A Phase IV, Double-Blind, Multicentre, Randomized, Placebo-Controlled

A phase IV, double-blind, multicentre, randomized, placebo-controlled, pilot study to assess the feasibility of switching individuals receiving efavirenz with continuing central nervous system adverse events to etravirine

Laura Watersa, Martin Fisherb, Alan Winstonc, Chris Higgsa, Wendy Hadleyb, Lucy Garveyc, Sundhiya Mandaliaa, Nicky Perryb, Nicola Mackiec and Mark Nelsona

Background: Two nucleoside reverse transcriptase inhibitors (NRTIs) and efavirenz (EFV) is a recommended initial regimen for HIV-1. Most EFV-related central nervous system (CNS) toxicity resolves early though symptoms may persist; we studied switching to etravirine (ETR) in these individuals. Methods: A randomized, double-blind trial in patients with viral suppression but ongoing CNS adverse events after more than 12 weeks EFV. Patients received 2NRTI/EFV/ETR-placebo (delayed switch) or 2NRTI/ETR/EFV-placebo (immediate switch) for 12 weeks followed by 12-week open-label phase (2NRTI/ETR). Primary end-point was percentage with G2-4 CNS adverse events at 12 weeks. Results: Thirty-eight men; 20/18 were randomized to immediate switch/delayed switch; median CD4 was 444/498 cells/ml, respectively. Baseline CNS adverse events were similar. Nineteen immediate switch patients completed follow-up (one lost to follow-up) and 13 on delayed switch (two lost to follow-up, two withdrawn consent, one adverse event). Immediate switch G2-4 CNS adverse event: 90% at baseline, 60% at week 12 (P ¼ 0.041). Delayed switch G2-4 CNS adverse event: 88.9% at baseline, 81.3% at week 12 (P ¼ ns). Combined (both arms) percentage decline in G2-4 CNS adverse event after 12 weeks of ETR was significant for overall adverse events, insomnia, abnormal dreams and nervousness (P ¼ 0.009, 0.016, 0.001, and 0.046, respectively). All participants on study maintained HIV-RNA below 50 and median week 24 CD4 was 593 and 607 cells/ml on immediate switch and delayed switch. Two participants experienced new G3-4 adverse events [delayed switch: G3 flatulence on EFV); immediate switch: G4 viral URTI on ETR (SAE)]. Conclusion: Switching EFV to ETR led to a significant reduction in overall G2-4 CNS adverse events, including insomnia, abnormal dreams and nervousness as individual adverse event. Lack of improvement for some events suggests other causative factors. ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

AIDS 2011, 25:65–71

Keywords: adverse events, central nervous system, efavirenz, etravirine, neuro-psychiatric, switch, toxicity

aChelsea & Westminster Hospital, London, bRoyal Sussex County Hospital, Brighton, and cSt Mary’s Hospital, London, UK. Correspondence to Dr Laura Waters, Department of HIV/GU Medicine, Chelsea and Westminster Hospital Foundation Trust, 369 Fulham Road, London SW10 9NH, UK. Tel: +44 20 8846 6503; fax: +44 20 8746 5628; e-mail: [email protected] Received: 9 June 2010; revised: 8 October 2010; accepted: 11 October 2010.

DOI:10.1097/QAD.0b013e328341685b

ISSN 0269-9370 Q 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins 65 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 66 AIDS 2011, Vol 25 No 1

