Effect of simplification from protease inhibitors to boosted atazanavir-based regimens in real-life conditions
Article first published online: 19 MAR 2010
© 2010 British HIV Association
Volume 11, Issue 9, pages 545–553, October 2010
How to Cite
Rubio, R., Serrano, O., Carmena, J., Asensi, V., Echevarría, S., Flores, J., Ribera, E., Zarraga, M., Ocampo, A., De La Fuente, B., Sepúlveda, M., Mariño, A., Minguez, C., Vicent, R., Cartón, J., Moyano, B., Esteban, H., Mahillo, B., Serrano, L., González-García, J. and for the GESIDA 44/04 SIMPATAZ study group (2010), Effect of simplification from protease inhibitors to boosted atazanavir-based regimens in real-life conditions. HIV Medicine, 11: 545–553. doi: 10.1111/j.1468-1293.2010.00827.x
- Issue published online: 3 SEP 2010
- Article first published online: 19 MAR 2010
- Accepted 15 December 2009
- antiretroviral therapy;
- HIV infection
Atazanavir (ATV) boosted with ritonavir (ATV/r) is a potent, well-tolerated, once-daily protease inhibitor (PI). Few data are available on this agent as a treatment simplification option for patients taking other PIs.
The aim of the study was to determine the effectiveness and safety of ATV-containing regimens in patients who have simplified their antiretroviral treatment.
SIMPATAZ was a multicentre, prospective, noninterventional study in patients who had undetectable HIV RNA on their current PI-containing therapy and who were switched to an ATV/r-based regimen. Patients underwent a routine physical examination, and data were collected on HIV RNA levels, CD4 cell counts, liver function, lipid parameters, adverse reactions, adherence to treatment and patient satisfaction.
A total of 183 patients were enrolled in the study and included in the analysis (80% were male, 29% had AIDS, and 52% were coinfected with HIV and hepatitis B virus or hepatitis C virus). The median baseline CD4 count was 514 cells/μL. Median exposure to previous HIV therapy was 8 years, and 32% of patients had a history of PI failures. Lopinavir boosted with ritonavir was the most frequent PI replaced (62%) and tenofovir+lamivudine /emtricitabine the backbone most used during the study (29%). The study drug was discontinued early by 25 patients (14%), two of whom discontinued as a result of adverse events (Hodgkin lymphoma and vomiting). Two patients died (lung cancer and myocardial infarction). At month 12, 93% of the study population had an undetectable HIV RNA viral load. Hyperbilirubinaemia >3 mg/dL and increased alanine aminotransferase levels>200 IU/L were observed in 38.5% and 4.4% of patients, respectively. Median changes from baseline to month 12 in total cholesterol, triglycerides and low-density lipoprotein cholesterol were −13 mg/dL (−7%; P<0.0001), −19 mg/dL (−13%; P<0.0001) and −7 mg/dL (−6%; P=0.021), respectively.
In a real-world setting, switching from other PIs to ATV/r is a well-tolerated and safe option for improving the lipid profile and for retaining virological response in controlled pretreated patients.
Highly active antiretroviral therapy (HAART) has decreased morbidity and mortality in HIV-positive patients, with the result that HIV infection is now an incurable chronic disease [1,2].
Significantly prolonged life expectancy and the availability of active potent antiretroviral (ARV) drugs have changed the way HIV specialists approach HAART . Current treatment guidelines highlight the importance of considering a potential regimen not only for its antiretroviral potency, but also in terms of how it affects food requirements, adverse events and pill burden, all of which can compromise long-term adherence [4–6]. The degree of adherence to ARV drugs is clearly associated with the outcome of treatment, which depends on sustained reduction in viral load, avoidance of resistance and maintenance of a broad range of treatment options .
HAART optimization strategies for virologically controlled patients are common in clinical practice. The ideal simplification regimen should maintain virological suppression while preserving immune function, improve adherence and quality of life, and reduce or prevent adverse events [6,7] such as morphological changes, metabolic events and the potential increase in cardiovascular risk [2,8].
The available simplification strategies  include switching from a protease inhibitor (PI) to a nonnucleoside reverse transcriptase inhibitor (NNRTI; e.g. nevirapine or efavirenz [10–13]), once-daily dosing  and coformulated fixed-dose ARV drug combinations.
