Highly active antiretroviral therapy (HAART) has resulted in a significant reduction in morbidity and mortality associated with HIV-related illnesses.1 Much of the improvement in clinical outcomes has been attributed to the use of protease inhibitors (PIs) in combination antiretroviral therapy.2 The long-term tolerability and clinical utility of HAART is limited by significant metabolic disorders, including hyperlipidemia,3-5 fat redistribution,6 hyperglycemia,7,8 and insulin resistance,9 that are particularly common in patients receiving PI-containing therapy. Results from epidemiologic studies have shown that the metabolic abnormalities associated with HAART may increase the risk of cardiovascular disease in patients with HIV infection.10-13
Concentrations of fasting triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, total cholesterol, and non-HDL cholesterol are well-established markers of risk for cardiovascular disease in the general population14 and are also associated with increased risk of myocardial infarction in HIV-infected patients on HAART.12,13 Although other biological markers, such as lipoprotein(a) and apolipoprotein B, have been correlated with an increased risk of cardiovascular disease,15 there are yet limited data regarding their influence in HIV-positive patients.16,17
Most PIs have been associated with variable magnitudes of metabolic abnormalities.18 Substitution of a medication may be warranted in a patient's antiretroviral treatment regimen to maintain therapeutic goals. If antiretroviral therapy-associated cardiovascular adverse effects cannot be managed with lifestyle modification, management recommendations include a switch to agents with less propensity for increasing cardiovascular risk factors.19 Healthy volunteer and clinical studies have demonstrated that atazanavir was not associated with clinically relevant increases in total cholesterol, fasting LDL cholesterol, fasting triglyceride concentrations, or glucose metabolism changes compared with other PIs.20-24
In 48-week studies involving antiretroviral-naive patients, once-daily atazanavir was not associated with clinically relevant increases in total cholesterol, fasting LDL cholesterol, or fasting triglyceride concentrations.21,22 In a rollover/switch study (Bristol-Myers Squibb [BMS] AI424-044), virologically suppressed patients (n = 63) switched from nelfinavir to atazanavir (400 mg once daily) showed significant mean percent decreases in total cholesterol (−16%), fasting LDL cholesterol (−21%), and fasting triglycerides (−28%) (P < 0.0001).25 Observational studies of antiretroviral-experienced patients have also indicated that switching to atazanavir results in improvements in lipid profiles.26,27 These studies highlight the need for randomized prospective trials to evaluate the effects on lipid profiles of virologically suppressed patients who switch to atazanavir.
Study AI424-067 was designed to evaluate whether virologically suppressed and hyperlipidemic patients would achieve reductions in serum levels of LDL cholesterol, without loss of viral suppression and immune reconstitution, after a switch to atazanavir from a prior PI-containing regimen. An interim analysis of this trial has been presented previously,28 and the complete results of the study are presented here.
This was a 48-week, open-label, randomized, prospective, multicenter study conducted between December 2002 and March 2005 at 58 study centers in Australia, Europe, North America, and South America. All patients provided written informed consent, which was approved by the institutional review board or ethics committee at each of the participating institutions.
The primary study objective was to compare the percent change in fasting LDL cholesterol levels from baseline to week 12 between 2 groups of patients with documented virologic suppression (<50 copies/mL) and elevated LDL cholesterol levels >130 mg/dL (>3.4 mmol/L). In the immediate-switch group, the PI component of the current antiretroviral regimen was changed to atazanavir 400 mg once daily at baseline. In the delayed-switch group, the current PI-containing antiretroviral regimen remained the same for the first 24 weeks, after which the PI component was changed to atazanavir 400 mg once daily (Fig. 1).
Secondary study objectives were safety and tolerability and comparison of the treatment groups through week 48 for changes from baseline in fasting serum lipid concentrations, including lipoprotein(a) and apolipoprotein B, fasting glucose and insulin concentrations, rate of virologic rebound, and CD4 cell count.
Patients were screened within 30 days of the baseline visit to determine eligibility for enrollment. Eligible patients were randomized in a 1:1 ratio at the baseline visit to the immediate-switch or delayed-switch group.
