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Efficacy of Once-Daily Darunavir/Ritonavir 800/100 mg in HIV-Infected, Treatment-Experienced Patients With No Baseline Resistance-Associated Mutations to Darunavir
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[Brief Report: Clinical Science]
JAIDS Journal of Acquired Immune Deficiency Syndromes:Volume 49(2)October 2008pp 179-182
De Meyer, Sandra M J PhD; Spinosa-Guzman, Sabrina MD; Vangeneugden, Tony J PhD; de Bethune, Marie-Pierre PhD; Miralles, G Diego MD
From the Tibotec BVBA, Mechelen, Belgium.
Financial assistance to support this service was provided by Tibotec.
Some of the data described in this communication have been previously presented as a poster at the 5th European HIV Drug Resistance Workshop, March 28-30, 2007, Cascais, Portugal.
Abstract
Objective: The objective of this study was to examine the potential of once-daily dosing with darunavir/ritonavir 800/100 mg in a HIV-infected, treatment-experienced patient population with no baseline darunavir resistance-associated mutations (RAMs).
Methods: Patients in the randomized controlled POWER 1 and 2 trials were treatment experienced, with ≥1 International AIDS Society-USA primary protease inhibitor (PI) mutation. The virological and immunological responses in patients with no baseline darunavir RAMs receiving darunavir/r 800/100 mg once daily (n = 23), darunavir/r 600/100 mg twice daily (n = 29), or currently available PI(s) (n = 28) plus an optimized background regimen were compared.
Results: The proportion of patients achieving HIV RNA <50 copies per milliliter at week 24 was 67% for the group receiving darunavir/r 800/100 mg once daily and 62% for the group receiving darunavir/r 600/100 mg twice daily (P = 0.774); both were superior to control PI(s) (11%; P < 0.0001). Mean HIV RNA change from baseline was 22.39 and 22.35 log10 copies per milliliter for the group receiving darunavir/r 800/100 mg once daily and for the group receiving 600/100 mg twice daily, respectively (P = 0.895); mean CD4 increases were 88 and 111 cells per milliliter, respectively (P = 0.526).
Conclusions: Treatment-experienced, HIV-infected patients with no baseline darunavir RAMs achieved similar high responses with darunavir/r 800/100 mg once daily and 600/100 mg twice daily. This suggests that once-daily darunavir/r 800/100 mg therapy, which has been shown effective in treatment-naive patients and is currently being studied in treatment-experienced patients, shows potential in patients with no darunavir RAMs.
INTRODUCTION
Once-daily protease inhibitor (PI)-based highly active antiretroviral therapy would be more convenient in an era where there are new, increasingly potent, once-daily antiretroviral agents with improved tolerability. The efficacy and tolerability of the HIV-1 PI darunavir (TMC114) coadministered with low-dose ritonavir (darunavir/r) at a dose of 800/100 mg once daily are being compared with lopinavir/r 800/200 mg total daily dose in an antiretroviral-naive HIV-1-infected population in the ongoing Phase III ARTEMIS trial. At 48 weeks, 84% of patients receiving darunavir/r versus 78% receiving lopinavir/r reached the primary endpoint of HIV RNA <50 copies per milliliter {estimated difference in response: 5.6% [95% confidence interval (CI): -0.1 to 11.3], noninferiority vs lopinavir/r; P < 0.001}.1 Darunavir/r was generally well tolerated, with lower incidence of gastrointestinal toxicities and triglyceride elevations, compared with lopinavir/r. These results suggest that darunavir/r 800/100 mg once daily could be a valuable treatment option for treatment-naive patients. We wanted to determine whether a defined subpopulation of treatment-experienced patients could also benefit from the same once-daily dose of darunavir/r.
