Sweating the Switch
When it comes to corporate positioning for protease inhibitor market share, every company has a yarn to spin. Merck loyalists insist that theirs be used first-line because it's so powerful and, "after all, really requires multiple mutations in order to significantly alter viral sensitivity." Roche (and later, Agouron, in lock step) claim that their protease is the only one to deserve a first-line indication because the mutations elicited with saquinavir and nelfinavir are unique and not nearly as predisposing to cross-resistance as are, say, the indinavir mutations. Since scientists at all the protease outfits seem capable of pulling what ever color rabbit out of their hats deemed most conducive to a successful marketing campaign (and since all cross-resistance analyses to date have been conducted in test tube experiments), trying to sort through the morass of claims and counter-claims has been at times Herculean; at others, Sisyphean. With the stunning and unexpectedly early results of ACTG 333 -- the first study to actually look at the effects of switching from one protease inhibitor to another in patients -- we may finally be getting an idea of how all this mumbo jumbo translates to clinical practice. We may finally be approaching objective truth.
ACTG 333 was a study designed to see how patients with long-term use (median 112 weeks) of saquinavir fared when they switched either to indinavir or to the new formulation of saquinavir, keeping their underlying nucleosides stable. While one could question the ethics of switching only one of a patient's drugs in a "failing" combination, ACTG 333 was terminated early when an interim analysis of the 72 patients (median baseline viral load= 21,000 copies/ml) showed only a negligible virologic benefit to the new protease inhibitor. The mean change in plasma HIV RNA for those switched to the saquinavir soft gel or indinavir was -0.23 log and -0.58 log, respectively. Since this fell short of the -0.7 log minimum acceptable viral load drop stipulated in the protocol design, participants will now be given the option of real-time viral RNA and CD4 measurements and switching to either open-label indinavir or saquinavir soft gel. A letter to patients also recommends that they consider changing their non-protease drugs as well when making the protease switch. (Monday morning QB!) Virology samples were collected on all study participants and the results of genotypic and phenotypic studies are eagerly awaited. Will it turn out that a mutation at 90 or 71 or 84 was responsible for the switching failure? Or will something even more nefarious (i.e., "cross-class" mechanisms) turn out to be the culprit, such as improved activity of the protease enzyme or reduced reliance on protease activity for replication? Remember ACTG 116B/117 and BMS 019? It may be time to beef-up our codon driven conception of antiviral drug resistance.