Bridging the Gap: Conference Record [Abstract book, International Conference on AIDS (12th: 1998: Geneva, Switzerland)]

12th World AIDS Conference

Abstracts 22413-22417 347

22413 Experience with proleukin (rlL2) in HIV-infected patients
Anne-Marie Dulibge, W. Capra, M. Giedlin, M. Owens. 4560 Horton Street
Emeryville, California; HIV-IL-2 Team, Chiron Corp., USA
- Interleukin-2 (proleukin) is a potent T cell growth factor and modulator of both
cellular and humoral immunity. Approximately 600 HIV-infected patients have received proleukin in combination with antiretroviral (AR) therapy in 11 collaborative
Phase I or II studies, in which various doses (2 to 24 mlU/day), regimens, and
routes of administration (IV or SC) have been evaluated. In summary:
- Proleukin can be safely administered on an outpatient basis, providing physicians are familiar with its side effects and their management. Flu like symptoms
are frequent but can be limited by reducing the proleukin dose and using intense
non-steroidal anti-inflammatories.
- An intermittent 5 day regimen in combination with AR therapy consistently
increases CD4 counts in the majority of HIV infected patients; level of increase
is dependent upon the baseline CD4 counts. Across all studies, 58% to 98% of
patients have shown at least a 25% increase in CD4-T cell counts, compared to
3% to 14% in control groups. Decreases in expression of activation markers on
CD8+ T lymphocytes, increases in expression of the alpha chain of IL2 receptor,
polyclonality of the TCR V/I repertoire, improved DTH responses, and studies of
lymphocytes proliferation show that these CD4 cells are functional. After 3 cycles
responder patients are able to maintain CD4 levels with less frequent cycles.
- Compared to intermittent CIV, the SC regimen (4.5-7.5 mlU/bid for 5 days)
is better tolerated and as effective in patients with relatively early disease. Responses to proleukin may be improved in more advanced patients in the setting
of highly active antiretroviral therapy. Long-term follow up of patients shows that
the benefit of proleukin on CD4 counts is maintained. No increase in viral load or
spectrum of viral resistance have been detected.
- In conclusion, proleukin could become an important adjunct to ART. A Phase
III study to determine the clinical benefit of proleukin is scheduled to begin this
year.
1 22414 A randomised clinical trial of d4T + 3TC + SQV + NFV with
or without interleukin-2 in early HIV infection: Preliminary
results
Haws-Juergen Stellbrink1, J. van Lunzen1, A. Adam3, C. Hoffmann4,
B. Kuhlmann5, S. Fenske1, G. Schmidt-Hartnack, S.P. Aries1, O. Degen6
C. Schneider1, F.T. Hufert7, K. Tenner-Racz8, P. Racz8. 1 University Hospital
Eppendorf, Martini Str. 52, 20246 Hamburg; 2Univ. Hospital Eppendorf,
Hamburg; 3 Praxis Brennerstrasse, Hamburg; 4 University Hospital, Kiel;
5Hannover; 6 University Hospital, Luebeck; 7Univ. Institute for Virology, Freiburg;
8Bernhard-Nocht Institute, Hamburg, Germany
Background: To compare the antiviral and immunological response to quadruple-drug antiviral therapy with or without interleukin-2 (r-IL-2) in early HIV infection
Methods: 46 male and I female unpretreated or minimally pretreated HIV+
subjects with recent seroconversion or stable asymptomatic infection were randomised to receive d4T + 3TC + SQV + NFV (24 pats) or d4T + 3TC + SQV
+ NFV + interleukin-2 (23 pats) at a dose of 9 MU/day for 5 days every 6 wks,
starting at day 28. Plasma viremia was measured by both PCR (conventional and
ultrasensitive assay) and bDNA. Lymphocyte subsets were determined by FACS.
Results: Mean baseline CD4+ T-cell count was 460/l1, mean plasma viremia
71629 (PCR)/44829 (bDNA) copies/mi. Plasma viremia decreased to below the
limit of quantification in 21/23 pats. (standard PCR) and 14/23 (ultrasensitive
PCR) after >3 months. CD4+ and CD8+ T-cell and CD4+CD45RA+ cell counts
increased to a higher extent in the IL-2 group. IL-2 was associated with transient profound lymphopenia and increased plasma viremia in some patients. The
quadruple-drug combination was tolerated well, but IL-2 exhibited significant toxicity (fever, liver enzyme elevations) requiring dose modification in most patients.
No patient withdrew due to IL-2 related side effects so far.
Conclusions: HAART + IL-2 leads to higher T-cell increases than HAART
alone. It is associated with significant toxicity. Immune activation due to IL-2
may lead to altered lymphocyte migration and homing patterns and enhanced
virus production despite highly active antiviral therapy. Updated results will be
presented.
S22415 Phenotypic expressions of CCR5-A2/A32 homozygosity
Thomas R. O'Brien1, G.T. Nguyen2, J.J. Goedert3, M. Carrington4, M. Dean4,
S.J. O'Brien4. 1National Cancer Institute, EPN/434 6130 Executive Bldg.
Rockville, MD; 2HHMI-NIH Research Scholars Program, Bethesda, MD; 3 Viral
Epidemiology Branch, NCI, Rockville, MD; 4Laboratory of Gemomic Diversity
NCI, Frederick, MD, USA
Background: Chemokine receptors are essential to immune cell trafficking. Homozygotes for a CC-chemokine receptor 5 (CCR5) deletion mutation (A32) resist
HIV-1 infection; HIV-1-infected CCR5-A32 heterozygotes have delayed progression to AIDS. Blockade of CCR5 has been proposed as therapy for HIV-1. To
determine phenotypic expressions of the CCR5-A32/A32 genotype, we compared

