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Phase 2 double-blind, randomized trial of etravirine versus efavirenz in treatment-naive patients: 48-week results

Gazzard, Briana; Duvivier, Claudineb; Zagler, Christianc; Castagna, Antonellad; Hill, Andrewe; van Delft, Yvonnef; Marks, Stephanf

doi: 10.1097/QAD.0b013e32834c4c06
CLINICAL SCIENCE
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Background: The Study of Etravirine Neuropsychiatric Symptoms versus Efavirenz (SENSE) trial compared etravirine with efavirenz in treatment-naive patients. The primary endpoint was neuropsychiatric adverse events up to week 12; HIV RNA suppression at week 48 was a secondary endpoint.

Methods: Patients with HIV RNA more than 5000 copies/ml were randomized to etravirine 400 mg once daily (n = 79) or efavirenz (n = 78), plus two nucleoside analogues. HIV RNA less than 50 copies/ml at week 48 was analysed using the time to loss of virological response (TLOVR) algorithm. Drug resistance at treatment failure and safety endpoints were also evaluated.

Results: At baseline, the median CD4 cell count was 302 cells/μl and HIV RNA was 4.8 log10 copies/ml. In the intent to treat TLOVR analysis at week 48, 60 of 79 (76%) patients on etravirine versus 58 of 78 (74%) on efavirenz had HIV RNA less than 50 copies/ml. In the on-treatment analysis, 60 of 65 (92%) taking etravirine had HIV RNA les than 50 copies/ml versus 58 of 65 (89%) for efavirenz: etravirine showed noninferior efficacy versus efavirenz in both analyses (P < 0.05). Four patients had virological failure in the etravirine arm: none developed resistance to nucleoside analogues or nonnucleosides. Seven patients had virological failure in the efavirenz arm: three developed treatment-emergent resistance to nucleoside analogues and/or nonnucleosides. At the week 48 visit, the percentage with ongoing neuropsychiatric adverse events was 6.3% for etravirine and 21.5% for efavirenz (P = 0.011).

Conclusion: First-line treatment with etravirine 400 mg once daily and two nucleoside reverse transcriptase inhibitors (NRTIs) led to similar rates of HIV RNA suppression, compared with efavirenz and two NRTIs. None of the patients with virological failure in the etravirine arm developed resistance to nonnucleosides.

aChelsea and Westminster Hospital, London, UK

bMaladies Infectieuses et Tropicales, Centre d’Infectiologie, Universite Paris Descartes, Faculte de Medecine, Paris, France

cHohe Otto-Wagner Hospital, Vienna, Austria

dFondazione San Raffaele, Milan, Italy

ePharmacology Research Laboratories, University of Liverpool, Liverpool, UK

fJanssen, Tilburg, The Netherlands.

Correspondence to Professor Brian Gazzard, St Stephens Centre, Chelsea and Westminster Hospital, London, UK. Tel: +44 0 208 746 8000; e-mail: brian.gazzard@chelwest.nhs.uk

Received 19 June, 2011

Revised 17 August, 2011

Accepted 24 August, 2011

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Introduction

International HIV treatment guidelines recommend first-line use of two nucleoside analogues [nucleoside reverse transcriptase inhibitors (NRTIs)] with either a nonnucleoside [nonnucleoside reverse transcriptase inhibitor (NNRTI)] or a boosted protease inhibitor [1–3]. Of the nonnucleosides, efavirenz (EFV) 600 mg once daily is the most widely recommended, owing to the high rates of efficacy seen in large randomized trials. The alternative nonnucleoside is nevirapine, which has shown levels of efficacy close to, but not equivalent with, EFV [4]. Nevirapine has recently been reformulated to a 400 mg once daily extended release dosing, which has shown noninferior efficacy to the original dose of 200 mg twice daily in treatment-naive patients [5].

