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» Volltext-Angebot » 4/1 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2010463395 Autoren: Bosch RJ; Pollard RB; Landay A; Aga E; Fox L; Mitsuyasu R Titel: Continuing or adding IL-2 in patients treated with antiretroviral therapy (ACTG Protocol A5051, a rollover trial of ACTG Protocol A328) Source: AIDS Research and Therapy; VOL: 7 /20100805/ http://www.aidsrestherapy.com/content/7/1/30 NCT: ClinicalTrials.gov-NCT00000923 ANR: 30 DOI: 10.1186/1742-6405-7-30 PU: BioMed Central Ltd. SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 1742-6405 Institution: Bosch RJ, Harvard School of Public Health, Boston MA, United States, [email protected] COU: United States DT: Journal Article RN: 0006 Keywords AB: Background: Effective antiretroviral therapy reduces HIV-1 RNA levels, improves CD4 T-cell counts, and lowers the risk of opportunistic and malignancies. Interleukin-2 (IL-2) has been shown to increase CD4 T-cell numbers mainly by expanding CD4 cells and by prolonging their half-lives. HIV-infected patients previously enrolled into A328 had been randomized to antiretroviral therapy (ART) alone or ART followed by IL-2. In A5051, 53 patients from A328 who had previously received IL-2 were allowed to continue IL-2 for an additional 80 weeks; 27 patients who had received ART alone received IL-2 for 80 weeks.Results: The patients previously receiving IL-2 continued to have elevated CD4 levels with extended use of IL-2. The prior ART-alone recipients had increases in CD4 levels to comparable levels as the prior IL-2 recipients (median 804 versus 847 cells/mm3 at week 72; 60% versus 9% had >50% increase in A5051 to week 72, p < 0.001). Those who had previously received IL-2 required fewer IL-2 cycles to maintain their CD4 T-cell counts compared to those newly initiating IL-2. The treatments were well tolerated with no significant differences in toxicity or discontinuations between those newly versus previously receiving IL-2. There were few clinical events observed.Conclusions: Although sustained CD4 T-cell count increases were seen with IL-2 administration as in other studies, the absence of clinical benefit in two recent randomized trials has demonstrated no apparent role for IL-2 as a therapy in HIV disease.Trial Registration: A5051 ClinicalTrials.gov Identifier: NCT00000923. © 2010 Bosch et al; licensee BioMed Central Ltd. PU: BioMed Central Ltd. 34 - 42 Cleveland Street, London, W1T 4LB, United Kingdom CNOTE: Copyright 2010 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/2 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2010299950 Autoren: Blish CA; Sangaré L; Herrin BR; Richardson BA; John-Stewart G; Walson JL Titel: Changes in plasma cytokines after treatment of Ascaris lumbrkoides in individuals with HIV-1 infection Source: Journal of Infectious Diseases; VOL: 201 (12); p. 1816-1821 /20100615/ NCT: ClinicalTrials.gov-NCT00130910 DOI: 10.1086/652784 PU: University of Chicago Press SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0022-1899 CO: JIDIA Institution: Walson JL, Box 359909, 325 Ninth Ave, Seattle, WA 98104, United States, [email protected] COU: United States DT: Journal Article JSC: E.5 ... Clinical Microbiology; B.2 ... Public Health RN: 0015 AB: Albendazole treatment of individuals with human immunodeficiency type 1 (HIV-1) and Ascaris lumbricoides coinfection has led to significantly improved CD4+ cell counts and a trend for lower plasma HIV-1 RNA levels in a previous randomized placebo-controlled trial. To define mechanisms by which deworming contributed to changes in markers of HIV-1 disease progression, plasma cytokine levels were evaluated. Albendazole treatment, compared with placebo, was associated with significantly decreased plasma interleukin (IL) 10 levels (P = .04) but was not associated with significant changes in levels of IL-1 beta , IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12p70, IL-13, gamma , tumor necrosis factor a, or thymic stromal lymphopoietin. Treatment of A. lumbricoides co-infection may delay HIV-1 disease progression by reducing helminth-in-duced, IL- 10-mediated immunosuppression. © 2010 by the Infectious Diseases Society of America. All rights reserved. PU: University of Chicago Press 1427 E. 60th Street, Chicago, IL 60637-2954, United States CNOTE: Copyright 2010 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/3 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2010228334 Autoren: Markowitz M; Vaida F; Bradley Hare C; Boden D; Mohri H; Hecht FM; Kalayjian RC; Conrad A; Mildvan D; Aberg J; Hogan C; Michael Kilby J; Balfour HH Jr.; Schafer K; Richman D; Little S Titel: The virologie and immunologic effects of cyclosporine as an adjunct to antiretroviral therapy in patients treated during acute and early HIV-1 infection Source: Journal of Infectious Diseases; VOL: 201 (9); p. 1298-1302 /20100501/ DOI: 10.1086/651664 PU: University of Chicago Press SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0022-1899 CO: JIDIA Institution: Markowitz M, Dr., Aaron Diamond AIDS Research Center, 455 First Ave, New York, NY 10016, United States, [email protected] COU: United States DT: Journal Article JSC: E.5 ... Clinical Microbiology; B.2 ... Public Health RN: 0015 Keywords AB: Acute human immunodeficiency virus type 1 (HIV-1) infection is characterized by high levels of immune activation. Immunomodulation with cyclosporine combined with antiretroviral therapy (ART) in the setting of acute and early HIV-1 infection has been reported to result in enhanced immune reconstitution. Fifty-four individuals with acute and early infection were randomized to receive ART with 4 weeks of cyclosporine versus ART alone. In 48 subjects who completed the study, there were no significant differences between treatment arms in levels of proviral DNA or CD4+ counts. Adjunctive therapy with cyclosporine in this setting does not provide apparent virologie or immunologic benefit. © 2010 by the Infectious Diseases Society of America. All rights reserved. PU: University of Chicago Press 1427 E. 60th Street, Chicago, IL 60637-2954, United States CNOTE: Copyright 2010 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/4 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2010179610 Autoren: Tavel JA; Babiker A; Carey C; Fisher M; Fox L; Gey D; Lopardo GD; Lopez JC; Markowitz N; Munroe D; Paton N; Ruxrungtham K; Standridge B; Wentworth D; Wyman N; Aagaard B; Borup L; Grarup J; Jansson P-O; Jensen K; Lundgren J; Mollerup D; Reilev S; Braimah N; Darbyshire J; Horton J; King E; Smith N; Van Hooff F; Cooper DA; Courtney-Rodgers D; Emery S; Finley E; Gordin F; Sánchez A; Thomas D; Bebchuk J; Bollenbeck P; Denning E; DuChene AG; Fosdick L; Harrison M; Krum E; Larson G; Neaton JD; Nelson R; Quan K; Quan S-FL; Schultz T; Thompson G; Collins S; Haerry DH; Meulbroek M; Peavy D; Rappoport C; Schwarze S; Valdez M; Watson J; Belloso WH; Davey R; Duprez D; Gatell JM; Hoy J; Lifson A; Pederson C; Perez G; Price R; Prineas R; Rhame F; Sampson JH; Worley J; Modlin JF; Beral V; Chaisson RE; Fleming TR; Hill C; Kim K; Murray BE; Pick B; Seligmann M; Weller I; Luzar MA; Martinez A; Costas V; Eckstrand J; Brown S; Lupo SH; Losso MH; Anderson J; Chuah J; Kelly M; Orth D; Wolff MJ; Rusconi S; Tambussi G; Horban A; Antunes F; Mansinho K; Da Conceicao Vera JAV; Himmich H; Chetchotisakd P; Kantipong P; Orkin C; Portsmouth S; Winston A; Wiselka MJ; Anstead GM; Arduino RC; Goetz MB; Hennessey K; El-Sadr W; Labriola AM; Nixon DE; Rodriguez-Barradas MC Titel: Effects of intermittent IL-2 alone or with peri-cycle antiretroviral therapy in early HIV infection: The STALWART study Source: PLoS ONE; VOL: 5 (2) /20100223/ http://www.plosone.org/article/fetchObjectAttachment.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0009334&representation=PDF NCT: ClinicalTrials.gov-NCT00110812 ANR: e9334 DOI: 10.1371/journal.pone.0009334 PU: Public Library of Science SU: EMBASE Sprache: English AL: English CY: United States EISSN: 1932-6203 Institution: Tavel JA, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States, [email protected] COU: United States DT: Journal Article RN: 0029

AB: Background: The Study of Aldesleukin with and without antiretroviral therapy (STALWART) evaluated whether intermittent interleukin-2 (IL-2) alone or with antiretroviral therapy (ART) around IL-2 cycles increased CD4+ counts compared to no therapy. Methodology: Participants not on continuous ART with >=300 CD4+ cells/mm³ were randomized to: no treatment; IL-2 for 5 consecutive days every 8 weeks for 3 cycles; or the same IL-2 regimen with 10 days of ART administered around each IL-2 cycle. CD4 + counts, HIV RNA, and HIV progression events were collected monthly. Principal Findings: A total of 267 participants were randomized. At week 32, the mean CD4+ count was 134 cells greater in the IL-2 alone group (p<0.001), and 133 cells greater in the IL-2 plus ART group (p<0.001) compared to the no therapy group. Twelve participants in the IL-2 groups compared to 1 participant in the group assigned to no therapy experienced an opportunistic event or died (HR 5.84, CI: 0.59 to 43.57; p = 0.009). Conclusions: IL-2 alone or with peri-cycle HAART increases CD4+ counts but was associated with a greater number of opportunistic events or deaths compared to no therapy. These results call into question the immunoprotective significance of IL-2-induced CD4+ cells. Trial Registration: ClinicalTrials.gov NCT00110812.

PU: Public Library of Science 185 Berry Street, Suite 1300, San Francisco, CA 94107, United States CNOTE: Copyright 2010 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/5 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2010199454 Autoren: Rabian C; Tschöpe I; Lesprit P; Katlama C; Molina J-M; Meynard J-L; Delfraissy J-F; Chêne G; Levy Y Titel: Cellular CD4 T cell responses to the diphtheria-derived carrier protein of conjugated pneumococcal and response to pneumococcal in HIV-infected adults Source: Clinical Infectious Diseases; VOL: 50 (8); p. 1174-1183 /20100415/ NCT: ClinicalTrials.gov-NCT00148824 DOI: 10.1086/651418 PU: University of Chicago Press SU: EMBASE Sprache: English AL: English CY: United States ISSN: 1058-4838 CO: CIDIE Institution: Levy Y, Service d'Immunologie, CHU Henri Mondor, Creteil France, 51 Avenue du Mal de Lattre de Tassigny, 94010 Creteil, France, [email protected] COU: France DT: Journal Article JSC: E.5 ... Clinical Microbiology RN: 0040

AB: Background. The French National Agency for AIDS and Viral Hepatitis Research (ANRS) 114 Pneumovac trial showed that a strategy combining a 7-valent pneumococcal (PCV) prime at week 0 followed by a 23-valent pneumococcal polysaccharide vaccine (PPV) boost at week 4 enhances the frequency and magnitude of immunoglobulin (Ig) G responses against Streptococcus pneumoniae polysaccharides (SPPs) compared with PPV alone. CD4 T cell responses specific to the diphtheria- derived carrier protein CRM197 were evaluated. Methods. Lymphocyte proliferative responses (LPRs) and TH1 cytokine T cell responses against the diphtheriaderived carrier protein CRM197 contained in the PCV were investigated at weeks 0, 4, and 24. Results. In the prime-boost PCV and PPV group, the magnitude of LPRs to diphtheria and CRM197 increased at week 4 (P < .001) and persisted until week 24 (P = .08 and .13, respectively, compared with week 4). Interferon-7 and interleukin-2 production to CRM197 increased significantly at week 4 (P = .02 and P< .001, respectively) and remained stable until week 24 (P = .28 and P = .08, respectively). No changes were detected in the PPV group. A strong association among the magnitude of LPRs to CRM197 at week 4, the breadth of SPP specific IgG responses at week 8 (P = .03), and sustained IgG responses at week 24 was observed. A high frequency of helper follicular CD4+CXCR5+ T cells at baseline was associated with a better LPR response to CRM197. Conclusions. The PCV prime-elicited memory T cell responses were associated with better and sustained humoral SPP specific IgG responses. ClinicalTrials.gov identifier. NCT00148824. © 2010 by the Infectious Diseases Society of America. All rights reserved. PU: University of Chicago Press 1427 E. 60th Street, Chicago, IL 60637-2954, United States CNOTE: Copyright 2010 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/6 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2010167740 Autoren: Neuhaus J; Angus B; Kowalska JD; Rosa AL; Sampson J; Wentworth D; Mocroft A Titel: Risk of all-cause mortality associated with nonfatal AIDS and serious non-AIDS events among adults infected with HIV Source: AIDS; VOL: 24 (5); p. 697-706 /March 2010/ DOI: 10.1097/QAD.0b013e3283365356 PU: Lippincott Williams and Wilkins SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 EISSN: 1473-5571 CO: AIDSE Institution: Neuhaus J, Division of Biostatistics, School of Public Health, University of Minnesota, 2221 University Avenue SE, Minneapolis, MN 55414, United States, [email protected] COU: United States DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0036

