About AVT
Browse Articles
Authors
Customer Services

Short communication

Efficacy and safety of etravirine at week 96 in treatment-experienced HIV type-1-infected patients in the DUET-1 and DUET-2 trials

Christine Katlama1,2,*, Bonaventura Clotet3,4, Anthony Mills5, Benoit Trottier6, Jean-Michel Molina7,8, Beatriz Grinsztejn9, William Towner10, Richard Haubrich11, Steven Nijs12, Johan Vingerhoets12, Brian Woodfall12, James Witek13

1Université Pierre et Marie Curie, Paris 6, France
2Service des Maladies Infectieuses et Tropicales, Hôpital Pitié-Salpêtrière, Paris, France
3Hospital Universitari Germans Trias i Pujol, Barcelona, Spain
4IrsiCaixa Foundation, Barcelona, Spain
5Private Practice, Los Angeles, CA, USA
6Clinique Médicale l’Actuel, Montréal, QC, Canada
7Service des Maladies Infectieuses et Tropicales, Hôpital Saint-Louis, Paris, France
8University of Paris Diderot, Paris 7, France
9Instituto de Pesquisa Clinica Evandro Chagas-Fiocruz, Rio de Janeiro, Brazil
10Kaiser Permanente, Los Angeles, CA, USA
11Division of Infectious Diseases, University of California San Diego, San Diego, CA, USA
12Tibotec BVBA, Beerse, Belgium
13Tibotec Inc., Titusville, NJ, USA

*Corresponding author e-mail: christine.katlama@psl.aphp.fr

Citation: Antiviral Therapy 2010; 15:1045-1052
doi: 10.3851/IMP1662

Date accepted: 22 April 2010
Date published online: 22 September 2010

Copyright (c) 2010 International Medical Press, all rights reserved.

Abstract

Background: Durable efficacy and long-term safety of antiretroviral therapy are important goals in the management of treatment-experienced patients. The 96-week efficacy and safety of the non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine were evaluated in the Phase III DUET trials.

Methods: HIV type-1-infected treatment-experienced adults with viral loads >5,000 copies/ml and NNRTI and protease inhibitor resistance were randomized to receive etravirine 200 mg or placebo, each twice daily and in combination with a background regimen of darunavir/ritonavir twice daily, nucleoside/nucleotide reverse transcriptase inhibitors and optional enfuvirtide. The primary end point was the proportion of patients with viral load <50 copies/ml (intent-to-treat analysis, time-to-loss of virological response algorithm) at week 24. Results from both trials were combined in the pre-specified pooled 96-week analysis.

Results: In total, 599 patients received etravirine and 604 received placebo. At week 96, 57% of patients in the etravirine group versus 36% in the placebo group had a viral load <50 copies/ml (P<0.0001); 91% and 88% of patients, respectively, had maintained this response from week 48. Mean increases in CD4+ T-cell count from baseline at week 96 were 128 cells/mm3 with etravirine versus 86 cells/mm3 with placebo (P<0.0001). With the exception of rash, which was reported more frequently with etravirine than placebo (21% versus 12%, respectively; P<0.0001), the safety and tolerability profile of etravirine was similar to placebo over the treatment period.

Conclusions: Etravirine, in combination with an antiretroviral background regimen, provided durable virological and immunological responses with no new safety concerns in treatment-experienced patients over 96 weeks in the DUET trials.

Introduction

The non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine has demonstrated significant clinical benefits in treatment-experienced HIV type-1 (HIV-1)-infected patients with antiretroviral resistance in the Phase III DUET-1 and DUET-2 trials [13]. At week 48, 61% of patients receiving etravirine in combination with an antiretroviral background regimen achieved a viral load <50 copies/ml compared with 40% of patients receiving placebo plus a background regimen (P<0.0001) [3]. The safety and tolerability of etravirine was comparable with placebo, except for the incidence of rash [3].

The durability of virological response and long-term safety and tolerability are key considerations in the choice of antiretrovirals for treatment-experienced patients. Furthermore, because of the lifelong duration of antiretroviral therapy, it is important to examine the long-term efficacy of antiretroviral agents. The long-term clinical profile of etravirine was evaluated in treatment-experienced patients in this final pooled week 96 analysis of the DUET trials.

Methods

Patients

Inclusion and exclusion criteria have been described elsewhere [1,2]. Patients were treatment-experienced HIV-1-infected adults virologically failing on a stable regimen, with screening viral load >5,000 HIV-1 RNA copies/ml, ≥1 NNRTI resistance-associated mutation (RAM) [4,5] and ≥3 primary protease inhibitor mutations [4]. All patients provided written informed consent. The trial protocols were approved by the appropriate independent ethics committees or institutional review boards and conducted according to the Declaration of Helsinki.