There are several concerns over the safety profiles of these two nonnucleosides. EFV showed teratogenicity in animal models, and it is uncertain whether the use of EFV during pregnancy could increase the risk of birth defects if used in pregnant women [6]. EFV also causes a range of neuropsychiatric adverse events – in particular, dizziness, mood and sleep disorders [7,8]. These adverse events are mild and short-term in most patients, but a minority have long-lasting neuropsychiatric problems. EFV also causes rises in lipids and there is a risk of rash [9,10]. Nevirapine is associated with severe skin reactions in a minority of patients, which can lead to Stevens–Johnsons syndrome, particularly if used in patients with high CD4 cell counts [6,11]; hepatotoxicity is an additional risk [12]. Patients with virological failure while taking first-line EFV or nevirapine have a high risk of developing resistance to nonnucleosides and nucleoside analogues, which can restrict future treatment options [12–14].

The nonnucleoside etravirine (ETR) has in-vitro activity versus both NNRTI-naive and NNRTI-resistant virus [15,16]. Etravirine was evaluated in the DUET trials of highly treatment-experienced patients, and this led to regulatory approval for treatment-experienced patients at the 200 mg twice daily dose [17]. In the DUET trials, there was no increase in neuropsychiatric adverse events or lipids for patients in the ETR arm versus placebo; there was a small rise in the risk of rash in the ETR arm [17].

A proof-of-concept trial showed significant reductions in HIV RNA for treatment-naive patients given ETR as monotherapy for 7 days [18]. The long half-life of ETR (30–40 h) supports once daily dosing. Pharmacokinetic studies have evaluated the 400 mg once daily dose of ETR [19]. The Study of Etravirine Neuropsychiatric Symptoms versus Efavirenz (SENSE) trial was designed to evaluate the safety and preliminary efficacy of first-line use of ETR versus the standard control arm of EFV, both combined with two nucleoside analogues, for 48 weeks. The primary endpoint of the trial was to compare the neuropsychiatric adverse events at week 12 between the arms, and this was published previously [20]. This article will concentrate on the efficacy, resistance and safety outcomes at week 48.

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Methods

Design, randomization and dosing

The SENSE trial recruited 157 antiretroviral treatment-naive individuals with HIV RNA levels above 5000 copies/ml and no genotypic or phenotypic resistance to study antiretrovirals at the screening visit [20]. The patients were recruited from Europe, Russia and Israel. Patients were randomized to receive either ETR 400 mg once daily or EFV 600 mg once daily, together with two investigator-selected NRTIs (either tenofovir/emtricitabine, abacavir/lamivudine or zidovudine/lamivudine). Etravirine was administered as four 100-mg tablets once daily (or matching placebo) and EFV as a single 600-mg tablet once daily (or matching placebo). The randomization was stratified for screening HIV RNA – either at/less than or more than 100 000 copies/ml.

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Efficacy and safety assessments

Patients attended study visits at screening, baseline and then weeks 2, 6, 12, 24, 36 and 48. There was a follow-up visit 2–8 weeks after week 48 when the patients were unblinded.

Plasma HIV RNA was measured using the Roche Amplicor HIV-1 Monitor assay (version 1.5, Roche Molecular Systems, Branchburg, New Jersey, USA). Viral genotype and predicted phenotype were evaluated at screening and baseline, using the virco TYPE HIV-1 assay (Virco BVBA, Beerse, Belgium). The presence of NRTI, NNRTI or protease inhibitor mutations at screening [21] was used to assess sensitivity to the study drugs. During the trial, patient samples were genotyped for several reasons: if the patient discontinued the trial with detectable HIV RNA levels; if the HIV RNA level had not fallen by 1 log10 by week 12, or was above 400 copies/ml at this time; if the patient had HIV RNA above 50 copies/ml at the week 48 visit, or had shown virological failure (HIV RNA >50 copies/ml) by the time to loss of virological response (TLOVR) algorithm.