AB: objectives: Among patients with HIV, the risk of death associated with different AIDS events has been quantified, but the risk of death associated with non-AIDS events has not been examined. We compared the risk of all-cause mortality following AIDS versus serious non-AIDS (SNA) events in the Strategies for Management of Antiretroviral Therapy (SMART) study and the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT). Design: Data from 9583 HIV-infected participants, 5472 with a CD4 cell count more than 350 cells/ mu l enrolled in SMART and 4111 with a CD4 cell count 300 cells/ mu l or more enrolled in ESPRIT, were analyzed. Methods: Cumulative mortality 6 months after AIDS and SNA events (cardiovascular, renal, hepatic disease, and malignancies) was estimated using the Kaplan-Meier method. Cox models were used to estimate hazard ratios associated with AIDS and SNA events on the risk of death overall and by treatment group within study. Results: AIDS and SNA events occurred in 286 and 435 participants with 47 (16%) and 115 (26%) subsequent deaths, respectively. Six-month cumulative mortality was 4.7% [95% confidence interval (CI) 2.8-8.0] after experiencing an AIDS event and 13.4% (95% CI 10.5-17.0) after experiencing an SNA event. The adjusted hazard ratio for all-cause mortality for those who experienced AIDS versus those who did not was 4.9 (95% CI 3.6-6.8). The corresponding hazard ratio for SNA was 11.4 (95% CI 9.0-14.5) (P < 0.001 for difference in hazard ratios). Findings were similar for both treatment groups in SMART and both treatment groups in ESPRIT. Conclusion: Among HIV-infected persons with higher CD4 cell counts, SNA events occur more frequently and are associated with a greater risk of death than AIDS events. Future research should be aimed at comparing strategies to reduce morbidity and mortality associated with SNA events for HIV-infected persons. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. PU: Lippincott Williams and Wilkins 250 Waterloo Road, London, SE1 8RD, United Kingdom CNOTE: Copyright 2010 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/7 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2009606809 Autoren: Hill A Titel: The ABC of HIV clinical trials Source: Pharmaceutical Medicine; VOL: 23 (4); p. 201-211 /2009/ PU: Adis International Ltd SU: EMBASE Sprache: English AL: English CY: New Zealand ISSN: 1178-2595 EISSN: 1179-1993 Institution: Hill A, Pharmacology Research Laboratories, University of Liverpool, 70 Pembroke Place, Liverpool L69 3GF, United Kingdom, [email protected] COU: United Kingdom DT: Review; Journal Article JSC: A.1 ... Pharmacology & Drug Therapy RN: 0050 AB: There are many different types of HIV clinical trials. For new antiretrovirals, efficacy is established from phase III regulatory trials, which normally include 150400 patients per treatment arm, studied for 96 weeks. Antiretrovirals used for first-line treatment are usually combined with approved antiretrovirals in triple combinations and compared with a control arm of standard triple antiretroviral drug treatment. Double-blinded trials are preferable, but several antiretrovirals have been approved from open-label trials. Most regulatory clinical trials are designed to show the non-inferiority of the new antiretroviral versus standard-of-care. The primary efficacy parameter is normally HIV RNA suppression below 50copiesmL by week 48, using a standardized efficacy endpoint (time to loss of virological response or confirmed virological response). If non-inferior efficacy is shown for the new antiretroviral, secondary analyses may then show other benefits, in terms of safety, convenience or drug resistance profiles. The antiretrovirals used in highly treatment-experienced patients are normally combined with a 'background regimen' of antiretrovirals, selected on the basis of drug resistance assays and treatment history. The results from trials in treatment-experienced patients are strongly dependent on baseline resistance profiles and the activity of the antiretrovirals used in the background regimen. The analysis of safety is well standardized, with toxicity grading systems for clinical and laboratory adverse events. Drug resistance at treatment failure could affect responses to second-line treatments. Where possible, patients should be followed-up after the failure of randomized medication, to assess longer term efficacy and safety outcomes on subsequent treatments. © 2009 Adis Data Information BV. All rights reserved. PU: Adis International Ltd 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, 1311, New Zealand CNOTE: Copyright 2009 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/8 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2009607986 Autoren: Abrams D; Lévy Y; Losso MH; Babiker A; Collins G; Cooper DA; Darbyshire J; Emery S; Fox L; Gordin F; Lane HC; Lundgren JD; Mitsuyasu R; Neaton JD; Phillips A; Routy JP; Tambussi G; Wentworth D Titel: Interleukin-2 therapy in patients with HIV infection Source: New England Journal of Medicine; VOL: 361 (16); p. 1548-1559 /20091015/ http://content.nejm.org/cgi/reprint/361/16/1548.pdf NCT: ClinicalTrials.gov-NCT00004978; ClinicalTrials.gov-NCT00013611 DOI: 10.1056/NEJMoa0903175 PU: Massachussetts Medical Society SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0028-4793 EISSN: 1533-4406 CO: NEJMA Institution: Neaton JD, Dr., Division of Biostatistics, School of Public Health, University of Minnesota, 221 University Ave. SE, Minneapolis, MN 55414, United States, [email protected] COU: United States DT: Journal Article JSC: C.0 ... Clinical Medicine RN: 0027 AB: BACKGROUND: Used in combination with antiretroviral therapy, subcutaneous recombinant interleukin-2 raises CD4+ cell counts more than does antiretroviral therapy alone. The clinical implication of these increases is not known. METHODS: We conducted two trials: the Subcutaneous Recombinant, Human Interleukin-2 in HIV-Infected Patients with Low CD4+ Counts under Active Antiretroviral Therapy (SILCAAT) study and the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT). In each, patients infected with the human immunodeficiency virus (HIV) who had CD4+ cell counts of either 50 to 299 per cubic millimeter (SILCAAT) or 300 or more per cubic millimeter (ESPRIT) were randomly assigned to receive interleukin-2 plus antiretroviral therapy or antiretroviral therapy alone. The interleukin-2 regimen consisted of cycles of 5 consecutive days each, administered at 8-week intervals. The SILCAAT study involved six cycles and a dose of 4.5 million IU of interleukin-2 twice daily; ESPRIT involved three cycles and a dose of 7.5 million IU twice daily. Additional cycles were recommended to maintain the CD4+ cell count above predefined target levels. The primary end point of both studies was opportunistic disease or death from any cause. RESULTS: In the SILCAAT study, 1695 patients (849 receiving interleukin-2 plus antiretroviral therapy and 846 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 202 cells per cubic millimeter were enrolled; in ESPRIT, 4111 patients (2071 receiving interleukin-2 plus antiretroviral therapy and 2040 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 457 cells per cubic millimeter were enrolled. Over a median follow-up period of 7 to 8 years, the CD4+ cell count was higher in the interleukin-2 group than in the group receiving antiretroviral therapy alone - by 53 and 159 cells per cubic millimeter, on average, in the SILCAAT study and ESPRIT, respectively. Hazard ratios for opportunistic disease or death from any cause with interleukin-2 plus antiretroviral therapy (vs. antiretroviral therapy alone) were 0.91 (95% confidence interval [CI], 0.70 to 1.18; P=0.47) in the SILCAAT study and 0.94 (95% CI, 0.75 to 1.16; P=0.55) in ESPRIT. The hazard ratios for death from any cause and for grade 4 clinical events were 1.06 (P=0.73) and 1.10 (P=0.35), respectively, in the SILCAAT study and 0.90 (P=0.42) and 1.23 (P=0.003), respectively, in ESPRIT. CONCLUSIONS: Despite a substantial and sustained increase in the CD4+ cell count, as compared with antiretroviral therapy alone, interleukin-2 plus antiretroviral therapy yielded no clinical benefit in either study. (ClinicalTrials.gov numbers, NCT00004978 [ESPRIT] and NCT00013611 [SILCAAT study].) Copyright © 2009 Massachusetts Medical Society. PU: Massachussetts Medical Society 860 Winter Street, Waltham, MA 02451-1413, United States CNOTE: Copyright 2009 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/9 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2009593141 Autoren: Sereti I; Dunham RM; Spritzler J; Aga E; Proschan MA; Medvik K; Battaglia CA; Landay AL; Pahwa S; Fischl MA; Asmuth DM; Tenorio AR; Altman JD; Fox L; Moir S; Malaspina A; Morre M; Buffet R; Silvestri G; Lederman MM Titel: IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection Source: Blood; VOL: 113 (25); p. 6304-6314 /2009/ http://bloodjournal.hematologylibrary.org/cgi/reprint/113/25/6304 NCT: ClinicalTrials.gov-NCT00099671 DOI: 10.1182/blood-2008-10-186601 PU: American Society of Hematology SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0006-4971 EISSN: 1528-0020 CO: BLOOA Institution: Sereti I, NIAID, Bldg. 10, 10 Center Dr, Bethesda, MD 20892, United States, [email protected] COU: United States DT: Journal Article JSC: C.1.5 ... Hematology RN: 0041 AB: Interleukin 7 (IL-7) is a common gamma chain receptor cytokine implicated in thymopoiesis and in peripheral expansion and survival of T lymphocytes. The safety and activity of recombinant human IL-7 (rhIL-7) administration were therefore examined in HIV-infected persons. In this prospective randomized placebo-controlled study, a single subcutaneous dose of rhIL-7 was well tolerated with biologic activity demonstrable at 3 mu g/kg and a maximum tolerated dose of 30 mu g/kg. Injection site reactions and transient elevations of liver function tests were the most notable side effects. Transient increases in plasma HIV-RNA levels were observed in 6 of 11 IL-7-treated patients. Recombinant hIL-7 induced CD4 and CD8 T cells to enter cell cycle; cell-cycle entry was also confirmed in antigen-specific CD8 T cells. Administration of rhIL-7 led to transient down-regulation of the IL-7 receptor alpha chain (CD127) in both CD4+ and CD8+ T cells. Single-dose rhIL-7 increased the numbers of circulating CD4+ and CD8+ T cells, predominantly of central memory phenotype. The frequency of CD4 + T cells with a regulatory T-cell phenotype (CD25high CD127low) did not change after rhIL-7 administration. Thus, rhIL-7 has a biologic and toxicity profile suggesting a potential for therapeutic trials in HIV infection and other settings of lymphopenia. This has been registered at http:// www.clinicaltrials.gov under NCT0099671. Silvestri Guido University of Pennsylvania, Philadelphia, PA, United States PU: American Society of Hematology 1900 M Street, Suite 2000, Washington, DC 20036, United States CNOTE: Copyright 2009 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/10 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2009531016 Autoren: Porter BO; Shen J; Kovacs JA; Davey RT; Rehm C; Lozier J; Csako G; Nghiem K; Costello R; Lane HC; Sereti I Titel: Interleukin-2 cycling causes transient increases in high-sensitivity C-reactive protein and D-dimer that are not associated with plasma HIV-RNA levels Source: AIDS; VOL: 23 (15); p. 2015-2019 /September 2009/ DOI: 10.1097/QAD.0b013e32832d72c6 PU: Lippincott Williams and Wilkins SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 EISSN: 1473-5571 CO: AIDSE Institution: Sereti I, Dr., National Institutes of Health, Clinical Center, Building 10, 10 Center Drive, Bethesda, MD 20892, United States, [email protected] COU: United States DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0022 Keywords AB: Objective: To determine the effects of interleukin (IL)-2 treatment on inflammatory and thrombotic biomarkers in chronically HIV- infected adults receiving antiretroviral therapy. Methods: Cryopreserved plasma was evaluated retrospectively for C-reactive protein (CRP) and D-dimer at baseline, end of an IL-2 cycle, and long-term follow up from two randomized, controlled trials: 57 IL-2-naive adults receiving either three to six cycles of IL-2 as well as antiretroviral therapy (nucleoside analogues) or antiretroviral therapy alone for 12 months, and 40 IL-2-experienced adults on highly active antiretroviral therapy who either interrupted or continued therapy for 6 months after a baseline IL-2 cycle. High-sensitivity CRP (hsCRP) was measured by immunonephelometry (detection limit 0.175 mg/l) and D-dimer by latex agglutination (detection limit 0.20 mg/l). Median within-group differences and pre and post- IL-2 changes between groups were assessed via nonparametric Wilcoxon signed-rank and Mann-Whitney U-tests. Spearman's rank test was used to assess correlations between changes in hsCRP, D-dimer, and HIV-RNA . Results: Significant increases in hsCRP (study 1: 138.6 mg/l; study 2: 58.9 mg/l) and D-dimer (study 1: 3.1 mg/l; study 2: 0.4 mg/l, all P < 0.0001) occurred by the end of the initial IL-2 cycle, returning to baseline by the end of study. No correlations were seen between changes in hsCRP or D- dimer and HIV-RNA, CD4 T-cell count, or proliferation (Ki67 expression). No thrombotic or cardiovascular serious adverse events occurred during these study periods. Conclusion: IL-2 dosing caused transient increases in plasma hsCRP and D-dimer levels, regardless of HIV-RNA viral load, suggesting the possibility of increased risk for thrombotic events. © 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins. PU: Lippincott Williams and Wilkins 250 Waterloo Road, London, SE1 8RD, United Kingdom CNOTE: Copyright 2009 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/11 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2009421909 Autoren: Viard J-P; Fagard C; Chaix M-L; Rouzioux C; Bouteloup V; Bentata M; De Verdière NC; Pahlavan G; Weiss L; Lévy Y; Chêne G Titel: Immunological success is predicted by enfuvirtide but not interleukin-2 therapy in immunodepressed patients Source: AIDS; VOL: 23 (11); p. 1383-1388 /July 2009/ NCT: ClinicalTrials.gov-NCT00113282 DOI: 10.1097/QAD.0b013e32832cdc26 PU: Lippincott Williams and Wilkins SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 EISSN: 1473-5571 CO: AIDSE Institution: Viard J-P, Service des Maladies Infectieuses et Tropicales, Hôpital Necker, 149 rue de Sévres, 75743 Paris cedex 15, France, jean- [email protected] COU: France DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0027 AB: OBJECTIVES:: To evaluate the efficacy of adding interleukin-2 (IL-2) to an optimized background treatment in HIV-1 patients with advanced failure. DESIGN:: Randomized, open-label, multicentre controlled trial. METHODS:: Patients with CD4 T-cell count of less than 200 cells/ mu l, plasma HIV-1 RNA of more than 10 000 copies/ml and a genotypic sensitivity score showing two or less active drugs were randomized to either eight IL-2 cycles with optimized background treatment or optimized background treatment alone. Optimization was made according to genotypic sensitivity score. Enfuvirtide was added in enfuvirtide-naive patients. Evaluation was performed at week 52 on the proportions of patients with CD4 cell count of at least 200 cells/ mu l (primary outcome), of patients with a CD4 cell count increase of at least 50 cells/ mu l from week 0, on plasma HIV-1 RNA and HIV-related events. RESULTS:: Fifty-six patients were analysed. Median age was 43 years, 61% were at Center for Disease Control and Prevention stage C, 43% had a genotypic sensitivity score of 0, median baseline CD4 cell count and plasma HIV-1 RNA values were 64 cells/ mu l and 4.9 log10 copies/ml, respectively. Treatment could be optimized in 23 patients. At week 52, in the IL-2 and control groups, the proportion of patients with CD4 cell count of at least 200 cells/ mu l (14 and 18%) or a CD4 cell count increase of at least 50 cells/ mu l (25 and 32%) and median plasma HIV-1 RNA were not significantly different. In multivariate analysis, optimization with enfuvirtide and baseline CD4 cell count were statistically associated with CD4 cell count of at least 200 cells/ mu l at week 52 (P = 0.003 and P = 0.01). Optimization with enfuvirtide was the only factor associated with a CD4 cell count gain of at least 50 cells/ mu l (P < 0.001). There was no difference in the rate of AIDS events between groups. CONCLUSION:: IL-2 failed to increase CD4 cell count in immunocompromised patients with multiple therapeutic failures. Enfuvirtide use was highly associated with success. © 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins. PU: Lippincott Williams and Wilkins 250 Waterloo Road, London, SE1 8RD, United Kingdom CNOTE: Copyright 2009 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/12 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2009395209 Autoren: Pett SL Titel: Immunotherapies in HIV-1 infection Source: Current Opinion in HIV and AIDS; VOL: 4 (3); p. 188-193 /May 2009/ DOI: 10.1097/COH.0b013e328329d090 PU: Lippincott Williams and Wilkins SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 1746-630X EISSN: 1746-6318 Institution: Pett SL, Dr., Faculty of Medicine, National Centre in HIV and Clinical Research, University of New South Wales, Darlinghurst, NSW 2010, Australia, [email protected] COU: Australia DT: Review; Journal Article RN: 0093 AB: Purpose of review: The purpose of this review is to describe the current status of immunotherapies for the treatment of HIV-1 infection. This review is timely, as the results of the phase III clinical trials of recombinant interleukin-2 (rIL-2) as adjuncts to combination antiretroviral therapy are about to be released. Recent findings: For many years, the use of rIL-2 in HIV-infected individuals has been explored. Although the results of the clinical endpoint studies of rIL-2 are awaited, there are now further data for rIL-2 as a stand-alone therapy for the treatment of HIV. Maraviroc, a recently approved anti-HIV agent, is a small molecule antagonist of human chemokine receptor-5. The recent observation that maraviroc-treated patients achieved higher CD4+ and CD8+ T-cell counts compared with comparator regimens (without a chemokine receptor-5 antagonist) for equivalent viral load reductions has fuelled interest in using these -directed therapies to enhance immune restoration. Summary: This review summarizes the most recent clinical data for rIL-2 and reviews other immunotherapies in earlier development including cytokines rIL-7, rIL-15, rIL- 21, new therapeutic vaccination approaches including infusion of overlapping HIV peptides and dendritic cell immunotherapy and novel agents including luteinizing hormonereleasing hormone analogues and vitamin D3-binding protein macrophage activating factor. © 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins. PU: Lippincott Williams and Wilkins 250 Waterloo Road, London, SE1 8RD, United Kingdom CNOTE: Copyright 2009 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/13 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2009360775 Autoren: Molina J-M; Levy Y; Fournier I; Hamonic S; Bentata M; Beck-Wirth G; Gougeon M-L; Venet A; Madelaine I; Sereni D; Jeanblanc F; Boulet T; Simon F; Aboulker J-P Titel: Interleukin-2 before antiretroviral therapy in patients with HIV infection: A randomized trial (ANRS 119) Source: Journal of Infectious Diseases; VOL: 200 (2); p. 206-215 /20090715/ NCT: ClinicalTrials.gov-NCT00120185 DOI: 10.1086/599989 PU: University of Chicago Press SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0022-1899 CO: JIDIA Institution: Molina J-M, Dr., Dept. of Infectious Diseases, Hôpital Saint-Louis, 1 ave. Claude Vellefaux, 75010 Paris, Jean- [email protected] DT: Journal Article JSC: E.5 ... Clinical Microbiology; B.2 ... Public Health RN: 0039 AB: Background. Interleukin (IL)-2 increases CD4 T cell counts when combined with antiretroviral therapy (ART). Whether IL-2 alone can increase CD4 cell counts is unknown. Methods. A total of 130 adults who had a CD4 cell count of 300-500 cells/ mu L (and, thus, were not eligible to receive ART) were randomized to receive either intermittent IL-2 therapy or no treatment. The primary end point was a drop in CD4 cell count to <300 cells/ mu L, initiation of ART, the occurrence of an AIDS-defining event, or death. Results. Through week 96, 35% of the patients in the IL-2 arm and 59% in the control arm reached the primary end point (P = .008). Median changes from baseline in the IL-2 and control arms were +51 and -64 cells/ mu L, respectively, for CD4 cell count (P<.001) and were +0.02 and +0.04 log10 copies/mL, respectively, for plasma viral load (P = .93). Among patients with a baseline viral load <4.5 log10 copies/mL, 64% in the IL-2 arm and 10% in the control arm did not reach the primary end point through week 150 (P<.001), and the time to ART initiation was deferred by 92 weeks in the IL-2 arm. The incidences of an AIDS-defining event, death, and grade 3 or 4 adverse events were similar between study arms. Conclusion. IL-2 increased CD4 cell counts without affecting HIV replication and allowed the initiation of ART to be deferred. Trial registration. ClinicalTrials.gov identifier: NCT00120185. © 2009 by the Infectious Diseases Society of America. All rights reserved. PU: University of Chicago Press 1427 E. 60th Street, Chicago, IL 60637-2954, United States CNOTE: Copyright 2009 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/14 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2009316281 Autoren: Angus B; Lampe F; Tambussi G; Duvivier C; Katlama C; Youle M; Williams I; Clotet B; Fisher M; Post FA; Babiker A; Phillips A Titel: TILT: A randomized controlled trial of interruption of antiretroviral therapy with or without interleukin-2 in HIV-1 infected individuals Source: AIDS; VOL: 22 (6); p. 737-740 /2008/ DOI: 10.1097/QAD.0b013e3282f511f1 PU: Lippincott Williams and Wilkins SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 EISSN: 1473-5571 CO: AIDSE PII: 0000203020080330000008 Institution: Angus B, Nuffield Department of Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9D4, [email protected] DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0012 AB: OBJECTIVE:: We aimed to see if structured treatment interruption (STI) could be supported safely with the use of two cycles of IL- 2 (4.5 MIU q12h subcutaneously 5 days) before STI to prolong the time before therapy restarted. METHODS:: Subjects were randomly allocated to either A - continuous ART; B - continue for 9 weeks, then STI; restart with the same ART when the CD4 count falls below 200 cells; or C - two cycles of IL-2, 8 weeks apart, while still on ART; at week 9 stop ART and use a new cycle of IL-2 alone whenever the CD4 count falls < 300 cells. Patients were followed until week 105. RESULTS:: 86 mostly white middle aged homosexual men with a baseline median CD4 count of 754 cells/ml (range 240-1400) and a nadir CD4 count of 268 cells/ml (range 62-822) enrolled. By 96 weeks there was a 66% probability of having restarted ART in arm B compared with 34% in arm C (p =< 0.002; log rank test). New drugs were used in 60% in arm A, 57% in arm B and 45% in arm C. 4 subjects had a dose modification in the first cycle due to toxicity with 2 interrupting. There were 39 SAEs with 21 in arm C. There were no deaths. CONCLUSIONS:: The primary aim of the trial was to gain experience in using IL-2. IL-2 delayed restarting drugs and fewer new drugs were used. © 2008 Lippincott Williams and Wilkins. AU: Angus B Angus Brian Nuffield Department of Medicine, John Radcliffe Hospital, Oxford; Medical Research Council, London; Nuffield Department of Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9D4 [email protected] PU: Lippincott Williams and Wilkins 250 Waterloo Road, London, SE1 8RD, United Kingdom CNOTE: Copyright 2009 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/15 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2009153632 Autoren: Stapleton JT; Chaloner K; Zhang J; Klinzman D; Souza IE; Xiang J; Landay A; Fahey J; Pollard R; Mitsuyasu R Titel: GBV-C viremia is associated with reduced CD4 expansion in HIV-infected people receiving HAART and interleukin-2 therapy Source: AIDS; VOL: 23 (5); p. 605-610 /20090313/ DOI: 10.1097/QAD.0b013e32831f1b00 PU: Lippincott Williams and Wilkins SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 CO: AIDSE Institution: Stapleton JT, Dr., Department of Internal Medicine, University of Iowa, College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, United States, [email protected] COU: United States DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0032 AB: Objective: lnterleukin-2 (IL-2) is a cytokine with multiple effects on lymphocytes including induction of CD4+ T-cell proliferation. IL-2 administration has been shown to increase CD4 cell counts in HIV-infected people receiving antiretroviral therapy. GB virus C (GBV-C) is an apparently nonpathogenic flavivirus that replicates in CD4+ T cells and inhibits HIV replication in vitro by mechanisms including downregulation of HIV entry coreceptors (CCR5 and CXCR4) and induction of chemokines (RANTES, MIP-1 alpha , MIP-1 beta , and SDF-1). GBV-C replication is significantly inhibited in vitro by activation of primary CD4+ cell cultures with IL-2 and phytohemagglutinin. We sought to determine if there is an interaction between GBV-C and IL-2 in vivo. Methods: GBV-C viremia status was characterized in 92 HIV-infected individuals participating in a randomized trial of IL-2 and antiretroviral therapy [AIDS Clinical Trials Group Study (ACTG) 328]. Changes in CD4 cell counts and HIV RNA levels in individuals assigned IL-2 were compared with those in individuals assigned antiretroviral therapy alone. Results: Individuals lacking GBV-C viremia had a significantly greater rise in CD4 cell count with IL-2, compared with GBV-C viremic individuals (by 511 cells/ mu l at week 84; interaction P = 0.02): GBV-C viremic individuals assigned IL-2 did not demonstrate a significant increase in CD4 cell count compared with individuals not assigned to receive IL-2 (95% CI for difference - 255 to 397 cells/ mu l). Conclusion: GBV-C viremia was associated with a block in CD4 cell expansion following IL-2 therapy in the ACTG 328 study, and GBV-C status may be an important factor in IL-2 treatment response. © 2009 Wolters Kluwer Health. PU: Lippincott Williams and Wilkins 250 Waterloo Road, London, SE1 8RD, United Kingdom CNOTE: Copyright 2009 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/16 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2009046655 Autoren: Porter BO; Anthony KB; Shen J; Hahn B; Keh CE; Maldarelli F; Blackwelder WC; Lane HC; Kovacs JA; Davey RT; Sereti I Titel: Inferiority of IL-2 alone versus IL-2 with HAART in maintaining CD4 T cell counts during HAART interruption: A randomized controlled trial Source: AIDS; VOL: 23 (2); p. 203-212 /20090114/ DOI: 10.1097/QAD.0b013e32831cc114 PU: Lippincott Williams and Wilkins SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 CO: AIDSE Institution: Sereti I, Dr., National Institutes of Health, Building 10-Magnuson Clinical Center, 10 Center Drive, Bethesda, MD 20982, United States, [email protected] COU: United States DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0062 AB: 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/l 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 - /) 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/I, 39389 copies/mI, 48.1%; C: 1246 cells/I, <50 copies/mI, 92.3%; P 0.001). Croup I was inferior to C (% difference = -44.2%; 95% CI: -64.2%, - 11.2%; P = 0.013). Minor statistically significant differences in HgbA1 c and energy level occurred at 6 months (/> C). Following HAART interruption, single cases of acute retroviral syndrome, secondary , 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. 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins. PU: Lippincott Williams and Wilkins 250 Waterloo Road, London, SE1 8RD, United Kingdom CNOTE: Copyright 2009 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/17 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2008556249 Autoren: McElrath MJ; De Rosa SC; Moodie Z; Dubey S; Kierstead L; Janes H; Defawe OD; Carter DK; Hural J; Akondy R; Buchbinder SP; Robertson MN; Mehrotra DV; Self SG; Corey L; Shiver JW; Casimiro DR Titel: HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis Source: The Lancet; VOL: 372 (9653); p. 1894-1905 /20081129/1205/ DOI: 10.1016/S0140-6736(08)61592-5 PU: Elsevier Limited SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0140-6736 CO: LANCA PII: S0140673608615925 Institution: McElrath MJ, Dr., Vaccine and Infectious Disease Institute and the HIV Vaccine Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, United States, [email protected] COU: United States DT: Journal Article JSC: C.0 ... Clinical Medicine RN: 0040 AB: Background: In the Step Study, the MRKAd5 HIV-1 gag/pol/nef vaccine did not reduce plasma viraemia after infection, and HIV-1 incidence was higher in vaccine-treated than in placebo-treated men with pre-existing adenovirus serotype 5 (Ad5) immunity. We assessed vaccine-induced immunity and its potential contributions to infection risk. Methods: To assess immunogenicity, we characterised HIV-specific T cells ex vivo with validated interferon- gamma ELISPOT and intracellular cytokine staining assays, using a case-cohort design. To establish effects of vaccine and pre-existing Ad5 immunity on infection risk, we undertook flow cytometric studies to measure Ad5-specific T cells and circulating activated (Ki-67+/BcL-2lo) CD4+ T cells expressing CCR5. Findings: We detected interferon- gamma -secreting HIV-specific T cells (range 163/106 to 686/106 peripheral blood mononuclear cells) ex vivo by ELISPOT in 77% (258/354) of people receiving vaccine; 218 of 354 (62%) recognised two to three HIV proteins. We identified HIV-specific CD4+ T cells by intracellular cytokine staining in 58 of 142 (41%) people. In those with reactive CD4+ T cells, the median percentage of CD4+ T cells expressing interleukin 2 was 88%, and the median co-expression of interferon gamma or tumor necrosis factor alpha (TNF alpha ), or both, was 72%. We noted HIV-specific CD8+ T cells (range 0·4-1·0%) in 117 of 160 (73%) participants, expressing predominantly either interferon gamma alone or with TNF alpha . Vaccine-induced HIV-specific immunity, including response rate, magnitude, and cytokine profile, did not differ between vaccinated male cases (before infection) and non-cases. Ad5-specific T cells were lower in cases than in non-cases in several subgroup analyses. The percentage of circulating Ki-67+BcL-2lo/CCR5+CD4+ T cells did not differ between cases and non-cases. Interpretation: Consistent with previous trials, the MRKAd5 HIV-1 gag/pol/nef vaccine was highly immunogenic for inducing HIV-specific CD8+ T cells. Our findings suggest that future candidate have to elicit responses that either exceed in magnitude or differ in breadth or function from those recorded in this trial. Funding: National Institute of Allergy and Infectious Diseases, US National Institutes of Health; and Merck Research Laboratories. © 2008 Elsevier Ltd. All rights reserved. PU: Elsevier Limited 32 Jamestown Road, London, NW1 7BY, United Kingdom CNOTE: Copyright 2008 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/18 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2008440223 Autoren: Smurzynski M; Collier AC; Koletar SL; Bosch RJ; Wu K; Bastow B; Benson CA Titel: AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT): Rationale, design, and baseline characteristics Source: HIV Clinical Trials; VOL: 9 (4); p. 269-282 /July/August 2008/ DOI: 10.1310/hct0904-269 PU: Thomas Land Publishers Inc. SU: EMBASE Sprache: English AL: English CY: United States ISSN: 1528-4336 CO: HCTIA Institution: Smurzynski M, Dr., Center for Biostatistics in AIDS Research, Harvard School of Public Health, FXB Building, 651 Huntington Avenue, Boston, MA 02115, United States, [email protected] COU: United States DT: Journal Article JSC: E.5.3 ... Virology RN: 0051 AB: Purpose: ALLRT is a longitudinal cohort study of HIV-infected subjects prospectively randomized into selected clinical trials for antiretroviral (ARV) treatment-naïve and ARV treatment-experienced individuals conducted by the AIDS Clinical Trials Group (ACTG). We describe the rationale, design, and baseline characteristics of the ALLRT cohort and its potential to address important research questions related to ARV therapy. Method: Standardized visits occur every 16 weeks to evaluate long-term clinical, virologic, and immunologic outcomes associated with ARV treatment. Results: A total of 4,371 subjects enrolled in ALLRT from January 2000 through June 2007. Of these, 3,146 (72%) were ARV naïve at parent study entry (18% female, 44% white, 32% black, 21% Hispanic; median age 37 years, CD4 count 218 cells/ mu L, follow-up 3.6 years; 343 [11 %] followed >=8 years) and 1,225 (28%) were treatment experienced (13% female, 59% white, 20% black, 17% Hispanic; median age 42 years, CD4 count 325 cells/pL, follow-up 5.7 years). Conclusions: ALLRT provides the opportunity to understand long-term ramifications of therapeutic ARV choices and determine whether these vary by treatment regimen, timing of treatment initiation, or treatment changes over long- term follow-up. Investigations based on uniform data and specimen collection in the context of randomized ARV treatments will be criticalt developing more successful long-term therapeutic strategies for HIV treatment. © 2008 Thomas Land Publishers, Inc. PU: Thomas Land Publishers Inc. 255 Jefferson Road, St. Louis, MO 63119, United States CNOTE: Copyright 2008 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/19 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2008391451 Autoren: Herzmann C; Cuthbertson Z; Fosdick L; Fisher M; Nelson M; Perry N; Law M; Wand H; Janossy G; Johnson MA; Youle M Titel: Long-term clinical and surrogate marker effects of subcutaneous intermittent interleukin-2 without antiretroviral therapy in HIV-infected patients Source: Journal of Antimicrobial Chemotherapy; VOL: 62 (3); p. 583-586 /2008/ NCT: ClinicalTrials.gov-NCT00000909 DOI: 10.1093/jac/dkn238 PU: Oxford University Press SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0305-7453 EISSN: 1460-2091 CO: JACHD Institution: Herzmann C, Department of Infectious Diseases, Vivantes Auguste Viktoria Klinikum, Rubensstr. 125, 12159 Berlin, Germany, [email protected] COU: Germany DT: Journal Article JSC: A.1 ... Pharmacology & Drug Therapy RN: 0009 AB: Objectives: Subcutaneous administration of interleukin-2 (IL-2) has been shown to increase CD4 counts in HIV-infected patients. It remains unclear whether this effect is associated with a clinical benefit. Patients and methods: We conducted a long-term follow-up in the cohort of the UK-Vanguard study in which three groups of 12 antiretroviral-naive subjects with CD4 cell counts >350 cells/mm³ received no treatment or IL-2 at either 4.5 or 7.5 MIU twice daily in 5 day cycles, respectively. Results Mean follow-up was 376 weeks. IL-2 therapy was associated with a higher area under the curve of CD4 cell count change from baseline at week 48 but not thereafter. HIV-RNA levels were unaffected. Highly active antiretroviral therapy (HAART) was initiated after a mean of 172, 175 and 152 weeks in the control group, low-dose and high-dose IL-2 treatment group, respectively, a statistically non- significant difference. There was a tendency to start HAART soon after discontinuation of IL-2 therapy which may have been triggered by the steep decay of CD4 counts. There were two serious adverse events in the control group, seven in the low-dose IL-2 group and eight in the high-dose IL-2 group. No pattern of disease was detected, making an association with IL-2 therapy unlikely. Conclusions: We could detect neither a benefit of IL-2 therapy after week 48 nor delayed initiation of HAART. This is currently the longest follow-up data comparing IL-2 therapy with no therapy in antiretroviral-naive HIV-infected patients and does not show a persistent benefit of the intervention. © The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. PU: Oxford University Press Great Clarendon Street, Oxford, OX2 6DP, United Kingdom CNOTE: Copyright 2008 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/20 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2008388891 Autoren: Khunnawat C; Mukerji S; Havlichek D Jr.; Touma R; Abela GS Titel: Cardiovascular Manifestations in Human Immunodeficiency Virus-Infected Patients Source: American Journal of Cardiology; VOL: 102 (5); p. 635-642 /20080901/ DOI: 10.1016/j.amjcard.2008.04.035 PU: Elsevier Inc. SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0002-9149 CO: AJCDA PII: S0002914908007935 Institution: Abela GS, Dr., Department of Internal Medicine, Division of Cardiology, Michigan State University East, Lansing, MI, United States, [email protected] COU: United States DT: Review; Journal Article JSC: C.1.1 ... Cardiology & Angiology RN: 0071 AB: Human immunodeficiency virus (HIV) is now a pandemic. It afflicts multiple organs, including the cardiovascular system. This occurs by direct invasion as well as opportunistic infections complicating acquired immunodeficiency syndrome. The presence of newer highly active antiretroviral therapy has led to longer survival of patients infected with HIV, but the cardiac abnormalities related to HIV have remained less well characterized. It is now evident that cardiac involvement in patients with acquired immunodeficiency syndrome is relatively common. This includes coronary artery disease, dilated cardiomyopathy, pericardial effusion, pulmonary hypertension, and ill effects of highly active antiretroviral therapy in the form of lipodystrophy, lipoatrophy, and dyslipidemia. In fact, HIV can now be viewed as a potential risk factor for coronary artery disease, and the dilemma facing clinicians is how to quantify this risk. Awareness of accelerated coronary artery disease and dilated cardiomyopathy is critical to implement preventive measures early in the course of HIV. However, better guidelines are still needed on the basis of prospective randomized controlled studies involving large populations. In conclusion, this review describes cardiac abnormalities associated with HIV, including possible molecular mechanisms. The co-morbid sequelae, their presentation, and pharmacologic management are also discussed. © 2008 Elsevier Inc. All rights reserved. PU: Elsevier Inc. 360 Park Avenue South, New York, NY 10010, United States CNOTE: Copyright 2008 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/21 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2008346849 Autoren: Tebas P; Henry WK; Matining R; Weng-Cherng D; Schmitz J; Valdez H; Jahed N; Myers L; Powderly WG; Katzenstein D Titel: Metabolic and immune activation effects of treatment interruption in chronic HIV-1 infection: Implications for cardiovascular risk Source: PLoS ONE; VOL: 3 (4) /20080423/ http://www.plosone.org/article/fetchObjectAttachment.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0002021&representation=PDF ANR: e2021 DOI: 10.1371/journal.pone.0002021 PU: Public Library of Science SU: EMBASE Sprache: English AL: English CY: United States EISSN: 1932-6203 Institution: Tebas P, University of Pennsylvania, Philadelphia, PA, United States, [email protected] COU: United States DT: Journal Article RN: 0025 AB: Background: Concern about costs and antiretroviral therapy (ART)-associated toxicities led to the consideration of CD4 driven strategies for the management of HIV. That approach was evaluated in the SMART trial that reported an unexpected increase of cardiovascular events after treatment interruption (TI). Our goal was to evaluate lasting metabolic charges associated with interruption of antiretroviral therapy and relate them to changes of immune activation makers and cardiovascular risk. Methodology: ACTG 5102 enrolled 47 HIV-1-infected subjects on stable ART, with <200 HIV RNA copies/mL and CD4 cell count >=500 cells/ mu L. Subjects were randomly assigned to continue ART for 18 weeks with or without 3 cycles of interleukin-2 (IL-2) (cycle=4.5 million IU sc BID × 5 days every 8 weeks). After 18 weeks ART was discontinued in all subjects until the CD4 cell count dropped below 350 cells/ mu L. Glucose and lipid paraments were evaluated every 8 weeks intially and at weeks 2, 4, 8 and every 8 weeks after TI. Immune activation was evaluated by flow-cytometry and solube TNFR2 levels. Principal Findings: By week 8 of TI, levels of total cholesterol (TC) (median (Q1, Q3) (-0.73 (- 1.19, -0.18) mmol/L, p<0.0001), LDL, HDL cholesterol (-0.36(-0.53,-0.03)mmol/L, p=0.0005). However the TC/HDL ratio remained unchanged (-0.09 (-1.2, 0.5), p=0.2). Glucose and insulin levels did not change (p=0.6 and 0.8, respectively). After TI there was marked increase in immune activation (CD8+/HLA-DR+/CD38+ cells, 34% (13, 43), p<0.0001) and soluble TNFR2 (1089 ng/L (-189, 1655), p=0.0008) coinciding with the rebound of HIV viremia. Conclusions: Our data suggests that interrupting antiretroviral therapy does not reduce cardiovascular disease (CVD) risk as the improvements in lipid parameters are modest and overshadowed by the decreased HDL levels. Increased immune cell activation and systemic inflammatory responses associated with recrudescent HIV viremia may provide a more cogent explanation for the increased cardiovascular risk associated with treatment interruption and HIV infection. © 2008 Tebas et al. PU: Public Library of Science 185 Berry Street, Suite 1300, San Francisco, CA 94107, United States CNOTE: Copyright 2008 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/22 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2008319996 Autoren: Wendler D; Krohmal B; Emanuel EJ; Grady C Titel: Why patients continue to participate in clinical research Source: Archives of Internal Medicine; VOL: 168 (12); p. 1294-1299 /20080623/ http://archinte.ama-assn.org/cgi/reprint/168/12/1294 DOI: 10.1001/archinte.168.12.1294 PU: American Medical Association SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0003-9926 EISSN: 1538-3679 CO: AIMDA Institution: Wendler D, Dr., Department of Bioethics, National Institutes of Health, Bldg. 10, Bethesda, MD 20892, United States, [email protected] COU: United States DT: Journal Article JSC: C.1 ... Internal Medicine RN: 0031 AB: Background: Clinical research exposes patient participants to unproved methods and research procedures in order to gather generalizable knowledge to benefit others. While some commentators argue that this process inappropriately exploits patient participants, there are few data available to evaluate this claim. Methods: Human immunodeficiency virus (HIV)-infected individuals from Argentina, , and Thailand who had been participating in the Evaluation of Subcutaneous Proleukin (Interleukin-2) in a Randomized International Trial (ESPRIT) study for at least 6 months were invited to complete a self- administered survey on their experience and were asked why they continued to participate. The ESPRIT study is a phase 3, multinational, randomized trial comparing antiretroviral therapy plus interleukin 2 (IL-2) with antiretroviral therapy alone in individuals with HIV disease. Results: From a list of 12 possible reasons regarding why patient participants continue to participate, 8 options were selected as "very important" by 75% or more of 582 respondents, including the possibility of benefiting personally and the potential to help others. When asked to indicate the most important reason from this list, respondents in the IL-2 arm (n=292) selected (1) increasing their CD4 lymphocyte count (26%); (2) finding better treatments for patients with HIV in their home country (22%); and (3) getting IL-2 (12%). Respondents in the no-IL-2 arm (n=290) selected (1) finding better treatments for patients with HIV in their home country (32%); (2) finding better treatments for HIV-infected patients in other countries (12%); and (3) increasing their CD4 lymphocyte count (11%). Also, 90% of the respondents indicated that participation in ESPRIT involved making a "major" or "moderate" contribution to society, and 84% felt "very" or "somewhat" proud to be making this contribution. Conclusions: Most respondents continue to participate in the ESPRIT study in hopes of benefiting personally. The majority also recognized that by participating in ESPRIT they were contributing to helping others; they experienced pride regarding this contribution and considered it an important reason to continue to participate. These results indicate that it is possible for patient participants, even those seeking treatment for a life-threatening illness, to recognize and embrace the goals of the research in which they participate. Future studies will be needed to determine to what extent these findings generalize to other studies and other countries and what steps can help patient participants recognize and embrace the goals of clinical research. ©2008 American Medical Association. All rights reserved. PU: American Medical Association 515 North State Street, Chicago, IL 60610, United States CNOTE: Copyright 2008 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/23 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2008309632 Autoren: Lifson AR; Belloso WH; Carey C; Davey RT; Duprez D; El-Sadr WM; Gatell JM; Gey DC; Hoy JF; Krum EA; Nelson R; Nixon DE; Paton N; Pedersen C; Perez G; Price RW; Prineas RJ; Rhame FS; Sampson J; Worley J Titel: Determination of the underlying cause of death in three multicenter international HIV clinical trials Source: HIV Clinical Trials; VOL: 9 (3); p. 177-185 /May/June 2008/ DOI: 10.1310/hct0903-177 PU: Thomas Land Publishers Inc. SU: EMBASE Sprache: English AL: English CY: United States ISSN: 1528-4336 CO: HCTIA Institution: Lifson AR, Dr., Division of Epidemiology, University of Minnesota, 1300 South Second Street, Minneapolis, MN 55454-1015, United States, [email protected] COU: United States DT: Journal Article JSC: E.5.3 ... Virology RN: 0057 AB: Purpose: Describe processes and challenges for an Endpoint Review Committee (ERC) in determining and adjudicating underlying causes of death in HIV clinical trials. Method: Three randomized HIV trials (two evaluating interleukin-2 and one treatment interruption) enrolled 11,593 persons from 36 countries during 1999-2008. Three ERC members independently reviewed each death report and supporting source documentation to assign underlying cause of death; differences of opinion were adjudicated. Results: Of 453 deaths reported through January 14, 2008, underlying causes were as follows: 10% AIDS-defining diseases, 21% non-AIDS malignancies, 9% cardiac diseases, 9% liver disease, 8% non-AIDS-defining infections, 5% suicides, 5% other traumatic events/accidents, 4% drug overdoses/acute intoxications, 11% other causes, and 18% unknown. Major reasons for unknown classification were inadequate clinical information or supporting documentation to determine cause of death. Half (51 %) of deaths reviewed by the ERC required follow-up adjudication; consensus was eventually always reached. Conclusion: ERCs can successfully provide blinded, independent, and systematic determinations of underlying cause of death in HIV clinical trials. Committees should include those familiar with AIDS and non-AIDS-defining diseases and have processes for adjudicating differences of opinion. Training for local investigators and procedure manuals should emphasize obtaining maximum possible documentation and follow-up information on all trial deaths. © 2008 Thomas Land Publishers, Inc. PU: Thomas Land Publishers Inc. 255 Jefferson Road, St. Louis, MO 63119, United States CNOTE: Copyright 2008 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/24 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2008279548 Autoren: Webb AL; Villamor E Titel: Update: Effects of antioxidant and non-antioxidant vitamin supplementation on immune function Source: Nutrition Reviews; VOL: 65 (5); p. 181-217 /May 2007/ DOI: 10.1301/nr.2007.may.181-217 PU: Blackwell Publishing Inc. SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0029-6643 CO: NUREA Institution: Webb AL, Dr., Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115, United States, [email protected] COU: United States DT: Review; Journal Article JSC: E.13 ... Nutrition RN: 0193 AB: The purpose of this manuscript is to review the impact of supplementation with vitamins E and C, carotenoids, and the B vitamins on parameters of innate and adaptive immune function as reported from clinical trials in humans. There is evidence to support causal effects of supplementation with vitamins E and C and the carotenoids singly and in combination on selected aspects of immunity, including the functional capacity of innate immune cells, lymphocyte proliferation, and the delayed-type hypersensitivity (DTH) response. Controlled intervention trials of B vitamin-containing multivitamin supplements suggest beneficial effects on immune parameters and clinical outcomes in HIV-positive individuals © 2007 International Life Sciences Institute. PU: Blackwell Publishing Inc. 350 Main Street, Malden, MA 02148, United States CNOTE: Copyright 2008 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/25 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2008271074 Autoren: Bart P-A; Goodall R; Barber T; Harari A; Guimaraes-Walker A; Khonkarly M; Sheppard NC; Bangala Y; Frachette M-J; Wagner R; Liljeström P; Kraehenbuhl J-P; Girard M; Goudsmit J; Esteban M; Heeney J; Sattentau Q; McCormack S; Babiker A; Pantaleo G; Weber J Titel: EV01: A phase I trial in healthy HIV negative volunteers to evaluate a clade C HIV vaccine, NYVAC-C undertaken by the EuroVacc Consortium Source: Vaccine; VOL: 26 (25); p. 3153-3161 /20080613/ DOI: 10.1016/j.vaccine.2008.03.083 SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0264-410X CO: VACCD PII: S0264410X0800385X Institution: McCormack S, MRC Clinical Trials Unit, 222 Euston Road, London, NW1 2DA, United Kingdom, [email protected] COU: United Kingdom DT: Journal Article JSC: E.4 ... Immunology & Serology; E.5 ... Clinical Microbiology RN: 0010 Keywords AB: NYVAC-C (vP2010), a recombinant vector expressing HIV subtype C gag, pol, and nef antigens, was tested in a phase I study in healthy, HIV negative volunteers in London and Lausanne. Twenty-four participants were randomised to receive NYVAC-C (20) or matching placebo (4) at weeks 0 and 4, and assessed for safety and immunogenicity over 48 weeks. There were no serious adverse events, and no clinical or laboratory abnormalities or other events that led to withdrawal, interruption or dose reduction of the NYVAC-C/placebo. Half of the 10 assessed responded in the ELISpot assay under stringent criteria, which informed the sample size for a DNA-NYVAC-C comparison to NYVAC-C alone. © 2008 Elsevier Ltd. All rights reserved. CNOTE: Copyright 2008 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/26 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2008154638 Autoren: Angus B; Lampe F; Tambussi G; Duvivier C; Katlama C; Youle M; Williams I; Clotet B; Fisher M; Post FA; Babiker A; Phillips A Titel: TILT: A randomized controlled trial of interruption of antiretroviral therapy with or without interleukin-2 in HIV-1 infected individuals Source: AIDS; VOL: 22 (6); p. 737-740 /200803/ DOI: 10.1097/QAD.0b013e3282f511f1 SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 CO: AIDSE PII: 0000203020080330000008 Institution: Angus B, Nuffield Department of Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9D4, United Kingdom, [email protected] COU: United Kingdom DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0012 AB: OBJECTIVE: We aimed to see if structured treatment interruption (STI) could be supported safely with the use of two cycles of IL-2 (4.5 MIU q12h subcutaneously 5 days) before STI to prolong the time before therapy restarted. METHODS: Subjects were randomly allocated to either A - continuous ART; B - continue for 9 weeks, then STI; restart with the same ART when the CD4 count falls below 200 cells; or C - two cycles of IL-2, 8 weeks apart, while still on ART; at week 9 stop ART and use a new cycle of IL-2 alone whenever the CD4 count falls < 300 cells. Patients were followed until week 105. RESULTS: 86 mostly white middle aged homosexual men with a baseline median CD4 count of 754 cells/ml (range 240-1400) and a nadir CD4 count of 268 cells/ml (range 62-822) enrolled. By 96 weeks there was a 66% probability of having restarted ART in arm B compared with 34% in arm C (p = 0.002; log rank test). New drugs were used in 60% in arm A, 57% in arm B and 45% in arm C. 4 subjects had a dose modification in the first cycle due to toxicity with 2 interrupting. There were 39 SAEs with 21 in arm C. There were no deaths. CONCLUSIONS: The primary aim of the trial was to gain experience in using IL-2. IL-2 delayed restarting drugs and fewer new drugs were used. © 2008 Lippincott Williams & Wilkins, Inc. CNOTE: Copyright 2008 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/27 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2008090321 Autoren: Davey RT; Pertel PE; Benson A; Cassell DJ; Gazzard BG; Holodniy M; Lalezari JP; Levy Y; Mitsuyasu RT; Palella FJ; Pollard RB; Rajagopalan P; Saag MS; Salata RA; Sha BE; Choudhri S Titel: Safety, tolerability, pharmacokinetics, and efficacy of an interleukin-2 agonist among HIV-infected patients receiving highly active antiretroviral therapy Source: Journal of Interferon and Cytokine Research; VOL: 28 (2); p. 89-100 /20080201/ DOI: 10.1089/jir.2007.0064 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 1079-9907 CO: JICRF Institution: Davey RT, Dr., NIAID, National Institutes of Health, DHHS, 10 Center Drive, Bethesda, MD 20892-1504, United States, [email protected] COU: United States DT: Journal Article JSC: E.4 ... Immunology & Serology; E.5.3 ... Virology RN: 0027 AB: We sought to determine the safety, maximum tolerated dose, optimal dose, and preliminary dose efficacy of intermittent subcutaneously (s.c.) administered BAY 50-4798 among patients with HIV infection receiving highly active antiretroviral therapy (HAART) compared with patients receiving HAART alone. A phase I/II randomized, double-blind, dose-escalation study was conducted of the safety, tolerability, pharmacokinetics, and efficacy of s.c. BAY 50-4798 administered to HIV-infected patients already receiving stable HAART. There were no unexpected safety findings in a population of HIV-infected patients receiving HAART plus SC BAY 50-4798 as adjunctive therapy. BAY 50-4798 exhibited nearly dose-proportional pharmacokinetics, and accumulation was minimal during multiple-dose treatment. Limited efficacy data indicated that treatment with BAY 50-4798 caused at least a transient increase in CD4+ T cell counts in some recipients, particularly at the early time points. In general, this effect appeared to increase with increasing dose. Bay 50-4798 was generally well tolerated across the dose range tested, but a lack of potent, sustained immunologic activity suggests that further optimization of dose and schedule will be necessary. © 2008 Mary Ann Liebert, Inc. CNOTE: Copyright 2008 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/28 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2008087509 Autoren: Michaelsson J; Long BR; Loo CP; Lanier LL; Spotts G; Hecht FM; Nixon DF Titel: Immune reconstitution of CD56dim NK cells in individuals with primary HIV-1 infection treated with interleukin-2 Source: Journal of Infectious Diseases; VOL: 197 (1); p. 117-125 /20080101/ DOI: 10.1086/524141 PU: University of Chicago Press SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0022-1899 CO: JIDIA Institution: Michaelsson J, Dr., Dept. of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden, [email protected] COU: Sweden DT: Journal Article JSC: E.5 ... Clinical Microbiology; B.2 ... Public Health RN: 0046 AB: Natural killer (NK) cells are believed to play a role in human immunodeficiency virus type 1 (HIV-1) disease progression, and NK cell levels are reduced in individuals with chronic HIV-1 infection. Interleukin (IL)-2 therapy results in an expansion of CD4+ T cells as well as NK cells; however, little is known about the detailed effects of IL-2 therapy on NK cells in HIV-1 infection in general and in early infection in particular. Here, we investigated the effects of combined IL-2 therapy and antiretroviral therapy (ART) on the number, frequency, phenotype, and interferon (IFN)-gamma production of NK cells in individuals with early HIV-1 infection. Patients randomized to receive combined ART and IL-2 therapy predominantly expanded CD56dim NK cells, and the expansion was greater than in patients randomized to receive ART alone. Importantly, NK cell receptor expression and IFN-gamma production were maintained over time. This reconstitution of NK cells may be useful in helping contain viremia if patients discontinue therapy or develop drug resistance. © 2007 by the Infectious Diseases Society of America. All rights reserved. PU: University of Chicago Press 1427 E. 60th Street, Chicago, IL 60637-2954, United States CNOTE: Copyright 2010 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/29 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2008058266 Autoren: Harari A; Bart P-A; Stöhr W; Tapia G; Garcia M; Medjitna-Rais E; Burnet S; Cellerai C; Erlwein O; Barber T; Moog C; Liljestrom P; Wagner R; Wolf H; Kraehenbuhl J-P; Esteban M; Heeney J; Frachette M-J; Tartaglia J; McCormack S; Babiker A; Weber J; Pantaleo G Titel: An HIV-1 clade C DNA prime, NYVAC boost vaccine regimen induces reliable, polyfunctional, and long- lasting T cell responses Source: Journal of Experimental Medicine; VOL: 205 (1); p. 63-77 /20080121/ http://www.jem.org/cgi/reprint/205/1/63 DOI: 10.1084/jem.20071331 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0022-1007 EISSN: 0022-1007 CO: JEMEA Institution: Pantaleo G, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland, [email protected] COU: Switzerland DT: Journal Article JSC: E.4 ... Immunology & Serology RN: 0042 AB: The EuroVacc 02 phase I trial has evaluated the safety and immunogenicity of a prime-boost regimen comprising recombinant DNA and the poxvirus vector NYVAC, both expressing a common immunogen consisting of Env, Gag, Pol, and Nef polypeptide domain from human immunodeficiency virus (HIV)-1 clade C isolate, CN54. 40 volunteers were randomized to receive DNA C or nothing on day 0 and at week 4, followed by NYVAC C at weeks 20 and 24. The primary immunogenicity endpoints were measured at weeks 26 and 28 by the quantification of T cell responses using the interferon gamma enzyme-linked immunospot assay. Our results indicate that the DNA C plus NYVAC C vaccine regimen was highly immunogenic, as indicated by the detection of T cell responses in 90% of vaccinees and was superior to responses induced by NYVAC C alone (33% of responders). The vaccine-induced T cell responses were (a) vigorous in the case of the env response (mean 480 spot-forming units/10 6 mononuclear cells at weeks 26/28), (b) polyfunctional for both CD4 and CD8 T cell responses, (c) broad (the average number of was 4.2 per responder), and (d) durable (T cell responses were present in 70% of vaccinees at week 72). The vaccine-induced T cell responses were strongest and most frequently directed against Env (91% of vaccines), but smaller responses against Gag-Pol-Nef were also observed in 48% of vaccinees. These results support the development of the poxvirus platform in the HIV vaccine field and the further clinical development of the DNA C plus NYVAC C vaccine regimen. JEM © The Rockefeller University Press. CNOTE: Copyright 2008 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/30 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2007620121 Autoren: Gelato M; McNurlan M; Freedland E Titel: Role of recombinant human growth hormone in HIV-associated wasting and cachexia: Pathophysiology and rationale for treatment Source: Clinical Therapeutics; VOL: 29 (11); p. 2269-2288 /200711/ DOI: 10.1016/j.clinthera.2007.11.004 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0149-2918 CO: CLTHD PII: S0149291807003530 Institution: Freedland E, Dr., EMD Serono, Inc., Rockland, MA, United States, [email protected] COU: United States DT: Journal Article JSC: A.1 ... Pharmacology & Drug Therapy RN: 0090 AB: Background: Wasting, or cachexia, is a significant, debilitating, and potentially life-threatening complication of HIV infection. It is associated with reduced strength and functional ability, reduced ability to with stand opportunistic infections, and increased risk of mortality. Although the incidence of HIV-associated wasting may have declined since the introduction of highly active antiretroviral therapy (HAART), it continues to be a concern in this patient population. Objective: This paper reviews available data on the etiology and clinical impact of HIV-associated wasting, the role of the growth hormone/insulin-like growth factor-I axis in the pathophysiology of this condition, and the rationale for its treatment with recombinant human growth hormone (rhGH). Methods: MEDLINE was searched for articles published in English through August 2007 using the terms HIV, wasting (and related terms), and growth hormone. Preference was given to clinical studies (including randomized clinical studies), meta-analyses, and guidelines. Review articles were evaluated and the bibliographies examined for additional relevant articles. The analysis was restricted to studies conducted in developed countries. Results: Alterations in the growth hormone/insulin like growth factor-I axis have been observed in patients with HIV-associated wasting, including elevated levels of the former and reduced levels of insulin- like growth factor I. In randomized, placebo-controlled studies, rhGH significantly improved lean body mass by ~3 kg compared with placebo (P < 0.001) and total body weight by ~3 kg (P < 0.001), and was associated with significant improvements in physical endurance and quality of life (P < 0.001). Common adverse events with rhGH therapy include blood glucose elevations, arthralgia (36.4%), myalgia (30.4%), and peripheral edema (26.1%), but these usually respond to dose reduction or drug discontinuation. Conclusions: Physicians should be alert to the possibility of wasting in HIV-infected patients receiving HAART and should consider treatment to improve patients' stamina and quality of life. The evidence supports a role for rhGH in the treatment of patients with HIV-associated wasting. Regular blood glucose monitoring is advised when treating wasting with rhGH. © 2007 Excerpta Medica, Inc. CNOTE: Copyright 2008 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/31 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2007499809 Autoren: Goujard C; Marcellin F; Hendel-Chavez H; Burgard M; Meiffrédy V; Venet A; Rouzioux C; Taoufik Y; El Habib R; Beumont- Mauviel M; Aboulker J-P; Lévy Y; Delfraissy J-F Titel: Interruption of antiretroviral therapy initiated during primary HIV-1 infection: Impact of a therapeutic vaccination strategy combined with interleukin (IL)-2 compared with IL-2 alone in the ANRS 095 randomized study Source: AIDS Research and Human ; VOL: 23 (9); p. 1105-1113 /200709/ NCT: ClinicalTrials.gov-NCT00196651 DOI: 10.1089/aid.2007.0047 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0889-2229 CO: ARHRE Institution: Goujard C, Service de Médecine Interne, Hôpital Bicêtre, AP-HP, 78 rue du General Leclerc, 94275 Le Kremlin Bicêtre Cedex, France, [email protected] COU: France DT: Journal Article JSC: E.4 ... Immunology & Serology; E.5.3 ... Virology RN: 0044 AB: HIV-specific T cell responses play a critical role in the control of infection. We evaluated the impact of immune-based interventions in patients first treated during primary HIV-1 infection (PHI). Forty-three patients were randomized within three groups, to receive either interleukin-2 (IL-2 group), or boosts of ALVAC-HIV (vCP1433) and LIPO-6T followed by interleukin-2 (Vac-IL2 group), compared with no immune intervention (control group), and were monitored for T cell responses. Impact of strategies on viral replication was subsequently assessed during long-term treatment interruption. HIV-specific CD4+ T cell responses did not change during the study period in immunized patients relative to controls, and vaccination had only a transient effect on interferon- gamma -producing CD8 responses. Viral rebound after treatment interruption was similar in immunized patients and controls. Forty percent of patients had HIV RNA values <10,000 copies/ml 12 weeks after interruption. The cumulative time off treatment represented almost half the total follow-up period. Immunological and virological status during PHI and HIV DNA load at interruption were predictive of the level of viral rebound after treatment interruption, whereas HIV RNA level during PHI and HIV DNA level at interruption were predictive of the time off treatment. Treatment interruption is safe in patients treated early after primary HIV infection. On the basis of this pilot study, HIV and interleukin-2 appear to have no supplementary benefit. © 2007 Mary Ann Liebert, Inc. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/32 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2007423977 Autoren: Durier C; Capitant C; Lascaux A-S; Goujard C; Oksenhendler E; Poizot-Martin I; Viard J-P; Weiss L; Netzer E; Delfraissy J-F; Aboulker J-P; Lévy Y Titel: Long-term effects of intermittent interleukin-2 therapy in chronic HIV-infected patients (ANRS 048-079 Trials) Source: AIDS; VOL: 21 (14); p. 1887-1897 /200709/ DOI: 10.1097/QAD.0b013e3282703825 SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 CO: AIDSE PII: 0000203020070912000008 Institution: Lévy Y, Unité d'Immunologie Clinique, Hôpital Henri Mondor, 51, Ave. du M. de Lattre de Tassigny, 94010 Creteil Cedex, France, [email protected] COU: France DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0037 CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/33 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2007417220 Autoren: Mkhitaryan LM; Davtyan TK; Gabrielyan ES; Gevorkyan LA Titel: Anti-HIV and anti-inflammatory action of iodine-lithium- alpha -dextrin is accompanied by the improved quality of life in AIDS patients Source: International Journal of Biotechnology; VOL: 9 (3-4); p. 301-317 /2007/ DOI: 10.1504/IJBT.2007.014252 SU: EMBASE Sprache: English AL: English CY: Switzerland ISSN: 0963-6048 CO: IJBNB Institution: Davtyan TK, Dr., Laboratory of Immunology and Virology, Research Center, CJSC Armenicum+, 37 Nalbandyan Street, 375001, , [email protected] COU: Armenia DT: Journal Article JSC: E.10 ... Biotechnology & Applied Science RN: 0027 AB: Clinical efficacy, tolerability and safety of various doses of Iodine-Lithium- alpha -Dextrin (IL alpha D) monotherapy have been evaluated in 56 HIV-infected patients enrolled in double blind uncontrolled randomised study during 48 weeks follow-up period. IL alpha D was administered intravenously three times over five days with intervals of 2-3 weeks between treatments for a total of 12 infusions in 4 cycles. HIV-1 RNA reduction and increase of CD4 + T-cell counts as well as decrease of serum levels of IgG, IgA, beta 2 microglobulin, tumour necrosis factor- alpha and soluble interleukin-2 receptor were observed on 4-24th weeks. Quality of life was dramatically improved on 4-48th weeks and more. The side-effects were phlebitis of punctured small veins and subfebrile fever, that did not lead to discontinuation of the treatment and did not require special treatment. IL alpha D appears to be safe and can be used as an adjuvant therapy for long term improvement of quality of life in AIDS patients. Copyright © 2007 Inderscience Enterprises Ltd. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/34 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2007366066 Autoren: Hardy GAD; Imami N; Nelson MR; Sullivan AK; Moss R; Aasa-Chapman MMI; Gazzard B; Gotch FM Titel: A phase I, randomized study of combined IL-2 and therapeutic immunisation with antiretroviral therapy Source: Journal of Immune Based Therapies and Vaccines; VOL: 5 /20070411/ ANR: 6 DOI: 10.1186/1476-8518-5-6 SU: EMBASE Sprache: English AL: English CY: United Kingdom EISSN: 1476-8518 Institution: Gotch F, Department of Immunology, Imperial College London, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, United Kingdom, [email protected] COU: United Kingdom DT: Journal Article JSC: E.4 ... Immunology & Serology RN: 0050 AB: Background: Fully functional HIV-1-specific CD8 and CD4 effector T-cell responses are vital to the containment of viral activity and disease progression. These responses are lacking in HIV-1-infected patients with progressive disease. We attempted to augment fully functional HIV-1-specific CD8 and CD4 effector T-cell responses in patients with advanced chronic HIV-1 infection. Design: Chronically infected patients with low CD4 counts T-cell counts who commenced antiretroviral therapy (ART) were subsequently treated with combined interleukin-2 and therapeutic vaccination. Methods: Thirty six anti-retroviral naive patients were recruited and initiated on combination ART for 17 weeks before randomization to: A) ongoing ART alone; B) ART with IL-2 twice daily for 5 days every four weeks starting at week 17 for 3 cycles; C) ART with IL-2 as in group B and Remune HIV-1 vaccine administered once every 3 months, starting at week 17; and D) ART with Remune vaccine as in group C. Patients were studied for 65 weeks following commencement of ART, with an additional prior 6 week lead-in observation period. CD4 and CD8 T-cell counts, evaluations of HIV-1 RNA levels and proliferative responses to recall and HIV-1 antigens were complemented with assessment of IL-4-secretion alongside quantification of anti-HIV-1 CD8 T-cell responses and titres. Results: Neither IL-2 nor Remune® vaccination induced sustained HIV-1-specific T-cell responses. However, we report an inverse relationship between HIV-1-specific proliferative responses and IL-4 production which continuously increased in patients receiving immunotherapy, but not patients receiving ART alone. Conclusion: Induction of HIV-1-specific cell-mediated responses is a major challenge in chronically HIV-1-infected patients even when combining immunisation with IL-2 therapy. An antigen-specific IL-4-associated suppressive response may play a role in attenuating HIV-specific responses. © 2007 Hardy et al; licensee BioMed Central Ltd. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/35 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2007342384 Autoren: Hicks CB; Gay C; Ferrari G Titel: Acute HIV infection: The impact of anti-retroviral treatment on cellular immune responses Source: Clinical and Experimental Immunology; VOL: 149 (2); p. 211-216 /200708/ DOI: 10.1111/j.1365-2249.2007.03437.x SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0009-9104 EISSN: 1365-2249 CO: CEXIA Institution: Ferrari G, Dr., Duke University Medical Center, Department of Surgery, PO Box 2926, Durham, NC 27710, United States, [email protected] COU: United States DT: Short Survey; Journal Article JSC: E.4 ... Immunology & Serology RN: 0059 AB: The overall value of initiating anti-retroviral therapy during the acute phase of human immunodeficiency virus type 1 (HIV-1) infection remains unclear. From a clinical perspective, the lack of data from controlled randomized clinical trials limits understanding of long-term effects of treatment on the clinical course of HIV infection. Based on available data, the impact of anti- retroviral therapy during acute infection on the immune response against HIV-1 is not particularly encouraging. Recent observations on the very early depletion of lymphocyte reservoirs in the gastrointestinal tract may partially explain the limited benefit of anti- retroviral therapy initiated during the acute phase of HIV-1 infection. This may also help to explain the dichotomy between early observations demonstrating apparent immunological benefit with early anti-retroviral treatment that were associated none the less with inability to control viral replication following treatment interruption. © 2007 British Society for Immunology. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/36 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2007290966 Autoren: Precopio ML; Betts MR; Parrino J; Price DA; Gostick E; Ambrozak DR; Asher TE; Douek DC; Harari A; Pantaleo G; Bailer R; Graham BS; Roederer M; Koup RA Titel: with virus induces polyfunctional and phenotypically distinctive CD8+ T cell responses Source: Journal of Experimental Medicine; VOL: 204 (6); p. 1405-1416 /20070611/ http://www.jem.org/cgi/reprint/204/6/1405 DOI: 10.1084/jem.20062363 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0022-1007 EISSN: 0022-1007 CO: JEMEA Institution: Koup RA, Immunology Laboratory, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, United States, [email protected] COU: United States DT: Journal Article JSC: E.4 ... Immunology & Serology RN: 0049 AB: Vaccinia virus immunization provides lifelong protection against smallpox, but the mechanisms of this exquisite protection are unknown. We used polychromatic flow cytometry to characterize the functional and phenotypic profile of CD8+ T cells induced by vaccinia virus immunization in a comparative of modified vaccinia virus Ankara (MVA) versus Dryvax immunization in which protection was assessed against subsequent Dryvax challenge. Vaccinia virus-specific CD8+ T cells induced by both MVA and Dryvax were highly polyfunctional; they degranulated and produced interferon gamma , interleukin 2, macrophage inflammatory protein 1 beta , and tumor necrosis factor alpha after antigenic stimulation. Responding CD8+ T cells exhibited an unusual phenotype (CD45RO-CD27intermediate). The unique phenotype and high degree of polyfunctionality induced by vaccinia virus also extended to inserted HIV gene products of recombinant NYVAC. This quality of the CD8+ T cell response may be at least partially responsible for the profound efficacy of these vaccines in protection against smallpox and serves as a benchmark against which other vaccines can be evaluated. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/37 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2007272930 Autoren: Smith KA; Andjelic S; Popmihajlov Z; Kelly-Rossini L; Sass A; Lesser M; Benkert S; Waters C; Ruitenberg J; Bellman P Titel: Immunotherapy with vaccine and interleukin-2 for HIV-1 infection: Termination of a randomized trial Source: PLoS Clinical Trials; VOL: 2 (1) /20070126/ http://clinicaltrials.plosjournals.org/archive/1555-5887/2/1/pdf/10.1371_journal.pctr.0020005-L.pdf ANR: e5 DOI: 10.1371/journal.pctr.0020005 SU: EMBASE Sprache: English AL: English CY: United States EISSN: 1555-5887 Institution: Smith KA, The Division of Immunology, Department of Medicine, Weill Medical College of Cornell University, New York, NY, United States, [email protected] COU: United States DT: Journal Article RN: 0033 AB: Objectives: To determine whether immunotherapy of chronic HIV-1 infection can prevent or attenuate viremia upon antiviral discontinuation. Design: This was a Phase II randomized, partially double blinded, 2×2 factorial study of three steps of 12 wk/step. Step I involved four groups: (1) vaccine placebo, (2) vaccine (ALVAC, vCP1452), (3) placebo + interleukin 2 (IL-2), and (4) vaccine + IL-2. Step II involved a 12-wk diagnostic treatment interruption (DTI). Step III involved an extension of the DTI for an additional 12 wk. Setting: The Weill-Cornell General Clinical Research Center. Participants: Chronically infected HIV-1 positive adults with undetectable HIV-1 levels and > 400 CD4+ T cells/ mu l. Interventions: An HIV canarypox vaccine (vCP1452) and vaccine placebo, administered every 4 wk for four doses, and low-dose IL-2 administered daily for 12-24 wk. Outcome measures: Primary endpoints: (1) Proportion of participants with undetectable plasma HIV RNA during trial Step II, (2) mean log10 HIV RNA copies/ml ([HIV]) from weeks 21-25, and (3) proportion of individuals eligible for trial Step III. Results: 44 participants were randomized, but 16 withdrew or were withdrawn before completing Step II. As all participants underwent viral relapse in Step II, the study was terminated after 28 participants completed Step II. Among the four groups, there was no difference in mean [HIV] or the proportion of individuals with < log10 4.48 HIV; no difference between the mean [HIV] of the two groups that received ALVAC (n = 17) versus placebo (n = 11); and no significant difference between the mean [HIV] of the two groups that received IL-2 (n = 11) versus placebo (n = 17). Conclusions: Neither ALVAC (vCP1452) nor low-dose daily IL-2 nor their combination prevented the relapse of viremia upon discontinuation of antiviral therapy. © 2007 Smith et al. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/38 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2007171281 Autoren: Hunt PW Titel: Role of immune activation in HIV pathogenesis Source: Current HIV/AIDS Reports; VOL: 4 (1); p. 42-47 /200702/ SU: EMBASE Sprache: English AL: English CY: United States ISSN: 1548-3568 EISSN: 1548-3576 Institution: Hunt PW, Dr., Positive Health Program, San Francisco General Hospital, Building 80, 995 Potrero Avenue, San Francisco, CA 94110, United States, [email protected] COU: United States DT: Review; Journal Article RN: 0061 AB: T-cell activation has long been considered a central mediator of HIV pathogenesis. High T-cell activation levels predict more rapid disease progression in untreated patients and decreased treatment-mediated CD4+ T-cell gains during antiretroviral therapy, independent of plasma HIV RNA levels, and may be the primary feature distinguishing pathogenic from nonpathogenic primate models of HIV infection. Studies in animal models and individuals with HIV infection continue to enhance our understanding of how T-cell activation causes immunodeficiency during HIV infection. The goal of these studies is to identify specific mechanisms that can be targeted by novel immune-based therapies for patients who have thus far been unable to recover normal immune function despite years of antiretroviral therapy. Although most immune-based therapies targeting T-cell activation have been unsuccessful to date, recent scientific developments have focused attention on specific pathways that may be exploited by future generations of immune-based therapies. Copyright © 2007 by Current Medicine Group LLC. AU: Hunt PW Hunt Peter W. Positive Health Program, San Francisco General Hospital, Building 80, 995 Potrero Avenue, San Francisco, CA 94110, United States [email protected] CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/39 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2007127422 Autoren: Fox Z; Antunes F; Davey R; Gazzard B; Klimas N; Labriola A; Losso M; Neaton JD; Phillips A; Ruxrungtham K; Staszewski S; Weiss L; Lundgren DJ; Aguilar L; Angel EB; Aquilia S; Belloso W; Benetucci J; Bittar V; Cahn P; Casiro A; Contarelli J; Corral J; Daciuk L; David D; Ferrari I; Fridman D; Galache V; Guaragna G; Ivalo S; Laplume H; Lanusse I; Lasala MB; Lattes R; Lasovsky J; Lopardo G; Losso M; Lourtau L; Lupo S; Maranzana A; Marson C; Massera L; Sanchez MdelL; Somenzini C; Tocci M; Algar S; Anderson J; Baker D; Blavius K; Bloch M; Boyle M; Bradford D; Britton P; Carrall L; Carr A; Chuah J; Curry M; D'Arcy-Evans C; Dobson P; Doong N; Egan C; Ferguson W; Finlayson R; French M; Frater A; Gold J; Habel P; Haig K; Holland R; Hyland N; Hoy J; Hudson J; James R; Leung J; Lowe K; MacRae K; McMurchie M; Medland N; Miller S; Murray J; Newman R; David O; Patching J; Primrose R; Ree H; Richardson R; Rogers G; Roney J; Roth N; Sarangapany J; Shaw D; Silberberg C; Skett A; Vale R; Villella C; Walker A; Watson A; Wendt N; Wood H; et al Titel: Predictors of CD4 count change over 8 months of follow up in HIV-1-infected patients with a CD4 count >= 300 cells/ mu L who were assigned to 7.5 MIU interleukin-2 Source: HIV Medicine; VOL: 8 (2); p. 112-123 /200703/ DOI: 10.1111/j.1468-1293.2007.00440.x SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 1464-2662 EISSN: 1468-1293 CO: HMIEA Institution: Fox Z, CHIP, Hvidovre University Hospital, DK-2650 Hvidovre, Denmark, [email protected] COU: Denmark DT: Journal Article JSC: C.0 ... Clinical Medicine; E.5.3 ... Virology RN: 0025 AB: Background: ESPRIT is a randomized trial comparing the clinical impact of interleukin (IL)-2 plus antiretrovirals vs antiretrovirals alone. Identification of factors that influence the relationship between IL-2 and CD4 count recovery will enable better personalization of treatment with IL-2 in HIV-1-positive individuals. The IL-2 induction phase consists of three dosing cycles over 6-8 months (7.5 MIU twice a day, for 5 days every 8 weeks). Methods: We included patients initiating IL-2 at the 7.5 MIU dose with an 8-month CD4 count, measured at least 30 days after their last cycle. We identified baseline predictors of CD4 count changes over 8 months using linear regression. Results: Of 2090 patients assigned IL-2, 1673 (80%) were included in the analysis. The median (interquartile range) baseline CD4 count was 461 (370, 587) cells/ mu L with a median increase of 233 (90, 411) cells/ mu L at month 8. After adjustments, significant predictors of CD4 count change included CD4 nadir (29.8 cells/ mu L greater increase per 100 cells/ mu L higher; P < 0.0001), last CD4 count before baseline (mean 36.0 cells/ mu L greater increase per 100 cells/ mu L higher; P < 0.0001), time from antiretroviral start to baseline (8.3 cells/ mu L smaller increase per year longer; P = 0.001), age (11.7 cells/ mu L smaller increase per 5 years older; P = 0.005) and race (79.7 cells/ mu L greater increase for black patients vs white patients; P = 0.003). A linear relationship existed between total IL-2 dose in the first cycle and CD4 count change (73.1 cells/ mu L greater increase per 15 MIU higher; P < 0.0001). Conclusions: Prior nadir and current CD4 counts, age and IL-2 dose are major determinants of CD4 increases induced by with intermittent administration of IL-2 in HIV-1-positive individuals on antiretrovirals. The clinical function of these induced CD4 cells is under study. © 2007 British HIV Association. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/40 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2007103675 Autoren: Lewis DE; Gross KL; Diez MM; Martinez ML; Lukefahr HN; Kozinetz CA; Arduino RC Titel: CD8 apoptosis may be a predictor of T cell number normalization after immune reconstitution in HIV Source: Journal of Translational Medicine; VOL: 5 /2007/ ANR: 9 DOI: 10.1186/1479-5876-5-9 SU: EMBASE Sprache: English AL: English CY: United Kingdom EISSN: 1479-5876 Institution: Lewis DE, Department of Immunology, Baylor College of Medicine, Houston, TX, United States, [email protected] COU: United States DT: Journal Article JSC: C.0 ... Clinical Medicine; E.0 ... Experimental Science RN: 0031 AB: Background: As part of the Houston Vanguard study, a subset of 10 patients randomized to receive IL-2 therapy were compared to 4 patients randomized to not receive IL-2, for markers of T cell activation and death during the first three cycles of IL-2. All patients were treated with combination antiretroviral therapy (ART) and were virally suppressed. The purpose of the study was to examine the role of CD8+ T cell death in responses to ART and IL-2 therapy. Methods: Lymphocytes were examined at Day 0, 5 and 30 days during three cycles of IL-2 therapy. CD25, CD38, HLA-DR expression and annexin (cell death) were examined on CD4 and CD8 subpopulations. Follow up studies examined CD4 levels and CD4:CD8 reconstitution after 6 years using both univariant and multivariate analyses. Results: Human lymphocytes responded to IL-2 therapy by upregulation of CD25 on CD4+ T cells, leading to an increase in CD4 cell counts. CD8+ T cells did not increase CD25 expression, but upregulated activation antigens (CD38 and DR) and had increased death. At baseline, 7 of the 14 patients had high CD8+ T cell apoptosis (mean 17.0% ± 6.0). We did an exploratory analysis of immune status after six years, and found that baseline CD8+ T cell apoptosis was correlated with CD4 cell count gain beginning two years post enrollment. Patients with low levels of CD8+ T cell apoptosis at baseline (mean 2.2% ± 2.1) had significantly higher CD4 cell counts and more normalized CD4:CD8 ratios than patients with high CD8+ T cell apoptosis (mean CD4 cell counts 1,209 ± 164 vs 754 ± 320 cells/mm³; CD4:CD8 ratios 1.55 vs. 0.70, respectively). Conclusion: We postulate that CD8+ T cell apoptosis may reflect inherent activation status, which continues in some patients even though viral replication is suppressed which influences the ability of CD4+ T cells to rebound. Levels of CD8+ T cell apoptosis may therefore be an independent predictor of immune status, which should be shown in a prospective study. © 2007 Lewis et al., licensee BioMed Central Ltd. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/41 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2007088228 Autoren: Temesgen Z Titel: Interleukin-2 for the treatment of human immunodeficiency virus infection Source: Drugs of Today; VOL: 42 (12); p. 791-801 /200612/ DOI: 10.1358/dot.2006.42.12.1025703 SU: EMBASE Sprache: English AL: English CY: Spain ISSN: 0025-7656 CO: MDACA Institution: Temesgen Z, Dr., AAHIVS, Mayo Clinic and Foundation, Division of Infectious Diseases, 200 First St. SW, Rochester, MN 55905, United States, [email protected] COU: United States DT: Review; Journal Article JSC: A.3 ... Pharmaceutical & Medicinal Chemistry; A.1.1 ... Clinical Pharmacology RN: 0070 AB: Notwithstanding the significant impact of highly active antiretroviral therapy (HAART) on human immunodeficiency virus (HIV)- associated morbidity and mortality, HAART-induced immune restitution is not complete. The potential utility of interleukin (IL)-2 to augment immune function has been extensively evaluated. Intravenous or subcutaneous IL-2 has been conclusively shown to induce significant increases in CD4 cell counts in HIV-infected patients, in particular when given concomitantly with HAART. Large randomized clinical trials are underway to investigate whether these CD4 cell increments will result in tangible clinical benefits. © 2006 Prous Science. All rights reserved. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/42 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2006608328 Autoren: Kilby JM; Bucy RP; Mildvan D; Fischl M; Santana-Bagur J; Lennox J; Pilcher C; Zolopa A; Lawrence J; Pollard RB; El Habib R; Sahner D; Fox L; Aga E; Bosch RJ; Mitsuyasu R Titel: 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) Source: Journal of Infectious Diseases; VOL: 194 (12); p. 1672-1676 /20061215/ DOI: 10.1086/509508 PU: University of Chicago Press SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0022-1899 CO: JIDIA Institution: Kilby JM, Dr., University of Alabama at Birmingham, Birmingham, AL 35294-2050, United States, [email protected] COU: United States DT: Journal Article JSC: E.5 ... Clinical Microbiology; B.2 ... Public Health RN: 0015 AB: Strategies to limit life-long dependence on antiretroviral therapy (ART) are needed. We randomized 81 human immunodeficiency virus (HIV)-infected subjects to 4 interventional arms involving continued ART plus ALVAC vCP1452 (or placebo) with or without interleukin (IL)-2 infusions. Viral load rebound 12 weeks after ART interruption was then analyzed to assess immune control. Fifty- two subjects reached the study end point. ALVAC recipients had 0.5 log10 lower virologic rebounds (P = .033). IL-2 plus vaccine boosted CD4+ T cell counts (P < .001) but did not diminish viral rebound. Significant changes were not detected for HIV-specific lymphoproliferative responses in any arm. This exploratory protocol provides useful clinical data for future therapeutic immunization trial design. © 2006 by the Infectious Diseases Society of America. All rights reserved. PU: University of Chicago Press 1427 E. 60th Street, Chicago, IL 60637-2954, United States CNOTE: Copyright 2010 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/43 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2006608326 Autoren: Graham BS; Koup RA; Roederer M; Bailer RT; Enama ME; Moodie Z; Martin JE; McCluskey MM; Chakrabarti BK; Lamoreaux L; Andrews CA; Gomez PL; Mascola JR; Nabel GJ; Larkin B; Scott M; Thomas C; Hubka S; Gordon I; Edmonds P; Rucker S; Novik L; Alley T; Gu L; McCurdy L; Catanzaro A; Parrino J; Casazza J; Flores J Titel: Phase 1 safety and immunogenicity evaluation of a multiclade HIV-1 DNA candidate vaccine Source: Journal of Infectious Diseases; VOL: 194 (12); p. 1650-1660 /20061215/ NCT: ClinicalTrials.gov-NCT00047931 DOI: 10.1086/509259 PU: University of Chicago Press SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0022-1899 CO: JIDIA Institution: Graham BS, Dr., Vaccine Research Center, NIAID, NIH, 40 Convent Dr., Bethesda, MD 20892-3017, United States, [email protected] COU: United States DT: Journal Article JSC: E.5 ... Clinical Microbiology; B.2 ... Public Health RN: 0036 AB: Background. Gene-based vaccine delivery is an important strategy in the development of a preventive vaccine for acquired immunodeficiency syndrome (AIDS). Vaccine Research Center (VRC) 004 is the first phase 1 dose-escalation study of a multiclade HIV-1 DNA vaccine. Methods. VRC-HIVDNA009-00-VP is a 4-plasmid mixture encoding subtype B Gag-Pol-Nef fusion protein and modified envelope (Env) constructs from subtypes A, B, and C. Fifty healthy, uninfected adults were randomized to receive either placebo (n = 10) or study vaccine at 2 mg (n = 5), 4 mg (n = 20), or 8 mg (n = 15) by needle-free intramuscular injection. Humoral responses (measured by enzyme-linked immunosorbant assay, Western blotting, and neutralization assay) and T cell responses (measured by enzyme-linked immunospot assay and intracellular cytokine staining after stimulation with antigen-specific peptide pools) were measured. Results. The vaccine was well tolerated and induced cellular and humoral responses. The maximal CD4+ and CD8+ T cell responses occurred after 3 injections and were in response to Env peptide pools. The pattern of cytokine expression by vaccine-induced HIV-specific T cells evolved over time, with a diminished frequency of interferon-gamma-producing T cells and an increased frequency of interleukin-2-producing T cells at 1 year. Conclusions. DNA vaccination induced antibody to and T cell responses against 3 major HIV-1 subtypes and will be further evaluated as a potential component of a preventive AIDS vaccine regimen. © 2006 by the Infectious Diseases Society of America. All rights reserved. PU: University of Chicago Press 1427 E. 60th Street, Chicago, IL 60637-2954, United States CNOTE: Copyright 2010 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/44 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2006540760 Autoren: Shor-Posner G; Hernandez-Reif M; Miguez M-J; Fletcher M; Quintero N; Baez J; Perez-Then E; Soto S; Mendoza R; Castillo R; Zhang G Titel: Impact of a massage therapy clinical trial on immune status in young Dominican children infected with HIV-1 Source: Journal of Alternative and Complementary Medicine; VOL: 12 (6); p. 511-516 /July/August 2006/ DOI: 10.1089/acm.2006.12.511 PU: Mary Ann Liebert Inc. SU: EMBASE Sprache: English AL: English CY: United States ISSN: 1075-5535 CO: JACPF Institution: Shor-Posner G, Dr., Division of Disease Prevention, Department of Psychiatry and Behavioral Sciences (D80), University of Miami Miller School of Medicine, 1400 NW 10th Avenue, Miami, FL 33136, United States, [email protected] COU: United States DT: Journal Article JSC: C.0 ... Clinical Medicine RN: 0016 AB: Purpose: The effectiveness of massage therapy on immune parameters was evaluated in young Dominican HIV+ children without current access to antiretroviral therapies. Methods: Eligible children, who were followed at the Robert Reid Cabral Hospital (San Domingo, Dominican Republic), were randomized to receive either massage treatment or a control/friendly visit twice weekly for 12 weeks. Blood was drawn at baseline and following the 3-month intervention for determinations of CD4, CD8, and CD56 cell counts and percentage, along with activation markers (CD25 and CD69). Results: Despite similar immune parameters at baseline in the two groups, significantly more of the control group exhibited a decline in CD4 cell count (>30%, p = 0.03), postintervention. The decrease was particularly evident in older (5-8 years) children in the control arm, who demonstrated a significant reduction in both CD4 and CD8 cell counts compared to massage-treated older children who remained stable or showed immune improvement. Additionally, a significant increase in CD4+CD25+ cells was observed over the 12-week trial in the massage-treated older children (p = 0.04) but not in the control group. In younger massage-treated children, (2-4 years old), a significant increase in natural killer cells was shown. Conclusion: Together these findings support the role for massage therapy in immune preservation in HIV+ children. © Mary Ann Liebert, Inc. PU: Mary Ann Liebert Inc. 140 Huguenot Street, New Rochelle, NY 10801-5215, United States CNOTE: Copyright 2010 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/45 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2006474211 Autoren: Reading C; Dowding C; Schramm B; Garsd A; Onizuka-Handa N; Stickney D; Frincke J Titel: Improvement in immune parameters and human immunodeficiency virus-1 viral response in individuals treated with 16alpha-bromoepiandrosterone (HE2000) Source: Clinical Microbiology and Infection; VOL: 12 (11); p. 1082-1088 /November 2006/ DOI: 10.1111/j.1469-0691.2006.01520.x PU: Blackwell Publishing Ltd SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 1198-743X EISSN: 1469-0691 CO: CMINF Institution: Reading C, Hollis Eden Pharmaceuticals Inc., 4435 Eastgate Mall, San Diego, CA, United States, [email protected] COU: United States DT: Journal Article JSC: E.5 ... Clinical Microbiology RN: 0037 AB: A randomised, double-blind, placebo-controlled study examined the safety, tolerance, immunological effect and anti-human immunodeficiency virus (HIV) activity of sub-cutaneously administered HE2000 (16alpha-bromoepiandrosterone) as monotherapy in treatment-naive patients with HIV-1. Twenty-four patients received five sequential daily doses of 50 or 100 mg of HE2000 or placebo every 6 weeks for up to three courses, and were followed thereafter for 3 months. HE2000 was safe, with transient injection site reactions being the main side-effect. Peripheral blood samples, collected serially, were analysed for changes in immune cell phenotypes. Significant increases were observed in the numbers of circulating dendritic cells, early activated (CD69+ CD25-) CD8 T-cells and T-NK cells after administration of 50-mg doses of HE2000 (p <0.05). Gene expression in peripheral blood mononuclear cells was analysed by real-time RT-PCR. Before treatment, HIV-1-infected patients had significantly elevated transcripts for a number of inflammatory mediators (p <0.012). After 50mg or 100mg HE2000, but not after placebo, there were significant sustained decreases in IL-1beta, TNF-alpha, IL-6 and Cox-2 transcripts (p <0.05). There were no significant differences in CD4 cell numbers, although patients receiving 50-mg doses demonstrated a significant decrease in viral load (-0.6 log; p <0.01). Anti-HIV-1 T-cell responses were analysed serially using GAG-peptides to stimulate cytoplasmic IFN-gamma responses. After three courses, the 50-mg dose group demonstrated a significant increase in CD8 T-cell response against two distinct GAG peptide pools (p <0.03). These findings suggest that immune-based therapies may be able to impact viral load by decreasing and/or stimulating CD8 T-cells. © 2006 European Society of Clinical Microbiology and Infectious Diseases. PU: Blackwell Publishing Ltd 9600 Garsington Road, Oxford, OX4 2XG, United Kingdom CNOTE: Copyright 2010 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/46 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2006420565 Autoren: Lifson AR; Rhame FS; Belloso WH; Dragsted UB; El-Sadr WM; Gatell JM; Hoy JF; Krum EA; Nelson R; Pedersen C; Pett SL; Davey RT Jr.; Neaton J; Abrams D; Cahn P; Clotet B; Cooper D; Darbyshire J; Sandra L; Emery S; Hengge U; Lane HC; Lange J; Levy G; Levy Y; Lundgren J; Mitsuyasu R; Routy JP; Tambussi G Titel: Reporting and evaluaton of HIV-related clinical endpoints in two multicenter international clinical trials Source: HIV Clinical Trials; VOL: 7 (3); p. 125-141 /200605/ DOI: 10.1310/7MER-XFA7-1762-E2WR SU: EMBASE Sprache: English AL: English CY: United States ISSN: 1528-4336 CO: HCTIA Institution: Lifson AR, Dr., Department of Epidemiology and Community Health, University of Minnesota, 1300 South Second Street, Minneapolis, MN 55454, United States, [email protected] COU: United States DT: Journal Article JSC: E.5.3 ... Virology RN: 0029 AB: Purpose: The processes for reporting and review of progression of HIV disease clinical endpoints are described for two large phase III international clinical trials. Method: SILCAAT and ESPRIT are multicenter randomized HIV trials evaluating the impact of interleukin-2 on disease progression and death in HIV-infected patients receiving antiretroviral therapy. We report definitions used for HIV progression of disease endpoints, procedures for site reporting of such events, processes for independent review of reported events by an Endpoint Review Committee (ERC), and the procedure for adjudication of differences of opinion between reviewers. Results: Of 473 events reported through May 1, 2006, 28% were judged by an ERC to meet "confirmed" criteria and 38% to meet "probable" criteria; 34% were classified "does not meet criteria." For diseases with >5 case reports, the proportion accepted as either "confirmed" or "probable" events was highest for (100%), non-Hodgkin's lymphoma (88%), cryptococcosis (82%), and cryptosporidiosis (80%) and was lowest for HIV encephalopathy (25%), HIV wasting syndrome (33%), and multidermatomal herpes zoster (35%). 25% of cases required adjudication between reviewers before diagnostic certainty was assigned. Conclusion: Important requirements for HIV trials using clinical endpoints include objective definitions of "confirmed" and "probable," a formal reporting process with adequate information and supporting source documentation, evaluation by independent blinded reviewers, and procedures for adjudication. © 2006 Thomas Land Publishers, Inc. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/47 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2006345637 Autoren: Pett SL; Wand H; Law MG; Arduino R; Lopez JC; Knysz B; Pereira LC; Pollack S; Reiss P; Tambussi G; Abrams DI; Cooper DA; Darbyshire JH; Duncan WR; Emery S; Clifford Lane H; Lehrman S; Lundgren JD; Neaton JD; Aguilar L; Angel EB; Aquilia S; Belloso W; Benetucci J; Bittar V; Cahn P; Casiro A; Contarelli J; Corral J; Daciuk L; David D; Ines F; Fridman D; Galache V; Guaragna G; Ivalo S; Laplume H; Lasala MB; Lattes R; Lasovsky J; Lopardo G; Losso M; Lourtau L; Lupo S; Maranzana A; Marson C; Massera L; del Lujan Sanchez M; Somenzini C; Tocci M; Algar S; Anderson J; Austin D; Baker D; Blavius K; Bloch M; Boyle M; Bradford D; Carrall L; Carr A; Chuah J; Curry M; D'Arcy-Evans C; Dobson P; Doong N; Ferguson W; Finlayson R; French M; Gold J; Habel P; Hoy J; Hudson J; James R; Jeganathan S; Leung J; Lowe K; MacRae K; Mallal S; McMurchie M; Medland N; Mijch A; Miller S; Murray J; Orth D; Patching J; Primrose R; Quan D; Rawlinson M; Ree H; Richardson R; Rogers G; Roney J; Roth N; Shaw D; Soo TM; Sowden D; Street A; Street A; Vale R; et al Titel: Evaluation of subcutaneous proleukin (interleukin-2) in a randomized international trial (ESPRIT): Geographical and gender differences in the baseline characteristics of participants Source: HIV Clinical Trials; VOL: 7 (2); p. 70-85 /200603/ DOI: 10.1310/4733-ACQF-F3P4-2QAC SU: EMBASE Sprache: English AL: English CY: United States ISSN: 1528-4336 CO: HCTIA Institution: Pett SL, Dr., National Centre in HIV Epidemiology and Clinic Research, University of New South Wales, 376 Victoria St., Sydney, NSW 2010, Australia, [email protected] COU: Australia DT: Journal Article JSC: E.5.3 ... Virology RN: 0030 AB: Background: ESPRIT, is a phase III, open-label, randomized, international clinical trial evaluating the effects of subcutaneous recombinant interleukin-2 (rIL-2) plus antiretroviral therapy (ART) versus ART alone on HIV-disease progression and death in HIV-1-infected individuals with CD4+ T-cells >=300 cells/ mu L. Objectives: To describe the baseline characteristics of participants randomized to ESPRIT overall and by geographic location. Method: Baseli ne characteristics of randomized participants were summarized by region. Results: 4,150 patients were enrolled in ESPRIT from 254 sites in 25 countries. 41%, 27%, 16%, 11%, and 5% were enrolled in , North America, South America, Asia, and Australia, respectively. The median age was 40 years, 81% were men, and 76%, 11%, and 9% were Caucasian, Asian, and African American or African, respectively. 44% of women enrolled (n = 769) were enrolled in Thailand and Argentina. Overall, 55% and 38% of the cohort acquired HIV through male homosexual and heterosexual contact, respectively. 25% had a prior history of AIDS-defining illness; Pneumocystis jirovecii pneumonia, M. , and esophageal candida were most commonly reported. Median nadir and baseline CD4+ T-cell counts were 199 and 458 cells/ mu L, respectively. 6% and 13% were or C virus coinfected, respectively. Median duration of antiretroviral therapy (ART) was 4.2 years; the longest median duration was in Australia (5.2 years) and the shortest was in Asia (2.3 years). 17%, 13%, and 69% of participants began ART before 1995, between 1996 and 1997, and from 1998 onward, respectively. 86% used ART from two or more ART classes, with 49% using a protease inhibitor-based regimen and 46% using a nonnucleoside reverse transcriptase inhibitor-based regimen. 78% had plasma HIV RNA below detection (<500 cp/mL). Conclusion: ESPRIT has enrolled a diverse population of HIV-infected individuals including large populations of women and patients of African-American/African and Asian ethnicity often underrepresented in HIV research. As a consequence, the results of the study may have wide global applicability. © 2006 Thomas Land Publishers, Inc. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/48 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2006284257 Autoren: Henry K; Katzenstein D; Cherng DW; Valdez H; Powderly W; Vargas MB; Jahed NC; Jacobson JM; Myers LS; Schmitz JL; Winters M; Tebas P Titel: 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 Source: Journal of Acquired Immune Deficiency Syndromes; VOL: 42 (2); p. 140-148 /June 2006/ DOI: 10.1097/01.qai.0000225319.59652.1e PU: Lippincott Williams and Wilkins SU: EMBASE Sprache: English AL: English CY: United States ISSN: 1525-4135 CO: JJASF PII: 0012633420060600000002 Institution: Henry K, Dr., HIV Program, Hennepin County Medical Center/University of Minnesota, Mailstop R7, 701 Park Avenue, Minneapolis, MN 55415, United States, [email protected] COU: United States DT: Journal Article JSC: E.4.1 ... Allergy & Clinical Immunology; E.5.3 ... Virology RN: 0059 AB: BACKGROUND: Although an intermittent antiviral treatment (ART) strategy may limit long-term toxicity and cost, there is concern about the risk for virologic failure, selection of drug resistance mutations, and disease progression. By boosting CD4 T-cell counts, interleukin 2 (IL-2) could safely prolong the duration of treatment interruption (TI) in a CD4-driven strategy. METHODS: The AIDS Clinical Trials Group (ACTG) study A5102 evaluated 3 cycles of IL-2 before TI, on clinical and immunologic outcomes, using a CD4 T-cell count of <350 cells/mm as the threshold for restarting ART. Forty-seven HIV-infected subjects on potent ART with CD4 T-cell counts of >=500 cells/mm or more and HIV RNA levels of less than 200 copies/mL were randomized to arm A (ART + three 5-day cycles of IL-2 at 4.5 million U, Sc, BID every 8 weeks, n <= 23) or arm B (ART alone, n <= 24) for 18 weeks (step 1). At the end of step 1, subjects with a CD4 T-cell count of >=500 cells/mm or more stopped ART until a CD4 count of <350 cells/mm (step 2). CD4 T-cell count, time to return of viremia, and the emergence of drug resistance mutations after TI were compared between study arms. RESULTS: IL-2 recipients maintained higher CD4 counts during TI for 48 weeks with a waning of the CD4 effect by 72 weeks. A sustained CD4 T-cell count of more than 350 cells/mm and more durable TI were associated with a higher nadir CD4 T-cell count before ART and higher naive CD4 T-cell count at entry. After TI, a higher viral set point and drug resistance mutations at virologic rebound were associated with a shorter time to CD4 T-cell count of less than 350 cell/mm. There were no differences in the magnitude of virologic rebound (at week 8 of step 2, median log10 HIV RNA level was 4.23 for arm A and 4.21 for arm B) or the steady-state HIV-1 RNA level after week 8. CONCLUSIONS: IL-2 before TI did not prolong time to CD4 of less than 350 cells/mm. A TI strategy utilizing a CD4 T-cell threshold of less than 350 cells/mm for restarting ART appears generally safe with most subjects in both arms remaining off ART for more than 1 year. Implications of our results for TI strategies include the potential advantage of starting ART at higher CD4 T-cell levels while avoiding any drug resistance and evaluating immunomodulators or drugs to reduce T-cell activation and HIV-1 RNA rebound during the TI. Copyright © 2006 by Lippincott Williams & Wilkins. PU: Lippincott Williams and Wilkins 530 Walnut Street, Philadelphia, PA 19106-3621, United States CNOTE: Copyright 2010 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/49 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2006264529 Autoren: Mocroft A; Neaton J; Bebchuk J; Staszewski S; Antunes F; Knysz B; Law M; Phillips AN; Lundgren JD Titel: The feasibility of clinical endpoint trials in HIV infection in the highly active antiretroviral treatment (HAART) era Source: Clinical Trials; VOL: 3 (2); p. 119-132 /2006/ DOI: 10.1191/1740774506cn138oa SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 1740-7745 EISSN: 1740-7753 Institution: Mocroft A, Royal Free Centre for HIV Medicine, Dept. Primary Care and Population Sciences, Royal Free and University College London Medical Schools, Rowland Hill St., London, NW3 2PF, United Kingdom, [email protected] COU: United Kingdom DT: Journal Article JSC: C.0 ... Clinical Medicine RN: 0022 AB: Background: Planning clinical-endpoint trials in patients with HIV remain difficult as long-term follow-up of many patients is required. Cohort studies of patients with HIV can provide key estimates of the likely disease progression, required sample size and follow-up. Objectives: To verify the assumptions used in designing ESPRIT, a large randomized clinical trial assessing the clinical benefit of interleukin-2 treatment in patients with HIV infection, to use EuroSIDA to mimic the inclusion criterion of ESPRIT in order to compare the observed event rate in ESPRIT with the projected rate in EuroSIDA, and to project the required length of ESPRIT. Methods: Patients in EuroSIDA who satisfied the ESPRIT recruitment criteria were selected. Patients were followed from baseline to new AIDS or death. Results: The incidence of clinical progression in the selected EuroSIDA patients (N = 4482) was 1.5 per 100 PYFU (95% Cl 1.3-1.7), and did not increase with increasing time from baseline, contrary to what was assumed in the design of the ESPRIT trial. In ESPRIT (N = 4150), for which the comparative data remain blinded, the incidence was 1.1 per 100 PYFU (95% Cl 0.9-1.3), with no increase over time. The average follow-up required to complete ESPRIT and accrue the 320 events required by protocol would be seven years, 10 months using the projected rates from the EuroSIDA study, and seven years, 11 months if the observed event rate in ESPRIT continued unchanged. Limitations: Differences between patients recruited to observational studies or clinical trials cannot always be adjusted for. Conclusions: Event rates in EuroSIDA were similar in the first two years to those used in the design of ESPRIT, but did not increase over time, leading to an increase in the expected duration of ESPRIT. Clinical endpoint trials in HIV infection remain feasible, and large cohort studies are critical to the planning and ongoing assessment of design assumptions in such trials. The underlying assumptions of the clinical trial should be re-examined to ensure the original trial assumptions remain valid. © Society for Clinical Trials 2006. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/50 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2006172352 Autoren: Moll M; Snyder-Cappione J; Spotts G; Hecht FM; Sandberg JK; Nixon DF Titel: Expansion of CD1d-restricted NKT cells in patients with primary HIV-1 infection treated with interleukin-2 Source: Blood; VOL: 107 (8); p. 3081-3083 /20060415/ http://www.bloodjournal.org/cgi/reprint/107/8/3081 DOI: 10.1182/blood-2005-09-3636 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0006-4971 EISSN: 0006-4971 CO: BLOOA Institution: Moll M, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Huddinge, 14186 Stockholm, Sweden, [email protected] COU: Sweden DT: Journal Article JSC: C.1.5 ... Hematology RN: 0020 AB: Innate CD1d-restricted natural killer T (NKT) cells are infected and lost in HIV-1-infected patients, and this could contribute to HIV-1 pathogenesis because NKT cells play an important role in directing both adaptive and innate immunity. Administration of interleukin-2 (IL-2) to HIV-1-infected patients leads to substantial and sustained CD4+ T-cell expansion, involving both naive and memory cells. We investigated whether IL-2 treatment could restore the NKT cell compartment in patients with primary HIV-1 infection. We show that IL-2 combined with effective antiretroviral therapy (ART) resulted in significant expansion of CD1d-restricted NKT cells. Expansion occurred in both the CD4+ and CD4+ subsets of NKT cells, and expanded cells expressed the CD161 maturation marker while expression of the HIV coreceptor CCR5 was reduced. These data indicate that IL-2 treatment in combination with effective ART is beneficial for the restoration of innate NKT cell immunity in patients with primary HIV-1 infection. © 2006 by The American Society of Hematology. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/51 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2006164837 Autoren: Wang J; Yang F-Z; Zhao M; Zhang Y-H; Zhang Y-X; Liu Y; Liu W-M; Wang F-S; Xu S-L; Yu Z-M; Xie Y-M; Zhou X-Z; Jiang T- J Titel: Randomized double-blinded and controlled clinical trial on treatment of HIV/AIDS by Zhongyan-4 Source: Chinese Journal of Integrative Medicine; VOL: 12 (1); p. 6-11 /March 2006/ DOI: 10.1007/BF02857422 PU: Chinese Journal of Integrated Traditional and SU: EMBASE Sprache: English AL: English CY: China ISSN: 1672-0415 Institution: Wang J, Department of AIDS, Institute of Basic Theory, China Academy of Chinese Medical Sciences, Beijing (100700), China, [email protected] COU: China DT: Journal Article JSC: A.0 ... Drugs & Chemicals; C.0 ... Clinical Medicine RN: 0011 AB: Objective: To assess the efficacy and safety of Zhongyan-4 ((Chinese characters), ZY-4, a Chinese herbal preparation worked out according to the therapeutic principle of supplementing qi, nourishing Yin, clearing heat and detoxication) in treating HIV/AIDS patients in the early or middle stage. Methods: Adopted was randomized double-blinded and placebo-parallel-controlled method, with 72 HIV/AIDS patients randomly divided into the ZY-4 group (36 patients) treated with ZY-4 and the control group (36 patients) treated with placebo. The treatment course was six months. The index of CD4 +, CD8+ counts, body weight, clinical symptom scoring were estimated at 4 time points (0, 1, 3 and 6 month in the course), and also the viral load before and after treatment. The whole course of observation was completed in 63 patients, 30 in the ZY-4 group and 33 in the control group. Results: CD4+ count in the ZY-4 group got elevated by 7.70 ± 150.96/mm³ on average, while that in the control group lowered by 27.33 ± 85.28/mm³. Fifteen out of the 30 patients in the ZY-4 group had their CD4+ count increased, which was evidently much higher than that in the control group (8/33, P<0.05), suggesting that the efficacy of ZY-4 is superior to that of placebo in elevating CD4+ count. Moreover, ZY-4 showed actions in elevating CD45RA+ and CD8+ count, reducing HIV virus load, improving clinical symptom/sign and increasing body weight of patients. No obvious adverse reaction was found in the clinical trial. Conclusion: ZY-4 has an immunity-protective and/or rebuilding function in HIV/AIDS patients in the early and middle stage, and also shows effects in lowering viral load, increasing body weight and improving symptoms and signs to a certain degree. PU: Chinese Journal of Integrated Traditional and 1 Caochang, Xiyuan, Beijing, 100091, China CNOTE: Copyright 2010 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/52 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2006139425 Autoren: Alric L; Thebault S; Peron J-M; Balard P; Metivier S; Pipy B; Izopet J; Vinel J-P Titel: Pilot study of interferon-alpha--interleukin-2 for treatment of nonresponder patients with severe liver disease infected by hepatitis C virus genotype 1 Source: Journal of Viral Hepatitis; VOL: 13 (2); p. 139-144 /February 2006/ DOI: 10.1111/j.1365-2893.2005.00694.x PU: Blackwell Publishing Ltd SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 1352-0504 EISSN: 1365-2893 CO: JVHEE Institution: Alric L, Service de Medecine Interne-Federation Digestive, Hopital Purpan, 31059 Toulouse, France, [email protected] COU: France DT: Journal Article JSC: C.1.8.1 ... Hepatology; E.5.3 ... Virology RN: 0024 AB: The aim of this randomized prospective study was to assess the efficacy and safety of a triple therapy with interferon-alpha (IFN- alpha)-ribavirin- interleukin-2 (IL-2) for the treatment of patients with genotype 1 infection and high viral load nonresponsive to primary IFN-ribavirin therapy. Twenty hepatitis C virus (HCV) genotype 1 patients with high viral load and Metavir fibrosis score >=2 without HIV co-infection who were previously nonviral responders to standard treatment with IFN plus ribavirin were intensively re-treated with IFN-alpha2a (3 millions (M) IU every 2 days) combined with ribavirin (1000-1200 mg/day) for a 24-week period. Patients were randomized to receive four cycles of subcutaneous injection of IL-2 (3 MIU/day, 5 days a week every 3 weeks) during either the first 12 weeks (group 1, n = 10) or the last 12 weeks (group 2, n = 10) of combination therapy. At the end of triple therapy, six patients (30%) achieved a biochemical response and 4 (20%) a viral response followed by a relapse after triple therapy withdrawal. After 12 weeks of therapy, no difference in viral oad was observed between the groups. The decrease in viral load in group 2 was not raised after the addition of IL-2 to IFN plus ribavirin combination therapy. No serious adverse effects were observed. In conclusion, in patients with poor predictive factors of response, the addition of IL-2 to IFN ribavirin combination therapy does not exert a favourable impact on HCV treatment. © 2005 Blackwell Publishing Ltd. PU: Blackwell Publishing Ltd 9600 Garsington Road, Oxford, OX4 2XG, United Kingdom CNOTE: Copyright 2010 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/53 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2006132646 Autoren: Levy Y; Durier C; Lascaux A-S; Meiffredy V; Gahery-Segard H; Goujard C; Rouzioux C; Resch M; Guillet J-G; Kazatchkine M; Delfraissy J-F; Aboulker J-P Titel: Sustained control of viremia following therapeutic immunization in chronically HIV-1-infected individuals Source: AIDS; VOL: 20 (3); p. 405-413 /February 2006/ DOI: 10.1097/01.aids.0000206504.09159.d3 PU: Lippincott Williams and Wilkins SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 CO: AIDSE PII: 0000203020060214000012 Institution: Levy Y, Prof., Unite d'Immunologie Clinique, Hopital Henri Mondor, 51, Ave. Marechal Lattre de Tassigny, 94010 Creteil Cedex, France, [email protected] COU: France DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0037 AB: Objective: Viral rebounds inevitably follow interruption of antiretroviral treatment in HIV-1-infected individuals. The randomized ANRS 093 aimed at investigating whether a therapeutic immunization was effective in containing the long-term viral replication following discontinuation of antiretroviral drugs in patients. Methods: Seventy HIV-1-infected patients effectively treated with antiretroviral drugs were randomized to continue treatment alone or in combination with four boosts of ALVAC 1433 and HIV- LIPO-6T vaccines followed by three cycles of subcutaneous interleukin-2. The impact of vaccination on viral replication was assessed by inter-rupting antiretroviral drugs first at week 40 and thereafter during follow-up until week 100. Antiretroviral drugs were re-initiated according to predefined criteria. Results: The median cumulative time (days) off treatment was greater in the vaccine group (177) than in the control group (89) (P = 0.01). The proportion of time (mean, SE) without antivirals per-patient was 42.8% (5.1) and 26.5% (4.2) in the vaccine and control groups, respectively (P = 0.005). Viremia (median log10 copies/ml), 4 weeks following the first, second and third treatment interruption was higher in control patients (4.81, 4.44, 4.53) in comparison with vaccinated patients (4.48, 4.00, 3.66) (P = 0.42, 0.015 and 0.024, respectively). HIV-specific CD4 and CD8 T-cell responses elicited by the therapeutic immunization strongly correlated with the reduction of the time of antiviral therapy (P = 0.0027 and 0.016, respectively). Conclusion: Our findings provide evidence that therapeutic immunization significantly impacts on HIV-1 replication. This translated into a decrease of up to 40% in the duration of exposure to antiretroviral drugs over 15 months of patients' follow-up. © 2006 Lippincott Williams & Wilkins. PU: Lippincott Williams and Wilkins 250 Waterloo Road, London, SE1 8RD, United Kingdom CNOTE: Copyright 2010 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/54 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2005529406 Autoren: Martin BK; Wu AW; Gelman R; Mitsuyasu RT Titel: Quality of life in a clinical trial of highly active antiretroviral therapy alone or with intravenous or subcutaneous lnterleukin-2 administration Source: Journal of Acquired Immune Deficiency Syndromes; VOL: 40 (4); p. 428-433 /200512/ DOI: 10.1097/01.qai.0000182848.45722.b7 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 1525-4135 CO: JJASF Institution: Martin BK, Dr., Johns Hopkins Center for Clinical Trials, Johns Hopkins Bloomberg, School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205, United States, [email protected] COU: United States DT: Journal Article JSC: E.4.1 ... Allergy & Clinical Immunology; E.5.3 ... Virology RN: 0021 AB: Objective: To assess the impact of subcutaneous and intravenous interleukin-2 (IL-2) on health-related quality of life (HRQOL) in adults with HIV-1 receiving highly active antiretroviral therapy (HAART). Design: Randomized clinical trial. Setting: Twenty-two institutions from the Adult AIDS Clinical Trials Group. Patients: One hundred forty-eight HIV-infected adults randomized, with baseline HRQOL data. Methods: HAART (indinavir plus 2 nucleoside analogues) for 12 weeks, followed by 72 weeks of continued HAART alone, HAART plus subcutaneous IL-2, or HAART plus intravenous IL-2. Outcome Measures: Scores for 8 dimensions of HRQOL, an unweighted summary score, and a visual analogue health rating score. Results: The IL-2 subcutaneous group had the best mean change in 6 of 8 dimension subscales and in the summary scale at 28 weeks (16 weeks after baseline). At 52 weeks, the IL-2 subcutaneous group had the best mean change in all the subscales and the summary scale. The differences were statistically significant for 3 subscales and the summary scale. Midcycle changes were statistically significantly worse for the subcutaneous IL-2 group for 4 subscales and the summary scale. Conclusions: We found evidence of a short-term but not long-term adverse impact of IL-2 on HRQOL and some evidence of long-term benefit for the subcutaneous group. Copyright © 2005 by Lippincott Williams & Wilkins. AU: Martin BK Martin Barbara K. Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States; Johns Hopkins Center for Clinical Trials, Johns Hopkins Bloomberg, School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205, United States [email protected] CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/55 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2005483386 Autoren: Brown PA; Angel JB Titel: Granulocyte-macrophage colony-stimulating factor as an immune-based therapy in HIV infection Source: Journal of Immune Based Therapies and Vaccines; VOL: 3; p. 7 /20050518/ http://www.jibtherapies.com/content/3/1/3 ANR: 3 DOI: 10.1186/1476-8518-3-3 SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 1476-8518 EISSN: 1476-8518 Institution: Angel JB, Department of Medicine, University of Ottawa, 501 Smyth, Ottawa, Ont. K1H 8L6, Canada, [email protected] COU: Canada DT: Review; Journal Article JSC: E.4 ... Immunology & Serology RN: 0038 AB: The HIV/AIDS epidemic continues to spread despite more than 20 years of significant research and major advances in its treatment. The introduction of highly active antiretroviral therapy in recent years has significantly improved disease treatment with a dramatic impact in HIV/AIDS associated morbidity and mortality in countries which have access to this therapy. Despite these advances, such therapies are imperfect and other therapeutic modalities, including immune-based therapies, are being actively sought. Potential benefits of immune-based therapies include: 1) the improvement of HIV-specific immunity to enhance control of viral replication, 2) the improvement of other aspects of host immunity in order to prevent or delay the development of opportunistic infections and 3) the potential to purge virus from cellular reservoirs which are sustained despite the effects of potent antiretroviral therapy. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been studied as one of these immune-based therapies. Several randomized, controlled trials have demonstrated benefits of using GM-CSF as an adjunct to conventional anti-retroviral therapy, although such benefits have not been universally observed. Individual studies have shown that GM-CSF increases CD4+T cells counts and may be associated with decreased plasma HIV RNA levels. There is limited evidence that GM-CSF may help prevent the emergence of antiretroviral drug resistant and that it may decrease the risk of infection in advanced HIV disease. Despite its high costs and the need to be administered subcutaneously, encouraging results continue to emerge from further studies, suggesting that GM-CSF has the potential to become an effective agent in the treatment of HIV infection. © 2005 Brown and Angel; licensee BioMed Central Ltd. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/56 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2005309560 Autoren: Tedaldi EM; Chen L; Markowitz N; Kelly L; Abrams D Titel: Effect of IL-2 on hepatitis C virus RNA levels in patients co-infected with human immunodeficiency virus receiving HAART Source: Journal of Viral Hepatitis; VOL: 12 (4); p. 414-420 /200507/ DOI: 10.1111/j.1365-2893.2005.00610.x SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 1352-0504 CO: JVHEE Institution: Tedaldi EM, Temple University School of Medicine, Temple General Internal Medicine, 1316 W. Ontario Street, Philadelphia, PA 19140, United States, [email protected] COU: United States DT: Journal Article JSC: C.1.8.1 ... Hepatology; E.5.3 ... Virology RN: 0031 AB: The effect of interleukin-2 (IL-2) on the plasma levels of hepatitis C RNA (HCV-RNA) has varied in published reports. We measured the impact of IL-2 on plasma HCV RNA levels in 54 human immunodeficiency virus (HIV)/ HCV coinfected patients enrolled in a randomized trial of 512 participants designed to compare the virologic and immunologic effects of cycled IL-2 plus antiretroviral therapy (ART) vs ART alone in the treatment of HIV in patients with CD4 cell counts >=300 cells/mm³. The mean decreases in average HCV RNA levels (copies/mL, log10) were 0.28 log in the IL-2 group (n = 26) and 0.04 log in the ART alone group (n = 28) at 12 months (P = 0.18). The changes in HCV RNA level were not associated with baseline or nadir CD4 cell counts, baseline aspartate aminotransferanse, CD4 cell response to IL-2, or changes in plasma HIV RNA values. Compared with those participants who only had HIV, the HIV/HCV co-infected patients did not have a significantly different CD4 cell response to IL-2 therapy. Intermittent IL-2 therapy does not produce a significant sustained decrease in plasma HCV RNA levels among patients co-infected with HIV/HCV who are on highly active ART. © 2005 Blackwell Publishing Ltd. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/57 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2005135917 Autoren: Lévy Y; Gahéry-Ségard H; Durier C; Lascaux A-S; Goujard C; Meiffrédy V; Rouzioux C; El Habib R; Beumont-Mauviel M; Guillet J-G; Delfraissy J-F; Aboulker J-P Titel: Immunological and virological efficacy of a therapeutic immunization combined with interleukin-2 in chronically HIV-1 infected patients Source: AIDS; VOL: 19 (3); p. 279-286 /20050218/ SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 CO: AIDSE Institution: Lévy Y, Prof., Unité d'Immunologie Clinique, Hôpital Henri Mondor, 51 avenue Marechal Lattre Tassigny, 94010 Creteil Cedex, France, [email protected] COU: France DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0029 AB: Objective: Several lines of evidence suggest that the immune system may control HIV-1 replication, but that it could fail in the long term. Strategies aimed to elicit specific immune responses may enable patients to contain virus replication. Methods: HIV-1-infected patients were randomized to continue either their antiviral therapy alone (controls; n = 37) or with four boosts of vaccination combining ALVAC-HIV (vCP1433) and Lipo-6T vaccines (weeks 0, 4, 8, 12) followed by three cycles of subcutaneous interleukin-2 (weeks 16, 24, 32) (Vac-IL-2 group; n = 34). Results: Of the Vac-IL-2 group, 15/32 (47%) exhibited a stable HIV p24 antigen-proliferative response compared with 8/33 (24%) controls (P = 0.049). After vaccination, 19/33 (58%) of the Vac-IL-2 group exhibited a multiepitopic HIV-1-specific CD4 cell proliferative response compared with 9/36 (25%) of controls (P = 0.006). The breadth and the magnitude of HIV-specific interferon- gamma -producing CD8 T cells improved in the Vac-IL-2 group. After stopping antiviral drugs, 24% of the Vac-IL-2 group lowered their viral set point compared with 5% of controls (P = 0.027). Logistic-regression analysis demonstrated that vaccine-elicited immunological responses were predictive of virological control (P = 0.046 and 0.014 for stable and multiepitopic CD4 T cell responses, respectively). Conclusion: This study provides proof of the concept that therapeutic immunization before cessation may contribute to the containment of HIV replication. © 2005 Lippincott Williams & Wilkins. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/58 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2005075898 Autoren: Lyseng-Williamson KA; Reynolds NA; Plosker GL Titel: fumarate: A review of its use in the management of HIV infection Source: Drugs; VOL: 65 (3); p. 413-432 /2005/ DOI: 10.2165/00003495-200565030-00006 SU: EMBASE Sprache: English AL: English CY: New Zealand ISSN: 0012-6667 CO: DRUGA Institution: Lyseng-Williamson KA, Adis International Limited, 41 Centorian Drive, Auckland 1311, New Zealand, [email protected] COU: New Zealand DT: Review; Journal Article JSC: A.3 ... Pharmaceutical & Medicinal Chemistry; A.1.1 ... Clinical Pharmacology RN: 0078 AB: Tenofovir disoproxil fumarate (tenofovir DF; Viread®), an ester prodrug of the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir, is indicated in combination with other antiretroviral agents in the treatment of HIV infection. As a component of an antiretroviral regimen, oral tenofovir DF 300mg once daily effectively reduces viral load in patients with HIV infection who are treatment-experienced with baseline NRTI resistance mutations or treatment-naive. Tenofovir DF provides a simple and convenient once-daily dosage regimen, and is generally well tolerated and able to produce sustained suppression of viral replication. Pharmacological Properties Tenofovir DF is metabolised to tenofovir diphosphate, which inhibits the activity of HIV reverse transcriptase and terminates the DNA chain. In vitro, the drug demonstrates good inhibitory activity against HIV strains, synergistic or additive activity when combined with certain other antiretroviral drugs, minimal cytotoxicity and no evidence of reduced mitochondrial DNA synthesis. Reduced susceptibility to tenofovir is associated with the reverse transcriptase mutation K65R. In patients with baseline resistance mutations in clinical trials, the greatest response to tenofovir DF was associated with the M184V mutation and no thymidine analogue-associated mutations. Reduced responses were associated with the L210W or M41L mutations, and a lack of response with the K65R mutation. The emergence of the K65R mutation during clinical trials using more than one class of antiretroviral therapy was specifically associated with tenofovir DF; however, the K65R mutation developed infrequently and was not associated with viral rebound. The oral bioavailability of tenofovir DF administered without food is 25%. After multiple doses of tenofovir DF 300mg once daily, the median maximum serum concentration of 326 ng/mL at steady state is reached after a median of 2.3 hours. Tenofovir has a median serum terminal elimination half-life of 14.4 hours, and undergoes primarily renal elimination as the unchanged drug. Exposure to tenofovir is increased in patients with moderate-to-severe renal impairment. Tenofovir does not inhibit cytochrome P450 enzymes, so few drug interactions are expected with drugs metabolised via this route. Coadministration of tenofovir DF with didanosine substantially increases didanosine exposure, coadministration with lopinavir/ritonavir increases tenofovir exposure and coadministration with atazanavir decreases atazanavir exposure. Therapeutic Efficacy In two well designed clinical trials in antiretroviral treatment-experienced patients with HIV infection, oral tenofovir DF 300mg once daily in combination with other antiretroviral drugs produced significantly greater time-weighted reductions from baseline in HIV RNA levels than placebo at week 4 and/or 24; these reductions were maintained at week 48 in the placebo cross-over phase of the trials. In the dose- ranging trial, tenofovir DF 75, 150 or 300mg once daily were all more effective than placebo; however, the greatest reduction in viral load at weeks 4, 24 and 48 was produced by tenofovir DF 300mg once daily, which is the approved dosage in patients with HIV infection. The proportion of antiretroviral therapy-naive patients with HIV infection achieving HIV RNA levels <400 copies/mL was similar with tenofovir DF 300mg once daily and 40mg twice daily at weeks 48, 96 and 144 in a well designed trial. All patients also received 150mg twice daily and efavirenz 600mg once daily. For the primary endpoint, the stratum- weighted lower 95% confidence interval of the difference between tenofovir DF and stavudine at week 48 slightly exceeded (by 0.4) the predefined equivalence criteria (-10.4 vs -10). In nonblind clinical trials, tenofovir DF 300mg once daily was effective in treating HIV infection when used in a regimen containing antiretroviral therapies from more than one class and as part of a simplified dosage regimen. However, as with other triple NRTI regimens, tenofovir DF with lamivudine plus either didanosine or abacavir showed high rates of suboptimal response and/or early failure. Tolerability Oral tenofovir DF 300mg once daily, as part of combination therapy, was generally well tolerated in controlled clinical trials. The tolerability profiles of tenofovir-containing regimens were similar to those of regimens containing placebo or stavudine in controlled clinical trials. Mild-to-moderate gastrointestinal disorders (e.g. nausea, diarrhoea, vomiting and flatulence) were the most commonly reported adverse events. The frequency of laboratory abnormalities with tenofovir DF was similar to that with placebo and stavudine. However, tenofovir DF was associated with a more favourable serum lipid profile than stavudine. The risk of adverse events potentially associated with mitochondrial dysfunction with tenofovir DF appears similar to that with placebo and lower than that with stavudine. In clinical trials, the incidence of tenofovir DF- related renal abnormalities was low and similar in frequency between tenofovir DF- and stavudine-containing regimens. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/59 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EMM19401609 PMID: 19401609 Autoren: Wilkin TJ; Taylor B; Olender S; Hammer SM Titel: Advances in antiretroviral therapy. Source: Topics in HIV medicine : a publication of the International AIDS Society, USA; VOL: 17 (2); p. 68-88 /2009 Apr-May/ SU: Medline Sprache: English AL: English CY: United States ISSN: 1542-8826 Institution: Wilkin TJ, Weill Medical College of Cornell University, New York, NY, USA. DT: Conference Paper; Journal Article AB: The 16th Conference on Retroviruses and Opportunistic Infections maintained its tradition of being recognized as the preeminent forum for detailing the state-of-the-art of antiretroviral therapy. Abundant new and updated information was presented on investigational drugs, approaches to the management of treatment-naive and -experienced patients, the use of drugs for prevention of mother-to-child HIV-1 transmission, and antiretroviral drug resistance. Of particular note were the continued advances in antiretroviral treatment and research emanating from resource-limited settings and the presentation of the results of 2 much- anticipated, phase III trials of interleukin-2, ESPRIT (Evaluation of Subcutaneous Proleukin in a Randomized International Trial) and SILCAAT (Subcutaneous, Recombinant Human Interleukin-2 in HIV-Infected Patients With Low CD4+ Counts Receiving Active Antiretroviral Therapy). CNOTE: MEDLINE® is the source for the citation and abstract of this record.

