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TMC114/ritonavir substitution for protease inhibitor(s) in a non-suppressive antiretroviral regimen: a 14-day proof-of-principle trial
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AIDS: Volume 19(9) 10 June 2005
.....Median change at day 14 was -1.38 and +0.02 log10 copies/ml for all TMC114/RTV groups and the control group.... A reduction of ≥ 0.5 and ≥ 1.0 log10 copies/ml was attained by 97% and 76% of patients....TMC114/RTV showed considerable antiviral activity in patients with extensive baseline PI resistance and was active against multi-PI-resistant HIV-1 as replacement for PIs in a non-suppressive regimen. This efficacy is especially noteworthy since 80% of patients (54% for lopinavir/RTV) were receiving an RTV-boosted PI at study entry..... No PI mutation(s) or mutational pattern influenced virological responses to TMC114/RTV. There were no significant changes in the fold change in EC50 to TMC114 during the study....
Arasteh, Keikawusa; Clumeck, Nathanb; Pozniak, Antonc; Lazzarin, Adrianod; De Meyer, Sandrae; Muller, Heidie; Peeters, Monikae; Rinehart, Alexf; Lefebvre, Ericg; for the TMC114-C207 Study Team
From the aEpimed, c/o Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany
bCHU-UMC Saint-Pierre, Brussels, Belgium
cPK Research Unit, Chelsea and Westminster Hospital, London, United Kingdom
dSan Raffaele Hospital, Milan, Italy
eTibotec BVBA, Mechelen, Belgium
fVirco Lab Inc., Durham, North Carolina, USA
gTibotec Inc., Yardley, Pennsylvania, USA.
Introduction
Protease inhibitors (PIs) have reduced morbidity and mortality in patients with HIV infection [1]. However, the emergence of resistance to these drugs has created a need for new PIs active against resistant viruses [2].
TMC114 is a novel PI containing 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF) and a sulfonamide isostere. X-ray crystallography of TMC114 bound to wild-type enzyme has indicated that it occupies a volume contained within the substrate envelope. Most currently approved PIs occupy an area that extends beyond the envelope, which is where many primary PI mutations seem to occur [3]. Crystallography also showed that TMC114 forms strong hydrogen bonds with residues in the main chains of the protease active site (Asp29 and Asp30) via the bis-THF group [3,4]. TMC114 has an individual 50% effective concentration (EC50) against wild-type HIV-1 of 4.6 nmol/l and little or no loss of activity against highly PI-cross-resistant clinical isolates [5,6]. The pharmacokinetics of TMC114 are enhanced by coadministration of low-dose ritonavir (RTV) [7].
This phase IIA trial assessed the antiretroviral activity, safety, and tolerability of substituting TMC114/RTV for current PIs in a non-suppressive antiretroviral regimen (ART) in multiple-PI-experienced, HIV-1-infected patients.
ABSTRACT
Objective: To evaluate antiviral activity, tolerability, and safety of the protease inhibitor (PI) TMC114 boosted with low-dose ritonavir (RTV).
Design: A randomized, open-label, controlled, phase IIA clinical trial in 15 sites in Europe with 50 HIV-1-infected patients who had taken multiple PIs.
Methods: At entry, PIs in non-suppressive regimens were replaced with TMC114/RTV (300/100 or 600/100 mg twice daily, or 900/100 mg once daily) or left unchanged for 14 days. The time-averaged difference (DAVG) in HIV-1 RNA from baseline, change in HIV-1 RNA from baseline, proportions achieving plasma HIV-1 RNA < 400 copies/ml and ≥ 0.5 and ≥ 1.0 log10 copies/ml reductions in HIV-1 RNA, and safety were assessed.
Results: DAVG responses in all TMC114/RTV groups (range, -0.56 to -0.81 log10 copies/ml) were significantly greater (P < 0.001) than in the controls (-0.03 log10 copies/ml).
Median change at day 14 was -1.38 and +0.02 log10 copies/ml for all TMC114/RTV groups and the control group, respectively.
A reduction of ≥ 0.5 and ≥ 1.0 log10 copies/ml was attained by 97% and 76% of patients, respectively, in all TMC114/RTV groups and by 25% and 17%, respectively, in the control group.
HIV-1 RNA < 400 copies/ml at any time during treatment was achieved by 40% in the TMC114/RTV groups and 8% in the control group.
Most common reported adverse events were gastrointestinal and central nervous system disorders (mild to moderate severity).
No dose relationship was observed. Biochemical, haematological and electrocardiographic parameters showed no significant changes.
Conclusions: TMC114/RTV demonstrated a potent antiretroviral effect over 14 days in multiple-PI-experienced patients and was generally well tolerated.
