Efavirenz / drug metabolism (CYP2B6*6)

CYP2B6 breaks down several medicines, including the HIV drug efavirenz, the antidepressant bupropion, and methadone. A common variant (*6) lowers its activity, so these drugs can build up to higher levels in carriers.

What the CYP2B6*6 variant does

CYP2B6 is a liver enzyme that clears a small but distinctive set of drugs, most notably efavirenz, an HIV medicine, along with methadone, bupropion and ketamine. This variant is the defining change of the *6 allele, which reduces enzyme activity.

With reduced clearance, efavirenz blood levels run higher on a standard dose, and efavirenz has a well-known dose-related side effect profile: dizziness, vivid dreams, insomnia and mood changes, mostly in the first weeks.

How strong the evidence is

CPIC rates the efavirenz association level A and recommends a reduced starting dose in poor metabolizers, meaning people with two reduced-function copies, rather than stopping the drug. ClinVar records the variant as a drug-response variant with three-star review status under efavirenz response, metabolism and toxicity.

The relationship between genotype, drug level and central nervous system side effects is one of the more consistent findings in HIV pharmacogenetics, which is unusual for a psychiatric-sounding side effect.

How common it is, and why that matters here

This is a common variant, most so where efavirenz has been most used: in 1000 Genomes reference data about 46% of African-ancestry individuals carry one copy and 15% carry two, against roughly 36% and 6% in European-ancestry samples.

Efavirenz-based regimens were long the backbone of HIV treatment in sub-Saharan Africa, which is precisely where reduced-function CYP2B6 is most frequent, and that overlap is one of the clearer real-world arguments for pharmacogenetics in global health.

Why this matters less than it used to

First-line HIV treatment has moved substantially toward integrase inhibitor regimens, particularly dolutegravir-based ones, so efavirenz is prescribed less than it was. The genotype has not changed, the clinical context has.

The enzyme still contributes to methadone, bupropion and ketamine metabolism, but the evidence there does not support genotype-guided dosing, and no guideline recommends it.

What each rs3745274 genotype means

rs3745274 has three possible genotypes: GG, GT and TT.

Normal CYP2B6 activity (rs3745274 GG). You have the normal-function version of CYP2B6, the enzyme that breaks down drugs like the HIV medicine efavirenz, bupropion and methadone. You clear them at the usual rate, so standard dosing generally fits.

Reduced CYP2B6 activity (rs3745274 GT). You carry one reduced-function (*6) copy of CYP2B6, so you break down efavirenz and some other drugs a bit more slowly, which can raise their blood levels. It mainly matters if you take those specific medicines, where a lower dose is sometimes considered.

Low CYP2B6 activity (rs3745274 TT). You have two reduced-function (*6) copies of CYP2B6, so drugs like efavirenz can build up to noticeably higher levels and cause more side effects. If you're ever prescribed efavirenz (or bupropion, methadone), this is worth flagging, since a lower dose may be appropriate.

Evidence & sources

Across global populations, about 7% of people carry two copies of this variant, and about 56% carry none.

CPIC provides dosing guidance for efavirenz based on this gene.

Common questions

Does this affect antidepressants? Only bupropion is a meaningful CYP2B6 substrate, and the evidence is not strong enough for any guideline to recommend dose adjustment on genotype. The established use is efavirenz.

I take efavirenz and feel dizzy. Is this why? It may contribute, since reduced-function genotypes produce higher drug levels and the central nervous system effects are dose-related. That is a conversation with your HIV clinician, who can measure levels or adjust the regimen, rather than something to change yourself.

Related

Abacavir hypersensitivity (HLA-B*57:01) · CYP2C19 metabolizer status (clopidogrel & others) · Fluoropyrimidine (5-FU) toxicity risk · Hepatitis C treatment response (IL28B) · Opioid receptor response (OPRM1 A118G) · Thiopurine metabolism (TPMT and NUDT15 genes) · Warfarin dose sensitivity