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October 25th, 2013
GARDEL Two-Active-Drug Study Not a Game-Changer, but Might Be a Paradigm-Shifter
Don’t look now, but a two-drug lamivudine (3TC) + LPV/r strategy did just as well as a standard three-drug regimen of two NRTIs + LPV/r. Better, actually, since virologic outcomes were the same and the two-drug regimen had fewer side effects.
Here are the key details about the GARDEL study, presented just this week by Pedro Cahn at the European AIDS Clinical Society meeting, or EACS:
- Study design: Open-label, randomized clinical trial in 426 treatment naive patients.
- Randomization was to 3TC 150 mg BID or 3TC plus an investigator-selected 2nd NRTI; all study participants received LPV/r twice-daily.
- At 48 weeks, 88% of the double-therapy and 84% of the triple-therapy arms had HIV RNA <50 copies/mL
- 1% vs 5% (p = 0.03) in the double- and triple-therapy arms met failure criteria due to no data at week 48 due to stopping treatment or death (mostly stopping treatment; there was only 1 death).
- Rates of virologic failure and resistance were not significantly different between arms.
Ah, but we’re all thinking, what about the high viral load stratum — surely this group would need the extra potency of a three-drug regimen.
But surely we’d be wrong: 87% vs 78% were <50 at week 48, so the difference favoring double-therapy was even greater.
In the “Timing is Everything” category, my recent review of the failed MODERN study of maraviroc + DRV/r included this bit of prescience when discussing why the various two-drug regimens have failed:
What remains unclear is why these two-drug regimens have been so disappointing. Is two drugs not enough? Or maybe just the two drugs tested to date in these clinical studies? Is there something magic about the NRTIs? Or certain NRTIs? (One vote could be for 3TC or FTC, which have been part of every truly great HIV regimen since the late 1990s.)
I added the bolding, because it’s always advisable to highlight when you’re right to help balance out all those times that you’re wrong.
(And believe me, there have been lots of the latter over the years. Just ask my kids. And in HIV treatment, too — remember ddI/d4T/hydroxyurea? What were we thinking?)
So in the HIV world, this study is pretty big news, that much is clear. A two-drug regimen has never done better than a three-drug treatment in a fully powered study.
But will it influence clinical practice? Not right now, I don’t think, which makes this more of a paradigm-shifter than a game-changer. (See, doctors can mobilize business-school cliches too.)
Here are at least four reasons why:
- It’s a three-pill, twice-daily regimen, and commonly used first line regimens are now all easier than that.
- Related, boosted-PI based regimens have lots (and increasing) competition in first-line therapy, especially from integrase-based strategies.
- Clinical practice and treatment guidelines have moved away from lopinavir/r due to study data and clinical experience showing that it has higher rates of adverse effects (GI, lipids) than once-daily atazanavir and darunavir.
- The generalizability of the study results might be limited given that the most common second NRTI chosen by the investigators was zidovudine (54%), followed by tenofovir (37%) and abacavir (9%).
These caveats notwithstanding, the GARDEL study raises several interesting questions:
- Would ATV/r or DRV/r have done as well with just 3TC? Or is LPV/r in this context better? I can’t see why, but of the various two-drug PI plus raltegravir studies, this one with LPV/r seemed to do the best.
- Would once-daily 3TC have done as well? Remember, half-life of 3TC is shorter than FTC.
- What future fixed-dose regimens could we envision, especially as cobicistat-based PI combinations emerge and 3TC is now generic?
- How would a two-drug, 3TC or FTC plus boosted-PI regimen fare as a maintenance strategy? I suspect quite well, though for published data all we have is this small study with ATV/r.
So there you have it, the GARDEL study in all its disruptive innovation glory. You can mail the MBA to my home address.