Other than switching to atazanavir at the preestablished time point, no component of any patient's antiretroviral regimen was allowed to be changed [unless a change in 1 or both nucleoside reverse transcriptase inhibitors (NRTIs) was deemed necessary by the investigator because of patient intolerance]. No adjustments to the atazanavir dose were allowed. Tenofovir was prohibited in this study due to the pharmacokinetic interaction between tenofovir and atazanavir 400 mg given without ritonavir.29
Male and female HIV-infected patients who met the following inclusion criteria were eligible for the study: aged 16 years or older, on their first PI-based antiretroviral regimen (with or without ritonavir) for ≥3 months, and no known history of virologic failure. Patients who had 1 PI switch for reasons of intolerance or convenience were considered on their first PI-based regimen, provided there was documentation of maintained viral suppression. Patients must have had 2 consecutive HIV RNA values <50 copies per milliliter within 6 months before the start of study therapy, a confirmed HIV RNA level <50 copies per milliliter within 30 days before the baseline visit, and fasting LDL cholesterol concentrations >130 mg/dL (>3.4 mmol/L). Inclusion of nonnucleoside reverse transcriptase inhibitors (NNRTIs) in antiviral regimens, either at the time of screening or during the study, was prohibited.
Patients were ineligible to participate in the study for the following reasons: use of any lipid-lowering agent within 4 weeks before or during the study; fasting serum triglyceride levels ≥1250 mg/dL (≥14 mmol/L); history of acute or chronic pancreatitis; proven or suspected acute hepatitis within 30 days before the study; chronic hepatitis with liver function tests >3 times the upper limit of normal; and any other clinical conditions or previous therapy that, in the investigator's opinion, would make the patient unsuitable for the study.
Assessments and Monitoring
At each visit, patients were given physical examinations and had blood drawn for laboratory tests that included a chemistry profile, fasting lipid profile (LDL cholesterol, total cholesterol, HDL cholesterol, non-HDL cholesterol, triglycerides, lipoprotein(a), and apolipoprotein B), fasting glucose and insulin, complete blood count, plasma HIV RNA levels, and CD4 cell counts. The National Cholesterol Education Program Adult Treatment Panel III guidelines were used to assess fasting LDL cholesterol levels.14
HIV RNA levels were measured at all study visits at a Roche-certified local laboratory using the Roche AMPLICOR HIV-1 MONITOR Ultrasensitive Assay, version 1.0 or 1.5 (Roche Diagnostics, Basel, Switzerland).
An estimated sample size of 200 patients was chosen to provide at least 90% power to detect a difference of at least 14% between the immediate-switch and delayed-switch regimens in the mean percent change from baseline to week 12 in fasting LDL cholesterol. A 2-sided significance level of 0.05 and a standard deviation of 30% for the percent change in fasting LDL cholesterol were assumed based on data from BMS Study AI424-008.22 The immediate-switch regimen was to be declared superior to the delayed-switch regimen if the upper limit of the 95% confidence interval for the difference between treatments was less than zero.
Although week 24 was the last time point at which direct comparison of the treatment groups was possible, noncomparative data were obtained from both treatment groups through week 48 and were included in the secondary analyses.
Treatment regimens were compared using the difference (values for the atazanavir regimen minus values for the comparator PI regimen) in mean percent changes from baseline at week 24 for each fasting lipid parameter. Comparisons were made using 95% confidence intervals and P values based on t tests. The frequencies of adverse events (AEs), AEs leading to discontinuation, Centers for Disease Control and Prevention Class C AIDS events, and laboratory test abnormalities were tabulated for treated patients. Deaths and serious adverse events (SAEs) were tabulated without regard to time of occurrence.
