Inferiority of IL-2 alone versus IL-2 with HAART in maintaining CD4 T cell counts during HAART interruption: a randomized controlled trial
Porter, Brian Oa; Anthony, Kara Ba; Shen, Jeanb; Hahn, Barbarab; Keh, Chris Ea; Maldarelli, Frankc; Blackwelder, William Ca; Lane, Henry Clifforda; Kovacs, Joseph Ad; Davey, Richard Ta; Sereti, Irinia
aNational Institute of Allergy & Infectious Diseases, USA
bCritical Care Medicine Department, USA
cNational Cancer Institute, USA
dClinical Center, National Institutes of Health, Bethesda, Maryland, USA.
Received 11 June, 2008
Revised 10 September, 2008
Accepted 29 September, 2008
Correspondence to Dr Irini Sereti, National Institutes of Health, Building 10-Magnuson Clinical Center, Room 11C103, 10 Center Drive, Bethesda, MD 20982, USA. Tel: +1 301 496 5533; fax: +1 301 402 4097; e-mail: email@example.com
Objective: To evaluate whether interleukin (IL)-2 in patients with chronic HIV infection can maintain CD4 T cell counts during 6 months of HAART interruption.
Design: Prospective, randomized, controlled, open-label phase II noninferiority trial comparing IL-2 with HAART interruption or continuous HAART.
Methods: Forty-one IL-2-experienced (three or more prior cycles) HIV-1-infected adults with CD4 cell count at least 500 cells/μl were randomized in the ratio 2: 1 to interrupted (I = 27) or continuous (C = 14) HAART for 6 months following an initial IL-2 cycle. Subsequent IL-2 cycles were triggered by CD4 T cell counts less than 90% of baseline. Immune, metabolic, and quality of life indices were compared (Mann–Whitney and Fisher's exact tests), defining noninferiority as a percentage difference (C– I) in treatment success (CD4 T cells ≥90% of baseline at 6 months) with a 95% confidence interval (CI) lower limit greater than −20%.
Results: Demographic and immune parameters were similar between the groups at baseline. Median CD4 T cell count, HIV viral load, and treatment success differed significantly at 6 months (I: 866 cells/μl, 39 389 copies/ml, 48.1%; C: 1246 cells/μl, <50 copies/ml, 92.3%; P ≤ 0.001). Group I was inferior to C (% difference = −44.2%; 95% CI: −64.2%, −11.2%; P = 0.013). Minor statistically significant differences in HgbA1c and energy level occurred at 6 months (I > C). Following HAART interruption, single cases of acute retroviral syndrome, secondary syphilis, non-Hodgkin's lymphoma, and Kaposi's sarcoma recurrence were observed.
Conclusion: IL-2 alone was inferior to IL-2 with HAART in maintaining baseline CD4 T cell counts. HAART interruption had a small impact on metabolic parameters and quality of life.
HAART has dramatically improved the outcome of HIV infection [1–3] but can be associated with high costs, medication fatigue, and adverse effects, including hepatotoxicity  and a metabolic lipodystrophy syndrome involving insulin resistance, hyperlipidemia, and fat redistribution [5,6]. HAART interruption strategies have been evaluated to minimize these adverse effects , but their safety was questioned by several large, randomized studies [8–12], which revealed increased rates of HIV disease progression and non-HIV-associated clinical events (e.g., the Strategies of Management of Anti-Retroviral Therapy (SMART) trial ).
In attempts to abrogate CD4 T cell losses and reemergence of HIV viremia seen with HAART interruption, immunomodulatory approaches, including interleukin (IL)-2 cytokine therapy, have been evaluated. When used with antiretroviral agents (ARV), intermittent courses of intravenous or subcutaneous IL-2 can significantly expand the CD4 T cell pool in HIV-infected patients [13,14]. This results primarily from increased survival of naive [15,16] and central memory [17,18] CD4 T cells, including a cytokine-expanded naive CD4+CD25+ FoxP3-expressing subset, which resembles regulatory T cells [19,20]. Two international, multicenter, phase III clinical trials [Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT), Study of IL-2 in People with Low CD4+ T Cell Counts on Active Anti-HIV Therapy (SILCAAT)] are currently underway to determine the clinical relevance of these IL-2 effects with regard to HIV disease progression [21,22].