Study design

DUET-1 (NCT00254046) and DUET-2 (NCT00-255099) were randomized, double-blind, placebo-controlled, identically designed international Phase III trials [1,2]. Patients were randomized to receive etravirine 200 mg or placebo, each twice daily and in combination with darunavir/ritonavir 600/100 mg twice daily, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) selected by the investigator and optional enfuvirtide. Patients with virological failure any time after week 24 could roll-over to an open-label trial (NCT00359021) and receive etravirine and darunavir/ritonavir with a background regimen. After week 48, treatment was unblinded and patients could continue into the optional extension period until week 96.

Assessments and statistical analyses

The primary efficacy end point was the proportion of patients with confirmed viral load <50 HIV-1 RNA copies/ml (intent-to-treat [ITT], time-to-loss of virological response [TLOVR] algorithm) at week 24. Efficacy and safety data from DUET-1 and DUET-2 were combined in a pre-specified pooled analysis at week 96. Assessments were carried out every 8 weeks between weeks 48 and 96, and completed as described previously [13]. Statistical analyses were performed as previously reported [13].

Results

Baseline characteristics

The 96-week analysis included all patients originally randomized and treated as described previously [13]: 599 patients in the etravirine group and 604 in the placebo group. A total of 7 and 17 patients, respectively, completed the trials after week 48 and did not enter the optional extension period. Overall, 191 (32%) patients in the etravirine group and 361 (60%) in the placebo group discontinued treatment, mainly because of virological failure (16% versus 40%, respectively) or adverse events (AEs; 9% versus 6%, respectively). Median treatment duration was 96.0 weeks in the etravirine group and 69.6 weeks in the placebo group (895.4 and 766.7 patient-years of exposure, respectively).

Baseline characteristics were balanced across the treatment groups [3]. Patients had a median baseline viral load of 4.8 log10 copies/ml, a median CD4+ T-cell count of 105 cells/mm3 and a median of two NNRTI RAMs and four primary protease inhibitor mutations.

Efficacy

At week 96, 344 (57%) etravirine-treated patients versus 219 (36%) placebo-treated patients had viral load <50 copies/ml (ITT-TLOVR; P<0.0001; Figure 1A). Of those with viral load <50 copies/ml at week 24, 83% of etravirine-treated patients and 78% of placebo-treated patients had undetectable viral loads at week 96; 91% and 88% of patients, respectively, maintained this response from week 48 to week 96. The difference between treatment groups in virological response rates was observed across various subgroups, including baseline etravirine sensitivity by phenotype and genotype (Table 1). Previous use of other NNRTIs did not affect the difference in virological response rate between treatment groups: 57% of etravirine-treated patients who had or had not previously used efavirenz achieved an undetectable viral load, versus 33% and 44% of placebo-treated patients, respectively. Similar results were observed according to previous nevirapine use, with 56% and 59% of etravirine-treated patients previously using or not using nevirapine achieving an undetectable viral load, versus 37% and 35% of placebo-treated patients, respectively. Increasing the number of active NRTIs in the background regimen resulted in increased virological response in both treatment groups, although responses were consistently higher in the etravirine group than the placebo group.

-
Figure 1.
Figure 1. Virological and immunological response over time to week 96 in the pooled DUET trials

Data are mean ±se. Imputations were used for missing values, with non-completer equals failure analysis for discontinuations before week 48 and/or for adverse events, and with the last observation carried forward for discontinuations after week 48 for reasons other than adverse events. (A) Proportion of patients with viral load <50 HIV type-1 (HIV-1) RNA copies/ml (intent-to-treat, time-to-loss of virological response). (B) Change in CD4+ T-cell count from baseline (intent-to-treat, imputed). BR, background regimen.

-
Table 1.  Virological response according to patient subgroup at week 96 in the pooled DUET trials
Table 1. Virological response according to patient subgroup at week 96 in the pooled DUET trials

Virological response defined as HIV type-1 RNA<50 copies/ml (intent-to-treat analysis, time-to-loss of virological response algorithm). P-values show the difference between etravirine and placebo responses from logistic regression analyses. a This subgroup reflects the baseline phenotypic susceptibility score, for which the calculation excluded etravirine. Darunavir was considered fully active if baseline fold change (FC) in 50% effective concentration was ≤10, enfuvirtide was considered fully active if used de novo and nucleoside reverse transcriptase inhibitors were considered to be fully active if individual baseline FC values were less than or equal to the cutoff values used in the Antivirogram® assay (Virco BVBA, Beerse, Belgium). b Excluding patients who discontinued for reasons other than virological failure. c The etravirine weighted genotypic score was the sum of the weighted factors of the individual etravirine resistance associated mutations (RAMs) present at baseline. Each RAM was assigned a weight factor of 1, 1.5, 2.5 or 3 based on its impact on response to etravirine at week 24 (from low to high, respectively) [6]. BR, background regimen.

