Biological therapies targeting the tumor necrosis factor-alpha (TNF-α) have emerged as a new class of drugs that are increasingly used for a rapidly expanding number of autoimmune rheumatic, digestive, and dermatologic diseases and have acceptable safety and tolerability profiles. However, a growing number of adverse events have been reported, ranging from asymptomatic analytical alterations to life-threatening situations. Because TNF-α plays an important role in host defense,30 patients treated with anti-TNF agents have a higher susceptibility to infections,3,22 especially to mycobacterial infections, although screening and preventive treatments have lowered the incidence of active tuberculosis in patients treated with these agents.
In patients with chronic viral infections, immunosuppression has been associated with viral reactivation. In patients with hepatitis B virus (HBV) infection, viral reactivation has been reported mainly in patients with chronic infection after treatment with chemotherapy and immunosuppressive agents administered for cancer, bone marrow/solid organ transplantations, and autoimmune diseases.27 The emergence of TNF-α-targeted therapies as a key therapeutic option for patients with rheumatic, digestive, and dermatologic autoimmune diseases has been associated with increasing reports of liver damage in HBV+ patients.16 This resulted in some concern about the use of these potent immunosuppressive drugs in patients with HBV infection, and some guidelines have even contraindicated their use in patients with chronic HBV infection.21 However, recent studies have suggested that anti-TNF agents are a safe option for patients with chronic HBV infection receiving antiviral prophylaxis.62
We conducted the current study to analyze and summarize the current evidence on the use of anti-TNF agents in patients with HBV infection through a systematic analysis of cases reported to date, and including 2 unreported cases.
Case 1 (Patient 34, Tables 1 and 2)
A 40-year-old woman was followed for Behçet disease diagnosed 15 years earlier whose manifestations included oral ulcers, folliculitis, arthritis, bilateral uveitis, and intestinal involvement (aphthous colitis). The patient was also diagnosed with chronic HBV infection (HBsAg positive, HBV-DNA negative). Colitis was refractory to oral prednisone, intravenous methylprednisolone, colchicine, sulfasalazine, thalidomide, and interferon alpha2b. In October 2005, infliximab (3 mg/kg at weeks 0, 2, 6 and every 8 weeks) was started in association with mesalazine and deflazacort 60 mg/d; due to a poor response, the dose of infliximab was increased to 5 mg/kg. In January 2006, infliximab was changed to etanercept (25 mg twice a week) in association with methotrexate (7.5 mg weekly) with a limited response. In June 2006, raised transaminase levels were detected (aspartate aminotransferase [AST] 98 IU/L, alanine aminotransferase [ALT] 150 IU/L), and methotrexate was stopped, with progressive normalization of transaminase levels. Because of a lack of response to etanercept, the patient was changed back to infliximab (5 mg/kg) in association with azathioprine (100 mg/d) with complete resolution of intestinal involvement. In March 2008, the patient was asymptomatic but transaminase levels were once again raised (AST 216 IU/L, ALT 225 IU/L); azathioprine was stopped and virologic tests showed HBsAg+, anti-HBs−, anti-HBc+ IgM, anti-HBe+, HBeAg−, and HBV-DNA serum load >109 IU/mL. HBV reactivation was diagnosed and treatment with entecavir was started, resulting in normalization of transaminase levels after 8 weeks of therapy and negativization of HBV-DNA viral load after 5 months.
Case 2 (Patient 35, Tables 1 and 2)
A 58-year-old woman was diagnosed with ulcerative colitis in 1984. The patient had several flares of pancolitis that were treated with high doses of oral prednisone and 5-aminosalicylic acid (5-ASA). A severe flare in September 2008 led to the initiation of infliximab (5 mg/kg at weeks 0, 2, 6 and every 8 weeks) in association with prednisone 60 mg/d, with a progressive clinical response. In June 2009, prednisone was stopped and azathioprine 100 mg/d was added. In September 2009, the patient presented with weakness and dyspepsia, and raised transaminase levels were detected (AST 1015 IU/L, ALT 994 IU/L). Azathioprine was stopped and serologies for viral hepatitis were tested, showing HBsAg+, anti-HBs−, anti-HBc+, anti-HBe+, HBeAg−, and HBV-DNA serum load of 463 IU/mL. A probable HBV reactivation in a patient with a previously undiagnosed chronic HBV infection was diagnosed (we have no previous determination of HBV-DNA viral load), and treatment with entecavir was started, resulting in normalization of transaminase levels after 8 weeks of therapy and negativization of HBV-DNA viral load after 3 months.