In addition to its adjuvant role in ARV therapy [13,23–25], IL-2 has also been studied with therapeutic immunization [26,27] and in the absence of ARV [14,28–30]. The potential role of IL-2 during HAART interruption was studied in AIDS Clinical Trials Group (ACTG) 5102 , which evaluated IL-2 recipients versus nonrecipients with chronic HIV infection following HAART interruption. Although higher CD4 T cell counts were observed with IL-2, no differences were noted in virologic rebound or in the time for CD4 T cell counts to fall below 350 cells/ml. The kinetics of CD4 T cell expansion with IL-2 was were also studied in a self-paired National Institutes of Health (NIH) cohort of HIV-infected patients – first, in the presence of continuous HAART and, second, followed immediately by HAART interruption. This revealed short-term CD4 T cell count increases in both settings, although to a lesser extent with HAART interruption .
The present study (ICARUS or Interrupted versus Continuous Antiretrovirals involving Randomization from the Umbrella Study) was a randomized, controlled trial in which HIV-infected, IL-2-experienced patients first underwent a baseline IL-2 cycle on HAART and were then randomized to either HAART interruption and intermittent IL-2 therapy or continuous ARV for a minimum of 6 months. The ability of IL-2 to maintain CD4 T cells off HAART was evaluated, as well as whether 6 months of HAART interruption could mitigate ARV-associated lipodystrophy syndrome, reduce hepatotoxicity, and improve quality of life.
Forty men and one woman with HIV-1 infection were recruited between September 2002 and June 2005, primarily from an NIH IL-2-recipient follow-up protocol . Inclusion criteria were a minimum of three preenrollment IL-2 cycles, a CD4 T cell count at least 500 cells/μl, and willingness to interrupt or maintain HAART for 6 months, per randomization. Exclusion criteria included chronic hepatitis B, participation in other HAART interruption studies within the previous 6 months, malignancy requiring chemotherapy within the past 2 years, HIV complications necessitating ongoing HAART, and multidrug-resistant HIV requiring salvage ARV therapy. The study was approved by the National Institute of Allergy and Infectious Diseases (NIAID) Institutional Review Board (IRB), and all participants signed informed consent.
The ICARUS study was a prospective, controlled, open-label phase II noninferiority trial. All participants received a baseline cycle of subcutaneous IL-2 upon enrollment [3–7.5 million international units (MIU) twice daily for 5 days] at the highest tolerated dose from their last IL-2 cycle. Participants were then randomized 2: 1 to interrupt or continue HAART, using a permuted block design with masked block size. For HAART interrupters, nonnucleoside reverse transcriptase inhibitors were stopped 2 days after the baseline IL-2 cycle, with all other ARV discontinued a week later. All participants had monthly clinical and laboratory evaluations. After the 6-month primary study period, HAART interrupters could continue this intervention over a 6-month extension phase, whereas participants randomized to continuous HAART could crossover to interrupt ARV (i.e., late HAART interrupters) for the next 6 months or end study participation.
Over the entire 12-month study period, intermittent courses of IL-2 were given up to every 8 weeks to participants in either group, if consecutive CD4 T cell counts drawn at least 1 week apart declined to less than 90% of baseline, allowing for a maximum of three additional IL-2 cycles during the 6-month primary study phase. HAART could be restarted at any point according to patient's desirability, clinical indication, or if CD4 cell count fell to less than 350 cells/μl on two occasions within 8 weeks of receiving an IL-2 cycle. HAART interrupters received 10 days of non-abacavir protease inhibitor-based HAART with each 5-day IL-2 cycle, starting 3 days before and stopping 2 days after its completion, to abate possible IL-2-induced HIV replication [31,32].
The primary outcome measure was CD4 T cell count at month 6 (and at least 4 weeks after the last IL-2 cycle), with treatment success defined as maintaining randomization assignment and having a CD4 T cell count at least 90% of baseline. Secondary end-points included HIV viral load at month 6, treatment success at month 12, and rates of change in CD4 T cells and HIV viremia following HAART interruption.
Recombinant human IL-2 was provided by Novartis (Emeryville, California, USA). ARV usage was recorded and monitored throughout the study.