Atazanavir (ATV) is a highly active azapeptide inhibitor of HIV protease. It was the first PI with a pharmacokinetic profile that allows once-daily oral administration for a variety of patients and indications in HIV therapy [3,15]. Randomized trials in treatment-naïve and treatment-experienced HIV-infected patients demonstrated that regimens containing ATV boosted with ritonavir (ATV/r; 300/100 mg/day) were as efficacious as those containing lopinavir/ritonavir (LPV/r) [16,17]. ATV/r has shown efficacy as a switch option for patients on stable LPV/r-based HAART . These and other trials have consistently shown a more favourable metabolic profile and better gastrointestinal tolerability with ATV than with other PIs [16–19].
The objective of the SIMPATAZ study was to determine the effectiveness and safety of ATV-containing regimens in patients whose physician has recommended simplification of their ARV treatment to improve ease of administration, patient satisfaction, tolerability, or lipid profile, while maintaining virological suppression.
SIMPATAZ was a multicentre, prospective, noninterventional, post-authorization, investigator-sponsored study that enrolled patients taking stable PI-based treatment whose physician recommended simplification of their ARV drug regimen to a boosted ATV-containing regimen (ATV 300 mg/ritonavir 100 mg once daily). Recruitment started in July 2005 and finished in October 2006. The study was conducted at 32 sites throughout Spain, and the protocol was approved by the Spanish Agency for Medicines and Healthcare Products and by the ethics committees at the participating sites.
Patients were followed up every 4 months for 1 year. At each visit, patients underwent a routine physical examination and data were collected on HIV RNA level, CD4 cell count, liver function, glucose levels, lipid values [total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides], adverse reactions, adherence and satisfaction. Adherence was measured using a validated simplified medication adherence questionnaire (SMAQ) , with six qualitative questions on adherence and pills missed during the last week and past 3 months. Satisfaction with ARV treatment was evaluated using an ad hoc questionnaire with six items on a visual scale (1=not satisfied to 5=very satisfied) for different treatment-related aspects such as ease of administration, tolerability, and disease control as perceived by the patient.
Eligible patients were HIV-1-infected adults who had been on their current PI-based regimen (unchanged) for at least 6 months and who had an HIV RNA level below the limit of quantification (LOQ) for at least 4 months before simplification. The decision to switch to an ATV-containing regimen was made before inclusion, and each participant provided signed informed consent.
Patients were excluded if they were pregnant, had not taken ARV drugs before the study or had previously taken ARV drugs not boosted with ritonavir, or if their life expectancy was<12 months. Other exclusion criteria were noncontrolled diabetes mellitus, current alcohol or drug abuse, acute hepatitis at the beginning of the study or advanced liver disease, specified heart conduction system abnormalities, triglycerides ≥1250 mg/dL, serum creatinine higher than twice the upper limit of normal, aminotransferase levels higher than five times the upper limit of normal, and serum bilirubin levels higher than 3 times the upper limit of normal.
The primary endpoint used to determine the effectiveness of ATV-based simplification regimens was the proportion of patients maintaining an undetectable viral load (as per the LOQ established by the local laboratory) after 1 year of follow-up. Secondary endpoints were the proportion of patients maintaining an undetectable viral load below 50 HIV-1 RNA copies/mL (in centres with an ultrasensitive assay), time to virological failure, changes in CD4 T-lymphocyte count, the frequency and severity of clinical and laboratory adverse events, withdrawals because of adverse events, change from baseline in fasting lipid values (total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides), glucose levels, the degree of adherence as reported by the patient and perceived quality of life/treatment satisfaction.
Effectiveness was measured according to the following final events.
- •Virological failure: detectable viral loads confirmed in at least two consecutive determinations separated by 1 month were considered as failures.
- •Treatment failure: virological failures, discontinuations for any reason, or death were considered as failures.
A sample size of 144 participants provided a power of at least 80% to establish 85% effectiveness with a precision of 6% (79–91%) and an alpha of 5%.
The primary analysis of effectiveness and safety was performed in all study patients who received at least one dose of ATV. The baseline characteristics of the participants were analysed using descriptive statistics.
Final events and missing study data were considered failures [intent-to-treat (ITT) analysis]. Bivariate and multivariate analyses were performed to study the factors associated with failure. Variables were included in the logistic regression model according to their significance in the bivariate analysis. Analysis of time to virological failure and time to treatment failure was performed using Kaplan–Meier survival curves.