We searched the MEDLINE (National Library of Medicine, Bethesda, MD) and EMBASE (Elsevier, Amsterdam, the Netherlands) databases using the MeSH term "hepatitis B virus" combined with the terms "infliximab," "etanercept," "adalimumab," "certolizumab," "golimumab," and "anti-TNF agents." Studies were eligible when 1) the study population included adults with autoimmune diseases (rheumatoid arthritis [RA], spondyloarthropathies, psoriasis, inflammatory bowel disease [IBD], and systemic autoimmune diseases); 2) the intervention consisted of therapy with a specific anti-TNF agent; 3) patients had confirmed chronic HBV infection or positive markers for HBV infection; 4) the study contained clear and sufficient information on the effect of the drug on viral reactivation. Reviews, experimental studies, duplicate publications, and abstracts were excluded.
Two authors (RPA and MRC) read the titles and abstracts (if available) identified by the search and selected studies that might comply with the eligibility criteria. Three authors (RPA, CDL, and PBZ) fully reviewed the selected studies to determine fulfillment of eligibility criteria, and disagreements were discussed with the other authors until consensus was reached. Study authors were contacted by MRC when necessary. We also searched the reference lists of relevant articles retrieved.
Some of the authors (RPA, CDL, FGH, LLR, PBZ, MRC) designed an Excel-based (Microsoft Corp., Redmond, WA) data extraction form, and the other authors amended and validated its design before data abstraction. Six authors (MPL, SR, AB, XB, XF, JMST) extracted the data independently. Two authors (CDL, PBZ) entered the data into the Excel file, and the remaining authors checked it.
The following variables were entered into the data extraction form: first author; year of publication; number of patients; study design; mean age; sex; disease for which the anti-TNF therapy was administered; previous immunosuppressive agents; liver parameters (transaminase levels, clinical manifestations of liver disease) and virologic tests (HBV markers, HBV-DNA levels) at baseline and at the end of follow-up; anti-TNF agent; antiviral prophylaxis; length of follow-up; other treatments; and outcomes.
HBV Infection Definitions
Resolved HBV infection was defined as negative HBV surface antigen (HBsAg) and antibodies against the HBV core antigen in serum (anti-HBc+ persons). Chronic HBV infection was defined as the persistent positive determination of HBsAg in serum (HBsAg+ carriers). The reappearance of serum HBV-DNA in a patient with previously inactive or resolved HBV infection was considered to be HBV reactivation,27 and was defined either as an increase of >1 log10 of viral load or >400 IU/mL (2000 copies/mL) with respect to the baseline HBV-DNA load before anti-TNF therapy, or as the appearance of serum HBV-DNA above standard cutoff values (>60 IU/L, equivalent to >300 copies/mL).18,35,67 Patients with clinical signs of liver disease and/or raised liver enzymes in the absence of positive serum HBV-DNA were not classified as having HBV reactivation.
We used the conventional chi-square and Fisher exact tests to analyze qualitative differences, the Student t test for comparison of means in large samples of similar variance, and the nonparametric Mann-Whitney U test for small samples. Values of quantitative variables are expressed as mean ± standard error of the mean. A bilateral value of p < 0.05 was taken to indicate statistical significance. The statistical analysis was performed using the SPSS statistical package (Chicago, IL).
