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Efavirenz Metabolism May Damage Neurons, Contribute to Neurocognitive Problems

Metabolites produces during processing of the widely used NNRTI efavirenz (Sustiva, also in the Atripla combination pill) can reach high levels in the brain, which can be toxic to neurons and interfere with cell signaling, according to a report in the September 19, 2012, online edition of the Journal of Pharmacology and Experimental Therapeutics.

Even in the era of effective combination antiretroviral therapy (ART), neurocognitive impairment remains common among people with HIV; some experts estimate that half will develop some HIV-associated neurocognitive disorders ranging from mild to severe. Its causes are not fully understood, but HIV infection itself, associated inflammation and metabolic changes, and side effects of antiretroviral drugs may all play a role.

Luis Tovar-y-Romo, Juston McArther, Norman Haughey, and colleagues at Johns Hopkins University School of Medicine looked at levels of efavirenz and its metabolites -- which are produced when the drug is processed by the liver (primarily by the enzyme CYP2B6) -- in blood and cerebrospinal fluid samples from participants in the Northeastern AIDS Dementia study.

Efavirenz is among the few antiretrovirals that cross the blood-brain barrier -- which some research indicates may help control HIV in the brain and associated neurocognitive decline. It is also known for its neuropsychiatric side effects such as strange dreams, insomnia, dizziness, and hallucinations.

In a laboratory study, the researchers tested the effects of efavirenz itself and its metabolites 7-hydroxyefavirenz (7-OH-efavirenz) and 8-hydroxyefavirenz (8-OH-efavirenz) on neuron cell cultures.

Results

• Efavirenz, 7-hydroxyefavirenz, and 8-hydroxyefavirenz all caused neuron damage in a dose-dependent manner.
• However, 8-OH-efavirenz was found to be at least 10 times more toxic to neurons than efavirenz itself.
• Even at low concentrations, 8-OH-efavirenz caused structural changes including damage to dendritic spines, which are crucial for cell-to-cell communication.
• A 10 nM concentration of 8-OH-efavirenz "caused considerable dendritic damage," while 100 n/M led to "frank cell death."
• 8-OH-efavirenz interfered with neuronal calcium homeostasis, causing "calcium flux" in neurons that was primarily mediated by L-type voltage-operated calcium channels.
• Conversely, blocking these calcium channels protected dendritic spines from damage due to efavirenz and its metabolites.
• Looking at calcium levels in patients, concentrations of efavirenz and 8-OH-efavirenz in cerebral spinal fluid were within the range that damaged neurons in cell cultures.

"These findings demonstrate that the 8-OH metabolite of efavirenz is a potent neurotoxin and highlight the importance of directly determining the effects of antiretroviral drugs, and drug metabolites on neurons and other brain cells," the study authors concluded.

"[T]hese data suggest that concentrations of the parent drug efavirenz in [the] brain may be within the range that can damage neurons, and that concentrations of 8-OH-efavirenz could be 3 times the minimal dose that produced dendritic damage to cultured neurons," they elaborated in their discussion. "Moreover, there may be a genetic susceptibility to the neurotoxic effects of efavirenz that is related to its rate of metabolism...Thus, a genetic susceptibility in some individuals may exaggerate the neurotoxic effects of efavirenz due to a rapid metabolism of efavirenz with accumulations of the 8-OH-efavirenz metabolite.

The researchers also determined that making a minor modification in the structure of efavirenz may be able block its neurotoxic effects without reducing its ability to inhibit HIV replication.

"[P]roximity of the OH group at position 8 to the nitrogen group in the benzoxazine structure is the critical determinant for forming a highly neurotoxic metabolite of efavirenz," they wrote. "Therefore, substituting the carbon at position 8 so that efavirenz cannot be hydroxylated at this position should produce a compound with decreased neurotoxicity."

10/2/12

Reference

LB Tovar-Y-Romo, NN Bumpus, D Pomerantz, NJ Haughey, et al. Dendritic spine injury induced by the 8-hydroxy metabolite of Efavirenz. Journal of Pharmacology and Experimental Therapeutics.September 19, 2012 (Epub ahead of print).

Other Source

Johns Hopkins. Popular HIV Drug May Cause Memory Declines. Press release. September 27, 2012.