The study was not statistically powered to detect antiviral effect. An efficacy analysis was performed on treated patients with baseline HIV RNA <50 copies per milliliter, and laboratory analyses were based on treated patients (randomized patients who received at least 1 dose of atazanavir or comparator PI therapy while on study). Efficacy end points included the proportions of patients with confirmed virologic rebound [limit of quantitation (LOQ) = 400 copies/mL] through week 48 for patients with baseline HIV RNA values <50 copies per milliliter and change in absolute CD4 cell counts from baseline at weeks 12, 24, and 48. Confirmed virologic rebound was defined as 2 consecutive on-study HIV RNA values or last available on-study HIV RNA value ≥400 copies per milliliter. Post hoc efficacy analyses tabulated the proportions of patients with virologic rebound through week 48 using LOQ = 50 copies per milliliter and the proportions with treatment failure (ie, virologic rebound or treatment discontinuation) through week 48 using LOQ = 400 copies per milliliter and LOQ = 50 copies per milliliter for patients with baseline HIV RNA <50 copies per milliliter.
Baseline characteristics and demographics are presented in Table 1. A total of 442 patients were enrolled in the study; of these, 246 (56%) were randomized: 127 to the immediate-switch group and 119 to the delayed-switch group. One patient in each group did not initiate treatment. Demographic and other patient characteristics were comparable between the 2 groups at baseline. Forty-two percent and 36% of patients were on ritonavir-boosted PI-containing regimens in the immediate-switch and delayed-switch groups, respectively. The majority of subjects were using a lamivudine (3TC)-containing NRTI backbone (93%), primarily zidovudine + 3TC (48%) or stavudine + 3TC (32%). NRTI substitutions during the study were made for 2% of the patients in the immediate-switch group and 3% of the patients in the delayed-switch group.
Serum lipid levels, the total cholesterol to HDL cholesterol ratio, the fasting LDL to HDL cholesterol ratio, and serum glucose levels were comparable between treatment groups at baseline. Fifty-six percent (70 of 126) of the patients in the immediate-switch group and 47% (56 of 118) of those in the delayed-switch group had fasting LDL cholesterol levels >160 mg/dL (>4.1 mmol/L) at baseline.
The mean time on atazanavir treatment for patients in the immediate-switch group was 45.4 weeks. In the delayed-switch group, the mean time on comparator PIs ranged from 21.9 to 23.5 weeks, and the mean time on atazanavir (after the week-24 switch) was 24.7 weeks.
One patient in the immediate-switch group and 2 patients in the delayed-switch group used serum lipid-lowering medications during the study. Data from these patients was excluded from the longitudinal analyses of lipid parameters.
Seven patients (6%) in the immediate-switch group and 10 (8%) in the delayed-switch group withdrew from the study before week 24 (Table 2). Before week 24, the primary reasons for discontinuation were AEs [4 (3%)] in the immediate-switch group and no longer meeting study criteria [7 (6%)] in the delayed-switch group.
Patients in the immediate-switch group experienced greater reductions in their LDL cholesterol levels at weeks 12 and 24 compared with those who remained on other PI-based therapy (ie, the delayed-switch group) (Fig. 2). The mean changes from baseline in fasting LDL cholesterol for the immediate-switch group were −15% [−24 mg/dL (−0.6 mmol/L) and −17% [−28 mg/dL (−0.7 mmol/L)] at weeks 12 and 24, respectively (Fig. 2). In the delayed-switch group, the mean changes from baseline in fasting LDL cholesterol were +1% and −3% at weeks 12 and 24, respectively (Fig. 2). At week 48, 24 weeks after the delayed-switch group had started atazanavir, the mean percent changes from baseline in fasting LDL cholesterol were −18% and −16% in the immediate-switch and delayed-switch group, respectively (Fig. 2).
In the delayed-switch group, the absolute changes from baseline in fasting LDL cholesterol were −2 mg/dL (−0.1 mmol/L) at week 24 (at the time of the switch to atazanavir) and −25 mg/dL (−0.6 mmol/L) at week 48 (after 24 weeks of treatment with atazanavir).
