Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naive patients in the ARTEMIS trial

Barts and The London NHS Trust, London, UK.
HIV Medicine (Impact Factor: 3.99). 10/2012; 14(1). DOI: 10.1111/j.1468-1293.2012.01060.x
Source: PubMed


This paper presents the final analysis of once-daily darunavir/ritonavir (DRV/r) vs. lopinavir/ritonavir (LPV/r) in treatment-naïve HIV-1-infected adults.
ARTEMIS (AntiRetroviral Therapy with TMC114 ExaMined In naïve Subjects; NCT00258557) was a randomized, open-label, phase-III, 192-week trial. Patients were stratified by baseline HIV-1 RNA and CD4 count, and randomized to once-daily DRV/r 800/100 mg or LPV/r 800/200 mg total daily dose (either once or twice daily) plus tenofovir/emtricitabine.
Of 689 randomized patients receiving treatment (DRV/r: 343; LPV/r: 346), 85 and 114 patients in the DRV/r and LPV/r arms, respectively, had discontinued by week 192. Noninferiority was shown in the primary endpoint of virological response (HIV-1 RNA < 50 copies/mL) [DRV/r: 68.8%; LPV/r: 57.2%; P < 0.001; intent to treat (ITT)/time to loss of virological response; estimated difference in response 11.6% (95% confidence interval 4.4–18.8%)]. Statistical superiority in virological response of DRV/r over LPV/r was demonstrated for the primary endpoint (P = 0.002) and for the ITT non-virological-failure-censored analysis (87.4% vs. 80.8%, respectively; P = 0.040). No protease inhibitor (PI) primary mutations developed and only low levels of nucleoside reverse transcriptase inhibitor (NRTI) resistance developed in virological failures in both groups. Significantly fewer discontinuations because of adverse events were observed with DRV/r (4.7%) than with LPV/r (12.7%; P = 0.005). Grade 2–4 treatment-related diarrhoea was significantly less frequent with DRV/r than with LPV/r (5.0% vs. 11.3%, respectively; P = 0.003). DRV/r was associated with smaller median increases in total cholesterol and triglyceride levels than LPV/r. Changes in low- and high-density lipoprotein cholesterol were similar between groups. Similar increases in aspartate aminotransferase and alanine aminotransferase for DRV/r and LPV/r were observed.
Over 192 weeks, once-daily DRV/r was noninferior and statistically superior in virological response to LPV/r, with a more favourable gastrointestinal profile, demonstrating its suitability for long-term use in treatment-naïve patients.

16 Reads
  • Source
    • "ATV/r was stopped earlier than LPV/r, although this difference was not statistically significant. Orkin et al.[22]reported that DRV/ r produced fewer treatment-related adverse gastrointestinal events and less discontinuation due to adverse events. The incidence of hyperbilirubinemia was also lower during DRV/r therapy. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: The efficacy of antiretroviral therapy (ART) has improved, and the adverse effects of antiretroviral drugs have been reduced. However, these adverse effects still significantly influence patient compliance, increasing the risk of tolerability failure. Therefore, we investigated the adverse effects and tolerability failure causing changes in the first ART regimen, and identified the regimens that were most vulnerable to switching. Materials and methods: We enrolled patients with human immunodeficiency virus (HIV) who commenced their first ART between January 1, 2011 and July 30, 2014. Patients who started their first ART regimen at the Kyungpook National University Hospital were included in the study if they were aged ≥18 years and were followed-up for ≥12 weeks. The primary dependent variable was the duration of treatment on the same ART regimen. We analyzed the maintenance rate of the first ART regimen based on the treatment duration between these groups using survival analysis and log rank test. The frequency of the adverse effects of ART regimens was analyzed by multiple response data analysis. Results: During the investigation period, 137 patients were enrolled. Eighty-one patients were maintained on the initial treatment regimen (59.1%). In protease inhibitor (PI)-based regimen group, 54 patients were maintained on the initial treatment regimen (54/98, 55.1%). In non-nucleoside reverse transcriptase inhibitor (NNRTI)-and integrase inhibitor (II)-based regimen group, 15 (15/26, 57.7%) and 12 (12/13, 92.3%) patients were maintained on the initial treatment regimen, respectively. Adverse effects that induced ART switching included rash (16/35, 45.7%), gastrointestinal discomfort or pain (7/35, 20%), diarrhea (7/35, 20%), hyperbilirubinemia (6/35, 17.1%), headache or dizziness (3/35, 8.5%). Among the treatment regimens, the group receiving an II-based regimen showed the least switching. The group receiving PI-and NRTI-based regimens were most likely to switch due to adverse effects during the early treatment period. However, after about 18 months, switching was rarely observed in these groups. Among the PI drugs, darunavir/ritonavir showed fewer drug changes than atazanavir/ritonavir (P = 0.004, log rank test) and lopinavir/ritonavir (P = 0.010). Among the NNRTI drugs, rilpivirne produced less switching than efavirenz (P = 0.045). Conclusions: Adverse effects to ART resulted in about a quarter of patients switching drugs during the early treatment period. II-based regimens were advantageous because they were less likely to induce switching within 18 months of treatment commencement. These findings indicated the importance of considering and monitoring the adverse effects of ART in order to improve adherence.
    Full-text · Article · Dec 2015
  • Source
    • "In some cases, newer compounds could be used even within single drug classes to provide patient benefit in the event of resistance. A good example of this has been the use of ritonavir-boosted darunavir (DRV) that has a high genetic barrier for resistance for use in the place of earlier protease inhibitors such as nelfinavir (NFV) and ritonavir-boosted lopinavir (LPV) that have lower genetic barriers to resistance [9–12]. Due to the fact that ritonavir helps to maintain higher levels of PIs in the blood and tissues of treated individuals, the action of these compounds is prolonged and their genetic barrier for resistance is increased. "
    [Show abstract] [Hide abstract]
    ABSTRACT: HIV drug resistance has been one of the major obstacles to HIV eradication and has contributed to the need for the constant development of new antiretroviral drugs over the past 25 years. With the recent approval of dolutegravir for human therapy by the U.S. Food and Drug Administration, health practitioners may soon have access to three integrase strand transfer inhibitors to treat individuals living with HIV. Here, we review the use of raltegravir, elvitegravir, and dolutegravir for use in first- and second-line HIV treatment regimens and the issue of HIV resistance against integrase inhibitors. Electronic supplementary material The online version of this article (doi:10.1007/s40121-013-0020-8) contains supplementary material, which is available to authorized users.
    Full-text · Article · Dec 2013
  • Source

    Preview · Article · Feb 2013 · Clinical Infectious Diseases
Show more