For lipid parameters, data were censored after any change in lipid-lowering agents. The analysis performed was based on the last on-treatment observation carried forward (LOCF).
For laboratory parameter analyses, proportions were compared using the χ2 test or phi coefficient as appropriate. Median baseline and 12-month values were compared using nonparametric tests for related samples (Wilcoxon test).
Adherence to treatment and patient satisfaction were measured as proportions. Baseline and 12-month values were compared using the McNemar test.
A significance level of P=0.05 was used in all cases. The statistical analysis was performed using spss software (version 14.0; SPSS, Chicago, IL, USA).
A total of 183 patients were included in the study and received at least one dose of ATV/r (Fig. 1). Patients were followed for a median of 11.9 months [interquartile range (IQR) 10.9–12.9 months]. Twenty-five patients (14%) did not complete the study; the main reasons were loss to follow-up and patient decision (Fig. 1).
Baseline characteristics and ARV drug history are shown in Table 1. The median CD4 T-lymphocyte count was 514 cells/μL (IQR 364–748 cells/μL) and 92% had a viral load<50 copies/mL. Slightly more than half of patients were coinfected with hepatitis C virus (HCV) and/or hepatitis B virus (HBV), and 29% had had category C events.
|Age (years) [median (IQR)]||44 (40–48)|
|Female [n (%)]||36 (20)|
|HIV-1 risk factor [n (%)]|
|CDC Class C [n (%)]||53 (29)|
|Coinfected (HBV or HCV) [n (%)]||95 (52)|
|Methadone consumption [n (%)]||31 (17)|
|CD4 count (cells/μL) [median (IQR)]||514 (364–748)|
|Undetectable HIV RNA [n (%)]*||183 (100)|
|Patients at sites with HIV RNA LOQ<20 or<50 copies/mL [n (%)]||168 (92)|
|Antiretroviral exposure (years) [median (IQR)]||7.9 (4.9–10.3)|
|Previous exposure to at least 2 PIs [n (%)]||145 (79)|
|No previous ARV failures [n (%)]||80 (46)|
|Previous failures on:|
|Any NNRTI [n (%)]||57 (33)|
|Any PI [n (%)]||55 (32)|
|NRTI, NNRTI, and PI [n (%)]||28 (16)|
|ARV treatment at entry [n (%)]|
|Switched from boosted Pls||124 (68)|
|Switched from unboosted PIs||59 (32)|
|Maintained NRTI backbone unchanged when switching||113 (62)|
|Modified NRTI backbone when switching||70 (38)|
At baseline, half of the patients had a history of previous ARV treatment failure. Most (62%) had an ARV regimen containing LPV/r at study entry. The top three PI-based regimens switched at study entry were zidovudine (ZDV)/stavudine (d4T)+lamivudine (3TC)+LPV/r (20%), ZDV/d4T+3TC+nelfinavir (NFV) (19%), and tenofovir (TDF)+3TC/emtricitabine (ETC)+LPV/r (11%).
At study entry, the top three ATV/r regimens were TDF+3TC/FTC+ATV/r (29%), ZDV/d4T+3TC+ATV/r (20%), and abacavir (ABC)+3TC+ATV/r (20%). 3TC (60%) and TDF (44%) were the most common ARV drugs administered with ritonavir-boosted ATV. Once-daily regimens were used in 131 patients (72%).
Primary and secondary analyses
The proportions of patients with undetectable HIV RNA as per the local HIV testing LOQ (20–400 copies/mL) were 82% (ITT) and 95% (on treatment) at 12 months; the results were the same for patients with HIV RNA<50 copies/mL at those sites with LOQ<20 or 50 copies/mL. Treatment failure and virological failure rates at month 12 were 18% (n=32) and 7% (n=13), respectively. The use of ritonavir in the regimen switched at study entry and previous failure with all three drug classes were the risk factors associated with virological failure at month 12 in the bivariate analysis. Only the latter was significantly associated with virological failure (odds ratio 3.72; 95% confidence interval 1.12–12.38) in the multivariate analysis (using a logistic regression model).
The median (IQR) change in CD4 T-lymphocyte count from baseline at month 12 was +8 cells/μL (−74 to 131 cells/μL) and the median CD4 T-lymphocyte count at 12 months was 560 cells/μL (426–746 cells/μL).
