Effect of intermittent interleukin-2 therapy on CD4+ T-cell counts following antiretroviral cessation in patients with HIV
Lévy, Yvesa,b,c,*; Thiébaut, Rodolphed,e,f,*; Gougeon, Marie-Liseg; Molina, Jean-Michelh; Weiss, Laurencei; Girard, Pierre-Mariej; Venet, Alaink; Morlat, Philipped,f; Poirier, Béatriceg; Lascaux, Anne-Sophiec; Boucherie, Célined; Sereni, Danielh; Rouzioux, Christinel; Viard, Jean-Paulm; Lane, Cliffn; Delfraissy, Jean-Françoiso; Sereti, Irinin; Chêne, Genevièved,e,f; the ILIADE Study Group
aINSERM, Unite U955
bUniversite Paris-Est, Faculte de Medecine, UMR-S 955
cAssistance Publique-Hôpitaux de Paris (AP-HP), Groupe Henri-Mondor Albert-Chenevier, service d’immunologie clinique, Creteil
eUniversity Bordeaux Segalen, ISPED
fCHU Bordeaux, Bordeaux
gInstitut Pasteur, Antiviral Immunity, Biotherapy and Vaccine Unit
hAP-HP, Saint Louis Hospital
iAP-HP, Hopital Européen Georges Pompidou
jAP-HP, Saint-Antoine Hospital, Paris
kINSERM, U1012, Kremlin-Bicêtre
lAP-HP, Hôpital Necker, Université Paris Descartes
mAP-HP, Hôtel Dieu, Paris, France
nNational Institutes of Health, Bethesda, Maryland, USA
oAP-HP, Hôpital Kremlin-Bicêtre, Kremlin-Bicêtre, France.
*Yves Lévy and Rodolphe Thiébaut contributed equally to the writing of this article.
†The investigators participating in the ILIADE study are listed in Acknowledgements section.
Correspondence to Professor Yves Lévy, Service d’Immunologie Clinique, Hopital Henri Mondor, 51 Avenue Marechal de Lattre de Tassigny, 94010 Créteil, France. E-mail: firstname.lastname@example.org
Received 16 April, 2011
Revised 4 January, 2012
Accepted 18 January, 2012
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Background: Interleukin (IL)-2 therapy impacts T-cell homeostasis. Whether IL-2 expanded CD4+ T cells may persist following viral rebound has not been fully investigated.
Methods: Patients with CD4+ T cells 500/μl or more and HIV RNA less than 50 copies/ml were randomized to continue antiretroviral therapy (ART) either alone (n = 67) or combined with three IL-2 cycles (n = 81; 6 million units) twice daily for 5 days at weeks 0, 8, and 16 before stopping ART (week 24). Patients were followed up to 168 weeks.
Results: At week 24, median CD4+ T-cell counts were 1198 and 703 cells/μl in the IL-2 and control groups, respectively (P < 0.001). At week 72, 27% (IL-2 group) and 45% (control group; P = 0.03) of patients were in failure (defined as no interruption of ART at week 24, CD4 drop below 350 cells/μl or ART resumption). After week 24, a biphasic decline (before and after week 32) of CD4 was noted −106 and −7 cells/μl per month in controls and −234 and −17 in IL-2 group (all P ≤ 0.0001). At week 96, IL-2-expanded CD4+CD25+ T cells remained higher than in the control group (26 vs. 16%, P = 0.006).
Conclusion: In IL-2-treated patients, CD4+CD25+ T cells persisting despite viral replication allow a longer period of ART interruption.
Intermittent interleukin (IL)-2 therapy leads to significant and sustained increases of CD4+ T cells in HIV-1-infected patients [1–5]. Recent phase III SILCAAT (Subcutaneous Recombinant, Human Interleukin-2 in HIV-infected Patients with Low CD4+ Counts Under Active Antiretroviral Therapy) and ESPRIT (Evaluation of Subcutaneous Interleukin-2 in a Randomized International Trial) studies show that IL-2 expansion of CD4+ T cells do not translate into better clinical outcomes as compared to patients treated with antiretroviral therapy (ART) alone . One hypothesis is that the CD4+ T cells generated with IL-2 do not confer the same quality of host defenses as compared to CD4+ T-cell restoration following ART. In support to this, our group found that a small proportion of these cells exhibited phenotypic and functional characteristics of regulatory T cells  that might be associated with a lower protection toward AIDS clinical progression. Another explanation is that there are harmful effects of IL-2 that counterbalance any positive effect.
