Published by the Students of Johns Hopkins since 1896
October 28, 2021

Popular HIV drug may cause cognitive impairment

By ELLE PFEFFER | October 11, 2012

Despite the development of new anti-retroviral drugs, commonly regarded as “good news” for HIV patients, 30 to 50 percent of these patients will still develop some form of cognitive impairment in the long-term.

Though normally mild – intense dementia is not seen frequently – the cognitive disability can still hinder a patient’s capability to live independently.

For Norman Haughey, a neurology professor at Hopkins School of Medicine, and other researchers, this led to questioning what caused this increased susceptibility to cognitive impairment. Is it spurred by the virus itself, a specific risk factor associated with the host, or a function related to anti-retroviral drugs?

The study by Haughey and other researchers, examined online in the Journal of Pharmacology and Experimental Therapeutics, suggests that efavirenz, a popular anti-retroviral drug, may contribute to the development of cognitive disability.

Haughey became interested in virus, specifically HIV, research during his graduate studies through his work in a neuroscience and virology lab. “I found them to be very fascinating little machines that were very good at what they do,” Haughey said.

HIV attacks the body’s immune system. It functions as a virus by incorporating its DNA (reverse transcribed from viral RNA) into the host cell’s genome. This new DNA is then replicated in the cell’s normal replication and division cycle causing the spread of the virus.

Typically, different types of anti-retroviral treatment are taken in a cocktail to slow the spread of HIV.

Once treatment starts, it continues for the rest of the patient’s life. There has only been one recent case of complete cure, and this was after a bone marrow transplant.

Efavirenz, a non-nucleoside reverse transcriptase inhibitor, suppresses the spread of HIV by stopping the reverse transcription from RNA to DNA. It is unusual in that it can cross the blood-brain barrier as well as attack hidden HIV reservoirs in the brain. Efavirenz is usually taken by mouth once a day in capsule or tablet form.

The researchers were concerned with the potential toxicity of efavirenz as a metabolite of the drug, 8-hydroxyefavirenz, proved toxic to cultured liver cells.

When Haughey and his team examined this metabolite’s effect on neurons in culture, even low concentrations caused damage to spines, the regions essential for neural communication.

The researchers then needed to see whether this metabolite reached toxic levels in people taking efavirenz. “In a living patient, our best window to the brain is cerebral spinal fluid,” Haughey said. The concentrations they found in the fluid reached the levels found toxic to the cultured neurons.

Since these drugs are taken over decades, the effects of drug build up can be great. According to the outcomes, efavirenz at accumulated levels may be contributing to mental impairment.

Haughey stressed that the results are far from suggesting that the drug should be taken off the market. “We certainly don’t want everyone to stop taking efavirenz. I think that what this work does is highlight the importance of taking a careful look at drugs…over a long period of time,” Haughey said. “Really it’s more of a cautionary note.”

Toxic effects of other anti-retroviral drugs have been presented at meetings, but are yet to be published. A different paper also suggests that efavirenz could be altered to remove the deleterious effects.

Haughey hopes the topic will continue to gain traction and questioning from the scientific community. The issue of long-term cognitive impairment in patients with HIV despite improvements in treatment remains; the enigma of what factors – virus, host, or drug – cause the issues is pertinent.

Haughey discussed possible new measures for the eradication of HIV with drugs searching out the hidden virus reservoirs in the brain, but that toxicity of drugs should be known before they are sent in to do the work.

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