European Journal of Medical Research - Deutsche AIDS ...

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