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June 27, 2007 EUROPEAN JOURNAL OF MEDICAL RESEARCH 89 D.26 (Poster) Efficacy of efavirenz-based HAART after switching from a protease inhibitor Khaykin P. 1 , Brenda D. 1 , Carlebach A. 2 , Knecht G. 3 , Müller A. 1 , Stürmer M. 4 , Staszewski S. 1 1 Klinikum der J.W.Goethe Unversität Frankfurt, HIVCEN- TER, Frankfurt, Germany, 2 Private Practice Friedenstrasse, Frankfurt, Germany, 3 Private Practice IFS, Frankfurt, Germany, 4 Klinikum der J.W.Goethe Unversität Frankfurt, Department of Virology, Frankfurt, Germany Objective: The aim of this database analysis was to investigate the efficacy and safety of efavirenz (EFV)-based HAART after switching from protease inhibitor (PI)-based regimens. Methods: Data were analyzed from 50 HIV+ patients who were taking two or three NRTIs and one PI or boosted PI (PI/r) and then switched the PI to EFV. The reasons for switching were side effects, virologic failure, and non-compliance. Summary of results: 22/50 patients were still on the EFV at the time of analysis. Viral load in the OT analysis decreased from 4.9 log10 to 1.6 log10 copies/ml. Of the patients who discontinued EFV, reasons given were virologic failure in 20%, adverse events in 22% and non-compliance in 14% of the patients. Patients who showed virologic failure had prior experience with different therapy regimens or showed 2 or 3- class resistance. Among the patients who stopped EFV therapy due to adverse events, CNS side effects were the most common. Conclusions: Modification of a HAART regimen may lead to viral suppression if EFV is substituted for a PI or PI/r. However, some patients in our study demonstrated adverse events or virologic failure. Most of the patients who discontinued EFV had 2- or 3-class resistance in their treatment history. D.27 (Poster) Darunavir (TMC114) in highly pre-treated HIV-1-infected patients: Clinical experience obtained from routine clinical practice Schmied B. 1 , Cichon P. 1 , Egle A. 2 , Geit M. 3 , Gmeinhart B. 4 , Haas B. 5 , Kanatschnigg M. 6 , Kapper A. 5 , Rieger A. 4 , Sarcletti M. 7 , Schlag M. 8 , Taylor N. 2 , Zangerle R. 7 1 Otto Wagner Hospital, II. Medical Department Pulmological Centre SMZ Baumgartner Höhe, Vienna, Austria, 2 III. Medical Department University of Salzburg, Division of Hematology , Oncology and Infectious Diseases, Salzburg, Austria, 3 General Hospital of Linz, Department of Dermatology and Venerology, Linz, Austria, 4 University of Vienna Medical School, Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, Vienna, Austria, 5 General Hospital – Graz West, I. Medical Department, Graz, Austria, 6 General Hospital Klagenfurt, I. Medical Department, Klagenfurt, Austria, 7 University of Innsbruck, Department of Dermatology and Venereology, Innsbruck, Austria, 8 Janssen-Cilag Pharma GmbH, Vienna, Austria Background: The activity of boosted Darunavir (DRV/r, 600/100 mg bid), a novel protease inhibitor (PI), against PIresistent virus has been proven in clinical trials. A Named Patient Program allowed to assess treatment results obtained in routine care settings. Objective: To evaluate the safety and efficacy of DRV/r containing ART when used in routine clinical practice and factors influencing outcomes. Methods: 31 HIV-1-infected patients were included. Patients were at least 3-class-experienced. All were naïve to DRV. Median baseline CD4 cell count: 160 (2-914), median HIVviral load: 3,99Log10 (1,69-6,18), 5 subjects had viral load (VL) < 50 c/ml. Patients were followed up according to local standard of care. Genotypes were used to determine DRVspecific resistance-associated mutations (DRV-RAMs) and genotypic sensitivity scores (GSS) for the optimized backbone regimen (OBR). Results: At cut-off (Feb 07), treatment with DRV/r was initiated in 28 patients. The OBR contained 2 or 3 NRTIs. TMC125 was added in 4 patients. Ten subjects (36%) used Enfuvirtide (ENF), thereof 7 (25%) naïvely. Median followup time: 25 weeks (range 4-84). 