Efficacy and Safety of Once-daily Boosted Darunavir (Prezista) versus Lopinavir/ritonavir (Kaletra) in Treatment-naive HIV Patients: ARTEMIS Trial

Prezista Tablet

Kaletra Tablet

It is widely accepted that use of first-line antiretroviral therapy (ART) provides the best opportunity for achieving full suppression of HIV and preventing the emergence of drug-resistant strains of the virus. The ideal initial ART regimen is potent, durable, capable of preventing or delaying emergence of drug-resistant virus, and offers a convenient dosing schedule.

Use of the protease inhibitor (PI) darunavir (Prezista) with low-dose ritonavir (Norvir) (600/100 mg twice-daily) has demonstrated durable efficacy and a favorable safety profile in both treatment-naive and treatment-experienced HIV patients.

On the basis of the POWER studies in treatment-experienced patients with PI resistance [1,2], 800/100 mg once-daily darunavir/ritonavir was selected for assessment in patients with no prior treatment experience. The long half-life of darunavir when used with ritonavir supports the suitability of once-daily dosing for this population [3].

The ARTEMIS study (AntiRetroviral Therapy with darunavir ExaMined In naive Subjects) is assessing the efficacy and safety of once-daily darunavir/ritonavir as compared with lopinavir/ritonavir (Kaletra) in treatment-naive HIV patients over 192 weeks. Interim 48-week results of the ARTEMIS study are published in the current (July 31, 2008) issue of AIDS, and are summarized below.

In this Phase III, open-label trial, 689 participants with HIV RNA levels of at least 5000 copies/mL were stratified by viral load and CD4 cell count and were randomly assigned to receive 800/100 mg once-daily (qd) darunavir/ritonavir or 800/200 mg total daily lopinavir/ritonavir, given once- or twice-daily (bid), plus fixed-dose tenofovir/emtricitabine (Truvada). At baseline, the mean baseline viral load was 4.85 log10 copies/mL and the median CD4 count was 225 cells/mm3.

The primary objective of the study was to demonstrate non-inferiority of darunavir/ritonavir as compared with lopinavir/ritonavir in HIV RNA less than 50 copies/mL per-protocol time-to-loss of virological response at 48 weeks.

Results

• At 48 weeks, 84% of patients in the darunavir/ritonavir arm and 78% of those receiving lopinavir/ritonavir achieved HIV RNA less than 50 copies/mL (estimated difference 5.6 %).

• This demonstrated non-inferiority of darunavir/ritonavir as compared with lopinavir/ritonavir (P < 0.001).

• Patients with baseline HIV RNA of at least 100,000 copies/mL had a significantly higher response rate with darunavir/ritonavir compared with lopinavir/ritonavir (79% vs 67%; P < 0.05).

• Median CD4 cell count increases (non-completer = failure analysis) were 137 cells/mm3 with darunavir/ritonavir and 141 cells/mm3 with lopinavir/ritonavir.

• Patients receiving darunavir/ritonavir had a lower incidence of possibly treatment-related grade 2-4 gastrointestinal adverse events (7% versus 14%) and moderate-to-severe diarrhea (4% versus 10%) than those taking lopinavir/ritonavir.

• Rates of adverse events leading to drug discontinuation were 3% in the darunavir/ritonavir arm and 7% in the lopinavir/ritonavir arm.

In conclusion, the study authors wrote, "darunavir/ritonavir 800/100mg qd was non-inferior to lopinavir/ritonavir 800/200 mg at 48 weeks, with a more favorable safety profile. Significantly higher response rates were observed with darunavir/ritonavir in patients with HIV RNA at least 100 000 copies/ml."

They added that, "Darunavir/ritonavir 800/100 mg offers a new effective and well tolerated once-daily, first-line treatment option for treatment-naive patients."

Discussion

Once-daily 800/100 mg darunavir/ritonavir together with a fixed NRTI background combination was a highly effective and tolerable regimen for HIV patients starting therapy for the first time. Furthermore, once-daily darunavir/ritonavir was shown to be non-inferior to lopinavir/ritonavir in achieving HIV RNA suppression below 50 copies/mL.

In their discussion, the study authors noted that all patients receiving darunavir/ritonavir reached darunavir plasma concentrations that exceeded the protein-binding corrected EC50 (50% effective concentration), suggesting that 800/100 mg once-daily darunavir/ritonavir achieves the intended exposure in a wide range of treatment-naive patients infected with wild-type (non-mutated) virus.

At week 48, 84% of patients achieved undetectable HIV RNA, providing evidence of the potency of darunavir/ritonavir in this population and representing one of the highest response rates observed in treatment-naive participants in clinical trials to date.

According to the study authors, the efficacy of once-daily darunavir/ritonavir was not compromised in the subgroups of patients that typically are more prone to virological failure, including those with high baseline HIV RNA, low CD4 cell count, or poor adherence. In fact, patients with high pre-treatment HIV RNA were more likely to respond to once-daily darunavir/ritonavir than once- or twice-daily lopinavir/ritonavir, demonstrating the robustness of the darunavir regimen.

In summary, the authors wrote, "….patients receiving once-daily darunavir/ritonavir achieved high durable virologic response rates (which were comparable in patients with less favorable baseline characteristics or suboptimal adherence), had a low rate of discontinuation due to virologic failure or adverse events or both, did not develop protease inhibitor resistance upon failure, and had suitable drug exposure."

Finally, they stated, "These benefits, coupled with the favorable safety and pharmacokinetic profile of darunavir/ritonavir, suggest that darunavir/ritonavir 800/100 mg qd has the potential to become a first-line, once-daily treatment option for treatment-naive patients."

Orlando Immunology Center, Orlando, Florida; AIDS Healthcare Foundation, Los Angeles, CA; Republican Hospital of Infectious Diseases Clinical AIDS Center, St Petersburg, Russia; Infectious Diseases Unit, University Medical Centre, Hamburg-Eppendorf, Germany; Hospital Civil de Guadalajara, Guadalajara, Mexico; Chronic Diseases of Lifestyle Unit, Tygerberg, South Africa; Tibotec BVBA, Mechelen, Belgium; Tibotec Department, Janssen-Cilag B.V., Tilburg, Netherlands.

7/15/08

Reference

R Ortiz, E DeJesus, H Khanlou, and others. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-infected patients at week 48. AIDS 22(12): 1389-1397. July 31, 2008.

Citations in article

1. C Katlama, R Esposito, JM Gatell, and others. Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week results of POWER 1. AIDS 21: 395-402. 2007.

2. R Haubrich, D Berger, P Chiliade, and others. Week 24 efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients. AIDS 21: F11-F18. 2007.

3. V Sekar, S Spinosa-Guzman, E Lefebvre, and others. Clinical pharmacology of TMC114 - a new HIV protease inhibitor. 16th International AIDS Conference. Toronto, Canada. August 13-18, 2006. Abstract TUPE0083.