Efavirenz

Efavirenz (brand name Sustiva) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used as part of antiretroviral therapy for HIV-1 infection.

It is commonly prescribed in combination with other agents to suppress viral replication and improve immune function in adults and children with HIV-1.

Efavirenz works by binding directly to the reverse transcriptase enzyme, causing a conformational change that inhibits viral DNA synthesis and prevents HIV from multiplying.

The CYP2B6 gene encodes an enzyme primarily responsible for metabolizing efavirenz in the liver. CYP2B6 activity varies between individuals depending on genetic variants, affecting how quickly the drug is processed.

Individuals with high‐activity variants of CYP2B6 may clear efavirenz faster, reducing drug exposure, while those with low‐activity variants may experience higher blood levels and an increased risk of side effects. Metabolizer status is categorized into groups based on combined genetic changes.

Variations in CYP2B6 produce distinct metabolizer phenotypes—ultrarapid, rapid, normal, intermediate, poor, and indeterminate—which influence efavirenz concentrations. Ultrarapid and rapid metabolizers may have lower drug levels and reduced efficacy risk, whereas intermediate and poor metabolizers have higher levels, leading to an increased likelihood of central nervous system adverse effects.

Ultrarapid Metabolizer

• Effect on drug levels: Lower than expected efavirenz concentrations
• Clinical consequence: Potential subtherapeutic exposure; risk of virologic failure
• Side effects: Fewer CNS side effects; generally mild, infrequent

Rapid Metabolizer

• Effect on drug levels: Slightly lower efavirenz concentrations
• Clinical consequence: Possible reduced efficacy if doses are not adjusted
• Side effects: Mild CNS symptoms; uncommon

Normal Metabolizer

• Effect on drug levels: Expected, standard efavirenz concentrations
• Clinical consequence: Typical efficacy and safety profile
• Side effects: Standard incidence of CNS complaints (e.g., vivid dreams); usually mild and transient

Intermediate Metabolizer

• Effect on drug levels: Higher efavirenz concentrations than normal
• Clinical consequence: Increased risk of central nervous system adverse events
• Side effects: Moderate CNS symptoms (dizziness, insomnia); relatively common

Poor Metabolizer

• Effect on drug levels: Significantly elevated efavirenz concentrations
• Clinical consequence: High risk of CNS toxicity and treatment discontinuation
• Side effects: Severe CNS events (hallucinations, depression); moderate frequency

Indeterminate/Not Available

• Effect on drug levels: Unknown
• Clinical consequence: No specific guidance; follow standard dosing with monitoring
• Side effects: Cannot predict; monitor for efficacy and toxicity

The following dosing guidelines are based on the CPIC recommendations for efavirenz metabolism by CYP2B6.

The CPIC and FDA guidelines do not provide specific alternative drug recommendations for efavirenz. Clinicians may consider other antiretroviral agents (e.g., nevirapine, integrase inhibitors) based on individual patient factors and resistance profiles.

• CPIC – Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2B6 and Efavirenz Dosing
• FDA – Table of Pharmacogenetic Associations