Blinded phase: Open-label phase: Introduction baseline to week 12 week 12 to 24

Efavirenz (EFV) is a non-nucleoside reverse transcriptase 2 NRTI + 2 NRTI + inhibitor (NNRTI) that, in combination with two ETR 400 mg ETR 400 mg q.d. nucleoside reverse transcriptase inhibitors (NRTIs), is a q.d. recommended first-line regimen for the treatment of + EFV-placebo HIV-1 infection [1–3]. Antiretroviral toxicity is the most common reason for modification of first-line therapy 2 NRTI + EFV 1 : 1 randomization [4,5]. Central nervous system (CNS) toxicity is a common side effect of EFV: 19.4% of patients experience 2 NRTI + EFV 600 mg 2 NRTI + at least moderate CNS adverse events on EFV compared q.d. ETR 400 mg q.d. with 9% on control regimens [6]; CNS toxicity is one of + ETR-placebo the most frequent reasons for switching or discontinuing highly active antiretroviral therapy (HAART) [4]. Fig. 1. Study design. EFV, efavirenz; ETR, etravirine; NRTI, nucleoside reverse transcriptase inhibitor; q.d., once daily. Although most CNS toxicity resolves after 2–4 weeks of EFV [6] some patients experience ongoing symptoms [7] required to have an undetectable plasma viral load (less and chronic low-grade CNS toxicity may be under- than 50 copies/ml) and CD4 cell count greater than estimated. Higher levels of stress, anxiety and abnormal 50 cells/ml at screening. Exclusion criteria included dreams were reported in patients on stable EFV- previous exposure to etravirine or rilpivirine, a serious containing HAART compared with matched controls medical or psychiatric condition, acute viral hepatitis, [8] and long-term (184 week) follow-up of a subset of an active AIDS-defining illness, significant laboratory patients from ACTG5095 showed EFV was associated abnormality, disallowed concomitant medication (as per with bad dreams and anxiety compared with baseline [9]. the summary of product characteristics for EFV and ETR), resolution of CNS toxicity between screening and Etravirine (ETR) is a second-generation NNRTI licensed baseline, and patients who were pregnant or breast- for treatment-experienced HIV-1-infected adults [10]. feeding. All patients provided written, informed consent Rates of nervous system and psychiatric adverse events and ethics approval was granted by local Research Ethics were similar when ETR was compared with placebo in Committees for each study site. treatment-experienced patients, each in combination with optimized background therapy [11]. ETR has a higher The study comprised of two phases as outlined in Fig. 1. genetic barrier to resistance than first-generation NNRTI. Eligible patients were randomized at baseline to one of Although ETR licensed for twice daily (b.i.d.) adminis- two arms: tration, pharmacokinetic data support once-daily (q.d.) dosing; 200 mg b.i.d. and 400 mg q.d. achieve similar 24-h (1) Immediate switch: 2 NRTI þ ETR 400 mg q.d. þ exposure and minimum plasma concentrations in healthy EFV-placebo volunteers [12]. EFV reduces ETR concentrations by (2) Delayed switch: 2 NRTI þ EFV 600 mg q.d. þ ETR- 30–40%, demonstrated in a healthy volunteer pharma- placebo cokinetic study, but this reduction was not considered clinically significant as all participants maintained plasma Study assessments concentrations well above the IC50 for wild-type virus. At each study visit patients underwent urine macro- The authors concluded that no dose adjustment is analysis and blood sampling for plasma HIV-RNA necessary when switching directly from EFV to ETR, (Chiron bDNA), CD4 cell count and percentage, CD8 whether the ETR was dosed q.d. or b.i.d. [13]. cell count and percentage, biochemistry (hepatic, renal and bone profiles), haematology (full blood count and The aim of this study was to assess the impact of switching differential), fasting lipids [total, high-density lipoprotein from EFV to ETR q.d. on CNS symptoms in patients on (HDL) and low-density lipoprotein (LDL) cholesterol, a stable, fully suppressive, EFV-based regimen. total: HDL cholesterol ratio and triglycerides] and fasting glucose. Adverse events were based on the summary of product characteristics and local clinical experience; these were documented at each visit and graded in a manner Methods based on the to the AIDS Clinical Trials Group (ACTG) Division of AIDS scale (2004). The following CNS HIV-1-infected adults who had received at least 12 weeks adverse events were investigated: of EFV and two NRTIs with ongoing CNS symptoms were recruited from three UK sites (Chelsea and West- (1) Dizziness minster and St Mary’s Hospitals, London and The Royal (2) Depression Sussex County Hospital, Brighton). Patients were (3) Insomnia

