June 8, 2012
Paul E. Sax, M.D., is director of the HIV Program and Division of Infectious Diseases at Brigham and Women's Hospital in Boston.
Ninety-three treatment-naive HIV-positive study subjects were randomized 2:1 to receive either a two-drug regimen of raltegravir 400 mg BID + atazanavir 300 mg BID, or a standard regimen of TDF/FTC + boosted atazanavir. (The higher ATV dose in the two-drug arm targeted ATV exposures comparable to those achieved by ritonavir-boosting.)
At week 24, virologic suppression rates numerically favored the two-drug regimen (75% vs 63%); as a small pilot study, the trial was not powered for a statistical comparison between the two arms. As has been observed in other studies of integrase inhibitors, the non-integrase group had a slower initial response and appeared to be catching up.
Despite these early favorable results, there were 6 virologic failures in the RAL + ATV group -- vs only 1 in the standard arm -- and 4 of these failures showed evidence of raltegravir resistance. Notably, all 4 of these patients with resistance had baseline HIV RNA > 100,000, a similar finding to ACTG 5162 (which examined RAL + darunavir/r). Rates of grade 3-4 and grade 4 hyperbilirubinemia were also higher in the ATV + RAL arm. Based on these efficacy and safety results, the sponsor elected to terminate the study.
As I've noted before, initial two-drug HIV therapy without NRTIs hasn't fared well, even when it includes our best drugs. In addition, we still don't know why these two-drug regimens don't do as well, especially in patients with high viral loads.
Furthermore, the protective effect that boosted PIs have on the development of NRTI resistance doesn't apply either to NNRTIs (as shown in ACTG 5142) or to raltegravir (again, ACTG 5162). And though in SPARTAN ritonavir-boosting wasn't used, it doesn't appear we can blame PK, as ATV exposures indeed were comparable to those seen with ATV/r dosed at 300/100 mg daily. Do the NRTIs provide some key antiviral component mechanistically? Do we just not have the right two active drugs? Or is there something magic about using 3 rather than 2 drugs, regardless of mechanism of action?
Suffice to say, the results of the fully powered NEAT study -- which compares RAL to TDF/FTC, with all study subjects receiving boosted darunavir -- will be of great interest, as will a similar study that uses maraviroc instead of raltegravir.
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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