At week 12, a higher proportion of patients in the immediate-switch group than in the delayed-switch group had LDL cholesterol levels <130 mg/dL (<3.4 mmol/L) (33% vs. 14%). In addition, at week 12, a greater proportion of patients in the immediate-switch group had improvements in their LDL to HDL cholesterol ratios <3 (43% vs. 17%) (Fig. 3). A greater proportion of patients in the immediate-switch group maintained LDL cholesterol levels <130 mg/dL (<3.4 mmol/L) through week 24 than in the delayed-switch group (37% vs. 18%). After the switch to atazanavir at week 24, the proportion of patients in the delayed-switch group showed improvement over that which was observed before the switch to atazanavir at week 24 (Fig. 3).
Secondary End Points
At week 12, significantly greater reductions in mean fasting total cholesterol, non-HDL cholesterol, triglyceride, and apolipoprotein B levels (P < 0.0001) occurred among patients in the immediate-switch group than among those who remained on other PI-based therapy (ie, the delayed-switch group) (Fig. 2). The reduction in lipoprotein(a) levels was also significant (P = 0.0014); however, the difference in mean percent change in fasting HDL cholesterol between the immediate-switch group and the delayed-switch group (5.1%) was not significant (P = 0.057) (Fig. 2). More patients in the immediate-switch group than the delayed-switch group at week 12 had total cholesterol levels <200 mg/dL (<5.2 mmol/L) (42% vs. 11%), HDL cholesterol levels ≥40 mg/dL (≥1 mmol/L) (68% vs. 54%), and triglyceride levels <250 mg/dL (<3 mmol/L) (85% vs. 54%) (Fig. 3).
The greater reduction in fasting total cholesterol, non-HDL cholesterol, triglycerides, apolipoprotein B, and lipoprotein(a) demonstrated by significant differences in mean percent change between patients in the immediate-switch and delayed-switch groups (P < 0.0001) were maintained at week 24. The difference in mean percent change in HDL cholesterol was significant at this time point, favoring the immediate-switch group (P = 0.0007) (Fig. 2).
There was little difference in change from baseline for fasting glucose levels between the groups at weeks 12, 24, and 48. The mean changes in the immediate-switch group were 0, 3, and 3 mg/dL (0, 0.17, and 0.17 mmol/L), respectively, and the mean changes in the delayed-switch group were 0, 2, and 2 mg/dL (0, 0.11, and 0.11 mmol/L), respectively.
Virologic and Immunologic Outcomes
Virologic suppression (<50 copies/mL) was maintained in 85% and 90% of patients in the immediate- and delayed-switch groups, respectively, through week 48. In treated patients with baseline HIV RNA <50 copies per milliliter, virologic rebound above 400 copies per milliliter occurred in 3 of the 112 patients (3%) in the immediate-switch group and 1 of the 97 patients (1%) in the delayed-switch group during the comparative period of the study (weeks 1-24). Through week 48, 6 (5%) and 3 (3%) patients in the immediate-switch and delayed-switch groups, respectively, had virologic rebounds.
On-study HIV isolates from 7 patients with confirmed virologic rebound (HIV RNA >500 copies/mL) were tested for genotypic and phenotypic resistance to HIV protease and reverse transcriptase inhibitors using the PhenoSense and Geneseq HIV assays (Monogram Biosciences, Inc., San Francisco, CA). One of the rebound isolates showed reduced susceptibility to atazanavir [fold change (FC), 6.7]; this isolate also showed reduced susceptibility to indinavir, nelfinavir, and ritonavir (FC range, 4.7-11) but remained sensitive to amprenavir, lopinavir/ritonavir, and saquinavir (FC range, 0.5-3). The genotypic analysis of this isolate revealed the presence of 5 International AIDS Society-defined minor mutations associated with atazanavir resistance: M36I, I54V, A71V, G73G/S, and I93I/L30; an additional 6 PI mutations of unknown significance were present. All other rebound isolates showed preserved sensitivity to atazanavir and to all other tested PIs.
The proportion of patients with baseline HIV RNA <50 copies per milliliter with treatment failure (ie, virologic rebound or treatment discontinuation) through week 48 (LOQ = 400 copies/mL) were 12% and 15% in the immediate-switch and delayed-switch groups, respectively. Using a LOQ = 50 copies per milliliter, the proportion of patients with treatment failure was 21% in each group.
