBV as a diagnosis, we performed a retrospective study of all hospitalisations in Spain the Spanish National Registry of Hospital Discharges. Information was retrieved from 1997 to 2017. RESULTS: From 73,939,642 nationwide hospital admissions during the study period, 129,634 (0.17%) included HBV as diagnosis. Their number doubled from 2007 to 2017 and the median age increased from 44 to 58 years. Most HBV admissions recorded chronic hepatitis B. In-hospital death occurred in 6.4%. Co-infection with HIV or hepatitis C virus occurred in 11.9% and 23.3%, respectively. Patients with HIV-HBV co-infection had significantly greater mortality than individuals with HBV mono-infection. The rate of HBV hospitalisations significantly increased over time with a transient drop around 2007, coincident with the arrival of new potent oral antivirals. Although the proportion of HBV hepatic decompensation events has declined, the rate of liver cancer continues to rise. The small subset of patients with hepatitis delta superinfection increasingly and disproportionately accounts for hepatic decompensation events and liver cancer. CONCLUSION: Hospital admissions of individuals with HBV infection are increasing in Spain. While hepatic decompensation events declined following the introduction of potent oral nucleos(t)ide therapy, HBV-related liver cancer is rising. No benefit of oral antiviral therapies is seen on hepatitis delta.

Treatment of hepatitis delta and HIV infection.

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.

Is SARS-CoV-2 the only cause of long-COVID?

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.

Pre-Exposure Prophylaxis for viral infections other than HIV.

The battle against human viral infections has historically relied on two medical strategies, namely vaccines to protect from contagion and antivirals to treat infected patients. In the absence of vaccines, antivirals have occasionally been used as peri-exposure prophylaxis, given either before (pre-exposure prophylaxis) or right after (post-exposure prophylaxis). In an unprecedented way, the use of antiretrovirals as chemoprophylaxis has triumphed in the HIV field. Indeed, oral antiretrovirals given either daily or at demand to HIV-uninfected individuals engaged in high-risk behaviors protect from contagion. More recently, the advent of long-acting formulations has allowed HIV protection following intramuscular injections every three months. Can we envision a similar prophylactic strategy for other human viral infections? The advent of such 'chemical vaccines' would fill an unmet need when classical vaccines do not exist, cannot be recommended, immune responses are suboptimal, escape mutants emerge or immunity wanes. In this review, we discuss the opportunities for antiviral chemoprophylaxis for viral hepatitis B and C, retroviruses HTLV-1 and HIV-2, and respiratory viruses influenza and SARS-CoV-2, among others.

Late presentation of human T-lymphotropic virus type 1 infection in Spain reflects suboptimal testing strategies.

OBJECTIVES: Although only 10% of persons infected with human T-lymphotropic virus type 1 (HTLV-1) may develop virus-associated illnesses over their lifetime, missing the earlier diagnosis of asymptomatic carriers frequently leads to late presentation. METHODS: A nationwide HTLV-1 register was created in Spain in 1989. We examined the main demographics and clinical features at the time of the first diagnosis for more than three decades. RESULTS: A total of 428 individuals infected with HTLV-1 had been reported in Spain until the end of 2021. Up to 96 (22%) individuals presented clinically with HTLV-1-associated conditions, including subacute myelopathy (57%), T-cell lymphoma (34%), or Strongyloides stercoralis infestation (8%). Since 2008, HTLV-1 diagnosis has been made at blood banks (44%) or clinics (56%). Native Spaniards and Sub-Saharan Africans are overrepresented among patients presenting with HTLV-1-associated illnesses suggesting that poor epidemiological and/or clinical suspicion, which led to the late presentation are more frequent in them than carriers from Latin America (LATAM) (31.7% vs 20.4%, respectively; P = 0.015). CONCLUSION: HTLV-1 infection in Spain is frequently diagnosed in patients presenting with characteristic illnesses. Although screening in blood banks mostly identifies asymptomatic carriers from LATAM, a disproportionately high number of Spaniards and Africans are diagnosed too late at the time of clinical manifestations. Expanding testing to all pregnant women and clinics for sexually transmitted infections could help to unveil HTLV-1 asymptomatic carriers.

Hepatitis C hospitalizations in Spain and impact of new curative antiviral therapies.

Chronic hepatitis C virus (HCV) infection is major cause of decompensated cirrhosis and liver cancer. The advent of curative new antiviral therapies since year 2015 has dramatically improved the prognosis of HCV patients. The real-life clinical benefits at country level of these therapies have not yet been assessed. This is a retrospective study of all hospitalizations in Spain including HCV as diagnosis using the Spanish National Registry of Hospital Discharges. Information was retrieved from 1997 to 2019. From 81,482,509 nationwide hospital admissions recorded during the study period, 1,057,582 (1.29%) included HCV as diagnosis. The median age of HCV hospitalized patients was 54 years old. Males accounted for 63.2% of cases. Most HCV admissions recorded chronic hepatitis C whereas acute hepatitis C was reported in less than 3%. In-hospital death occurred in 6.4% of HCV admissions. Coinfection with HIV or hepatitis B virus was seen in 14.8% and 6.4%, respectively. Patients hospitalized with HIV-HCV coinfection represented 14.8% of cases and were on average 17 years younger than HCV-monoinfected individuals. The rate of HCV hospitalizations significantly increased until 2005, and then stabilized for one decade. A significant reduction was noticed since 2015. However, whereas the proportion of HCV-associated hepatic decompensation events declined since then, liver cancer diagnoses increased. In conclusion, hospital admissions of HCV individuals significantly declined in Spain since 2015 following a wide prescription of new oral direct-acting antivirals. This reduction was primarily driven by a fall of hepatic decompensation events whereas HCV-related liver cancer continues rising.

