Forty-eight-week results from a randomized, multicentre, part-blinded, phase IIb clinical trial assessing the efficacy and safety of 400 and 800 mg etravirine twice daily (phase IIb formulation) and optimized background regimen versus standard-of-care regimen are presented. Both etravirine doses demonstrated sustained virological suppression at 48 weeks and a favourable tolerability profile. Etravirine demonstrated higher efficacy than control, irrespective of the number of detectable nonnucleoside reverse transcriptase inhibitor-resistance-associated mutations at baseline or active background antiretrovirals.
aCommunity Research Initiative of New England, Boston, Massachusetts, USA
bNorthstar Medical Center, Chicago, Illinois, USA
cCircle Medical LLC, Norwalk, Connecticut, USA
dFenway Community Health, Boston, Massachusetts, USA
eUniversity of Miami, Miami, Florida, USA
fSwedish Medical Center, Seattle, Washington, USA
gAIDS Research Consortium of Atlanta, Atlanta, Georgia, USA
hTibotec BVBA, Mechelen, Belgium
iTibotec Inc., Yardley, Pennsylvania, USA.
Received 13 December, 2007
Revised 30 July, 2008
Accepted 13 August, 2008
Correspondence to Calvin J. Cohen, Community Research Initiative of New England, 23 Miner Street, Boston, New England, MA 02215-3319, USA. Tel: +1 617 502 1740; fax: +1 617 504 1701; e-mail: email@example.com
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are frequently used components of combination antiretroviral therapy. Etravirine (TMC125) is a second-generation NNRTI with a high genetic barrier to resistance [1,2]. In proof-of-principle trials, etravirine produced rapid and significant reductions in plasma viral load in both treatment-naive HIV-1-infected patients  and those with NNRTI-resistant virus . In the TMC125-C223 study , etravirine and optimized background regimen (OBR) achieved significantly greater virological responses at 24 weeks in treatment-experienced patients than the optimized standard-of-care control (SOC). We report the 48-week analysis of this randomized, multicenter, part-blinded, phase IIb clinical trial.
Patients received etravirine (400 mg) or (800 mg) twice daily (phase IIb formulation; 800 mg equivalent to 200 mg with phase III formulation) and OBR or SOC. OBR included at least two approved antiretrovirals [nucleotide reverse transcriptase inhibitors (NRTIs) or lopinavir/ritonavir or enfuvirtide or a combination of the three]. SOC included at least three antiretrovirals (NRTIs or approved protease inhibitors or enfuvirtide or a combination of all three).
The primary efficacy parameter was mean viral load change from baseline (log10 HIV-1 RNA copies/ml). Safety and tolerability were assessed. Study analyses used the intention-to-treat population. All analyses were prespecified unless otherwise stated. All methodologies have been published previously .
In total, 199 patients were randomized and treated. Ninety-nine patients completed the study, and 100 prematurely discontinued. The proportion of discontinuations was higher in the control group than in the etravirine groups (97.5 versus 38.4%, respectively). The majority of control patients discontinued because of virological failure [31 (77.5) versus 14 patients (8.8%) for control and etravirine groups, respectively]. Baseline patient characteristics were generally well balanced across treatment groups .
At week 48, the mean change from baseline in plasma viral load was −0.88 and −1.01 log10 copies/ml with etravirine (400 mg) and (800 mg) twice daily, respectively, both significantly higher than the –0.14 log10 change observed with control (P = 0.018, P = 0.002, respectively; Fig. 1a) . Plasma viral load reduction was maintained throughout the treatment, with little difference between weeks 24 and 48 (0.16 log10 copies/ml change in both etravirine groups). The proportion of patients with a viral load decrease of more than 1.0 log10 copies/ml from baseline was significantly higher with etravirine (400 mg) and (800 mg) than with control [31.3 (P = 0.016) and 34.2% (P = 0.004), respectively, versus control (7.5%)].
Significantly more patients achieved viral load of less than 50 copies/ml (undetectable) in the etravirine groups than in the control group [22.5 and 21.5% for 400 and 800 mg twice daily, respectively, versus 0% with control (P < 0.001)]. Virological response was maintained to 48 weeks; 88.2 and 87.5% of patients receiving etravirine (400 mg) and (800 mg) twice daily, respectively, with undetectable viral load at 24 weeks, remained undetectable at week 48. Virological responses occurred earlier and more frequently in both etravirine groups than in the control group; no dose-dependent differences were observed.
The two etravirine doses showed comparable efficacy for most virological endpoints. However, subgroup analyses demonstrated that patients achieved a higher reduction in mean change from baseline in plasma viral load at week 48 with etravirine (800 versus 400 mg twice daily) for patients not using enfuvirtide (−0.69 versus −0.17 log10 copies/ml, respectively), those not using either enfuvirtide or a protease inhibitor in the OBR (−0.88 versus +0.13 log10 copies/ml, respectively), and those with less than two active antiretrovirals in the OBR (Fig. 1b).
Subgroup analyses of patients using etravirine (800 mg twice daily) showed that virological responses generally increased with increasing number of active background antiretrovirals (not including etravirine), and those taking at least two active antiretrovirals displayed the highest reduction in plasma viral load as compared with control (Fig. 1b). Although some subgroups were small, a higher reduction in log10 plasma viral load was consistently observed with etravirine (800 mg) than with control in the following patient groups (Fig. 1c): use of lopinavir/ritonavir, lopinavir/ritonavir not used, enfuvirtide not used, and patients who did not use a protease inhibitor but used either de-novo enfuvirtide or reused enfuvirtide. In a post-hoc analysis, the highest reductions in plasma viral load were observed in patients with fewer detectable baseline etravirine-resistance-associated mutations (Fig. 1d).