RESULTS
The trial, conducted at 15 centres in Europe from March to August 2002 randomized 51 patients, of whom 50 started treatment. Baseline characteristics were similar among groups; 80% (40/50) of patients were receiving an RTV-boosted PI in their non-suppressive regimen, with 54% (27/50) taking lopinavir/RTV. All patients continued their existing ART throughout the run-in period, during which compliance was monitored by witnessing at least one dose each day, with all other doses recorded in patient diaries. The number of patients with baseline phenotypic resistance (as the fold change in EC50 values greater than the biological or clinical cut-off values) to each PI across all TMC114 treatment groups was approximately equal to or greater than that in the control group. At baseline, 51% of patients (25/49) harboured virus phenotypically resistant to all PIs commercially licensed at the time of the study, whereas only 27% (13/49) had virus sensitive to two or more PIs. There were no significant differences among groups for median fold change in EC50 to TMC114, baseline phenotypic sensitivity to other PIs, and protease mutations at entry.
Median DAVG responses were -0.56, -0.70 and -0.81 log10 copies/ml for the TMC114/RTV 300/100 mg twice daily, 900/100 mg daily and 600/100 mg twice daily groups, respectively, and -0.03 log10 copies/ml for the control group (all P < 0.001). The median change in plasma HIV-1 RNA at day 14 for all TMC114/RTV groups was -1.38 log10 copies/ml (P < 0.001 versus control). The median log10 plasma HIV-1 RNA nadir for all TMC114 groups was 2.75 log10 copies/ml versus 3.58 log10 copies/ml for the control group. The percentages of patients with ≥ 0.5 and ≥ 1.0 log10 copies/ml reductions in HIV-1 RNA and with HIV-1 RNA < 400 copies/ml are shown in Fig. 1c,d, respectively. One patient in the 900/100 mg daily group achieved HIV-1 RNA < 50 copies/ml. The presence of lopinavir/RTV in the non-suppressive regimen did not influence any of these results.
Median changes in CD4 cell counts from baseline to day 15 were 16.0, 5.0, 63.0 and 0.5 x 106 cells/l for the 300/100 mg twice daily, 900/100 mg daily, 600/100 mg twice daily and control groups, respectively. Changes in CD4 cell count after a 2-week treatment period were variable, and no firm conclusions could be drawn.
Baseline TMC114 fold-change (FC) did not predict the change in log10 plasma HIV-1 RNA at day 14, nadir change in log10 plasma HIV-1 RNA, or DAVG response. No PI mutation(s) or mutational pattern influenced virological responses to TMC114/RTV. There were no significant changes in the fold change in EC50 to TMC114 during the study.
The most common adverse events across all TMC114/RTV groups were gastrointestinal (diarrhoea 32%, flatulence 18%) and central nervous system (CNS) (headache 16%, dizziness 11%). Most adverse events were grade 1 or 2 in severity, and no dose relationship was observed. Two patients treated with TMC114/RTV 900/100 mg daily discontinued; one because of grade 2 or 3 gastrointestinal and CNS events, and the other because of oesophageal candidiasis and stenosis (judged as related to HIV, not TMC114/RTV). Four (11%) TMC114/RTV-treated patients reported grade 3 adverse events (primarily gastrointestinal and CNS events). Two grade 4 adverse events were reported. The first was hepatotoxicity with clinical symptoms judged as 'probably related' to TMC114/RTV in a patient treated with 600/100 mg twice daily, which resolved without sequelae upon discontinuation of all ART. The second was a recurrence of moderate eczema in a patient with a prior history of this condition who was treated with TMC114/RTV 300/100 mg twice daily. The subsequent mild oral blistering that immediately followed this skin event led to the grade 4 classification but did not lead to a treatment interruption. Four patients in the control group reported adverse events (all grade 1 or 2 in severity).
Treatment-emergent grade 3/4 laboratory abnormalities were reported for 13% (5/38) of TMC114/RTV patients versus 33% (4/12) in the control group. Most were transient and did not require intervention. None resulted in discontinuation. There were no consistent abnormalities in liver function tests; and no clinically relevant changes in blood chemistry, haematology, urinalysis, electrocardiograms or vital signs.
Discussion
TMC114/RTV showed considerable antiviral activity in patients with extensive baseline PI resistance and was active against multi-PI-resistant HIV-1 as replacement for PIs in a non-suppressive regimen. This efficacy is especially noteworthy since 80% of patients (54% for lopinavir/RTV) were receiving an RTV-boosted PI at study entry. It is unlikely that the efficacy of TMC114/RTV was influenced by differences in PI resistance among treatment groups; based on fold changes in EC50, PI resistance was at least as common for virus from patients in the TMC114/RTV groups as for control patients.