Currently, darunavir/r at a dose of 600/100 mg twice daily is indicated in combination with other antiretrovirals for the treatment of HIV-1 infection in antiretroviral-experienced adults, such as those with HIV-1 strains resistant to more than 1 PI.2 The indication is based on findings from the POWER 1 and 2 trials, supplemented with additional data from a larger patient population in the POWER 3 analysis.3-5 POWER 1 and 2 were phase IIb, randomized controlled studies in treatment-experienced, HIV-1-infected patients, with the first 24 weeks of each study consisting of a dose-finding phase. The primary analysis at week 24 showed that all doses of darunavir/r had significant virological and immunological benefit compared with investigator-selected control PI(s) and that darunavir/r was generally well tolerated.3,4 Because the highest virological and immunological responses were obtained with darunavir/r 600/100 mg twice daily, this dose was selected for further evaluation in treatment-experienced patients. As the 800/100 mg once-daily dose of darunavir/r also demonstrated substantial antiviral activity compared with the current PI-based standard of care in POWER 1 and 2 trials,3,4 we considered that this dose may be suitable for patients with less treatment experience compared with those in the overall POWER population. Therefore, data from the early dose-finding stages of the POWER 1 and 2 trials were retrospectively analyzed to examine the efficacy of darunavir/r 800/100 mg once daily in patients with no baseline mutations associated with resistance to darunavir. A set of 11 protease mutations has been identified that are associated with a diminished virological response to darunavir/r when they occur at baseline in a background of multiple protease mutations [each of the mutations was found in association with a median of at least 10 International AIDS Society-USA (IAS-USA) PI resistance-associated mutations (RAMs)].6,7 The presence of these specific darunavir RAMs is predictive of both phenotypic susceptibility and virological response to darunavir/r.7 Patients in POWER 1 and 2 trials who had no darunavir RAMs at baseline were evaluated, as the highest response is expected in this population. The virological and immunological responses between patients receiving darunavir/r 800/100 mg once daily or 600/100 mg twice daily were compared. These preliminary data from less PI-resistant patients should provide important background information for ongoing and future trials of darunavir/r.
CONCLUSIONS
Treatment-experienced, HIV-1-infected patients with no darunavir RAMs at baseline in the POWER 1 and 2 trials achieved comparably high levels of virological suppression and immunological response, regardless of whether they were receiving darunavir/r 800/100 mg once daily or 600/100 mg twice daily. Although the numbers of patients in each of the subgroups were relatively small, these results provide a rationale for further studies with darunavir/r 800/100 mg once daily as a therapeutic option for treatment-experienced patients who have no baseline darunavir RAMs.
The relevance of this analysis to the general PI-experienced population in clinical practice can be gaged from 2 recent studies. A clinical cohort study of 885 PI-experienced patients in the United Kingdom showed that 86% of patients harbored no darunavir RAMs.10 Similarly, an analysis of 108,500 clinical samples with evidence of PI resistance, which were submitted to Virco for routine resistance testing between July 1998 and June 2006, revealed that 68% contained no darunavir RAMs.11
Although these results are suggestive of the suitability of darunavir/r 800/100 mg once daily for early treatment-experienced patients, a prospective, randomized trial is currently ongoing to further evaluate efficacy and safety of this dose in treatment-experienced patients (ODIN: Once-daily Darunavir In treatment-experieNced patients; http://ClinicalTrials.gov no. NCT00524368). Long-term efficacy and safety data for darunavir/r 800/100 mg once daily in treatment-naive patients will be provided by the ongoing Phase III ARTEMIS trial. Results from this trial at 48 weeks provide a further rationale to evaluate darunavir/r as an effective and more convenient once-daily regimen in earlier lines of therapy.1
RESULTS
Baseline Characteristics
The analysis included patients with no darunavir RAMs at baseline receiving darunavir/r 800/100 mg once daily (n = 23), darunavir/r 600/100 mg twice daily (n = 29), and control PI(s) (n = 28). Baseline characteristics were generally similar across the treatment groups (Table 1). In this population, there was a median of 6-7 IAS-USA-listed PI RAMs9 at baseline and a median darunavir fold change in EC50 of 0.6 (range 0.2-3.0). The median fold change in EC50 (range) of the PIs used in the control group was 1.4 (0.4-12.7) for amprenavir, 1.8 (0.2-8.8) for atazanavir, 87.1 (6.5-107.1) for lopinavir, and 4.4 (0.2-38.4) for saquinavir.
Virological Response
In patients with no darunavir RAMs at baseline, the proportion who achieved HIV RNA <50 copies per milliliter at week 24 was similar for darunavir/r 800/100 mg once daily and 600/100 mg twice daily [67% vs 62%, respectively, P = 0.774; difference in response 800/100 mg once daily - 600/100 mg twice daily: +5% (95% CI: -23% to +31%); Fig. 1A]. Both darunavir/r doses were associated with a significantly greater proportion of patients reaching plasma HIV RNA <50 copies per milliliter than control PI(s) (11%; P < 0.0001 compared with both darunavir/r doses).
