JAIDS Journal of Acquired Immune Deficiency Syndromes:
Efficacy and Safety of Switching From Boosted Lopinavir to Boosted Atazanavir in Patients With Virological Suppression Receiving a LPV/r-Containing HAART: The ATAZIP Study
Mallolas, Josep MD, PhD*; Podzamczer, Daniel MD†; Milinkovic, Ana MD*; Domingo, Pere MD‡; Clotet, Bonaventura MD§; Ribera, Esteve MD‖; Gutiérrez, Félix MD¶; Knobel, Hernando MD#; Cosin, Jaime MD**; Ferrer, Elena MD†; Arranz, José Alberto MD††; Roca, Victor MD‡‡1; Vidal, Francesc MD§§; Murillas, Javier MD‖‖; Pich, Judit PharmD¶¶; Pedrol, Enric MD##; Llibre, Josep M MD***; Dalmau, David MD†††; García, Isabel MD‡‡‡; Aranda, Miquel MD§§§; Cruceta, Ana MD¶¶; Martínez, Esteban MD*; Blanco, José L MD*; Lazzari, Elisa de MS‖‖‖; Gatell, José M MD*; and the ATAZIP Study Group
From the *Hospital Clinic Universitari-IDIBAPS, University of Barcelona, Barcelona, Spain; †Hospital Universitari de Bellvitge, Barcelona, Spain; ‡Hospital de Sant Pau, Barcelona, Spain; §Fundacio IrsiCaixa, HIV, Barcelona, Spain; ‖Hospital Vall d'Hebron, Barcelona, Spain; ¶Hospital General Universitario de Elche, Elche, Spain; #Hospital del Mar, Barcelona, Spain; **Hospital Gregorio Marañon, Madrid, Spain; ††Hospital Principe de Asturias, Madrid, Spain; ‡‡Hospital Clínico San Carlos, Madrid, Spain; §§Hospital Universitari de Tarragona Joan XXIII and Universitat Rovira i Virgili, Tarragona, Spain; ‖‖Hospital Son Dureta, Palma de Mallorca, Spain; ¶¶Hospital Clinic Universitari, Pharmacology-UASP, Barcelona, Spain; ##Hospital de Granollers, Granollers, Spain; ***Hospital de Calella, Calella, Spain; †††Hospital Mutua de Terrasa, Terrassa, Spain; ‡‡‡Hospital de Hospitalet, Hospitalet de Llobregat, Spain; §§§Consorci Sanitari de Terrasa, Terrassa, Spain; and ‖‖‖Hospital Clinic Universitari, Biostatistics, Barcelona, Spain.
Received for publication July 18, 2008; accepted December 17, 2008.
Supported in part by unrestricted research grants from Bristol Myers Squibb and a grant from Fondo de Investigaciones Sanitarias (PI041075) and Red Temática Cooperativa de Investigación en SIDA, Ministerio de Sanidad y Consumo, Spain.
1Dr. V. R. died on June 19, 2007.
Clinical trial registry number: ISRCTN24813210.
Registration number in AEM (Agencia Española del Medicamento): 02-0551.
Prism Ideas (United Kingdom) provided assistance in preparing and editing the article.
Correspondence to: Josep Mallolas, MD, PhD, Infectious Diseases Service, Hospital Clinic, Villarroel, 170, 08036 Barcelona, Spain (e-mail: firstname.lastname@example.org).
Objectives: To evaluate the efficacy and safety of switching from boosted lopinavir (LPV/r) to boosted atazanavir (ATV/r) in virologically suppressed HIV-1-infected patients versus continuing LPV/r.
Methods: Forty-eight weeks analysis of a randomized, open-label, noninferiority trial including patients with virological suppression (≤200 copies/mL for ≥6 months) on LPV/r-containing triple highly active antiretroviral therapy. Patients (n = 248) were randomized 1:1 either to continue LPV/r twice a day (n = 127) or to switch to ATV/r every day (ATV/r; n = 121), with no change in nucleoside reverse transcriptase inhibitor backbone. Those known to have >4 protease inhibitor (PI)-associated mutations and/or who had failed >2 PI-containing regimens were excluded.