The search strategy yielded 3 prospective cohort studies, 9 retrospective studies, and 26 case reports,1,2,5-8,11-14,17,20,23,29,32-36,39-42,44-50,56,58,60-64,69 including 255 patients with positive HBV markers who received anti-TNF therapy (Figure 1). Together with the 2 new reported cases, the study included 257 cases, including 89 patients with chronic HBV infection (HBsAg+ carriers) and 168 with resolved HBV infection (anti-HBc+ persons). We summarize the main characteristics of the 44 (17%) patients classified as having HBV reactivation in Tables 1 and 2.
Patients With Chronic HBV Infection (HBsAg+ Carriers)
Of the 89 patients with chronic HBV infection, individual characteristics were detailed in 82 (Table 3). Anti-TNF agents used were infliximab in 41 cases, etanercept in 27, and adalimumab in 14 cases. They were administered for RA in 24 patients, spondyloarthropathies in 19, IBD in 18, psoriasis in 8, Behçet disease in 1, and adult-onset Still disease in 1 patient. Demographic data were available in 69 cases: there were 32 (46%) women and 37 (54%) men, with a mean age of 45.71 ± 1.81 years (range, 22-77 yr) and mean disease duration of 10.82 ± 1.37 years (range, 1-36 yr). Time of diagnosis of HBV infection with respect to anti-TNF therapy was detailed in 53 patients: in 35, HBV infection was diagnosed before therapy, in 16 it was detected in the screening, and in 2 patients, infection was diagnosed after initiation of anti-TNF therapy. Previous therapies were detailed in 47 cases and included methotrexate in 23 (49%) patients, corticosteroids in 20 (43%), sulfasalazine in 17 (38%), azathioprine in 11 (23%), cyclosporine A in 4 (9%), leflunomide in 3 (6%), and other biological therapies in 3 (6%) patients. Before the patient started anti-TNF agents, liver enzymes were abnormal in 15/64 (23%) patients, while serum HBV-DNA was positive in 12/60 (20%). Antiviral prophylaxis was administered in 39 cases (lamivudine in 35, entecavir in 3, and telbivudine in 1 case).
The mean follow-up was 14 months, ranging from 1 to 77 months after initiation of anti-TNF therapy (Table 4). Twenty-five of 60 (42%) patients had raised transaminase levels; levels were specified in 19 cases: 9 (47%) patients had levels between 40 and 200 IU/L, 3 (16%) had levels between 200 and 1000 IU/L, and 6 (37%) patients had levels >1000 IU/L. We compared the main baseline characteristics between patients with and without raised transaminase levels (Table 5). Raised transaminase levels were more frequent in patients with IBD (41% vs. 8%, p = 0.013), patients with previous immunosuppressive therapy (100% vs. 65%, p = 0.006), and patients treated with infliximab (78% vs. 27%, p = 0.001); patients with raised transaminase levels had less frequently received antiviral prophylaxis (18% vs. 54%, p = 0.017). Clinical symptoms and signs of liver disease were reported in 13 (16%) patients after initiation of anti-TNF therapy (see Table 4), including weakness in 8 cases, jaundice/choluria in 4, abdominal pain in 2, liver decompensation in 2 (ascites in 1, encephalopathy in 1), and liver failure in 2 (specific symptoms were not detailed).
We compared the main baseline characteristics between asymptomatic patients and those who developed clinical symptoms and signs of liver disease (Table 6). Symptoms developed more frequently in patients with IBD (61% vs. 18%, p = 0.004) and in those treated with infliximab (92% vs. 41%, p = 0.003); patients with a previously known HBV infection developed symptoms less frequently (44% vs. 87%, p = 0.018); the difference approached significance in those who received antiviral prophylaxis (15% vs. 49%, p = 0.055).