Regardless of the explanation, CD4+ T-cell counts generated in the context of IL-2 therapy cannot be considered as a valid surrogate marker of clinical benefit. Therefore, additional analyses of the effects of IL-2 on CD4+ T cells in various clinical situations may provide useful information about T-cell homeostasis in HIV-1 infection and insights about emerging immune-based therapies. To achieve this aim, several groups of investigators initiated different phase II studies prior or in parallel to the SILCAAT and ESPRIT trials in order to evaluate the potential benefit of intermittent IL-2 therapy as a strategy to defer ART initiation [8,9] or to maintain CD4+ T cells following ART cessation in patients with high CD4+ T-cell counts under ART.
Patients may have a similar survival to uninfected individuals once they reach normal ranges of CD4+ T-cell counts . It is, therefore, of utmost importance to study new treatment strategies that may allow patients to restore or maintain the CD4+ T-cell pool [10–13]. Despite a large set of data generated in IL-2-treated patients, whether IL-2 expanded CD4+ T cells may persist in the long term following viral rebound was not completely investigated [14–17]. Previous studies evaluating IL-2 in the context of antiretroviral interruption showed that the immunotherapy helps in maintaining higher CD4+ T-cell counts [15,16], thanks to an effect on CD4+ T-cell turnover even with detectable viremia . Whether IL-2 expanded CD4+CD25+ T cells and ‘conventional CD4+CD25−′ T cells behave differently over the long term following viral rebound in patients who stop ART is unknown.
Several studies have shown an inverse correlation between T-cell activation and impaired CD4 restoration in ART-treated patients [18,19]. Based on previous phenotypic studies, IL-2-expanded CD4+ T cells may be of potential importance as a population of cells with low activation phenotype (low expression of CD38 and/or DR molecules) [15,16] because virologically suppressed patients on ART still maintain levels of activated CD4 and CD8 T cells that are significantly higher than those in HIV-negative individuals.
We assessed whether CD4+ T-cell increases under IL-2 therapy may help maintain high CD4+ T-cell counts following ART cessation in chronically HIV-infected patients with CD4+ T-cell counts above 500 cells/μl over 3 years. We also compared the homeostasis of IL-2-expanded CD4+ T cells during ART and following ART cessation.
This multicenter, randomized, open-label trial carried out at 23 centers in France and one site in the USA was approved by the ethics committee of the Hospital Henri Mondor (Clinical trials registration number NCT00071890) and the National Institute of Allergy and Infectious Diseases (NIAID). All patients gave written informed consent. Patients were randomly assigned 1 : 1 to intermittent IL-2 therapy or to no IL-2. In the IL-2 group, patients underwent three cycles of 6 million international units (MIU) of recombinant IL-2 (aldesleukin; Chiron, Emeryville, California, USA) subcutaneously twice a day for 5 consecutive days at weeks 0, 8 and 16. At week 24, patients who had CD4+ T-cell counts 500 cells/μl or more were proposed to interrupt ART. IL-2 maintenance therapy was not administered during the period of interruption of antiretroviral treatment. ART could be resumed at any point after interruption if the patients or their doctors wished so, if the CD4+ T-lymphocyte counts dropped below 350 cells/μl, or in case it was clinically indicated (Figure 1a).
Eligible patients were asymptomatic HIV-1-infected adults who had CD4+ T-cell counts at least 500 cells/μl and plasma HIV RNA less than 50 copies/ml at screening and within the previous 3 months. They had to receive an ART regimen (defined as two nucleoside reverse transcriptase inhibitors and either one nonnucleoside reverse transcriptase inhibitors or a boosted protease inhibitor) for at least 12 months and nadir CD4+ T-cell counts more than 200 cells/μl prior to study entry. Major exclusion criteria were a history of autoimmune disease, coinfection with hepatitis B virus treated with lamivudine, pregnancy, and concomitant or previous treatment with interferon, other cytokines, anti-HIV vaccines, steroids or any other immunomodulators.