Viral load <400 copies/ml at week 96 was observed in 68% of etravirine-treated patients and 43% of placebo-treated patients (P<0.0001); mean change in viral load from baseline was -2.16 and -1.42 log10 copies/ml, respectively (P<0.0001). Mean change in CD4+ T-cell count from baseline was 128 cells/mm3 in the etravirine group and 86 cells/mm3 in the placebo group (P<0.0001; Figure 1B).

Resistance

The number of baseline etravirine RAMs and the baseline etravirine weighted genotypic score [6] were significant predictors of virological response to etravirine at week 96 (both P<0.0001). The presence of the NNRTI RAM K103N at baseline was not found to affect virological response to etravirine.

Over the 96-week treatment period, 93 patients in the etravirine group experienced virological failure by rebound. The most frequently emerging NNRTI RAMs in these patients were V179F (n=15), V179I (n=13) and Y181C (n=10), usually emerging in a background of multiple other mutations [7]. Of the 18 patients experiencing rebound after week 48, emerging etravirine RAMs were observed in five patients (all ≤2 RAMs), and ≥2 emerging darunavir RAMs were reported in five patients.

Clinical end points

Over 96 weeks, 8% of patients in the etravirine group and 11% in the placebo group experienced a clinical end point (confirmed or probable AIDS-defining illness [ADI] and/or death; P=0.27). Adjusting for the difference in treatment exposure, 5.37 etravirine-treated patients versus 8.37 placebo-treated patients experienced a clinical end point per 100 patient-years (relative risk 0.64 [95% confidence interval 0.39–0.89]). Deaths occurred in 19 (3%) and 23 (4%) etravirine-treated and placebo-treated patients, respectively; all deaths in the etravirine group were considered not, or doubtfully, related to study medication.

The incidence of new onset ADIs after the 48-week analysis was low in both the etravirine and placebo groups (eight and six patients, respectively). ADIs reported in ≥1 etravirine-treated patients after the 48-week analysis were multidermatomal herpes zoster, herpes simplex, Hodgkin’s disease, oesophageal candidiasis, diffuse large B-cell lymphoma and Kaposi’s sarcoma.

Safety

The overall incidence and severity of AEs was similar between treatment groups over the 96-week treatment period (Table 2), with little change from that previously reported at week 48 [3]. Rash was more frequent in the etravirine than placebo group, and generally occurred within the first 2 weeks of therapy [3]. Changes in hepatic and lipid laboratory parameters were generally comparable between groups, with low incidences of grade 3 and 4 laboratory abnormalities (Table 2).

-
Table 2.  Overview of treatment-emergent AEs and laboratory abnormalities over the 96-week treatment period in the pooled DUET trials
Table 2. Overview of treatment-emergent AEs and laboratory abnormalities over the 96-week treatment period in the pooled DUET trials

Data are n (%) unless indicated otherwise. a Grouped term combining all rash-related events; P<0.0001 for etravirine versus placebo (pre-specified Fisher’s exact test). b Injection-site reaction associated with enfuvirtide use. c Etravirine and placebo groups were not significantly different in a pre-specified analysis for these adverse events (AEs; P=0.3140 for nervous system disorders and P=0.7204 for psychiatric disorders, both Fisher’s exact test). The most common terms that made up the nervous system events of interest were headache, dizziness, somnolence, memory impairment, amnesia, disturbance in attention, balance disorder and restless legs syndrome; the most common terms that made up the psychiatric events of interest were depression, insomnia, anxiety, sleep disorders, decreased libido, abnormal dreams, stress, confusional state, nightmare and panic attack. d Grade 3 (751–1,200 mg/dl) and grade 4 (>1,200 mg/dl). e Grade 3 (2–5× the upper limit of normal [ULN]) and grade 4 (>5×ULN). f Grade 3 (>300 mg/dl); according to the Division of AIDS grading scale, there is no grade 4 category for total cholesterol. g Grade 3 (>190 mg/dl); according to the Division of AIDS grading scale, there is no grade 4 category for low-density lipoprotein (LDL). h Grade 3 (5.1–10×ULN) and grade 4 (>10×ULN). ALT, alanine aminotransferase; AST, aspartate aminotransferase; BR, background regimen.

