July 20, 2010
Eugenia Vispo brought us results from the ODIS trial, a study of 222 people in Spain who had been on stable, effective (read: viral load below 50 copies/mL) PI-based therapy for at least 24 weeks. Volunteers were randomized to 1) remain on their current regimen, 2) switch their PI to once-daily raltegravir or 3) switch their PI to twice-daily raltegravir. Those who switched to twice-daily raltegravir continued on it for three months; if their viral load was still undetectable at that point, they were then further randomized to either continue taking raltegravir twice daily or switch to the once daily dose. (If this study design seems somewhat similar to that of the SWITCHMRK study, that's because it is. Vispo noted that ODIS was designed before the SWITCHMRK results came out.) The analysis presented by Vispo covered 24-week results.
Across all three arms of the study, rates of virologic failure were pretty low. Interestingly, virologic failure rates trended a bit lower among people who switched to twice-daily raltegravir (2.9%) than among people who stayed on their current, just-fine-thank-you regimen (5.9%), but the difference was not statistically significant. Failure rates were slightly higher across the board among people who had experienced a prior virologic failure at some point in their treatment history, and considerably higher among those with prior NRTI resistance. In all cases, failure rates were pretty similar between people who stayed on their PI and people who switched to once-daily raltegravir; likewise, in all cases, failure rates trended lower among people who switched to twice-daily raltegravir when compared to the other two arms, but this never reached statistical significance. The trends were apparently enough to warrant shutting down the once-daily arm of the study, however; Vispo said that none of the study participants were taking once-daily raltegravir anymore.
That almost-offhanded statement from Vispo contrasted with her conclusion that, "in this setting," it didn't matter whether a person switched to once-daily or twice-daily dosing. Perhaps she said it that way because the upshot is that there appears to be little point to switching from a successful PI-based regimen to raltegravir in the first place, aside from long-term toxicity concerns.
Speaking of studies that remind you of SWITCHMRK, Jose Gatell provided a summary of 48-week results from the SPIRAL study, which ... well, was an awful lot like SWITCHMRK. (Like Vispo, Gatell noted that SPIRAL was designed before the SWITCHMRK results came out, and said that a data safety monitoring board determined it was fine to continue.) I won't go much into the details here, since the results by and large were quite similar to that of SWITCHMRK. Perhaps Gatell sensed those similarities, because he blasted through many of his slides faster than my eyes could even settle on them. Virologic success rates were high in both the switch and continuation arms (meeting non-inferiority criteria for raltegravir); CD4+ cell gain was similar; adverse events were similar. If anything, actually, raltegravir performed a bit better in this study than it had in SWITCHMRK, but not remarkably so.
It's worth noting that the volunteers in SPIRAL had been on antiretroviral therapy for a median of about 10 years, and had been virologically suppressed for a median of about 6 years. That's a long time to be doing well on treatment -- and it raises even more starkly the question of why these people would need to switch therapy at all. Presumably, a person who's on a regimen that long and is doing that well is unlikely to be experiencing any side effects that would leave them wanting to switch. Yes, the long-term effects associated with some protease inhibitors (cardiovascular risk, lipid levels, etc.) are nothing to shake a stick at, but those long-term effects are also less impactful than more "standard" risk factors such as smoking, lack of exercise, poor diet and the like. So while it's comforting to know that switching to raltegravir is out there as an option, the need to employ such a strategy is probably quite limited.
Incidentally, at this conference we saw the first reported case of transmitted integrase inhibitor resistance (presented in a poster by Ben Young, which I hope to link to in the near future). This obviously will not be the last case. And it serves as a reminder that switching drugs -- and switching classes -- can be pretty serious business with potential implications for the development of resistance and the compromising of future treatment options. Transmitted HIV drug resistance on the whole has been decreasing in wealthy nations, not increasing, but it's still important to be cautious.
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