» Volltext-Angebot » 4/60 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EMM18431498 PMID: 18431498 Autoren: Tebas P; Henry WK; Matining R; Weng-Cherng D; Schmitz J; Valdez H; Jahed N; Myers L; Powderly WG; Katzenstein D Titel: Metabolic and immune activation effects of treatment interruption in chronic HIV-1 infection: implications for cardiovascular risk. Source: PLoS ONE; VOL: 3 (4); p. e2021 /2008/ NCT: ClinicalTrials.gov-NCT00015704 DOI: 10.1371/journal.pone.0002021 SU: Medline Sprache: English AL: English CY: United States EISSN: 1932-6203 Institution: Tebas P, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America., [email protected] DT: Journal Article AB: BACKGROUND: Concern about costs and antiretroviral therapy (ART)-associated toxicities led to the consideration of CD4 driven strategies for the management of HIV. That approach was evaluated in the SMART trial that reported an unexpected increase of cardiovascular events after treatment interruption (TI). Our goal was to evaluate fasting metabolic changes associated with interruption of antiretroviral therapy and relate them to changes of immune activation markers and cardiovascular risk. METHODOLOGY: ACTG 5102 enrolled 47 HIV-1-infected subjects on stable ART, with <200 HIV RNA copies/mL and CD4 cell count >or=500 cells/microL. Subjects were randomly assigned to continue ART for 18 weeks with or without 3 cycles of interleukin-2 (IL-2) (cycle = 4.5 million IU sc BID x 5 days every 8 weeks). After 18 weeks ART was discontinued in all subjects until the CD4 cell count dropped below 350 cells/microL. Glucose and lipid parameters were evaluated every 8 weeks initially and at weeks 2, 4, 8 and every 8 weeks after TI. Immune activation was evaluated by flow-cytometry and soluble TNFR2 levels. PRINCIPAL FINDINGS: By week 8 of TI, levels of total cholesterol (TC) (median (Q1, Q3) (-0.73 (-1.19, -0.18) mmol/L, p<0.0001), LDL, HDL cholesterol (-0.36(-0.73,-0.03)mmol/L, p = 0.0007 and -0.05(-0.26,0.03), p = 0.0033, respectively) and triglycerides decreased (-0.40 (-0.84, 0.07) mmol/L, p = 0.005). However the TC/HDL ratio remained unchanged (-0.09 (-1.2, 0.5), p = 0.2). Glucose and insulin levels did not change (p = 0.6 and 0.8, respectively). After TI there was marked increase in immune activation (CD8+/HLA-DR+/CD38+ cells, 34% (13, 43), p<0.0001) and soluble TNFR2 (1089 ng/L (-189, 1655), p = 0.0008) coinciding with the rebound of HIV viremia. CONCLUSIONS: Our data suggests that interrupting antiretroviral therapy does not reduce cardiovascular disease (CVD) risk, as the improvements in lipid parameters are modest and overshadowed by the decreased HDL levels. Increased immune cell activation and systemic inflammatory responses associated with recrudescent HIV viremia may provide a more cogent explanation for the increased cardiovascular risk associated with treatment interruption and HIV infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT00015704. CNOTE: MEDLINE® is the source for the citation and abstract of this record.