Patients were assessed at baseline, and every 8 weeks thereafter until they completed week 72. Routine analyses were performed at each site throughout the follow-up period and included a complete blood count, CD4+ T-cell count, measurement of plasma HIV-1 RNA (using the Ultrasensitive Roche Amplicor assay with a lower limit of detection of 50 copies/ml). When a CD4+ T-cell counts of 350 cells/μl or less was measured at a visit, a second sample had to be drawn 2 weeks later for confirmation of immunologic failure. In that case, initiation of ART was recommended. Further phenotypic tests were performed at baseline and at weeks 24 and 48 among the first 60 patients enrolled in centers located in the Paris area for an immunologic substudy. Phenotyping of naive (CD45RA+CCR7+), central memory (CD45RA−CCR7+), effector memory (CD45RA−CCR7−), and effector (CD45RA+CCR7−) CD4+ and CD8+ T cells was performed as previously described by flow cytometry . Expression of activation markers (CD38) on CD4+ and CD8+ T cells was assessed as well as the proportion of CD4+ T cells expressing CD25, the α chain of the IL-2 receptor. Among these patients, three had an additional phenotypic evaluation performed twice a week at weeks 25, 26 and 28.
Safety was assessed through the reporting of adverse events and laboratory abnormalities, the severity of which was assessed with use of the Agence Nationale de recherche sur le sida et les hepatites (ANRS) toxicity grading scale .
Study end points
The primary study end point was the cumulative proportion of patients with protocol-defined treatment success through 72 weeks. Success was defined as the absence of the following components at week 72: lack of ART interruption at week 24, CD4 less than 350 cells/μl on two consecutive measurements, resumption of ART after week 24 for any reason, occurrence of an AIDS-defining event, death or loss to follow-up. Patients who reached either week 72 or the primary outcome were asked to resume ART. After week 72, patients were enrolled in an extended follow-up of 120 (last patients included) to 228 weeks (first patients included). Secondary end points included time to treatment failure, changes from baseline in CD4 and CD8 T-cell counts, changes in plasma HIV RNA levels, probability of any clinical event included in the category C of the 1993 classification of the Centers for Disease Control and Prevention  or death, and time to ART initiation. Safety endpoints included the probability of occurrence of grades 3–4 adverse events and laboratory abnormalities. At its fourth meeting in December 2007, the independent Data Safety Monitoring Board recommended to close the study and to proceed to the final analysis.
The sample size was calculated to detect a 20% difference in the proportion of patients in success of the strategy between the two groups. Based upon a predicted success rate of approximately 60% in the control group through 72 weeks, a total of 90 patients per group were required with a two-sided α level of 0.05, and a statistical power of 80%.
The primary efficacy endpoint was analyzed on an intention-to-treat basis. χ2 tests or Fisher's exact tests were used to compare categorical variables between both groups. Differences in continuous variables between groups were analyzed with Wilcoxon rank-sum tests, and Wilcoxon's signed-rank tests for comparisons within groups. The probability of first occurrence of the events of interest was estimated using the Kaplan–Meier method. The date of origin was the date of randomization.
The estimation of mean changes in CD4+ and CD8+ T-cell counts, and in plasma HIV-1 RNA levels and of the effect of explanatory variables were performed using piece-wise linear mixed effect models separately before and after 24 weeks. Statistical analysis was performed with SAS software v9.1 (SAS Institute Inc., Cary, North Carolina, USA).
From 2003 to 2006, 179 patients underwent screening and 148 were randomized: 81 in the IL-2 group and 67 in the control group (Fig. 1b). The baseline characteristics of these patients were well balanced between the groups (Table 1).
In the IL-2 group, 96% (78 patients), 85% (69 patients) and 79% (64 patients) of patients received first, second and third cycles of IL-2 therapy, respectively. At baseline, week 8 and 16, 22, 30 and 27% experienced a dose reduction, respectively.
Through 72 weeks, 59 patients (73%) in the IL-2 group as compared to 37 patients (55%) in the control group had protocol-defined strategy success (log rank test: P = 0.025). In the IL-2 group, among 22 failures, there were six patients who did not stop ART at week 24, eight patients who experienced two CD4 less than 350 cells/μl (and then resumed ART) and eight who resumed ART for other reasons. In the control group, among 30 failures, there were five, 13 and 10 in each category, respectively. In addition, progression to Center for Diseases Control (CDC) class C events was observed in only one patient (B-cell isolated intraocular lymphoma) through week 72 and one patient was lost to follow-up.