Results: Baseline characteristics were balanced. 30% harboured ≥1 PI-associated mutation (10% harboured ≥1 major mutation). Treatment failure at 48 weeks (primary end point) occurred in 20% (25 of 127) of the LPV/r arm and in 17% (21 of 121) of the ATV/r arm (difference −2.3%; 95% confidence interval: −12.0 to 8.0; P = 0.0018). Virological failure occurred in 7% (9 of 127) of the LPV/r arm and in 5% (6 of 121) of the ATV/r arm (difference −2.1%; 95% confidence interval: −8.7% to 4.2%, P < 0.0001 for noninferiorating). CD4+ changes from baseline were similar in each arm (approximately 40 cells/mm3). Adverse event rate leading to study drug discontinuation was 5% in both arms. Median fasting triglycerides and total cholesterol decreased significantly in the ATV/r arm (−53 and −19 mg/dL, respectively versus −4 and −4 mg/dL in the LPV/r arm; P < 0.001 in both comparisons). Alanine aminotransferase/aspartate aminotransferase hepatic abnormalities were similar in the 2 arms.
Conclusions: Switching to ATV/r in virologically suppressed patients who were receiving a LPV/r-containing highly active antiretroviral therapy provided comparable (noninferior) efficacy and a safety profile with improved lipid parameters [ISRCTN24813210].
Highly active antiretroviral therapy (HAART) for HIV-1 infection commonly consists of a combination of a protease inhibitor (PI) plus 2 nucleoside analogue reverse transcriptase inhibitors (NRTIs).1 However, the success of HAART is dependent upon close adherence to the treatment regimen,2 which may be compromised as a result of adverse events (AEs), frequent dosing, and high pill burden.3,4 HIV therapy is commonly associated with metabolic changes such as increased triglycerides (TGs) and total cholesterol (TC), the development of insulin resistance, and changes in body fat distribution, which all contribute to an increase in cardiovascular risk.5
Atazanavir (ATV) has been extensively studied in treatment-naive and experienced HIV patients, and its potency and efficacy for suppressing HIV RNA has been demonstrated with good tolerability and once-daily (every day) dosing. The SWAN study demonstrated that switching from regimens containing a first-generation PI [either with or without ritonavir (r) boosting] to an unboosted ATV-containing regimen maintained virological suppression with improvement in plasma lipids for up to 48 weeks. However, patients with previous failures during PI-containing therapy or previous resistance to PI were excluded.6 An observational study of switching from a PI-containing regimen to boosted atazanavir (ATV/r)-containing regimen was presented in the European AIDS Conference in 2007 showing that this strategy was effective in maintaining virologic suppression, provides a way to build convenient and generally well-tolerated once-daily regimens, and significantly improves the lipid profile.7
There are limited data available relating to the effect of switching virologically suppressed patients (including those with previous failures on PI-containing regimens or those with PI-associated mutations) from ritonavir-boosted lopinavir (LPV/r) or other boosted regimens to a more lipid neutral boosted PI such as ATV/r. The ATAZIP study was designed to investigate the safety and efficacy of ATV/r-based HAART in virologically suppressed patients receiving a LPV/r-containing regimen, including patients with 1 or 2 previous failures to PI regimens or with a history of PI-associated mutations (4 or fewer) before starting the LPV/r-based regimen.
Data from treatment-experienced patients receiving either boosted or unboosted treatment with ATV suggest that the incidence of severe hypertransaminasemia with ATV is low and that hyperbilirubinemia is benign.8 Therefore, it is possible that ATV/r could offer patients lipid profile improvements.
Recently, a randomized clinical trial has been published which compares ATV/r versus LPV/r in treatment-naive patients. ATV/r once daily demonstrated similar antiviral efficacy to LPV/r twice daily, with less gastrointestinal toxicity but with a higher rate of hyperbilirubinemia.9
ATAZIP was a noninferiority trial with 2 parallel arms designed to compare the efficacy and tolerability of switching to ATV/r from LPV/r while continuing NRTIs in patients whose disease was under stable management compared with continuing on LPV/r.
This was a 24-month, prospective, open-label, parallel group, Spanish, multicenter clinical trial that enrolled 265 virologically suppressed HIV-1-infected patients who were stable on LPV/r-based regimens. The study was conducted in accordance with the declaration of Helsinki and approved by the Ethics Committee at each center and by the Spanish Medicines Evaluation Agency [ISRCTN24813210]; all patients gave written informed consent.
