Switching from efavirenz to etravirine improves mood and sleep

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Switching from efavirenz to etravirine is associated with significant improvements in central nervous system side-effects, UK investigators report in the online edition of AIDS.

Patients were less likely to report insomnia, bad dreams and nervousness after changing treatment.

“The study demonstrates an improvement in several measures of CNS [central nervous system] toxicity when switching from efavirenz to etravirine,” comment the researchers.

Glossary

central nervous system (CNS)

The brain and spinal cord. CNS side-effects refer to mood changes, anxiety, dizzyness, sleep disturbance, impact on mental health, etc.

toxicity

Side-effects.

placebo

A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

insomnia

Sleeplessness.

nucleoside

A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

However, separate research reported here on aidsmap.com found that patients who were currently taking efavirenz did not prefer etravirine therapy.

Efavirenz (Sustiva, also in the combination pill Atripla) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and is recommended for use in first-line antiretroviral therapy. Central nervous system side-effects are common in patients who are taking efavirenz. They often fade within a month, but persist in a minority of patients and some individuals stop taking the drug because of them.

A second-generation NNRTI is etravirine (Intelence) and there is no evidence that it causes central nervous system side-effects. It also has a high barrier to resistance, and research suggests that it can be taken once daily.

Investigators at four large London HIV treatment centres wished to see if switching from efavirenz to etravirine was associated with an improvement in central nervous system side-effects.

They therefore designed a double-blind, placebo-controlled study involving 38 men who were taking stable antiretroviral therapy that included efavirenz.

The patients were randomised into one of two arms. One group of patients switched therapy immediately and took a combination of drugs that comprised two nucleoside reverse transcriptase inhibitors (NRTIs) plus etravirine and an efavirenz placebo. Individuals in the other arm received a combination of two NRTIs, efavirenz and an etravirine placebo.

After twelve weeks the study was unblinded and all the patients were treated with etravirine.

The study’s primary endpoint was the proportion of patients who had central nervous system side-effects at week twelve.

All the patients had been taking efavirenz-based antiretroviral therapy for at least twelve weeks and had a viral load below 50 copies/ml. Their median CD4 cell count was 510 cells/mm3.

At baseline, 90% of patients in the immediate-switch arm and 89% of those who were randomised to change treatment later had at least one moderate-to-severe central nervous system side-effect.

After twelve weeks, only 60% of those who had changed to etravirine reported such side-effects. This was a significant reduction (p = 0.041). The proportion of patients reporting central nervous system side-effects in the delayed-change arm remained unchanged.

However, improvements in central nervous side-effects were seen in individuals in the delayed-switch arm once they changed treatment to etravirine.

After twelve weeks of therapy with etravirine, there were significant reductions in the proportion of patients reporting any moderate-to-severe central nervous system side-effect (89% to 60%, p = 0.0009), insomnia (63% to 37%, p = 0.016), abnormal dreams (57% to 20%, p = 0.001), and nervousness (29% to 9%, p = 0.046).

The mean number of central nervous system side-effects fell after therapy was switched (3 to 1, p < 0.001).

Viral load remained fully suppressed in all the patients. CD4 cell counts increased significantly after treatment was switched to etravirine (twelve-week increase = 43 cells/mm3, p = 0.027).

Lipid profiles also improved after treatment was changed. There were significant reductions in both total and LDL-cholesterol (both p < 0.001).

“The advent of newer, once-daily agents should encourage active questioning about central nervous system toxicity in patients on efavirenz,” according to the investigators,  who add, “proactive switch from efavirenz may yield significant reductions in central nervous system toxicity.”

They conclude, “once-daily etravirine offers an efficacious, tolerable and lipid-friendly alternative to efavirenz in patients with persistent central nervous system toxicity.”

References

Water L et al. 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. AIDS, 24: online edition, DOI: 10.1097/QAD.0b013e32841685b, 2010 (click here for access to the article text).