» Volltext-Angebot » 4/61 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EMM16880169 PMID: 16880169 Autoren: Lifson AR; Rhame FS; Belloso WH; Dragsted UB; El-Sadr WM; Gatell JM; Hoy JF; Krum EA; Nelson R; Pedersen C; Pett SL; Davey RT Jr. Titel: Reporting and evaluation of HIV-related clinical endpoints in two multicenter international clinical trials. Source: HIV clinical trials; VOL: 7 (3); p. 125-141 /2006 May-Jun/ SU: Medline Sprache: English AL: English CY: United States ISSN: 1528-4336 Institution: Lifson AR, Department of Epidemiology and Community Health, University of Minnesota, 1300 South Second Street, Minneapolis, MN 55454, USA., [email protected] DT: Journal Article JSC: E.5.3 ... Virology AB: PURPOSE: The processes for reporting and review of progression of HIV disease clinical endpoints are described for two large phase III international clinical trials. METHOD: SILCAAT and ESPRIT are multicenter randomized HIV trials evaluating the impact of interleukin-2 on disease progression and death in HIV-infected patients receiving antiretroviral therapy. We report definitions used for HIV progression of disease endpoints, procedures for site reporting of such events, processes for independent review of reported events by an Endpoint Review Committee (ERC), and the procedure for adjudication of differences of opinion between reviewers. RESULTS: Of 473 events reported through May 1, 2006, 28% were judged by an ERC to meet "confirmed" criteria and 38% to meet "probable" criteria; 34% were classified "does not meet criteria." For diseases with >5 case reports, the proportion accepted as either "confirmed" or "probable" events was highest for cervical cancer (100%), non-Hodgkin's lymphoma (88%), cryptococcosis (82%), and cryptosporidiosis (80%) and was lowest for HIV encephalopathy (25%), HIV wasting syndrome (33%), and multidermatomal herpes zoster (35%). 25% of cases required adjudication between reviewers before diagnostic certainty was assigned. CONCLUSION: Important requirements for HIV trials using clinical endpoints include objective definitions of "confirmed" and "probable," a formal reporting process with adequate information and supporting source documentation, evaluation by independent blinded reviewers, and procedures for adjudication. CNOTE: MEDLINE® is the source for the citation and abstract of this record.

