Rare gene causes massive increases in efavirenz levels in twelve-year-old leading to psychosis

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A rare genetic mutation meant that a twelve-year-old girl had seven-to-eight times the normal blood concentration of efavirenz (Sustiva) leading to psychosis, American doctors report in the November 15th edition of Clinical Infectious Diseases (now online). The investigators suggest that patients who develop “prolonged psychiatric symptoms” after starting efavirenz should have tests to determine concentrations of the drug in their blood, and possibly for the genetic mutation underlying the excess levels of efavirenz observed in their patient.

HIV infection has been associated with excess rates of mental illness in both adults and children. The exact causes of psychiatric illness in HIV-positive children are thought to include a predisposition to mental illness, stress, the direct effects of HIV on the brain, and the side-effects of anti-HIV medication.

Efavirenz is known to cause neuropsychiatric side-effects in both adults and children, but earlier studies have failed to show a statistically significant relationship between the use of the drug and an increased risk of hospitalisation for psychiatric complaints in children.



Mental health problems that stop someone from thinking clearly and telling the difference between reality and their imagination.

concentration (of a drug)

The level of a drug in the blood or other body fluid or tissue.


Cost-effectiveness analyses compare the financial cost of providing health interventions with their health benefit in order to assess whether interventions provide value for money. As well as the cost of providing medical care now, analyses may take into account savings on future health spending (because a person’s health has improved) and the economic contribution a healthy person could make to society.


A tentative explanation for an observation, phenomenon, or scientific problem. The purpose of a research study is to test whether the hypothesis is true or not.

statistical significance

Statistical tests are used to judge whether the results of a study could be due to chance and would not be confirmed if the study was repeated. If result is probably not due to chance, the results are ‘statistically significant’. 

Against this background, investigators from Rhode Island reported the first case of psychosis in a child receiving treatment with efavirenz. The case involved a twelve-year-old girl who had been HIV-positive since birth with no previous history of mental illness.

Psychotic behaviour had been developing for over a year before hospitalisation and involved withdrawal, decreased concentration and social skills, delusions, and suicidal and homicidal thoughts.

The onset of symptoms had coincided with an increase in the patient’s daily efavirenz dose from 400mg to 600mg. The girl’s antiretroviral therapy also consisted of Kaletra, d4T (stavudine, Zerit) and ddI (didadosine, Videx).

Tests at the time of admission to hospital revealed that the girl had a CD4 cell count of over 1000 cells/mm3 and an undetectable viral load. An MRI scan failed to find any reason for psychosis.

Blood tests were also normal with the exception of a drug level monitoring test that showed that level of efavirenz was 19,013ng/ml, some seven and eight times the expected level.

Further tests revealed that the girl had the rare CYP2B6-516 genotype polymorphism which has been associated with poor clearance of efavirenz.

Her doctors concluded that her psychosis was related to the excess levels of efavirenz in her blood. This hypothesis was supported by the gradual improvement of her symptoms after treatment with efavirenz was stopped. Within a year the patient’s condition had returned to normal.

The investigators do not believe it is practical or cost effective to screen patients for the presence of this polymorphism before initiating treatment with efavirenz. However they suggest that patients who develop psychotic symptoms whilst taking efavirenz should have tests to monitor levels of the drug and “possibly for the presence of the CYP2B6-G516T genotype.”


Lowenhaupt EA et al. Psychosis in a 12-year-old HIV-positive girl with an increased serum concentration of efavirenz. Clin Infect Dis 45 (online edition), 2007.