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GARDEL Two-Active-Drug Study Not a Game-Changer, but Might Be a Paradigm-Shifter

By Paul E. Sax, M.D.

October 25, 2013

Don't look now, but a two-drug lamivudine (3TC) + LPV/r strategy did just as well as a standard 3-drug regimen of 2 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:

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 maravirc + 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:

  1. It's a 3-pill, twice-daily regimen, and commonly used first line regimens are now all easier than that.
  2. Related, boosted-PI based regimens have lots (and increasing) competition in first-line therapy, especially from integrase-based strategies.
  3. 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.
  4. 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:

So there you have it, the GARDEL study in all it's disruptive innovation glory. You can mail the MBA to my home address.

Paul Sax is Clinical Director of Infectious Diseases at Brigham and Women's Hospital. His blog HIV and ID Observations is part of Journal Watch, where he is Editor-in-Chief of Journal Watch AIDS Clinical Care.




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