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June 27, 2007 EUROPEAN JOURNAL OF MEDICAL RESEARCH 91 prove this entry inhibitor for further HIV gene therapy approaches we are developing an antiviral gene product that is secreted from transduced cells to provide a bystander protective effect for the prevention of HIV infection of the transduced as well as non-transduced cells. Methods: As the C46 peptide itself is too short for secretion, we are testing different strategies to achieve secretion: First, the C46 was elongated by different linker sequences, further on a “multimer” of several C46 units linked by protease cleavage sites was generated. A third approach is the fusion of C46 to a secretable scaffold protein. Cell lines were transfected or transduced with vectors encoding the different secretable C46-derived peptides (sC46). Cell lysates and cell culture supernatants were analysed in respect of protein expression and secretion rates as well as inhibitory capacities. In addition, the impact of glycosylation of the peptides on the secretion rates and inhibitory potential was analysed. Results: The transfection and transduction of cell lines with the different sC46-encoding vectors resulted in reasonable expression and secretion of sC46 peptides. Mutation of multiple glycosylation sites lead to a decrease of expression and secretion. In a single round infection assay the supernatants from transfected cells were able to inhibit the entry of viral particles into two different cell lines, but they were quite ineffective compared to the closely related fusion inhibitor T-20. Conclusions: Subsequent work will be directed at further improvement of the inhibitory efficacy of the peptides. Afterwards reduction of the immunogenicity of the peptides and further testing of their efficacy in T lymphocytes will be analyzed. D.32 (Poster) Efficacy data of the German open-label study to assess the safety of tipranavir co-administered with low-dose ritonavir (TPV/r) in patients with advanced HIV-1 infection and limited treatment options Goldbach J. 1 , Moll A. 2 , Esser S. 3 , Theobald T. 4 , Mauss S. 5 , van Lunzen J. 6 , Eskoetter H. 1 1 Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany, 2 HIV specialised practice, Berlin, Germany, 3 University Hospital, Essen, Germany, 4 HIV specialised practice, Munich, Germany, 5 HIV specialised practice, Duesseldorf, Germany, 6 University Medical Center, Hamburg- Eppendorf, Germany Purpose: To assess the safety and efficacy of TPV/r under conditions comparable to those to be expected for TPV/r in a real world clinical setting. Methods: Adult patients (pts) had to be triple antiretroviral (ARV) class experienced having failed at least two previous PI-based regimens. The study medication was TPV/r 500/200 mg, twice daily added to a optimised background regimen based on genotypic resistance data chosen by the treating physician. Results: Data of 254 HIV-1 infected pts (median age 44 years, 229 males, 25 females) from 70 centres were available for analysis. Most pts were in stage CDC B3 (28%) and C3 (57.1%). Pts were highly pre-treated with a median prior exposure to 12 ARVs: 5 NRTIs; 1 NNRTI and 4 PIs. 17.7% of pts were pre-treated with the fusion inhibitor enfuvirtide (ENF). Hepatitis B and C co-infection was reported from medical history for 12.6% and 3.9% of the pts respectively. In an on treatment analysis after 12 months of therapy pts achieved a median VL reduction from baseline (median 4.7 log10 copies/mL) of -1.9 log10 copies/mL and the median increase of CD4 cell count from baseline (median 157 cells/mL) was +71.5 cells/mL. 55.9% of pts started ENF with TPV/r at baseline. After 12 months use of ENF in conjunction with TPV/r compared to TPV/r without ENF provided a greater median decrease of VL (-2.28 vs. -1.43 log10 copies/mL respectively) and a greater median increase in CD4 cell count (+87 vs. +59 cells/mL respectively). Conclusions: Patients participating in the German open label safety study were in an advanced stadium of HIV-1 infection and highly pre-treated with low CD4 cell count and high viral load. Treatment with TPV/r, especially in combination with a new class (ENF) was associated with potent and durable VL reduction and increase of CD4 cell count, demonstrating an improvement of immunological status. D.33 (Poster) Switch to a completely ONce daily regimen containing Emtricitabine/Tenofovir-fixed dose combination plus Third QD partner: 24 weeks interim analysis of the SONETT trial Weitner L. 1 , Kuhlmann B. 2 , Fenske S. 3 , Freiwald M. 4 , Ebrahimi R. 5 , Mertenskoetter T. 6 , Ranneberg B. 6 , Arasteh K. 7 1 Infektionsmedizinisches Centrum Hamburg, Praxis St. Georg, Hamburg, Germany, 2 Praxis Georgstrasse, Hannover, Germany, 3 Infektionsmedizinisches Centrum Hamburg, Grindelpraxis, Hamburg, Germany, 4 Private Practice, Berlin, Germany, 5 Gilead Sciences, Foster City, United States of America, 6 Gilead Sciences, Martinsried, Germany, 7 Epimed, Berlin, Germany Background: Study GS-934 found superior responses in terms of virologic suppression, CD4 response and discontinuations for adverse events in ART-naive pts randomized to TDF+FTC+EFV in comparison to AZT+3TC+EFV. We evaluated