Overall, two patients died: one before week 72 from pulmonary embolism 13.5 months after the last IL-2 injection, and one in the control group after week 72 from bronchial carcinoma.
Between week 72 and the end of follow-up at week 168, when considering all available follow-up, median survival without failure was 133 weeks in the IL-2 group and 87 weeks in control group (P = 0.09; Fig. 2). Figure 3a shows median CD4+ T-cell counts from baseline in both groups throughout the study before ART resumption. At week 24, after three cycles of IL-2, median CD4+ T cells/μl (interquartile range) was 1198 (902; 1428) and 703 (590; 836) in the IL-2 and control group, respectively (P < 0.001). At week 48 and 72, CD4+ T cells/μl were 624 and 541 in the IL-2 group and 526 and 453 in the control group (P < 0.001 and 0.07 at week 48 and week 72, respectively). Beyond week 72, there were no differences in CD4+ T-cell counts between groups (Fig. 3a).
The estimated mean increase in CD4+ T-cell counts between weeks 0 and 24 was more than 78 cells/μl per month [95% confidence interval (CI) +66 to 90] in the IL-2 group, whereas it was stable (more than 2 cells/μl per month, 95% CI −11 to +15) in the control group. When adjusting for other factors (Table 1), the cumulative duration of exposure to ART before inclusion and the level of HIV-1 DNA were associated with the CD4 T-cell counts dynamics before antiretroviral interruption. Indeed, the increase of CD4 T-cell counts was blunted for longer exposure to antiretrovirals (four cells per month less per year of exposure, P = 0.04) and for higher levels of HIV-1 DNA (28 cells/month less per log10 copies/million of peripheral blood mononuclear cells, P = 0.02). None of these factors modified the effect of IL-2 on CD4+ T-cell counts change.
After week 24, we identified a biphasic decline of CD4 with a first slope before week 32 and a weaker decline between week 32 and week 168. These slopes (in cells/μl per month) were significantly different (all P ≤ 0.0001) between the two groups being more pronounced in the IL-2 group (−234 and −17) than in the control group (−106 and −7).
Figure 3b shows actual median plasma HIV-RNA over time. All patients had viral loads less than 50 copies/ml at week 24. Following ART cessation, plasma HIV RNA rebounded up to 4.33 log10 copies/ml (3.86; 4.79) in the IL-2 group and 4.39 log10 copies/ml (3.92; 4.76) in the control group (P = 0.71) and did not change throughout the follow-up period.
Thirty patients from each group participated in an immunologic substudy. Baseline characteristics of these patients were globally similar to the study population with the exception of sex (Table 2 in SDC 1, http://links.lww.com/QAD/A204). In this substudy, at week 24, median CD4+ T cells/μl were 1143 and 653 in IL-2 and control groups, respectively (P < 0.001). These values were 811 and 645 at week 48 (P = 0.01) and 594 and 541 at week 96 (P = 0.57). Analyses of CD4+ T-cell subpopulations in the IL-2 group show that naive, central memory, effector memory cells increased from 356, 284, 57 to 461, 458 and 144 cells/μl (P < 0.006 for all comparisons) at week 24, whereas no changes in terminally differentiated effector memory cells were noted (47 and 42). As expected [2,7], IL-2-expanded-CD4+ T cells expressed CD25 (41% of all CD4 T cells at week 24; Fig. 4a). The proportion of CD4+ T cells expressing CD38 or human leucocyte antigen (HLA-DR) decreased significantly between baseline and week 24 (P < 0.001 and P = 0.041) in the IL-2 group. No significant changes for any of the above markers were noted in the control group (Fig. 4b). Following interruption of ART, between weeks 24 and 48, the median decline of naive, central memory, effector memory and terminally differentiated effector memory populations at week 48 was −96, −119, −40 and −20 cells/μl in the IL-2 group. These values were similar in the control group (P > 0.07 for all comparisons): −61, −35, −12 and −5 cells/μl, so that differences observed at week 24 persisted at week 48. The proportion of CD4+ T cells expressing activation markers (CD38 or HLA-DR) tended to remain lower in IL-2 recipients as compared to controls at weeks 24 and 48 (P = 0.023 and P = 0.081, respectively). IL-2-expanded CD4+CD25+ T cells decreased to 26% at week 96 but remained higher than in the control group (26 vs. 16%, P = 0.006). Conversely, the number of CD4+CD25− T cells decreased after week 24 but did not differ between the two groups (P > 0.07 for all comparisons). The differential expression of the activation markers CD38 and HLA-DR on CD4+CD25+ T cells between IL-2 recipients and controls was even more pronounced than in the total CD4+ T-cell population (Fig. 4b). The pattern of the dynamics of the markers seemed remarkably defined very early after viral rebound as seen in the three patients with highly repeated measurements after treatment interruption (Table 3 in SDC 1, http://links.lww.com/QAD/A204).