(4) Anxiety Results (5) Impaired concentration (6) Headache Thirty-eight men were enrolled; median age was 43 years (7) Somnolence (range 26–64) and median duration of EFV exposure at (8) Fatigue baseline was 21.4 months (range 3.5–117.5 months). (9) Abnormal dreams Median baseline CD4 cell count was 510 cells/ml (IQR (10) Nervousness 365–611 cells/ml) and plasma viral load was less than (11) Hallucinations 50 copies/ml in all patients at screening and baseline. Twenty patients were randomized to immediate switch Study participants were specifically questioned by a and 18 to delayed switch; patient disposition is illustrated research doctor at each study visit about each neuro- in Table 1. NRTI backbones were: tenofovir/emtrici- psychiatric and CNS adverse events as listed above; these tabine fixed-dose combination [60% immediate switch were graded on a four-point scale (0 ¼ absent, 1 ¼ mild, arm, 61% delayed switch arm (50% as Atripla in each 2 ¼ moderate, 3 ¼ severe, 4 ¼ life-threatening). CNS arm)], abacavir/lamivudine fixed-dose combination adverse events were described as the proportion of (35% immediate switch arm, 22% delayed switch arm), patients with any grade 2–4 adverse events and individual abacavir/tenofovir (5% immediate switch arm, 11% grade 2–4 adverse events; the median number of grade delayed switch arm) and tenofovir/lamivudine (6% 2–4 CNS adverse event was also calculated. A ‘CNS delayed switch arm); none of the differences in backbone score’ was calculated based on the sum total of all grades of use between the two study arms were statistically CNS adverse events; for example, a patient with grade 1 significant. depression, grade 3 anxiety, grade 2 insomnia and no other CNS adverse events would have a CNS score of 6. Central nervous system adverse events Rates of baseline CNS toxicity were similar in the The primary endpoint of the study was change in the two arms (Table 2); 90% in the immediate switch arm proportion of patients experiencing grade 2–4 CNS and 88.9% in the delayed switch arm had at least one toxicity at week 12. Secondary endpoints were as follows: grade 2–4 CNS adverse events and the frequency of individual grade 2–4 CNS adverse events were similar (1) Change in CNS score with the exception of insomnia (75% in the immediate (a) At week 12 and week 24 switch arm compared with 39% in the delayed switch (b) Combined (immediate switch and delayed switch) arm; P ¼ 0.024). Baseline CNS score was 14 (IQR 6– after 12 weeks on ETR 17.5) in the immediate switch arm and 10 (IQR 5.5– 17.5) in the delayed switch arm; this difference was not (2) Median number of grade 2–4 CNS adverse events significant (P ¼ 0.534). (a) At week 12 and week 24 (b) Combined (immediate switch and delayed switch) Change from baseline to week 12 after 12 weeks on ETR At week 12 (Table 3) the proportion of patients with grade 2–4 CNS adverse events (primary endpoint) had (3) Viral suppression at week 12 and week 24 declined to 60% in the immediate switch arm and (4) CD4 change at week 12 and week 24 remained unchanged (81.3%) in the delayed switch arm (5) Fasting lipids (P ¼ 0.041 and P ¼ 0.999 compared with baseline, (6) Safety and non-CNS tolerability respectively). In terms of individual grade 2–4 CNS adverse events there were no significant changes in the delayed switch arm; the proportion experiencing Statistical analyses abnormal dreams declined significantly in the immediate All data analyses were performed in SAS V9 (SAS switch arm (from 50% at baseline to 20% at week 12; Institute Inc., Cary, North Carolina, USA). Quantitative P ¼ 0.041) and was significantly less than in the delayed data with hypergeometric distribution is presented as switch arm (62.5%; P ¼ 0.009). The median number of medians with interquartile ranges (IQRs); qualitative data grade 2–4 CNS adverse events at baseline was 4 in the have been presented as proportions. Between-group quantitative comparisons were analysed with Mann– Table 1. Subject disposition. Whitney U test, between-groups qualitative comparisons Immediate switch Delayed switch with chi-squared testing (þ/ Yates’ correction for small Baselined 20 18 numbers). Within-participant changes over time were Completed 19 13 analysed using: Wilcoxon signed-rank test (quantitative Lost to follow-up 1 2 data) or McNemar’s chi-squared test (qualitative data). Withdrawal of consent 0 2 Due to the relatively small sample size, P values are Adverse event 0 1 presented as Yate’s corrected; all P values are two-tailed. Virological failure 0 0

Table 2. Rates of overall and individual central nervous system events in immediate switch and delayed switch arms.

