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"Novel" Approaches to Initial HIV Therapy

By Paul E. Sax, M.D.

September 6, 2011

It's been several years since the "preferred" or "recommended" initial regimens for HIV treatment have been consolidated into one of the following four:

  1. TDF/FTC + efavirenz
  2. TDF/FTC + atazanavir/r
  3. TDF/FTC + darunavir/r
  4. TDF/FTC + raltegravir

Any room for improvement in this "TDF/FTC + key third drug" approach? With the recent approval of TDF/FTC/rilpivirine, certainly this will have a role in some patients, but the issues of excess virologic failure and resistance in those with high viral loads will likely limit its use.

And though extended release nevirapine has been available for months, I confess it hasn't really occurred to me to use it in a patient starting treatment given the other options out there. (And even those who are currently stable on NVP twice daily don't seem eager to switch -- I've offered.)

Now along come two interesting papers testing alternative initial treatment strategies. Both have quite interesting results that definitely got my attention when presented earlier this year at major meetings, small size of the studies notwithstanding.

The first is a blinded, randomized trial comparing etravirine and efavirenz, both given with TDF/FTC. Note that the etravirine was dosed once-daily -- not the twice-daily manner in which it is approved -- and given in the older 100 mg (very crumbly) tablet formulation. Note also that the primary endpoint was the percentage of patients with Grade 1-4 drug-related CNS side effects, and not virologic efficacy. Since it was powered off differences in this side effect, only 157 patients were enrolled, not the 600 or so typically seen in a comparative study of efficacy.

Nonetheless, the results are impressive: 76% vs 74% in the etravirine and efavirenz arms respectively have VL < 50 at week 48, and for the group with baseline VL > 100,000, the results are 74% vs 67% -- which is perhaps the first time in HIV study history that a regimen is numerically superior to EFV in this high viral load stratum. Also of interest, among the four patients with virologic failure on etravirine, zero show emergent resistance mutations -- very unusual for an NNRTI -- vs 3 of 7 for efavirenz.

Oh, and the primary endpoint -- the occurrence of CNS side effects -- significantly favors etravirine, as do lipid changes.


These results have to be considered encouraging on multiple fronts, including efficacy (caveat: small sample size, I know), resistance, tolerability, and lipid effects. Plus, with the newer 200 mg formulation of etravirine, this is an initial regimen of just three pills once-daily. Consider me impressed.

(Nerdy HIV specialist historical quiz question: how many pills/day was etravirine when in phase I/II studies? Hint, it was a lot.)

The second paper is a single-arm (n=112) study of darunavir/r (once daily) plus raltegravir, the latest riff on the "NRTI sparing" approach.

As I mentioned when I first covered this study, the high rate of virologic failure -- 26% overall, and a whopping 43% (21 of 49) with viral loads > 100,000 -- came as a complete shock. In fact, I would have bet good money that this regimen would work just fine. (Glad I''m not a betting man -- except in poker.) Five of the 28 virologic failures developed integrase resistance, all of them from the high VL stratum.

Why is this so surprising? You have the antiviral potency of raltegravir plus the high genetic resistance barrier of boosted darunavir -- so what went wrong?

The study authors offer some possible explanations for these disappointing results (suboptimal adherence, asymmetrical dosing, lowered darunavir concentrations from raltegravir, minority variants resistant to raltegravir), but the bottom line is that this regimen just didn't work very well. A fully-powered comparative study (darunavir/r plus raltegravir or TDF/FTC) is ongoing in Europe; I'm sure their DSMB is keeping a close eye on the results.

So two non-standard approaches to initial HIV therapy, with TDF/FTC + etravirine looking promising, and darunavir/r + raltegravir much less so.

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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