Safety and tolerability
A high number of adverse events related to IL-2 administration were reported during the first 24 weeks of the trial. The vast majority of these events were mild (grades 1 to 2). Constitutional symptoms (such as asthenia, fever, nausea…) were the most frequent complaints and accounted for 50% of all adverse events. Among the 17 patients who decided to stop IL-2, adverse effects of IL-2 were involved as the main reason in 11 of them. The number of severe adverse events was low (n = 10 patients; seven in IL-2 group and three in control group). Also, 11 patients (14%) in the IL-2 group and 16 (24%) in the control group experienced grade 3 or 4 laboratory abnormalities (P = 0.11), with a similar number of events in each group. One patient from the IL-2 group (esophageal candidasis) at week 196 and three patients from the control group (ocular B-cell lymphoma, B-cell lymphoma, esophageal candidasis at week 43, 104 and 82, respectively) experienced an AIDS-defining event. Six cardiovascular events occurred in four patients after week 24 (antiretroviral interruption): one myocardial infarction with coronary bypass in a patient presenting an abdominal aneurysm, two strokes (same patient), one pulmonary embolism, one arterial thrombosis. Only one occurred in the IL-2 group (i.e. pulmonary embolism).
The ANRS-National Institute of Health (NIH) ILIADE trial showed that administration of three cycles of IL-2 in HIV-infected patients with high CD4+ T-cell counts and controlled viral load while on ART may significantly delay indication of ART resumption following ART interruption. Longitudinal phenotypic analyses showed a unique behavior and phenotype of IL-2-expanded CD4+ T cells. Despite viral replication, IL-2-expanded CD4+ T cells remained significantly higher than in the control group up to 72 weeks. This effect was related to a significant increase of CD4+ T cells harboring CD25 and expressing a low level of activation markers.
The ANRS/NIH ILIADE trial was designed at a period in which several clinical studies evaluating the potential interest of structured treatment interruption (STI) [22,23] were initiated. The major safety problem for patients enrolled in a study with STI of a short-term duration (less than 6 months) is related to CD4+ T-cell counts drop below 350 cells/μl. Recent studies from our group and others have shown that patients’ survival might be affected if they are exposed to CD4+ T-cell counts less than 500 cells/μl [24,25]. Although the value of CD4+ T-cell counts as a surrogate marker for disease progression in IL-2 therapy setting is highly challenged, the rationale of the use of IL-2 before treatment interruption was to limit CD4+ T-cell decline. Moreover, our study differed in several aspects to the large majority of ART interruption studies [26,27]. First, the population of patients eligible to participate was expected to have a high CD4+ T-cell counts at inclusion (higher than 500) and most patients had still high CD4+ T-cell counts at week 48. Second, the decrease of CD4+ T cells following ART interruption was steeper in the present study and even more pronounced in IL-2-treated patients. The same magnitude of CD4 steep decrease and viral load plateau was reported by the ACTG A5132 among IL-2-treated patients after ART interruption included . This observation may be seen as unexpected in regard of previous studies demonstrating clearly that IL-2-expanded CD4+ T cells exhibit a longer half-life as compared to ‘conventional’ CD4+ T cells . However, one mechanistic explanation is that the drop of CD4+ T cells at a given time is proportional to the number of cells in addition to the death rate. Therefore, for a given death rate, the decline of CD4+ T-cell counts will be steeper for a patient with a higher number of CD4+ T cells at the time of antiretroviral treatment interruption. This could also be the explanation of observed differences in CD4+ T-cell drop in the control group (with a median of 703 cells/μl at week 24) compared to the previously published studies (with a median around 350 cells/μl before interruption). As previously reported, we also found that the frequency of CD4+ T cells expressing activation markers, even following treatment interruption, was lower in IL-2-treated patients as compared to those treated with ART only. Altogether, these data suggest at least two phases in the homeostasis of T-cell pool in IL-2-treated patients following viral rebound. The initial phase is marked by drop of CD4+ T cells highly correlated with the CD4+ T-cell gain at the end of IL-2 cycling (week 24). In contrast, the second phase is characterized by a slow decline of long-living CD4+CD25+ T cells that were not activated, quiescent, and therefore prone to resist HIV infection.