At weeks 12, 24, and 48, median increases from baseline in CD4 cell counts were 11 and 15 cells per cubic millimeter, 25 and 40 cells per cubic millimeter, and 27 and 28 cells per cubic millimeter for the immediate-switch and delayed-switch groups, respectively.
No deaths were reported during the study. The incidence of SAEs up to week 24 was 2% in the immediate-switch group and <1% in the delayed-switch group. After week 24, the SAE incidence was 2% in the immediate-switch group and 4% in the delayed-switch group (Table 3). Up to week 24, 1 SAE reported in the immediate-switch group and 2 in the delayed-switch group were considered related to study therapy. After week 24, 2 SAEs reported in the delayed-switch group were considered related to study therapy.
Through week 24, the 2 groups had comparable AE frequencies except for jaundice, which occurred in 6% of the immediate-switch group vs. less than 1% of the delayed-switch group, and vomiting, which occurred in less than 1% vs. 6% of the immediate-switch and delayed-switch groups, respectively. No patient in the immediate-switch group discontinued treatment during the first 24 weeks because of jaundice or hyperbilirubinemia.
Grade 3 to grade 4 laboratory abnormalities are presented in Table 3. Reversible, unconjugated hyperbilirubinemia, not associated with hepatotoxicity, was the most frequently reported laboratory abnormality. Grade 3 to grade 4 elevations in total bilirubin were reported before week 24 in 23% and <1% of patients in the immediate-switch and delayed-switch groups, respectively, and in 26% and 20% of patients, respectively, after week 24. Despite 10% of patients being coinfected with the hepatitis B and/or hepatitis C virus, grade 3 to grade 4 elevations in hepatic transaminases were reported in 3 or fewer patients in both treatment groups.
PI-based regimens have been associated with hyperlipidemia and insulin resistance, which may lead to increased cardiovascular risk for HIV-infected patients.10,11,31 BMS Study AI424-067 prospectively evaluated the changes in lipid profiles of patients with hyperlipidemia on PI-containing regimens after a switch to atazanavir. This study was powered to assess mean percent change from baseline in fasting LDL cholesterol at 12 weeks in patients who switched to atazanavir. Also evaluated were the effects of a switch to atazanavir on lipoprotein(a) and apolipoprotein B, 2 atherogenic lipid fractions not routinely evaluated that have been shown to be independently associated with cardiovascular events.15
The switch from a boosted or unboosted PI to atazanavir 400 mg once daily was associated with significant reductions in fasting LDL cholesterol, total cholesterol, triglyceride, non-HDL cholesterol, lipoprotein(a), and apolipoprotein B levels at week 12. Clinically relevant beneficial changes consistent with the National Cholesterol Education Program Adult Treatment Panel III guidelines were observed in all lipid parameters by the 12th week after the switch to atazanavir. The improved lipid profiles in the immediate-switch group were maintained through week 48. When patients switched to atazanavir at 24 weeks, comparable improvements in lipid profiles were observed.
Previous evidence demonstrated that atazanavir did not result in substantive increases in fasting glucose, fasting insulin, or insulin resistance indices,32 which is further substantiated by the findings of this study that no significant changes in mean fasting glucose levels occurred in patients in the immediate-switch group after 48 weeks of atazanavir treatment. Patients in both treatment arms (ie, immediate or delayed switch to atazanavir) maintained comparable virologic control, had low rates of virologic rebound, and had comparable increases in CD4 cell counts. In patients with baseline HIV RNA <50 copies per milliliter, virologic rebound above 400 copies per milliliter occurred in 5% of patients in the immediate-switch group and 3% of patients in the delayed-switch group through week 48.