16/23 subjects (70%) reached VL2 DRV-RAMs, respectively. Response at week 12 was decreased in patients with a GSS of £ 0,5 (less than 1 fully active drug in OBR) and in the presence of > 2 DRV-RAMs. There was no difference in response of ENF-users (ENFnaïve) as compared to ENF non-users, however, in patients using ENF naïvely, ENF represented the only fully active drug in the OBR. Conclusions: DRV-based cART showed very good safety and efficacy in a group of highly pre-treated patients in routine care settings. Careful consideration of treatment history, DRV-RAMs and GSS can help to design the optimal DRVbased cART. Further follow up of efficacy and safety is needed to prove long-term outcomes. D.28 (Vortrag) Transfer of autologous gene-modified T lymphocytes in HIV-infected patients with advanced immunodeficiency and multidrug resistant virus von Laer D. 1 , von Lunzen J. 2 , M87o study group 1 Georg-Speyer-Haus, Frankfurt am Main, Germany, 2 Universitätskrankenhaus Eppendorf, Infektiologie, Hamburg, Germany Aims: Drug toxicity and viral resistance limit long-term efficacy of antiviral drug treatment for HIV infection. Thus, alternative therapies need to be explored. Methods: Here, we tested the infusion of T lymphocytes transduced with a retroviral vector (M87o) that expresses an HIV entry inhibitory peptide (maC46). Gene-modified autologous T cells were infused into 10 HIV-infected patients with advanced disease and multidrug resistant virus during antiretroviral combination therapy. Results: T cell infusions were tolerated well with no severe side effects. A significant increase of CD4 counts was observed post infusion. At the end of the one-year follow-up, the CD4 counts of all patients were still around or above baseline. Gene-modified cells could be detected in peripheral blood, lymph nodes and bone marrow throughout the one-year fol-
90 EUROPEAN JOURNAL OF MEDICAL RESEARCH June 27, 2007 low-up, whereby marking levels correlated with the cell dose. No significant changes of viral load were observed during the first four months. Four of the seven patients that changed their antiviral drug regimen thereafter responded with a significant decline in plasma viral load. Conclusions: The transfer of gene-modified cells was safe, led to sustained levels of gene marking and may improve immune competence in HIV-infected patients with advanced disease and multidrug resistant virus. D.29 (Poster) Efficacy and tolerability of TDF/FTC-containing first line HAART in clinical practice – 24 week data from a German outpatient cohort van Lunzen J. 1 , Fätkenheuer G. 2 , Lutz T. 3 , Klauke S. 4 , Mauss S. 5 , Knechten H. 6 , Braun P. 6 , Gallo L. 7 , Mertenskoetter T. 7 , Ranneberg B. 7 1 Universitätsklinikum Eppendorf, Ambulanzzentrum des UKE GmbH, Bereich Infektiologie, Hamburg, Germany, 2 Med. Einrichtungen der Universität Köln, Klinik I für Innere Medizin, Köln, Germany, 3 Infektiologikum Frankfurt, Praxis Friedensstraße, Frankfurt, Germany, 4 Infektiologikum Frankfurt, Praxis Stresemannallee, Frankfurt, Germany, 5 Center for HIV and Hepatogastroenterology, Düsseldorf, Germany, 6 Praxiszentrum Blondelstrasse, Aachen, Germany, 7 Gilead Sciences, Martinsried, Germany Background: First line HAART in recent pivotal trials has been associated with high efficacy and good tolerability. However, clinical practice often differs from the trial situation – patients have comorbidities, coinfections and monitoring can be more limited. To evaluate efficacy and safety of first line HAART in a day to day setting, this Gilead-sponsored non-interventional cohort was established. Methods: 554 HIV-postive antiretroviral naïve adult patients were enrolled in 50 German centres between July 2005 and August 2006. All patients will be followed up for three years; efficacy (VL, CD4), tolerability and regimen changes are documented every three months. In addition, resistance profile and renal safety are monitored. All patients received TDF/FTC in combination with an NNRTI or PI/r as their first regimen. Results: BL data are available for 524/554 patients. To date, 411/554 (74%) patients have reached week 24. Patients were mostly male (81%) with a median age of 39 years (IQR 33 – 45 years). At BL, median CD4 count