CD4 and CD8 T cell counts (total and percentage) were measured monthly in a Clinical Laboratory Improvement Amendments- approved laboratory. CD4+CD25+ T cells (previously shown to expand with IL-2 ) and peripheral blood mononuclear cell (PBMC) 3H-thymidine proliferation assays using HIV p24, tetanus toxoid, and phytohemagglutinin  were also followed.
HIV viral load was measured by ultrasensitive branched DNA assay (bDNA version 3, Chiron Corporation, Emeryville, California, USA) with a lower detection limit of 50 copies/ml. HIV genotyping (TRUGENE, Visible Genetics Inc., Suwanee, Georgia, USA) was performed at baseline or a preenrollment time point with HIV RNA more than 1000 copies/ml, the initial time point with similar viral rebound following HAART interruption, and at end-of-study or prior to resuming ARV (whichever occurred first) to check for new resistance mutations, using TRUGENE Guidelines. Additional preenrollment genotypes were completed as needed to determine whether mutations were preexistent, though not detected at baseline. Participants who remained off HAART after end-of-study were followed up to 4 years to assess their capacity to suppress HIV viremia upon restarting ARV.
Metabolic function and quality of life measures
Metabolic indices measured at baseline and month 6 included external body composition (weight; BMI; % body fat; multisite skinfold widths, including suprailiac, subscapular, biceps, triceps, calf, and abdomen; limb circumferences for forearm, mid-arm, calf, and thigh; body widths at the hips, waist, abdomen, and neck) and both subcutaneous and visceral adiposity determined via single-slice axial computed tomography at lumbar vertebral levels 2–3 and 4–5 . Markers of endocrine and hepatic function included total cholesterol, high-density lipoprotein, low-density lipoprotein, fasting triglycerides, apolipoprotein A1 and B, glycosylated hemoglobin (HgbA1c), oral glucose tolerance testing (75 gm bolus), thyrotropin, free and total thyroxine, triiodothyronine, reverse triiodothyronine, uric acid, L-lactate, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and total bilirubin. The MOS-HIV Health Survey, an established tool in HIV-related quality of life research [36–38], was also administered.
Both intent to treat and per protocol analyses were performed. For the primary study end-point, the likelihood score method  was used to determine a two-sided 90% confidence interval (CI) to estimate the difference in proportions of participants with treatment success between interrupted and continuous HAART groups at month 6. The target sample size of 65 participants would have provided 79% power to obtain a lower confidence limit greater than −0.2 for P (interrupted) − P (continuous), assuming 90% treatment success and 10% attrition [equivalent to 79% power to reject H0: P (interrupted) − P (continuous) ≤−0.2 at a one-sided 5% significance level]. Due to slow recruitment, enrollment was closed at 41 participants, providing 80% power for two-sample t-tests of laboratory parameters with an effect size at least one SD at a two-sided 5% significance level. Mann–Whitney and Wilcoxon signed-rank tests were used for nonparametric median comparisons between and within groups, respectively, whereas Fisher's exact test was used for proportional comparisons.
Safety monitoring was completed via interview and laboratory assessment, following the Food and Drug Administration adverse event criteria and NIAID IRB guidelines. Adverse events were graded on a predetermined toxicity scale from 0–4.
Protocol flow of study participants is summarized in Fig. 1. Demographic and baseline characteristics are shown in Table 1.
Interleukin-2 cycling and HAART resumption
Following the baseline IL-2 cycle, the need for additional on-study IL-2 cycling triggered by CD4 T cell counts less than 90% of baseline differed between the groups, with eight (29.6%) HAART interrupters receiving a single IL-2 cycle each during the primary phase (median of 52.5 MIU per participant) and 15 (51.9%) receiving a total of 17 cycles during the secondary phase (median of 45 MIU per participant). In contrast, no one in the continuous HAART group required IL-2 during the primary phase and only three (30%) late HAART interrupters received a single IL-2 cycle each during the secondary phase (median of 45 MIU per participant).
No early HAART interrupters restarted ARV during the primary phase, although six (22.2%) restarted during the extension phase due to falling CD4 cell counts or rising HIV viremia, and one restarted after end-of-study due to a B cell lymphoma. By comparison, two (20%) late HAART interrupters restarted ARV while on-study (Fig. 1) due to an acute ARV syndrome and a case of secondary syphilis, with another restarting at end-of-study for recurrent Kaposi's sarcoma. Of the remaining participants, all but two early and two late HAART interrupters restarted ARV after end-of-study due to decreased CD4 cell counts or increasing viremia.