A key challenge in developing disease-modifying interventions is showing that a biomarker or combination of biomarkers is a surrogate for disease progression. Results from SILCAAT and ESPRIT studies have shown that CD4+ T-cell counts under IL-2 therapy cannot be considered as a valuable surrogate marker of disease progression. Our results suggest that in addition to total CD4 cell counts, markers such as T-cell immunophenotypic analyses (e.g., activated and regulatory T cells), and possibly functional assays or other markers of inflammation and activation, should be considered. We show that IL-2 administration before ART interruption tips the balance in favor of CD4+CD25+ as compared to ‘conventional’ CD4+CD25−. Long-term clinical consequences of this new equilibrium are not obvious. In one hand, the recent observation in ART-treated patients that these cells may suppress effector T cells responses, suggest a potential harmful effect . On the other hand, a limited expansion and persistence of these cells might help to contain immune activation and to prevent the development of opportunistic infections as recently suggested in more advanced patients with a benefit of IL-2 restricted to a narrow range of CD4+ T-cell counts . More recently, further analyses of SILCAAT and ESPRIT studies have also shown that the effect of IL-2 on all causes of death may vary by baseline D-dimer levels . These results underscore the need to pursue researches aiming at identifying a target population who might benefit from disease-modifying interventions and specifically from gamma chain-utilizing cytokines such as IL-7 and IL-15.
In conclusion, this study shows that the administration of IL-2 before antiretroviral treatment interruption in individuals with nonadvanced HIV disease led to a longer period before antiretroviral resumption that might be explained by the expansion of CD4+ T cells with a unique phenotype [29,32] and a long survival despite the presence of replicating virus.
Presented in part at the 16th Conference on Retroviruses and Opportunistic Infections, Montreal, February 2009, ML, USA (abstract H-110).
We thank Chiron laboratories for graciously providing Interleukin 2 for this trial. We are grateful to Jean-Pierre Aboulker, Pablo Tebas, Claude Bazin and Dominique Emilie, members of the Data and Safety Monitoring Board of the study.
We acknowledge the excellent work performed by the events validation committee: Geneviève Beck-Wirth, Véronique Joly, A.S.L., Corinne Rancinan and I.S.
We thank Cecile François and Daniel Commenges for their contribution to the modeling analysis.
ILIADE ANRS 118 study team: The following institutions and investigators participated in the ILIADE trial. CH Annecy: C Michon, JP Bru, J Gaillat; CH Belfort: JP Faller; Hôpital Jean Verdier, Bondy: V Jeantils, M Thomas; CHU Bordeaux, Hôpital Saint-André: J Beylot, P.M., Hôpital Pellegrin: JM Ragnaud; CHU Clermont-Ferrand: J Beytout, C Jacomet; Hospices Civils de Lyon, Hôtel Dieu: L Cotte, C Trepo; Hôpital Edouard Herriot: JL Touraine, F Jeanblanc; CHU Montpellier: J Reynes; CH Mulhouse: G Beck-Wirth; CHU Nantes, Hôtel Dieu: F Raffi; Assistance Publique-Hôpitaux de Marseille, Hôpital Sainte Marguerite: JA Gastaud, I Poizot-Martin; Assistance Publique-Hôpitaux de Paris, Hôpital Avicenne, Bobigny: M Bentata; Hôpital de Bicêtre, Le Kremlin Bicêtre: J.F.D., C Goujard; Hôpital Antoine Béclère, Clamart: F Boué, P Galanaud; Hôpital Henri Mondor, Créteil: Y.L., A Sobel; Hôpital Bichat Claude-Bernard: E Bouvet, P Yéni; Hôpital Européen Georges Pompidou: M Kazatchkine, L.W.; Hôpital Lariboisière: JF Bergmann, P Sellier; Hôpital Necker: B Dupont, J.P.V.; Hôpital Saint-Antoine: P.M.G.; Hôpital Saint-Louis: C Lascoux-Combe, J.M.M., E Oksenhendler, D Séréni; National Institutes of Health Clinical Center, Bethesda (USA): C.L., T Miller, I.S.
