Interactions Between HAART and Phenytoin/Carbamazepine
Carbamazepine and phenytoin are contraindicated with many antiretroviral medications due to significant drug-drug interactions that can lead to treatment failure of HIV therapy and potential toxicity. 1
Mechanism of Interaction
- Both phenytoin and carbamazepine are potent inducers of cytochrome P450 enzymes (particularly CYP3A4) and P-glycoprotein (P-gp), which significantly decrease plasma concentrations of many antiretroviral drugs 1
- These interactions occur through enzyme induction, leading to accelerated metabolism and reduced efficacy of antiretroviral medications 1
- The interaction is bidirectional - some antiretrovirals can also affect levels of antiepileptic drugs 2
Specific Effects on Antiretroviral Drug Levels
- Carbamazepine and phenytoin can reduce concentrations of protease inhibitors, non-nucleoside reverse transcriptase inhibitors, and integrase inhibitors 1
- Real-life investigations show that co-administration of carbamazepine or oxcarbazepine with atazanavir or dolutegravir resulted in significantly lower trough concentrations:
- These reductions in antiretroviral drug levels can lead to virological failure and development of HIV resistance 2
Specific Antiretroviral Classes Affected
Protease Inhibitors
- Carbamazepine and phenytoin significantly reduce plasma concentrations of atazanavir, darunavir, and other protease inhibitors 1, 2
- Ritonavir-boosted regimens may be affected less severely but still require careful monitoring 1
Integrase Inhibitors
- Dolutegravir levels are dramatically reduced (by up to 83%) when co-administered with carbamazepine or oxcarbazepine 2
- This reduction is clinically significant and may lead to treatment failure 2
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
- Efavirenz, etravirine, and nevirapine levels can be significantly reduced by enzyme induction 1
- These combinations should generally be avoided 1
Recommendations for Management
- Avoid co-administration of carbamazepine or phenytoin with antiretrovirals whenever possible 1
- If anticonvulsant therapy is required in patients on HAART, consider alternative antiepileptic drugs with minimal enzyme-inducing properties, such as:
- If carbamazepine or phenytoin must be used with antiretrovirals:
Bidirectional Interactions
- Not only do antiepileptics affect antiretroviral levels, but some antiretrovirals can affect antiepileptic drug concentrations:
- Phenytoin levels can increase when combined with certain antiretrovirals 5
- Carbamazepine can increase phenytoin serum concentration and reduce phenytoin clearance 5
- The combination of phenytoin and carbamazepine offers no additional therapeutic advantage over either drug alone and may increase toxicity 6
Clinical Pitfalls and Caveats
- The interaction between HAART and enzyme-inducing antiepileptics can take several weeks to fully develop as enzyme induction is a gradual process 1
- Withdrawal of the enzyme-inducing antiepileptic may lead to toxicity from the antiretroviral if doses were increased to compensate 1
- Patients may not report all medications they are taking, so a thorough medication reconciliation is essential 1
- Over-the-counter medications and herbal supplements (particularly St. John's wort) can further complicate these interactions 1
Summary of Key Points
- Carbamazepine and phenytoin are contraindicated with many antiretroviral medications 1
- These interactions can lead to HIV treatment failure and development of resistance 2
- Alternative non-enzyme-inducing antiepileptics should be preferred in patients on HAART 3
- If co-administration cannot be avoided, therapeutic drug monitoring and dose adjustments are essential 2