HBV reactivation was reported in 35 cases after initiation of anti-TNF therapy (see Table 2). The clinical presentation of HBV reactivation showed the following patterns: 1) 6/26 (23%) patients had raised serum HBV-DNA with no clinical or analytical evidence of liver disease; 2) 8/26 (31%) had raised serum HBV-DNA and slightly raised transaminase levels (ranging between 40 and 200 IU/L); and 3) 12/26 (46%) patients had raised serum HBV-DNA with clinical and biochemical evidence of liver disease (5 had liver failure). Treatment of HBV reactivation included withdrawal of anti-TNF agents in 18/35 (51%) cases and the introduction of antiviral agents in 16/35 (46%) (lamivudine in 11, entecavir in 3, adefovir in 1, and lamivudine + tenofovir in 1 case). We compared the main baseline characteristics of patients with and without HBV reactivation in which individual characteristics were detailed (Table 7). The frequency of HBV reactivation was higher in patients previously treated with immunosuppressive agents (96% vs. 70%, p = 0.033) and lower in those who had received antiviral prophylaxis (23% vs. 62%, p = 0.003). Demographic features, underlying disease, and the anti-TNF agent used were not associated with HBV reactivation. There were 2 cases of negativization of serum HBV-DNA after anti-TNF therapy,1,34 both of which were accompanied by transient, asymptomatic raised transaminase levels.
Acute liver failure was reported in 5 patients (Patients 5, 7, 11, 13, 15) after a mean follow-up of 11 months (range, 1-77 mo), of whom 4 died. We compared the main baseline characteristics of patients with and without acute liver failure (Table 8), which was more frequent in patients with raised baseline transaminase levels (75% vs. 13%, p = 0.016). The difference approached significance in those treated with infliximab (100% vs. 47%, p = 0.053). Histopathologic liver studies were carried out in only 3 cases,33,40,63 and showed liver atrophy with advanced fibrosis.
In 11 cases, anti-TNF therapy was reinitiated to control the active underlying disease once the HBV reactivation was treated and resolved (Patients 1, 10, 12, 17, 20, 21, 22, 31, 32, 33, 34). In 3 cases, the same biological agent was used together with antiviral prophylaxis, and there was no HBV reactivation. In the remaining 8 cases, the anti-TNF agent was switched to etanercept (4 cases) and adalimumab (4 cases). Only 1 patient64 had HBV reactivation with adalimumab. In 5 cases, a second course of antiviral prophylaxis was started with a different antiviral agent (entecavir in 2 cases, adefovir in 2, and tenofovir in 1 case) because of liver biopsy results,62 incomplete negativization of HBV-DNA,13 a second episode of HBV reactivation,64 and the development of a codon 204 mutation.7,62
Patients With Resolved HBV Infection (Anti-HBc+ Persons)
A total of 168 patients with resolved HBV infection treated with anti-TNF agents are reported.6,8,17,35,36,39,42,47,61,62 HBV was reactivated in 9 (5%) patients (Patients 36-44), whose main characteristics are summarized in Tables 1 and 2. Six patients had RA, 2 IBD, and 1 spondyloarthropathy, and all had negative HBsAg with positive anti-HBc and/or anti-HBs antibodies at screening. Three patients received infliximab and 6 etanercept without antiviral prophylaxis. HBV reactivation occurred after a mean follow-up of 11 months (range, 1-36 mo). Three cases had a high viral load (>100,000 IU/mL). Two patients presented clinical symptoms of liver disease, 1 of whom died due to fulminant liver failure (Patient 37). Antiviral treatment was administered in 8 cases (lamivudine in 3, entecavir in 5), and in 1 case was administered together with plasma exchange and HBV immunoglobulins (Patient 37). In 1 patient (Patient 36), an HBeAg-defective genotype D (e-minus chronic infection) was detected, while in another patient (Patient 39), negativization of anti-HBs+ coincided with the peak of HBV-DNA serum, suggesting an occult HBV infection. In 1 patient (Patient 38), etanercept was reintroduced after 4 months of lamivudine with no further reactivation.