Steering Committee: G.C., JF Delfraissy, M.L.G., C Goujard, Y.L., J.M.M., C Rancinan, C.R., AM Taburet, A.V., J.P.V., L.W., S Couffin-Cadiergues (representing ANRS), M Beumont (representing Chiron), and invited experts: V Avettand-Fenoel, M Bocquentin, C Jung, C Lacabaratz, A.S.L., B.P., L Rogge, R.T.
Funding: This study was supported by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS, Trial No. 118) and the Intramural Research Program of NIAID/NIH (NIH 04-I-0018 trial).
Clinical Trials Unit/INSERM U897, Bordeaux School of Public Health (ISPED), University Victor Segalen Bordeaux 2: M Badets, M Bonarek, C.B., G.C., S Desjardins, C Fagard, M François, A Frosch, L Lallemand, G Poizat, C Rancinan, R Winum.
Sponsor: ANRS (French National Agency for Research on AIDS and Viral Hepatitis): M.J. Commoy, S. Couffin-Cadiergues, A. Metro.
Conflicts of interest
None of the authors declare conflict of interest.
1. Levy Y, Capitant C, Houhou S, Carriere I, Viard JP, Goujard C, et al. Comparison of subcutaneous and intravenous interleukin-2 in asymptomatic HIV-1 infection: a randomised controlled trial. ANRS 048 study group
2. Sereti I, Anthony KB, Martinez Wilson H, Lempicki R, Adelsberger J, Metcalf JA, et al. IL-2-induced CD4(+) T-cell expansion in HIV-infected patients is associated with long-term decreases in T-cell proliferation
3. Levy Y, Durier C, Krzysiek R, Rabian C, Capitant C, Lascaux AS, et al. Effects of interleukin-2 therapy combined with highly active antiretroviral therapy on immune restoration in HIV-1 infection: a randomized controlled trial
4. Farel CE, Chaitt DG, Hahn BK, Tavel JA, Kovacs JA, Polis MA, et al. Induction and maintenance therapy with intermittent interleukin-2 in HIV-1 infection
5. Durier C, Capitant C, Lascaux AS, Goujard C, Oksenhendler E, Poizot-Martin I, et al. Long-term effects of intermittent interleukin-2 therapy in chronic HIV-infected patients (ANRS 048-079 Trials)
6. Abrams D, Levy Y, Losso MH, Babiker A, Collins G, Cooper DA, et al. Interleukin-2 therapy in patients with HIV infection
. N Engl J Med
7. Weiss L, Letimier FA, Carriere M, Maiella S, Donkova-Petrini V, Targat B, et al. In vivo expansion of naive and activated CD4+CD25+FOXP3+ regulatory T cell populations in interleukin-2-treated HIV patients
. Proc Nat Acad Sci USA
8. Molina JM, Levy Y, Fournier I, Hamonic S, Bentata M, Beck-Wirth G, et al. Interleukin-2 before Antiretroviral Therapy in Patients with HIV Infection: A Randomized Trial (ANRS 119)
. J Infect Dis
9. Tavel JA, Babiker A, Fox L, Gey D, Lopardo G, Markowitz N, et al. Effects of intermittent IL-2 alone or with peri-cycle antiretroviral therapy in early HIV infection: the STALWART study
. PLoS One
10. Levy Y, Lacabaratz C, Weiss L, Viard JP, Goujard C, Lelievre JD, et al. Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment
. J Clin Invest
11. Angel JB, High K, Rhame F, Brand D, Whitmore JB, Agosti JM, et al. Phase III study of granulocyte-macrophage colony-stimulating factor in advanced HIV disease: effect on infections, CD4 cell counts and HIV suppression. Leukine/HIV Study Group
12. Napolitano LA, Schmidt D, Gotway MB, Ameli N, Filbert EL, Ng MM, et al. Growth hormone enhances thymic function in HIV-1-infected adults
. J Clin Invest
13. Hansen BR, Kolte L, Haugaard SB, Dirksen C, Jensen FK, Ryder LP, et al. Improved thymic index, density and output in HIV-infected patients following low-dose growth hormone therapy: a placebo controlled study
14. Kilby JM, Bucy RP, Mildvan D, Fischl M, Santana-Bagur J, Lennox J, et al. A randomized, partially blinded phase 2 trial of antiretroviral therapy, HIV-specific immunizations, and interleukin-2 cycles to promote efficient control of viral replication (ACTG A5024)