Median times to virological failure and treatment failure were 131 days (117–241 days) and 157 days (123–250 days), respectively (Fig. 2).
As a result of the observational nature of the study, patients were followed using the routine practice of each participating centre. Consequently, some patients remained in the study for >12 months and, in 11 cases, >15 months. Nevertheless, no cases of virological failure after month 12 were observed, and only one patient discontinued treatment (at month 14).
|Adverse event||n/total (%)|
|Total number of AEs of any grade||48/183 (26)|
|ATV/r-related* AEs of any grade||27/183 (15)|
|Subjects experiencing any severe AE||11/183 (6)|
|ATV/r-related severe AEs||0/183 (0)|
|Patients experiencing moderate-to-severe AEs (≥2%) and AEs of interest|
|AEs leading to discontinuation||2‡/183 (1)|
|Elevated transaminases||3/183 (2)|
|Gastrointestinal disorders||1/183 (<1)|
The overall incidence of adverse events of any grade was 26% (n=48): 27 were related to ATV/r but only seven (3.8%) moderate-to-severe adverse events were considered to be ATV/r-related. Adverse event-related discontinuation was 1%, and only one event was possibly related to ATV/r (vomiting).
Hyperbilirubinaemia or jaundice of any grade was reported for 11% of patients, but was of moderate grade in only 2% of patients and mild in all other cases, and none discontinued the study for this reason. There were no cases of diarrhoea.
The proportion of patients with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) plasma levels above 200 U/L during the first 12 months of follow-up was 1.6% and 4.4%, respectively. The rate of total bilirubin levels above 3 mg/dL was 38.5% during the first 12 months of follow-up.
AST/ALT elevations >200 U/L during the first 12 months of follow-up were seen in 3.3%/8.7% and 0%/0% of HCV/HIV-coinfected and HIV-monoinfected patients, respectively (P=0.246 for AST and P=0.007 for ALT). The proportion of patients with bilirubin levels above 3 mg/dL was similar for the two groups during the first 12 months of follow-up: 40.2% and 36.7%, respectively (P=0.650).
Significant differences in the levels of median fasting total cholesterol (−13 mg/dL; −7%) (P<0.001), triglycerides (−19 mg/dL; −13%) (P<0.001), LDL cholesterol (−7 mg/dL; −6%) (P=0.021), and the total cholesterol:HDL cholesterol ratio (−0.5) (P<0.001) were observed after 12 months of treatment with the ATV/r-containing regimen. No changes were observed in HDL cholesterol levels (−0 mg/dL; 0%) (Fig. 3a).
The improvement in the lipid profile was also confirmed by a reduction in the proportion of patients above National Cholesterol Education Program (NCEP) recommendations (Fig. 3b) for each lipid parameter, and a significant reduction in the proportion of patients receiving concomitant lipid-lowering agents, from 20% (n=36) at baseline to 12% (n=20) at month 12 (P=0.002)
Adherence to treatment and patient satisfaction
Responses to adherence and treatment satisfaction questionnaires were analysed. Adherence was assessed using the SMAQ questionnaire. The proportion of patients classified as adherent improved slightly during follow-up, from 68% at baseline to 73% at 12 months (P=0.560). The median grade of satisfaction with ARV treatment rose from 3 at baseline to 5 at month 12, and the proportion of patients classified as highly satisfied (those responding 4 or 5) increased from 47% to 91% (P<0.001).
HAART currently provides sustained control of viral replication in most HIV-infected patients, but many regimens are difficult to administer or are affected by tolerance/toxicity issues. The development of better-tolerated drugs that can be administered once daily has enabled us to simplify treatment. Numerous simplification strategies have been explored in order to improve quality of life and adherence, as well as to manage drug-related toxicity while maintaining viral suppression [10–14].
Once-daily ATV/r is the only approved once-daily option for treatment-experienced patients, although other once-daily regimens have been studied in nonregistrational trials .
Switching the PI to ATV/r in virologically controlled patients may reduce the likelihood of virological rebound and treatment discontinuation, while sparing patients exposure to a new drug class.