Patients were randomized 1:1 either to continue their existing regimen of LPV/r (400/100 mg twice a day) or to switch to ATV/r (300/100 mg every day); the NRTI backbone remained unchanged in both groups. Randomization was not stratified by sites. In addition to selection and randomization, clinic visits during the first year of follow-up were scheduled for weeks 4, 16, 24, and 48. Clinical evaluation (including assessment of side effects), biochemistry and hematology, CD4+ and CD8+ T-cell counts, and plasma viral load (HIV RNA) were measured at all clinic visits.
Eligible patients were aged ≥18 years and were being treated for HIV-1 infection according to a stable regimen of LPV/r plus 2 NRTIs for ≥6 months (with viral load <200 copies/mL for the last 6 months and within 1 month of the baseline visit). The clinical stage of HIV infection or AIDS was determined according to the Centers for Disease Control and Prevention (CDC) classification system for HIV infection.10 Patients had to have experienced not more than 2 previous virological failures while receiving PI-based HAART and harbor fewer than 5 PI-associated mutations, if any genotypic resistance test11 was performed in the past, to be eligible for enrollment.
Females who were nursing, pregnant, or intending to become pregnant during the study period were not included. Patients with plasma transaminase levels ≥5 times or total plasma bilirubin ≥3 times the upper limit of normal, plasma creatinine level ≥2.0 mg/dL, significant active cardiac conduction disorder, or a history of prolonged QTc or known electrocardiogram abnormalities suggesting atrioventricular blockage were also excluded from the study. Alcoholism, drug abuse, and a contraindication for any of the study drugs were also exclusion criteria.
Efficacy End Points
The primary efficacy end point was the proportion of patients with treatment failure [intent-to-treat (ITT) switching = failure] at any time and for any reason during the 48-week study period. Prolongation of the study up to 96 weeks was preplanned. Treatment failure definition included virological rebound (defined as ≥200 copies/mL in 2 consecutive determinations at least 2 weeks apart); being lost to follow up; withdrawal of consent; discontinuation of study therapy because of side effects, clinical abnormalities, or any other reason; progression to a new CDC event or death. Secondary end points were virological failure on treatment during the 48-week study period which comprised either virological rebound as described above at any time on treatment or death, time to treatment and virological failure, changes in CD4+ T-cell lymphocytes, the effects of therapy on lipid profile, other side effects, progression to a new CDC class C event, and mortality.
Safety End Points
Safety end points included the incidence of grades 3-4 AEs, including clinical and laboratory abnormalities, AEs leading to treatment discontinuation, changes in lipid profile [TG, TC, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and TC/HDL-C ratio], and the changes and incidences of hepatic abnormalities over the course of the study. The severity of AEs was assessed by the investigator using the Division of AIDS Toxicity Grading Scale.12
Patients were followed for the entire trial period, regardless of whether or not they discontinued prematurely from the assigned study medication. All randomized patients, except those who were found to have violated the entry criteria and those who never started the study medication, were included in the analysis. In the ITT analysis, switches in nucleoside backbone components were not considered to indicate treatment failure as long as HIV-1 RNA levels remained at <200 copies per milliliter.
The sample size was computed to detect noninferiority between the treatment groups in the proportion of patients with treatment failure at 48 weeks because very few virological failures, clinical events, or deaths were expected. It was calculated that 265 treated patients would be sufficient to provide 80% power to demonstrate the noninferiority of ATV/r to LPV/r. This calculation assumed a 2-sided 95% confidence interval (CI), and noninferiority was to be accepted if the upper CI limit was <12.5%. Statistical analysis was performed with the use of STATA software (release 9.2) and StatXaxt, version 6, with Cytel Studio. Qualitative variables were described with frequency and percentages and were compared between groups using χ2 or Fischer exact tests. Quantitative variables were described with median and interquartile range (IQR) and compared between groups using Wilcoxon rank sum test. For testing noninferiority of ATV/r relative to LPV/r, exact 97.5% upper confidence bound for difference in binomial proportions of treatment and virological failure and the exact 1-sided P value were calculated. A logistic regression model was used for testing the potential confounding baseline characteristics when estimating the proportions of treatment and virological failure. The time to treatment or virological failure were estimated using the Kaplan-Meier product-limit method. The equality of distribution between groups of the time to an event was estimated using a generalized log-rank test. Simple comparisons were made using a 2-sided alpha level of 0.05.
