(MPC-4326) Resistance Is Common among Treatment-naive
and Protease inhibitor-experienced HIV Patients
About one-third of previously untreated
HIV patients and even more of those with
protease inhibitor-resistant virus showed
evidence of decreased susceptibility to
the experimental HIV maturation inhibitor
(MPC-4326), according to a study published
18, 2009 issue of AIDS.
is a derivative
of betulinic acid, a triterpenoid isolated
from the leaves of the Chinese herb, Syzygium
claviflorum, which was found to have potent
inhibitory activity against HIV-1.
inhibitors interfere with the final steps of the HIV
lifecycle, preventing the formation of functional
new virus particles that can infect additional cells.
Myriad Pharmaceuticals' bevirimat (formerly known
as PA-456) is furthest along in the development pipeline.
demonstrated promising activity in early studies,
but the tablet formulation had poor bioavailability
and produced a lower-than-expected response. However,
researchers recently reported that individuals
with specific HIV Gag gene variations (polymorphisms)
are more likely to respond.
Verheyen from the University of Cologne and colleagues
performed a study to evaluate the sequence variability
of the Gag region targeted by bevirimat in people
with HIV subtype B.
this laboratory study, the researchers sequenced the
Gag region (comprising amino acids at positions 357-382)
of 484 HIV isolates from 270 treatment-naive and 214
treatment-experienced patients. In the latter group,
48 HIV isolates carried mutations associated with
reverse transcriptase inhibitor resistance only, while
166 isolates carried mutations associated with protease
bevirimat activity can be expected in one-third of treatment-naive
HIV subtype B isolates and significantly more in protease
inhibitor-resistant HIV," the study authors concluded.
"These data indicate that screening for bevirimat
resistance mutations before administration of the drug
30% of patients in the treatment-naive group carried
HIV with at least 1 mutation associated with a
reduced susceptibility to bevirimat (H358Y, L363M,
Q369H, V370A/M/del, and T371del).
HIV isolates with protease inhibitor resistance,
45% had bevirimat resistance mutations.
researchers observed accumulation of mutations
at 4 positions in the bevirimat target region:
S368C, Q369H, V370A, and S373P.
associated with bevirimat resistance were detected
more frequently in HIV isolates with 3 or more
protease inhibitor resistance mutations than in
those with fewer mutations.
previously reported, Myriad announced last week
that it has initiated a Phase 2b trial of bevirimat,
which will be limited to participants with specific
Gag variations associated with favorable response.
of Virology, University of Cologne, Cologne, Germany;
AIDS Reference Laboratory, Ghent University, Ghent,
Belgium; Department of Medical Microbiology, University
Medical Center Utrecht, Utrecht, Netherlands.
J Verheyen, C Verhofstede, E Knops, and others. High
prevalence of bevirimat resistance mutations in protease
inhibitor-resistant HIV isolates. AIDS (Abstract).
November 18, 2009 [Epub ahead of print].