» Volltext-Angebot » 4/62 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2004471857 Autoren: Lindemann M; Witzke O; Winterhagen T; Ross B; Kreuzfelder E; Reinhardt W; Roggendorf M; Mann K; Philipp T; Grosse-Wilde H Titel: T-cell function after interleukin-2 therapy in HIV-infected patients is correlated with serum cortisol concentrations Source: AIDS; VOL: 18 (15); p. 2001-2007 /20041021/ SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 CO: AIDSE Institution: Grosse-Wilde H, Dr., Institute of Immunology, University Hospital Essen, Virchowstrasse 171, 45122 Essen, Germany, [email protected] COU: Germany DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0024 AB: Objectives: To examine the effects of interleukin (IL)-2 therapy on in-vitro lymphocyte responsiveness in HIV-infected patients and to correlate these data with serum cortisol concentrations. Design: German prospective study. Methods: In adult patients (n = 32) treated with 9 × 106 IU/day interleukin-2, lymphocyte transformation tests (LTT), serum cortisol concentrations and CD4 T-cell counts were assessed before, during and after IL-2 therapy. Results: A significant decrease in responses towards mitogens and recall antigens (P < 0.05) was observed on day 7 after starting a 4- to 5-day IL-2 therapy as compared to baseline. Serum cortisol levels increased (P < 0.0001) reaching a maximum on day 4, and were still elevated on day 7 (P < 0.005). CD4 T-cell counts significantly decreased with a minimum on day 2 before increasing 2.4-fold above baseline on day 7 (P < 0.005 each). A positive correlation (P < 0.05 each) was observed for changes in cortisol levels and in LTT mitogen and antigen reactions (both day 7 - 0), changes in cortisol levels (day 3 - 0) and CD4 cell counts on day 2, and corticotrophin releasing hormone test results and LTT antigen reactions on day 7. LTT responses, cortisol levels and CD4 T-cell counts returned to baseline on day 30. Conclusion: Serum cortisol concentrations are predictive of functional and numerical changes of T cells induced by IL-2 therapy. © 2004 Lippincott Williams & Wilkins. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/63 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2004365924 Autoren: Torre D; Speranza F; Ghezzi S; Nozza S; Tambussi G; Soldini L; Dorigatti F; Lazzarin A; Tambini R; Poli G Titel: Nitric oxide production in HIV-1 infected patients receiving intermittent cycles of interleukin-2 and antiretrovirals Source: HIV Clinical Trials; VOL: 5 (3); p. 146-151 /200405/ DOI: 10.1310/MB7D-MKTM-QPG5-HHUD SU: EMBASE Sprache: English AL: English CY: United States ISSN: 1528-4336 CO: HCTIA Institution: Torre D, Dr., Department of Infectious Diseases, General Hospital, Viale Borri 57, 21100 Varese, Italy, [email protected] COU: Italy DT: Journal Article JSC: E.5.3 ... Virology RN: 0021 AB: Background: Interleukin-2 (IL-2) has been investigated as an adjunct to antiretroviral therapy (ART) because of its well- demonstrated capacity of stably increasing the number of peripheral CD4+ T cell lymphocytes. However, IL-2-related adverse events (AEs), including fever, tachycardia, hypotension, and respiratory failure, are typically dose- and schedule-dependent and can potentially limit the application of IL-2 therapy in an outpatient setting. Nitric oxide (NO) is a potent vasodilator potentially responsible for some of the AEs caused by IL-2. Purpose: In this study, we determined NO production in a cohort of HIV-1 infected individuals receiving ART either alone ortogether with IL-2. Method: NO production, detected as plasma nitrate/nitrite levels by the Griess reaction, was evaluated in 3 groups of 10 individuals each. In the first group, subcutaneous (sc) administration of 12-15 million international units per day (MIU/d) of IL-2 was administered for 5 days every 8 weeks for 6 cycles together with ART; in the second group, IL-2 (6 MIU/d) was given sc for 5 days every 4 weeks for 12 cycles together with ART; whereas the third group received ART alone. Results: At baseline, the plasma nitrate/nitrite levels in the 2 groups of patients who received high and low doses of the cytokine along with ART were 28.5 ± 18.1 mu mol/L and 34.2 ± 29.0 mu mol/L, respectively. These levels were comparable to those of patients treated with only ART (18.6 ± 22.4 mu mol/L) and to those of 20 healthy controls (19.9 ± 5.9 mu mol/L). No significant increase of plasma nitrate/nitrite levels was observed by administration of either ART or ART+IL-2. In addition, NO production was not associated significantly with different levels of tumor necrosis factor-alpha, IL-6, or soluble IL-2 receptor alpha chain in 9 individuals with WHO grade 2 and 3 AEs. Conclusion: Our results indicate that NO is unlikely to be responsible for most side effects of IL-2 therapy in HIV-1 infected individuals. Because both IL-2 and virus multiplication have been reported to independently stimulate NO production, concomitant ART may curtail NO production through inhibition of HIV-1 replication. © 2004 Thomas Land Publishers, Inc. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/64 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2004289754 Autoren: Arduino RC; Mannini EC; Rodriguez-Barradas M; Schrader S; Losso M; Ruxrungtham K; Allende MC; Emery S; Fosdick L; Neaton J; Tavel JA; Davey RT; Lane HC Titel: CD4 cell response to 3 doses of subcutaneous interleukin 2: Meta-analysis of 3 vanguard studies Source: Clinical Infectious Diseases; VOL: 39 (1); p. 115-122 /20040701/ DOI: 10.1086/421775 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 1058-4838 CO: CIDIE Institution: Arduino RC, Dr., University of Texas-Houston, 6431 Fannin, Houston, TX 77030, United States, [email protected] COU: United States DT: Journal Article JSC: E.5 ... Clinical Microbiology RN: 0011 AB: Background. In advance of a large clinical end point trial evaluating the effectiveness of subcutaneous interleukin 2 (scIL-2) for treatment of patients with human immunodeficiency virus (HIV) infection, 3 identically designed Vanguard trials were conducted in Buenos Aires, Argentina; Bangkok, Thailand; and Houston, Texas. To more precisely quantitate the effect on CD4 cell response of 3 different doses of scIL-2 that were administered twice daily for 5 days every 8 weeks, the results of these 3 trials were pooled in a meta-analysis. Methods. Two hundred eighteen HIV-1-infected subjects who were receiving antiretroviral therapy and who had a baseline CD4 cell count of >=350 cells/mm³ were consecutively randomized to receive scIL-2 at a dose of 1.5 mIU (n = 36) or a control regimen (n = 36); or scIL-2 at a dose of 4.5 mIU (n = 36) or a control regimen (n = 36); or scIL-2 at a dose of 7.5 mIU (n = 37) or a control regimen (n = 37). After completion of 3 cycles of therapy, the subjects were enrolled in an extension phase (months 6-12). Subjects were encouraged to receive additional cycles of scIL-2 to maintain a CD4 cell count of more than twice the baseline count or >1000 cells/mm³. Results. After completion of 3 cycles of scIL-2, the mean CD4 cell count changes from baseline (calculated as changes from baseline in a scIL-2 group minus changes from baseline in its contemporaneous control group) were 67 (P = .14), 339 (P <. 0001), and 605 cells/mm³ (P < .0001) for the 1.5, 4.5, and 7.5 mIU dose groups, respectively (P < .0001 for differences among dose groups). Between months 6 and 12, a total of 78%, 39%, and 32% of subjects assigned to the 1.5, 4.5, and 7.5 mIU dose groups, respectively, needed at least 1 additional cycle to achieve the CD4 cell count goal. At 12 months, the differences in the mean change in CD4 cell count from baseline between each scIL-2 dose group and its contemporaneous control group were 184, 369, and 432 cells/ mm³, respectively (P = .01 for differences among dose groups). Conclusions. Although CD4 cell count increases were seen in all 3 dose groups, higher scIL-2 doses resulted in greater CD4 cell count changes after 6 months, compared with control groups. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/65 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2004288968 Autoren: Marchetti G; Meroni L; Molteni C; Taskaris G; Gazzola L; Galli M; Clerici M; Moroni M; Franzetti F; Gori A Titel: IL-7/IL-7 receptor system regulation following IL-2 immunotherapy in HIV-infected patients Source: Antiviral Therapy; VOL: 9 (3); p. 447-452 /200406/ SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 1359-6535 CO: ANTHF Institution: Marchetti G, Inst. of Infect. Dis. and Trop. Med., 'Luigi Sacco' Hospital, University of Milan, Milan, Italy, [email protected] COU: Italy DT: Journal Article JSC: A.1 ... Pharmacology & Drug Therapy RN: 0031 AB: Interleukin-2 (IL-2) and IL-7 are the most intriguing molecules in immune-based HIV infection treatment. An in vitro IL-2/IL-7 cross-talk due to IL-2-driven IL-7 receptor- alpha -chain (IL-7R alpha ) down-modulation, potentially blocking IL-7 signalling has been described. We investigated the in vivo IL-2 effect on IL-7/IL-7R system, measuring free IL-7, and IL-7R alpha CD4 and CD8 in 12 HIV-positive patients enrolled in a randomized IL-2 trial. Compared to HAART alone, IL-2 induced a parallel expansion in total and naive CD4, TRECs and IL-7 plasma levels, with no IL-7R alpha CD4 and IL-7R alpha CD8 changes (P>0.05), suggesting that in vivo IL-2 boosts IL-7 production without down-modulating IL-7R alpha , preserving IL-7-mediated T-lymphocyte homeostatic regulation. Our data confirm the pivotal role of IL-2 and IL-7 in the regulation of T-lymphocyte homeostasis in HIV infection. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/66 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2004190491 Autoren: Vogler MA; Teppler H; Gelman R; Valentine F; Lederman MM; Pomerantz RJ; Pollard RB; Cherng DW; Gonzalez CJ; Squires KE; Frank I; Mildvan D; Mahon LF; Schock B Titel: Daily Low-Dose Subcutaneous Interleukin-2 Added to Single- or Dual-Nucleoside Therapy in HIV Infection Does Not Protect Against CD4 + T-Cell Decline or Improve Other Indices of Immune Function: Results of a Randomized Controlled Clinical Trial (ACTG 248) Source: Journal of Acquired Immune Deficiency Syndromes; VOL: 36 (1); p. 576-587 /20040501/ SU: EMBASE Sprache: English AL: English CY: United States ISSN: 1525-4135 CO: JJASF Institution: Vogler MA, New York Univ. School of Medicine, Adult AIDS Clinical Trials Unit, Bellevue C and D Building, 550 First Avenue, New York, NY 10016, United States, [email protected] COU: United States DT: Journal Article JSC: E.4.1 ... Allergy & Clinical Immunology; E.5.3 ... Virology RN: 0022 AB: Context: Approaches to preserve or enhance immune function in HIV-1 infection are needed. Objectives: To examine the ability of daily low-dose interleukin-2 (IL-2) in combination with antiretroviral therapy to preserve circulating CD4+ T-cell counts, the clinical safety and tolerability of this treatment, and safety with respect to changes in plasma HIV-1 RNA levels. Design: Twenty-four-week, phase 2, multicenter, randomized, open-label trial conducted at 12 AIDS Clinical Trials Units between September 1995 and May 1997. Participants: A total of 115 HIV-infected persons with screening CD4 + T-cell counts between 300 and 700 cells/mm³ who were on stable single- or dual-nucleoside therapy for at least 2 months, 11% of whom were also on a protease inhibitor at study entry. Interventions: Patients were randomly assigned to receive IL-2 at a dose of 1 million IU subcutaneously once daily plus continued antiretroviral therapy (ART + IL-2, n = 57) vs. continued ART alone (ART alone, n = 58). IL-2 dose reductions were made for objective or subjective toxicities. All subjects randomly assigned to the IL-2 arm who interrupted ART were also required to discontinue IL-2 for the same period. Main Outcome Measures: The primary endpoint was a decrease in CD4+ T-cell count from baseline; the safety analysis was based on change in plasma HIV RNA by bDNA; and clinical safety and tolerability were analyzed by standard clinical criteria. Results: Of the patients with a baseline CD4+ T-cell count recorded, 15 (27%) of 55 patients randomly assigned to ART alone had a drop of >=25% in their CD4+ T-cell count and 23 (41%) of 56 patients randomly assigned to ART + IL-2 had a drop of >=25% in their CD4 + T-cell count at some time over the 24 weeks of the study. This difference was not statistically significant. There was a statistically significant greater variance in CD4+ T-cell counts in the IL-2-treated group. More patients in the IL-2 group had at least a 25% increase in CD4+ T-cell counts over baseline (34 vs. 13%, P = 0.007). A comparison of grade 3 or worse toxicity showed no differences between the arms, but IL-2 was associated with significantly more grade 2 or worse general body symptoms, primarily discomfort and fatigue. There was no significant difference between the groups with regard to changes in plasma HIV RNA, lymphocyte proliferation, natural killer cell activity, skin test responses to recall antigens, or antibody responses to immunization. Plasma markers of immune activation all increased significantly in IL-2 recipients. Conclusions: In patients with baseline CD4+ T-cell counts >=300 cells/mm ³ primarily treated with single- or dual-nucleoside ART, subcutaneously administered IL-2 at a dose of 1 million IU daily for up to 24 weeks had low toxicity but showed no consistent benefit in preventing decline in CD4+ T-cell counts and minimal evidence of immunologic improvement vs. continued ART alone. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/67 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2004095562 Autoren: Marchetti G; Meroni L; Molteni C; Bandera A; Franzetti F; Galli M; Moroni M; Clerici M; Gori A Titel: Interleukin-2 immunotherapy exerts a differential effect on CD4 and CD8 T cell dynamics Source: AIDS; VOL: 18 (2); p. 211-216 /20040123/ SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 CO: AIDSE Institution: Marchetti G, Dr., Inst. of Infect. Dis. and Trop. Med., 'Luigi Sacco' Hospital, University of Milan, Via G.B. Grassi, 74-20157 Milan, Italy COU: Italy DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0031 AB: Background: Emerging evidence indicates that CD4 and CD8 T cell recovery is differentially regulated during HIV infection. The hallmark of interleukin-2 (IL-2)-induced immune reconstitution is the selective outgrowth of CD4 through undefined mechanisms. Objective: To delineate the effect of IL-2 on T cell homeostasis by analysing the differential impact of IL-2 immunotherapy on CD4 and CD8 dynamics. Design: A randomized trial of 15 HIV-positive patients, eight receiving IL-2 immunotherapy with highly active antiretroviral therapy (HAART) and seven with HAART alone. Patients were followed for a 48-week period following three IL-2 cycles (overall, 10 weeks in duration). Methods: CD4 and CD8 count, naive and memory immunophenotype, proliferation by Ki67, and CD8+CD38+ activated pattern were measured longitudinally by flow cytometry. Thymic output contribution to both CD4 and CD8 was evaluated by measurement of T cell receptor excision circles (TREC). Wilcoxon test was used to compare results. Results: Compared with changes seen with HAART alone, IL-2 induced a more significant rise in CD4 than CD8 T cell count (P < 0.01), associated with a significant increase in Ki67-proliferating CD4 (P < 0.05), whereas no changes were seen in CD8+Ki67+ (P > 0.05). Furthermore, IL-2 administration was associated with CD4 TREC increase, whereas CD8 TREC remained stable (P > 0.05). Modifications in CD4 and CD8 T cells seen in patients taking only HAART were not associated with changes in CD4 and CD8 TREC. Conclusions: By showing a differential impact on CD4 and CD8 homeostasis, the study suggests that IL-2-associated immune reconstitution results from protean interactions between T cell compartments; this has significant implications for the correct planning of immunotherapeutic strategies. © 2004 Lippincott Williams & Wilkins. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/68 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2003339042 Autoren: Tavel JA; Sereti I; Walker RE; Hahn B; Kovacs JA; Jagannatha S; Davey RT Jr.; Falloon J; Polis MA; Masur H; Metcalf JA; Stevens R; Rupert A; Baseler M; Lane HC Titel: A randomized, double-blinded, placebo-controlled trial of intermittent administration of interleukin-2 and prednisone in subjects infected with human immunodeficiency virus Source: Journal of Infectious Diseases; VOL: 188 (4); p. 531-536 /20030815/ DOI: 10.1086/377285 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0022-1899 CO: JIDIA Institution: Tavel JA, Dr., National Institutes of Health, Natl. Inst. of Allerg./Infect. Dis., 9000 Rockville Pike, Bethesda, MD 20892, United States, [email protected] COU: United States DT: Journal Article JSC: E.5 ... Clinical Microbiology; B.2 ... Public Health RN: 0015 AB: Intermittent administration of interleukin (IL)-2 produces significant and sustained increases in CD4+ T lymphocyte count in human immunodeficiency virus (HIV)-infected subjects but can be associated with dose-limiting toxicities. The primary objective of this study was to determine whether concomitant administration of prednisone could decrease these toxicities. HIV- seropositive adults receiving highly active antiretroviral therapy (HAART) were randomized to receive either (1) intermittent subcutaneous IL-2 and placebo, (2) intermittent subcutaneous IL-2 and prednisone, (3) intermittent prednisone, or (4) intermittent placebo. Prednisone decreased levels of proinflammatory cytokines during IL-2 cycles but, despite induction of expression of CD25, blunted increases in IL-2-associated CD4+ T lymphocyte count. Whereas intermittent administration of IL-2 reduced basal proliferation of CD4+ T cells, this effect was inhibited by prednisone, suggesting that prednisone potentially interferes with IL-2's long-term effects on survival of T lymphocytes. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/69 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2003324050 Autoren: Delaugerre C; Gourlain K; Tubiana R; Carcelain G; Marcelin A-G; Chouquet C; Mouroux M; Duvivier C; Autran B; Costagliola D; Katlama C; Calvez V Titel: Increase of HIV-1 pro-viral DNA per million peripheral blood mononuclear cells in patients with advanced HIV disease (CD4<200 cells/mm³) receiving interleukin 2 combined with HAART versus HAART alone (ANRS-082 Trial) Source: Antiviral Therapy; VOL: 8 (3); p. 233-237 /200306/ SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 1359-6535 CO: ANTHF Institution: Calvez V, Department of Virology-EA2387, Pitie-Salpetrière Hospital, Paris, France, [email protected] COU: France DT: Journal Article JSC: A.1 ... Pharmacology & Drug Therapy RN: 0030 AB: Objective: To assess the effect of interleukin (IL)-2 combined with highly active antiretroviral therapy (HAART) on HIV-1 pro- viral DNA quantification in HIV-1-infected patients with CD4<2OO/mm³. Patients and methods: Seventy patients with CD4<200 cells/mm³ and CV<1000 copies/ml were enrolled in a 6-month randomized controlled study to evaluate the subcutaneous injection of IL-2 in addition to HAART versus HAART alone. Then, in a non-comparative phase from week 28 to week 80, IL-2 was proposed to patients from both groups. The HIV-1 pro-viral DNA was quantified at baseline, week 24 and week 50 by a real-time polymerase chain reaction (PCR) assay in peripheral blood mononuclear cells (PBMC). Analysis of resistance mutations was performed at baseline and after 6-months of IL-2. Results: HIV-1 DNA level in PBMC increased significantly in patients treated with 6 months of HAART combined to IL-2 (+0.24 log10 P=0.009) compared to a slight decrease in patients treated with HAART alone (-0.05 log10). Moreover, a DNA increase was observed in control group patients when receiving 6 months of IL-2 (+0.34 log10). No increase of HIV-1 DNA was seen when this measure was expressed per million CD4 cells; it was probably hidden by the intense increase of CD4 lymphocytes after 6 months of IL-2 administration. No evolution of resistance mutations in pro-viral DNA was observed during 6 months of IL-2, despite the increase of pro-viral DNA and the occurrence of transient increase of viraemia. Conclusion: Administration of IL-2 combined with HAART in HIV-1 infected- patients with advanced disease led to an increase of HIV-1 pro-viral DNA per million PBMC without virological failure or emergence of resistance. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/70 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2003187479 Autoren: Carcelain G; Saint-Mézard P; Altes HK; Tubiana R; Grenot P; Rabian C; De Boer R; Costagliola D; Katlama C; Debré P; Autran B Titel: IL-2 therapy and thymic production of naive CD4 T cells in HIV-infected patients with severe CD4 lymphopenia Source: AIDS; VOL: 17 (6); p. 841-850 /20030411/ DOI: 10.1097/00002030-200304110-00009 SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 CO: AIDSE Institution: Autran B, Laboratoire d'Immunologie Cellulaire, CNRS-UMR 7527, Hop. Pitie-Salpetriere, Paris, France, [email protected] hop-paris.fr COU: France DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0028 AB: Objectives: IL-2 therapy increases memory and naive CD4 T cells in HIV-infected patients, but its effect on thymopoiesis is unknown. To investigate this effect, we quantified T-cell receptor rearrangement excision circles (TREC) in CD4 T cells from lymphopenic AIDS patients treated with highly active antiretroviral therapy and IL-2. Methods: CD4 cell subsets were evaluated by flow cytometry using anti-CD45RO/RA, CD62L, Ki67 and CD95 monoclonal . The proportion of recent thymic emigrant had been quantified by a real-time polymerase chain reaction assay for signal joint TREC in peripheral blood mononuclear and purified CD4 T cells. Results: At initiation of IL-2, TREC copies/ mu l of blood were correlated with naive T cell numbers and age. Both naive and TREC numbers/ mu l significantly increased over time in all patients, with a wide range of TREC increases. Higher percentages of CD4+CD45RO-negative cells positive for the Ki67 cell-cycle marker were found in patients with a low TREC increase, but remained stable under IL-2. TREC and naive cell recovery were correlated; they also correlated with the numbers of TREC and naive cells at the start of IL-2, and with age, suggesting a thymic origin for naive T-cell recovery. A mathematical model showing the linear recovery of naive cells and TREC under IL-2 also strongly suggested that a naive T-cell increase reflects thymic export and involves little net death and proliferation. Conclusion: Although we cannot rule out a mechanism of altered proliferation or death rate, the thymus plays an important role in the long-term recovery of naive T cells under IL-2 therapy. © 2003 Lippincott Williams & Wilkins. AU: Costagliola D Costagliola Dominique CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/71 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2003156753 Autoren: De Boer AW; Markowitz N; Lane HC; Saravolatz LD; Koletar SL; Donabedian H; Yoshizawa C; Duliege A-M; Fyfe G; Mitsuyasu RT Titel: A randomized controlled trial evaluating the efficacy and safety of intermittent 3-, 4-, and 5-day cycles of intravenous recombinant human interleukin-2 combined with antiretroviral therapy (ART) versus ART alone in HIV-seropositive patients with 100-300 CD4+ T cells Source: Clinical Immunology; VOL: 106 (3); p. 188-196 /20030301/ DOI: 10.1016/S1521-6616(02)00038-4 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 1521-6616 CO: CLIIF Institution: De Boer AW, Chiron Corporation, Clinical Development, M/S U-140, 4560 Horton Street, Emeryville, CA 94608-2916, United States, [email protected] COU: United States DT: Journal Article JSC: C.11 ... Clinical Pathology; E.4.1 ... Allergy & Clinical Immunology RN: 0034 AB: The effect of length of therapy on the safety and efficacy profile of continuous intravenous (CIV) interleukin-2 (IL-2) in combination with antiretroviral therapy (ART) was evaluated in 81 HIV-seropositive patients with CD4+ T-cell counts of 100-300/mm³. Patients were randomized to CIV IL-2 (12 mIU/day) for 3, 4, or 5 days plus ART every 8 weeks for six cycles, or to ART alone. The mean percent increase in CD4+ T-cell counts was 24.5% for IL-2 recipients compared with a mean percent decrease of 30.5% for control patients (P = 0.005). Increasing duration of CIV IL-2 therapy resulted in improved CD4+ T-cell response. The most frequent clinical adverse events and laboratory abnormalities were predominantly of grade 1 or 2 severity. However, grade 3 or 4 events were reported in 57%, 60%, and 84% of the 3-, 4-, and 5-day CIV IL-2 patients, respectively. Serious adverse events, mainly due to the requirement of hospitalization, occurred in 20% of IL-2 recipients, compared with 10% of control patients. Viral load during the course of the study was not different among the treatment groups. IL-2 therapy in cycles of 5 days resulted in an optimal increase in CD4+ T-cell counts and is the preferred cycle length for IL-2 therapy geared toward increasing CD4+ T-cell numbers. © 2003 Elsevier Science (USA). All rights reserved. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/72 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2003111873 Autoren: Pido-Lopez J; Burton C; Hardy G; Pires A; Sullivan A; Gazzard B; Aspinall R; Gotch F; Imami N Titel: Thymic output during initial highly active antiretroviral therapy (HAART) and during HAART supplementation with interleukin 2 and/or with HIV type 1 immunogen (Remune) Source: AIDS Research and Human Retroviruses; VOL: 19 (2); p. 103-109 /20030201/ DOI: 10.1089/088922203762688603 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0889-2229 CO: ARHRE Institution: Imami N, Department of Immunology, ICSTM, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, United Kingdom, [email protected] COU: United Kingdom DT: Journal Article JSC: E.4 ... Immunology & Serology; E.5.3 ... Virology RN: 0030 AB: The thymic output of patients receiving highly active antiretroviral therapy (HAART) was assessed by sjTREC (signal joint T cell receptor rearrangement excision circle) analysis to determine the thymic contribution to CD4+ T cell reconstitution during initial therapy and during interleukin 2 (IL-2) and/or Remune supplementation of HAART. Levels of sjTRECs were observed to decline dramatically after the first 4 weeks of HAART and then increased without significant associated changes in CD4+ T cell counts. HAART supplementation with IL-2 was observed to lead to rapid increases in CD4+ T cells that were accompanied by sjTREC decreases. No notable changes in CD4+ T cell counts and sjTRECs were seen in patients receiving HAART supplemented with Remune alone. The results indicate CD4+ T cell maintenance during initial treatment of HIV-1 with HAART and early CD4+ T cell reconstitution of patients receiving IL-2 with HAART is largely due to thymus-independent mechanisms, with the thymus making a limited contribution. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/73 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2003082229 Autoren: Levy Y; Durier C; Krzysiek R; Rabian C; Capitant C; Lascaux A-S; Michon C; Oksenhendler E; Weiss L; Gastaut J-A; Goujard C; Rouzioux C; Maral J; Delfraissy J-F; Emilie D; Aboulker J-P; Gougeon M-L; Metro A; Viard J-P; Bouchenafa K; Jung C; Mortier E; Bloch M; Chandemerle C; Gérard L; Martinie M; Kazatchkine M; Laureillard D; Dinh T-T; Dalmas A-M; Peretti D; Rannou M-T; Bazin C; Verdon R; Six M; Goubin P; Vittecoq D; Escaut L; Malet M; Maignan A; Bouvet E; Prevot M-H; Fournier I; Gaudebout C; Yéni P; Belarbi L; Mandet C; Zucman D; Majerholc C; Boue F; Estocq G-A; Delavalle A-M; Pasquali J-L; Lalanne H; Bouchet- Delbos L; Chambenoit C; Carmagnat M-V; Grangeot-Keros L; Ameisen J-C; Estaquier J; Monnier D; Ferchal F; Girard P-M; Laplanche A; Bazin B; Foubert V; Izard S; Martins J; Netzer E Titel: Effects of interleukin-2 therapy combined with highly active antiretroviral therapy on immune restoration in HIV-1 infection: A randomized controlled trial Source: AIDS; VOL: 17 (3); p. 343-351 /20030214/ DOI: 10.1097/00002030-200302140-00008 SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 CO: AIDSE Institution: Levy Y, Dr., Unité d'Immunologie Clinique, Hôpital Henri Mondor, 51, ave. Marechal Lattre de Tassigny, 94010 Créteil Cedex, France COU: France DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0024 AB: Background: Intermittent interleukin-2 (IL-2) therapy leads to a sustained increase of CD4 T cells in HIV-1-infected patients. Methods: Symptom-free HIV-1-infected patients who were naive to all antiretroviral drugs (n = 68) and/or to protease inhibitors (n = 50) and had a CD4 cell count of 200-550 x 106 cells/I were randomly assigned to start lamivudine/stavudine/indinavir alone (controls) or combined from week 4 with subcutaneous IL-2 (5 x 106 IU twice daily for 5 days: every 4 weeks for three cycles, then every 8 weeks for seven cycles). Immunological and virological results were monitored until week 74. Results: CD4 T cell counts increased more in the IL-2 group than in the controls (median increases 865 and 262 x 106 cells/I, respectively; P<0.0001); an 80% increase in CD4 T cells was achieving by 89% of the IL-2 group and by 47% of the controls (P<0.0001). Decrease of plasma viral loads was similar in both groups. Compared with controls, IL-2 induced a greater increase of naive and memory CD4 T cells, lymphocyte expression of CD28 and CD25 (P<0.0001) and natural killer cells (P<0.001). In a logistic regression analysis, odds of being responders to recall antigens in vitro was 8.5-fold higher in IL-2 recipients (P=0.002) than in controls. The former experienced a higher level of antibody response to tetanus vaccination at week 64 than controls (32 and 8 haemagglutinating units/ml, respectively; P=0.01). Conclusions: The combination of antiviral drugs and IL-2 induced a greater expansion and function of CD4 T cells than antiretroviral drugs alone. © 2003 Lippincott Williams & Wilkins. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/74 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2002376851 Autoren: Katlama C; Carcelain G; Duvivier C; Chouquet C; Tubiana R; De Sa M; Zagury L; Calvez V; Autran B; Costagliola D Titel: Interleukin-2 accelerates CD4 cell reconstitution in HIV-infected patients with severe immunosuppression despite highly active antiretroviral therapy: The ILSTIM study - ANRS 082 Source: AIDS; VOL: 16 (15); p. 2027-2034 /20021018/ DOI: 10.1097/00002030-200210180-00007 SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 CO: AIDSE Institution: Katlama C, Dr., Hopital Pitie-Salpetriere, 47-83 Bld de l'Hopital, 75651 Paris Cedex 13, France COU: France DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0037 AB: Background: Despite effective highly active antiretroviral therapy (HAART), some patients infected with HIV have persistently low CD4 cell counts with risk of HIV disease progression. The addition of interleukin-2, a cytokine that stimulates CD4 T lymphocyte helper cells, may benefit patients with discordant responses. Methods: A total of 72 HIV-infected patients with CD4 cell counts of 25-200 × 106 cells/I (median 145) and plasma HIV RNA < 1000 copies/ml were randomized in a multicentre study to receive open-label 4.5 × 106 IU interleukin-2 subcutaneously twice daily for 5 days every 6 weeks plus their ongoing HAART or were maintained on HAART alone (control group). After 24 weeks, all patients received interleukin-2 therapy plus HAART up to week 80. Primary end-point was the CD4 T cell area under the curve minus baseline up to week 24. Results: After four cycles of interleukin-2, in an intent-to-treat analysis, the respective median CD4 cell area under the curve minus baseline values were +51 and +11 cells in the interleukin-2 (n = 34) and the control group (n = 36)(P < 0.0001). The percentage of patients in the two groups with CD4 cell counts > 200 × 106 cells/I was 81% and 33%, respectively (P < 0.0001). At week 80, the median CD4 cell counts in the two groups were 380 and 270 × 106 cells/I, respectively. Interleukin-2 treatment was reasonably well tolerated and did not result in sustained increases in plasma HIV RNA levels. Conclusions: Administration of interleukin-2 produces significant and sustained increase in CD4 cell counts in HAART-treated patients with persistent CD4 cell counts < 200 × 106 cells/I. © 2002 Lippincott Williams & Wilkins. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/75 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2002304070 Autoren: Marchetti G; Meroni L; Varchetta S; Terzieva V; Bandera A; Manganaro D; Molteni C; Trabattoni D; Fossati S; Clerici M; Galli M; Moroni M; Franzetti F; Gori A Titel: Low-dose prolonged intermittent interleukin-2 adjuvant therapy: Results of a randomized trial among human immunodeficiency virus-positive patients with advanced immune impairment Source: Journal of Infectious Diseases; VOL: 186 (5); p. 606-616 /20020901/ DOI: 10.1086/342479 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0022-1899 CO: JIDIA Institution: Marchetti G, Dr., Inst. of Infect. Dis. and Trop. Med., Luigi Sacco Hospital, University of Milan, Via G.B. Grassi 74, 20157 Milan, Italy, [email protected] COU: Italy DT: Journal Article JSC: E.5 ... Clinical Microbiology; B.2 ... Public Health RN: 0066 AB: Twenty-two patients with CD4+cell counts =<200 cells/ mu L after 12 months of stable highly active antiretroviral therapy (HAART; "immunologic nonresponders") were randomly assigned to receive subcutaneous low-dose prolonged intermittent interleukin (IL)-2 in addition to HAART (n = 12) or to continue HAART alone (n = 10). At 48 weeks of follow-up, no IL-2-related serious adverse events and no significant differences in plasma human immunodeficiency virus (HIV) RNA level were observed in the 2 groups. A higher incidence of HIV-related clinical events was observed among patients receiving HAART alone (3/10) than among subjects receiving HAART plus IL-2 (0/12). Significant increases in CD4+, naive, and CD4+CD7+ cells and plasma levels of IL-7 were observed in patients receiving IL-2 versus patients receiving HAART alone. A significant increase in cell turnover did not lead to a decrease in the frequency of T cell receptor excision circles, which remained stable. Rather, increased numbers of T cell receptor excision circles per microliter of blood were observed (not statistically significant). Thus, adjuvant IL-2 therapy in immunologic nonresponders resulted in a clinical benefit, suggesting that the quantitative cell recovery involves functionally competent immune cells. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/76 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2002299095 Autoren: Natarajan V; Lempicki RA; Sereti I; Badralmaa Y; Adelsberger JW; Metcalf JA; Prieto DA; Stevens R; Baseler MW; Kovacs JA; Lane HC Titel: Increased peripheral expansion of naive CD4+ T cells in vivo after IL-2 treatment of patients with HIV infection Source: Proceedings of the National Academy of Sciences of the United States of America; VOL: 99 (16); p. 10712-10717 /200208/ DOI: 10.1073/pnas.162352399 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0027-8424 CO: PNASA Institution: Lane HC, Laboratory of Immunoregulation, Natl. Inst. of Allerg./Infect. Dis., National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, United States, [email protected] COU: United States DT: Journal Article JSC: E.9.2 ... Molecular Biology RN: 0030 AB: Intermittent interleukin-2 (IL-2) therapy has been shown to increase the number of CD4+ T cells, preferentially cells with a naive phenotype, in patients with HIV infection. For this report we investigated the mechanism underlying this expansion by studying the relative roles of peripheral expansion and thymic output. In a cohort of six patients receiving IL-2 over a period of 1 year, the mean number of naive CD4+ T cells increased from 139 to 387 cells per mu l while levels of T cell receptor rearrangement excision circles (TRECs) declined from 47,946 to 26,510 copies per 106 naive T cells, thus making it unlikely that the CD4+ T cell count increases were secondary to increase in thymic output. To examine directly the impact of IL-2 on peripheral expansion, peripheral blood mature, naive CD4+ T cells were labeled ex vivo with 5-bromodeoxyuridine as well as stained directly for Ki67. These studies revealed a 7-fold increase in the percentage of 5-bromodeoxyuridine-positive cells and a 20-40-fold increase in Ki67 staining in the naive CD4+ T cell pool in the setting of IL-2 administration. This degree of increase in mature CD4+ T cell turnover induced by IL-2 does not compromise the future replicative potential of these cells, because longitudinal measurements of telomere length went from 6,981 to 7,153 bp after 1 year of IL-2 therapy. These data strongly suggest that much of the increase in CD4+ cells associated with IL-2 treatment is caused by peripheral expansion of existing naive CD4+ T cells rather than increased thymic output and that these increases occur without compromising the potential of these cells for further cell division. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/77 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2002274634 Autoren: Pau AK; Tavel JA Titel: Therapeutic use of interleukin-2 in HIV-infected patients Source: Current Opinion in Pharmacology; VOL: 2 (4); p. 433-439 /20020801/ DOI: 10.1016/S1471-4892(02)00177-7 SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 1471-4892 CO: COPUB Institution: Pau AK, National Institutes of Health, Clinical Center Pharmacy Department, Building 10, Bethesda, MD 20892, United States, [email protected] COU: United States DT: Journal Article JSC: E.8.1 ... Developmental Biology RN: 0033 AB: Highly active antiretroviral therapy has improved the morbidity and survival of patients with the human immunodeficiency virus (HIV) infection. Currently available antiretroviral agents can suppress viral replication and partially reverse cellular immunity defects in HIV patients. Immune-based therapy with interleukin-2 when used as adjunctive therapy to antiretroviral therapy may further improve immune responses, as demonstrated by an increase in CD4+ T-lymphocyte counts in recent clinical trials. AU: Pau AK Pau Alice K National Institutes of Health, Clinical Center Pharmacy Department, Building 10, Bethesda, MD 20892, United States [email protected] AU: Tavel JA Tavel Jorge A National Institutes of Health, National Institute of Allergy and Infectious Diseases, Building 10, Bethesda, MD 20892, United States [email protected] CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/78 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2002274361 Autoren: Lafeuillade A; Hittinger G; Chadapaud S; Maillefet S; Rieu A; Poggi C Titel: The hydile trial: Efficacy and tolerance of a quadruple combination of reverse transcriptase inhibitors versus the same regimen plus hydroxyurea or hydroxyurea and interleukin-2 in HIV-infected patients failing protease inhibitor-based combinations Source: HIV Clinical Trials; VOL: 3 (4); p. 263-271 /2002/ SU: EMBASE Sprache: English AL: English CY: United States ISSN: 1528-4336 CO: HCTIA Institution: Lafeuillade A, Unité d'Infectiologie, Hôpital Chalucet, Department of Infectious Diseases, 83000 Toulon, France, avps@club- internet.fr COU: France DT: Journal Article JSC: E.5.3 ... Virology RN: 0027 AB: Purpose: To compare the efficacy and tolerance of a stavudine (d4T), didanosine (ddl), efavirenz (EFV), and abacavir (ABC) combination regimen with an identical regimen plus hydroxyurea (HU), or plus HU and interleukin-2 (IL-2), in patients failing protease inhibitor-based combinations and naive of EFV and ABC. Method: This was a randomized prospective trial in 69 HIV- infected patients recruited in one clinical center. Antiretroviral drugs were administered at standard doses according to weight. HU was added at week 6 at 500 mg twice daily. Three courses of IL-2 were given subcutaneously at 4.5 MU twice daily for 5 consecutive days, between weeks 24 and 40. The proportion of patients reaching plasma HIV-1 RNA <200 and <50 copies/mL was compared in the three trial groups at weeks 6, 24, and 48 using intent-to-treat and as-treated analyses. CD4+ T-cell count changes from baseline were also assessed at the same time points, along with anthropometric and metabolic measurements. Results: After 48 weeks, only 25% of patients receiving antiretrovirals had plasma HIV-1 RNA <200 copies/mL versus 59.1% in the group receiving HU and 56.5% in the group receiving HU and IL-2 (intent-to-treat; p < .01). At the 50 copies/mL cutoff, the results were 20.8%, 54.5%, and 47.8%, respectively. Most treatment discontinuations were due to failure in the first group and adverse events in the two others. A median decline of 27 CD4+ cells was observed in patients receiving antiretrovirals plus HU, against a gain of 78-118 cells at week 48 in patients receiving antiretrovirals alone or in combination with HU and IL-2. More patients were affected by clinical fat atrophy symptoms at week 48 than at baseline. Additionally, a trend toward increased cholesterol levels was observed throughout the study. Conclusion: During this trial, virologic response in patients failing previous regimens was clearly enhanced by the addition of HU, despite d4T and ddl recycling. Although adverse events were more frequent in the HU-containing arms, no unexpected toxicity was observed and the blunted CD4 response prompted by HU was corrected by the addition of IL-2. The combination of HU with reverse transcriptase inhibitors can therefore be regarded as a valuable alternative for patients with few remaining therapeutic options. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/79 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2002266564 Autoren: Stellbrink H-J; Van Lunzen J; Westby M; O'Sullivan E; Schneider C; Adam A; Weitner L; Kuhlmann B; Hoffmann C; Fenske S; Aries PS; Degen O; Eggers C; Petersen H; Haag F; Horst HA; Dalhoff K; Möcklinghoff C; Cammack N; Tenner-Racz K; Racz P Titel: Effects of interleukin-2 plus highly active antiretroviral therapy on HIV-1 replication and proviral DNA (COSMIC trial) Source: AIDS; VOL: 16 (11); p. 1479-1487 /20020726/ DOI: 10.1097/00002030-200207260-00004 SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 CO: AIDSE Institution: Stellbrink H-J, Dr., Infektionssprechstunde Pav. 33, Medizinische Kernklinik/Poliklinik, Universitatskrankenhaus Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany COU: Germany DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0044 AB: Background: The effect of interleukin-2 (IL-2) in combination with antiretroviral therapy on HIV-1 replication and reservoirs was investigated. Methods: In a prospective, open-label trial, 56 asymptomatic HIV-1-infected subjects (CD4 T cell count > 350 × 106 cells/l) were randomized to highly active antiretroviral therapy (HAART: stavudine, lamivudine, nelfinavir, ) with or without IL-2 (9 megaunits daily for 5 days in 6-weekly intervals for a total of eight cycles). Productive and latent infection were analysed in peripheral blood, and residual virus replication in the lymphoid tissue and in the cerebrospinal fluid. The influence of IL-2 on viral rebound after treatment discontinuation was studied. Results: Virus replication was detected in 21 of 31 on-treatment lymph nodes despite undetectable plasma viraemia. Viral RNA was found in resting as well as in proliferating cells. RNA-negative patients tended towards more rapid proviral DNA elimination. Supplementary IL-2 led to a greater increase in CD4 T cell counts than HAART alone (P < 0.001), resulting in normalization in ~90% of IL-2-treated patients compared with ~50% HAART-only subjects. IL-2 had no beneficial effect on virus replication and on proviral DNA in peripheral blood. Conclusions: Viral persistence during HAART is partly a result of continued low-level replication, calling for more active regimens. IL-2 accelerates the normalization of CD4 T cell counts but does not impact on virus production or latency. © 2002 Lippincott Williams & Wilkins. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/80 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2002207093 Autoren: Deeks SG; Wagner B; Anton PA; Mitsuyasu RT; Scadden DT; Huang C; Macken C; Richman DD; Christopherson C; June CH; Lazar R; Broad DF; Jalali S; Hege KM Titel: A phase II randomized study of HIV-specific T-cell gene therapy in subjects with undetectable plasma viremia on combination antiretroviral therapy Source: Molecular Therapy; VOL: 5 (6); p. 788-797 /2002/ DOI: 10.1006/mthe.2002.0611 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 1525-0016 CO: MTOHC Institution: Hege KM, Cell Genesys Inc., 342 Lakeside Drive, Foster City, CA 94404, United States, [email protected] COU: United States DT: Journal Article JSC: E.9.2 ... Molecular Biology RN: 0038 AB: Highly active antiretroviral therapy (HAART) can suppress HIV replication to undetectable levels in plasma, but it is unlikely to eradicate cellular reservoirs of virus. Immunotherapies that are cytolytic may be useful adjuncts to drug therapies that target HIV replication. We have generated HIV-specific CD4+ and CD8+ T cells bearing a chimeric T-cell receptor (CD4 zeta ) composed of the extracellular and transmembrane domain of human CD4 (which binds HIVgp120) linked to the intracellular- zeta signaling chain of the CD3 T-cell receptor. CD4 zeta -modified T cells can inhibit viral replication, kill HIV- infected cells in vitro, and survive for prolonged periods in vivo. We report the results of a phase II randomized trial of CD4 zeta gene-modified versus unmodified T cells in 40 HIV-infected subjects on HAART with plasma viral loads < 50 copies/ml. Serial analyses of residual blood and tissue HIV reservoirs were done for 6 months postinfusion. No significant between-group differences were noted in viral reservoirs following therapy. However, infusion of gene-modified, but not unmodified, T cells was associated with a decrease from baseline in HIV burden in two of four reservoir assays and a trend toward fewer patients with recurrent viremia. Both groups experienced a treatment-related increase in CD4+ T-cell counts. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/81 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2002181793 Autoren: Jacobson MA; Spritzler J; Landay A; Chan E; Katzenstein D; Schock B; Fox L; Roe JD; Kundu S; Pollard R; Arri C; Gary D; Caballero A; Pickthall M; Norris J; Valle S; Kessler H; Agnoli M; Goldman M; Heise D; McCord A; Berzins B; Frank I; Quinn J; Reid J; Greisberger C; Kalams S; Koziol C; Vanr Horst C de; Marcus C Titel: A phase I, placebo-controlled trial of multi-dose recombinant human interleukin-12 in patients with HIV infection Source: AIDS; VOL: 16 (8); p. 1147-1154 /20020524/ DOI: 10.1097/00002030-200205240-00008 SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 CO: AIDSE Institution: Jacobson MA, Ward 84, 995 Potrero, San Francisco, CA 94110, United States COU: United States DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0035 AB: Objectives: Interleukin (IL)-12 is a cytokine that stimulates T lymphocytes and natural killer cells to generate a Type 1 T-helper lymphocyte immune response. The primary objective of this study was to determine the safety and immunologic activity of repeated recombinant human IL-12 (rhlL-12) dosing in HIV-infected patients over a broad range of the HIV disease spectrum. Design: A randomized, placebo-controlled, Phase 1 trial design was chosen to control for the effects of HIV disease alone on safety and immunologic measurements. Methods: HIV-infected patients on antiretroviral therapy received rhlL-12 or placebo twice weekly for 4 weeks. Subjects were monitored for safety and changes in absolute lymphocyte subset number, serum interferon (IFN) gamma and neopterin levels, plasma HIV RNA level, peripheral blood mononuclear cell (PBMC)-inducible IFN gamma responses to mitogen, and PBMC proliferative responses to phytohemagglutinin, tetanus, Candida, Mycobacterium avium complex, streptokinase, and HIV p24 and gp160 antigens. Results: rhlL-12 was well tolerated at doses up to 100 ng/kg in subjects enrolled with CD4 cell counts < 50 × 106 cells/I and at all doses in subjects with CD4 cell counts of 300 × 106-500 × 106 cells/I. rhlL-12 resulted in dose-related increases in serum neopterin (particularly in subjects with baseline CD4 cell counts of 300-500 × 106 cells/I) but in no significant changes in other immunologic measurements or plasma HIV RNA levels. Conclusions: rhlL-12 dosed twice weekly at =< 100 ng/kg was well tolerated in HIV-infected patients and resulted in dose-related increases in serum neopterin (possibly reflecting the effect of some degree of IFN gamma induction). However, there was no evidence of improvement in antigen-specific immune response. © 2002 Lippincott Williams & Wilkins. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/82 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2002173049 Autoren: Fortis C; Soldini L; Ghezzi S; Colombo S; Tambussi G; Vicenzi E; Gianotti N; Nozza S; Veglia F; Murone M; Lazzarin A; Poli G Titel: Tumor necrosis factora, interleukin 2, and soluble interleukin 2 receptor levels in human immunodeficiency virus type 1-infected individuals receiving intermittent cycles of interleukin 2 Source: AIDS Research and Human Retroviruses; VOL: 18 (7); p. 491-499 /2002/ DOI: 10.1089/088922202317406637 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0889-2229 CO: ARHRE Institution: Fortis C, San Luigi AIDS Center, Via Stamira D'Ancona, 20, 20127 Milan, Italy, [email protected] COU: Italy DT: Journal Article JSC: E.4 ... Immunology & Serology; E.5.3 ... Virology RN: 0040 AB: HIV-infected individuals with 200-500 CD4 T cell/ mu l were enrolled in a controlled study of three interleukin 2 (IL-2) plus antiretroviral therapy (ART) regimens: (1) continuous intravenous administration of 12 million international units (MIU) of IL-2 followed by subcutaneous high-dose IL-2 (7.5 MIU, twice daily) for 5 days every 8 weeks; (2) high-dose subcutaneous IL-2 for 5 days every 8 weeks; (3) low-dose (3 MIU, twice daily) subcutaneous IL-2 for 5 days every 4 weeks; and (4) ART alone. Serum concentrations of IL-2, soluble IL-2 receptor (sIL-2R), tumor necrosis factor alpha (TNF- alpha ), and IL-6 were determined. A progressive decrease over time of the circulating levels of IL-2 was observed in individuals receiving the highest doses of IL-2, but not in those belonging to the low-dose arm. Conversely, increased levels of sIL-2R were observed in all cytokine-treated individuals. The levels of TNF- alpha increased in the high-dose IL-2 regimens, but decreased in individuals receiving low-dose IL-2. IL-2- related toxicity was significantly correlated to the peak IL-2 serum levels, and was substantially lower in those individuals receiving low-dose IL-2. In conclusion, intermittent IL-2 administration causes the elevation of peripheral CD4 T cells, but also a profound cytokine response and systemic toxicity. The latter was correlated to the peak serum level of IL-2, but not to those of TNF- alpha and IL-6. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/83 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2002172771 Autoren: Mitsuyasu R Titel: Immune therapy: Non-highly active antiretroviral therapy management of human immunodeficiency virus- infected patients Source: Journal of Infectious Diseases; VOL: 185 (SUPPL. 2); p. S115-S122 /2002/ DOI: 10.1086/340201 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0022-1899 CO: JIDIA Institution: Mitsuyasu R, Dr., Department of Medicine, UCLA CARE Center, BH-412 CHS, 10833 Le Conte Ave., Los Angeles, CA 90095- 1793, United States, [email protected] COU: United States DT: Journal Article JSC: E.5 ... Clinical Microbiology; B.2 ... Public Health RN: 0064 AB: The complexity of human immunodeficiency virus (HIV) immunopathogenesis has prompted multiple strategic approaches to re- establish normal immune responses. Highly active antiretroviral therapy (HAART) can control viral replication, but it is unable to restore HIV-specific immunity. Newer approaches for managing HIV infection are focusing on cell-mediated immune responses, including the potential for improved immunologic control over HIV replication. Cytokines, such as interleukin (IL)-2 and IL-12, are being evaluated for their ability to enhance cell-mediated immunity, which is thought to be critical for immunologic control. Initial studies with IL-2 have demonstrated an improvement in CD4 cell counts, and large randomized trials are underway to determine the long-term clinical efficacy of IL-2 in combination with antiretroviral therapy, including HAART. Stimulating the immune response against HIV by use of exogenous (therapeutic vaccination) or endogenous (structured treatment interruption) antigens with or without immune adjuvants or cytokines, such as IL-2, is another approach currently being explored. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/84 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2002170224 Autoren: Hasson H; Saniabadi A; Alfano M; Trabattoni D; Ferrante P; Lillo F; Clerici M; Lazzarin A; Beretta A Titel: Granulocyte/monocyte apheresis induces sustained increases in CD4 T cells in HIV-1 infected patients with poor CD4 T cell restoration after suppression of viral replication by HAART Source: Journal of Biological Regulators and Homeostatic Agents; VOL: 16 (1); p. 58-63 /2002/ SU: EMBASE Sprache: English AL: English CY: Italy ISSN: 0393-974X CO: JBRAE Institution: Beretta A, Dr., Clinica di Malattie Infettive, Istituto Scientifico San Raffaele, Via Stamira d'Ancona 20, 20127 Milano, Italy, [email protected] COU: Italy DT: Journal Article JSC: C.1.3 ... Oncology; E.4 ... Immunology & Serology RN: 0016 AB: Current antiretroviral regimens (HAART) are generally effective in reducing viral replication to undetectable levels and inducing a raise in CD4 T cells. However, in approximately 5 to 15% of patients suppression of viral replication is not followed by an increase in CD4 T cells. Such patients may be at increased risk for opportunistic infections. Here we report the results from a phase II open label randomised trial on 30 patients classified as poor responders to HAART who were either subjected to eight consecutive cycles of selective monocyte apheresis or maintained under HAART alone. The results show that monocyte apheresis results in increased CD4 T cell counts which are maintained for at least 31 weeks after last apheresis. This effect was observed only on patients with complete suppression of viral replication. Other effects of monocyte apheresis included a strong reduction of TNF- alpha production in patients with high baseline levels of this cytokine and activation of resting T cells during the apheresis cycles. In two patients with high cellular HIV DNA load apheresis was followed by a 98% reduction, suggesting purging of infected cells. There was no evidence of increased viral replication during or after the apheresis cycles. The data show that monocyte apheresis is safe, well tolerated and may be indicated in patients who respond poorly to HAART. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/85 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2002132024 Autoren: Calabrese LH; Lederman MM; Spritzler J; Coombs RW; Fox L; Schock B; Yen-Lieberman B; Johnson R; Mildvan D; Parekh N Titel: Placebo-controlled trial of cyclosporin-A in HIV-1 disease: Implications for solid organ transplantation Source: Journal of Acquired Immune Deficiency Syndromes; VOL: 29 (4); p. 356-362 /20020401/ SU: EMBASE Sprache: English AL: English CY: United States ISSN: 1525-4135 CO: JJASF Institution: Calabrese LH, Department of Rheumatic Diseases, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, United States, [email protected] COU: United States DT: Journal Article JSC: E.4.1 ... Allergy & Clinical Immunology; E.5.3 ... Virology RN: 0021 AB: Objective: Earlier open-label clinical trials have provided conflicting data on the effects of cyclosporin-A (CsA) on the clinical course and immune status of patients with HIV disease. With the prospects for wider use of CsA in the setting of solid organ transplantation in HIV-infected persons, data on the safety and immunologic activity of this agent are needed. We report here the results of a randomized, double-blind, placebo-controlled trial to assess the safety and immunologic activity of CsA administration in early HIV disease. Methods: Twenty-eight patients with confirmed HIV infection, CD4 cell counts greater than 500 × 106/L, and plasma HIV RNA >600 copies/mL were randomized to receive 2 mg/kg of CsA (Neoral) twice daily or identical placebo for 12 weeks. Subjects were stratified for the presence or absence of stable concomitant antiviral therapy. The primary end point was the effect of therapy on immune activation as assessed by the levels of soluble interleukin-2 receptors. Secondary end points included safety and effects of treatment on plasma HIV RNA, CD4 cell count, and other markers of immune activation and function. Results: The low dose of CsA used in this study did not suppress immune activation or increase circulating CD4 cell counts. Delayed-type hypersensitivity responses were not affected; however, lymphocyte proliferative responses tended to decrease. CsA-treated patients experienced a small but significant rise in plasma HIV RNA levels. Conclusions: Low-dose CsA has no benefit in patients with stable early HIV disease, and its administration may be associated with an increase in plasma HIV RNA. The use of CsA in HIV-infected patients undergoing organ transplantation should be undertaken with caution. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/86 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2002126118 Autoren: Emery S; Abrams DI; Cooper DA; Darbyshire JH; Lane HC; Lundgren JD; Neaton JD Titel: The Evaluation of Subcutaneous Proleukin® (interleukin-2) in a Randomized International Trial: Rationale, design, and methods of ESPRIT Source: Controlled Clinical Trials; VOL: 23 (2); p. 198-220 /2002/ DOI: 10.1016/S0197-2456(01)00179-9 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0197-2456 CO: CCLTD PII: S0197245601001799 Institution: Emery S, Dr., Nat. Ctr. HIV Epidemiol./Clin. Res., University of New South Wales, 376 Victoria Street, Sydney, NSW 2010, Australia, [email protected] COU: Australia DT: Journal Article JSC: A.1.1 ... Clinical Pharmacology RN: 0052 AB: The Evaluation of Subcutaneous Proleukin® in a Randomized International Trial (ESPRIT) is a large ongoing randomized trial of subcutaneous interleukin-2 (IL-2) plus antiretroviral therapy versus antiretroviral therapy alone in patients with HIV (human immunodeficiency virus) disease and CD4 cell counts of at least 300 cells/mm³. The primary objective is to determine whether the addition of IL-2 to combination antiretroviral therapy improves morbidity and mortality. The aim is to recruit 4000 participants and follow them for an average of 5 years. Eligible subjects will be recruited at 275 investigational sites in 23 countries around the world. Coupled with broad eligibility criteria this will ensure widely applicable results. A range of secondary objectives will also be addressed in this setting that will include the conduct of observational studies and nested substudies with a public health focus. This article describes the rationale supporting the trial in addition to reviewing the study design, coordination, and governance. © 2002 Elsevier Science Inc. All rights reserved. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/87 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2002094578 Autoren: Abrams DI; Bebchuk JD; Denning ET; Davey RT; Fox L; Lane HC; Sampson J; Verheggen R; Zeh D; Markowitz NP Titel: Randomized, open-label study of the impact of two doses of subcutaneous recombinant interleukin-2 on viral burden in patients with HIV-1 infection and CD4+ cell counts of >=300/mm³: CPCRA 059 Source: Journal of Acquired Immune Deficiency Syndromes; VOL: 29 (3); p. 221-231 /20020301/ SU: EMBASE Sprache: English AL: English CY: United States ISSN: 1525-4135 CO: JJASF Institution: Abrams DI, Dr., San Francisco General Hospital, UCSF Positive Health Program, Building 80, 995 Potrero Avenue, San Francisco, CA 94110, United States, [email protected] COU: United States DT: Journal Article JSC: E.4.1 ... Allergy & Clinical Immunology; E.5.3 ... Virology RN: 0035 AB: The effect of intermittent courses of recombinant interleukin-2 (rIL-2) on HIV-1 load in patients receiving combination antiretroviral therapy remains uncertain. CPCRA 059 was an open-label, randomized, multicenter trial in which 511 patients with HIV-1 infection and CD4+ cell counts of >=300/mm³ who were receiving anti-retroviral therapy were assigned to receive no rIL-2 (255 patients [controls]) or subcutaneous rIL-2 in dosages of 4.5 MIU (130) or 7.5 MIU (126) twice daily for 5-day courses every 8 weeks to maintain CD4+ cell counts that were twice the baseline value or >=1,000/mm³. The primary objective of this study was to compare the effects of the two doses of rIL-2 and no rIL-2 on viral load and CD4+ cell counts over 12 months. There was no difference in the following viral load measurements between the rIL-2 treatment groups and the control treatment group: percentage of patients with viral loads of =<50 copies/mL at 12 months (p = .55), time to viral load of >=50 copies/mL for patients who had baseline viral loads of <50 copies/mL (p = .35), and change in viral load from baseline for patients who had viral loads of >=50 copies/mL at baseline (p = .63). At each follow-up visit, the change in CD4+ cell count from baseline was significantly greater in the rIL-2 treatment groups than in the control treatment group, with a mean difference of 251/mm³ at month 12 (95% confidence interval, 207-295; p < .0001). No unanticipated adverse experiences were seen in this trial, to our knowledge the largest randomized evaluation of rIL-2 treatment conducted to date. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/88 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2002068710 Autoren: De Paoli P; Bortolin MT; Zanussi S; Monzoni A; Pratesi C; Giacca M Titel: Changes in thymic function in HIV-positive patients treated with highly active antiretroviral therapy and interleukin-2 Source: Clinical and Experimental Immunology; VOL: 125 (3); p. 440-446 /2001/ DOI: 10.1046/j.1365-2249.2001.01615.x SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0009-9104 CO: CEXIA Institution: De Paoli P, Dr., Immunology and Virology, Centro di Riferimento Oncologico, IRCCS, 33081 Aviano, Italy, [email protected] COU: Italy DT: Journal Article JSC: E.4 ... Immunology & Serology RN: 0040 AB: Despite its potent antiviral activity, highly active antiretroviral therapy (HAART) only exerts a marginal effect on CD4+ T-cell regeneration in HIV-infected subjects. Combination therapies aimed at boosting T-cell activity and maturation may provide an important contribution to the restoration of immune function. Here, we report the results obtained by a two-year follow-up of a cohort of HIV-infected patients treated with a combination of HAART and interleukin-2 (IL-2). In these patients, in addition to a series of quantitative virological and immunological parameters, we investigated T-cell regeneration by an immunophenotypic assay monitoring CD4+ naïve T cells, and by analysis of thymic function, through the quantification of the excision DNA products of T-cell receptor rearrangement (TRECs) in lymphocytes. Compared with HAART alone, we found that the IL-2 combination therapy was equally effective in reducing the levels of viremia and marginally more effective in decreasing proviral DNA load. Strikingly, the IL-2 combination produced a marked increase in the number of CD4+ T cells bearing a naïve phenotype (CD45RA+, CD62L+), which was apparent for over 96 weeks after therapy. To assess whether these cells were the product of improved T-cell generation, we exploited a competitive quantitative molecular assay to quantify TRECs in peripheral blood lymphocytes. Surprisingly, we found that the levels of these molecules were unchanged in these patients. These findings indicate that improved thymic function does not account for the early rise of CD4 naïve cells in HIV-positive patients treated with IL-2, and suggest that alternative mechanisms of T-cell maturation and differentiation are responsible for this event. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/89 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2002032880 Autoren: Ten RM; Anderson PM; Zein NN; Temesgen Z; Clawson ML; Weiss W Titel: Interleukin-2 liposomes for primary immune deficiency using the aerosol route Source: International Immunopharmacology; VOL: 2 (2-3); p. 333-344 /2002/ DOI: 10.1016/S1567-5769(01)00143-6 SU: EMBASE Sprache: English AL: English CY: Netherlands ISSN: 1567-5769 CO: IINMB PII: S1567576901001436 Institution: Anderson PM, Mayo Clinic, Pediatrics E9A, 200 First St. SW, Rochester, MN 55905, United States, [email protected] COU: United States DT: Journal Article JSC: A.1 ... Pharmacology & Drug Therapy; E.4 ... Immunology & Serology RN: 0031 AB: This is the first report of aerosol interleukin 2 (IL-2) liposome administration to individuals with immune deficiency. Parenteral IL- 2 therapy has shown beneficial effects in some patients with cancer, common variable immunodeficiency (CVID), and human immunodeficiency virus (HIV) but is problematic because of side effects including fever and malaise as well as local swelling (delayed type hypersensitivity like reaction) after each subcutaneous IL-2 injection. Provision of an IL-2:human albumin liposome formulation via the aerosol route had few side effects in a recent clinical trial in cancer patients. Details of good manufacturing practice (GMP) synthesis and analysis of IL-2 liposomes (N = 6 lots) made without albumin carrier protein and placebo liposomes (three lots) are presented. After centrifugation, IL-2 was closely associated with the liposome pellet (99%). Mean diameter of liposomes was 1.1 mu m. Patient acceptance, safety, toxicity, and immune effects of IL-2 liposomes were studied in individuals with primary immune deficiency (N = 15) and subsequently, a larger cohort of patients with hepatitis C. Experience in the immune deficient patients is the subject of this report. Placebo liposomes (12 weeks) and IL-2 liposomes (12 weeks) were provided using a nebulizer. Aerosol placebo liposomes and IL-2 liposomes were well tolerated. No changes in chest X-ray or pulmonary function were seen. Since biologic activity of aerosol IL-2 liposomes has been seen in viral disease (hepatitis C), additional studies of aerosol IL-2 liposomes in individuals with hepatitis C and HIV are planned. © 2002 Elsevier Science B.V. All rights reserved. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/90 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2002019510 Autoren: Dybul M; Hidalgo B; Chun T-W; Belson M; Migueles SA; Justement JS; Herpin B; Perry C; Hallahan CW; Davey RT; Metcalf JA; Connors M; Fauci AS Titel: Pilot study of the effects of intermittent interleukin-2 on human immunodeficiency virus (HIV)-specific immune responses in patients treated during recently acquired HIV infection Source: Journal of Infectious Diseases; VOL: 185 (1); p. 61-68 /20020101/ DOI: 10.1086/338123 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0022-1899 CO: JIDIA Institution: Dybul M, Dr., Natl. Inst. of Allergy/Infect. Dis., National Institutes of Health, Building 10, Bethesda, MD 20892, United States, [email protected] COU: United States DT: Journal Article JSC: E.5 ... Clinical Microbiology; B.2 ... Public Health RN: 0041 Keywords AB: Highly active antiretroviral therapy (HAART) initiated during acute human immunodeficiency virus (HIV) infection may preserve HIV-specific CD4+ T cell responses that are thought to enhance HIV-specific CD8+ T cell function. The present pilot study was designed to determine whether preserved HIV-specific immune responses are augmented by the administration of the immunomodulatory agent interleukin (IL)-2. Nine persons recently (<6 months) infected with HIV were randomized to receive HAART alone or HAART plus 3 cycles of intermittent IL-2 during a 12-month period. Although HAART plus IL-2 significantly increased counts of total and naive CD4+ T cells, compared with HAART alone, there was no increase in CD4+ or CD8+ HIV-specific immune responses. In addition, adjuvant IL-2 therapy did not reduce the pool of HIV-infected resting CD4+ T cells. Thus, although intermittent IL-2 plus HAART quantitatively increased CD4+ T cells, this increase was not selective for HIV-specific CD4+ or CD8+ T cell responses in recently infected persons. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/91 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2001424593 Autoren: Lafeuillade A; Poggi C; Chadapaud S; Hittinger G; Khiri H; Halfon P Titel: Impact of immune interventions on proviral HIV-1 DNA decay in patients receiving highly active antiretroviral therapy Source: HIV Medicine; VOL: 2 (3); p. 189-194 /2001/ DOI: 10.1046/j.1468-1293.2001.00065.x SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 1464-2662 CO: HMIEA Institution: Lafeuillade A, Unité d'Infectiologie, Hôpital Chalucet, F-83056 Toulon, France, [email protected] COU: France DT: Journal Article JSC: C.0 ... Clinical Medicine; E.5.3 ... Virology RN: 0022 AB: Objective. To measure the evolution of proviral HIV-1 DNA levels in patients receiving highly active antiretroviral therapy (HAART) compared to those treated with HAART plus interleukin-2 (IL-2) and hydroxyurea. Design. Prospective randomised trial. Methods. Twenty-two HIV-1 infected patients were randomly assigned to a five-drug antiretroviral regimen for 72 weeks, with or without IL-2, followed by a three-drug regimen up to week 120 with additional hydroxyurea in patients having received IL-2. HIV-1 DNA levels in peripheral blood mononuclear cells (PBMC) were measured regularly using the Amplicor Monitor kit from Roche Diagnostics (Meylan, France). Potentially infectious HIV-1 was cultured in enhanced conditions from circulating CD4 T cells at week 120. Results. During the study period of 120 weeks, HIV-1 DNA levels in PBMC decreased by -1.1 log in patients treated with HAART only compared with -1.8 log in patients with additional IL-2 and hydroxyurea. A two-phase decay rate was observed, with an inflexion point at 12 weeks. The second decay was slow, with mean half-lives of 130.1 ± 21.3 weeks and 95.1 ± 26.3 weeks for patients on HAART and those receiving additional IL-2 and hydroxyurea, respectively. At week 120, one out of 11 patients with HAART alone compared to six out of 11 in the group with IL-2 and hydroxyurea had undetectable proviral DNA levels and three of them had unsuccessful recovery of replication-competent HIV-1 from blood CD4 T cells. Conclusion. Therapeutic strategies combining HAART and immune interventions have higher potency to decrease the number of infected cells than HAART alone. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/92 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2001376224 Autoren: Scott-Algar D; Aboulker J-P; Durier C; Badel E; Marcellin F; Prud'Homme M; Jouann C; Meiffredy V; Brun-Vezinet F; Pialoux G; Raffi F Titel: Cd4 T cell recovery is slower in patients experiencing viral load rebounds during HAART Source: Clinical and Experimental Immunology; VOL: 126 (2); p. 295-303 /2001/ DOI: 10.1046/j.1365-2249.2001.01680.x SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0009-9104 CO: CEXIA Institution: Scott-Algar D, Dr., Institut Pasteur, Svc. d'Immuno-Hematol./Immunopathol., 28 rue du Dr Roux, 75015 Paris, France, [email protected] COU: France DT: Journal Article JSC: E.4 ... Immunology & Serology RN: 0017 AB: To determine whether viral load rebounds during HAART impact on CD4+ T cell recovery and immune reconstitution, we studied a prospective cohort of 355 antiretroviral naive patients enrolled to be randomized in a trial of three strategies of induction/maintenance HAART. The extent of immune reconstitution in blood through 72 weeks of antiretroviral treatment was evaluated. Lymphocyte subset markers (CD4, CD8, CD45RA, CD62L, CD16, CD19), activation markers (HLA-DR, CD38, CD25) were performed by cytometry analysis. Our results showed that plasma HIV-1 RNA was suppressed to below 500 copies per ml through week 72 in 240 patients (group 1) while the remaining 115 patients experienced at least one viral rebound (group 2). At baseline, CD4 cell count was higher and HIV-1 RNA was lower in group 1 than in group 2. Over 72 weeks, mean increase in CD4+ T cell count was 0.32 cell/mm3/day in group 1 and only 0.14 cell/mm3/day in group 2 (P < 0.0001). However, the patterns of changes in CD4+ and CD8+ T cell subsets during therapy were very similar across the two groups with only subtle and very limited differences. We conclude that permanent control of HIV replication could be necessary for faster immune reconstitution. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/93 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2001355340 Autoren: Imami N; Hardy G; Burton C; Pires A; Pido-Lopez J; Moss R; Gazzard B; Gotch F Titel: Immune responses and reconstitution in HIV-1 infected individuals: Impact of anti-retroviral therapy, cytokines and therapeutic vaccination Source: Immunology Letters; VOL: 79 (1-2); p. 63-76 /20011101/ DOI: 10.1016/S0165-2478(01)00267-X SU: EMBASE Sprache: English AL: English CY: Netherlands ISSN: 0165-2478 CO: IMLED PII: S016524780100267X Institution: Imami N, Department of Immunology, Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW 10 9NH, United Kingdom, [email protected] COU: United Kingdom DT: Journal Article JSC: E.4 ... Immunology & Serology RN: 0054 AB: Most patients with chronic HIV-1 infection lack functional CD4+ and CD8+ HIV-1-specific T cells with proliferative and cytolytic capacity, respectively. This is despite being able to produce intracellular cytokines in response to viral antigens. Protease inhibitor (PI)-based highly active anti-retroviral therapy (HAART) is unable to completely eradicate virus and fails to enable total restoration of immunity including induction of anti-HIV-1 responses. We have taken novel approaches towards the treatment of chronic HIV-1 disease with the aim of instigating long-term non-progressor status and depletion of virus reservoirs. HIV-1-specific CD4+ and CD8+ T cell responses were measured following the administration of cytokines, during therapeutic vaccination, and following treatment interruption (TI) or drug therapy change. Administration of cytokines, with or without therapeutic vaccination, in HAART treated patients, improved both CD4+ and CD8+ HIV-1-specific T cell responses even in late-stage disease. Virus-specific T cell responses were also seen during TI or when transient viraemia was apparent, and following therapy change from a PI- to a non-nucleoside-based HAART regimen. Reconstitution of HIV-1-specific immune responses was found to be transient and reversal to the previous anergic state was rapid. Viral reservoirs in the latently infected resting CD4+ T cells, on follicular dendritic cells of germinal centers or even in infected thymic epithelium may be involved in clonal suppression and anergy. These may present major obstacles to the maintenance of HIV-1-specific responses and the eventual eradication of HIV-1. © 2001 Published by Elsevier Science B.V. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/94 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2001340980 Autoren: Caggiari L; Zanussi S; D'Andrea M; Bortolin MT; Crepaldi C; Caffau C; De Paoli P Titel: Effects of interleukin-2 therapy on the proliferation and differentiation of CD4/CD25 positive and CD4/CD25 negative cells in HIV+ patients Source: European Cytokine Network; VOL: 12 (3); p. 430-436 /2001/ SU: EMBASE Sprache: English AL: English CY: France ISSN: 1148-5493 CO: ECYNE Institution: De Paoli P, Microbiology, Immunol. and Virology, Centro di Riferimento Oncologico, Aviano, Italy, [email protected] COU: Italy DT: Journal Article JSC: E.4 ... Immunology & Serology RN: 0036 AB: Interleukin-2 has been widely used in HIV-1+ subjects as an immunoactivating agent. In this study, we investigated cytokine production, Ki67 antigen expression and the modulation of the surface phenotype of the CD4/CD25+ subset as compared to the reciprocal CD4/CD25- subset in IL-2-treated HIV+ patients. Our findings suggest that CD4 T cells are heterogeneous in responding to IL-2, because CD4/CD25+ cells sharply increased their "memory" phenotype, their Ki67 antigen expression and were the main in vivo targets for IL-2-dependent proliferation during therapy, while the percentages of IFN- gamma + (terminally differentiated) cells remained unchanged at the end of therapy. Conversely, the CD4+/CD25- subpopulation showed an expansion of differentiated cells and a slight increase in the proliferation rate. The use of anti-retroviral therapy alone (HAART) reduced the proliferation and increased the differentiation of both CD4 subsets. Our data suggest that IL-2 has a moderate capacity to activate resting T cells in vivo and is probably unable to boost HIV-1 from latency to the replicative state. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/95 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2001339007 Autoren: Caggiari L; Zanussi S; Crepaldi C; Bortolin MT; Caffau C; D'Andrea M; De Paoli P Titel: Different rates of CD4+ and CD8+ T-cell proliferation in interleukin-2 - Treated human immunodeficiency virus-positive subjects Source: Cytometry; VOL: 44 (4); p. 233-237 /20010815/ SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0196-4763 CO: CYTOD Institution: De Paoli P, Dr., Division of Microbiology, Centro di Riferimento Oncologico, 33081 Aviano, Italy, [email protected] COU: Italy DT: Journal Article JSC: C.1.5 ... Hematology RN: 0026 AB: Background: Interleukin-2 (IL-2) has been used successfully to increase CD4 cell counts in patients who are human immunodeficiency virus (HIV) positive. The mechanisms involved in this phenomenon are unknown. We hypothesized that a differential proliferation rate of CD4+ compared with CD8+ lymphocytes could be related to the increase of CD4 counts and of CD4/CD8 ratios that occur in HIV+ patients during IL-2 treatment. Methods: We enrolled in our study 14 HIV+ patients treated with IL-2 or with highly active antiretroviral therapy (HAART) during a 96-week observation period. Using flow cytometry, we measured longitudinally the expression of the Ki67 antigen in peripheral blood CD4+ and CD8+ lymphocyte subsets. Results: Compared with HAART alone, IL-2 produced a rapid increase of Ki67+ proliferating CD4 cells and a concomitant increase of the CD4/CD8 ratios, whereas the corresponding CD8 proliferation increased slightly. On the contrary, HAART alone was effective in suppressing equally both CD4 and CD8 proliferation. Conclusions: Our results suggest a selective activity of IL-2 on CD4 T-cell proliferation; on the contrary, CD8-specific proliferation is affected minimally during treatment. This information may offer the potential to plan correctly immune activating regimens. © 2001 Wiley-Liss, Inc. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/96 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2001332334 Autoren: Gorse GJ; Patel GB; Belshe RB Titel: HIV type 1 vaccine-induced T cell memory and cytotoxic T lymphocyte responses in HIV type 1-uninfected volunteers Source: AIDS Research and Human Retroviruses; VOL: 17 (12); p. 1175-1189 /2001/ DOI: 10.1089/088922201316912781 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0889-2229 CO: ARHRE Institution: Gorse GJ, Division of Infectious Diseases, Saint Louis Univ. Hlth. Sci. Center, 3635 Vista Avenue (FDT-8N), St. Louis, MO 63110, United States, [email protected] COU: United States DT: Journal Article JSC: E.4 ... Immunology & Serology; E.5.3 ... Virology RN: 0059 AB: T cell memory to human immunodeficiency virus type 1 (HIV-1) antigens and anti-HIV-1 cytotoxic T lymphocyte (CTL) activity were assessed after administration of live canarypox virus (ALVAC) expressing HIV-1 env, gag, and protease (vCP205) vaccine given alone, vCP205 given with SF-2 recombinant gp120 (rgp120) vaccine, and placebos at 0, 1, 3, and 6 months. Healthy, HIV-1- uninfected subjects reporting high-risk and low-risk behavior for HIV-1 were enrolled. Anti-HIV-1 Env CD8+ CTLs (HIV-1MN and/or HIV-1 subtype B and C primary isolate sequences) were detected in 12 (60%) and anti-HIV-1 Gag CD8+ CTLs in 7 (35%) of the 20 vCP205 vaccine recipients tested by CTL assay 3.5 months after the final immunization. Fourteen days after the fourth immunization, lymphocyte proliferation in response to HIV-1 Gag antigen was detected in 14 (48%) of 29 vCP205 vaccine recipients, but secreted cytokine levels to HIV-1 Gag antigen were not above unstimulated levels. Coadministration of SF-2 rgp120 vaccine with vCP205 vaccine enhanced lymphocyte proliferation in response to HIV-1 envelope glycoprotein and broadened the envelope-stimulated cytokine secretion pattern, so that it consisted of both Th1 and Th2 cytokines compared with only interferon gamma (IFN- gamma ) after vCP205 vaccine given alone. There was a possible association between HIV-1 envelope glycoprotein-stimulated interleukin 2 secretion and CD8+ CTLs against HIV-1 envelope glycoprotein, and an inverse relation between lymphocyte proliferation and CTLs against HIV-1 Gag antigens. Thus, a durable anti-HIV-1 CD8+ CTL response was detected after immunization with the live canarypox virus vaccine and preexisting helper T cell memory responses did not necessarily predict later CD8+ CTL activity. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/97 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2001216614 Autoren: Ruiz L; Carcelain G; Martínez-Picado J; Frost S; Marfil S; Paredes R; Romeu J; Ferrer E; Morales-Lopetegi K; Autran B; Clotet B Titel: HIV dynamics and T-cell immunity after three structured treatment interruptions in chronic HIV-1 infection Source: AIDS; VOL: 15 (9); p. F19-F27 /20010615/ DOI: 10.1097/00002030-200106150-00001 SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 CO: AIDSE Institution: Ruiz L, Dr., 'IrsiCaixa' Foundation, Hosp. Univ. Germans Trias i Pujol, Universidad Autonoma de Barcelona, 08916 Badalona, Barcelona, Spain, [email protected] COU: Spain DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0035 AB: Objective: To evaluate whether controlled re-exposures to autologous HIV-1 could boost HIV-specific immunity and limit virus replication in patients with chronic HIV-1 infection. Patients and design: Subjects with at least 2 years virus suppression during antiretroviral therapy and a CD4: CD8 ratio > 1 were randomly assigned to interrupt highly active antiretroviral treatment (HAART) three times (n = 12) or to continue their previous HAART (n = 14). Results: In 10/12 interrupter patients a rebound of HIV-1 RNA was detected in all three structured treatment interruptions (STI). Plasma virus doubling time was shorter during the first STI than in the second and third STI, corresponding to an average 13% reduction in viral basic reproductive rate. However, the mean time before plasma viral load rose to > 50 copies/ml was significantly shorter in the second and third STI. The average frequency of HIV- specific CD8 T cells in the interrupter patients at the end of the third STI cycle was significantly higher compared with the baseline and the end of the first STI. A substantial increase in HIV-specific CD8 T cell frequencies was found in four interrupter patients, whereas there were no changes in all 14 non-interrupter individuals. A weak p24-specific T helper response developed in 5/12 interrupter patients compared with no response in non-interruptors, but these responses were transient and disappeared rapidly. Conclusion: The increase in the control of viral replication, and positive effects of STI on immune responses in this population should encourage the further development of HIV-specific immune-based therapeutic strategies. © 2001 Lippincott Williams & Wilkins. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/98 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2001190731 Autoren: Giovannetti A; Pierdominici M; Mazzetta F; Salemi S; Marziali M; Kuonen D; Iebba F; Lusi EA; Cossarizza A; Aiuti F Titel: T cell responses to highly active antiretroviral therapy defined by chemokine receptors expression, cytokine production, T cell receptor repertoire and anti-HIV T-lymphocyte activity Source: Clinical and Experimental Immunology; VOL: 124 (1); p. 21-31 /2001/ DOI: 10.1046/j.1365-2249.2001.01502.x SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0009-9104 CO: CEXIA Institution: Giovannetti A, Dr., Division of Clinical Immunology, University of Rome La Sapienza, Viale dell'Università 37, 00185 Rome, Italy, [email protected] COU: Italy DT: Journal Article JSC: E.4 ... Immunology & Serology RN: 0040 AB: The immunological correlates of highly active antiretroviral therapy (HAART)-induced suppression of human immunodeficiency virus type 1 (HIV-1) replication have been investigated. 20 HIV-1-infected patients with mean CD4+ T cell count of 298/ mu l, plasma viral load of 4.7 log10 copies/ml and naive for protease inhibitors (PI) were studied during 12 months of HAART. An increased number of both CD4+ and CD8+ naive T cells and a normalization of the frequency of CCR5- and CXCR4-expressing CD4+ T cells were readily observed after starting therapy. Single cell analysis of cytokine production after 12 months of HAART showed an increased number of interleukin (IL)-2-, but not IL-4- and (IFN)- gamma -, producing T cells and a decreased percentage of CD8+ IFN- gamma + cells. A correlation between the frequency of IFN- gamma -producing T cells and that of memory, CCR5+ and CD95+ T cells was demonstrated in both CD4+ and CD8+ subsets. The diversity of T cell receptor (TCR) variable beta (BV) chain repertoire significantly increased after 12 months of HAART within the CD4+ but not the CD8+ T cell subset. However, the level of perturbation of the third complementarity-determining region (CDR3), was not significantly modified by effective therapy. The number of anti-HIV Gag and Pol cytotoxic T lymphocytes precursors (CTLp) decreased during HAART and highly correlated with the CD8 IFN- gamma response. Ameliorated clinical conditions were observed in all patients in absence of any opportunistic infections during all the study period. These observations indicate that a better restoration of immunity may be obtained in patients starting HAART at less advanced stages of the disease. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 4/99 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2001183848 Autoren: Kovacs JA; Vogel S; Metcalf JA; Baseler M; Stevens R; Adelsberger J; Lempicki R; Hengel RL; Sereti I; Lambert L; Dewar RL; Davey RT Jr.; Walker RE; Falloon J; Polis MA; Masur H; Lane HC Titel: Interleukin-2 induced immune effects in human immunodeficiency virus-infected patients receiving intermittent interleukin-2 immunotherapy Source: European Journal of Immunology; VOL: 31 (5); p. 1351-1360 /2001/ DOI: 10.1002/1521-4141(200105)31:5<1351::AID-IMMU1351>3.0.CO;2-9 SU: EMBASE Sprache: English AL: English CY: Germany ISSN: 0014-2980 CO: EJIMA Institution: Kovacs JA, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Building 10, Bethesda, MD 20892- 1662, United States, [email protected] COU: United States DT: Journal Article JSC: E.4 ... Immunology & Serology RN: 0022 AB: To characterize the immunological effects of intermittent IL-2 therapy, which leads to selective increases in CD4+ T lymphocytes in HIV-infected patients, 11 patients underwent extensive immunological evaluation. While IL-2 induced changes in both CD4+ and CD8+ cell number acutely, only CD4+ cells showed sustained increases following discontinuation of IL-2. Transient increases in expression of the activation markers CD38 and HLA-DR were seen on both CD4+ and CD8+ cells, but CD25 ( alpha chain of the IL-2 receptor) increased exclusively on CD4+ cells. This increase in CD25 expression was sustained for months following discontinuation of IL-2, and was seen in naive as well as memory cells. IL-2 induced cell proliferation, but tachyphylaxis to these proliferative effects developed after 1 week despite continued IL-2 administration. It thus appears that sustained CD25 expression selectively on CD4+ cells is a critical component of the immunological response to IL-2, and that intermittent administration of IL-2 is necessary to overcome the tachyphylaxis to IL-2, induced proliferation. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. » Fenster schließen » vorherige Dokumente weitere Dokumente

