European Journal of Medical Research - Deutsche AIDS ...

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-