Primary outcome: treatment success at month 6
A larger proportion of participants (92.3%) in the continuous HAART group maintained CD4 T cell counts within 10% of baseline at month 6 (the primary study end-point), compared with HAART interrupters [48.1%, P = 0.013, Fisher's exact test] (Table 2). The 95% CI for the difference in these proportions (from −64.2 to −11.2%, interrupted–continuous) had a lower limit well below the predetermined noninferiority standard of −20%. Figure 2a depicts lower median CD4 T cell counts in interrupted in comparison with continuous HAART groups throughout the primary study phase and at month 6 (P < 0.001). Thus, IL-2 with HAART interruption was inferior in terms of treatment success at month 6, compared with IL-2 with continuous HAART.
One participant in the continuous HAART arm withdrew from the study after 4 months in order to stop ARV. Inclusion of that participant as a treatment nonsuccess gives P value 0.041 for the difference in treatment success rates, and the noninferiority criterion is still not met. As month 6 data are unavailable for that participant, he was excluded from all other analyses.
Secondary metabolic and quality of life analyses
No significant differences were observed in anthropometric indices between the interrupted and continuous HAART groups at baseline or month 6 (Mann–Whitney test; data not shown). For laboratory measures (Table 3), significantly lower values were seen at month 6 in the interrupted compared with continuous HAART group for total cholesterol (161 versus 190 mg/dl, P < 0.05) and apolipoprotein A1 (98.5 versus 111 mg/dl, P < 0.05). In contrast, HgbA1c was significantly higher in HAART interrupters at month 6 (5.4 versus 4.95%, P < 0.001). However, medians in both groups at baseline and month 6 were within normal range (<6%).
Physical and mental health scores on the MOS-HIV did not differ significantly between the groups at either time point (data not shown). However, the change in score from baseline to month 6 on the Energy/Fatigue subscale (a vitality measure from 0 to 100) was significantly greater in HAART interrupters compared with continuous HAART participants (interrupted: median change = 5, 95% CI: 0, 15; continuous: median change = −5, 95% CI: −25, 0; P < 0.001). Of note, completion rates for the MOS-HIV were lower at month 6 (interrupted = 74.1%, continuous = 84.6%) than at baseline (interrupted = 96.3%, continuous = 92.3%).
Secondary treatment success analyses
Treatment success rates at month 6 versus month 12 within early HAART interrupters (48.1 versus 22.2%; P = 0.016; McNemar test) indicated declines in CD4 T cells observed in the primary study phase did not abate during the extension phase. Treatment success rates in early HAART interrupters at month 6 (n = 27) and late HAART interrupters at month 12 (n = 10) revealed no difference whether HAART interruption occurred immediately (48.1%) or 6 months (50%) after the baseline IL-2 cycle (Fisher's exact test; P = 1.0).
Rates of change in HIV viral load and CD4 T cell count
Logistic regression analysis was used to calculate median rates of change in HIV viral load and CD4 T cell count over the first 6 months of HAART interruption, using all data points until first HAART reexposure (i.e., either IL-2 cycling or resumption of HAART). To evaluate the effects of timing of HAART interruption relative to the baseline IL-2 cycle, median rates of change were compared between early and late HAART interrupters. No significant difference in rate of HIV viral load increase was seen (early: 6356 copies/ml per month, late: 1162 copies/ml per month; P = 0.16; Mann–Whitney test). However, the rate of CD4 T cell decline was steeper in late (−96 cells/μl per month) than in early (−38 cells/μl per month) HAART interrupters (P < 0.001), indicating that 6 months of HAART following a baseline IL-2 cycle did not mitigate and, in fact, may have exacerbated this decline (Fig. 2b).
Median rates of change were also compared in intragroup analyses within early or late HAART interrupters between subjects considered treatment successes versus nonsuccesses. Within early HAART interrupters, although the rates of HIV viral load increase did not differ significantly (nonsuccesses: 7631 copies/ml per month, successes: 3174 copies/ml per month; P = 0.20), treatment nonsuccesses had a steeper CD4 T cell decline compared with treatment successes (77 versus 3 cells/μl per month; P < 0.001; Fig. 2c). Similar comparisons among late HAART interrupters did not reveal any significant differences (data not shown).