» Volltext-Angebot » 3/100 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2001170201 Autoren: Tambussi G; Ghezzi S; Nozza S; Vallanti G; Magenta L; Guffanti M; Brambilla A; Vicenzi E; Carrera P; Racca S; Soldini L; Gianotti N; Murone M; Veglia F; Poli G; Lazzarin A Titel: Efficacy of low-dose intermittent subcutaneous interleukin (IL)-2 in antiviral drug-experienced human immunodeficiency virus-infected persons with detectable virus load: A controlled study of 3 IL-2 regimens with antiviral drug therapy Source: Journal of Infectious Diseases; VOL: 183 (10); p. 1476-1484 /20010515/ DOI: 10.1086/320188 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0022-1899 CO: JIDIA Institution: Tambussi G, Dr., Clinic of Infectious Diseases, San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20137 Milan, Italy, [email protected] COU: Italy DT: Journal Article JSC: E.5 ... Clinical Microbiology; B.2 ... Public Health RN: 0034 AB: To evaluate the safety and efficacy of 3 regimens of intermittent subcutaneous (sc) interleukin (IL)-2 in a phase 2 study, 61 antiviral drug-experienced human immunodeficiency virus (HIV)-positive patients were randomly assigned to one of the following study arms: Antiretroviral therapy (ART) plus IL-2 (12 million IU [MIU] by continuous intravenous infusion, followed by 7.5 MIU twice a day, sc, every 8 weeks); ART plus IL-2 (7.5 MIU twice a day, sc, every 8 weeks); ART plus IL-2 (3 MIU twice a day, sc, every 4 weeks); or ART alone. A significant increase of circulating CD4 cells was observed in IL-2-treated subjects, compared with those given ART alone. Low doses of IL-2 were better tolerated. Despite the incomplete suppression of viral replication, IL-2 with ART did not increase either plasma viremia or cell-associated HIV DNA levels. Low doses of intermittent sc IL-2 induced a stable increase of peripheral CD4 cells that was indistinguishable from those associated with higher, less well-tolerated doses of IL-2. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 3/101 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2001149757 Autoren: Miller KD; Spooner K; Herpin BR; Rock-Kress D; Metcalf JA; Davey RT Jr.; Falloon J; Kovacs JA; Polis MA; Walker RE; Masur H; Lane HC Titel: Immunotherapy of HIV-infected patients with intermittent interleukin-2: Effects of cycle frequency and cycle duration on degree of CD4+ T-lymphocyte expansion Source: Clinical Immunology; VOL: 99 (1); p. 30-42 /2001/ DOI: 10.1006/clim.2001.5001 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 1521-6616 CO: CLIIF Institution: Miller KD, Critical Care Medicine Department, Warren Grant Magnuson Clin. Center, Natl. Inst. of Allergy/Infect. Dis., Bethesda, MD 20892, United States COU: United States DT: Journal Article JSC: C.11 ... Clinical Pathology; E.4.1 ... Allergy & Clinical Immunology RN: 0044 AB: The ability of IL-2 to induce expansion of the CD4+ T lymphocyte pool has made it the most studied cytokine in the treatment of HIV infection. The majority of trials have used an empirical regimen of 5-day IL-2 cycles given every 8 weeks - a regimen based upon early pharmacodynamic studies and patient preference. To better define optimal duration and frequency of cycles, a randomized trial was conducted in which patients who received this "standard" regimen were compared to patients who received cycles of variable duration (based on individual patterns of cell cycle progression) and to patients who received cycles of variable frequency (based on individual CD4+ T lymphocyte responses to previous cycles). Twenty-two patients with HIV-1 infection and CD4+ T lymphocyte counts > 200 cells/mm³ were randomized to one of three treatment groups for 32 weeks of study. Eight participants received four 5-day IL-2 cycles (controls) every 8 weeks; 7 participants received four cycles of longer duration (mean 7.7-days); and 7 participants received an increased frequency of 5-day cycles (every 4.1 weeks on average). All three groups experienced significant increases in mean CD4+ T lymphocytes. However, there were no statistically significant differences in CD4+ T lymphocyte increases between the group that received longer cycles (median increase 239 cells/mm³, P = 0.78) or between the group that received more frequent cycles (median increase 511 cells/mm³, P = 0.54) and the control group (median 284 cells/mm³). HIV-1 viral loads decreased during the study period in all three groups. Our inability to demonstrate a significant advantage of increased frequency or duration of IL-2 administration provides corroborating experimental evidence for the use of an IL-2 regimen consisting of 5-day cycles administered no more frequently than every 8 weeks in future clinical trials aimed at expanding the CD4+ T lymphocyte pool. © 2001 Academic Press. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 3/102 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2001137953 Autoren: Kuhn L; Meddows-Taylor S; Gray G; Trabattoni D; Clerici M; Shearer GM; Tiemessen C Titel: Reduced HIV-stimulated T-helper cell reactivity in cord blood with short-course antiretroviral treatment for prevention of maternal-infant transmission Source: Clinical and Experimental Immunology; VOL: 123 (3); p. 443-450 /2001/ DOI: 10.1046/j.1365-2249.2001.01460.x SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0009-9104 CO: CEXIA Institution: Kuhn L, Dr., Columbia University, Sergievsky Center, 630 W 168th Street, New York, NY 10032, United States, [email protected] COU: United States DT: Journal Article JSC: E.4 ... Immunology & Serology RN: 0045 AB: T-helper cell responses to HIV have been associated with protection against maternal-infant HIV transmission in the absence of antiretroviral treatment, but the effects of antiretroviral treatment, now widely used for prevention, on development of these cell- mediated responses is unknown. We tested whether development of T-helper cell responses to HIV and other antigens would be affected by exposure to short-course regimens of zidovudine-lamivudine (ZDV-3TC) given to prevent maternal-infant HIV transmission. Cord blood samples were collected from 41 infants of HIV-infected mothers enrolled in a clinical trial in which they were treated with regimens of ZDV-3TC and from 29 infants whose HIV-infected mothers were not treated with any antiretroviral drugs. T-helper cell reactivity to HIV envelope peptides and other antigens was measured in vitro using a sensitive culture supernatant titration assay based on IL-2-dependent proliferation. Infants in the clinical trial were followed to 18 months to determine their HIV infection status, and venous blood samples were re-tested at 4.5 and 9 months for T-cell reactivity to HIV. HIV-stimulated T-helper cell reactivity in cord blood was detected 10-fold less frequently among those exposed to antiretroviral prophylaxis (2.4%) than among those unexposed (24.1%) (P = 0.007). Reductions in HIV-stimulated responses in cord blood occurred despite detectable HIV RNA (mean 3.38 standard deviation 0.76 log10 copies per ml) at delivery among treated women and occurred independent of treatment duration. Our results suggest that short-course antiretroviral treatment given to prevent maternal-infant HIV transmission may attenuate HIV-stimulated T-cell memory responses in the neonate. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 3/103 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2001093192 Autoren: Micke P; Beeh KM; Schlaak JF; Buhl R Titel: Oral supplementation with whey proteins increases plasma glutathione levels of HIV-infected patients Source: European Journal of Clinical Investigation; VOL: 31 (2); p. 171-178 /2001/ DOI: 10.1046/j.1365-2362.2001.00781.x SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0014-2972 CO: EJCIB Institution: Micke P, Dr., Pulmonary Division, III, Medical Department, Mainz University Hospital, D-55101 Mainz, Germany, p.micke@3- med.klinik.uni-mainz.de COU: Germany DT: Journal Article JSC: C.0 ... Clinical Medicine RN: 0035 AB: Background: HIV infection is characterized by an enhanced oxidant burden and a systemic deficiency of the tripeptide glutathione (GSH), a major antioxidant. The semi-essential amino acid cysteine is the main source of the free sulfhydryl group of GSH and limits its synthesis. Therefore, different strategies to supplement cysteine supply have been suggested to increase glutathione levels in HIV-infected individuals. The aim of this study was to evaluate the effect of oral supplementation with two different cysteine-rich whey protein formulas on plasma GSH levels and parameters of oxidative stress and immune status in HIV-infected patients. Methods: In a prospective double blind clinical trial, 30 patients (25 male, 5 female; mean age (± SD) 42 ± 9.8 years) with stable HIV infection (221 ± 102 CD4 + lymphocytes L-1) were randomized to a supplemental diet with a daily dose of 45 g whey proteins of either Protectamin (Fresenius Kabi, Bad Hamburg, Germany) or Immunocal (Immunotec, Vandreuil, Canada) for two weeks. Plasma concentrations of total, reduced and oxidized GSH, superoxide anion (O2-) release by blood mononuclear cells, plasma levels of TNF- alpha and 2 and 12 were quantified with standard methods at baseline and after therapy. Results: Pre-therapy, plasma GSH levels (Protectamin: 1.92 ± 0.6 mu M; Immunocal: 1.98 ± 0.9 mu M) were less than normal (2.64 ± 0.7 mu M, P = 0.03). Following two weeks of oral supplementation with whey proteins, plasma GSH levels increased in the Protectamin group by 44 ± 56% (2.79 ± 1.2 mu M, P = 0.004) while the difference in the Immunocal group did not reach significance (+ 24.5 ± 59%, 2.51 ± 1.48 mu M, P = 0.43). Spontaneous O2- release by blood mononuclear cells was stable (20.1 ± 14.2 vs. 22.6 ± 16.1 nmol h-1 10-6 cells, P = 0.52) whereas PMA-induced O2- release decreased in the Protectamin group (53.7 ± 19 vs. 39.8 ± 18 nmol h-1 10-6 cells, P = 0.04). Plasma concentrations of TNF- alpha and interleukins 2 and 12 (P > 0.08, all comparisons) as well as routine clinical parameters remained unchanged. Therapy was well tolerated. Conclusion: In glutathione-deficient patients with advanced HIV-infection, short-term oral supplementation with whey proteins increases plasma glutathione levels. A long-term clinical trial is clearly warranted to see if this 'biochemical efficacy' of whey proteins translates into a more favourable course of the disease. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 3/104 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2001058888 Autoren: Tavel JA; Fosdick L Titel: Closeout of four phase II Vanguard trials and patient rollover into a large international phase III HIV clinical endpoint trial Source: Controlled Clinical Trials; VOL: 22 (1); p. 42-48 /2001/ DOI: 10.1016/S0197-2456(00)00114-8 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0197-2456 CO: CCLTD PII: S0197245600001148 Institution: Tavel JA, Dr., Natl. Inst. Allerg./Infectious Dis., Building 10, 9000 Rockville Pike, Bethesda, MD, 20892-1880, United States, [email protected] COU: United States DT: Journal Article JSC: A.1.1 ... Clinical Pharmacology RN: 0013 AB: Large phase III clinical trials typically require many years of planning and preparation. During this time, proposed study methods and overall trial feasibility can be assessed in smaller pilot studies. However, the patients enrolled in these pilot studies are not routinely included in the larger study. In preparation for a multinational randomized clinical end point trial of interleukin-2 in HIV- infected patients, four phase II "Vanguard" studies were initiated. These Vanguard trials served to increase safety and surrogate marker data in diverse patient cohorts, increase clinical experience with the study medication, and identify the optimal dose of medication for the phase III trial. These trials also served to assess patient recruitment potential and to develop international clinical trial coordination experience. The Vanguard trials were designed to allow continued follow-up of their patients as participants of the phase III trial once the feasibility of the phase III trial was confirmed. The purpose of this paper is to describe the steps taken in the closeout of these four phase II trials while reconsenting these patients to the phase III trial. Specifically, the reconsent process, the data collection transition plan, and the steps taken to minimize bias due to differential reconsent according to the assigned treatment arm in the phase II trial are described. The procedures employed are relevant to the reconsent of patients for long-term follow-up at the completion of clinical trials. © Elsevier Science Inc. 2001. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 3/105 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2001016654 Autoren: Nielsen SD; Sørensen TU; Ersbøll AK; Ngo N; Mathiesen L; Nielsen JO; Hansen J-ES Titel: Decrease in immune activation in HIV-infected patients treated with highly active antiretroviral therapy correlates with the function of hematopoietic progenitor cells and the number of naive CD4+ cells Source: Scandinavian Journal of Infectious Diseases; VOL: 32 (6); p. 597-603 /2000/ DOI: 10.1080/003655400459487 SU: EMBASE Sprache: English AL: English CY: Norway ISSN: 0036-5548 CO: SJIDB Institution: Nielsen SD, Dr., Department of Infectious Diseases, 144 Hvidovre Hospital, DK-2650 Hvidovre, Denmark COU: Denmark DT: Journal Article JSC: E.5 ... Clinical Microbiology RN: 0042 AB: This study was conducted to determine the impact of immune activation, cytokine production and apoptosis on the naive CD4+ cell count and the function of hematopoietic progenitor cells during the initial phase of highly active antiretroviral therapy (HAART). Blood samples from 11 HIV-infected patients were collected prior to HAART and after 4 and 12 weeks of therapy. Flow cytometry was used to determine the naive CD4+ count and activated T cells. The cloning efficiency of progenitor cells was determined using a colony-forming cells assay. Finally, apoptosis and cytokine production were determined. During the study period, the naive CD4+ count and the cloning efficiency increased significantly. Immune activation was found in HIV-infected patients and decreased during HAART. The level of immune activation correlated negatively with both the naive CD4+ count and the function of progenitor cells. A negative correlation was found between apoptosis and the naive CD4+ count. Alterations in cytokine production during HAART or correlation between cytokine production and the naive CD4+ count or the cloning efficiency of progenitor cells were not detected. In conclusion, immune activation in HIV-infected patients treated with HAART is inversely correlated with the function of progenitor cells and the naive CD4+ count. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 3/106 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2000407237 Autoren: Ruxrungtham K; Suwanagool S; Tavel JA; Chuenyam M; Kroon E; Ubolyam S; Buranapraditkun S; Techasathit W; Li Y; Emery S; Davey RT; Fosdick L; Kunanusont C; Lane HC; Phanuphak P; Cooper DA; Lange JA; Ungsedhapand C; Rongkavilit C; Yimsuan N; Newell M; Duncombe C; Sonjai A; Chungprasert N; Tiengrim S; McNay L Titel: A randomized, controlled 24-week study of intermittent subcutaneous interleukin-2 in HIV-1 infected patients in Thailand Source: AIDS; VOL: 14 (16); p. 2509-2513 /2000/ DOI: 10.1097/00002030-200011100-00013 SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 CO: AIDSE Institution: Ruxrungtham K, Thai Red Cross, AIDS Research Centre, 104 Rajadamri Road, Lumpini, Bangkok 10330, Thailand COU: Thailand DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0012 AB: Objectives: To assess the immunological and virological effects, safety profile and feasibility of subcutaneous interleukin-2 (sclL-2) therapy in an HIV-infected Thai population. Design: Seventy-two patients with baseline CD4 cell count of >= 350 x 106/l and no history of were randomized to receive antiretroviral therapy plus scIL-2 (scIL-2 group) or antiretroviral therapy alone (control group). scIL-2 was administered at one of three doses for at least 24 weeks. The main measure of treatment efficacy was change in CD4 cell count. Results: The time-weighted mean change in CD4 cell count from baseline to week 24 was + 252 x 106/l for the scIL-2 group compared with + 42 x 106/l for the control group (P< 0.0001). Changes in plasma HIV RNA were not significantly different between the groups over the same time period: there was a 0.83 log10 copies/ml decrease for the sclL-2 group and a 0.70 log copies/ml decrease for the control group (P = 0.362). Conclusions: This study provides the most extensive experience of sclL-2 therapy in HIV-1 infected women and Asians, and demonstrates the immunological efficacy, tolerability and feasability of sclL-2 therapy in this population. Data from this study were instrumental in guiding the selection of the sclL-2 dosing regimen for ongoing phase III trials. (C) 2000 Lippincott Williams and Wilkins. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 3/107 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2000301145 Autoren: Emery S; Capra WB; Cooper DA; Mitsuyasu RT; Kovacs JA; Vig P; Smolskis M; Saravolatz LD; Clifford Lane H; Fyfe GA; Curtin PT Titel: Pooled analysis of 3 randomized, controlled trials of interleukin-2 therapy in adult human immunodeficiency virus type 1 disease Source: Journal of Infectious Diseases; VOL: 182 (2); p. 428-434 /2000/ DOI: 10.1086/315736 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0022-1899 CO: JIDIA Institution: Emery S, Dr., Natl. Ctr. HIV Epidemiol./Clin. Res., 376 Victoria St., Sydney, NSW 2010, Australia, [email protected] COU: Australia DT: Journal Article JSC: E.5 ... Clinical Microbiology; B.2 ... Public Health RN: 0044 AB: We collected human immunodeficiency virus (HIV) disease progression, survival, most recent CD4 cell count, and plasma HIV RNA levels from patients (n = 157) who participated in randomized clinical trials of interleukin (IL)-2 that commenced before 1995. Data were available for 155 (99%) patients. Statistical analyses were based on the intention-to-treat principle. Median follow- up was 28 months and 30 months for control and IL-2 patients, respectively. Twenty-five (16%) patients developed AIDS or died during follow-up (16 control patients vs. 9 IL-2 patients; R² = 0.57; P = .22). Mean change from baseline CD4 cell count was significantly higher in patients randomized to receive IL-2 (368 vs. 153 cells/ mu L; P = .003). Mean change from baseline plasma HIV RNA was significantly lower in patients randomized to receive IL-2 (-0.98 vs. -0.63 log copies/mL; P = .004). Significant improvements in CD4 cell count and plasma HIV RNA in recipients of IL-2 relative to control patients were associated with a nonsignificant trend toward improved clinical outcome. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 3/108 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2000253745 Autoren: Davey RT; Murphy RL; Graziano FM; Boswell SL; Pavia AT; Cancio M; Nadler JP; Chaitt DG; Dewar RL; Sahner DK; Duliege A- M; Capra WB; Leong W-P; Giedlin MA; Lane HC; Kahn JO Titel: Immunologic and virologic effects of subcutaneous interleukin 2 in combination with antiretroviral therapy: A randomized controlled trial Source: Journal of the American Medical Association; VOL: 284 (2); p. 183-189 /20000712/ SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0098-7484 CO: JAMAA Institution: Davey Jr. RT, Dr., Bldg 10, National Institutes of Health, Bethesda, MD 20892-1880, United States, [email protected] COU: United States DT: Journal Article JSC: C.0 ... Clinical Medicine RN: 0026 AB: Context. While interleukin 2 (lL-2) is capable of inducing a marked expansion of the CD4 T-lymphocyte pool, limited data exist on whether lL-2 treatment can add significantly to the immunologic and virologic effects of potent antiretroviral therapy (ART). Objective. To determine the rate and magnitude of CD4 cell recovery and viral suppression when using a combination therapy of lL- 2 and ART compared with ART alone. Design and Setting. Randomized, controlled multicenter trial conducted from April 1996 through April 1998 at 8 clinical sites in the United States. Patients. Eighty-two adult outpatients who were infected with human immunodeficiency virus (HIV) and had baseline CD4 cell counts of 200 x 106/L to 500 x 106/L and baseline RNA levels of fewer than 10000 copies/mL were randomized; 78 completed the study. Interventions. Thirty-nine patients were randomly assigned to receive a combination therapy of subcutaneous lL-2 (administered in 5-day courses every 8 weeks at a starting dosage of 7.5 mlU twice per day) and ART; 43 were to receive ART therapy alone. Main Outcome Measures. Interleukin 2 safety and differential effects on CD4 cell counts, CD4 cell percentages, and plasma HIV RNA levels. Results. The mean (SD) percentage increase in CD4 cell counts at 1 year for patients who received lL-2 was 112% (113%) compared with 18% (35%) in recipients of ART alone (P<.001). Both groups had mean (SD) increases in CD4 cell percentage: from 20.4% (6.3%) to 32.3% (12.4%) for the combination therapy group compared with 20.4% (5.1%) to 23.0% (7.2%) for recipients of ART alone (P<.001). Using a sensitive viral RNA assay, mean viral load changes were -0.28 and 0.09 log10 copies for lL-2 recipients and control patients, respectively (P=.03). Twenty (67%) of 30 evaluable patients receiving lL-2 achieved final viral loads of fewer than 50 copies/mL compared with 13 (36%) of 36 control patients (P=.02). Toxic effects were common among patients who received lL-2 and were managed with antipyretics, hydration, rest, and dosage reduction as needed. Conclusions. Intermittent therapy with lL-2 and ART produced a substantially greater increase in CD4 cells and was associated with a larger decrease in viral load than ART alone. Clinical end- point trials will be necessary to determine whether the enhanced viral suppression and CD4 cell increases associated with lL-2 therapy will translate into improved clinical outcomes. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 3/109 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2000252477 Autoren: Sabbaj S; Mulligan MJ; Hsieh R-H; Belshe RB; McGhee JR; Schwartz D; Burke D; Gorse GJ; Frey S; Mestecky J; Jackson S; Gnann JW; Goepfert PA; Dolin R; Keefer MC; Evans TG; McElrath MJ; Corey L; Graham BS; Wright P; Spearman P; Matthews T; Montefiori D; Weinhold K; Bolognesi D; Allen M; Savarese B Titel: Cytokine profiles in seronegative volunteers immunized with a recombinant canarypox and gp120 prime-boost HIV-1 vaccine Source: AIDS; VOL: 14 (10); p. 1365-1374 /2000/ DOI: 10.1097/00002030-200007070-00009 SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 CO: AIDSE Institution: Mulligan MJ, Dr., Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, 845 19th Street South, Birmingham, AL 35294-2170, United States COU: United States DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0045 AB: Objectives: To study memory T cell proliferative responses and cytokine profiles induced in HIV-1 seronegative volunteers immunized with a live recombinant canarypox vector expressing HIV-1 antigens (ALVAC-HIV) and boosted with a recombinant gp120 . Design: HIV-specific T cell proliferative responses and cytokines were measured 2 weeks after vaccination. Cytokines secreted by T helper 1 cells (Th1) [interleukin (IL)-2 and interferon- gamma (IFN- gamma )] and T helper 2 (Th2) cells (IL-4, IL-5, IL-6, and IL-10) were assessed both at the mRNA and the protein level. Methods: Peripheral blood mononuclear cells (PBMC) were stimulated in vitro with HIV antigens. Subsequently, T cell proliferation was measured in a standard lymphoproliferation assay; secreted cytokines were measured using an enzyme-linked immunosorbent assay and upregulation of cytokine mRNA was measured using reverse transcriptase polymerase chain reaction. Results: All individuals who had received ALVAC-HIV followed by the protein vaccine exhibited HIV-1-specific T cell proliferative responses. Moreover, the PBMC of all prime-boost vaccinated individuals produced detectable IFN- gamma and IL-10 in response to stimulation with HIV-1 envelope glycoprotein antigens; 83% also had detectable levels of IL-2 and IL-6, 71% had detectable levels of IL-4, and 86% had detectable levels of IL-5. Conclusions: These data indicate that this vaccination regimen was inducing both Th1- and Th2-type responses to HIV-1 envelope antigens. This prime-boost vaccination approach elicited T cell help for the generation of cytotoxic T lymphocyte responses as well as help for antibody production and so promises to generate a broad HIV-1-specific immune response. (C) 2000 Lippincott Williams and Wilkins. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 3/110 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2000205692 Autoren: Piconi S; Trabattoni D; Fusi ML; Milazzo F; Dix LP; Rizzardini G; Colombo F; Bray D; Clerici M Titel: Effect of two different combinations of antiretrovirals (AZT+ddI and AZT+3TC) on cytokine production and apoptosis in asymptomatic HIV infection Source: Antiviral Research; VOL: 46 (3); p. 171-179 /20000601/ DOI: 10.1016/S0166-3542(00)00076-0 SU: EMBASE Sprache: English AL: English CY: Netherlands ISSN: 0166-3542 CO: ARSRD PII: S0166354200000760 Institution: Clerici M, Cattedra Immunologia, Universita di Milano, DISP LITA Vialba, Via G.B. Grassi 74, 20154 Milano, Italy, [email protected] COU: Italy DT: Journal Article JSC: A.1 ... Pharmacology & Drug Therapy; E.5.3 ... Virology RN: 0028 AB: Nineteen HIV-seropositive antiretroviral therapy-naive and asymptomatic individuals (200-500 CD4/ mu l) were enrolled in a prospective study aimed at analyzing the immunologic and virologic effects of two different combinations of nucleoside reverse transcriptase inhibitors (AZT+ddI and AZT+3TC), and randomly assigned to one of the treatment group. Immunologic (CD4 and CD8 counts, mitogen-stimulated cytokine production, unstimulated and mitogen-stimulated apoptosis) and virologic (HIV viral load) determinations were performed pre-therapy and 15, 30, 90, 200 and 360 days after initiation of therapy. Results showed that the two combinations had comparable effects on increasing CD4 counts and the CD4/CD8 ratio and in reducing HIV viral load. In contrast, AZT+3TC was more efficient in improving interleukin-2 (IL-2) and interferon gamma (IFN gamma ) production as well as the type 1/type 2 cytokine ratio and in down modulating the susceptibility of peripheral blood mononuclear cells to in vitro mitogen- stimulated apoptotic cell death. These data suggest that the combination of AZT+3TC has a stronger effect on potentially beneficial immune parameters (IL-2 production; reduction of apoptosis) than the one between AZT+ddI. The combination of AZT+3TC could be more advantageous in the therapy of HIV infection even when used in association with a protease inhibitor. Copyright (C) 2000 Elsevier Science B.V. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 3/111 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2000175636 Autoren: Amendola A; Poccia F; Martini F; Gioia C; Galati V; Pierdominici M; Marziali M; Pandolfi F; Colizzi V; Piacentini M; Girardi E; D'Offizi G Titel: Decreased CD95 expression on naive T cells from HIV-infected persons undergoing highly active anti- retroviral therapy (HAART) and the influence of IL-2 low dose administration Source: Clinical and Experimental Immunology; VOL: 120 (2); p. 324-332 /2000/ DOI: 10.1046/j.1365-2249.2000.01223.x SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0009-9104 CO: CEXIA Institution: D'Offizi G, 4a Divisione Clinica, Istituto per le Malattie Infettive, I.R.C.C.S. 'L. Spallanzani', Via Portuense 292, 00149 Rome, Italy, [email protected] COU: Italy DT: Journal Article JSC: E.4 ... Immunology & Serology RN: 0046 AB: The functional recovery of the immune system in HIV-infected persons receiving HAART and the role of adjuvant immune therapy are still matters of intensive investigation. We analysed the effects of HAART combined with cytokines in 22 naive asymptomatic individuals, randomized to receive HAART (n = 6), HAART plus a low dose (1000 000 U/daily) of rIL-2 (n = 8), and HAART plus rIL-2 after previous administration of granulocyte colony-stimulating factor (n = 8). After 3 months of therapy, increased CD4+ T cell counts and diminished viral loads were observed in all patients, independently of cytokine addition. A decreased expression of CD95 (Apo l/Fas) was evident in all groups when compared with values before therapy. The percentages of peripheral blood mononuclear cells (PBMC) expressing CD95 after therapy decreased by 15%, 22% and 18% in the three treatment groups, respectively (P < 0.05). Analysis of PBMC subsets demonstrated that CD95 expression was significantly reduced on CD45RA+ CD62L+ naive T cells (25.3%, 22.4%, and 18.6%, respectively; P < 0.05) in each group, after therapy. Accordingly, all patients showed a reduced rate of in vitro spontaneous apoptosis (P < 0.05). Another effect induced by HAART was a significant increase in IL2R alpha expression on total PBMC (P < 0.05), independently of cytokine addition. Altogether, our results suggest that very low dose administration of rIL-2 (1000 000 U/daily) may be not enough to induce a significant improvement in the immune system as regards HAART alone. The employment of higher doses of recombinant cytokines and/or different administration protocols in clinical trials might however contribute to ameliorate the immune reconstitution in patients undergoing HAART. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 3/112 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2000104981 Autoren: Dianzani F; Antonelli G; Aiuti F; Turriziani O; Riva E; Capobianchi MR; Pandolfi F; D'Offizi G Titel: The number of HIV DNA-infected mononuclear cells is reduced under HAART plus recombinant IL-2 Source: Antiviral Research; VOL: 45 (2); p. 95-99 /2000/ DOI: 10.1016/S0166-3542(99)00080-7 SU: EMBASE Sprache: English AL: English CY: Netherlands ISSN: 0166-3542 CO: ARSRD PII: S0166354299000807 Institution: Dianzani F, Institute of Virology, University La Sapienza, Viale di Porta Tiburtina 28, 00185 Rome, Italy, [email protected] COU: Italy DT: Journal Article JSC: A.1 ... Pharmacology & Drug Therapy; E.5.3 ... Virology RN: 0022 AB: It is common opinion that, in addition to potent antiretroviral regimens which effectively reduce plasma viremia, new strategies should be developed to ensure the reduction of cell-associated HIV DNA load together with HIV RNA plasma levels. The present study explored whether the number of provirus-infected cells can be reduced by combined antiviral and immunomodulatory regimens. Thus, 14 naive patients (with CD4 >400/ mu l and plasma HIV RNA copies>5000/ml) were randomly assigned to receive highly active antiretroviral therapy (HAART) alone or HAART plus rIL-2. Plasma viremia (measured by a commercial RT-PCR assay) and the number of provirus-infected cells (measured by an endpoint cell dilution PCR assay) were monitored at the enrollment and after 12 weeks of treatment. The results indicate that while HAART and HAART plus rIL-2 are both able to significantly reduce plasma viremia after 12 weeks of treatment, a significant reduction of the number of provirus-infected cells can be achieved only by treatment with HAART plus rIL-2. Copyright (C) 2000 Elsevier Science B.V. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 3/113 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2000095752 Autoren: Pandolfi F; Pierdominici M; Marziali M; Livia Bernardi M; Antonelli G; Galati V; D'Offizi G; Aiuti F Titel: Low-dose IL-2 reduces lymphocyte apoptosis and increases naive CD4 cells in HIV-1 patients treated with HAART Source: Clinical Immunology; VOL: 94 (3); p. 153-159 /200003/ DOI: 10.1006/clim.2000.4837 SU: EMBASE Sprache: English AL: English CY: United States ISSN: 1521-6616 CO: CLIIF Institution: Aiuti F, Department of Clinical Medicine, University of Rome 'La Sapienza', Viale dell'Universita' n. 37, 00185 Rome, Italy, [email protected] COU: Italy DT: Journal Article JSC: C.11 ... Clinical Pathology; E.4.1 ... Allergy & Clinical Immunology RN: 0038 AB: During HIV disease an increased in vitro apoptosis of peripheral blood mononuclear cells has been demonstrated. This can be reversed in vitro by interleukin (IL)-2. Recent trials with highly active antiretroviral therapy (HAART) and IL-2 in HIV-1-infected patients showed promising immunological and clinical results. Here we investigated the effects of subcutaneous low- dose IL-2 administration in combination with HAART on in vitro apoptosis and the relationship between apoptosis, CD4+ counts, and HIV replication. Twenty-two asymptomatic HIV patients were randomized for HAART (arm I) and HAART plus IL-2 (arm II). Spontaneous apoptosis was decreased in both arms after 28 weeks of therapy but the reduction was highly significant only in arm II (P = 0.05 vs P = 0.001). As the percentage of apoptosis decreased, there was a significantly higher increase of both CD4+ and CD4+ naive T cells in arm II vs arm I. HIV plasma viremia was reduced in all patients after therapy. Our data suggest that intermittent therapy with low-dose subcutaneous IL-2 in addition to HAART induces a positive immunomodulation in asymptomatic HIV-infected patients. (C) 2000 Academic Press. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 3/114 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EM2000050433 Autoren: Berneis K; Battegay M; Bassetti S; Nuesch R; Leisibach A; Bilz S; Keller U Titel: Nutritional supplements combined with dietary counselling diminish whole body protein catabolism in HIV- infected patients Source: European Journal of Clinical Investigation; VOL: 30 (1); p. 87-94 /2000/ DOI: 10.1046/j.1365-2362.2000.00591.x SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0014-2972 CO: EJCIB Institution: Keller U, Department of Internal Medicine, Div. Endocrinol. Diabet. Clin. Nutr., University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland, [email protected] COU: Switzerland DT: Journal Article JSC: C.0 ... Clinical Medicine RN: 0036 AB: Background. Weight loss and protein malnutrition are frequent complications in HIV-infected patients. The effect of an oral nutritional supplement combined with nutritional counselling on whole body protein metabolism was assessed. Materials and methods. HIV-infected individuals with a body mass index < 21 kg m-2 or CD4-T cells < 500 mu L-1 in stable clinical condition were randomly allocated to [1] receive either oral nutritional supplements (containing 2510 kJ, complete macro- and micronutrients) and dietary counselling (n = 8), or [2] identical monitoring but no supplements or specific nutritional advice (controls, n = 7). Whole body leucine kinetics and leucine oxidation rate were determined by [l-¹³C]-leucine infusions and lean and fat mass were measured before and 12 weeks after intervention. Results. Leucine oxidation (protein catabolism) decreased in the group receiving nutritional intervention from 0.33 ± 0.02 to 0.26 ± 0.02 mu mol kg-1 min-1 after 12 weeks (P < 0.05; P < 0.05 vs. control group) but remained unchanged in the control group. Whole body leucine flux showed a tendency to decrease in the intervention group from 1.92 ± 0.19 to 1.73 ± 0.14 mu mol kg-1 min-1 (P = 0.07) and remained unchanged in the control group (2.21 ± 0.16 and 2.27 ± 0.14 mu mol kg-1 min-1, respectively). Lean body mass determined by bioelectrical impedance analysis increased in the nutritional intervention group from 84 ± 2 to 86 ± 2 per cent (P < 0.05) and fat mass decreased from 17 ± 2 to 14 ± 2 per cent (P < 0.05) of total body weight whereas neither mass changed in the control group. Nutritional intervention had no significant effect on lymphocyte CD4 counts, on plasma TNFR 55, TNFR 75 and ILR 2 concentrations and on quality of life. Conclusions. The data demonstrate an anticatabolic effect of nutritional supplements combined with dietary counselling in HIV-infected subjects. They suggest that diminished whole body protein catabolism resulted in a change of body composition (increased lean mass, decreased fat mass). CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 3/115 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EMM14523786 PMID: 14523786 Autoren: Markowitz N; Bebchuk JD; Abrams DI Titel: Nadir CD4+ T cell count predicts response to subcutaneous recombinant interleukin-2. Source: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America; VOL: 37 (8); p. e115-120 /15 Oct 2003/ SU: Medline Sprache: English AL: English CY: United States EISSN: 1537-6591 Institution: Markowitz N, Division of Infectious Diseases, Henry Ford Hospital, Detroit, Michigan 48202, USA., [email protected] DT: Journal Article JSC: E.5 ... Clinical Microbiology AB: Community Program for Clinical Research on AIDS 059 was a multicenter study conducted among human immunodeficiency virus (HIV)-infected individuals with CD4+ cell counts > or =300 cells/mm3 who were randomly assigned to receive antiretroviral therapy with or without intermittent subcutaneously administered recombinant interleukin-2 (rIL-2). To identify factors associated with a response to IL-2, a secondary analysis was performed that included the subset of rIL-2 recipients who were able to complete all 3 initial treatment cycles. Predictors of a change in CD4+ cell count between baseline and 1 month after the start of treatment cycle 3 were examined in a multivariate model that included sex, race, body surface area, rIL-2 dose, HIV load, and both baseline and nadir CD4+ cell count. The combination of race and sex (P=.027) and the nadir CD4+ cell count (P=.005) were significant predictors of mean CD4+ cell count response. Baseline CD4+ cell count had no significant effect. The strong association between nadir CD4+ cell count and CD4+ cell count response suggests that immunologic losses resulting from HIV-mediated CD4+ cell depletion may be irreversible. CNOTE: MEDLINE® is the source for the citation and abstract of this record.

