August 28, 2013
Final results of a pivotal double-blind study of the new HIV integrase inhibitor dolutegravir (Tivicay) were presented at IAS 2013. These final results fully confirm early, 24-week results shown at CROI 2013.
Subjects with virologic failure (a viral load above 400 copies/mL) and who had resistance to at least two drug classes (but were integrase naive) were randomized to dolutegravir 50 mg once-daily or raltegravir 400 mg twice-daily, along with a background regimen of two antiretrovirals (one of which was required to be fully active). Randomization was stratified by plasma viral load (greater or less than 50,000 copies/mL), darunavir/ritonavir use and the number of fully active drugs.
A total of 715 subjects were included, with a median CD4+ cell count of 193 to 205 cells/mm3. Approximately half of all patients had resistance to three or more antiretroviral classes, and only 20% had darunavir/ritonvair use and no primary protease inhibitor mutations.
At 48 weeks, 71% of dolutegravir pateints and 64% of raltegravir patients had a plasma viral load below 50 copies/mL in a snapshot of an exploratory modified intent-to-treat analysis (treatment difference 7.4%, 95% CI 0.7, 14.2), thus demonstrating dolutegravir superiority. The difference was mainly driven by virologic non-response rates: 6% vs 12%, respectively, at 48 weeks. Dolutegravir was also superior in subjects with a baseline plasma viral load above 50,000 copies/mL, a PS score of 2 (but not in those with a PS score less than 2), those with no darunavir/ritonavir use, and those with darunavir/ritonvair use who had primary protease inhibitor mutations. Of importance, dolutegravir was also found to be superior in an efficacy-related discontinuation=failure analysis.
No differences were observed in the median CD4+ cell change or in adverse events.
In terms of resistance data, 1% of dolutegravir patients vs. 5% of raltegravir patients had emergence of integrase resistance, which was not depicted at the IAS 2013 presentation. It must be remembered that in the 24-week presentation at CROI 2013, subjects who failed raltegravir had complete resistance to the drug, while subjects who failed dolutegravir had virus that selected R263 substitutions, which conferred only low fold-change increases for both dolutegravir and raltegravir -- not resistance. Of interest, treatment-emergent resistance to the background regimen was also significantly lower with dolutegravir: 1% vs 3% (difference -2.2%; -4.3, -0.1).
Two separate reports (MOPE014 and MOPE022) from Mark Wainberg's group at McGill University explained how difficult it is for HIV-1 to develop resistance against dolutegravir, due to the fact that so far no secondary mutations accompanying R263K have been shown to restore the infectivity and replication defects (viral fitness), and that the mutations only modestly increase dolutegravir resistance.
This study will likely wipe raltegravir from any salvage regimen. It underlines the urgent need of dolutegravir in such a scenario.
Which other studies presented at IAS 2013 will have lasting impact long after memories of the conference itself have faded? Read more of Dr. Llibre and Dr. Young's top picks.