the impact of switching patients with adherence or tolerability problems from CBV (AZT/3TC) + 3rd partner to a regimen of TVD (TDF/FTC) + divergent qd partner in a 48 wk prospective open label single arm multicenter Phase III trial. Methods: 52 patients on a stable CBV-containing HAART for 12 wks with VL < 50 c/mL and CD4 > 50 cells/mm3 were switched to TVD + 3rd partner. Assessments including VL and CD4 were performed at BL and wks 4, 12, and 24 postswitch. Summary of Results: 7/52 patients discontinued early. At BL, median CD4 was 526 (IQR: 317-774) cells/mm3, median Hb was14.8 (IQR: 14.1-15.3) g/dL. 41/52 patients had taken CBV for >1 yr; 26 switched to TVD for simplification, 20 due to AEs, 6 for both reasons. TVD was mainly combined with EFV (n=30) or NVP (n=13). Viral Suppression was maintained with viral load < 50 copies/mL at week 24 in 43/51 (84%) enrolled patients. In 2 additional patients viral loads of 50 and 59 were observed at Week 24; both dropped to
92 EUROPEAN JOURNAL OF MEDICAL RESEARCH June 27, 2007 Conclusions: Results support switching from a stable CBVcontaining HAART to a completely qd regimen of TVD plus third divergent partner given that virologic (< 50 c/mL) and immunologic control were maintained with the additional benefit of Hb increasing significantly. D.34 (Poster) Successful salvage therapy with Darunavir and TMC-125 in a patient with a four-class drug resistant Tipranavir-experienced HIV-1 strain Harrer E. 1 , Müller S.M. 1 , Korn K. 2 , Walter H. 2 , Schmidt B. 2 , Harrer T. 1 1 Universitätsklinikum Erlangen, Medizinische Klinik 3, Klinische Infektionsimmunologie, Erlangen, Germany, 2 Universitätsklinikum Erlangen, Institut für Klinische und Molekulare Virologie, Erlangen, Germany Introduction: Multiresistant HIV-1-infected patients failing therapy with tipranavir and T20 have only limited treatment options. TMC-125 and darunavir are newly introduced antiretroviral drugs with potent activity against resistant HIV-1- variants. Here, we report on the successful salvage therapy in a multiresistant patient using TMC-125 and darunavir. Methods: The then 34-year old patient was diagnosed with HIV-1-infection in 1993 when he presented with herpes zoster and a CD4 count of 120/l. Since 5/1993 he was treated with all available antiretroviral drugs: AZT, AZT+DDC, AZT+DDI, then 3-5 drug combinations including D4T, 3TC, DDI, ABC, TDF, loviride, EFV, HU, RTV, SQV, NLV, IDV, APV, LPV, TPV, alpha-IFN, T20. Most newly started therapies could induce a transient rise of CD4-counts and a reduction of HIV-1 viremia, but viral load could never be suppressed below the limit of detection. In July 2006 he showed a high viral load on treatment with AZT, 3TC, TDF and tipranavir/r. Genotypic resistance analysis showed resistance to all drugs of the current and preceding antiretroviral regimens with following mutations: NRTI: M 41 L, E 44 A, D 67 N, L 74 I, V 75 M, F 77 L, V 118 I, M 184 V, H 208 Y, L 210 W, R 211 K, T 215 Y, K 219 N; NNRTI: K103N; PI: L 10 I, I 13 V, K 20 R, L 33 F, M 36 I, I 54 V, L 63 P, A 71 V, V 82 T, I 84 V, L 90 M. gp41 was not analysed, but T20 resistance had been documented two years ago. Results: In August 2006, as his viral load increased to 170 000 and his CD4-count fell to 45/l, tipranavir/r was exchanged by a combination of darunavir/r and TMC-125. AZT,3TC and tenofovir were continued and, in addition, T20 was reinitiated, but was stopped after 4 days due to strong local injection site reactions. For the first time in the patient´s treatment history, this combination could decrease viral load below 50 copies/ml. 6 months after switching therapy his viral load is still suppressed and his CD4 count increased to 226/l. Conclusion: This case demonstrates that the combination of darunavir/r and TMC-125 can exert a potent antiretroviral effect even on highly resistant HIV-1 variants. Due to different patterns of resistance mutations darunavir/r may retain activity against tipranavir resistant HIV-1 strains. D.35 (Poster) Behandlung von Patienten mit Darunavir im klinischen Alltag – Woche 12 Ergebnisse Therapieverlauf, Vorhersagbarkeit des Therapieansprechens mithilfe verschiedener Resistenzalgorhythmen Baumgarten A. 1 , Berg T. 2 , Dupke S. 1 , Carganico A. 1 1 Gemeinschaftspraxis Dupke/Carganico/Baumgarten, HIV- Schwerpunktpraxis, Berlin, Germany, 2 Labor Berg, Berlin, Berlin, Germany Ziel: Behandlung von 19 Patienten mit einer chronischen HIV-Infektion im Rahmen einer antiviralen Therapie mit DRV im Rahmen von Studien in unserer HIV-Schwerpunktpraxis. Es handelte sich um intensiv vorbehandelte Patienten mit multiplen Resistenzen. Die Umstellung erfolgte aufgrund von virologischen Versagen der Vortherapien bei Multiresistenzen. Methoden: Die Umstellungen erfolgten resistenzgesteuert auf ein DRV-haltiges Regime mit begleitendem optimalen Backbone. Als OBR wurde bevorzugt TZV und TDF (58%) eingesetzt. 32% der Patienten (n=6) erhielten zusätzlich ENV. Ergebnisse nach Woche 12: Eine VL-Reduktion von 1log Stufe gelang bei 95% der Pat. (n=18), eine Reduktion um 2log Stufen bei 84% (n=16). 58% der Pat. (n=11) hatten nach drei Monate eine Viruslast von
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