» Volltext-Angebot » 3/116 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EMM12015902 PMID: 12015902 Autoren: Fortis C; Soldini L; Ghezzi S; Colombo S; Tambussi G; Vicenzi E; Gianotti N; Nozza S; Veglia F; Murone M; Lazzarin A; Poli G Titel: Tumor necrosis factor alpha, interleukin 2, and soluble interleukin 2 receptor levels in human immunodeficiency virus type 1-infected individuals receiving intermittent cycles of interleukin 2. Source: AIDS research and human retroviruses; VOL: 18 (7); p. 491-499 /1 May 2002/ SU: Medline Sprache: English AL: English CY: United States ISSN: 0889-2229 Institution: Fortis C, Division of Infectious Diseases, San Raffaele Scientific Institute, 20127 Milan, Italy., [email protected] DT: Journal Article JSC: E.4 ... Immunology & Serology; E.5.3 ... Virology AB: HIV-infected individuals with 200-500 CD4(+) T cell/microl were enrolled in a controlled study of three interleukin 2 (IL-2) plus antiretroviral therapy (ART) regimens: (1) continuous intravenous administration of 12 million international units (MIU) of IL-2 followed by subcutaneous high-dose IL-2 (7.5 MIU, twice daily) for 5 days every 8 weeks; (2) high-dose subcutaneous IL-2 for 5 days every 8 weeks; (3) low-dose (3 MIU, twice daily) subcutaneous IL-2 for 5 days every 4 weeks; and (4) ART alone. Serum concentrations of IL-2, soluble IL-2 receptor (sIL-2R), tumor necrosis factor alpha (TNF-alpha), and IL-6 were determined. A progressive decrease over time of the circulating levels of IL-2 was observed in individuals receiving the highest doses of IL-2, but not in those belonging to the low-dose arm. Conversely, increased levels of sIL-2R were observed in all cytokine-treated individuals. The levels of TNF-alpha increased in the high-dose IL-2 regimens, but decreased in individuals receiving low-dose IL-2. IL-2- related toxicity was significantly correlated to the peak IL-2 serum levels, and was substantially lower in those individuals receiving low-dose IL-2. In conclusion, intermittent IL-2 administration causes the elevation of peripheral CD4(+) T cells, but also a profound cytokine response and systemic toxicity. The latter was correlated to the peak serum level of IL-2, but not to those of TNF-alpha and IL-6. CNOTE: MEDLINE® is the source for the citation and abstract of this record.

» Volltext-Angebot » 3/117 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EMM11514956 PMID: 11514956 Autoren: Caggiari L; Zanussi S; Crepaldi C; Bortolin MT; Caffau C; D'Andrea M; De Paoli P Titel: Different rates of CD4+ and CD8+ T-cell proliferation in interleukin-2-treated human immunodeficiency virus- positive subjects. Source: Cytometry; VOL: 46 (4); p. 233-237 /15 Aug 2001/ SU: Medline Sprache: English AL: English CY: United States ISSN: 0196-4763 Institution: Caggiari L, Division of Microbiology, Immunology and Virology, Centro di Riferimento Oncologico, IRCCS, 33081 Aviano, Italy. DT: Journal Article JSC: C.1.5 ... Hematology AB: BACKGROUND: Interleukin-2 (IL-2) has been used successfully to increase CD4 cell counts in patients who are human immunodeficiency virus (HIV) positive. The mechanisms involved in this phenomenon are unknown. We hypothesized that a differential proliferation rate of CD4+ compared with CD8+ lymphocytes could be related to the increase of CD4 counts and of CD4/CD8 ratios that occur in HIV+ patients during IL-2 treatment. METHODS: We enrolled in our study 14 HIV+ patients treated with IL-2 or with highly active antiretroviral therapy (HAART) during a 96-week observation period. Using flow cytometry, we measured longitudinally the expression of the Ki67 antigen in peripheral blood CD4+ and CD8+ lymphocyte subsets. RESULTS: Compared with HAART alone, IL-2 produced a rapid increase of Ki67+ proliferating CD4 cells and a concomitant increase of the CD4/CD8 ratios, whereas the corresponding CD8 proliferation increased slightly. On the contrary, HAART alone was effective in suppressing equally both CD4 and CD8 proliferation. CONCLUSIONS: Our results suggest a selective activity of IL-2 on CD4 T- cell proliferation; on the contrary, CD8-specific proliferation is affected minimally during treatment. This information may offer the potential to plan correctly immune activating regimens. Copyright 2001 Wiley-Liss, Inc. CNOTE: MEDLINE® is the source for the citation and abstract of this record.

» Volltext-Angebot » 3/118 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EMM11430457 PMID: 11430457 Autoren: Abrams D Titel: Benefit of IL-2 therapy in HIV patients confirmed. Source: American family physician; VOL: 63 (12); p. 2424 /15 Jun 2001/ SU: Medline Sprache: English CY: United States ISSN: 0002-838X Institution: Abrams D, University of California, San Francisco, USA. DT: Journal Article JSC: C.0 ... Clinical Medicine AU: Abrams D Abrams D University of California, San Francisco, USA. CNOTE: MEDLINE® is the source for the citation and abstract of this record.

» Volltext-Angebot » 3/119 von 127 DIMDI: EMBASE (EM00) © 2010 Elsevier B.V. ND: EMM11590500 PMID: 11590500 Autoren: Lalezari JP; Beal JA; Ruane PJ; Cohen CJ; Jacobson EL; Sundin D; Leong WP; Raffanti SP; Wheeler DA; Anderson RD; Keiser P; Schrader SR; Goodgame JC; Steinhart CR; Murphy RL; Wolin MJ; Smith KA Titel: Low-dose daily subcutaneous interleukin-2 in combination with highly active antiretroviral therapy in HIV+ patients: a randomized controlled trial. Source: HIV clinical trials; VOL: 1 (3); p. 1-15 /2000 Nov-Dec/ SU: Medline Sprache: English AL: English CY: United States ISSN: 1528-4336 Institution: Lalezari JP, Quest Clinical Research, San Francisco, CA, USA. DT: Journal Article JSC: E.5.3 ... Virology AB: PURPOSE: Previous studies with intermittent interleukin-2 (IL-2) therapy using intermediate and high levels of IL-2 have demonstrated significant increases in the CD4 + T cell count in HIV-infected patients. Intermittent regimens are amenable to outpatient use, but severe adverse events are frequently experienced with intermediate- and high-dose levels of IL-2. Therefore in this study, the effect of daily, subcutaneous low-dose IL-2 therapy on safety and immunological endpoints was investigated to determine whether immunological benefit could be achieved without toxicity in HIV-infected patients also receiving highly active antiretroviral therapy (HAART). METHOD: A total of 115 patients were enrolled in the trial. Fifty-six asymptomatic HIV-infected patients who had CD4 + T cell counts less than 300 cells/microL at screening and a stable HIV viral load received low-dose IL-2 (1.2 million IU [MIU]/m 2 beginning dose) once daily in conjunction with HAART (IL-2 group). Fifty-nine patients received HAART alone (control group). RESULTS: A dramatic effect of IL-2 on the natural killer (NK) cell population was observed with mean increases of 156 cells/microL in the IL-2 group compared to 19.93 cells/microL in the control group (p <.001). Additionally, IL-2-treated patients experienced a statistically significant increase in the mean percentage of CD4 + T cells (3.52% increase) when compared to control patients (1.33% increase) (p <.001). The expanded CD4 + T cell population was primarily of the naive phenotype, with mean increases of 4.53% for the IL-2 group and 0.31% for the control group (p <.001 for between-group difference). In addition, a higher proportion of IL-2-treated patients (67%) compared to control patients (33%) achieved increases of greater than 50% in the CD4+ T cell count (p =.08). Adverse events of grade 3 or grade 4 toxicity were infrequent in the current study and were substantially lower by comparison to those in studies of intermittent dose IL-2 therapy. Also, negligible changes in the HIV viral load from baseline to final measurement were observed in both groups. A trend toward a reduced number of modifications of antiretroviral therapy was apparent in the IL-2 group when compared to control patients. CONCLUSION: Daily, low-dose subcutaneous IL-2 therapy in conjunction with HAART is safe and well tolerated and is effective in expanding lymphocyte cell types including NK cells and naive T cells in individuals who have <300 CD4+ T cells. CNOTE: MEDLINE® is the source for the citation and abstract of this record.

» Volltext-Angebot » 3/120 von 127 DIMDI: EMBASE (EM47) © 2010 Elsevier B.V. ND: EMM10726142 PMID: 10726142 Autoren: Moser-Junemann C; Jager H Titel: HIV: Interleukin-2 stutzt Immunsystem. HIV: interleukin 2 supports the immune system Source: MMW Fortschritte der Medizin; VOL: 141 (49-50); p. 24 /9 Dec 1999/ SU: Medline Sprache: German CY: Germany ISSN: 1438-3276 Institution: Moser-Junemann C, DT: Journal Article Keywords CNOTE: MEDLINE® is the source for the citation and abstract of this record.

