Darunavir/ritonavir superior virologically and immunologically to comparator drugs over one year

The boosted protease inhibitor darunavir/ritonavir (formerly TMC114/r and licensed as Prezista in the United States) provides superior suppression of HIV compared to comparator boosted protease inhibitors in highly treatment experienced individuals, according to the combined results of the POWER 1 and POWER 2 studies presented to the Sixteenth International AIDS Conference in Toronto on August 15^th. Almost half of protease-inhibitor experienced patients still had viral load below 50 copies/ml 48 weeks after starting treatment with darunavir.

The investigators from the POWER studies also found that darunavir had a side-effect profile similar to that of comparator protease inhibitors, but was less likely to cause diarrhoea.

Interim 24-week analysis of the POWER 1 and POWER 2 studies showed that darunavir boosted by low-dose ritonavir had superior anti HIV activity than comparator ritonavir-boosted protease inhibitors in highly treatment-experienced individuals. The best results were seen in patients wo received the 600/100mg twice daily dose of darunavir/ritonavir together with an optimised background of other antiretroviral drugs.

To assess the long-term safety and efficacy of darunavir/ritonavir investigators performed a 48-week combined analysis of the POWER 1 and POWER 2 studies.

Patients in both trials has previously received therapy with drugs from each of the three main classes of antiretrovirals and had a median of three major resistance-conferring protease inhibitor mutations. Because a number of different doses of darunavir/ritonavir were investigated in the POWER studies, the investigators selected the 600/100mg twice-daily dose, which subsequently went forward for licensing in the US, for comparison with the alternative regimens in the studies. The primary outcome was the proportion of patients with a 1 log₁₀ reduction in viral load.

Participants also received a background antiretroviral regimen that had been optimised by resistance testing, and almost two-thirds of patients in both arms had virus sensitive to only one remaining protease inhibitor. Approximately 72% in each arm had virus sensitive to one or more nucleoside analogues.

At weeks 24 and 48 the 600/100mg twice-daily dose of darunavir/ritonavir achieved a significantly superior virological and immunological response than the comparator boosted protease inhibitors.

The investigators first looked at the proportion of patients with a 1 log₁₀ reduction in viral load. At 24 weeks, 70 of the 131 patients randomised to take darunavir/ritonavir had achieved this outcome, compared to only 21 of the 124 individuals taking a comparator protease inhibitor, a highly significant difference (p < 0.001). Similar results were seen at 48 weeks, with 61% of the 110 individuals taking darunavir/ritonavir experiencing a 1 log₁₀ reduction in viral load compared to only 15% of the 110 patients taking a comparator boosted protease inhibitor (p < 0.001).

Attention was then focused on the proportion of patients who achieved a fall in their viral load to below 50 copies/ml. This outcome was achieved by 45% of the 131 individuals taking darunavir/ritonavir at week 24, but by only 12% of the 124 patients taking a comparator drug (p < 0.01). At week 48, 46% of the 110 individuals taking darunavir/ritonavir had an undetectable viral load, compared to only 10% of the 110 individuals taking a comparator drug, once again, this difference was highly statistically significant (p = 0.003).

Mean reduction in viral load at 24 and 48 weeks was then examined. Once again, patients taking darunavir/ritonavir had superior results. At week 24, the mean reduction in viral load was 1.89 log₁₀ for patients taking darunavir/ritonavir, but only 0.48 log₁₀ for patients taking a comparator drug (p < 0.001). At 48 weeks. mean reduction in viral load was 1.63 log₁₀ amongst the darunavir/ritonavir-treated patients, versus only 0.35 log₁₀ in the comparator arm (p < 0.001).

When virological efficacy was analysed according to components of the background regimen and baseline sensitivity to darunavir, investigators found:

• Darunavir-treated patients who were naive to enfuvirtide had a significantly greater viral load reduction if they included enfuvirtide in their background regimen. Twenty-one of 36 achieved a viral load reduction of at least 1 log, compared with only four of 35 enfuvirtide-naive patients who did not receive darunavir. However, a similar effect was not seen if darunavir was added to a regimen that already included enfuvirtide.
• Almost half (24 of 55) of patients with three primary protease inhibitor mutations at baseline who received darunavir achieved a viral load reduction of at least 1 log, compared to just four of 74 patients in the control arm.
• More than half of patients with a 10-40-fold reduction in susceptibility to darunavir at baseline achieved a 1 log viral load reduction in the darunavir arm, compared to 11 of 76 in the control arm. However, none of the ten patients with a reduction in susceptibility of greater than 40-fold achieved a 1 log viral load reduction.

Unsurprisingly, the superior virological efficacy of darunavir/ritonavir resulted in a greater increase in CD4 cell count than that seen in the comparator arm. At 24 weeks, the mean increase in CD4 cell count was 92 cells/mm³ amongst patients taking darunavir/ritonavir but only 17 cells/mm³ in the comparator arm (p < 0.001). Similar results were seen at week 48, the mean increase in CD4 cell count being 102 cells/mm³ in the darunavir/ritonavir arm and 19 cells/mm³ in the comparator arm (p = 0.005).

Finally, the investigators looked at data regarding the safety of darunavir/ritonavir and the comparator protease inhibitors. The side-effects most commonly associated with darunavir/ritonavir were, as would be expected with a protease inhibitor, diarrhoea (20%), nausea (18%) and headache (15%). The investigators noted, however, that significantly more patients taking a comparator protease inhibitor reported both diarrhoea (28%) and headache (20%).

The investigators conclude that darunavir/ritonavir “has demonstrated sustained efficacy in this treatment experienced population.”