Potential Interactions Between Valproate and HAART Regimens
Valproate levels can be significantly reduced by ritonavir-boosted protease inhibitors, potentially leading to loss of seizure control and exacerbation of bipolar disorder. 1 Careful monitoring and dose adjustments are essential when using valproate with HAART regimens.
Key Interaction Mechanisms
- Valproate is primarily metabolized through glucuronidation (50%) and mitochondrial β-oxidation (40%), with less than 10% eliminated by cytochrome P450 enzymes 1
- Ritonavir and other protease inhibitors can induce glucuronidation, potentially decreasing valproate concentrations by up to 48% 1
- NNRTIs have variable effects on CYP450: nevirapine is an inducer, delavirdine is an inhibitor, and efavirenz is a mixed inducer/inhibitor 2
- Integrase inhibitors without pharmacologic boosters have lower potential for drug-drug interactions with valproate 2
Specific Interactions by Antiretroviral Class
Protease Inhibitors (PIs)
- Ritonavir-boosted PIs can significantly reduce valproate levels through induction of glucuronidation 1
- A case report showed a 48% decrease in valproate concentration after starting lopinavir/ritonavir, resulting in exacerbation of bipolar symptoms 1
- PIs inhibit the CYP450 pathway, which can affect other concomitant medications but has less direct impact on valproate metabolism 2
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
- NNRTIs have variable effects on drug metabolism: nevirapine induces, delavirdine inhibits, and efavirenz both induces and inhibits CYP450 enzymes 2
- These effects may indirectly impact valproate metabolism, though the clinical significance is less pronounced than with PIs 2
- Newer NNRTIs like etravirine and rilpivirine may have fewer interactions than older agents like efavirenz and nevirapine 3
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
- NRTIs generally have a low potential for drug-drug interactions with valproate 3
- However, NRTIs can cause mitochondrial toxicity, which may theoretically compound valproate's rare but serious adverse effect of lactic acidosis 2
- Zidovudine-associated bone marrow suppression could potentially compound valproate's effects on platelets 2, 4
Integrase Strand Transfer Inhibitors (INSTIs)
- Unboosted integrase inhibitors (raltegravir, dolutegravir) have fewer drug interactions and are preferred in patients requiring valproate 2, 5
- Elvitegravir is given with cobicistat (a booster), which may increase the risk of interactions similar to ritonavir-boosted regimens 3
Monitoring and Management Recommendations
- Monitor valproate levels before starting HAART and 2-4 weeks after initiation or changes to antiretroviral therapy 1
- Increase valproate dosage when used with ritonavir-boosted PIs; some patients may require up to double the usual dose 1, 6
- Monitor for clinical efficacy of valproate (seizure control or mood stability) and adjust dosing accordingly 1
- Consider using integrase inhibitor-based regimens without pharmacologic boosters when possible in patients requiring valproate 2, 5
- Watch for signs of valproate toxicity if antiretrovirals that inhibit metabolism are discontinued 4
- Monitor for overlapping toxicities, particularly:
Preferred Antiretroviral Options with Valproate
- Integrase inhibitor-based regimens without pharmacologic boosters (raltegravir, dolutegravir) have the lowest potential for interactions 2, 5
- NRTIs generally have minimal interactions with valproate but monitor for overlapping toxicities 3
- If a PI-based regimen is necessary, anticipate the need for valproate dose increases and more frequent monitoring 1
By understanding these interactions and implementing appropriate monitoring strategies, clinicians can effectively manage patients requiring both valproate and HAART therapy while minimizing the risk of treatment failure or toxicity.