Clinical and laboratory abnormalities were classified using the division of AIDS grading tables [22]. This system classifies adverse events as either grade 1 (mild), grade 2 (moderate), grade 3 (severe) or grade 4 (life-threatening). Investigators recorded the duration of adverse events and judged whether they were related to randomized medication. The medDRA coding dictionary was then used to classify adverse events into System Organ Classes and individual categories.

Written informed consent was obtained from all participating individuals prior to study entry. Trial protocols were reviewed and approved by the appropriate institutional ethics committees and health authorities and were undertaken in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP). The Data Safety Monitoring Board reviewed the safety data after all patients had completed week 12 or discontinued prematurely and recommended continuation of the trial (ClinicalTrials.gov identifier: NCT00903682).

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Role of the funding source

The trial was designed and conducted by Janssen EMEA Medical Affairs, a division of Janssen International N.V., which acted as the study sponsor. The statistical analysis was conducted independently by an external statistician (SGS, Mechelen, Belgium), and was reviewed and validated by the trial statistician (A.H.). The authors had full access to the data and the corresponding author had the final responsibility to submit the manuscript for publication.

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Statistical methods

The primary endpoint was the percentage of patients with at least one grade 1–4 treatment-emergent, drug-related neuropsychiatric adverse event at the week 12 analysis.

The treatment arms were compared using the protocol-defined endpoint of TLOVR algorithm [23]. Using this endpoint, success is two consecutive HIV RNA levels below 50 copies/ml up to week 48, with no subsequent confirmed rebound. Treatment failure is defined as two consecutive HIV RNA levels above 50 copies/ml at week 48 or discontinuation of randomized treatment either due to adverse events or other reasons.

The treatment arms were compared for noninferiority, using multiple logistic regression adjusting for the stratification variable of baseline HIV RNA. A delta estimate of −12% was used for the noninferiority analysis, which is consistent with other recently published HIV clinical trials [24,25]. It should be noted that the SENSE trial was not statistically powered to demonstrate noninferior efficacy of ETR versus EFV – this would require a sample size in the region of 300–400 patients per arm [26].

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Results

Baseline characteristics

Of 193 screened, 157 individuals were randomized and treated (79 in the ETR arm and 78 in the EFV arm) and were included in the intent to treat (ITT) analysis. Genotypic resistance testing at screening was used to exclude patients with evidence of transmitted drug resistance. Among the 36 who were screen failures, the main reasons were the presence of NRTI, NNRTI or protease inhibitor drug resistance (14 patients), lack of predicted phenotypic sensitivity to NRTIs and NNRTIs (four patients), or HIV RNA levels below 5000 copies/ml at screening (five patients). Of the 36 screen failures, 10 patients had either genotypic or phenotypic resistance to EFV, but none of the patients showed either genotypic or phenotypic resistance to ETR.

Baseline characteristics of the 157 randomized patients are shown in Table 1 and were well balanced between the treatment arms. The patients were predominantly white men of mean age of 38 years. The most common mode of HIV transmission was MSM (79 patients, 50%). The nucleoside analogues used with randomized NNRTIs were tenofovir plus emtricitabine for 94 patients (60%), abacavir plus lamivudine for 41 patients (26%) and zidovudine plus lamivudine for 22 patients (14%). At baseline, the median HIV RNA level was 4.8 log10 copies/ml and the median CD4 cell count was 302 cells/μl. The baseline HIV RNA level was above 100 000 copies/ml for 34% of the patients. At the baseline visit, 12 patients in the ETR arm and four in the EFV arm had one International AIDS Society, United States of America (IAS-USA) NNRTI mutation each. These NNRTI mutations were E138A (n = 5), V106I (n = 4), V108I (n = 1) and V90I (n = 6). None of these NNRTI mutations was in the Bennett list of transmitted drug mutations used to exclude patients from the trial [21]. Almost all patients were phenotypically sensitive to the NNRTI they were randomized to (Table 1). Five patients in the ETR arm had IAS-USA NRTI mutations at baseline, three whom also had Bennett NRTI mutations – these three patients were protocol violators. No patient in the EFV arm had NRTI mutations at baseline.

