July 20, 2010
Myles is the editorial director of TheBody.com and TheBodyPRO.com.
The first set of scientific presentations at AIDS 2010 brought us some new research on raltegravir (Isentress), a study on raltegravir and some new data on ... let me see here ... ah, yes! Raltegravir! How could I forget.
Five presentations comprised the conference's opening set of oral abstract presentations; of them, three focused on various strategies for the use of raltegravir, currently the only integrase inhibitor on the market. (Of the other two presentations, one was devoted to a competing integrase inhibitor in the pipeline; the other discussed TBR-652, a CCR5 antagonist with potential anti-inflammatory properties.) In quick-shot summary, the studies found:
In less-quick summary:
The PROGRESS study results were presented by Jacques Reynes, M.D. The study involved 206 antiretroviral-naive people (about 85% male and 75% white, with an average age of about 39 years) with an HIV-1 viral load above 1,000 copies/mL. (People of all CD4+ cell counts were eligible.) About half the group was randomized to receive 400 mg/100 mg Kaletra with 400 mg raltegravir, both taken twice daily. The other half received the same Kaletra dose along with 300 mg/200 mg of Truvada once daily. This will ultimately be a 96-week study, but 48-week efficacy results were presented here.
I should note that for readers in wealthy countries, what's noteworthy here is the head-to-head comparison of these two drugs, not the regimens of which they were a part. Kaletra isn't prescribed nearly as much as first-line therapy in rich countries as it used to be just a few years ago; it's been pushed out of that market a bit by other drugs that are tied to fewer side effects, and is no longer on the preferred list of drugs in the official U.S. guidelines. It's still pretty heavily used in developing countries, though.
Back to the core results: Discontinuations were similar between both arms (around 10%), with side effects or virologic failure accounting for an extremely small number. Through 48 weeks, a virtually identical proportion of people (around 84%) in each arm achieved the study's primary endpoint, which was to achieve a viral load below 40 copies/mL (using an intent-to-treat, time-to-loss-of-virologic-response analysis). People in the raltegravir arm achieved that below-40 mark much faster than people in the Truvada arm, however: It took 24 weeks for 75% of people to reach sub-40 levels on the Truvada arm, but just 8 weeks for the same thing to happen on the raltegravir arm. Given that the rate of CD4+ cell increase was nearly identical between both arms, I think we could debate whether there's much clinical relevance to getting undetectable more quickly on raltegravir than Truvada. Only one person in each arm developed a new mutation during the course of the study (one raltegravir mutation and one emtricitabine mutation).
Side effect numbers were similar overall between the two arms, although diarrhea appeared to occur more frequently in the Truvada arm (Reynes said the difference was not statistically significant) and lipid effects (specifically total cholesterol, HDL cholesterol and triglycerides) appeared worse on the raltegravir arm, a bit of an odd finding given that a study presented last year found raltegravir's effect on lipids to be modest at best. (In fielding a question on this finding from the audience, Reynes suggested that tenofovir's lipid-lowering effects may account for the statistical significance of the lipid difference between the two arms -- which is a fair point, but doesn't get around the fact that abnormally high lipid levels were reported more often on the raltegravir arm.) Creatinine phosphate levels were also much more likely to be elevated (13%) among people on the raltegravir arm. Reynes noted that the 96-week results will include breakdowns that further explore lipid issues, as well as adherence.
The upshot here is that, overall, both drugs appeared to be fine options for first-line therapy -- which is nice to hear, since both drugs are currently listed as preferred antiretrovirals in U.S. guidelines. Meanwhile, the NRTI-sparing regimen of Kaletra plus raltegravir performed as well as the NRTI-rich regimen of Kaletra plus Truvada, with the exception of some disparate side-effect blips. That's also nice news, but as I mentioned earlier, neither regimen is considered ideal first-line therapy; regimens based on atazanavir (Reyataz), darunavir (Prezista) or efavirenz (Sustiva, Stocrin) should probably be considered before turning to Kaletra.
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.