This study shows that switching to ATV/r can provide additional advantages to patients taking a stable PI-based regimen, without increased risk of virological failure, at least during 1 year of follow-up. These advantages are as follows: (a) improvement in the lipid profile, despite the presence of ritonavir (associated with an increase in lipid levels and a significant reduction in total cholesterol, LDL cholesterol, triglycerides, and the total cholesterol:HDL cholesterol ratio), leading to reduced use of lipid-lowering agents; (b) once-daily dosing with a low pill burden; and (c) significant improvement in patient satisfaction with treatment.
The results for effectiveness, safety and lipid profile are consistent with those observed in clinical trials (ATAZIP and ReAL [17,19]) that explore switching to ATV/r while on a stable PI-based regimen. In both trials, virological failure was 5%, similar to the 7% found in our cohort. The overall treatment failure rates were reported only in ATAZIP and were also similar (17%) to those reported in the present study. The improved lipid parameters observed are also consistent with the results of these trials. ReAL shows that total cholesterol fell by 13%, triglycerides by 23.8%, LDL cholesterol by 10.4%, and HDL cholesterol by 6.2%. In ATAZIP, total cholesterol levels fell by 9%, triglycerides by 29%, LDL cholesterol by 7%, and HDL cholesterol by 6%.
The results for transaminases and bilirubin were analysed in the context of coinfection with HCV; similarly to previous results using PI-based regimens, ALT levels >200 U/L were observed more frequently in HCV/HIV-coinfected patients. Results for bilirubin >3 mg/dL in patients infected and not infected with HCV during the first 12 months of follow-up are consistent with previous data from observational studies  showing that the frequency of hyperbilirubinaemia was not significantly higher in HIV-infected patients with chronic viral hepatitis than in patients who were not coinfected.
No unexpected adverse events occurred with ATV/r during the study; there were no discontinuations because of jaundice, and only 2% of patients presented grade 2–4 hyperbilirubinaemia, which is consistent with results obtained elsewhere . Only one of the adverse event-related discontinuations was considered to be possibly related to ATV/r.
The study limitations are mainly a consequence of its observational, noninterventional design. Firstly, there was no control group – each patient was considered as his/her own control – and we used baseline data for comparison.
Another limitation is the lack of data on PI mutations in patients with previous failure on PIs. In a subanalysis of the ATAZIP study, switching to ATV/r in virologically suppressed patients taking an LPV/r-containing regimen with previous PI virological failures or at least three mutations led to higher rates of virological failure than in the overall population, although rates were similar between the arms. Consistent with this observation, previous failure with all three drug classes in the present study was the only factor significantly associated with virological failure in the multivariate analysis. However, in the 045 study, patients with more than three PI mutations did better on LPV/r than on ATV/r .
Despite the noncomparative design of the study, these results provide further evidence of the efficacy and safety of treatment simplification strategies using ATV/r-based regimens in a HAART-experienced population (median approximately 8 years on HAART) on regimens containing PIs (almost 80% of the patients had received at least two PIs before switching to ATV/r). These results seem to be a more accurate reflection of routine clinical practice and may complement those from clinical trials.
Consistent with other recently reported findings from clinical trials, the present results show that switching from other PIs to ATV/r in routine clinical practice could be a well-tolerated and safe option for retaining virological response in virologically controlled pretreated patients. Additionally, this strategy allows once-daily dosing, and improves the lipid profile and patient-perceived quality of life.
Conflicts of interest: R.R. has received speaker, advisory and/or investigator fees from Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Abbott Laboratories, Boehringer-Ingelheim, Gilead Sciences, Roche-Pharma and Janssen-Cilag. O.S. is a Bristol-Myers Squibb employee. A.O. has received speaker, advisory and/or investigator fees from Bristol-Myers Squibb and Abbot Laboratories. B.d.l.F. has received speaker and/or investigator fees from Bristol-Myers Squibb. C.M. has received research funding, consultancy fees, or lecture sponsorships from, or served on advisory boards for, Abbott Laboratories, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, Pfizer, Roche, and Schering-Plough. J.G.-G. has received speaker, advisory and/or investigator fees from Bristol-Myers Squibb, Glaxo SmithKline, Merck Sharp & Dohme, Abbott Laboratories, Boehringer-Ingelheim, Gilead Sciences, Roche-Pharma, Janssen-Cilag and Pfizer. J.C., V.A, S.E., J.F., M.Z., M.A.S., A.I.M., R.V., J.A.C., B.M., H.E., B.M. and L.S. do not have any conflicts of interest. E.R. does not have any conflicts of interest, financial or otherwise, regarding this work.
