SUMMARY: Taking ritonavir-boosted darunavir (Prezista) once instead of twice per day leads to equally good virological suppression in previously treated individuals, according to a presentation at the 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010) last week in San Francisco. The once-daily regimen was associated with fewer side effects and did not lead to development of drug-resistance mutations.

By Liz Highleyman

Pedro Cahn presented findings from the ODIN Trial (TMC114-C229), a Phase 3b open-label study comparing the efficacy, safety, and tolerability of once-daily versus twice-daily boosted darunavir in treatment-experienced patients. Once-daily darunavir/ritonavir is currently approved for first-line therapy, but not for previously treated individuals.

The study included 590 participants. A majority (64%) were men and the mean age was 40 years. All had detectable viral load (mean of approximately 15,000 copies/mL), a CD4 cell count > 50 cells/mm3 (median 228 cells/mm3), and no pre-existing darunavir resistance-associated mutations. They were stratified according to whether their viral load was above or below 50,000 copies/mL.

Participants had been on a stable combination antiretroviral therapy (ART) regimen for at least 12 weeks at the time of screening. Overall, 46% had never been exposed to protease inhibitor and 13% had not used non-nucleoside reverse transcriptase inhibitors (NNRTIs). More than half (60%) had at least 2 other active drugs in their background regimen.

Participants were randomly assigned (1:1) to receive either darunavir/ritonavir 800/100 mg once-daily or darunavir/ritonavir 600/100 mg twice-daily for 48 weeks, along with an optimized nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone. Baseline characteristics were similar in the 2 treatment arms.

Unlike some drugs, the once-daily darunavir/ritonavir dose does not simply double the twice-daily dose and take it all at once, but rather allows patients to use a considerably lower total amount per day.

The study was designed to establish non-inferiority of the once-daily regimen with a margin of 12%.

Results

	At week 48, similar proportions of patients in the once-daily darunavir/ritonavir arm (72.1%) and the twice-daily arm (70.9%) achieved HIV RNA < 50 copies/mL.
	The difference in response was 1.2%, falling comfortably within the 12% margin and thus establishing non-inferiority (P < 0.001).
	Within the low baseline viral load group, the respective virological response rates were 78.4% in the once-daily arm vs 76.8% in the twice-daily arm.
	Among those with high baseline viral load, the response rate was 52.8% in both arms.
	There were 65 instances of virological failure in the once-daily arm (22.1%) compared with 54 (18.2%) in the twice-daily arm.
	Median CD4 cell gains were 100 cells/mm3 in the once-daily arm and 94 cells/mm3 in the twice-daily arm, not a significant difference.
	10 people (3.4%) in the once-daily arm and 14 (4.7%) in the twice-daily arm discontinued the study due to adverse events.
	Moderate-to-severe adverse events were about half as frequent in the once-daily arm (7.8%) compared with the twice-daily arm (15.2%).
	This difference was largely due to differences in lipid abnormalities, as grade 2-4 lipid changes were about half as common.
	Only 1 individual developed a primary protease inhibitor resistance-associated mutation, in the once-daily arm.

"Once-daily [darunavir/ritonavir] 800/100 mg was effective and non-inferior to [darunavir/ritonavir] 600/100 mg bid over 48 weeks," the investigators summarized.

"Virological failure was low and rarely resulted in resistance," they continued. "[Darunavir/ritonavir] was generally well tolerated" and there were "few discontinuations due to adverse events."

"These findings suggest that once-daily [darunavir/ritonavir] could be considered an option for patients failing previous treatments with no [darunavir] resistance-associated mutations."

Fndn Huesped, Buenos Aires, Argentina; Med Res Council, Tygerberg, South Africa; Inst de Pesquisa Clin Evandro Chagas-Fiocruz, Rio de Janeiro, Brazil; Univ of Med and Dentistry of New Jersey, Newark, NJ; Hosp St-Louis, Paris, France; Thai Red Cross AIDS Res Ctr, Chulalongkorn Univ, Bangkok; Ground Zero Med Ctr, Darlinghurst, Australia; Tibotec BVBA, Mechelen, Belgium; Tibotec Inc, Yardley, PA.

2/26/10

Reference
P Cahn, J Fourie, B Grinsztejn, and others. Efficacy and Safety at 48 Weeks of Once-daily vs Twice-daily DRV/r in Treatment-experienced HIV-1+ Patients with No DRV Resistance-associated Mutations: The ODIN Trial. 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 57.