Once-Daily Raltegravir "Not Non-Inferior" to Twice-Daily

November 29, 2010

In your electronic in-box this AM, this press release from Merck:

... although the treatment regimen that included ISENTRESS once daily enabled more than 80 percent of patients to achieve viral suppression, ISENTRESS once daily did not demonstrate non-inferiority to the treatment regimen that included ISENTRESS twice daily. Merck said that based on the initial results, and following the recommendation of an independent Data Monitoring Committee, Merck will end the study

Raltegravir is of course still a great HIV drug, and its approval in 2007 marked one of the great steps forward in the history of HIV therapeutics.

I still remember John Mellors at CROI 2007 preparing us to see the BENCHMRK data for the first time -- his exact words were probably not, "this will knock your socks off", but they could have been. Never before had any antiretroviral agent done so spectacularly well in patients with high-level resistance, and it's hard to estimate how many patients with longstanding HIV infection have had their lives literally saved with raltegravir.

But is it a once-daily drug? Probably not based on the results of this study, where twice-daily was simply better -- or, to be more statistically precise, once-daily did not demonstrate non-inferiority.

And in an odd recapitulation of the early days of the protease-inhibitor era, the story is quite similar to what happened to indinavir, another Merck antiretroviral:

  • Both drugs were major advances in the field
  • Both drugs had an odd disconnect between PK and response
  • Both drugs failed tests of less-frequent dosing

The major difference, of course, is that even the once-daily raltegravir arm in this study did quite well -- an 83% response is not too shabby.

It's just that today, our standard-of-care for first-line therapy is (wonderfully) high, and the twice-daily treatment arm had an 89% success rate, with the advantage seen in particular in patients with HIV RNA > 100k. The difference in response put the once-daily approach just outside of the protocol-specified criterion for non-inferiority.

And this steep price of entry for treatment-naive options is why both elvitegravir/c and 572, though promising, still have their work cut out for them.

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.

This article was provided by NEJM Journal Watch. NEJM Journal Watch is a publication of the Massachusetts Medical Society.

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