Switching from Efavirenz to Etravirine Reduces Central Nervous System Side Effects

HIV patients who started antiretroviral treatment using the next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (Intelence) experienced fewer neuropsychiatric side effects such as abnormal dreams and anxiety compared with those taking efavirenz (Sustiva), and those who switched from efavirenz to etravirine saw an improvement in such symptoms, according to 2 studies presented last month at the XVIII International AIDS Conference (AIDS 2010) in Vienna.

Efavirenz, a component of the popular Atripla combination pill, is one of the most frequently used HIV medications, and is part of one of the preferred regimens in U.S. antiretroviral treatment guidelines. It often causes central nervous system (CNS) side effects, however, leading some people to discontinue the drug.

SENSE Trial

In the first study, Brian Gazzard from Chelsea and Westminster Hospital and fellow investigators with the SENSE trial evaluate whether 12 weeks of treatment with etravirine could lead to fewer neuropsychiatric side effects than efavirenz.

The trial included 157 treatment-naive patients with HIV RNA > 5000 copies/mL and no genotypic drug-resistance mutations. Most participants (81%) were men, 85% were white, the median age was 36 years, and the baseline CD4 cell count was 302 cells/mm3.

Participants were randomly assigned to receive 400 mg once-daily etravirine or 600 mg once-daily efavirenz, both with 2 investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) for 48 weeks. Eligible NRTI combinations were tenofovir/emtricitabine (Truvada), abacavir/lamivudine (Epzicom), or zidovudine/lamivudine (Combivir).

The primary endpoint of the study was the percentage of patients with grade 1-4 (mild to severe) treatment-emergent drug-related neuropsychiatric adverse events. Data were presented from an interim analysis at week 12.

Results

• 18 participants dropped out of the study by week 12 -- 10 in the etravirine arm and 8 in the efavirenz arm.
• Patients in both arms achieved similar viral suppression (-2.9 log).
• 87.9% of patients in the etravirine arm and 92.6% in the efavirenz arm achieved HIV RNA < 400 copies/mL.
• The median CD4 cell gain was 146 cells/mm3 in the etravirine arm compared with 121 cells/mm3 in the efavirenz arm (not a significant difference).
• In an intent-to-treat analysis at 12 weeks, 16.5% of patients in the etravirine arm reported at least 1 drug-related neuropsychiatric adverse event, compared with 46.2% in the efavirenz arm, a highly significant difference (P < 0.001).
• A majority of these side effects, however, were mild.
• Looking at people with at least 1 grade 2-4 (moderate to severe) treatment-emergent neuropsychiatric adverse event, the corresponding proportions were 5.1% vs 16.7, respectively (P = 0.019).
• People taking etravirine reported better neuropsychiatric tolerability on the HIV-Patient Symptoms Profile questionnaire than those taking efavirenz.
• Etravirine recipients also had fewer grade 3-4 (serious to severe) elevations in total cholesterol (1 vs 6 patients) and LDL "bad" cholesterol (1 vs 5 patients) compared with efavirenz recipients.
• 1 person in the efavirenz arm with persistently high HIV RNA developed treatment-emergent NRTI and NNRTI mutations.     

"After 12 weeks, first-line treatment with etravirine 400 mg once-daily + 2NRTIs led to significantly fewer neuropsychiatric adverse events than efavirenz + 2 NRTIs," the SENSE investigators concluded.

"There were larger rises in total cholesterol and LDL cholesterol during treatment with efavirenz plus 2 NRTIs, compared with etravirine + 2 NRTIs," they continued. "The short-term virologic and immunologic efficacy profiles were similar in the 2 arms."

U.K. Study

In the second study, Laura Waters, also from Chelsea and Westminster, investigate the impact of switching from efavirenz -- the preferred drug in the British HIV treatment guidelines -- to etravirine in patients with ongoing CNS adverse events.

This Phase 4 study included 38 patients recruited at 3 U.K. study sites (Chelsea and Westminster and St. Mary's Hospital in London, and Royal Sussex County Hospital in Brighton). All were men, all but 1 were white, and the median age was 43 years. All had HIV RNA < 50 copies/mL at baseline and median CD4 cell count was 468 cells/mm3.

All participants were taking efavirenz at study entry (median duration of 21 months), had undetectable plasma viral load (< 50 copies/mL) for at least 12 weeks, and were experiencing CNS symptoms.

They were randomly assigned to continue taking efavirenz (600 mg once-daily) plus an etravirine placebo, or else switch to etravirine (400 mg once-daily) plus an efavirenz placebo for 12 weeks. All participants then received open-label etravirine for an additional 12 weeks. In addition, 58% were taking the tenofovir/emtricitabine NRTI backbone at baseline (29% using the Atripla coformulation), 29% were using abacavir/lamivudine, and the rest were using other NRTI combinations.