15 CCR5-A32/A32 homozygotes to other subjects.
Methods: We reviewed study and clinical records of 312 HIV-1 uninfected
hemophilic or homosexual white males enrolled in prospective cohort studies of
HIV incidence. CCR5-A32 genotype was determined by PCR followed by SSCP
analysis.
Results: Other than conditions attributable to hemophilia, hypertension was
the only frequent diagnosis among CCR5-A32/A32 subjects. CCR5-A32/A32 ho
mozygotes had a 2.8-fold higher prevalence of hypertension than age-matched
CCR5-+/+ subjects (95% CI, 1.2-6.4; p = 0.01), but none of the homozygotes had severe hypertension. Total lymphocyte counts were 20% higher in
CCR5-A32/A32 subjects than in CCR5-+/+ subjects (p < 0.05). Among hepatitis
C virus (HCV)-infected hemophiliacs, mean ALT levels were 117% higher among
CCR5-A32/A32 homozygotes (p < 0.05), but serum HCV levels did not differ by
CCR5-A32 genotype.
Conclusions: CCR5-A32/A32 homozygotes had an increased prevalence of
hypertension, modestly increased lymphocyte counts, and higher hepatic enzyme
levels in the presence of HCV infection. These possible phenotypic expressions
of CCR5- A32/A32 homozygosity should be considered in the development of
therapeutic modalities that mimic this genotype.
S224161 Chemokines and chemokine receptors expression during
combined anti HIV-1 IL-2 therapy
Julia Blanco1, C. Cabrera1, L. Ruiz1, A. Jou2, B. Clotet1, J.A. Este1. Fundacio
Irsi Caixa Hospital Germans Trias I Pujol, Badalona; 2Unitat VIH Hosp. Germans
Trias I Pujol, Badalona, Spain
Immunomodulation with IL-2 is one of the complementary treatments used in combined anti HIV-1 therapy. Administration of IL-2 is expected to improve immune
responses and to activate latently infected cells; however, IL-2 may increase the
pool of susceptible cells, by triggering, not only proliferation, but also expression
of chemokine receptors in CD4 cells. In order to address this latter point, we
studied the levels of CC-chemokines and chemokine receptors in a group of 12
patients with viral load <200 RNA copies/ml, receiving combined antiretroviral
therapy supplemented with IL-2 (3* 106 Units every 4 weeks for a period of 24
weeks). Data was compared to a control group of 12 patients receiving combined
antiretroviral therapy.
Methods: The levels of RANTES, MIP 1-a and MIP 1-f were determined by
ELISA in serum samples collected every 4 weeks. The expression of chemokine
receptors CXCR4 and CCR5 was studied by flow cytometry analysis of CD4
stained peripheral blood mononuclear cells, using monoclonal antibodies 12G5
and 2D7, respectively.
Results: Serum levels of RANTES, MIP 1-a and MIP 1- f were not modified by
IL-2 administration; i. e., RANTES levels in IL-2 treated group were 50 ~ 19 ng/ml
at 0 weeks and 47 ~ 21 ng/ml at 24 weeks of treatment; similar values were found
