Third of patients in Botswana have a gene that slows efavirenz clearance and increases risk of CNS side-effects

Michael Carter
Estimated reading time 2 minutes
This article is more than 16 years old.

Many HIV-positive patients in Botswana have a gene associated with slow metabolising of the key antiretroviral drug efavirenz, according to a report in the November edition of the Journal of Acquired Immune Deficiency Syndromes. Slow metabolising of efavirenz can result in a greater risk of central nervous system (CNS) side-effects. Identifying patients with the gene associated with slow metabolising of efavirenz could enable doctors to adjust the efavirenz dose and reduce the risk of side-effects.

Efavirenz (Sustiva) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that is recommended for first-line antiretroviral therapy by treatment guidelines around the world. It is widely used in fixed-dose antiretroviral therapy in resource-limited settings, including in Botswana.

The body processes efavirenz using a pathway in the liver called P450 2B6. Genetic mutations in this pathway can affect the speed with which the body processes the drug and subsequent concentrations of the drug. High concentrations of efavirenz are associated with an increased risk of central nervous system side-effects, such as mood and sleep disturbance, whereas low efavirenz concentrations can mean that the drug fails to adequately suppress HIV.

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.

reverse transcriptase

A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV. Several classes of anti-HIV drugs interfere with this stage of HIV’s life cycle: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 

nucleoside

A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

metabolism

The physical and chemical reactions that produce energy for the body. Metabolism also refers to the breakdown of drugs or other substances within the body, which may occur during digestion or elimination.

Investigators wanted to see how frequently a gene called CYP2B6*6 (associated with slow metabolism of efavirenz) is found in HIV-positive patients of African origin in Botswana. They tested 101 patients in July 2007. These patients were a "convenience sample" recruited from 800 HIV-positive patients attending a clinic over a five day period.

Just over half (52%) the patients were women, the median age was 39 years, median CD4 cell count was 352 cells/mm3, and median viral load was 150,000 copies/ml.

The investigators found that 37% of patients had the CYP2B6*6 gene. “This finding has potentially important implications for the treatment of HIV within this setting”, write the investigators, noting that the gene was associated with higher concentrations of efavirenz, which, in turn, have been linked to “increased incidence of central nervous system toxicity.”

One study found that reducing the dose of efavirenz decreased the risk of central nervous system side-effects but maintained HIV suppression. However, the investigators note that “this tailored approach to dosing would need to be tested in larger studies before being adopted more broadly.”

References

Gross R et al. Slow efavirenz metabolism genotype is common in Botswana. J Acquir Immune Defic Syndr 49: 336-337, 2008.

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