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Antibody no bar to enfuvirtide's anti-HIV effect

By David Douglas

NEW YORK (Reuters Health) - Existing antibodies to glycoprotein 41 (gp41) of
HIV may cross-react with the new HIV fusion inhibitor enfuvirtide (Fuzeon,
formerly T20), but this does not impair the efficacy or safety of therapy,
according to researchers from Europe and North America.

Enfuvirtide is a synthetic peptide based on a motif within gp41 that
regulates the binding of HIV-1 to host-cell membranes. In the December 15th
issue of
the Journal of Infectious Diseases, Dr. Sharon Walmsley of Toronto General
Hospital and colleagues note that "most HIV-1 infected patients express antibody
to gp41, which has the potential to cross-react with enfuvirtide."

To investigate whether such reactions might affect treatment, the researchers
examined data from 2 phase III clinical trials of enfuvirtide involving more
than 900 HIV patients.

Subjects were randomized to receive 90 mg enfuvirtide subcutaneously twice
daily in combination with optimized background treatment or to optimized
background treatment alone.

At baseline, most patients had detectable levels of the gp41 antibody. In 78%
of enfuvirtide patients, levels fell by at least 30%. This was true of only
43% of control patients.

Baseline antibody status did not influence virological response. "In fact,"
Dr. Walmsley told Reuters Health, "those people who responded best to the drug
had lower levels of antibody--a reflection of a decreased viral load."

Overall, the researchers conclude that "there was no evidence that
enfuvirtide cross-reactive gp41 antibody affects the efficacy and safety of
enfuvirtide."

Nevertheless, Dr. Walmsley also pointed out that it was not possible to
"differentiate between antibody formed against the gp 41 of the virus and
antibody
against the drug."

J Infect Dis 2003;188:1827-1833.

ORIGINAL ARTICLE

Enfuvirtide (T-20) Cross-Reactive Glycoprotein 41 Antibody Does Not Impair
the Efficacy or Safety of Enfuvirtide

The Journal of Infectious Diseases 2003;188:1827-1833

Sharon Walmsley,1 Keith Henry,2 Christine Katlama,5 Mark Nelson,7 Antonella
Castagna,8 Jacques Reynes,6 Bonaventura Clotet,9 James Hui,3 Miklos Salgo,4
Ralph DeMasi,3 and John Delehanty3

University of Toronto, Toronto, Ontario, Canada; 2Hennepin County Medical
Center, Minneapolis, Minnesota; 3Trimeris, Durham, North Carolina; 4Roche
Diagnostics, Nutley, New Jersey; 5Pitié-Salpêtrière Hospital, Paris, and 6CHU
Gui de
Chauliac, Montpellier, France; 7Chelsea and Westminster Hospital, London,
United Kingdom; 8Clinic of Infectious Diseases, Istituto de Recerca de la SIDA,
RCCS Ospedale San Raffaele, Milan, Italy; 9Hospital Universitari Germans Trias i
Pujol and IRSI-Caixa Foundation, Badalona, Barcelona, Spain

ABSTRACT
The present study investigated the effect of enfuvirtide cross-reactive
glycoprotein 41 (gp41) antibody on the efficacy or safety of enfuvirtide in
patients participating in 1 of 2 24-week phase 3 clinical trials (T-20 vs.
optimized
regimen only [TORO] 1 and TORO 2).

Serum samples from human immunodeficiency virusinfected patients receiving
enfuvirtide plus optimized background (OB) and from patients receiving OB only
were evaluated for enfuvirtide cross-reactive gp41 antibodies. Most patients
had detectable levels of antibody at baseline; 78% of patients treated with
enfuvirtide plus OB had a 30% decrease in level of antibody, compared with 43%
of
patients treated with OB only.

Baseline antibody status did not influence virological responses to
enfuvirtide-containing treatment. Favorable virological responses were more
common
among patients who experienced a 30% decrease from baseline than among those who
experienced either an increase or a lesser decrease. A decrease in virus load
correlated with a decrease in level of antibody. Safety was unaffected by the
presence of positive antibody at any time point or change in level of antibody.

There was no evidence that enfuvirtide cross-reactive gp41 antibody affects
the efficacy or safety of enfuvirtide.

BACKGROUND

Enfuvirtide (T-20) is a human immunodeficiency virus (HIV)1 fusion inhibitor,
the first member of a new class of antiretroviral agents for the treatment of
HIV infection. The efficacy and safety of chronically administered
enfuvirtide in HIV-1infected adults have been demonstrated in multiple phase 2
and 3
clinical trials.