The researchers assessed occurrence of 12 CNS side effects: insomnia, abnormal dreams, somnolence, fatigue, dizziness, depression, anxiety, nervousness, pain, impaired concentration, headache, and hallucinations. They considered the proportion of patients with grade 2-4 CNS adverse events, the median number of such events, and a CNS score, calculated as the sum of all grades of side effects (for example, a person with grade 1 dizziness + grade 3 abnormal dreams would have a CNS score of 4).

The primary endpoint was the change in the proportion of patients with grade 2-4 CNS adverse events from baseline to week 12. Secondary endpoints included changes in CNS score and median number of CNS side effects from baseline to week 12, and from week 12 to week 24, as well as changes in lipid levels, viral load, and CD4 counts.

Results

• 4 patients discontinued the study -- 1 in the etravirine switch arm and 3 in the continued efavirenz arm.
• All participants in both arms maintained HIV RNA < 50 copies/mL at all visits.
• CD4 changes through week 24 were 68 cells/mm3 in the etravirine switch arm and 60 cells/mm3 in the continued efavirenz arm (not a significant difference).
• During the 12-week blinded phase, CNS side effects decreased in the etravirine switch arm:
  • Overall grade 2-4 CNS adverse events: 90% to 60% (P = 0.041);
  • Grade 2-4 abnormal dreams: 50% to 20% (P = 0.041);
  • Insomnia: 75% to 50% (P = 0.074 trend).
• There were no significant changes in any grade 2-4 CNS side effects in the continued efavirenz arm.
• During the open-label phase from week 12 to week 24, there were no further significant changes in CNS adverse events in the randomized etravirine arm.
• People who newly switched to open-label etravirine, however, experienced a significant reduction in grade 2-4 abnormal dreams (63% to 20%; P = 0.023).
• From baseline through week 12, the median number of grade 2-4 CNS side effects fell from 4 to 1.5 in the etravirine switch arm while remaining unchanged at 3 in the continued efavirenz arm (P = 0.08).
• From week 12 through week 24, CNS adverse events dropped further to 0.5 in the randomized etravirine arm (non-significant) and from 3 to 1 in the open-label switch arm (P = 0.008).
• The average CNS score declined from 14 to 6 between baseline and week 12 in the etravirine switch arm (P = 0.001) and from 10 to 7.5 in the continued efavirenz arm (non-significant).
• Changes from week 12 to week 24 were not significant in either open-label arm.
• Switching from efavirenz to etravirine resulted in a significant reduction in total and LDL cholesterol, with no change in HDL "good" cholesterol.

"Switching efavirenz to etravirine led to significant reductions in grade 2-4 CNS adverse events overall, insomnia, abnormal dreams and nervousness," the investigators concluded. "Lack of improvement for some adverse events and patients suggests causes other than [ART]."

Taken together, these studies indicate that etravirine is an effective and well-tolerated option, whether started as part of a first-line regimen or substituted for efavirenz.

Investigator affiliations:

Gazzard and others: St Stephen’s Centre, Chelsea and Westminster Hospital, London, UK; Ospedale Amedeo di Savoia, Turin, Italy; Inselspital, Berne, Switzerland; Hospital de la Santa Cruz I Sant Pablo, Barcelona, Spain; Pharmacology Research Laboratories, University of Liverpool, Liverpool, UK; Janssen-Cilag B.V., Tilburg, Netherlands; Tibotec BVBA, Beerse, Belgium; Janssen-Cilag EMEA, Neuss, Germany.

Waters and others: Chelsea & Westminster Hospital, St Stephen's AIDS Research, London, UK; Royal Sussex County Hospital, GU/HIV Medicine, Brighton, UK; St Mary's Hospital, Imperial College, GU/HIV Medicine, London, UK.

8/20/10

References

B Gazzard, G Di Perri, H Furrer, and others. The SENSE Trial: Etravirine (ETR) shows fewer Neuropsychiatric Adverse Events than Efavirenz (EFV) in Treatment-naive HIV-1 Infected Patient. XVIII International AIDS Conference (AIDS 2010). Vienna, July 18-23, 2010. Abstract LBPE19.

L Waters, M Fisher, A Winston, and others. A phase IV, double blind, multi centre, randomised, placebo controlled, pilot study to assess the feasibility of switching individuals receiving efavirenz (EFV) with continuing central nervous system (CNS) adverse events (AE) to etravirine (ETR). XVIII International AIDS Conference (AIDS 2010). Vienna, July 18-23, 2010.