November 18th, 2012

The 800-mg Darunavir Tablet Arrives, and Scoring the Top Protease Inhibitors

The FDA has approved an 800-mg tablet of darunavir for treatment naive patients. This single tablet will obviously replace the two darunavir 400-mg tablets in first-line therapy. (Yes, my math is that good.) Darunavir will still require 100-mg ritonavir boosting plus two NRTIs to make a complete regimen.

Once upon a time I might have thought this was no big deal, but patients love taking fewer pills, even if it’s only reduced by one.

More importantly, it brings the darunavir-based regimen pill burden into parity with boosted atazanavir, with both now at three — PI (one), ritonavir (two), and TDF/FTC or ABC/3TC (three). What was once a win for atazanavir — fewer pills — is now a wash.

(I should mention here parenthetically that some day this could all be one pill made up of darunavir, cobicistat, FTC, and the recently named “TAF” — a.k.a., tenofovir alafenamide, GS-7340.)

So let’s assume you’re starting with a boosted-PI based regimen; which of these two “preferred” PIs should you choose, atazanavir or darunavir? Pending the results of ACTG A5257 — which is a fully-powered three-way comparison of atazanavir vs. darunavir vs. raltegravir — we have to make some inferences from existing data:

  • Efficacy — Atazanavir was not demonstrably different from efavirenz in A5202, and that’s saying something (efavirenz generally beats PIs); plus, it recently all but tied TDF/FTC/EVG/c (“Quad”). Fewer studies have looked at darunavir in naives — there’s really only this one vs. LPV/r — but there’s abundant evidence darunavir works well in treatment-experienced patients, who are arguably harder to treat. ASSESSMENT:  EVEN.
  • Safety and tolerability — Atazanavir can (rarely) cause jaundice, and kidney stones, and even gallstones. Darunavir seems to have a higher rate of rash, though this isn’t completely clear from clinical studies (but anecdotally it is). Darunavir also has a special warning about liver toxicity in the package insert, but LFT abnormalities are not significantly different from comparators in clinical trials. ASSESSMENT:  DARUNAVIR WINS.
  • Metabolics — Among the PIs, atazanavir has consistently had the most favorable metabolic profile, and in A5202, lipids were actually better than efavirenz. Moreover, it’s been given the A-OK on cardiovascular risk from the D:A:D folks — not enough data yet for darunavir. And while this small study suggests no major differences between atazanavir and darunavir in lipid effects, if you squint at the data, they sort of favor atazanavir. Finally, did you know that raising bilirubin might actually have some favorable cardiovascular attributes?  ASSESSMENT:  ATAZANAVIR WINS.
  • Resistance — These are both boosted PIs, which means they are unfathomably and inexplicably and consistently great at preventing resistance. Patients can start and stop and start and stop and start and stop these regimens, and they will still work once people commit to treatment. Who can explain this mysterious property? Not me. ASSESSMENT:  EVEN.
  • Drug-drug interactions — Atazanavir requires stomach acidity for optimal absorption, which means that PPIs are generally to be avoided. Yes, the package insert has some advice about taking acid-reducing therapy and atazanavir, but why risk it? Darunavir has something funny going on with pravastatin, but there are plenty of other (better) statin options anyway. Similarly, even though only atazanavir among the PIs can be given with telaprevir, who will be using that drug in 12-24 months? ASSESSMENT:  DARUNAVIR WINS.
  • Pharmacokinetics:  Let’s imagine that your patient is a ritonophobe, and periodically (or regularly) takes everything in the regimen but ritonavir. (Not that anyone would ever do that. Sarcasm.) Unboosted atazanavir is almost a legitimate first-line option, whereas darunavir without ritonavir isn’t even close. ASSESSMENT:  ATAZANAVIR WINS.
  • Pill burden — weren’t you listening? Both are now the same. ASSESSMENT:  EVEN.
Note I didn’t include the “sequencing” argument — you know, that darunavir is our most important PI in patients with extensive PI resistance, so we should save it for that setting, using atazanavir as the initial PI. First, very few patients get high-level PI resistance cases these days, and second, all the prior sequencing arguments (e.g., nelfinavir before lopinavir, d4T before AZT, nevirapine before efavirenz) have been more about marketing than science. And some were just wrong.

Cost is another factor I didn’t include, since the prices of these drugs are pretty close, vary by payor, and also differ based on region. Given how similar they are clinically, it seems to me that if one were significantly cheaper that would make a big difference.

In sum, as you can see from my list above, I have atazanavir vs. darunavir as a draw.

What do you think?

Now that both atazanavir and darunavir are one pill each, which is the better first choice?

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6 Responses to “The 800-mg Darunavir Tablet Arrives, and Scoring the Top Protease Inhibitors”

  1. E says:

    “Who can explain this mysterious property?”
    Daniel Rosenbloom:

    Seriously, you’re gonna have to fight through a bit of math, but if you do, you’ll find that this paper has a beautiful explanation of what makes PIs so… resistant… to resistance.

  2. Francois Kidd says:

    what about nephrotoxicity of TDF/FTC ATV ?

    • Paul Sax says:

      what about nephrotoxicity of TDF/FTC ATV ?

      Good point — I considered mentioning this, but lots of the data are still observational, and not from comparative clinical trials. But let’s see what A5257 shows!


  3. David Ferris says:

    How big is the 800mg pill?

  4. Juan Pablo Caeiro says:

    Great summary, I always enjoy Dr. Sax humor and knowledge.
    Very practical tips.
    What about HIV infected patients and solid organ transplant.
    Lots of drug-drug interactions. Darunavir wins?

    • Paul Sax says:

      Hi Juan,
      Numerically, darunavir probably does have more drug-drug interactions than atazanavir (though I confess I haven’t counted). But I chose darunavir as the winner in this one since the PPI interaction with atazanavir comes up very frequently in clinical practice, much more so than any of the others.

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Paul E. Sax, MD

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