In patients who had no darunavir RAMs at baseline, both darunavir/r doses also provided comparable mean changes from baseline in plasma HIV RNA. These were -2.39 log10 copies per milliliter (SE = 0.29) for darunavir/r 800/100 mg once daily and -2.35 log10 copies per milliliter (SE = 0.18) for darunavir/r 600/100 mg twice daily [P = 0.895 for comparison between darunavir/r 800/100 mg once daily and 600/100 mg twice daily; difference in response between the 2 dose regimens: -0.04 log10 copies/mL (95% CI: -0.70 to +0.62); Fig. 1B]. Patients receiving darunavir/r at either dose had a greater reduction in HIV RNA from baseline compared with those receiving control PI(s) [-0.68 log10 copies/mL (SE = 0.17); P < 0.0001 compared with both darunavir/r doses].
Immunological Response
Mean CD4 cell count increases were 88 cells per cubic millimeter (SE = 30) in the group receiving darunavir/r 800/100 mg once daily and 111 cells per cubic millimeter (SE = 23) in the group receiving darunavir/r 600/100 mg twice daily [P = 0.526 for comparison between darunavir/r 800/100 mg once daily and 600/100 mg twice daily; difference in response 800/100 mg once daily - 600/100 mg twice daily: -24 cells per cubic millimeter (95% CI: -98 to +51)]. Patients receiving control PI(s) had a mean CD4 count increase of 33 cells per cubic millimeter (SE = 20) (P = 0.117 for darunavir/r 800/100 mg once daily vs control; P = 0.012 for darunavir/r 600/100 mg twice daily vs control).
METHODS
Study Design
POWER 1 and 2 trials had similar inclusion criteria and baseline characteristics.3,4 In the 24-week dose-finding phase, patients received darunavir/r (400/100 mg once daily, 800/100 mg once daily, 400/100 mg twice daily, or 600/100 mg twice daily) or investigator-selected control PI(s). In addition to darunavir/r or control PI treatment, all patients received an optimized background regimen, which consisted of 2 or more nucleoside/nucleotide reverse transcriptase inhibitors with or without enfuvirtide; this was selected based on history of antiretroviral treatment and genotypic resistance testing (Virtual Phenotype; Virco, Mechelen, Belgium). After the 24-week primary analysis, all patients receiving darunavir/r were switched to the selected 600/100 mg twice-daily dose. A detailed methodology of POWER 1 and 2 trials is described elsewhere.3,4
Patients
The POWER 1 and 2 trials enrolled treatment-experienced, HIV-1-infected patients aged at least 18 years, who had a plasma HIV RNA >1000 copies per milliliter, and had ≥1 primary PI mutation (based on the 2003 IAS-USA list8). Treatment experience was defined as prior treatment with 2 or more nucleoside/nucleotide reverse transcriptase inhibitors for at least 3 months, with 1 or more nonnucleoside reverse transcriptase inhibitors in a failing regimen and with 1 or more PIs for at least 3 months.
Analyses
Phenotyping (Antivirogram) and genotyping of plasma viruses were performed by Virco. Patients from POWER 1 and 2 trials who were randomized to receive darunavir/r 800/100 mg once daily or 600/100 mg twice daily were included in the analysis (24 weeks; cutoff date: September 24, 2005) if they had no darunavir RAMs at baseline. Darunavir RAMs were defined as the mutations at baseline that were associated with a diminished virological response to darunavir/r at week 24 in the POWER studies (V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, and L89V).7
Virological and immunological responses at week 24 (before all patients switched to the recommended darunavir/r 600/100 mg twice-daily dose) were compared between the 2 darunavir/r doses and the control PI group. Virological responses were defined as the proportion of patients reaching plasma HIV RNA <50 copies per milliliter (intent-to-treat analysis and time to loss of virological response algorithm) and change from baseline in log10 plasma HIV RNA (noncompleter = failure analysis). Immunological response was defined as the change in CD4 cell count (last observation carried forward analysis). The Fisher exact test was used to compare treatment groups with respect to virological response, and the 2-sample t test was used to compare treatment with respect to change in viral load and CD4 cell count.
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