The mean increase in CD4 cell count was higher with both etravirine doses than with control at week 48 (+58 and +61 versus +13 cells/μl, respectively), although it was not significant. Enfuvirtide use (de-novo and reuse of enfuvirtide) had a favourable effect on CD4 cell count increase in both etravirine groups and controls (+82 and +77 versus +30 cells/μl) as compared with patients not using enfuvirtide (+16 and +29 versus −10 cells/μl).
The 48-week safety and tolerability profile of etravirine was generally favourable, with no dose-related differences reported. Comparisons between the etravirine and control groups were, however, confounded because of substantial differences in treatment duration [median treatment duration was 47.9 weeks (both etravirine groups) versus 17.9 weeks (control group)]. This was predominantly caused by the high discontinuation due to virological failure in the control group.
The most commonly reported adverse events (≥10.0% of patients) in the combined etravirine groups were diarrhoea (22.0%), injection-site reaction (enfuvirtide related; 20.1%), pyrexia (20.1%), rash (any type; 20.1%), fatigue (15.7%), headache (15.7%), and nausea (15.1%). Overall, 27.0 and 17.5% of patients in the combined etravirine groups and the control group, respectively, reported at least one serious adverse event (SAE). Incidence of SAEs in the etravirine groups was not dose dependent. Adverse events leading to discontinuation occurred in 15.0 and 19.0% of patients in the etravirine (400 mg) and (800 mg) twice-daily groups, respectively. One of three deaths in the 400 mg etravirine group was considered as possibly related to etravirine and was due to cardiopulmonary failure and myocardial infarction in a patient with multiple risk factors for cardiovascular disease. Of the remaining two patients, one died due to central nervous system lymphoma and one of pseudomonal sepsis. A fourth patient in the 800 mg etravirine twice-daily group died 1.5 months after trial termination as a result of catheter sepsis. No clear treatment-emergent hepatic or neuropsychiatric events were observed.
The incidence of rash was 22.5 and 17.7% in the etravirine (400 mg) and (800 mg) twice-daily groups, respectively, as compared with 7.5% in the control group. No dose-related effects on rash were observed. Four patients (2.5%) experienced grade three rash (three with 400 mg twice-daily and one with 800 mg twice-daily etravirine). No patients experienced rash as an SAE, and six etravirine patients (3.8%) discontinued because of rash. Treatment-related rash occurred relatively early, predominantly during the first 2–4 weeks of therapy, and generally resolved within 2 weeks with continued dosing.
Despite the limitations of the open-label study design  and the high discontinuation rate in the control group, in this 48-week analysis, treatment-experienced patients with multidrug-resistant virus achieved and maintained superior virological suppression with an etravirine-containing regimen (400 or 800 mg twice daily) than with investigator-selected control regimens. Etravirine is the first NNRTI to demonstrate durable efficacy over 48 weeks in patients with NNRTI-resistant infection and offers substantial efficacy benefits over control.
Virological responses increased with increasing active background antiretrovirals. However, the greatest difference between etravirine (800 mg twice daily) and control was in patients with fewer active background agents. Additionally, improved virological responses were achieved with etravirine (800 mg) than with (400 mg) twice daily by patients who did not use enfuvirtide or a protease inhibitor. On the basis of the results of this trial, the 800 mg twice-daily dose was selected for further development and is equivalent to the 200 mg twice-daily dose (phase III formulation) used in the DUET trials [7,8].
At 48 weeks, etravirine's tolerability profile was comparable to 24-week data . In general, no dose-dependent differences in the incidence of adverse events were observed. No consistent pattern of neuropsychiatric events was seen. The incidence of hepatic adverse events was low, and rashes were primarily early onset and mild-to-moderate in severity. These data suggest that etravirine may offer advantages in safety and tolerability over first-generation NNRTIs, whose use can be limited by adverse events [9–11].
In conclusion, etravirine was well tolerated and showed sustained superior virological suppression at week 48, confirming the 24-week findings . For those remaining on study at week 48, a higher efficacy was achieved with etravirine than with control, irrespective of baseline characteristics or the number of active antiretrovirals in the OBR. Although both etravirine doses showed similar efficacy, 800 mg was found to offer more benefits in some patient subgroups.
We would like to thank the patients, investigators, the Data and Safety Monitoring Board, study centre staff and study personnel from Tibotec. This clinical trial was sponsored by Tibotec. All authors were involved in the collection, analysis or interpretation of data, critical review of the manuscript and final approval of the submitted version. The authors received medical writing support from Louise Marks of Gardiner-Caldwell Communications Ltd., Macclesfield, UK, which was funded by Tibotec.
All study investigators received research funding from Tibotec to support their patients' participation in this trial, and M.P., M.-P.deB., E.V., R.M. and B.W. are full-time Tibotec employees. In addition, D.S.B., G.B., C.J.C., H.A.G., D.T.J., P.S. and M.T. have received honoraria from Tibotec for their participation in meetings, advisory boards or speakers' bureaus.
Previous presentation: Cohen C, Steinhart CR, Ward DJ, et al. 48-week durable efficacy and safety results of TMC125 in HIV patients with NNRTI and PI resistance: Study TMC125-C223 [poster 2]. In: 12th Annual Conference of the British HIV Association (BHIVA); 29 March–1 April 2006; Brighton, UK; 2006.
TMC125-C223 Writing Group. Efficacy and safety of etravirine (TMC125) in patients with highly resistant HIV-1: primary 24-week analysis. AIDS 2007; 21:F1–F10
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