The hepatitis B virus (HBV) is a DNA virus of the Hepadnaviridae family transmitted percutaneously, sexually, and perinatally, that affects nearly 400 million people worldwide.9 The key component proteins of the virus that are used as antigens in commercially available tests are an envelope protein (the surface antigen, HBsAg) and 2 structural nucleocapsid proteins (the core antigen, HBcAg, and the soluble e antigen, HBeAg). After acute infection, most patients eliminate the virus (resolved HBV infection), demonstrated by negativization of HBsAg and positive anti-HBc in serum, although nearly 10% of patients develop chronic HBV infection, defined as persistent HBsAg positivity. HBsAg-negative subjects may infrequently have positive HBV-DNA in the serum or liver (occult HBV infection).4,67,68 Some patients with chronic HBV infection may have a reactivation (abrupt reappearance of serum HBV-DNA), spontaneously19 or after intense immunosuppression,27 mainly chemotherapy or immunosuppressive drugs. However, the rate of HBV reactivation varies widely according to the length and degree of immunosuppression. In patients receiving chemotherapy, HBV reactivation ranges between 38% and 53% of patients, with a mortality rate of up to 40%,43 while in patients with rheumatic autoimmune diseases receiving nonbiologic immunosuppressive agents (corticosteroids, azathioprine, methotrexate), reactivation is reported in only isolated cases.27
Experimental studies suggest that pharmacologic blockade of TNF-α facilitates HBV replication by allowing the virus to escape the antiviral immune defense mechanisms of the host. As hypothesized for mycobacterial infection, TNF-α has been postulated as one of the key cytokines involved in controlling HBV infection, and raised levels of TNF-α53,59 and TNF-α receptor p7537,55,65 have been found in the serum and liver of patients with HBV infection. Some studies suggest a pivotal role of TNF-α in suppressing HBV replication through a synergistic effect with interferon,24,51 since TNF-α stimulates HBV-specific cytotoxic T cells26,28 that inhibit HBV gene expression by secreting interferon-γ, which induces the apoptosis of HBV-infected hepatocytes.25 The emergence of TNF-α-targeted therapies as a key therapeutic option in patients with rheumatic and autoimmune diseases has been associated with increasing reports of HBV reactivation. In 2003, Michel et al40 reported acute liver failure requiring urgent transplantation in an HBsAg+ carrier treated with infliximab for adult-onset Still disease. Although HBV reactivation was not confirmed (IgM anti-HBc antibodies were negative and serum HBV-DNA undetectable), this case was the first, to our knowledge, to reveal the possible risk of using anti-TNF agents in HBV patients, and led to an as yet unfinished debate on their use. In the current study we have identified 42 cases of HBV reactivation in patients treated with anti-TNF agents included in uncontrolled studies (overwhelmingly retrospective) and case reports over the last 7 years. The overall analysis of these cases highlights several interesting points.
Our results show that the risk of HBV reactivation clearly differs according to the serologic status before initiating anti-TNF therapy. Of the 255 reported HBV+ patients treated with anti-TNF agents, HBV reactivation occurred in 33 of the 87 HBsAg+ patients compared with only 9 of the 168 anti-HBc+ persons (37% vs. 5%, p < 0.001). Even assuming a certain degree of publication bias, these figures suggest that reactivation is infrequent in anti-HBc+ persons. This supports the results of a 2010 study62 suggesting that it is safe to use anti-TNF agents in anti-HBc+ persons without antiviral prophylaxis. However, that study62 also found that TNF blockade significantly reduces titers of anti-HBs antibodies, which might facilitate viral reactivation in some patients. Thus, close monitoring of liver enzymes and HBV-DNA levels in patients with resolved HBV infection receiving anti-TNF treatment is advisable, as some could have occult HBV infection due to HBsAg escape mutants unrecognized by commercially available assays or very low levels of viremia with undetectable HBsAg.31