Grade 2–4 CNS conditions at baseline N ¼ 20 (%; 95% CI) N ¼ 18 (%; 95% CI) P value

Proportion with any grade 2–4 CNS AE 18 (90.0; 68.3–98.8) 16 (88.9; 65.3–98.6) 0.676 Dizziness 2 (10.0) 3 (16.7) 0.544 Depression 7 (35.0) 6 (33.3) 0.914 Insomnia 15 (75.0) 7 (38.9) 0.024 Anxiety 7 (35.0) 5 (27.8) 0.633 Pain 2 (10.0) 1 (5.6) 0.612 Impaired concentration 7 (35.0) 4 (22.2) 0.386 Headache 2 (10.0) 4 (22.2) 0.302 Somnolence 8 (40.0) 6 (33.3) 0.671 Fatigue 9 (45.0) 8 (44.4) 0.973 Abnormal dreams 10 (50.0) 12 (66.7) 0.299 Nervousness 5 (25.0) 4 (22.2) 0.841 Hallucinations 1 (5.0) 1 (5.6) 0.939

AE, adverse event; CI, conﬁdence interval; CNS, central nervous system.

immediate switch arm and 3 in the delayed switch arm switch arm (P ¼ 0.085) and a decline from 3 to 1 in the and at week 12 this had changed to 1.5 in the immediate delayed switch arm (P ¼ 0.003). switch arm (P ¼ 0.003) and was unchanged in the delayed switch arm. Finally, CNS score declined from 14 at Combined analyses baseline to 6 at week 12 in the immediate switch arm Combined analyses were performed to calculate the (P ¼ 0.001) and from 10 to 7.5 in the delayed switch arm change in CNS adverse events after 12 weeks of (P ¼ 0.192). ETR; changes from baseline to week 12 in the immediate switch arm and from week 12 to week 24 in the delayed switch arm were combined for statistical analysis. After Change from week 12 to week 24 12 weeks of ETR there were significant reductions in In the immediate switch arm there was no further the proportion of patients reporting any grade 2–4 CNS significant change in overall or individual grade 2–4 CNS adverse events (89–60%; P ¼ 0.009), grade 2–4 insomnia adverse events from week 12 to week 24 (P values for (63–37%; P ¼ 0.016), abnormal dreams (57–20%; week 12 vs. week 24 not presented). In the delayed switch P ¼ 0.001) and nervousness (29–9%; P ¼ 0.046) com- arm there was a numerical reduction in proportion of pared with baseline. Combined change in other CNS patients with any grade 2–4 CNS adverse events in the events was not significant. Median number of grade 2– delayed switch arm from week 12 to week 24, although 4 CNS adverse events declined from 3 at baseline to 1 at this was not statistically significant; there was, however, a 12 weeks (P < 0.001) and CNS score from 10 to 7 significant reduction in abnormal dreams in delayed (P ¼ 0.001). switch arm from week 12 to week 24 (P ¼ 0.023). In terms of median number of grade 2–4 CNS adverse Virological and immunological efficacy events at week 24 there was a further small reduction All participants on study maintained viral suppression (less compared with week 12 from 1.5 to 1 in the immediate than 50 copies/ml) at all visits. By on-treatment analysis

Table 3. Rates of grade 3–4 CNS events at week 12 and week 24 by study arm (P values refer so difference at each time point compared with event rates at baseline).

Week 12 Week 24

IS (n ¼ 20) (%) DS (N ¼ 16) (%) IS (n ¼ 20) (%) DS (n ¼ 15) (%)