Funding: This study was supported by a research grant from Bristol–Myers Squibb.
We are grateful to Thomas O'Boyle for the English translation.
- 4Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Department of Health and Human Services. January 29, 2008; 1–128. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf (accessed 2 December 2008).
- 6Panel de Expertos de GESIDA y Plan Nacional sobre el SIDA. Recommendations from the GESIDA/Spanish AIDS Plan regarding antiretroviral treatment in adults with human immunodeficiency virus infection (update January 2008). Available at http://www.gesida.seimc.org/pcientifica/dcconsensos.asp?apnv0=pcientifica&apnvA=dcconsensosyrc&appag=dcconsensos_txt.htm (accessed 2 December 2008).
- 15Summary of Product Characteristics. Reyataz. Available at http://www.emea.europa.eu/humandocs/PDFs/EPAR/reyataz/H-494-PI-en.pdf (accessed 2 December 2008).
- 17CASTLE Study Team. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet 2008; 23: 646–655., , et al.
Appendix: The GESIDA 44/04 SIMPATAZ team
Hospital 12 de Octubre, Madrid: R. Rubio. Hospital Dr. Peset, Valencia: J. Carmena, R. Vicent, M.C. Ricart. Hospital Univ. Central de Asturias, Oviedo: V. Asensi, A. Moreno, J.A. Cartón, J.A. Maradona, M. Telentí. Hospital Univ. Marqués de Valdecilla, Santander, Cantabria: S. Echevarría, M.C. Fariñas, J.D. García, J.P. García. Hospital Arnau de Vilanova, Valencia; J. Flores. Hospital General Vall D'Hebrón, Barcelona: E. Ribera, M. Díaz, I. Ocaña, C. Azuaje. Hospital San Agustín, Avilés, Asturias; M.A. de Zárraga, M.J. Tuya, M. Cembellín. Hospital Xeral-Cies, Vigo, Pontevedra: A. Ocampo, C. Miralles, A.M. López, A. Rodríguez da Silva. Hospital Cabueñes, Gijón, Asturias: B. de la Fuente, M.L. García-Alcalde. Hospital Virgen de la Salud, Toledo: M.A. Sepúlvedal, F. Cuadra, J. Layo, R.M. Yuste. Hospital Arquitecto Marcide, Ferrol, La Coruña: A. Il Mariño, V. Trasancos, H. Álvarez. Hospital General Universitario, Castellón: C. Minguez, B. Roca, J. Usó, J.A. Soler. Hospital General Universitario, Alicante: V. Boix, J. Portilla, L. Giner, E. Merino, S. Reus. Hospital Clínico Univ. De Santiago de Compostela, La Coruña: A. Prieto, E. Losada, A. Antela. Hospital General Univ. Morales Meseguer, Murcia: R.M. Blázquez, F.J. Espinosa, I. Carpena. Complejo Hospital La Mancha Centro, Alcázar de San Juan, Ciudad Real: J.R. Barberá. Hospital Virgen de la Luz, Cuenca: M.P. Geijó, C. Rosa Herranz. Hospital de Mataró, Barcelon: P. Barrufet, L. Force. Hospital General Reina Sofía, Murcia: A. Cano, M.Á. Muñoz. Hospital Sierrallana de Torrelavega, Cantabria: F.G. Peralta. Hospital de Palamós, Girona: Á. Masabeu. Hospital General de Granollers, Barcelona: E. Pedrol, E. Deig. Hospital Sta Ma del Rosell, Cartagena, Murcia: J. García, O. Martínez, F. Vera. Hospital Valle del Nalón, Riaño-Langreo, Asturias: M. Rodríguez, V. Carcaba. Hospital Virgen de la Cinta, Tortosa, Tarragona: A.J. Orti. Hospital ‘Vega Baja’ de Orihuela, Alicante: V. Navarro, J. Gregori Colomé, E. González. Hospital Clínico Universitario, Valencia: M.J. Galindo, J. Guix, F. Alcácer. Hospital Son Llatzer, Son Ferriol, Palma de Mallorca, Baleare: F. Homar Borrás, A. Bassa, M.C. Cifuentes, A. Payeras. Fundación SEIMC-GESIDA: J. González-Garcia, B. Moyano, H. Esteban, L. Serrano, B. Mahillo.