John,
Do you know if data presented at the conference showed support for Agouron's earlier data that indicated that failure on Viracept tended to still allow successful treatment by the other PI's, while failure on the other PI's tended to produce resistance to Viracept as well?
(Which, if true, would strongly support starting on Viracept and only switching if it fails).
Here is some info on their claims from last year (sorry that the formatting is a little screwed up):
National AIDS Treatment Advocacy Project
Report from ACTG Meeting--July 31, 1996: Nelfinavir Resistance Profile, studies of eradication and immediate
vs. deferred use of protease inhibitor therapy
We are indeed living in an exciting new frontier of treatment and research of HIV, as new developments are unfolding very quickly.
This report discusses new developments: the first is from Agouron regarding a their resistance profile for nelfinavir; followed by a
discussion of eradication and immediate vs. deferred protease inhibitor therapy.
Nelfinavir resistance profile
Agouron Pharmaceuticals' Amy Patick, PhD, reported first at the 5th International HIV Drug Resistance Workshop in Vancouver
British Columbia (just prior to the Int'l. Conference), and again here at this meeting, of a finding that may indicate a unique mutation
profile for their protease inhibitor, nelfinavir. Dr. Patick reported that nelfinavir-resistant HIV isolated from 5 patients was tested for
susceptibility to indinavir, saquinavir, ritonavir and 141W94; it was found that the nelfinavir resistant virus was susceptible to each of
the other 4 drugs. It is premature to apply Agouron's findings too broadly, but it is important to be aware of and to follow this
development.
Agouron reported results from both an in vitro study and the one described above. Resistance was created by taking a laboratory
HIV-1 strain and subjecting it to increasing amounts of nelfinavir after starting with a sub-optimal dosing regimen. That is a standard
way researchers create in vitro resistance to examine the mutation profile that results. Bear in mind these resistance patterns need
confirmation, and further studies to this end are both ongoing and planned.
In the other study, virus from humans (clinical isolates) that had become resistant to nelfinavir from previously conducted dose
ranging studies were examined.
The results of both studies were comparable. From the in vitro study, after the lab strain had been passaged 22 times (the virus was
subjected 22 times to nelfinavir, at increasing doses), and the virus was 8 fold resistant to nelfinavir, this virus was not
cross-resistant to ritonavir, indinavir or saquinavir; the mutations that occurred after 22 passages were at positions 30 and 71. After
28 passages, and 32 fold resistance to nelfinavir emerged, resistance to ritonavir was 11 fold, indinavir 9 fold, and saquinavir 5 fold.
Generally, 4-5 fold is considered resistant.
From analysis of clinical isolates of 17 study subjects who particpated in the human dose ranging study, the predominant mutation
change in those that were resistant to nelfinavir was at position 30. This muation was stably maintained during the time period of the
study (28 weeks). Other changes were also observed but at a lower incidence at positions--35, 36, 46, 71, 77, and 88. Mutations
described for other protease inhibitors were never observed--48 (saquinavir) and 84 (indinavir and ritonavir); rarely observed was a
mutation at 90 (saquinavir). One subject had a mutation at 82, but also had a change at 48 at baseline and was using surreptitously
using saquinavir.
The clinical isolates which exhibited a reduction in susceptibilty to nelfinavir contained the same mutation at 30, while all clinical
isolates which were sensitive to nelfinavir did not. Viruses containing this 30 mutation and having a 5 to 100 fold reduction in
susceptibility to nelfinavir were fully susceptible to saquinavir, indinavir, ritonavir and 141W94 (Glaxo Wellcome protease inhibitor).
This is a unique resistance profile, as the 30 mutation has not been associated with resistance to the three approved protease
inhibitors. This is suggestive that after treatment with nelfinavir, if resistance to nelfinavir develops, treatment with other protease
inhibitors may be effective. However, the opposite would not necessarily apply; that is, if resistance develops from prior treatment
with ritonavir, saquinavir, indinavir or 141W94, it would not necessarily follow that then the resistant virus would be susceptible to
nelfinavir. Agouron would have to study viruses resistant to other protease inhibitors from initial treatment and subsequently expose
that virus to nelfinavir and, of course, that study needs to be conducted.
In Vancouver, this information created some controversy. Some observers said they were suspect of this data. Another prominent
researcher said "the data are the data." Although it is too soon to place much stock into this information, it is important to closely
follow this development, as it may be crucial. |
