p.s., Deeks' full comments on the post-nelfinavir salvage presentation were:
"Ritonavir/saquinavir after nelfinavir: a prospective study
In clinical trials, nelfinavir selects for the D30N mutation in the
protease gene. As D30N emerges, drug resistance and viral rebound
invariably occur. In vitro, virions containing the D30N mutation retain
full sensitivity to other protease inhibitors. To many investigators,
this observation suggested that nelfinavir should be a first line
protease inhibitor, saving other protease inhibitors for salvage
therapy. This hypothesis has not been tested in clinical trials.
Keith Henry and colleagues presented their experience with patients who
failed nelfinavir during controlled clinical studies at the University
of Minnesota. In a prospective manner, patients with evidence of
virologic failure to nelfinavir were enrolled in a prospective rollover
study evaluating ritonavir (400 mg bid), saquinavir (400 mg bid),
stavudine (40 mg bid) and lamivudine (150 mg).
Patients were stratified into two groups depending on their extent of
prior treatment with nucleoside analogues. A total of 12 patients with
limited prior nucleoside experience were recruited from two Agouron
studies: Agouron 506 (a study evaluating d4T/nelfinavir in d4T na‹ve
patients) and Agouron 511 (a study evaluating AZT/3TC/nelfinavir in
treatment na‹ve patients). All 12 patients had clear virologic evidence
of failing nelfinavir therapy. At the time of the switch from nelfinavir
to the ritonavir/saquinavir combination, the baseline CD4 was 208
cells/mm2, the baseline viral load was 61,000 copies/ml and the median
prior duration of treatment with nelfinavir was 41 weeks. The majority
of patients had the D30N mutation commonly associated with nelfinavir
resistance; L90M (commonly seen with saquinavir therapy) was seen in 2
patients. All 12 patients achieved undetectable levels (< 500 copies/mL)
at at least one point prior to week 16. Six of 7 patients had
undetectable levels at the week 16 visit.
An additional 7 patients with more advanced disease were recruited from
Agouron 525 (a study evaluating two nucleoside analogues plus nelfinavir
in patients with extensive prior nucleoside analogue experience). Again,
all 7 patients had failed nelfinavir therapy. In these relatively
advanced patients (baseline CD4 109 cells/mm2, baseline viral load
233,000 copies/mL), 3 of 7 patients achieved undetectable levels of
viral load at at least one point prior to week 16 [Henry, ICAAC].
Conclusion: This encouraging data suggests that salvage therapy after
failing nelfinavir may be possible. This is in contrast to evolving
experience in patients failing indinavir and ritonavir therapy. If these
trends persist, using nelfinavir as a first line protease inhibitor, and
saving other drugs for salvage, may prove to be an appropriate
therapeutic strategy." |