Table 1

Table 1

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Efficacy

Figure 1 shows the percentage of patients with HIV RNA less than 50 copies/ml at week 48, by the TLOVR algorithm. Results are shown for the overall trial population (Fig. 1a) and for the predefined subgroups with baseline HIV RNA 100 000 copies/ml or less (Fig. 1b) and more than 100 000 copies/ml (Fig. 1c). Two analyses are shown for each figure – the main TLOVR analysis includes all patients who discontinued treatment for adverse events or other reasons as treatment failures. The ‘non-VF censored’ analysis excludes data from patients who discontinued for adverse events or other reasons – only the virological failures are included.

Fig. 1

Fig. 1

In the overall trial population (Fig. 1a), the percentage with HIV RNA suppression was similar in the two treatment arms. In the ETR arm, 60 of 79 (75.9%) patients had HIV RNA less than 50 copies/ml at week 48. Of the 19 treatment failures, four had virological failure, six discontinued for adverse events and nine for other reasons. In the EFV arm, 58 of 78 (74.4%) patients had HIV RNA less than 50 copies/ml at week 48. Of the 20 treatment failures, seven had virological failure, 13 discontinued for adverse events and two for other reasons. In the main TLOVR analysis, the difference in suppression rates was +1.6% in favour of the ETR arm, with 95% confidence intervals of −12.0 to +15.2%, which met the criteria for noninferiority with a delta of −12% (P < 0.05). In the non-VF censored analysis (including only virological failures), the difference in suppression rates also favoured the ETR arm (+2.9%) with 95% confidence intervals of −5.8 to +11.7%. This result also showed noninferiority for ETR versus EFV (P = 0.001, delta = −12%).

In the predefined subgroups by baseline HIV RNA, the response rates were similar in two arms (Fig. 1b and c). Given the small number of patients in each subgroup, statistical testing was not performed to compare the treatment arms.

Table 2 shows the details of the 11 patients who had virological failure by the TLOVR algorithm up to week 48. There were four patients in the ETR arm: none showed evidence of treatment-emergent NRTI or NNRTI mutations. The levels of HIV RNA in these four patients tended to be low – three of the four patients had HIV RNA below 200 copies/ml at week 48, but were defined as failures because of earlier rises in HIV RNA, or not having two consecutive HIV RNA levels below 50 copies/ml at the end of the trial.

Table 2

Table 2

There were seven patients with virological failure in the EFV arm: three developed treatment-emergent NRTI or NNRTI mutations. One patient developed the NNRTI mutation V106I together with the 3TC mutation M184I. One patient developed the NNRTI mutation K103N alone and the third patient developed the NNRTI mutations K103N plus P225H, and the 3TC mutation M184V. The HIV RNA levels at the time of virological failure tended to be higher in the EFV arm than in the ETR arm (Table 2).

In addition to the patients genotyped at virological failure, seven patients in the ETR arm and two in the EFV arm were genotyped at discontinuation, with HIV RNA more than 50 copies/ml: eight of these nine patients developed no new NRTI or NNRTI mutations. There was a single patient in the ETR arm who had a single NNRTI mutation (V90I) at week 12 when the HIV RNA level was 501 copies/ml. This patient sample remained phenotypically sensitive to ETR by virtual phenotype and the HIV RNA fell to less than 50 copies/ml at the next visit, remaining fully suppressed up to week 48 with no changes in randomized treatment.

In the ETR arm, there were 16 patients with either an IAS-USA NRTI or NNRTI mutation at baseline in the ETR arm: 14 had HIV RNA less than 50 copies/ml at week 48. Ten of these 16 patients had only NNRTI mutations (E138A, n = 3; V106I, n = 3; V90I, n = 3; V108I, n = 1); all 10 patients had HIV RNA below 50 copies/ml at week 48. Four patients had NRTI mutations only – three had HIV RNA less than 50 copies/ml at the week 48 visit and the other discontinued for adverse events at week 2. Two patients had both NRTI and NNRTI mutations at baseline: one had HIV RNA less than 50 at week 48 and one was lost at follow-up after the baseline visit.

