Switching from efavirenz to lopinavir/ritonavir has no meaningful impact on neurological function, says UK study

Switching from efavirenz does not significantly improve the neurological function of patients taking virologically suppressive antiretroviral therapy, investigators from the UK report in HIV Medicine.

The open-label, single-centre study involved 16 people taking long-term efavirenz-based HIV therapy. Efavirenz was replaced with lopinavir/ritonavir. Patients underwent a number of tests to assess cognitive function prior to switching and ten weeks after this treatment change.

“We explored the hypothesis that chronic EFV [efavirenz] therapy is associated with adverse effects on CNS [central nervous system] function,” write the authors. “We observed no objective changes in neurocognitive performance across multiple domains, in cerebral metabolites, or in brain activity.” However, sleep quality did improve after replacement of efavirenz with lopinavir/ritonavir.

Despite effective antiretroviral therapy, mild cognitive impairment remains common in people living with HIV. The reasons for this are poorly understood and little is known about the impact of specific anti-HIV drugs on neurological function.

However, efavirenz – one of the most commonly used antiretrovirals – has been associated with sleep disturbances and cognitive disturbances. Investigators in Newcastle designed a pilot study involving people taking efavirenz long-term, to see if changing to lopinavir/ritonavir improved cognitive function. Cognitive function was assessed using a battery of tests to measure detection, identification, attention/working memory, visual learning/memory and problem-solving. Proton magnetic resonance spectroscopy was performed to measure brain metabolites and brain activity was evaluated by use of MRI (magnetic resonance imaging) scanning during task performance. Participants in the study were also asked to keep diaries recording sleep quality and quantity.

The 16 participants had a median age of 50 years and had been taking efavirenz for a median of 4.5 years. All had an undetectable viral load and median CD4 cell count was 660 cells/mm³. The most widely used NRTI (nucleoside reverse transcriptase inhibitor) backbone (the other drugs in their treatment combination) was tenofovir/emtricitabine, which was taken by 14 people. The median baseline plasma efavirenz concentration was 2455ng/ml.

CNS symptoms were widely reported at baseline and ten weeks after switching:

• Memory problems: 81% baseline, 31% post treatment change.
• Vivid/intrusive dreams: 75% baseline, 44% post treatment change.
• Fatigue: 69% baseline, 25% post treatment change.
• Concentration difficulties: 63% baseline, 75% post treatment change.
• Sleep problems: 51% baseline, 81% post treatment change.

Prior to the treatment change, two patients showed evidence of severe cognitive impairment with 56% having symptoms of mild impairment.

Changing treatment had no impact on cognitive function, brain metabolites, or brain activity. Almost all the assessments performed before and after the switch from efavirenz to lopinavir/ritonavir had comparable results.

However, switching therapy did appear to improve sleep quality for some, despite the fact that more participants reported some form of sleep problem after switching. Daytime sleepiness did not improve but some people reporting poor sleep quality on efavirenz did experience improvement after switching. Based on a series of questions about sleep in the past month, seven patients reported poor sleep before the treatment change, falling to four individuals after the treatment change.

The researchers say that their study is the most thorough investigation of what happens to neurocognitive performance, brain activity and sleep quality after switching from efavirenz. In particular, they say that previous studies have not used objective measures of central nervous system function.

“For almost all parameters studied, the effect sizes observed were very close to zero, and there were no consistent trends in direction of change across related domains,” comment the authors. “We therefore conclude that we are unlikely to have missed any clinically important effects.”