» Volltext-Angebot » 3/121 von 127 DIMDI: EMBASE (EM47) © 2010 Elsevier B.V. ND: EMM10609454 PMID: 10609454 Autoren: Romanelli F Titel: Interleukin-2 for the management of HIV infection. Source: Journal of the American Pharmaceutical Association (Washington,D.C. : 1996); VOL: 39 (6); p. 867-868 /1999 Nov-Dec/ SU: Medline Sprache: English CY: United States ISSN: 1086-5802 Institution: Romanelli F, College of Pharmacy, University of Kentucky, Lexington, USA. DT: Review; Journal Article RN: 0025 AU: Romanelli F CNOTE: MEDLINE® is the source for the citation and abstract of this record.

» Volltext-Angebot » 3/122 von 127 DIMDI: EMBASE (EM47) © 2010 Elsevier B.V. ND: EMM09683118 PMID: 9683118 Autoren: Grady C; Anderson R; Chase GA Titel: Fatigue in HIV-infected men receiving investigational interleukin-2. Source: Nursing research; VOL: 47 (4); p. 227-234 /1998 Jul-Aug/ SU: Medline Sprache: English AL: English CY: United States ISSN: 0029-6562 Institution: Grady C, Clinical Therapeutics Laboratory, National Institute of Nursing Research, National Institutes of Health, Bethesda, MD, USA., [email protected] DT: Journal Article JSC: B.5 ... Nursing AB: BACKGROUND: Although fatigue is an almost universal clinical complaint of people with human immunodeficiency virus (HIV) infection, little has been done to study systematically the etiology, frequency, severity, response to, or management of HIV-related fatigue. In addition, HIV-related treatments may contribute to fatigue. OBJECTIVES: To describe the extent and severity of perceived fatigue in a cohort of HIV-infected men (N= 50) who, as participants in a randomized clinical trial, were randomized to receive or not to receive investigational interleukin-2 (IL-2). METHOD: A modified Piper Fatigue Scale was used to measure fatigue at baseline, at the end of 5 days of IL-2 therapy, 1 week later at home, and 1 month later for three consecutive cycles of IL-2 therapy. RESULTS: Against a variable background of baseline fatigue in all subjects, those receiving IL-2 reported a significant increase in their level of fatigue after receiving IL-2. Fatigue levels remained elevated 1 week later but returned to baseline by 1 month. Fatigue was related to the dose of IL-2 but not to the reported amount or quality of sleep. CONCLUSIONS: Against a background of fatigue related to HIV infection and its multiple manifestations and treatments, therapy with IL-2 dramatically increases the experience of fatigue. Although this increase is transient and tends to return to baseline by 1 month, during that month the patient's life function and quality may be severely affected. CNOTE: MEDLINE® is the source for the citation and abstract of this record.

» Volltext-Angebot » 3/123 von 127 DIMDI: EMBASE (EM47) © 2010 Elsevier B.V. ND: EMM11322258 PMID: 11322258 Autoren: Staszewski S; Miller V; Kober A; Colebunders R; Vandercam B; Delescluse J; Clumeck N; Van Wanzeele F; De Brabander M; De Cree J; Moeremans M; Andries K; Boucher C; Stoffels P; Janssen PA Titel: Evaluation of the efficacy and tolerance of R 018893, R 089439 (loviride) and placebo in asymptomatic HIV-1- infected patients. Loviride Collaborative Study Group. Source: Antiviral therapy; VOL: 1 (1); p. 42-50 /Jan 1996/ SU: Medline Sprache: English CY: United Kingdom ISSN: 1359-6535 Institution: Staszewski S, Johann Wolfgang Goethe Universitat, Frankfurt, Germany. DT: Journal Article JSC: A.1 ... Pharmacology & Drug Therapy Miller V Johann Wolfgang Goethe Universitat, Frankfurt, Germany. AU: Kober A Kober A Johann Wolfgang Goethe Universitat, Frankfurt, Germany. AU: Colebunders R CNOTE: MEDLINE® is the source for the citation and abstract of this record.

» Volltext-Angebot » 3/124 von 127 DIMDI: EMBASE (EM47) © 2010 Elsevier B.V. ND: EM1994105357 Autoren: McMahon DK; Armstrong JA; Huang X-L; Rinaldo CR Jr.; Gupta P; Whiteside TL; Pazin GJ; Tripoli C; Ho M Titel: A phase I study of subcutaneous recombinant interleukin-2 in patients with advanced HIV disease while on zidovudine Source: AIDS; VOL: 8 (1); p. 59-66 /199401/ SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 CO: AIDSE Institution: Ho M, Dr., A427 Crabtree Hall, University of Pittsburgh, Pittsburgh, PA 15261, United States COU: United States DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology RN: 0021 AB: Objective: A Phase I study of subcutaneous recombinant interleukin-2 (rIL-2). Design: Sixteen patients with advanced HIV infection receiving 600-1200 mg zidovudine per day were divided into three groups, which received sequentially 0.2 x 106, 0.7 x 106 or 2 x 106 units/m² per day of rIL-2 subcutaneously for 5 consecutive days. Setting: Five-day admission to an academic tertiary care hospital. Patients, participants: Sixteen unblinded, non-randomized volunteers. Interventions: Subcutaneous rIL-2. Main outcome measures: Tolerance, toxicity, hematologic, immunologic and antiviral responses. Results: rIL-2 was well-tolerated at the highest dosage, except in two patients who developed significant lymphopenia by the second day of rIL-2 administration, with rebound within 48 h after rIL-2 therapy. The number of eosinophils, CD4+ and CD8+ cells, and percentage of CD16+ (natural killer) cells, remained elevated above baseline for up to 10 weeks. Circulating rIL-2 receptor levels increased transiently during and immediately following rIL-2 administration. A twofold increase in natural killer cell activity against uninfected and HIV-infected targets was observed, but did not persist beyond 10 weeks following rIL-2 administration. There was a transient decrease in blastogenesis to phytohemagglutinin of patients receiving the highest dose of r-IL-2, but no significant change in viral burden. Conclusions: Subcutaneous rIL-2 in advanced HIV-infected patients on zidovudine was tolerated with side-effects similar to intravenous IL-2. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 3/125 von 127 DIMDI: EMBASE (EM47) © 2010 Elsevier B.V. ND: EM1992205070 Autoren: Oliver RTD; Nouri AME Titel: T cell immune response to cancer in humans and its relevance for immunodiagnosis and therapy Source: Cancer Surveys; VOL: 13; p. 173-204 /1992/ SU: EMBASE Sprache: English AL: English CY: United States ISSN: 0261-2429 CO: CASUD Institution: Oliver RTD, Department of Medical Oncology, Royal London Hospital, Medical College, Turner Street, London E1 2AD, United Kingdom COU: United Kingdom DT: Review; Journal Article JSC: C.1.3.1 ... Clinical Oncology AB: Review of the relationship between the degree of immunosuppression and malignancy in patients on immunosuppressive drugs or immunosuppressed by HIV infection, postoperative blood transfusion or pregnancy provides the most convincing evidence of the importance of intact T cell immunity in resistance to cancer. Defective HLA class I and II antigen expression on tumours arising in non-immunosuppressed individuals and correlation of these changes with increased malignancy and diminished TIL provide the most convincing evidence that one factor necessary to ensure survival of most spontaneous tumours is mutation that enables tumour cells to escape rejection by cytotoxic T cells. These changes are less frequent in tumours in immunosuppressed patients, and preliminary data suggest that use of cytokine therapy is more successful in these tumours and the one in five spontaneous tumours demonstrating normal expression of HLA antigens and high levels of T cell infiltration. These observations suggest that future use of this therapy should be focused on these cases. All modalities of cancer therapy except hormone therapy (ie surgery, radiotherapy and chemotherapy) suppress immune responses. Defects of HLA antigen expression are less marked in early cancer. Combinations of immunotherapy with conventional treatment at presentation, including hormone therapy in view of data demonstrating regeneration of the thymus after castration, needs further investigation. Preliminary results from randomized trials involving nearly 300 individuals accidentally exposed to carcinogens demonstrated nearly 60% reduction of incidence of malignancy at 5 years in the arm receiving non-specific immunotherapy. If confirmed, such an approach might be more cost-effective as an approach for cancer prevention than organ specific cancer screening or vaccination against cancer associated viruses such as hepatitis B or papillomaviruses. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 3/126 von 127 DIMDI: EMBASE (EM47) © 2010 Elsevier B.V. ND: EM1991252257 Autoren: Garber GE; Cameron DW; Hawley-Foss N; Greenway D; Shannon ME Titel: The use of ozone-treated blood in the therapy of HIV infection and immune disease: A pilot study of safety and efficiacy Source: AIDS; VOL: 5 (8); p. 981-984 /1991/ SU: EMBASE Sprache: English AL: English CY: United Kingdom ISSN: 0269-9370 CO: AIDSE Institution: Garber GE, Dr., Divis of Infectious Diseases, Ottowa General Hospital, 501 Smyth Road, Ottawa, Ont. K1H 8L6, Canada COU: Canada DT: Journal Article JSC: E.5.3 ... Virology; E.4.1 ... Allergy & Clinical Immunology AB: The use of ozone therapy is reported to be effective in a variety of viral illnesses, including HIV disease. We performed a phase I study of ozone blood treatments in 10 patients in whom no significant toxicity was observed. Three patients with moderate immunodeficiency showed improvement in surrogate markers of HIV-associated immune disease. A phase II controlled and randomized double-blinded study was initiated comparing reinjection of ozone-treated blood, and reinjection of unprocessed blood for 8 weeks, followed by a 4-week observation period. Ozone had no significant effect on hematologic, biochemical or clinical toxicity when compared with placebo. CD4 cell count, interleukin-2, gamma -inteferon, beta 2-microglobulin, neopterin and p24 antigen were also unaffected by both treatment arms. In conclusion, ozone therapy does not enhance parameters of immune activation nor does it diminish measureable p24 antigen in HIV-infected individuals. CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

» Volltext-Angebot » 3/127 von 127 DIMDI: EMBASE Alert (EA08) © 2010 Elsevier B.V. ND: EA2010463395 Autoren: Bosch RJ; Pollard RB; Landay A; Aga E; Fox L; Mitsuyasu R Titel: Continuing or adding IL-2 in patients treated with antiretroviral therapy (ACTG Protocol A5051, a rollover trial of ACTG Protocol A328) Source: AIDS Research and Therapy; VOL: 7 /20100805/ http://www.aidsrestherapy.com/content/7/1/30 ANR: 30 DOI: 10.1186/1742-6405-7-30 PU: BioMed Central Ltd. Sprache: English AL: English CY: United Kingdom ISSN: 1742-6405 Institution: Bosch RJ, Harvard School of Public Health, Boston MA, United States, [email protected] COU: United States DT: Journal Article RN: 0006 AB: Background: Effective antiretroviral therapy reduces HIV-1 RNA levels, improves CD4 T-cell counts, and lowers the risk of opportunistic infections and malignancies. Interleukin-2 (IL-2) has been shown to increase CD4 T-cell numbers mainly by expanding CD4 cells and by prolonging their half-lives. HIV-infected patients previously enrolled into A328 had been randomized to antiretroviral therapy (ART) alone or ART followed by IL-2. In A5051, 53 patients from A328 who had previously received IL-2 were allowed to continue IL-2 for an additional 80 weeks; 27 patients who had received ART alone received IL-2 for 80 weeks.Results: The patients previously receiving IL-2 continued to have elevated CD4 levels with extended use of IL-2. The prior ART-alone recipients had increases in CD4 levels to comparable levels as the prior IL-2 recipients (median 804 versus 847 cells/mm3 at week 72; 60% versus 9% had >50% increase in A5051 to week 72, p < 0.001). Those who had previously received IL-2 required fewer IL-2 cycles to maintain their CD4 T-cell counts compared to those newly initiating IL-2. The treatments were well tolerated with no significant differences in toxicity or discontinuations between those newly versus previously receiving IL-2. There were few clinical events observed.Conclusions: Although sustained CD4 T-cell count increases were seen with IL-2 administration as in other studies, the absence of clinical benefit in two recent randomized trials has demonstrated no apparent role for IL-2 as a therapy in HIV disease.Trial Registration: A5051 ClinicalTrials.gov Identifier: NCT00000923. © 2010 Bosch et al; licensee BioMed Central Ltd. PU: BioMed Central Ltd. 34 - 42 Cleveland Street, London, W1T 4LB, United Kingdom CNOTE: Copyright 2010 Elsevier B.V., All rights reserved.

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Anlage 2 Klinische Studien zu Aldesleukin mit Charakteristika

Surrogatmarker‐ Studie Arme offen verblindet randomisiert Endpunkte primär klinische Endpunkte n ESPRIT IL‐2 vs. IL‐2 ja ja ja 4111 SILCAAT ART+/‐ IL‐2 ja ja ja 1695 STALWART no Tx vs. ART+IL‐2 ja ja ja 267 ACTG A5051 ART+IL‐2 imm./def. ja ja ja 80 ANRS 119 INTERSTART IL‐2 vs. No IL‐2 ja ja ja 130 ANRS 123 ETOILE IL‐2 vs. ART optimization ja ja ja 56 Porter BO NIAID IL‐2 vs. IL‐2+ART in STI ja ja ja 41 VANGUARD ART+/‐ IL‐2 ja ja ja 218 TILT IL‐2 v.s no IL‐2 in STI ja ja ja 86 Smith KA (ALVAC, vCP1452) vaccine +/‐ IL‐2 in STI ja ja ja 44 Hardy GA (Remune) ART+ vaccine +/‐ IL‐2 ja ja ja 36 ACTG 328 ART +/‐ IL‐2 ja ja ja 159 / 204 PRIMOVAC‐ANRS 095 ART+vaccine+/‐ IL‐2 ja ja ja 43 ACTG A5024 ART+vaccine+/‐ IL‐2 ja ja ja 81 ACTG A5102 IL‐2 v.s no IL‐2 in STI ja ja ja 47 ANRS 093 ART +/‐ IL‐2+Vaccine ja ja ja 71 ACTG 248 ART +/‐ IL‐2 ja ja ja 115 Tavel JA NIAID ART +/‐ IL‐2 +/‐Prednison ja ja ja 10 de Boer AW (Chiron) ART +/‐ IL‐2 ja ja ja 81 ANRS 079 ART +/‐ IL‐2 ja ja ja 68 ANRS 082 ILSTIM ART +/‐ IL‐2 ja ja ja 72 Marchetti G ART +/‐ IL‐2 ja ja ja 22 HYDILE ART +/‐ HU +/‐ IL‐2 ja ja ja 69 COSMIC ART +/‐ IL‐2 ja ja ja 56 CPCRA 059 ART +/‐ IL‐2 ja ja ja 511 Dybul M NIAID ART +/‐ IL‐2 ja ja ja 9 Lafeuillade A ART +/‐ IL‐2 ja ja ja 22 Tambussi G ART +/‐ IL‐2 ja ja ja 61 Lalezari JP ART +/‐ IL‐2 ja ja ja 115 Ruxruntham K ART +/‐ IL‐2 ja ja ja 72 Losso MH ART +/‐ IL‐2 ja ja ja 73 Dianzani F IRHAN ART +/‐ IL‐2 ja ja ja 14 Pandolfi F ART +/‐ IL‐2 ja ja ja 22 ANRS 048 ART +/‐ IL‐2 iv vs‐ s.c. ja ja ja 94 Arnó A ART +/‐ IL‐2 ja ja ja 25 Davey JT NIAID ART +/‐ IL‐2 ja ja ja 49 Hengge UR ART +/‐ IL‐2 ja ja ja 44 Carr A ART +/‐ IL‐2 ja ja ja 115 Kovacs A ART +/‐ IL‐2 ja ja ja 60

Anlage 3

Studienextraktionsbögen

Nr. Feld Bearbeitung 1 Quelle SILCAAT-Studie (NCT00013611): Abrams D, Lévy Y, Losso MH, Babiker A, Collins G, Cooper DA, et al. Interleukin-2 therapy in patients with HIV infection. The New England Journal of Medicine 2009;361(16):1548-59. 2 Studientyp vom Autor Prospektiv, randomisiert, offen, Phase III bezeichnet als 3 Studientyp nach Offene Therapiestudie mit randomisierter Durchsicht Vergleichsgruppe

4 Formale Evidenzkriterien 1++: Qualitativ hochwertige RCT mit sehr geringem gemäß SIGN Risiko von Bias

5 Bezugsrahmen Sponsor: National Institute of Allergy and Infectious Diseases (NIAID), bis Februar 2003 Chiron. Prinzipiell besteht durch die Koautorenschaft von H.C. Lane (NIH) ein potenzieller Interessenkonflikt, da Lane einer der Patentinhaber für „Immunological Enhancement with intermittent interleukin-2 therapy“ ist, ebenso wie A. Fauci (ebenfalls NIAID). Bis Februar 2003 wurde die Studie von der Firma Chiron gesponsort und ging dann in die Sponsorship des NIH über. Nach der Übernahme von Chiron durch Novartis im Februar 2003 wurde die Durchführung der Studie durch Novartis finanziell unterstützt. Die Medikation wurde durch Chiron, später Novartis, gestellt. Die Autoren stellen in der Publikation klar, dass weder Chiron noch Novartis bei der Interpretation der Daten noch beim Verfassen des Manuskripts beteiligt waren. Die Sammlung und Auswertung der Daten erfolgte am koordinierenden Zentrum an der Universität von Minnesota. Angesichts des Negativergebnisses der Studie dürften diese potenziellen Interessenkonflikte unproblematisch sein. Nach dem Wechsel des Sponsors im Februar 2003 war es einigen Zentren nicht mehr möglich, an der Studie teilzunehmen. Auch verweigerten etliche Patienten eine Erneuerung ihrer Einverständniserklärung. Daher wurden nur an den Zentren alle randomisierten Patienten in die Auswertung einbezogen, an denen mindestens 2/3 der Patienten ihr Einverständnis erneuerten bzw. bereits verstorben waren. 6 Indikation Adjuvante Therapie der HIV-1-Infektion 7 Fragestellung / Primär: Nachweis einer Reduktion der Rate von Zielsetzung opportunistischen Erkrankungen und Mortalität durch eine adjuvante Aldesleukin-Therapie Nr. Feld Bearbeitung Sekundär: Mortalität und Grad 4-Ereignisse (potenziell lebensbedrohlich), Veränderung immunologischer Parameter, vordefinierte Subgruppenanalysen 8 Relevante Ein- und >= 18 Jahre alte HIV-1-infizierte Patienten mit einer Ausschlusskriterien CD4+-Zellzahl von 50-299/µL bei Screening, seit mindestens 4 Monaten unter einer seit 4 Monaten unveränderten antiretroviralen Therapie mit mindestens 2 Substanzen, darunter einer Plasmavirämie von <10000 Kopien/mL. Falls nur 2 Substanzen gegeben wurden, musste eine von beiden ein PI sein. Patienten mit einer kürzlich zurückliegenden AIDS- definierenden Erkrankung, einer aktiven Infektion oder ernsthaften sonstigen Erkrankung zum Zeitpunkt des Screenings sowie Schwangere, Stillende und Patienten mit Gabe von Corticosteroiden oder Immunsuppressiva wurden nicht aufgenommen.

9 Prüfintervention Gabe von Aldesleukin zusätzlich zu einer bereits vorher eingeleiteten frei gewählten antiretroviralen Therapie in einer Dosis von 4,5 MU pro Tag subkutan für je 5 Tage. Angestrebt wurden 6 Zyklen im Abstand von 8 Wochen innerhalb der ersten 12 Monate (Induktionsphase). In der Erhaltungsphase danach wurden ja nch CD4+-Zellzahl weitere Zyklen gegeben, um die CD4+-Zellzahl bei den Pat. mit einem Ausgangswert von 200-299/µL über 175 Zellen/µL oberhalb des Ausgangswerts zu halten, bei den Pat. mit 50-199 Zellen mindestens 125 Zellen/µL oberhalb des Ausgangswerts. Die Zuordnung zu Aldesleukin + ART oder nur ART erfolgte offen, da die typischen Aldesleukin- Nebenwirkungen sofort die Zuordnung zu einer Verumgruppe verraten hätten. 10 Vergleichsintervention Frei gewählte antiretrovirale Therapie (falls nur 2 Substanzen: mindestens ein Proteaseinhibitor) 11 Evtl. weitere - Behandlungsgruppen 12 Studiendesign Anzahl der Behandlungsarme: 2 Typus: Primäre Endpunkte: Parallelgruppendesign Sekundäre Endpunkte: Prae-Post-Vergleich Die Fallzahlkalkulation basierte zunächst auf der Annahme von 210 primären Endpunkten und einem Unterschied der CD4+-Zellzahl von mindestens 75 Zellen/µL. Die Zahl wurde 2/2003 auf 300 erhöht, sodass eine 80% Power bei der Detektion einer 28%igen Reduktion der primären Endpunkte in der Behandlungsgruppe resultierte. Eine Interimanalyse nach Erreichen von 200 Endpunkten wurde dem Data Safety Monitoring Board vorgelegt und nicht veröffentlicht. Die SILCAAT- Nr. Feld Bearbeitung Studie wurde solange fortgeführt, bis in der ESPRIT- Studie 300 primäre Endpunkte erreicht wurden. 13 Subgruppen Es wurden 12 Subgruppenauswertungen prospektiv geplant, dabei erfolgte keine Adjustierung für den Typ-1-Error. Weiterhin sind Auswertungen weiterer post hoc definierter oder in Auswertung gefundener Subgruppen geplant, die für diese Bewertung keine Bedeutung haben.

14 Zahl der Zentren Um Zentrumseffekte zu minimieren, erfolgte eine Stratifizierung nach Zentren 15 Randomisierung Keine detallierte Beschreibung der Randomisation (Verhältnis 1:1), stratifiziert nach CD4+-Zellzahl (50- 199 und 200-299) und Prüfzentrum 16 Concealment Keine genaue Darstellung im Protokoll („Maskierung“ der Randomisierung)

17 Verblindung der Erfolgte eine Verblindung der Behandlung? Behandlung Nein, offene Behandlung

18 Beobachtungsdauer Aufgrund der Art der Analyse (Kaplan-Meier, Cox Proportional Hazards) wurden Patienten bis zum Erreichen des ersten Endpunkts gewertet. Für die getrennte Analyse der Mortalität wurden Patienten auch nach dem Erreichen des ersten Endpunkts (wenn nicht Tod) bis zum Tod bzw. zur letzten Beobachtung gewertet (zensiert bei Loss-to-Follow- Up oder am 15.11.2008) 19 Primäre Zielkriterien Auftreten einer opportunistischen Erkrankung oder Tod, beide patientennah und hoch relevant. Die Erfassung erfolgte prospektiv und unter kontrollierten Bedingungen. Endpunkte wurden verifiziert.

20 Sekundäre Zielkriterien Mortalität und Grad-4-Toxizität (potenziell lebensbedrohlich) 21 Statistische Methoden Cox-Modelle, zweiseitige p-Werte, Vergleich der für die Analyse der vorhergesagten und der tatsächlichen Event-Raten primären Endpunkte 22 Anzahl der behandelten Es wurden 1695 Patienten eingeschlossen Patienten 23 Zahl und Charakteristika 849 Patienten wurden in den Aldesleukin-+ART-Arm der eingeschlossenen randomisiert, 845 in den ART-Arm. Die mediane und ausgewerteten Beobachtungsdauer betrug 7,6 Jahre, mit einer Patienten Gesamtzahl an ca. 5700 Patientenjahren Follow-up. Drop-outs sind dokumentiert und im CONSORT- Diagramm dargestellt. Die Analyse erfolgte nach dem ITT-Prinzip. Darstellung des Patientenflusses nach dem CONSORT-Flussdiagramm (s.u.) 24 Vergleichbarkeit der Die Angaben liegen getrennt nach Behandlungsgruppen Behandlungsgruppen in tabellarischer Form nachvollziehbar vor. Die Behandlungsgruppen unterscheiden sich bezüglich der entscheidenden Kriterien untereinander kaum. Die ART wurde frei gewählt und angesichts der Vielzahl der möglichen Kombinationen nicht für jede einzelne Substanz getrennt analysiert, ist aber bezüglich der Substanzklassen vergleichbar. Das virologische Ansprechen in beiden Gruppen ist ebenfalls vergleichbar.

25 Ergebnisse 110 Patienten der Aldesleukin (IL-2)+ART-Gruppe und 119 Patienten der ART-Gruppe erreichten einen primären Endpunkt. Dies entspricht einer Hazard Ratio (HR) von 0,91 (95% CI 0,70-1,18; p=0.47). Auch die Analyse der einzelnen Endpunkte ergab keinen Unterschied (Anlage 4). Die anhand des CD4+-Zellzahl-Unterschieds (log-transformierte CD4+-Zellzahl) vorhergesagte HR betrug 0,80 (95% CI 0,78-0,83) und lag damit unter der beobachteten HR. 72,3% der Patienten vollendeten 6 Zyklen IL-2, die mediane Zahl an Zyklen betrug 7. Subgruppenanalysen nach Geschlecht, Ethnizität, Alter, Ausgangs-CD4+-Zellzahl und –HIV-RNA ergaben keine signifikanten Unterschiede. Die CD4+-Zellzahl in der IL-2-Gruppe war über die Beobachtungsdauer signifikant höher als im ART- Arm, wobei der Unterschied nach der Induktionsphase bis zum Ende des Beobachtungszeitraums abnahm. 26 Unerwünschte In der IL-2-Gruppe traten mehr Grad 4-Ereignisse auf; Therapiewirkung dieser Unterschied war jedoch nicht statistisch signifikant 27 Fazit der Autoren Die adjuvante Therapie mit Aldesleukin bei HIV- positiven Patienten unter ART mit einer Ausgangs- CD4+-Zellzahl zwischen 50 und 299/µL führt zu einer signifikant höheren CD4+-Zellzahl als unter ART allein. Diese ist jedoch nicht mit einer Abnahme der Progression zu opportunistischen Erkrankungen oder Tod verbunden. Entsprechend sind die der Planung zugrunde gelegten vorhergesagten Hazard Ratios niedriger als die beobachteten. Offensichtlich haben die durch IL-2 induzierten CD4+Zellerhöhungen keine funkionelle Relevanz oder negative Effekte der IL2- Therapie wiegen mögliche positive Effekte auf.^ Zusammenfassend bietet eine adjuvante Therapie mit IL-2 in Verbindung mit einer ART keinen positiven Effekt. 28 Abschließende Die vorliegende Publikation wird berücksichtigt Bewertung durch den Bearbeiter

Nr. Feld Bearbeitung 1 Quelle ESPRIT-Studie (NCT00110812): Abrams D, Lévy Y, Losso MH, Babiker A, Collins G, Cooper DA, et al. Interleukin-2 therapy in patients with HIV infection. The New England Journal of Medicine 2009;361(16):1548-59. 2 Studientyp vom Autor Prospektiv, randomisiert, offen, Phase III bezeichnet als 3 Studientyp nach Therapiestudie mit randomisierter Vergleichsgruppe Durchsicht 4 Formale Evidenzkriterien 1++: Qualitativ hochwertige RCT mit sehr geringem gemäß SIGN Risiko von Bias

5 Bezugsrahmen Sponsor: National Institute of Allergy and Infectious Diseases (NIAID). Prinzipiell besteht durch die Koautorenschaft von H.C. Lane (NIH) ein potenzieller Interessenkonflikt, da Lane einer der Patentinhaber für „Immunological Enhancement with intermittent interleukin-2 therapy“ ist, ebenso wie A. Fauci (ebenfalls NIAID). Die Medikation wurde durch Chiron, später Novartis, gestellt. Die Autoren stellen in der Publikation klar, dass weder Chiron noch Novartis bei der Interpretation der Daten noch beim Verfassen des Manuskripts beteiligt waren. Die Sammlung und Auswertung der Daten erfolgte am koordinierenden Zentrum an der Universität von Minnesota. Angesichts des Negativergebnisses der Studie dürften diese potenziellen Interessenkonflikte jedoch unproblematisch sein. 6 Indikation Adjuvante Therapie der HIV-1-Infektion 7 Fragestellung / Primär: Nachweis einer Reduktion der Rate von Zielsetzung opportunistischen Erkrankungen und Mortalität durch eine adjuvante Aldesleukin-Therapie Sekundär: Mortalität und Grad 4-Ereignisse (potenziell lebensbedrohlich), Veränderung immunologischer Parameter, vordefinierte Subgruppenanalysen 8 Relevante Ein- und >= 18 Jahre alte HIV-1-infizierte Patienten mit einer Ausschlusskriterien CD4+-Zellzahl von über 300/µL bei Screening, keine aktive Erkrankung im vorausgehenden Jahr. Teilnehmer von vier VANGUARD-Studien in Argentinien, Thailand und den USA konnten sich an der Studie beteiligen. Bei 3 dieser Studien lag die untere CD4-Zellzahlgrenze bei Einschluss bei 350/µL. Die IL-2-Dosis bei diesen Patienten lag bei 1,5 oder 4,5 MU/Tag und musste nicht erhöht werden. Patienten mit einer Autoimmunerkrankung zum Zeitpunkt des Screenings sowie Schwangere, Stillende und Patienten mit Gabe von Corticosteroiden oder Immunsuppressiva wurden nicht aufgenommen. 9 Prüfintervention Gabe von Aldesleukin zusätzlich zu einer bereits vorher eingeleiteten frei gewählten antiretroviralen Therapie in einer Dosis von 7,5 MU pro Tag subkutan für je 5 Tage. Angestrebt wurden 3 Zyklen im Abstand von 8 Wochen innerhalb der ersten 12 Monate (Induktionsphase). In der Erhaltungsphase danach wurden ja nch CD4+-Zellzahl weitere Zyklen gegeben, um die CD4+-Zellzahl oberhalb des Doppelten des Ausgangswertes oder >= 1000 Zellen/µL zu halten. Die Zuordnung zu Aldesleukin + ART oder nur ART erfolgte offen, da die typischen Aldesleukin- Nebenwirkungen sofort die Zuordnung zu einer Verumgruppe verraten hätten. 10 Vergleichsintervention Frei gewählte antiretrovirale Therapie (falls nur 2 Substanzen: mindestens ein Proteaseinhibitor) 11 Evtl. weitere - Behandlungsgruppen 12 Studiendesign Anzahl der Behandlungsarme: 2 Typus: Primäre Endpunkte: Parallelgruppendesign Sekundäre Endpunkte: Prae-Post-Vergleich Die Fallzahlkalkulation basierte zunächst auf der Annahme von 320 primären Endpunkten und einem Unterschied der CD4+-Zellzahl von 140 Zellen/µL, sodass eine 80% Power bei der Detektion einer 27%igen Reduktion der primären Endpunkte in der Behandlungsgruppe resultierte, bei einer Hazard Ratio von 0,73 mit einem zweiseitigen p-Wert von 0,05. Dabei wurde eine 10%ige Spontanmortalität angenommen. Eine Interimanalyse nach Erreichen von 200 Endpunkten wurde dem Data Safety Monitoring Board vorgelegt und nicht veröffentlicht. 13 Subgruppen Es wurden 12 Subgruppenauswertungen prospektiv geplant, dabei erfolgte keine Adjustierung für den Typ-1-Error. Weiterhin sind Auswertungen weiterer post hoc definierter oder in Auswertung gefundener Subgruppen geplant, die für diese Bewertung keine Bedeutung haben.

14 Zahl der Zentren Um Zentrumseffekte zu minimieren, erfolgte eine Stratifizierung nach Zentren 15 Randomisierung Keine detallierte Beschreibung der Randomisation (Verhältnis 1:1), Stratifizierung nach Prüfzentrum 16 Concealment Keine genaue Darstellung im Protokoll („Maskierung“ der Randomisierung)

17 Verblindung der Erfolgte eine Verblindung der Behandlung? Behandlung Nein, offene Behandlung 18 Beobachtungsdauer Aufgrund der Art der Analyse (Kaplan-Meier, Cox Proportional Hazards) wurden Patienten bis zum Erreichen des ersten Endpunkts gewertet. Für die getrennte Analyse der Mortalität wurden Patienten auch nach dem Erreichen des ersten nicht Endpunkts (wenn nicht Tod) bis zum Tod bzw. zur letzten Beobachtung gewertet (zensiert bei Loss-to-Follow- Up oder am 15.11.2008) 19 Primäre Zielkriterien Auftreten einer opportunistischen Erkrankung oder Tod, beide patientennah und hoch relevant. Die Erfassung erfolgte prospektiv und unter kontrollierten Bedingungen. Endpunkte wurden verifiziert.

20 Sekundäre Zielkriterien Mortalität und Grad-4-Toxizität (potenziell lebensbedrohlich) 21 Statistische Methoden Cox-Modelle, zweiseitige p-Werte, Vergleich der für die Analyse der vorhergesagten und der tatsächlichen Event-Raten primären Endpunkte 22 Anzahl der behandelten Es wurden 4111 Patienten eingeschlossen, davon Patienten 729, die zuvor in VANGUARD-Studien behandelt worden waren. Diese wurden in der Auswertung nur berücksichtigt, wenn im jeweiligen Zentrum mindestens 90% der VANGUARD-Teilnehmer in ESPRIT übernommen worden waren. 23 Zahl und Charakteristika 2071 Patienten wurden in den Aldesleukin-+ART-Arm der eingeschlossenen randomisiert, 2040 in den ART-Arm. Die mediane und ausgewerteten Beobachtungsdauer betrug 7 Jahre, mit einer Patienten Gesamtzahl an ca. 14000 Patientenjahren Follow-up. Drop-outs sind dokumentiert und im CONSORT- Diagramm dargestellt. Die Analyse erfolgte nach dem ITT-Prinzip. Darstellung des Patientenflusses nach dem CONSORT-Flussdiagramm (s. Anlage) 24 Vergleichbarkeit der Die Angaben liegen getrennt nach Behandlungsgruppen Behandlungsgruppen in tabellarischer Form nachvollziehbar vor. Die Behandlungsgruppen unterscheiden sich bezüglich der entscheidenden Kriterien untereinander kaum. Die ART wurde frei gewählt und angesichts der Vielzahl der möglichen Kombinationen nicht für jede einzelne Substanz getrennt analysiert, ist aber bezüglich der Substanzklassen vergleichbar. Das virologische Ansprechen in beiden Gruppen ist ebenfalls vergleichbar.

25 Ergebnisse 159 Patienten der Aldesleukin (IL-2)+ART-Gruppe und 165 Patienten der ART-Gruppe erreichten einen primären Endpunkt. Dies entspricht einer Hazard Ratio (HR) von 0,94 (95% CI 0,75-1,16; p=0.55). Auch die Analyse der einzelnen Endpunkte ergab keinen Unterschied (s. Anlage 4). Die anhand des CD4+-Zellzahl-Unterschieds (log-transformierte CD4+-Zellzahl) vorhergesagte HR betrug 0,74 (95% CI 0,71-0,77) und lag damit unter der beobachteten HR. 83,4 % der Patiernten schlossen drei IL-2-Zyklen ab. Die mediane Zahl der Zyklen lag bei vier. Subgruppenanalysen nach Geschlecht, Ethnizität, Alter, Ausgangs-CD4+-Zellzahl und –HIV-RNA ergaben keine signifikanten Unterschiede. Die CD4+-Zellzahl in der IL-2-Gruppe war über die Beobachtungsdauer signifikant höher als im ART- Arm. 26 Unerwünschte In der IL-2-Gruppe traten mehr Grad 4-Ereignisse auf; Therapiewirkung dieser Unterschied war statistisch signifikant mit einer HR von 1,23 (95% CI 1,07-1,41; p=0,003). Dies beinhaltete einer erhöhte Rate vaskulärer Ereignisse, insbesondere tiefer Beinvenenthrombosen (10 vs. 2 Ereignisse). 27 Fazit der Autoren Die adjuvante Therapie mit Aldesleukin bei HIV- positiven Patienten unter ART mit einer Ausgangs- CD4+-Zellzahl über 300/µL führt zu einer signifikant höheren CD4+-Zellzahl als unter ART allein. Diese ist jedoch nicht mit einer Abnahme der Progression zu opportunistischen Erkrankungen oder Tod verbunden. Entsprechend sind die der Planung zugrunde gelegten vorhergesagten Hazard Ratios niedriger als die beobachteten. Offensichtlich haben die durch IL-2 induzierten CD4+Zellerhöhungen keine funkionelle Relevanz oder negative Effekte der IL2-Therapie wiegen mögliche positive Effekte auf. Die adjuvante Therapie mit IL-2 geht darüber hinaus mit einer signifikanten Zunahme potenziell lebensbedrohlicher Ereignisse (Grad 4-Ereignisse) einher. Patienten mit über 450 CD4+-Zellen bei Einschluss erreichten häufiger den primären Endpunkt, wobei dies ein Zufallseffekt sein könnte. Zusammenfassend bietet eine adjuvante Therapie mit IL-2 in Verbindung mit einer ART bei Patienten mit über 300 CD4+-Zellen/µL bei Einschluss keinen positiven Effekt und erhöht die Morbidität. 28 Abschließende Die vorliegende Publikation wird berücksichtigt Bewertung durch den Bearbeiter

Auszug aus den Supplemental data der Originalpublikation beider Studien: CONSORT- Diagramme

Anlage 4

Hazard Ratios für die primären und wesentlichen sekundären Endpunkte in SILCAAT und ESPRIT nach Therapiegruppe

Aldesleukin + ART ART allein Hazard Ratio für p‐Wert Aldesleukin (95% Konfidenzintervall) SILCAAT‐Studie Patientenzahl (Rate/100 Personenjahre) Primärer Endpunkt: 110 (1,94) 119 (2,13) 0,91 (0,7‐1,18) 0,47 Opportunistische Erkrankung oder Tod (alle Ursachen) Tod (alle Ursachen) 81 (1,38) 77 (1,31) 1,06 (0,77‐1,44) 0,73 Opportunistische 49 (0,86) 66 (1,18) 0,73 (0,51‐1,06) 0,10 Erkrankung Grad 4‐Ereignis* 203 (3,93) 186 (3,58) 1,10 (0,90‐1,34) 0,35

ESPRIT‐Studie Primärer Endpunkt: 159 (1,14) 165 (1,21) 0,94 (0,75‐1,16) 0,55 Opportunistische Erkrankung oder Tod (alle Ursachen) Tod (alle Ursachen) 107 (0,75) 116 (0,83) 0,90 (0,69‐1,17) 0,42 Opportunistische 68 (0,49) 63 (0,64) 1,05 (0,75‐1,48) 0,78 Erkrankung Grad 4‐Ereignis* 466 (3,80) 383 (3,09) 1,23 (1,07‐1,41) 0,003

Grad 4‐Ereignisse sind definiert als potenziell lebensbedrohliche Ereignisse (unter Ausschluss opportunistischer Erkrankungen), die eine medizinische Intervention benötigen (s.a. unter http://rcc.tech‐res.com)