Efavirenz dose reduction safe for patients with gene associated with high drug levels and side-effects

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Doses of efavirenz (Sustiva) can be safely reduced by up to two-thirds in patients who develop side-effects if these are due to a genetic mutation resulting in high concentrations of the drug, Japanese investigators report in the January 28th edition of AIDS. Furthermore, a Japanese company has developed a low-cost test to see which patients have this mutation.

Efavirenz is metabolised by the liver using the p450 2B6 (CYP2B6) pathway. Earlier research has shown that patients who have a mutation, or polymorphism, in the gene associated with metabolising efavirenz called CYP2B6 516G>T have extremely high blood levels of the drug when treated with the drug’s standard once-daily dose of 600mg.

Japanese investigators performed a study to see if was possible to reduce the dose of efavirenz in patients with this polymorphism who had high concentrations of efavirenz.

Glossary

gene

A unit of heredity, that determines a specific feature of the shape of a living organism. This genetic element is a sequence of DNA (or RNA, for viruses), located in a very specific place (locus) of a chromosome.

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.

Their study involved twelve individuals. Five had their dose of efavirenz reduced to 400mg once daily, the other seven to 200mg daily. Viral load remained undetectable in all twelve individuals.

Nine of the patients had experienced chronic central nervous system side-effects when taking full-dose efavirenz. However, these side-effects improved in nine individuals on reduction of the efavirenz dose.

They highlight the case of a 71-year-old man who had reported virtually nightly nightmares after starting full-dose efavirenz treatment. His blood concentrations of the drug were extremely high and tests revealed that he had the genetic mutation associated with high levels of the drug.

Reduction of his efavirenz dose to 400mg daily resulted in a dramatic improvement in his dreams. His efavirenz concentrations nevertheless remained high and further reduction of the daily dose to 200mg resulted in a complete disappearance of his dreams. Levels of the drug in his blood were within target levels and his viral load was still undetectable two years after the dose of the drug was reduced to 200mg.

Cost had been highlighted as a potential barrier to testing efavirenz-treated patients for the mutation associated with high concentrations of the drug. However, the investigators report that a Japanese company has developed a test costing approximately US$75, “thus, the financial benefits of reducing efavirenz dosage should compensate for the cost of genotyping,” they suggest. However ,they note “further larger-scale studies are needed to discuss genotype-based tailored efavirenz treatment.”

References

Gatanaga H et al. Successful genotype-tailored treatment with small-dose efavirenz. AIDS 23: 433, 2009.