. J Infect Dis
15. Keh CE, Shen JM, Hahn B, Hallahan CW, Rehm CA, Thaker V, et al. Interruption of antiretroviral therapy blunts but does not abrogate CD4 T-cell responses to interleukin-2 administration in HIV infected patients
16. Henry K, Katzenstein D, Cherng DW, Valdez H, Powderly W, Vargas MB, et al. A pilot study evaluating time to CD4 T-cell count < 350 cells/mm(3) after treatment interruption following antiretroviral therapy +/- interleukin 2: Results of ACTG A5102
. J Acquir Immune Defic Syndr
17. Porter BO, Anthony KB, Shen J, Hahn B, Keh CE, Maidarelli F, et al. Inferiority of IL-2 alone versus IL-2 with HAART in maintaining CD4 T cell counts during HAART interruption: a randomized controlled trial
18. Hunt PW, Martin JN, Sinclair E, Bredt B, Hagos E, Lampiris H, Deeks SG. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy
. J Infect Dis
19. Hunt PW, Brenchley J, Sinclair E, McCune JM, Roland M, Page-Shafer K, et al. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy
. J Infect Dis
21. Centers for Disease Control. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morb Mortal Wkly Rep
22. Marchou B, Tangre P, Charreau I, Izopet J, Girard PM, May T, et al. Intermittent antiretroviral therapy in patients with controlled HIV infection
23. El Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, Arduino RC, et al. CD4+count-guided interruption of antiretroviral treatment
. N Engl J Med
24. Lewden C, Chene G, Morlat P, Raffi F, Dupon M, Dellamonica P, et al. HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population
. J Acquir Immune Defic Syndr
25. Zwahlen M, Harris R, May M, Hogg R, Costagliola D, de Wolf F, et al.Mortality of HIV-infected patients starting potent antiretroviral therapy: comparison with the general population in nine industrialized countries
. Int J Epidemiol
26. Skiest DJ, Su Z, Havlir DV, Robertson KR, Coombs RW, Cain P, et al. Interruption of antiretroviral treatment in HIV-infected patients with preserved immune function is associated with a low rate of clinical progression: a prospective study by AIDS Clinical Trials Group 5170
. J Infect Dis
27. Thiébaut R, Pellegrin I, Chêne G, Viallard JF, Fleury H, Moreau JF, et al. Immunological markers after long-term treatment interruption in chronically HIV-1 infected patients with CD4 cell count above 400x10(6) cells/I
28. Bosch RJ, Pollard RB, Landay A, Aga E, Fox L. Mitsuyasu For The Aids Clinical Trials Group ATRA randomized trial of interleukin-2 during withdrawal of antiretroviral treatment
. J Interferon Cytokine Res
29. Kovacs JA, Lempicki RA, Sidorov IA, Adelsberger JW, Sereti I, Sachau W, et al. Induction of prolonged survival of CD4(+) T lymphocytes by intermittent IL-2 therapy in HIV-infected patients
. J Clin Invest
30. Fontas E, Kousignian I, Pradier C, Poizot-Martin I, Durier C, Weiss L, et al. IL-2 therapy: potential impact of the CD4 cell count at initiation on clinical efficacy – results from the ANRS CO4 cohort
. J Antimicrob Chemother
31. Lane C. Baseline D-dimer Levels Identify a Subset of Patients at Higher Risk of Death following IL-2 Administration (abstract)
. 18th Conference on Retroviruses and Opportunistic Infections
. Boston 2011. http://www.retroconference.org
32. Sereti I, Imamichi H, Natarajan V, Imamichi T, Ramchandani MS, Badralmaa Y, et al. In vivo expansion of CD4(+)CD45RO-CD25(+) T cells expressing foxP3 in IL-2-treated HIV-infected patients
. J Clin Invest
antiretroviral therapy interruption; HIV; interleukin-2
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