Baseline demographic characteristics and clinical information are shown in Tables 1 and 2. The groups were evenly balanced, with the exception that significantly more patients who continued on LPV/r had a diagnosis of AIDS at baseline compared with patients who switched to ATV/r (P = 0.007), and a difference in the age of patients at baseline (P = 0.039). Most patients (90%) had CD4+ counts >200 cells per milliliter and approximately 20% of patients in each group had elevated TC (>240 mg/dL) and LDL-C (>130 mg/dL). Nearly 30% of patients in both arms had elevated (>40 U/L) alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at baseline. Hepatitis C coinfection was diagnosed in 44 patients (36%) in the ATV/r arm and in 35 patients (27%) in the LPV/r arm.
Before study entry, a genotypic resistance analysis of HIV was available in 53 of 121 patients (44%) in the ATV/r group. At least 1 PI resistance mutation was detected in 43 of 53 patients screened (ie, at least 36% of patients in this arm) and at least 1 major PI resistance mutation in 17 of 53 (at least 14%) patients in this treatment arm (14 with 1 and 3 with 2 major PI resistance mutation). Genotypic analysis was available in 63 of 127 patients (50%) in the LPV/r group, revealing that 41 of 63 (minimum 32% of LPV/r patients) patients had at least 1 PI resistance mutation and 13 of 63 (minimum 10%) had at least 1 major mutation (6 with 1, 6 with 2, and 1 with 3 major PI resistance mutation) (Table 1). Fifty patients (25 per arm) had previous PI failures: 8 cases while receiving indinavir alone, 8 nelfinavir alone, 3 saquinavir alone, and 6 PI combinations in the ATV/r arm and 3 while receiving indinavir alone, 12 nelfinavir alone, 4 saquinavir alone, and 6 PI combinations in the LPV/r arm (Table 1).
A total of 265 patients were randomized in the study. Eleven patients in the ATV/r arm and 6 in the LPV/r arm were excluded. Reasons were violation entry criteria (8 and 6 patients in the ATV/r and LPV/r arms, respectively) and randomization error (3 patients in the ATV/r arm). Two hundred fourty-eight of 265 randomized patients were eligible and received at least 1 dose of study medication (121 patients switched to ATV/r and 127 patients remained on LPV/r). Overall, 105 patients (87%) who switched to ATV/r and 109 (86%) of those who continued on LPV/r completed the study to week 48. The trial flow chart is shown in Figure 1.
Primary and Secondary Efficacy Analyses
At week 48, the number of patients who experienced treatment failure was 21 (17%) in the ATV/r group and 25 (20%) in the LPV/r group in the ITT analysis (difference analysis −2.3%; 95% CI −12.0% to 8.0%; P = 0.0018; Fig. 2), demonstrating noninferiority for the primary end point.
Virological failure developed in 6 ATV/r patients (5%) and nine LPV/r patients (7%) in the on-treatment analysis (difference analysis -2.1%; 95% CI: −8.7% to 4.2%, P < 0.0001; Fig. 2, again demonstrating noninferiority of ATV/r versus LPV/r). Six patients (5%) experienced virological rebound in the ATV/r arm versus 8 (6%) in the LPV/r arm (P = 0.597). The characteristics of patients experiencing virological rebound are shown in Table 3. Potentially confounding unbalanced baseline characteristics (diagnosis of AIDS at baseline and age) did not show any association with outcomes either in estimating the difference in treatment effects or in virological failure.
There were no significant differences between treatment arms in survivor functions (P = 0.652). Time to treatment failure and time to virological failure did not differ between groups. CD4+ T-cell counts during the study are shown in Figure 3. The median changes at 48 weeks were +27 cells per cubic millimeter (IQR: −42 to 119) with ATV/r and +48 cells per cubic millimeter (IQR: −5 to 112) with LPV/r (P = 0.315). Inclusion of those patients who had entry criteria violations or who never took the study medication in the analysis did not significantly affect the overall results (data not shown). We have also performed an exploratory subanalysis including only those patients with a high baseline risk, defined as those who previously had ≥1 PI failure, ≥3 PI resistance mutations, or ≥1 major PI resistance mutation. Treatment failure developed in 8 of 45 (18%) in the ATV/r arm and in 7 of 39 (18%) in the LPV/r arm. Virological failure rate was higher in this subgroup of patients for both treatment arms: 11% for ATV/r and 13% for LPV/r. Moreover, virological failure was developed in 6 of 43 and in 1 of 41 patients in the ATV/r and LPV/r, respectively, for those patients with a previous ≥1 PI mutations. In those patients with a previous ≥1 major PI mutation, virological failure was developed in 2 of 17 and in 1 of 13 in the ATV/r and LPV/r arm, respectively. One of 49 and 3 of 73 patients with prior AIDS diagnosis developed virological failure in the ATV/r and LPV/r arm, respectively.