The risk of HBV reactivation may also be influenced by the type of anti-TNF agent used. In the current analysis, we found that infliximab was associated with higher rates of induced liver disease (raised transaminase levels, clinical signs, viral reactivation, and acute liver failure) compared with etanercept. A 2010 study54 in 6861 patients with RA reported a 2.4-fold higher risk of raised transaminase levels (>2-fold the upper limit of normal) in patients treated with infliximab, after adjustment for other variables such as concomitant immunosuppressive drugs. Why the risk of liver damage is higher in patients treated with monoclonal antibodies than in patients treated with soluble receptor agents is not known, but the authors of that study54 suggest that different half-lives or the potential immunogenicity of each agent may play a part, since monoclonal antibodies facilitate the formation of immune complexes more than soluble receptors, possibly resulting in differential effects on hepatocyte activation.57
The utility of antiviral prophylaxis in preventing HBV reactivation is supported by controlled trials and meta-analyses in HBsAg+ patients,27,67 but not in patients treated with anti-TNF agents. The lack of standardized recommendations means that fewer than half the reported HBsAg+ cases treated with anti-TNF agents received prophylaxis. However, recommendations4,43,52 to use antiviral prophylaxis before starting anti-TNF therapy have now been followed in studies such as that by Vassilopoulos et al,62 in which all HBsAg+ patients received prophylaxis. Of the reported cases of HBsAg+ patients treated with anti-TNF agents, HBV reactivation was 2.5-fold higher in patients not receiving prophylaxis (64% vs. 26%). While we await the results of controlled studies, the current findings seem sufficient to support the use of antiviral prophylaxis in HBsAg+ patients who are candidates for anti-TNF therapy. However, the choice of antiviral agent is a matter of debate. Lamivudine has been used in 90% of reported cases of HBsAg+ patients treated with anti-TNF agents. Current international guidelines on the management of HBV infection suggest that lamivudine alone would be sufficient for patients receiving immunosuppressive therapy for less than 6 months.18 However, the risk-benefit ratio of lamivudine is less clear in patients requiring long-term immunosuppressive therapy, as usually occurs with anti-TNF therapy. Longer courses of lamivudine prophylaxis have been associated with the emergence of lamivudine-resistant HBV strains,10 and the risk of developing the mutation on codon 204 has been estimated at 40% after 2 years of lamivudine treatment and 50% after 3 years.15 Two cases7,62 of mutations on codon 204 in patients receiving long-term anti-TNF therapy cast doubt on the desirability of lamivudine as the first-choice antiviral agent in these patients, and suggest that antivirals with a lower rate of mutation, such as entecavir, tenofovir, or adefovir, may be an option, especially when HBV-DNA levels are high.18 Entecavir, due to its efficacy and rapid action, may be the preferred treatment,10 after taking into account its costs and availability in certain countries.66
Based on current reported evidence and until the results of controlled studies become available, some tentative recommendations can be made. In all patients who are candidates for anti-TNF therapy, standard serologic HBV markers (HBsAg, anti-HBc) should be investigated, together with anti-HBs (a 2010 study38 in patients with lymphoma reported a higher risk of reactivation in anti-HBs− patients compared with anti-HBs+ patients) and viral load in patients with positive HBsAg. In patients known to have positive HBV markers, management should depend on the serologic status and disease activity,18,20,43,62,63 as follows:
- - In HBsAg+ carriers with active liver disease (clinical symptoms, raised liver enzymes, and/or high viral load), HBV infection should be treated and controlled before starting TNF-targeted therapies.
- - In asymptomatic HBsAg+ carriers, antiviral prophylaxis is recommended and should be started 2-4 weeks prior to anti-TNF therapy and continued for at least 6 months after cessation. The choice of antiviral drug depends on the foreseen duration of anti-TNF treatment; antivirals with a low risk of resistance are recommended in therapies lasting more than 1 year. Patients receiving lamivudine for more than 1 year should be closely monitored for the development of viral resistance (liver and viral tests), since most patients with the mutation on codon 204 are asymptomatic or develop mild hepatitis.
- - In anti-HBc+ persons, routine prophylaxis is not recommended, although individual factors such as the degree of immunosuppression, the length of therapy, and the degree of local HBV endemicity should be taken into account. In any case, these patients should always be carefully monitored (liver and viral tests every 1-3 months) while anti-TNF therapy lasts, especially monoclonal therapy.