In the EFV arm, four patients had IAS-USA NNRTI mutations at baseline (E138A, n = 2; V90I, n = 1; V106I, n = 1): all four patients had HIV RNA less than 50 copies/ml at week 48.

The mean rise in CD4 cell count by week 48 was +232 cells/μl in the ETR arm and +236 cells/μl in the EFV arm (observed data analysis).

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Neuropsychiatric adverse events

The primary endpoint of the trial was the percentage of patients with grade 1–4 treatment-emergent neuropsychiatric adverse events at week 12. Figure 2 shows the percentage of patients with ongoing grade 1–4 drug-related adverse events at each study visit to week 48. The prevalence of grade 1–4 drug-related neuropsychiatric adverse events peaked at week 2 (13.9% in the ETR arm and 39.7% in the EFV arm, P <0.001); at the week 48 visit, the percentage of patients with ongoing neuropsychiatric adverse events was 6.3 for ETR and 21.5 for EFV (P = 0.011).

Fig. 2

Fig. 2

Table 3 shows the percentage of patients with grade 2–4 drug-related neuropsychiatric adverse events at any time during the trial: this analysis excludes the grade 1 (mild) adverse events. The percentage of patients with at least one grade 2–4 drug-related nervous system adverse event was one of 79 (1%) in the ETR arm and 13 of 78 (17%) in the EFV arm (P < 0.01). The most common nervous system adverse event in the EFV arm was dizziness (n = 7). The percentage of patients with at least one grade 2–4 drug-related psychiatric adverse event was four of 79 (5%) in the ETR arm versus 12 of 78 (15%) in the EFV arm (P < 0.05). The most common psychiatric adverse events in the EFV arm were related to sleep (insomnia: n = 4; nightmare: n = 3; sleep disorder, n = 2). Four patients discontinued from the EFV arm for nervous system or psychiatric adverse events versus none in the ETR arm.

Table 3

Table 3

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Clinical and laboratory adverse events

Table 3 shows the number of patients in each arm with grade 2–4 drug-related clinical adverse events or grade 3–4 laboratory abnormalities during the trial. The clinical adverse events are presented by System Organ Class. There were 21 of 79 (27%) patients in the ETR arm with at least one grade 2–4 drug-related clinical adverse event versus 33 of 78 (42%) in the EFV arm. The main differences between the arms were for nervous system disorders and psychiatric disorders. There were nine patients in each arm with grade 2–4 drug-related skin/subcutaneous adverse events. Of these patients, four per arm discontinued the trial for these adverse events (two in each arm with grade 2 skin/subcutaneous adverse events, two in each arm for grade 3 events).

The main difference between the arms in grade 3–4 laboratory abnormalities was for lipids: there was one patient in the ETR arm with a grade 3 elevation in total cholesterol versus six (8%) in the EFV arm; two patients had grade 3 elevations in LDL in the ETR arm versus eight (10%) in the EFV arm. Use of lipid-lowering drugs in the trial was infrequent: one patient in the ETR arm used fish oil, whereas six patients in the EFV arm used lipid-lowering drugs (two used pravastatin and four used fish oil).

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Discussion

In the SENSE trial of treatment-naive patients, there were similar rates of HIV RNA suppression at week 48 for patients taking ETR 400 mg once daily and EFV 600 mg once daily, both with two nucleoside analogues. In addition, there was a lower risk of neuropsychiatric adverse events in the ETR arm that persisted over time; also, there were fewer lipid elevations in the ETR arm. The risk of skin or subcutaneous adverse events was similar in the two treatment arms.