Overall, 12 patients discontinued therapy due to AEs (6 patients in each arm), and there was only 1 death (hepatic encephalopathy, LPV/r group). No new cases of CDC class C events were recorded (Table 4).
The proportions of patients with abnormal levels of hepatic transaminases and bilirubin are shown in Table 5. There was a similarly low incidence of abnormal levels of hepatic enzymes in each treatment group, although patients with elevated ALT or AST at baseline were at an increased risk of experiencing abnormal ALT or AST levels after 48 weeks' treatment, in both arms. Hyperbilirubinemia (bilirubin >2.5 mg/dL and >5 mg/dL) was present in 66 patients (55%) and 21 patients (17%), respectively in the ATV/r arm and in 6 patients (5%) and 2 (2%) patients, respectively, in the LPV/r arm. However, only 2 patients (2%) in the ATV/r arm discontinued study medication due to jaundice.
The median changes in fasting plasma lipids from baseline to 48 weeks are shown in Figures 4A and B. There were significant reductions in TG (P < 0.001), TC (P < 0.001), and TC/HDL-C ratio (P = 0.043) for patients who switched to ATV/r compared with those who continued on LPV/r, with no significant differences between groups regarding changes in LDL-C or HDL-C.
At week 96, there were no major changes in terms of efficacy and safety when compared with week 48. Treatment failure occurred in 30% (40 of 127) in the LPV/r arm and in 25% (33 of 121) in the ATV/r arm (difference −4.2%; 95% CI −15.6% to 7.1%) and virological failure occurred in 9% (12 of 127) in the LPV/r arm and in 8% (11 of 121) in the ATV/r arm (difference −0.36%; 95% CI −7.6% to 6.9%). Median CD4 changes from baseline were 100.5 and 40 cells per cubic millimeter in the LPV/r and ATV/r arm, respectively. Median fasting TG and TC decreased significantly in the ATV/r arm, −53 and −24 mg/dL, respectively.
This study demonstrated that, overall, in patients with virological suppression who received a stable LPV/r-based antiretroviral regimen and with no more than 2 previous virological failures of PI therapy or fewer than 5 PI resistance-associated mutations, a switch from LPV/r to ATV/r provided comparable efficacy, safety and tolerability, and improvements in lipid parameters, particularly TGs, at 48 weeks. However, the study has not enough statistical power to test for noninferiority among subgroups.
This study was adequately powered, and the ATV/r group met the predefined noninferiority criteria versus the LPV/r group. The proportions of patients experiencing virologic (HIV RNA load ≥200 copies/mL) or treatment failure over 48 weeks were similar in the 2 arms. These results were confirmed with additional analyses involving a subset of patients with a high baseline risk of treatment failure.
In the ATV/r, 11 patients were excluded after randomization due to protocol violation in 8 cases and due to randomization error in 3 cases, and 6 additional patients were excluded in the LPV/r arm due to protocol violation. Consequently, this 17 excluded cases after randomization must be considered as a study limitation.