Ultra-long-acting antivirals as chemical vaccines to prevent viral diseases.

For two centuries, vaccines have been successful in the fight against viruses, triggering immune protection. Indeed, the elimination of smallpox, the only infectious disease eradicated to date, was made possible through vaccination. For measles, polio and hepatitis B, vaccines are available but significant challenges exist for universal coverage. For other viruses, such as HIV and hepatitis C, vaccines have remained elusive. Recent advances in medicinal chemistry have resulted in the production of antivirals that can extend activity for months. We envision the use of ultra-long-acting antivirals for the prevention of certain viral illnesses, halting either contagions or reactivations under immunosuppression. Such 'chemical vaccines' would fill an immediate need in providing protection when classic vaccines do not exist, responses are suboptimal, escape mutants emerge or immunity wanes.

Liver cancer and hepatic decompensation events in patients hospitalized with viral hepatitis in Spain.

BACKGROUND: Chronic viral hepatitis B, C, and D are the main causes of decompensated cirrhosis and liver cancer worldwide. Newborn HBV vaccination was implemented more than 2 decades ago in most EU countries. Furthermore, potent oral antivirals have been available to treat HBV for 15 years and to cure HCV since 2014. The real-life clinical benefits of these interventions at country level have not been assessed, especially regarding major hepatic outcomes such as cirrhotic decompensation events and hepatocellular carcinoma (HCC). METHODS: Retrospective study of all hospitalizations in Spain having HBV, HCV, and HDV as diagnosis using the Spanish National Registry of Hospital Discharges. Information was retrieved from 1997 up to 2017. RESULTS: From a total of 73,939,642 hospital admissions during the study period, a diagnosis of HBV, HCV, and HDV was made in 124,915 (1.7‰), 981,985 (13.3‰), and 4850 (0.07‰) patients, respectively. The median age of patients hospitalized within each group was 53.2, 55.9, and 47.0 years, respectively. Significant increases in mean age at hospitalization occurred in all groups (0.6 years older per calendar year on average). The overall rate of hepatic decompensation events for HBV, HCV, and HDV was 12.1%, 14.1%, and 18.8%, respectively. For HCC hospitalizations, these figures were 6.7%, 8.0%, and 7.8%, respectively. Whereas, the rate of decompensation events declined in recent years for HBV, and more recently for HCV, it continued rising up for HDV. Likewise, liver cancer rates recently plateaued for HBV and HCV, but kept growing for HDV. CONCLUSION: The rate of hepatic decompensation events and liver cancer has declined and/or plateaued in recent years for patients hospitalized with HBV and HCV infections, following the widespread use of oral antiviral therapies for these viruses. In contrast, the rate of decompensated cirrhotic events and HCC has kept rising up for patients with hepatitis delta, for which effective antiviral treatment does not exist yet.

The unexpected high prevalence of HBV subgenotype D4 in patients with chronic hepatitis B in Galicia, a northwestern Spanish region, reflects strong links with Latin America.

BACKGROUND: Hepatitis B virus (HBV) comprises 9 genotypes and multiple subgenotypes that depict differences in geographic distribution, clinical outcome and response to antiviral therapy. However, the molecular epidemiology of HBV geno/subgenotypes is globally scarce. In Spain, HBV genotype D seems to be more prevalent in the northwestern regions compared to the rest of the country for unclear reasons. METHODS: HBV genotyping was performed using geno2pheno on a S gene fragment amplified from plasma collected from all chronic hepatitis B individuals attended at one reference hospital in Santiago de Compostela, the Galicia's capital town. Phylogenetic and phylogeographic analyses using a fragment of 345 bp were performed in all viremic specimens. To avoid misleading allocation as consequence of short fragment analysis, several bioinformatic controls were used. RESULTS: A total of 320 individuals with persistent serum HBsAg+ and detectable HBV-DNA were seen between 2000 and 2016 (male 68.4%; median age, 52 years-old; native Spaniards 83.8%). HBV genotype distribution was as follows: A 15.3%; B 1.6%; C 2.5%; D 71.6%; E 3.1%; F 2.2%; G 3.1%; and H 0.6%. HBV genotype D was mostly represented by D4 and D2 subgenotypes (33.4% and 15% of total, respectively). Compared to chronic hepatitis B patients with genotypes B, C, E and G, HBV-D4 carriers tended to be older (54.2% had >50 years-old) and HBeAg-negative (85%). Moreover, 43% were female, 4.7% had cirrhosis, 10.2% hepatitis C and 6.4% HIV coinfection. Phylogenetic analyses could be performed on 82 HBV-D4 specimens; and 79 were confirmed as HBV-D4 using PhyML. Phylogeography using FasTree suggested at least two distinct introductions of HBV-D4 in Galicia, one from the Caribbean and South America, and another from India. CONCLUSIONS: HBV subgenotype D4 is the most prevalent HBV variant in chronic hepatitis B patients living in the northwest of Spain, representing 33.4% (107/320) of all chronic hepatitis B infections. This rate of HBV-D4 is among the highest reported worldwide. Epidemiological and phylogenetic analyses suggest a strong association with historical migrant exchanges with Latin America, and especially with the Caribbean basin.