HIV
and Hepatitis.com Coverage of the 14th
Annual Conference on Retroviruses and Opportunistic Infections (14th CROI) February
25 - 28, 2007, Los Angeles, CA
Development
of V82L/T Mutation Following Tipranavir Therapy Has Limited Effect on Susceptibility
to Darunavir and Brecanavir
The
protease inhibitors (PIs) darunavir
(Prezista) and brecanavir have demonstrated in vitro activity against
clinical HIV isolates that are resistant to other PIs.
In treatment-experienced
patients, the V82L or V82T protease mutation is the most common pathway leading
to tipranavir (Aptivus) resistance.
In the current study, presented at the 14th Conference on Retroviruses and Opportunistic
Infections last month in Los Angeles, researchers analyzed the change in susceptibility
to darunavir and brecanavir following development of the V82L/T mutation after
treatment with tipranavir, and the relationship between viral responsiveness to
tipranavir, darunavir, and brecanavir.
The investigators evaluated susceptibility
to tipranavir, darunavir, and brecanavir using the Phenoscript phenotypic resistance
assay, using matched samples of HIV from baseline and after virological failure
that developed the V82L/T mutation during the RESIST 1 and 2 trials.
The
analysis showed that virological failure on tipranavir was accompanied by loss
of the amprenavir-associated I50V mutation if present at baseline (n = 5). Acquisition
of the V82L/T mutation accompanied by loss of the baseline I50V mutation was associated
with increased susceptibility to amprenavir (20- to 9-fold change), darunavir
(14- to 8-fold change), and brecanavir (21- to 6-fold change).
No correlation
was seen between susceptibility to tipranavir and darunavir or brecanavir, while
a strong correlation between susceptibility to darunavir and brecanavir, darunavir
and amprenavir, and brecanavir and amprenavir was observed.
Based on these
results, the authors concluded, "Development of the V82L/T mutations following
tipranavir therapy has limited effect on the susceptibility to darunavir and brecanavir."
Further, they noted, "The resistance profiles of amprenavir, darunavir,
and brecanavir are closely related, whereas there is no correlation between the
resistance profiles of tipranavir with those of darunavir or brecanavir."
In closing, they stated, "These data support the option of using
darunavir or brecanavir if patients fail tipranavir-based therapy and develop
a V82L/T protease mutation.
[Editor's note: GlaxoSmithKline
halted development of the PI brecanavir in December 2006 due to an inability to
develop a viable oral formulation capable of delivering the desired drug levels
in patients with multidrug-resistant HIV]. Link
to full study abstract
03/16/07
Reference R
Elston, D Kuritzkes, and R Bethell. An Investigation into the Influence of the
Tipranavir-associated V82L/T Mutations on the Susceptibility to Darunavir and
Brecanavir. 14th Conference on Retroviruses and Opportunistic Infections. February
25-28, 2007. Los Angeles, CA. Abstract 602 (poster).