Short-term exposure to TMC114/RTV was generally well tolerated among all dosage groups, with gastrointestinal and CNS adverse events being the most commonly reported. TMC114 was formulated as an oral solution in PEG400. The laxative properties of PEG are well established and may have contributed to the onset of the gastrointestinal events [10]. The majority of phase I studies and the phase IIA study have been performed with an experimental PEG400-containing oral solution. No differences in the frequency or type of adverse events were noted among the three TMC114/RTV dosage groups. A direct compression tablet is now in use in phase IIB clinical studies. Results from a recent pharmacokinetic study have demonstrated that the tablets are bioequivalent to the oral solution [11].
TMC114 is a potent PI that, when boosted with low doses of RTV, demonstrates broad activity against wild-type and multi-PI-resistant HIV-1 virus. In this study, TMC114/RTV resulted in a significant decrease in plasma HIV-1 RNA (median 1.38 log10 copies/ml) when used as the replacement for PIs in a non-suppressive ART regimen over a 14-day period. TMC114/RTV therapy was safe and generally well tolerated. The efficacy, safety, tolerability and durability of the antiretroviral effect of TMC114/RTV are currently being investigated in phase IIB clinical trials.
Methods
The trial enrolled HIV-infected patients aged ≥ 18 years with ≥ 2 months' prior exposure to two to four PI drugs. Total daily dose of < 800 mg ritonavir was not counted as PI usage. At entry, patients demonstrated a lack of virological suppression (plasma HIV-1 RNA > 2000 copies/ml) on their current ART containing nucleoside reverse transcriptase inhibitors and at least one PI. This regimen must have been initiated ≥ 8 weeks prior to study entry. Exclusion criteria included non-nucleoside reverse transcriptase inhibitor in the non-suppressive regimen; receipt of an investigational drug within 30 days; CD4 cell count < 50 x 106 cells/l at screening; life expectancy of < 6 months; acute hepatitis A or acute or chronic hepatitis B or C; or prior exposure to TMC114. Serum creatinine > 2 x upper limit of normal (ULN); pancreatic amylase or lipase > 1.5x ULN; haemoglobin < 5.7 mmol/l (men) or < 5.6 mmol/l (women); platelets < 75 x 109 cells/l; absolute neutrophils < 1.0 x 109 cells/l; alanine aminotransferase, aspartate aminotransferase or gammaglutamyl-aminotransferase > 2.5 x ULN; or total bilirubin > 1.5 x ULN also resulted in exclusion. Female patients were excluded if they were pregnant, breast-feeding, or planning to become pregnant during the study.
The study followed a randomized, multicentre, controlled, open-label design approved by local, independent ethics committees. All patients provided written, informed consent.
Screening evaluations 4 weeks before randomization included complete medical history, plasma HIV-1 RNA measurement (Amplicor HIV-1 Monitor™ version 1.5 ultrasensitive method; Roche Diagnostics, Branchburg, New Jersey, USA) and genotypic and phenotypic resistance analyses (Virtual Phenotype™ and Antivirogram®, respectively; Virco BVBA, Mechelen, Belgium). Patients were randomized to TMC114/RTV 300/100 mg twice daily, 900/100 mg daily, or 600/100 mg twice daily as substitution for existing PIs or to remain on their current regimen for 14 days. TMC114 doses were based on results from a prior dose-escalating trial of TMC114/RTV and supported by pharmacokinetic modelling (data on file, Tibotec BVBA, Mechelen, Belgium). TMC114 was formulated as an oral solution (20 mg/ml) in polyethylene glycol 400 (PEG400). Patients could not change any other component of their ART during screening or change nucleoside reverse transcriptase inhibitors during treatment.
The primary efficacy parameter was the time-averaged difference of plasma HIV-1 RNA (DAVG; area under the plasma concentration-time curve of the plasma HIV-1 RNA on a log10 basis divided by time on treatment), with differences among groups assessed using analysis of variance. Secondary efficacy parameters included change from baseline in HIV-1 RNA at all time points, nadir and nadir of the change, and change in CD4 cell count, all analysed using analyses of covariance with baseline values as covariates; the proportions of patients with ≥ 0.5 and ≥ 1.0 log10 copies/ml decreases from baseline and HIV-1 RNA < 400 and < 50 copies/ml, all analysed with Fisher's exact tests. Effects of lopinavir/RTV in the non-suppressive regimen and number of baseline primary PI mutations were also evaluated. The significance level for all tests was P < 0.05, and all patients who were randomized and received one or more TMC114/RTV dose or who continued their pre-trial ART regimen were included in all analyses.
Genotypic and phenotypic resistance was determined at screening, baseline, end of treatment/withdrawal, and at 3-week follow-up visits with PI resistance mutations defined according to the Drug Resistance Mutations Group of the International AIDS Society-USA [8]. Adverse event severity was graded using a modified version of the Adult AIDS Clinical Trial Group (AACTG) Table for Grading Severity of Adult Adverse Experiences [9].
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