Of the patients with safety data beyond week 48 (n=470 and n=395 in the etravirine and placebo groups, respectively), AEs with onset after this time point were reported in 75% of etravirine-treated patients and 68% of placebo-treated patients, with grade 3 or 4 AEs in 19% and 13%, respectively. The incidence of AEs with onset after week 48 is shown in Table 3. Low proportions of patients experienced new-onset rash (4% with etravirine and 2% with placebo); no new grade 3 or 4 rashes, hypersensitivity reactions or rash-related discontinuations were reported. One patient (0.2%) in the etravirine group experienced new-onset rash after week 48 that was considered by the investigator to be possibly related to etravirine. Incidences were similar between groups for new-onset nervous system, psychiatric and hepatic AEs (Table 3).

-
Table 3.  Overview of treatment-emergent AEs with onset after week 48 in the pooled DUET trials
Table 3. Overview of treatment-emergent AEs with onset after week 48 in the pooled DUET trials

Data are n (%) unless indicated otherwise. Adverse events (AEs) with onset after week 48 (after day 336) are shown. a Grouped term combining all rash-related events. b Injection-site reaction associated with enfuvirtide use. BR, background regimen.

Discussion

The results of this pooled DUET analysis confirm those observed at weeks 24 and 48 [13], showing that response rates were consistently higher with etravirine than placebo across all virological and immunological end points over 96 weeks. Of note, >80% of etravirine-treated patients with a viral load <50 copies/ml at week 24 sustained this response to week 96, and >90% maintained it from week 48 to week 96. Sustained suppression was also observed in the placebo group.

Despite the longer duration of treatment, etravirine demonstrated a safety and tolerability profile that was generally similar to that of placebo over 96 weeks, except for the incidence of rash. Notably, low incidences of grade 3 and 4 lipid abnormalities were observed. Importantly, no new safety concerns were identified after week 48, with few rash, neuropsychiatric and hepatic AEs reported. Consistent with earlier analyses [13], rash was more common with etravirine than placebo, although new-onset rash after week 48 was very infrequent and mild to moderate in severity. With broader use of etravirine following marketing approval, few incidences of severe cutaneous and hypersensitivity reactions, including Stevens–Johnson syndrome and toxic epidermal necrolysis, have been reported. As these can be life-threatening, clinical guidance requires immediate discontinuation of etravirine when such severe reactions are suspected [8,9].

The DUET trials represent the first time an NNRTI has demonstrated durable efficacy and tolerability, with less virological failure, in a population with extensive treatment experience and documented NNRTI resistance. The results of this analysis confirm the potential of etravirine in expanding antiretroviral therapy options for treatment-experienced patients with antiretroviral resistance, a prospect supported by recent data from several clinical studies of etravirine used in combination with other agents [1012]. Indeed, such an approach is also in line with current treatment guidelines [13,14].

In summary, over 96 weeks in the DUET trials, etravirine, in combination with a background regimen, demonstrated sustained antiretroviral activity and tolerability, providing evidence over the longer term that etravirine has the ability to provide durable clinical benefit in treatment-experienced patients.

Acknowledgements

The authors thank the patients and their families, the study coordinators, the investigators who participated in the DUET clinical trials and Tibotec study personnel. They also acknowledge Benny Baeten, Stephan Marks and David Anderson for their important contributions to the manuscript. Assistance in drafting the manuscript and collating author contributions was provided by Emily de Looze (Medical Writer; Gardiner-Caldwell Communications, Macclesfield, UK). This service was funded by Tibotec Pharmaceuticals, Ltd.

Data have been presented in part at the 18th Annual Canadian Conference on HIV/AIDS Research, Vancouver, BC, Canada, 23–26 April 2009 (abstract P148) and the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, South Africa, 19–22 July 2009 (abstracts MOPEB036, MOPEB038 and MOPEB043).