Overall CNS events 12 (60%) 95% CI 36–81% 13 (81.3%) 95% CI 54–96% 14 (70%) 95% CI 46–88% 9 (60%) 95% CI 32–84% Dizziness 3 (15%) P ¼ 0.999 3 (18.8%) P ¼ 0.618 3 (15%) P ¼ 0.999 0 P ¼ 0.248 Depression 4 (20%) P ¼ 0.371 3 (18.8%) P ¼ 0.372 5 (25%) P ¼ 0.724 5 (33%) P ¼ 0.683 Insomnia 10 (50%) P ¼ 0.074 7 (43.8%) P ¼ 0.999 7 (35%) P ¼ 0.013 3 (20%) P ¼ 0.371 Anxiety 5 (25%) P ¼ 0.617 7 (43.8%) P ¼ 0.617 5 (25%) P ¼ 0.683 4 (26.7%) P ¼ 0.999 Impaired concentration 6 (30%) P ¼ 0.999 5 (31.3%) P ¼ 0.999 7 (35%) P ¼ 0.617 4 (26.7%) P ¼ 0.999 Headache 1 (5%) P ¼ 0.999 4 (25%) P ¼ 0.617 3 (15%) P ¼ 0.999 4 (26.7%) P ¼ 0.999 Somnolence 6 (30%) P ¼ 0.683 5 (31.3%) P ¼ 0.999 4 (20%) P ¼ 0.134 6 (40%) P ¼ 0.999 Fatigue 7 (35%) P ¼ 0.480 7 (43.8%) P ¼ 0.999 5 (25%) P ¼ 0.134 6 (40%) P ¼ 0.999 Abnormal dreams 4 (20%) P ¼ 0.041 10 (62.5%) P ¼ 0.724 2 (10%) P ¼ 0.027 3 (20%) P ¼ 0.077 Nervousness 2 (10%) P ¼ 0.371 4 (25%) P ¼ 0.617 3 (15%) P ¼ 0.617 1 (6.7%) P ¼ 0.371 Hallucinations (auditory) 0 P ¼ 0.999 1 (6.7%) P ¼ 0.480 0 P ¼ 0.999 0 P ¼ 0.999

CNS, central nervous system; DS, delayed switch; IS, immediate switch.

Table 4. Lipid changes (mmol/l) after 12 weeks of etravirine-based HAART (from baseline to week 12 in immediate switch arm and from week 12 to week 24 in delayed switch arm).

IS arm DS arm Total

Number Baseline 20 18 38 Week 12 20 16 36 Week 24 20 15 35 Total Mean 5.33 5.26 Cholesterol (mmol/l) Change at W12 (SD) 0.64 (1.09) S0.63 (0.97) S0.64 (1.02) P value P U 0.017 P U 0.024 P < 0.001 HDL-cholesterol (mmol/l) Mean 1.34 1.09 Change at W12 (SD) S0.05 (0.24) S0.04 (0.17) S0.04 (0.21) P value P U 0.342 P U 0.433 P U 0.212 LDL-cholesterol (mmol/l) Number 13 9 22 Mean 3.58 3.41 Change at W12 (SD) S0.74(1.18) S0.34(0.95) S0.58(1.09) P value P U 0.043 P U 0.311 P U 0.021 Triglycerides (mmol/l) Number 17 15 32 Mean 1.45 1.73 Change at W12 (SD) S0.10(0.59) S0.30(0.64) S0.19(0.62) P value P U 0.517 P U 0.096 P U 0.092

Note not all patients underwent triglyceride and low-density lipoprotein (LDL)-cholesterol measurement (see numbers). DS, delayed switch; HDL, high-density lipoprotein; IS, immediate switch.

viral suppression rates were 100% at weeks 12 and 24 for 24 in the delayed switch arm) reductions in total cholesterol both treatment arms. and LDL-cholesterol were signiﬁcant at 0.64mmol/l (P < 0.001) and 0.58mmol/l (P ¼ 0.021), respectively. Week 12 CD4 rise from baseline was þ40 cells/ml in the immediate switch arm and þ6 cells/ml in the delayed In terms of lipid-lowering agents, at baseline 3 participants switch arm; at week 24 CD4 rises from baseline were in the immediate switch arm were on a statin. In the þ68 cells/ml and þ 60 cells/ml, respectively. In the delayed switch arm two patients were receiving a statin at combined analysis the median CD4 rise after 12 weeks of baseline and one was taking ﬁsh oil supplements. Lipid- ETR was þ43 cells/ml(P ¼ 0.027 compared with base- lowering drug use remained stable during the study and no line). new agents were started.