Unlike conventional antiretroviral agents that work intracellularly,
enfuvirtide is a peptide that exerts its antiviral activity outside the cell. It
is a
36-aa synthetic peptide with a primary sequence derived from the naturally
occurring motif (residues 643678) within the HR2 domain of the HIV-1HXB2 gp41
transmembrane glycoprotein. This protein plays a role in enabling fusion and
entry of HIV into CD4 cells. Enfuvirtide inhibits de novo infection and
cell-to-cell virus transmission by binding specifically to a region of gp41 that
regulates the fusion of HIV-1 to host-cell membranes.

The envelope glycoproteins of HIV-1, gp41 and gp120, are recognized by the
immune system as foreign and elicit humoral antibody responses after natural
infection or immunization with recombinant proteins. Antibody responses to gp41
and gp120 occur soon after acute infection and can exert neutralizing effects.
This finding has raised the hope that it should be possible to develop an
effective vaccine based on recombinant gp120 or recombinant gp160 (the
unprocessed
precursor of gp120 and gp41).

Since it is identical to a fragment of gp41, enfuvirtide may cross-react with
existing antibodies to gp41 or may elicit its own humoral response and become
neutralized by anti-enfuvirtide antibodies. Cynomolgus monkeys that
previously had not been exposed to HIV-1, simian immunodeficiency virus, or
enfuvirtide
mounted a substantial antibody response when given enfuvirtide. On the basis
of these findings, it was thought that enfuvirtide might elicit a humoral
response in humans.

Most HIV-1infected patients express antibody to gp41, which has the potential
to cross-react with enfuvirtide. Although enfuvirtide-specific antibodies did
not reduce plasma levels of the drug in cynomolgus monkeys, the same
situation cannot be assumed to occur in HIV-infected humans. Antibodies elicited
in
response to other exogenously administered agentssuch as insulin, factor VIII,
erythropoietin, granulocyte-macrophage colony-stimulating factor, and
interferons (IFNs)have modified the biological effects and/or pharmacokinetics
of these
agents in humans. Neutralizing and nonneutralizing anti-IFN antibodies have
been detected and are implicated in the failure of IFN therapy.

Given these observations, it is important to determine the immune response to
long-term administered enfuvirtide in humans and to establish whether gp41
antibodies or antibodies induced during treatment with enfuvirtide influence its
efficacy or safety in HIV-1infected patients. The present study estimates the
incidence of cross-reactive gp41 antibody in HIV-infected patients at study
entry, the incidence of changes in serum gp41 antibody status during treatment
with either enfuvirtide plus optimized background (OB) or OB only, the presence
and effect of serum gp41 antibody at study entry, and the change of level of
antibody during treatment, on selected efficacy and safety end points.

DISCUSSION by authors

The present study has investigated whether enfuvirtide cross-reactive gp41
antibody influences the performance of enfuvirtide during therapy in phase 3
clinical trials. Antibody was assessed by the presence or absence of antibody at
baseline and week 24, by the maximum level of antibody achieved, and by
incremental changes in level of antibody during treatment. Results demonstrate
that
enfuvirtide cross-reactive gp41 antibody does not negatively affect the
efficacy or safety of chronically administered enfuvirtide.

Serum from almost all patients had some evidence of positive levels of
enfuvirtide cross-reactive gp41 antibody at baseline (77.4% in the
enfuvirtide-plus-OB group and 74.2% in the OB-only group), most likely due to
naturally
occurring antibody to gp41 in HIV-infected patients. The level of enfuvirtide
cross-reactive gp41 antibody was nonquantifiable in 20%25% of patients in both
treatment groups. It was rare (1.3% in both treatment groups) for a patient to
test
negative for enfuvirtide cross-reactive gp41 antibody at baseline, which
highlights the ability of patients' immune systems to recognize gp41.

Greater HIV RNA suppression was associated with a decrease in levels of
enfuvirtide cross-reactive gp41 antibody. This suggests that antiretroviral
therapy, particularly with enfuvirtide, in this patient population can affect
levels
of gp41 antibody by presumably reducing antigen burden. It would therefore
follow that the decrease in level of antibody would be significantly greater in
the enfuvirtide-plus-OB group than in the OB-only group, since
enfuvirtide-plus-OB treatment had a superior effect on suppression of HIV-1 RNA
in the TORO 1
and TORO 2 trials.