T cell phenotype and function
The percentage of CD4+CD25+ T cells did not differ between the groups at baseline (17% for both groups, P = 0.77) but was significantly lower in HAART interrupters at month 6 (18 versus 29%, P = 0.018). No significant differences in PBMC proliferative responses to HIV p24, tetanus toxoid, or phytohemagglutinin were observed between interrupted and continuous HAART groups or early and late HAART interrupters during the primary or secondary phases (data not shown). Proportional (Fisher's exact test) and median (Mann–Whitney test) comparisons were done to identify predictors of treatment success in either early or late interrupters, including baseline HIV viral load less than 50 copies/ml, peak on-study HIV viral load, nadir and baseline CD4 T cell counts, %CD4, and %CD4+CD25+ T cells. Only nadir CD4 count in early HAART interrupters significantly differed between treatment successes (422 cells/μl) and nonsuccesses (248.5 cells/μl; P = 0.023).
Grade 3 adverse events were constitutional symptoms previously reported with IL-2 therapy , including fatigue (n = 8), fever (n = 2), and abdominal pain (n = 2). The only Grade 4 event was an episode of transient hyperbilirubinemia due to underlying Gilbert's syndrome. Significant clinical events were detailed in the section on HAART resumption.
HIV genotypic analysis indicated no novel resistance mutations emerged following HAART interruption, although two changes were noted. An early HAART interrupter with a reverse transcriptase T215Y change prior to enrollment developed a T215NTDA mutation, which reflects preexisting polymorphisms in ARV-naive individuals, as reversion from T215Y often occurs after HAART interruption. Another common polymorphism in ARV-naive individuals (protease I15V mutation; Stanford HIV Drug Resistance Database ) was observed in a late HAART interrupter. All participants who restarted HAART had virologic suppression to less than 50 copies/ml, except for two who continued treatment interruption beyond end-of-study: the first had documented medication nonadherence and the second had no prior HIV viral loads of less than 50 copies/ml, though after restarting HAART, his viral load decreased by more than 1 log from 9742 to 781 copies/ml.
The present prospective, randomized trial demonstrated IL-2 alone was inferior in maintaining CD4 T cell counts at least 90% of baseline in IL-2-experienced recipients after 6 months of HAART interruption, compared with IL-2 along with HAART. Despite a baseline IL-2 cycle administered in the setting of moderate to high CD4 T cell counts (range: 538–1390 cells/μl) and largely suppressed HIV viremia, this immune intervention could not sufficiently overcome the CD4 T cell declines associated with HAART interruption, as compared with patients who received IL-2 and remained on HAART.
Several phase II studies [13,18,24,25,42] have documented IL-2 dose-dependent expansions of CD4 T cells, with increases in naive and memory subsets due to improved survival and decreased immune activation when administered with HAART. The immune restoration conferred by HAART alone is incomplete, however, despite reductions in CD4 T cell activation, turnover, and lymphopenia [43–46]. Thus, significant interest remains in IL-2 to augment the benefits of HAART by further reducing immune activation , as changes in plasma HIV RNA explain only 3–6% of the variability in CD4 T cell loss [48,49].
Regarding its use with HAART interruption, the results of Agence Nationale de Recerche sur le Sida (ANRS) 095  and ACTG 5102  suggested IL-2 conferred no benefit to HIV-infected persons, regardless of whether ARV were initiated during primary infection or later in the disease. Nonetheless, earlier data from the ICARUS cohort comparing preenrollment and baseline IL-2 cycling indicated CD4 T cell increases were achievable with IL-2 followed by HAART interruption .
The recently published TILT trial demonstrated IL-2 could reduce the probability of restarting ARV by 50% following 2 years of HAART interruption . The different conclusions in ICARUS and TILT may be explained by the stricter criterion for treatment success used in the former. Whereas we sought to maintain CD4 T cells within 10% of baseline levels (947 cells/μl), in TILT, IL-2 cycles were triggered by CD4 T cell counts less than 350 cells/μl, and HAART was restarted for CD4 T cell counts less than 200 cells/μl . In fact, CD4 T cell increases following IL-2 with HAART were similar in these studies, with half the HAART interrupters in ICARUS qualifying as treatment successes at month 6. This occurred despite the potential for self-referral bias within the ICARUS cohort of patients who tolerated IL-2 well and had high baseline CD4 T cell counts.