Approximately, 30% of patients in each group had elevated levels of liver transaminases (ALT and AST) at baseline; and approximately, one-third were coinfected with hepatitis C virus. In each case, the proportion was marginally higher in the ATV/r group than in the LPV/r group. Similarly, at week 48, the proportion of patients with abnormal levels of transaminases remained marginally higher among those who switched to ATV/r. One concern when using ATV/r could be the occurrence of hyperbilirubinemia/jaundice, and although in our study we observed a high incidence of hyperbilirubinemia, it was considered mild in terms of clinical management and only 2 patients discontinued study medication due to jaundice. Another concern when using ATV/r is some drug-drug interaction, specially the contraindicated use of proton pump inhibitors. This combination decreases the bioavailability of ATV by approximately 50% and consequently will be not recommended. Overall, both arms were associated with similar rates of AE-related discontinuation. One major difference between treatment groups was that ATV/r arm was associated with a significant reduction in levels of TGs and TC at week 48. Overall, a switch to ATV/r demonstrated comparable efficacy, safety, and tolerability and was associated with an improvement in lipid profiles in a clinical trial that did not require lipid-related abnormalities as study entry criteria. The improved lipid parameters observed in this study are also consistent with findings from earlier trials that evaluated both boosted and unboosted atazanavir therapy in a variety of treatment populations.6,13-18
The results of this study should be interpreted in view of study design limitations, in particular, that this was an open-label, stable-switch study. Although the intention was to enroll patients to simplify their antiretroviral dosing, it is possible that some patients may have been somewhat disenchanted if allocated to their current PI regimen. On the other hand, one factor that may influence outcomes within switch arms in studies of this type is that possible short-term tolerability issues with the new drug initiated could penalize the switch group.
Currently, ATV/r-containing regimens have been extensively evaluated in both naive and experienced HIV-infected subjects. Consistently, efficacy outcomes in treatment-naive patients, simplification strategies, and rescue therapy were comparable to LPV/r-containing regimens with improved lipid profile and in some cases improved gastrointestinal tolerability.9,14,19
In summary, switching to a simplified PI-based regimen containing ATV/r provided comparable virological suppression, as demonstrated by rates of virological rebound, and treatment failure similar to those observed with continued unmodified therapy with LPV/r. No unexpected drug-related AE was observed, and the ATV/r group was associated with similar safety and tolerability profile to the comparator, LPV/r. Improved lipid parameters were observed in the ATV/r arm of the study, and changes were sustained up to 48 weeks. However, the long-term clinical significance of these changes in lipid parameters in HIV-1-infected patients has not been determined.
Based on the results of this study, the treatment simplification strategy of switching patients to once-daily ATV/r can provide an effective and well-tolerated treatment option.
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Members, ATAZIP Study Team:
Trial chair: J.M.G.; Trial coordinators and monitors: Helena Agell, Juan A. Arnaiz, Ana Cruceta, and Judit Pich, Trial statisticians: Elisa de Lazzari.
Participating Centers and Investigators (in alphabetical order):
1. Hospital de Bellvitge, L'Hospitalet (E.F., Gabriela Leibenger, and D.P.)
2. Hospital Clínic, Barcelona (J.L.B., J.M.G., J.M., E.M., A.M., José M. Miró)
3. Hospital Clínico de San Carlos, Madrid (Maria Jesús Téllez, V.R.*, and Javier Vergas)
4. Hospital General Universitario de Elche, Elche (Enrique Bernal, F.G., Mar Masiá, and Sergio Padilla)
5. Hospital Germans Trías i Pujol, IrsiCaixa Foundation, Badalona (Carmen Alcalde, B.C., and Patricia Echeverría)
6. Hospital de Granollers (Elissabet Deig and E.P.)
7. Hospital Gregorio Marañón, Madrid (Juan Berenguer, Jaime Cosín, Isabel Gutiérrez, Margarita Ramírez, and Matilde Sánchez)
8. Hospital de l'Hospitalet, Hospitalet de Llobregat (I.G.)
9. Hospital Universitari de Tarragona Joan XXIII, Universitat Rovira i Virgili, Tarragona (Joaquim Peraire, Sergio Veloso, F.V., and Consuelo Viladés)
10. Hospital del Mar, Barcelona (Alicia González, H.K., Gabriel Mestre, and Gabriel Vallecillo)
11. Hospital de Mútua de Terrassa, Terrassa (Mireia Cairó, D.D., and Carol García)
12. Hospital Príncipe de Asturias, Alcalá de Henares (J.A.A., Esperanza Casas, and José Sanz)
13. Hospital Sant Jaume, Calella (J.M.L. and Silvia Valero)
14. Hospital Sant Pau (P.D., Mar Gutiérrez, and Gracia Mateo)
15. Hospital Son Dureta, Palma de Mallorca (J.M. and Maria Peñaranda)
16. Hospital Consorci Sanitari de Terrassa, Terrassa (M.A.)
17. Hospital Vall d'Hebron, Barcelona (Esteban Ribera and Sara Villar)
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© 2009 Lippincott Williams & Wilkins, Inc.
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