Lipids Non-central nervous system adverse events and Lipid changes are illustrated in Table 4. Analysing the two laboratory abnormalities arms of the study individually, there was a significant There were two new grade 3/4 adverse events: one reduction in total cholesterol in each arm after 12 weeks patient in the delayed switch arm developed grade 3 of ETR (0.64 mmol/l in the immediate switch arm flatulence (deemed probably drug-related) during the and 0.63 mmol/l in the delayed switch arm; P ¼ 0.017 blinded phase (i.e. on EFV with ETR placebo) and one and P ¼ 0.024, respectively). In addition there was a patient in the immediate switch arm was hospitalized significant reduction in LDL-cholesterol in the immedi- during the blinded phase with a viral upper respiratory ate switch arm after 12 weeks of ETR (0.74mmol/l; tract infection [grade 4 (serious adverse event); not drug- P ¼ 0.043). There were no significant changes in HDL- related]. Patient subsequently experienced full recovery. cholesterol or triglycerides. All other adverse events were grade 2 or less. Grade 2 When the changes after 12 weeks of ETR in each arm adverse events deemed at least probably study drug related were combined (i.e. the change from baseline to week 12 are outlined in Table 5. in the immediate switch arm and from week 12 to week There were no changes in liver function tests, no grade 2 or greater nausea and no cases of rash at any time point in Table 5. Grade 2 adverse events (probably/definitely drug related) by study arm. the study.

Adverse events IS (n ¼ 20) (%) DS (n ¼ 18) (%) P value

Fatiguea 4 (20.0) 4 (20.0) 0.999 Headacheb 1 (0.0) 3 (16.7) 0.097 Discussion Reduced libidoa 1 (5.0) 0 (0.0) 0.998 The study demonstrates an improvement in several DS, delayed switch; IS, immediate switch. aBetween baseline and week 12. measures of CNS toxicity when switching from EFV to bBetween week 12 and 24. ETR in patients stable on an EFV-based regimen. All

patients were required to have been on EFV for at least better lipid parameters and may be a switch option for 12 weeks but the median EFVexposure at study entry was metabolic reasons. much longer (21.4 months). These data further confirms the persistence of CNS toxicity in some EFV-treated Several studies have shown that switching therapy in patients as demonstrated in other studies and cohorts. patients with viral suppression maintains efficacy [18–20]. Until recent years the switch options available to patients Although the study was open to male and female patients, with EFV-related CNS toxicity were mainly limited to by chance all recruited patients were men; this was protease inhibitors. Switching from efavirenz to nevira- consistent with the patient demographics across the three pine results in improvements in CNS toxicity [21] and sites. The study population reported high rates of CNS lipids [22] but is limited by the CD4 restrictions for NVP toxicity at baseline; majority of individuals had at least one use [23]. The advent of newer, once-daily agents should grade 2–4 CNS adverse event and a median of three grade encourage active questioning about CNS toxicity in 2–4 CNS adverse events in total. By definition our study patients on EFV. Proactive switch away from EFV may selected patients with persistent CNS toxicity and it is yield significant reductions in CNS toxicity. Patients can possible that the time commitment required of parti- be reassured that, in the absence of noticeable improve- cipants, and the higher pill burden (six pills or more during ment, they can resume an EFV-containing regimen. the blinded phase), further selected individuals with more severe toxicity. The prevalence of CNS toxicity cannot In conclusion, once-daily etravirine offers an efficacious, therefore be applied to the general clinic population. tolerable and lipid-friendly alternative to efavirenz in patients with persistent CNS toxicity. Switching to ETR most improved sleep-related CNS adverse events (abnormal dreams and insomnia), as well as nervousness, but yielded no significant improvement in other CNS adverse events. The study was not powered to Acknowledgement detect significant differences for each of the individual adverse event. It may be that individuals with other possible Funding: This study was funded by an investigator-led EFV-related CNS adverse events, such as depression, had research grant from Tibotec, a division of Janssen-Cilag already switched away to alternative regimens or were less Ltd, UK. likely to enter the study. Alternatively, some CNS symptoms on stable EFV regimens may be secondary to other factors and not drug-related. 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