As in past studies [28,52,53], higher CD4 T cell nadirs were associated with treatment success (i.e., higher CD4 cell counts) in the ICARUS cohort, although baseline CD4 cell count [52,54] and HIV viral suppression  were not. Whereas lack of CD4+CD25+ T cell expansion in early HAART interrupters suggested the importance of viral suppression in the IL-2-induced expansion of this subset [19,20,33], delaying HAART interruption for 6 months after a baseline IL-2 cycle was not more successful in maintaining CD4 T cells, despite greater CD4 cell count increases and prolonged viral suppression prior to interruption. This was reflected in similar treatment success rates in early and late HAART interrupters, with a steeper CD4 cell count decline in the latter (−96 cells/μl per month), similar to previous studies [28,55]. By comparison, CD4 declines in IL-2-naive patients following HAART interruption range widely in the literature from −10 to −200 cells/μl per month [28,55–57].
Six months of HAART interruption in our study also provided little benefit to HAART interrupters, with only small decreases in total cholesterol (similar to ACTG 5102 ) and apolipoprotein A1. Although HgbA1c was lower in the continuous HAART group at month 6, the clinical relevance of this is unclear, as values in both groups remained within normal range. This may reflect the expected increase in erythrocyte life span after stopping nucleoside reverse transcriptase inhibitors and reducing subclinical hemolysis . A small (10% median group difference) though significant increase in energy level from baseline to month 6, as measured by the MOS-HIV Health Survey, was also observed in interrupted compared with continuous HAART participants, indicating IL-2 cycling (which was more frequent in HAART interrupters) did not adversely affect this quality of life measurement.
The findings of the ICARUS trial showed that IL-2 alone was inferior in maintaining baseline CD4 T cell counts after 6 months of HAART interruption, compared with IL-2 along with HAART. In the post-SMART era , HAART interruptions are of limited scope and conducted under close supervision in clinical trials. However, adjunctive therapies to limit HAART exposure and abrogate the chronic inflammation of HIV infection (presumed to be a major cause of non-HIV-related complications [12,60]) merit exploration. Studies are underway to evaluate the capacity of IL-2 to delay HAART initiation in early HIV infection (STALWART) , and preliminary data from ANRS 119 suggest IL-2 can delay CD4 T cell decline and prolong time to an AIDS-defining event or HAART initiation in ARV-naive individuals . Although unlikely to be of value as part of a HAART interruption strategy, the clinical impact of IL-2 in HIV disease will become clearer with the availability of data from the ESPRIT and SILCAAT trials.
The authors would like to thank all study participants and the staff of outpatient clinic 8 at NIAID for their help in completing this trial, Christine Salaita for collecting anthropometric measurements, and Francine Thomas for reading the CT scans. B.P. contributed to data organization, analysis, and interpretation, and wrote the article. K.A., B.H., C.L., J.K., and R.D. contributed to the development and implementation of the protocol, and review of the article. J.S. contributed to the implementation of the protocol, data organization and analysis, and review of the article. C.K. and F.M. contributed to data organization, analysis, and interpretation, and review of the article. W.B. contributed to development of the protocol, data organization, analysis, and interpretation, and review of the article. I.S. contributed to the development and implementation of the protocol, data organization, analysis, and interpretation, and editing of the article. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy & Infectious Diseases, Clinical and Molecular Retrovirology Section (Bethesda, Maryland).
The US Government has been granted a patent for the use of intermittent subcutaneous IL-2 as therapy in HIV infection, listing H.C. Lane and J.A. Kovacs as coinventors.
This work was funded through the National Institute of Allergy & Infectious Diseases Clinical and Molecular Retrovirology Section of the National Institutes of Health (Bethesda, Maryland, USA). Human recombinant IL-2 was provided by Novartis (Emeryville, California, USA).
These findings have not been published previously in their present form. However, preliminary data from this study were presented at the 2008 Conference on Retroviruses and Opportunistic Infections (CROI) and were published in abstract form (Abstract #706) in the 2008 CROI Proceedings (Boston, Massachusetts; February 3-6, 2008).
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