Guidelines for the use of antiretroviral agents recommend using ritonavir-boosted atazanavir in both treatment-naive and treatment-experienced patients, with unboosted atazanavir recommended as an alternative choice for treatment-naive patients who are unable to tolerate ritonavir.19 Current guidelines do not recommend unboosted atazanavir for use in PI-experienced patients. Although there is some loss of lipid benefit with the use of ritonavir-boosted atazanavir, the favorable effects of atazanavir on lipid profiles are still observed. In 2 substudies of an expanded access program, switching to antiretroviral therapy containing ritonavir-boosted atazanavir in HIV-infected patients with hyperlipidemia was associated with significant improvements in plasma lipids without an increased risk of virologic failure. In a substudy of 162 patients, after 6 months' treatment, the median percentage change in total cholesterol, triglyceride, and non-HDL cholesterol levels was significant (−13%, −21%, and −14%, respectively; P < 0.05).33 Results from the second substudy in 31 patients followed for 24 weeks, switching to boosted atazanavir demonstrated rapid and significant decreases in triglycerides and total cholesterol.26
Lifestyle changes that are recommended to reduce cardiovascular risk in the general population (eg, dietary therapy, increased exercise, cessation of cigarette smoking) are also recommended for antiretroviral-treated, HIV-infected patients.14,34-36 However, lifestyle modifications have produced mixed results, and other interventions are often needed.37 Switching the NRTI component of the regimen, particularly stavudine to either tenofovir or abacavir, has demonstrated sustained improvement of dyslipidemias.38,39 Patients receiving PI-containing antiretroviral therapy may achieve improvements in hyperlipidemia by switching to a PI or NNRTI with less propensity to elevate lipids in patients with dyslipidemia.35 Use of an NNRTI-containing regimen frequently leads to improvements in lipid profiles, but some studies have not found beneficial effects on lipid levels after substitution of PIs with nevirapine or efavirenz.40 The most recent antiretroviral treatment guidelines cite atazanavir as having the least adverse effect on lipid metabolism of all currently approved PIs.19 Atazanavir was shown to have more significant decreases than efavirenz in the mean percent changes from baseline in total cholesterol, fasting LDL cholesterol, and fasting triglycerides (P < 0.0001).23
Use of lipid-lowering therapy may be necessary when lifestyle modifications and switching treatment are ineffective or not applicable. Drugs with the lowest risk of pharmacologic interactions should be used, such as pravastatin, fluvastatin, gemfibrozil, or fenofibrate.37 After 12 months, fibrates induced a reduction of 41% and 22% vs. baseline triglyceride and total cholesterol levels, respectively; statins obtained a reduction of 35% and 25% vs. baseline triglyceride and total cholesterol levels, respectively, in HIV-infected patients on PI-based antiretroviral therapy.41 In study AI424-067, switching the PI component of HAART to atazanavir (400 mg) demonstrated reductions of a similar magnitude; at week 48, in the immediate-switch atazanavir group, a reduction of 35% and 17% was observed in triglyceride and total cholesterol levels, respectively. However, a study directly comparing switching to atazanavir to the use of lipid-lowering agents has not been performed.
Treatment with atazanavir was generally safe and well tolerated. A switch to atazanavir resulted in no change in overall safety and no new safety issues among patients exposed to atazanavir for the full 48 weeks or after switching from their comparator PIs at week 24. The rates of discontinuation due to AEs were low (≤3%). Consistent with the known effects of atazanavir on serum bilirubin levels, 26% of patients in the immediate-switch group and 20% in the delayed-switch group were reported to have grade 3 to grade 4 abnormalities in total bilirubin. In this study population, with 10% of patients coinfected with hepatitis B and/or C, a switch to atazanavir resulted in very low rates (3 or fewer patients) of grade 3 to grade 4 elevations in hepatic transaminases.
These results provide the first evidence from a powered randomized study to suggest that a switch from a stable regimen containing a boosted or unboosted PI to unboosted atazanavir in HIV-infected patients with elevated fasting LDL cholesterol levels is associated with an improved lipid profile that is sustained through 48 weeks. The safety risk of a switch to an atazanavir-based regimen seems to be low. In determining how to manage hyperlipidemia in HIV-infected patients on HAART, clinicians need to compare the risks of new treatment-related toxicities and the possibility of virologic relapse when antiretroviral drugs are switched with the risks of potential drug interactions and new treatment-related toxicities from lipid-lowering agents that are added to existing regimens.35 Considering a change to atazanavir to achieve an improvement in plasma lipids for patients with no prior history of virologic failure on PI-based regimens is a viable option, but clinicians should evaluate the benefits and risks of such a treatment change carefully.
