What are the treatment considerations for a patient who is a CYP2B6 (cytochrome P450 2B6) poor metabolizer taking efavirenz (Sustiva)?

Management of CYP2B6 Poor Metabolizers Taking Efavirenz

For patients who are CYP2B6 poor metabolizers taking efavirenz (Sustiva), dose reduction to 400 mg daily (instead of standard 600 mg) is strongly recommended to prevent toxicity while maintaining efficacy.

Understanding CYP2B6 and Efavirenz Metabolism

CYP2B6 is a key enzyme in the cytochrome P450 system that metabolizes approximately 25% of clinically used medications, including efavirenz 1. Poor metabolizers have no functional CYP2B6 enzyme activity due to genetic variants, affecting about 5-10% of Caucasians and less than 1% of Asian populations 1.

Efavirenz is predominantly metabolized by CYP2B6 into its major metabolite, 8-hydroxyefavirenz 2. When this metabolism is impaired in poor metabolizers:

• Efavirenz plasma concentrations can become significantly elevated
• Risk of central nervous system toxicity increases substantially
• Higher rates of treatment discontinuation may occur

Clinical Implications for Poor Metabolizers

Increased Toxicity Risk

Poor metabolizers experience:

• Higher plasma concentrations of efavirenz
• Increased risk of neuropsychiatric adverse effects, including:
  • Dizziness
  • Insomnia
  • Abnormal dreams
  • Impaired concentration
  • Depression
  • Psychosis in severe cases

Documented Evidence

Research has shown that CYP2B6 polymorphisms, particularly those with 516G>T (CYP2B66 and CYP2B69) and 983T>C (CYP2B616 and CYP2B618) variants, cause diminished or loss-of-function for efavirenz metabolism 2. Case reports have documented severe neuropsychiatric symptoms in patients with compound homozygosity for loss-of-function CYP2B6 alleles 3.

Management Recommendations

Dose Adjustment

1. Reduce efavirenz dose to 400 mg daily (instead of standard 600 mg) for confirmed CYP2B6 poor metabolizers 4
2. Monitor closely for clinical response and side effects
3. Consider therapeutic drug monitoring if available to ensure plasma concentrations remain within therapeutic range

Alternative Therapy Considerations

If toxicity persists despite dose reduction:

• Consider switching to an alternative antiretroviral agent not primarily metabolized by CYP2B6
• Integrase inhibitors or boosted protease inhibitors may be suitable alternatives
• Consult with an HIV specialist for individualized therapy selection

Drug Interaction Management

Poor metabolizers are particularly susceptible to drug interactions:

• Avoid concomitant medications that inhibit CYP2B6, which could further increase efavirenz levels 5
• Be cautious with medications that can cause additive central nervous system effects
• Review all medications, including over-the-counter drugs and supplements

Monitoring Recommendations

For CYP2B6 poor metabolizers on efavirenz:

1. More frequent clinical monitoring during the first 4-8 weeks of therapy
2. Assess for neuropsychiatric symptoms at each visit
3. Consider therapeutic drug monitoring if available
4. Monitor HIV viral load to ensure continued efficacy with reduced dosing
5. Educate patients about potential side effects and when to seek medical attention

Genetic Testing Considerations

• CYP2B6 genotyping is valuable before initiating efavirenz therapy, particularly in patients with risk factors for toxicity 1
• Testing can identify poor metabolizers who would benefit from initial dose adjustment
• Consider testing for patients who develop unexpected toxicity on standard doses

Conclusion

Managing CYP2B6 poor metabolizers on efavirenz requires careful dose adjustment and monitoring. Reducing the dose to 400 mg daily can maintain efficacy while reducing the risk of toxicity. Close monitoring and consideration of alternative therapies when necessary can help ensure optimal outcomes for these patients.