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Benefits
of Enfuvirtide Persist Despite High Viral Load
By
Anne Harding
Enfuvirtide
(Fuzeon) has immunological and clinical benefit for HIV-infected
patients resistant to a number of antiretroviral drugs, and also
can help some whose viremia persists during enfuvirtide (ENF) treatment,
a new study by an international team of researchers shows.
During ENF
treatment, HIV envelope changes or drug pressure may lead to a shift
from viruses with tropism for T cells to viruses that infect macrophages,
"which may result in increased CD4 counts and lower T-cell
activation despite evidence of significant HIV replication,"
Dr. Vincent Soriano of Hospital Carlos III in Madrid told Reuters
Health.
ENF is a new
antiretroviral drug that binds to the HR1 domain of the gp41 region,
preventing viral and cellular membrane fusion. Mutations in both
HR1 and HR2 may be involved in resistance to the drug, Dr. Soriano
and his team note in the September issue of the Journal of Medical
Virology.
The researchers
evaluated immunological and genetic features of four highly experienced
patients failing
antiretroviral therapy who developed ENF resistance, yet either
maintained stable levels of CD4 cells or experienced an increase
in CD4 cell counts. "All these patients have experienced a
dramatic clinical improvement," Dr. Soriano said.
All four were
resistant to several protease
and reverse transcriptase inhibitors. They were followed for
80 weeks after initiation of ENF-based rescue therapy, with genetic
analysis of HIV RNA performed at baseline and every 8 weeks thereafter.
Their immunologic
responses were compared with those of three control groups: a similar
set of multidrug-resistant patients given salvage therapy without
ENF with similar viral loads; patients on highly active antiretroviral
therapy (HAART) with no detectable viral load; and untreated HIV
patients with viral loads similar to those of the study patients.
Viral load
dropped in the study group during the first weeks of ENF therapy,
but eventually rebounded. Two of the patients continued to have
stable CD4 counts despite increased viremia, while CD4 counts rose
in the two others.
A mutation
in the HR1 region appeared at the same time as treatment
failure in all four patients, specifically in the 36-45 amino
acid domain. While changes in the HR2 region also occurred during
ENF therapy, it was not clear if these changes had anything to do
with the development of resistance.
Viral replication
appeared to have a weaker impact on immune activation among the
study group patients, compared with patients failing HAART who were
not on ENF. ENF-treated patients also showed lower levels of T-cell
turnover and CTL responses, comparable to those seen with the control
group of patients with no detectable viremia during HAART.
The inhibition
of fusion by ENF may weaken the impact of the virus on CD4 cells
by promoting compensatory HIV entry into cells via the endocytosis
pathway, the researchers propose. "The virion endocytosis by
macrophages results in productive infection of these cells, but
this same pathway results in abortive infection in CD4+ T cells,"
they write.
"In spite
of high viral loads, an immunologic
benefit may occur in patients undergoing ENF-based therapies,"
they conclude. "Further studies are needed to clarify to what
extent ENF activity may go beyond its direct antiretroviral activity."
10/15/04
J Med Virol
2004;74:21-28.
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