was 204 cells/mm3 (IQR 110–293 cells/mm3), median VL was 5.0 log10 copies/ml (IQR 4.4–5.3). Last HIV-status (CDC) was C in 22%, 48% started therapy with CD4 < 200 cells/mm3. Primary resistance data have been obtained for 342 patients; overall rate for primary resistance was 10%. At week 24 in an AT(as treated)- analysis 84.9% reached VL < 50 copies/ml (VL < 500 copies/ml: 98%), CD4 increased to 360 cells/mm3 (median, IQR: 249–491). TDF/FTC was combined with an NNRTI (38%) or PI/r (61%). TDF/FTC was discontinued in 17/411 patients (4.1%), virological failures were rarely reported (n=8, 1.9%). Overall tolerability of 1st line HAART was good; 97 adverse events and 7 SAEs were reported. Mean creatinine clearance (Cockcroft-Gault) stayed within the normal range (112 ml/min at BL and 106 ml/min at week 24). Conclusion: In clinical practice, 1st line HAART including TDF/FTC in antiretroviral naive patients proved efficacious and showed good short term tolerability. D.30 (Poster) C2F5 as a secretable fusion inhibitor for gene therapy of HIV infection Kimpel J. 1 , Newrzela S. 1 , Hermann F. 1 , Egerer L. 1 , von Laer D. 1 1 Georg-Speyer-Haus, AG von Laer, Frankfurt/ Main, Germany Objectives: The HIV entry mechanism is an attractive target for gene therapy approach. Antibodies directed against epitopes of gp41 (eg C2F5) act as fusion inhibitors. Two major aims should be achived with an effective HIV entry inhibitor: Protection of the transduced (selective advantage) and the untransduced cells (bystander-effect). In an earlier study we have demonstrated that membrane-anchored fusion inhibitor C46 leads to protection from HIV infection of the transduced T cells. The disadvantage of this approach is that only a fraction of T cells can be transduced and no bystander-effect is achieved. A secreted principle for HIV entry inhibition could enable effective protection of the transduced cells and also give a bystander effect. Methods: The aim of the present study was to generate a secreted entry inhibitor by cloning a retroviral vector for expression of HIV neutralizing antibody C2F5. Human T and B cell lines were transduced with the retroviral vector and analyzed for C2F5 secretion via a T20-binding ELISA. Functionality of produced antibodies was examined in a single round infection assay with HIV pseudotyped lentiviral particles. Primary murine T cells as well as hematopoietic stem cells were transduced with the retroviral vector construct for expression of C2F5 in vivo. For this purpose Rag-1deficient mice were repopulated with genetically modified cells. Results: After transduction of human cell lines as well as primary murine cells C2F5 production could be detected in therapeutic concentrations. Secreted antibodies showed effective entry inhibition in a single round infection assay. Transplantation of primary cells into Rag-1 deficient mice lead to significant titers of C2F5 in mice sera. Both, T and B cells expressed functional active C2F5 antibodies. Conclusion: In summary we could show that after retroviral gene transfer C2F5 antibody was produced in vitro and in vivo. Functionality of secreted antibody was proofed in a single round infection assay. This approach is especially interesting as transduced T cells can migrate into tissues like lymphe nodes in which HIV infection is elevated. We propose that a bystander-effect renders high transduction efficacy unnecessary, thus lowering the risk of insertional mutagenesis. D.31 (Poster) Development of retroviral vectors encoding secretable entry inhibitory peptides for HIV gene therapy Egerer L. 1 , Hermann F. 1 , von Laer D. 1 1 Georg-Speyer-Haus, Applied Virology and Gene Therapy, Frankfurt am Main, Germany Objective: We are working on the development of retroviral vectors encoding secretable C-peptides for HIV gene therapy. C-peptides are efficient inhibitors of viral entry into target cells. In a previous clinical trial, our group used a retroviral vector (M87o) encoding a membrane-bound version of the C- peptide C46 to protect T cells from HIV infection. To im-
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