Our search of the current evidence yielded a total of 42 cases of HBV reactivation reported in 257 patients treated with anti-TNF agents (a rate of reactivation of 16%), of which 80% occurred in HBsAg+ carriers. The use of anti-TNF agents in HBsAg+ patients was associated with a substantial rate of liver involvement, including raised transaminase levels, signs and symptoms of liver disease, the reappearance of serum HBV-DNA, and a not-inconsiderable mortality rate of 5%. Today, the therapeutic role of TNF blockade in rheumatic diseases is well established, and the identification of an increased risk of some infections in these patients, especially tuberculosis, has resulted in specific preventive strategies that have significantly reduced these complications. The increasing number of reported cases of HBV reactivation following TNF-targeted therapies and the associated morbidity and mortality demand a similar effort. Until the results of controlled studies are available, therapeutic decisions should be based not only on reported evidence, but also on the common sense garnered through clinical experience.
The authors thank David Buss, BA (independent medical writer) for editorial assistance.
THE BIOGEAS STUDY GROUP
The members of the Spanish Study Group of Biological Agents in Autoimmune Diseases (BIOGEAS) of the Spanish Society of Internal Medicine (SEMI) are as follows:
M. Ramos-Casals (Coordinator, Hospital Clínic, Barcelona), M. M. Ayala (Hospital Carlos Haya, Málaga), M. J. Barragán-González (Hospital Valle del Nalón, Asturias), X. Bosch (Hospital Clínic, Barcelona), A. Bové (Hospital Clínic, Barcelona), P. Brito-Zerón (Hospital Clínic, Barcelona), G. Calvo (Hospital Clínic, Barcelona), J. L. Callejas (Hospital San Cecilio, Granada), L. Caminal-Montero (Hospital Central Asturias, Asturias), M. T. Camps (Hospital Carlos Haya, Málaga), J. Canora-Lebrato (Hospital Universitario de Fuenlabrada, Madrid), M. J. Castillo-Palma (Hospital Virgen del Rocío, Sevilla), A. Colodro (Complejo Hospitalario de Jaen, Jaen), E. de Ramón (Hospital Carlos Haya, Málaga), C. Díaz-Lagares (Hospital Clínic, Barcelona), C. Donate (Hospital Clínic, Barcelona), M. V. Egurbide (Hospital Cruces, Barakaldo), O. Escoda (Hospital Clínic, Barcelona), D. Galiana (Hospital de Cabueñes, Gijón), F. J. García Hernández (Hospital Virgen del Rocío, Sevilla), A. Gil (Hospital La Paz, Madrid), R. Gómez de la Torre (Hospital San Agustín, Avilés), R. González-León (Hospital Virgen del Rocío, Sevilla), C. Hidalgo (Hospital Virgen de las Nieves, Granada), J. Jiménez-Alonso (Hospital Virgen de las Nieves, Granada), A. Martínez-Berriotxoa (Hospital Cruces, Barakaldo), F. Medrano (Hospital Universitario de Albacete, Albacete), M. L. Micó (Hospital La Fe, Valencia), S. Muñoz (Hospital Clínic, Barcelona), C. Ocaña (Hospital Virgen del Rocío, Sevilla), J. Oristrell (Hospital Parc Taulí, Sabadell), N. Ortego-Centeno (Hospital San Cecilio, Granada), L. Pallarés (Hospital Son Dureta, Mallorca), I. Perales-Fraile (Hospital Universitario de Fuenlabrada, Madrid), M. Pérez de Lis (Hospital Meixoeiro, Vigo), R. Perez-Alvarez (Hospital Meixoeiro, Vigo), J. Rascón (Hospital Son Dureta, Mallorca), S. Retamozo (Hospital Clínic, Barcelona), J. J. Ríos-Blanco (Hospital La Paz, Madrid), A. Robles (Hospital La Paz, Madrid), G. Ruiz-Irastorza (Hospital Cruces, Barakaldo), L. Saez (Hospital Universitario Miguel Servet, Zaragoza), G. Salvador (Hospital de Sagunt, Valencia), J. Sánchez-Roman (Hospital Virgen del Rocío, Sevilla), A. Selva-O'Callaghan (Hospital Vall d'Hebron, Barcelona), A. Sisó (CAPSE/GESCLINIC, Barcelona).
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