Etravirine showed noninferior efficacy to EFV in the ITT TLOVR and non-VF censored analyses and the results were consistent for the predefined subgroups of patients with HIV RNA above versus equal or below 100 000 copies/ml. However, the primary endpoint of the SENSE trial was neuropsychiatric adverse events and the trial was not statistically powered to demonstrate noninferior efficacy of ETR versus EFV. Clinical trials to demonstrate noninferior rates of HIV RNA suppression normally require from 300 to 400 patients per treatment arm [26], and several recently conducted trials have used a noninferiority margin of −10% [27–29], rather than the wider −12% margin used in this trial: clearly, a larger trial would be required to establish the efficacy and safety profile of ETR in treatment-naive patients at the 400 mg once daily dose.

The SENSE trial involved a detailed analysis of drug resistance, with all samples tested when HIV RNA rebounded above 50 copies/ml or was above 50 copies/ml at week 48, at the time of discontinuation, or if initial reductions in HIV RNA were judged to be suboptimal. In the ETR arm, none of the four patients with protocol-defined virological failure had treatment-emergent NRTI or NNRTI resistance. By contrast, in the EFV arm, three of the seven patients with virological failure developed NRTI and/or NNRTI mutations associated with phenotypic resistance. One patient in the ETR arm developed a single IAS-USA NNRTI mutation with a decline in the HIV RNA, but had full HIV RNA suppression less than 50 copies/ml from the next visit onward with no change in treatment and was not classified as a virological failure. The percentage of patients in the EFV arm of the SENSE trial who developed treatment-emergent resistance to NRTIs and NNRTIs is consistent with a recent meta-analysis of clinical trials evaluating first-line NNRTI-based HAART [12].

Additional trials would be needed to support the findings from this study, which suggest that ETR could lower the risk of NRTI and NNRTI resistance emergence after first-line treatment failure. Results using standard population sequencing should be repeated using more sensitive methods such as ultradeep sequencing. A reduction in the risk of treatment-emergent drug resistance could have important long-term implications for the preservation of treatment options. This potential benefit could be especially important in developing countries where the monitoring of HIV RNA and drug resistance is limited. In the DUET trials, treatment-experienced patients were treated with either ETR or placebo and a background regimen that included darunavir/ritonavir for all patients. In the ETR arm, there was a lower risk of treatment-emergent resistance to darunavir, suggesting that ETR may prevent the development of resistance to other antiretrovirals used in combination [30].

At baseline, there were more patients with NRTI or NNRTI mutations in the ETR arm (n = 16) versus the EFV arm (n = 4). There was no correlation between baseline mutations and HIV RNA suppression at week 48 in the either treatment arm. However, patients with key NRTI or NNRTI mutations (in the Bennett list) had already been excluded from the trial. A recent study has shown no correlation between ‘minor’ NNRTI mutations and the risk of virological failure [31].

In this study, 100 mg ETR tablets were used, but a new 200 mg formulation of ETR has recently been approved in North America [32] and is under regulatory review in Europe. This will improve the convenience of ETR dosing.

In the SENSE trial, there were significantly fewer nervous system or psychiatric adverse events in the ETR arm compared with the EFV arm, and this difference was still statistically significant at the week 48 visit. Some clinical trials have shown a higher risk of neuropsychiatric adverse events for EFV only in the first few weeks of treatment [28,33]. Results from a ‘stepped dose’ trial of EFV suggest that the short-term risk of neuropsychiatric adverse events can be lessened by gradually raising the dose of EFV during the first 6 weeks of treatment [34]. However, results from another double-blind trial show that long-term grade 2 (moderate) neuropsychiatric adverse events may resolve after patients switch from EFV to ETR [35]. In a trial recruiting patients with or without neuropsychiatric adverse events on EFV, there was no significant improvement after switching to ETR [36].