in the control group (49 ~ 17 ng/ml and 46 ~ 13 ng/ml, respectively). In contrast,
after 24 weeks of IL-2 treatment, the number of CD4 cells expressing CXCR4
increased from 32 ~ 26% to 48 ~ 26%. A lower iincrase was observed in CCR5
expressing CD4 cells (37 ~ 32% compared to 49 ~ 25%). Consistently, in vitro
experiments confirmed that IL-2 stimulation of PBMC induces a rapid increase
of CXCR4 expression (maximal effect was reached at day 3) and a slower but
important increase of CCR5 expression (maximal effect observed at day 10).
Conclusion: IL-2 treatment increases cell-surface expression of chemokine
receptors, without modifying serum levels of CC-chemokines. Although this stimulatory effect increases the number of HIV target cells, IL-2 treatment does
not result in increased viral load, thus suggesting that it may be beneficial in
enhancing anti HIV immune responses.
22417 Immunological parameters modified in HIV disease by
the macrophage activity immunomodulator WF10 (A
phase II pathogenesis study)
Brian Herndier1, R. Lull2, O. Ah Ching3, M. Broz3, F.W. Kuehne3, J. Kahn4.
1UCSF Box 0874, San Francisco, 94143 CA; 2San Francisco General Hospital,
San Francisco, CA; 4 University of California, San Francisco, San Francisco, CA,
USA; 30XO Chemie AG, Fribourg, Switzerland
Background: A pathogenesis-based Phase 2 clinical study was designed to
test the safety and mechanism of the proposed immunomodulator, WF10, in
18 patients with HIV disease. WF10 is an intravenous formulation of TCDO
(tetrochlorodecaoxygen).
Methods: Patients received two cycles of WF-10 (0.5 ml/kg IV/day x 5 days
with 16 days between cycles) over a 47 day testing period. This pattern of administration resulted in increased macrophage function. Immunological parameters of
circulating blood cells were measured by 3-color FACS analysis and phagocytosis
assays. The phagocytic assay measures ingested fluorescent e. coli. in blood
monocytes by FACS. Cell surface antigens measured included CD3, CD4, CD8,
CD20, CD28, CD38, CD56, and DR. Statstical methods included Wilcoxon rank
statistic and Spearman rank correction coefficient.
Results: During the trial, the following parameters significantly changed (p <
0.05 one tailed exact):

CD3+, CD4+, CD38-T
CD3+, CD8+, CD38-1
CD3+, CD8+, CD28-1
CD3+, CD8+, CD56+1

CD3+, CD4+, CD38+1
CD3+, CD8+, CD28+~
CD20+, DR+1
CD14+ (all) I

Phagocytosis index showed the most dramatic increases in patients with a low
baseline phagocytosis index. The majority of these patients had low initial CD4
counts.
Conclusion: WF10 is a safe (see James Kahn abstract, this meeting) drug in
the treatment of HIV disease. Although WF10 does not appear to affect viral load,
the drug may be effective in the treatment of HIV disease by affecting monocyte
or macrophage function. WF10 may prove beneficial in the treatment of patients