Disclosure statement

All study investigators received research funding from Tibotec to support their patients’ participation in this trial. CK has served on advisory boards for Abbott Laboratories, Boehringer Ingelheim, GlaxoSmithKline, Janssen–Cilag, Merck, Pfizer, Roche and Tibotec. BC has received research funding, consultancy fees, or lecture sponsorships from, or has served on advisory boards for Abbott Laboratories, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Janssen–Cilag, Merck, Panacos, Pfizer, Roche and Tibotec. AM has received research support from Tibotec, Merck, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Pfizer and Schering–Plough; he has served as a consultant for Tibotec, Merck, Gilead Sciences, Abbott Laboratories and Solvay, and has been on speakers’ bureaus for Tibotec, Merck, Gilead Sciences, Serono, Bristol–Myers Squibb and Boehringer Ingelheim. BT has received honoraria for participation in advisory boards or as a speaker from Abbott Laboratories, Boehringer Ingelheim, Bristol–Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Roche and Tibotec. J-MM has received honoraria for participation in advisory boards and/or lectures for Abbott Laboratories, Bristol–Myers Squibb, Gilead Sciences, Pfizer, GlaxoSmithKline and Tibotec. WT has received research support from Tibotec, Pfizer, Bristol–Myers Squibb, Schering–Plough, Merck and Gilead Sciences. On behalf of RH, the University of California San Diego has received research grants from Tibotec, GlaxoSmithKline and Abbott Laboratories; RH has received honoraria for consulting/lectures from Abbott Laboratories, Bristol–Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Progenics, Schering–Plough, Tibotec and Virco. SN, JV, BW and JW are full-time employees of Tibotec. BG declares no competing interests.

References

-
1. Madruga JV, Cahn P, Grinsztejn B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 2007; 370: 29-38. Medline doi:10.1016/S0140-6736(07)61047-2
-
2. Lazzarin A, Campbell T, Clotet B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 2007; 370: 39-48. Medline doi:10.1016/S0140-6736(07)61048-4
-
3. Katlama C, Haubrich R, Lalezari J, et al. Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled week 48 analysis of two randomized, controlled trials. AIDS 2009; 23: 2289-2300. Medline doi:10.1097/QAD.0b013e3283316a5e
-
4. Johnson VA, Brun-Vezinet F, Clotet B, et al. Drug resistance mutations in HIV-1: fall 2005. Top HIV Med 2005; 13: 125-131. Medline
-
5. Tambuyzer L, Vingerhoets J, Azijn H, et al. Development of a list of mutations associated with NNRTI resistance for use in clinical research. 5th European HIV Drug Resistance Workshop. 28–30 March 2007, Cascais, Portugal. Abstract 67.
-
6. Vingerhoets J, Tambuyzer L, Azijn H, et al. Resistance profile of etravirine: combined analysis of baseline genotypic and phenotypic data from the DUET studies. AIDS 2010; 24: 503-514. Medline doi:10.1097/QAD.0b013e32833677ac
-
7. Tambuyzer L, Vingerhoets J, Azijn H, et al. Characterization of genotypic and phenotypic changes in HIV-1-infected patients with virologic failure on an etravirine-containing regimen in the DUET-1 and DUET-2 clinical studies. AIDS Res Hum Retroviruses 2010; in pressMedline
-
8. Tibotec, Inc. INTELENCE® (etravirine) tablets: full prescribing information. (Updated July 2010. Accessed 14 September 2010.) Available from http://www.intelence-info.com/intelence/assets/pdf/INTELENCE_PI.pdf
-
9. European Medicines Agency. Intelence (etravirine). (Updated 26 July 2010. Accessed 14 September 2010.) Available from www.emea.europa.eu/humandocs/Humans/EPAR/intelence/intelence.htm
-
10. Yazdanpanah Y, Fagard C, Descamps D, et al. High rate of virologic suppression with raltegravir plus etravirine and darunavir/ritonavir among treatment-experienced patients infected with multidrug-resistant HIV: results of the ANRS 139 TRIO trial. Clin Infect Dis 2009; 49: 1441-1449. Medline doi:10.1086/630210
-
11. Nozza S, Visco F, Soria A, et al. Excellent short-term CD4 recovery with a PI- and NRTI-sparing regimen in triple-class failure HIV-infected patients: raltegravir, maraviroc, etravirine. 9th International Congress on Drug Therapy in HIV Infection. 9–13 November 2008, Glasgow, UK. Abstract P45.
-
12. Towner W, Lalezari J, Sension MG, et al. Efficacy, safety, and tolerability of etravirine with and without darunavir/ritonavir or raltegravir in treatment-experienced patients: analysis of the etravirine early access program in the United States. J Acquir Immune Defic Syndr 2010; 53: 614-618. Medline
-
13. Thompson MA, Aberg JA, Cahn P, et al. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society–USA panel. JAMA 2010; 304: 321-333. Medline doi:10.1001/jama.2010.1004
-
14. Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. (Updated 1 December 2009. Accessed 10 January 2010.) Available from http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

Copyright © 2021 Nucleus Holdings Ltd. Part of Nucleus Global.
Design and Technology by Nucleus Global
Company registration No. 321 0712 (England & Wales). Registered Office address: Admiral House 76-78 Old Street, London EC1V 9AZ.