A once-daily dose of 800mg darunavir was as effective at suppressing viral load as a 600mg twice-daily dose in treatment-experienced patients who did not have resistance mutations to darunavir at the start of the trial. The once-daily dose was also less likely to cause lipid disturbances.
These findings from the ODIN (Once-daily Darunavir In treatment-experieNced patients) study were presented on Wednesday morning at the 17th Conference on Retroviruses and Opportunistic Infections (CROI) in San Francisco.
Darunavir (Prezista) has been approved at a dose of 600mg twice daily, boosted with low-dose (100mg) ritonavir.
Once-daily darunavir has not been approved for use in treatment-experienced patients.
Last October, published results of a small study of 80 patients indicated that once-daily darunavir might be effective in this group.
Now, the ODIN study has reported similar outcomes in a larger group of patients.
The randomised, open-label, post-licensing (Phase 3b) ODIN trial studied a total of 590 treatment-experienced patients.
To enter the study, patients were required to have been on a stable combination of anti-HIV drugs for at least three months and to have no known resistance mutations associated with darunavir.
They were randomised to take a once-daily dose of darunavir 800mg boosted by ritonavir 100mg, or the licensed twice-daily dose of darunavir 600mg boosted by ritonavir 100mg. All patients also received optimised therapy including two active nucleoside reverse transcriptase inhibitors (NRTIs).
The primary end point of the study was the proportion of virally suppressed patients (those with a viral load below 50 copies/ml) in each arm. The hope was to show the once-daily dose to be non-inferior to the twice-daily dose, that is, to have no more than a 12% difference in outcomes between the two arms after 48 weeks.
Baseline characteristics were comparable between the two study arms, mean viral load being 4.16 log10 and mean CD4 cell count 228 cells/mm3. Thirty-six percent were female, the median age was just over 40 years, and the group was racially diverse.
Overall, 46% of patients had never taken a protease inhibitor (PI) before. The median number of PI resistance mutations was three in the once-daily group and four in the twice-daily, with no primary PI mutations in either group. Patients with any darunavir-associated mutations were excluded from the study.
Discontinuation rates were 13.9% (once-daily) and 16.2% (twice-daily).
At week 48, by intent-to-treat analysis, 72.1% of those taking once-daily darunavir had a viral load below 50 copies/ml, compared to 70.9% of those taking the drug twice daily. This 1.2% difference (95% confidence interval [CI], -6.1% to +8.5%) fell within the ±12% allowable range, establishing the non-inferiority of the once-daily dose (p < 0.001).
Patients were also stratified into two groups according to their viral load – either ≤ 50,000 copies/ml or > 50,000 copies/ml. Response rates were extremely similar between the two arms in both the lower viral load group (78.4% once daily vs 76.8% twice daily) and in the higher viral load group (52.8% for both arms).
Increases in CD4 cell count were also comparable between those taking the drug once daily or twice daily (100 cells/mm3 vs 94 cells/mm3).
The proportion of patients discontinuing because of side-effects was similar between the two study arms (3.4% vs 4.1%).
However, once-daily dosing appeared to have a better safety profile. Serious adverse events were less frequent with once-daily dosing (5.4% vs 9.1%), as were grade 3 or 4 adverse events (7.8% vs 15.2%). Lipid profiles were better for once-daily dosing, with significantly fewer grade 2-4 elevations in triglycerides (5.2% vs 11.0%), total cholesterol (10.1% vs 20.6%) and LDL cholesterol (9.8% vs 16.7%).
Liver toxicity was slightly less common at once-daily dosing, although falling short of statistical significance, with fewer experiencing elevations in ALT (1.7% vs 3.5%, p = 0.20) and AST (2.1% vs 3.5%, p = 0.32) enzymes.
The investigators concluded that once-daily ritonavir-boosted darunavir (800/100mg) was effective and non-inferior to twice-daily (600/100mg) in treatment-experienced HIV-positive individuals with no darunavir resistance-associated mutations. When virologic failure did occur, it rarely led to resistance, with only one patient developing primary PI and darunavir-associated mutations after failure.
In a post-presentation question and answer session, one delegate commented on the relative lack of pre-existing PI resistance in the study population. Presenter Pedro Cahn noted that it would be possible to split out the results according to the number of baseline PI mutations, but did not state whether such a post-hoc analysis would be done.
Cahn P et al. Efficacy and safety at 48 weeks of once-daily vs. twice-daily darunavir/ritonavir in treatment-experienced HIV-1-positive patients with no darunavir resistance-associated mutations: the ODIN Trial. Seventeenth Conference on Retroviruses and Opportunistic Infections, abstract 57, San Francisco, 2010.