Odin -- Darunavir-Ritonavir Once or Twice Daily

Darunavir (Prezista) is a protease inhibitor that is an effective part of HAART when prescribed at a dose of 600 mg, taken with 100 mg of ritonavir (Norvir), both drugs taken twice daily. The presence of ritonavir raises and prolongs the levels of darunavir in the blood, allowing for once daily dosing of darnunavir when used at a dose of 800 mg together with 100 mg of ritonavir.

In the clinical trial Odin (TMC 144-229), researchers compared the effects of once-daily vs. twice-daily darunavir-ritonavir, both regimens taken with two nukes in moderately treatment-experienced participants. Importantly, all participants had HIV that was sensitive to darunavir and none had previously used drugs such as T-20 (enfuvirtide, Fuzeon), tipranavir (Aptivus) or darunavir.

Results after 48 weeks showed that once-daily darunavir-ritonavir was similarly effective to twice-daily darunavir-ritonavir.

Study Details

The average profile of participants at the start of the study was as follows:

• 36% females, 64% males
• age: 40 years
• CD4+ count: 225 cells
• viral load: 16,000 copies

Treatment History

About 45% of participants had never previously used a protease inhibitor. Indeed, most participants (85%) had HIV that was sensitive to the antiviral activity of approved protease inhibitors.

Based on treatment history and HIV resistance testing, most participants (75%) received two nukes in addition to darunavir-ritonavir.

Researchers randomly assigned participants to receive one of the following regimens:

• darunavir 800 mg together with 100 mg ritonavir, both taken once daily
• darunavir 600 mg together with 100 mg ritonavir, both taken twice daily

Results

After 48 weeks, the proportion of participants whose viral load was less than 50 copies/mL was as follows:

• once-daily darunavir-ritonavir: 72%
• twice-daily darunavir-ritonavir: 71%

Another way to assess the effectiveness of study medications is to examine the proportion of people whose viral loads at the start of the study were more or less than 50,000 copies/mL and how treatment affected the proportion whose viral loads later fell below 50 copies/mL.

Virologic success when baseline viral loads were more than 50,000 copies:

• once-daily darunavir-ritonavir: 53%
• twice-daily darunavir-ritonavir: 53%

Changes in CD4+ cell counts were as follows:

• once-daily darunavir-ritonavir: 100 more CD4+ cells
• twice-daily darunavir-ritonavir: 94 more CD4+ cells

What About Drug Levels?

Although darunavir levels in the blood of participants taking the once-daily regimen were less (1,896 ng/mL) than detected in participants who took this drug twice daily (3,197 ng/mL), it was still many times greater than needed to suppress HIV.

Resistance

The proportion of participants with virologic failure in both groups was as follows:

• once-daily dose: 22%
• twice-daily dose: 18%

This difference was not statistically significant. In most cases of virologic failure, participants' regimens were never able to suppress their viral loads below the 50-copy/mL mark. A detailed analysis of why this happened has not yet been publicly released. Preliminary findings suggest that only one case of resistance to darunavir developed in people with virologic failure.

Side Effects

Historically, protease-inhibitor-based regimens have been difficult to tolerate. However, newer regimens based on lopinavir (in Kaletra), atazanavir (Reyataz) or darunavir are generally better tolerated. Regarding some specific side effects, here is the proportion of participants who experienced mild-to-moderate symptoms that researchers stated were "at least possibly related to darunavir":

Nausea

• once-daily darunavir: 4%
• twice-daily darunavir: 4%

Vomiting

• once-daily darunavir: 2%
• twice-daily darunavir: 3%

Diarrhea

• once-daily darunavir: 4%
• twice-daily darunavir: 4%

The proportion of participants who had severe-to-life-threatening adverse events were as follows:

• once-daily darunavir: 8%
• twice-daily darunavir: 15%

Unfortunately, no details are yet publicly available about these adverse events.

Two people died in the once-daily group and six in the twice-daily group, but investigators did not consider these deaths to be related to exposure to darunavir.

Lab Tests

In general, levels of lipids -- triglycerides, total cholesterol and bad (LDL) cholesterol -- in the blood were greater among people taking the twice-daily rather than the once-daily regimen; these differences were statistically significant.

The proportion of people with elevated liver enzymes (ALT and AST) ranged between 2% in the once-daily group and 4% in the twice-daily group, but these differences were not statistically significant.

Summary

In moderately treatment-experienced participants, half of whom had never used a protease inhibitor before, a regimen that included once-daily darunavir-ritonavir 800-100 mg was similarly effective to a twice-daily regimen of darunavir-ritonavir 600-100 mg.

Rates of virologic failure were low and in only one case did resistance to darunavir develop.

The once-daily regimen was well tolerated with low rates of diarrhea and few dropouts due to side effects.

Results from Odin suggest that once-daily darunavir-ritonavir 800-100 mg could be considered for people whose previous regimens have failed and who have no mutations in their HIV that enable it to resist the effect of darunavir.

Reference

1. Cahn P, Fourie J, Grinsztejn B, et al. Efficacy and safety at 48 weeks of once-daily vs. twice-daily darunavir/ritonavir in treatment-experienced HIV-1 patients with no darunavir resistance-associated mutations: the Odin trial. In: Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections, 16-19 February 2010, San Francisco, U.S. Abstract 57.