There were greater rises in lipids in the EFV arm of the SENSE trial. The clinical implications of rises in lipids during treatment with EFV are unknown. EFV treatment has been associated with lipid elevations similar to that of protease inhibitors [9] and an elevated risk lipodystrophy compared with lopinavir/ritonavir [14]. The risk of grade 2–4 skin or subcutaneous adverse events was similar in the two arms of the SENSE trial. A ‘Dear doctor’ letter was sent to the trial investigators during the recruitment to the trial, reporting two cases of severe rash on ETR detected from routine monitoring for adverse events [37]. Consequently, there was a review of all cases of rash during the early stages of the SENSE trial. However, the final results at week 48 showed no increased risk of grade 2–4 skin or subcutaneous rash for ETR relative to EFV; there was a slightly higher risk of mild (grade 1) rash in the ETR arm. These results are consistent with the DUET trials, wherein most cases of rash on ETR were mild and resolved within the first 6 weeks of treatment [17].

In summary, ETR showed a lower risk of neuropsychiatric adverse events and lipid elevations than EFV in the SENSE trial: both safety benefits were sustained through week 48. There were similar rates of HIV RNA suppression in the two treatment arms, and none of the patients with virological failure in the ETR arm developed resistance to NRTIs or NNRTIs.

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Acknowledgements

We thank the investigators, study coordinator (Marjolein Janssen), protocol virologist (Johan Vingerhoets) site and data managers and the patients for their contributions.

B.G., S.M., Y.D. and A.H. provided scientific input into the study design and study protocol. A.H. wrote the first draft of the manuscript. All authors assessed clinical data from the study and reviewed and edited the manuscript. All investigators (B.G., C.D., C.Z., A.C.) were involved in enrolment of patients. A.H. conducted the statistical analyses.

Study of Etravirine Neuropsychiatric Symptoms versus Efavirenz (SENSE) Study Team: Austria: A. Reiger (Vienna); N. Vetter (Vienna), R. Greil (Salzburg). Denmark: C. Pedersen (Odense), M. Storgaard (Aarhus). France: P. Morlat (Bordeaux), C. Katlama (Paris), J. Durant (Nice), L. Cotte (Lyon), C. Duvvier (Paris), D. Rey (Strasbourg). Germany: S. Esser (Essen), C. Stellbrink (Hamburg), W. Schmidt (Berlin), M. Stoll, (Hannover), C. Stephan (Frankfurt), G. Fatkenheuer (Cologne); A. Stoehr (Hamburg), J. Rockstroh (Cologne). Hungary: D. Banhegyi (Budapest). Israel: L. Itzchak (Ramat-Gan), E. Shahar (Haifa), S. Maayan (Jerusalem), D. Turner (Tel-Aviv). Italy: A. Lazzarin (Milan); A. Antinori (Rome); G. Carosi (Brescia); L. Minoli (Pavia), G. di Perri (Turin), G. Filice (Pavia), M. Andreoni (Rome). Romania: D. Duiculescu (Bucharest), S. Rugina (Constanta), S. Erscoiu (Bucharest), A. Streinu (Bucharest). Russia: A. Pronin (Moscow), V. Pokrovsky (Moscow); B. Gruzdev (Moscow), A. Yakovlev (St Petersburg), E. Voronin (St Petersburg). Spain: B. Clotet (Barcelona); J. Gatell (Barcelona), J. Arribas (Madrid), D. Podzamczer (Barcelona), P. Domingo (Barcelona), C. Miralles Alvarez (Vigo), J. Hernandez Quero (Granada). Switzerland: H. Furrer (Berne), J. Feher (Zurich). UK: M. Johnson (London); J. Fox (London); M. Nelson (London), M. Fisher (Brighton), C. Orkin (London).

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Conflicts of interest

B.G. has received ad hoc consultancy fees for speaking over the past 2 years from the following companies: Bristol-Myers Squibb, Janssen, Glaxo, ViiV, Merck, Gilead Sciences. A.H. has received consultancy payments from Janssen. Y.D. and S.M. are employees of Janssen. None of the other authors has a conflict of interest.

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Keywords:

antiretroviral treatment; drug resistance; HIV RNA; nonnucleoside reverse transcriptase inhibitors; nucleoside analogues

© 2011 Lippincott Williams & Wilkins, Inc.