The authors are grateful to the many persons with HIV infection who volunteered for this study. In addition, we acknowledge Dr. Stacey Shehin, i3 Statprobe, Ann Arbor, MI, for assistance in preparation and editing of this article.
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The following members of the 067 Study Group participated in subject recruitment, enrollment, medical management, and data collection: William Powderly, MD, St. Louis, MO; Joseph Jemsek, MD, Huntersville, NC; Robert Eng, MD, East Orange, NJ; Dorece Norris, MD and Daniel Seekins, MD, Tampa, FL; Margaret Fischl, MD, Miami, FL; Chris Tsoukas, MD, Montreal, Canada; Livette Johnson, MD, New York, NY; Sharon Walmsley, MD, Toronto, Canada; Juan Sierra, MD, Mexico city, District Federal Mexico; Stefan Esser, MD and Essen, Germany; Prof Reinhold Schmidt, Hannover, Germany; Fernando Aiuti, MD, Rome, Italy; Alain Lafeuillade, MD, Toulon, France; Prof Jacques Reynes, Montpellier, France; Prof Daniel Vittecoq, Villejuif, France; Michele Bentata, MD, Bobigny, France; Prof Frederic Lucht, Saint Etienne, France; Miguel Jimenez Gorgolas, MD, Madrid, Spain; Juan Gonzalez Garcia, MD, Madrid, Spain; Juan Maria Gonzalez Lahoz, MD, Madrid, Spain; Pere Domingo, MD, Barcelona, Spain; Giuliano Stagni, MD, Perugia, Italy; Karam Mounzer, MD, Philadelphia, PA; Margaret Johnson, MD, London, United Kingdom; Gary L. Simon, MD, Washington, DC; Gracy McComsey, MD, Cleveland, OH; Mark Bloch, MD, Darlinghurst, Australia; Cheryl K. MacDonald, MD, Fort Worth, TX; Javier O. Morales Ramirez, MD, San Juan, Puerto Rico; Rohut Talwani, MD, Columbia, SC; Leonard Slater, MD, Oklahoma City, OK; Isidro G. Zavala Trujillo, MD, Zapopan, Jal, Mexico; Prof Jean-Michel Molina, Paris, France; Cecilia Shikuma, MD, Honolulu, HI; Prof Francisco Antunes, Lisbon, Portugal; Beatriz Grinsztejn, MD, Rio de Janeiro, Brazil; Jose Henrique Piloto, MD, Rio de Janeiro, Brazil; Flavio Telles, MD, Curitiba, Brazil; Jose Luiz Andrade, MD, Curitiba, Brazil; Waldo Belloso, MD, Buenos Aires, Argentina; Carlos Zala, MD, Buenos Aires, Argentina; Claudia Rodriguez, MD, Buenos Aires, Argentina; Sergio Lupo, MD, Santa Fe, Argentina; Elida Pallone, MD, Buenos Aires, Argentina; Angel Minguez, MD, Cordoba, Argentina; Arnaldo Casiro, MD, Buenos Aires, Argentina; Norma Luna, MD, Cordoba, Argentina; Jorge Corral, MD, Buenos Aires, Argentina; Abel Jasovich, MD, Buenos Aires, Argentina; Isabel Cassetti, MD, Buenos Aires, Argentina; Luis Noriega, MD, Santiago, Chile; Carlos Perez, MD, Santiago, Chile; Marcelo Wolff, MD, Santiago, Chile; Juan Echevarria, MD, Lima, Peru; Raul Salazar, MD, Lima, Peru; Andres Paredes, MD, Lima, Peru; and Frederico Rangel, MD, Recife, Brazil.