Maximum changes from baseline in level of antibody showed a clear
relationship with efficacy, according to all measures of virological response.
Enfuvirtide-plus-OB recipients who experienced a maximum decrease in level of
antibody
of 30% from baseline showed a greater mean decrease in HIV-1 RNA load from
baseline and fewer virological failures, and there was a higher proportion of
those patients with l.0 log10 decrease in HIV-1 RNA load from baseline, compared
with enfuvirtide-plus-OB recipients who experienced either less change (i.e.,
±30%) or a maximum increase in level of antibody of 30% from baseline.

Increases in the level of enfuvirtide cross-reactive gp41 antibody were
uncommon in both treatment groups, suggesting that chronic exposure to
enfuvirtide
is unlikely to elicit a marked humoral response. Since enfuvirtide
cross-reactive gp41 antibody has no effect on the pharmacokinetics of
enfuvirtide,
treatment-emergent increases in level of antibody is unlikely to compromise the
efficacy of enfuvirtide.

None of the safety assessments revealed any clear evidence to suggest that
the presence of enfuvirtide cross-reactive gp41 antibody influences the safety
of enfuvirtide during 24 weeks of therapy. Results from the TORO trials
indicate that enfuvirtide-plus-OB treatment has a comparable safety profile to
OB-only treatment. There were few cases in which the incidence of clinical or
laboratory toxicity occurred in >5% more patients in the enfuvirtide-plus-OB
group
than in the OB-only group. One exception was eosinophilia, which occurred in
10.1% of patients receiving enfuvirtide plus OB and in 2.4% of patients
receiving OB only, but in only 1.8% and 0.9% of patients, respectively, was the
incidence of eosinophila greater than twice the upper limit of normal. Overall,
any
manifestation of hypersensitivity occurred in 19.3% of patients receiving
enfuvirtide plus OB versus 17.4% of patients receiving OB only. The incidences
of
adverse events, hypersensitivity reactions, or ISRs in enfuvirtide-plus-OB
recipients were similar, irrespective of baseline or maximum during-treatment
antibody status. Only 1 patient tested negative for enfuvirtide cross-reactive
gp41 antibody at baseline and subsequently tested positive for antibody (i.e.,
seroconverted), with a level of antibody at week 24 of 0.258 g/mL. In addition
to an ISR, this patient had diarrhea (study day 1), bronchitis (study day 24),
fatigue (study day 33), bronchitis (study day 103), back pain (study day
109), and paresthesia (study day 135), but none of these events suggested an
immune-mediated reaction.

The overall incidences of treatment-emergent grade 3 or 4 laboratory
abnormalities indicated that the presence of enfuvirtide cross-reactive gp41
antibody
had no apparent influence on the safety of enfuvirtide during 24 weeks of
therapy. The differences between treatment groups are mostly attributable to a
higher incidence of eosinophilia in the enfuvirtide-plus-OB group than in the
OB-only group, which is consistent with observations of specimens obtained from
patients receiving enfuvirtide. Hematoxylin-eosin staining of excisional biopsy
specimens obtained from patients participating in phase 2 and 3 clinical
trials of enfuvirtide have revealed an inflammatory response with conspicuous
eosinophils and histiocytes.

Antibodies against gp41 may be elicited to viral debris that is expelled
after cell lysis rather than as a response to intact virions. This debris could
include incomplete or defective viral particles and peptides in various stages
of processing. Since these antibodies may recognize various oligomeric
conformations of gp41, they may also bind to enfuvirtide. The immune-based assay
used
in the present study cannot distinguish between antibodies directed
specifically against enfuvirtide and gp41 antibodies that cross-react with
enfuvirtide.
Irrespective of
the antigen responsible for the cross-reacting antibodies, the findings of
the present study are compatible with those of previous studies indicating the
low neutralizing antibody activity in HIV-1 infection. Even if antibodies that
recognize various oligomeric conformations of gp41 do bind to enfuvirtide,
they do not appear to influence its antiviral activity.

The analysis of the combined TORO clinical trial population revealed that
there was no meaningful influence on the clinical antiviral activity of
enfuvirtide by cross-reacting antibodies, and suppression of HIV-1 RNA was
associated
with the decrease in level of enfuvirtide cross-reacting gp41 antibody. No
association was detected between presence and level of antibody and any safety
measure during 24 weeks of treatment with enfuvirtide.



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