US investigators have reported a significant interaction between efavirenz (Sustiva) and phenytoin, an anti-epilepsy drug. The case is reported in the January 2nd edition of AIDS.
It is known that antiretroviral drugs and medicines used to treat epilepsy can potentially interact. But only one interaction between efavirenz and phenytoin has been previously reported.
However, doctors from Seattle have reported a significant interaction between the two drugs which meant that a patient had undetectable levels of efavirenz in his blood and poor control of his HIV viral load.
A 35-year-old man with newly diagnosed HIV was referred to a specialist HIV clinic at the University of Washington by his GP. The patient had oral thrush and had lost 45 kg over the past six months. The patient did have a previous history of morbid obesity (his weight having a peak of 130 kg). In addition, the patient was taking phenytoin (400 mg twice daily) and pregabalin (150 mg twice daily) to control epileptic seizures.
Examinations revealed that the patient had a weight of 70 kg, oral thrush and cachexia (weight loss, muscle atrophy, weakness and loss of appetite). Blood tests showed that his CD4 cell count was only 11 cells/mm3 and his viral load 1,000,000 copies/ml. Cultures for opportunistic infections were negative.
Presumptive treatment with fluconazole (200 mg once daily) was initiated for presumptive oesophageal candidiasis. Fluconazole can interact with phenytoin so blood levels of this drug were monitored. It was indeed the case that levels of phenytoin were elevated by fluconazole co-administration so the dose of phenytoin was reduced to 200 mg twice daily.
The patient also started prophylactic treatment with antibiotics against PCP and MAI.
After three weeks, there had been an improvement in the patient’s condition and he had gained 4.5 kg in weight. Antiretroviral therapy including efavirenz (800 mg once daily), and FTC/tenofovir (200/300 mg) once daily was initiated. The dose of efavirenz was increased to 800 mg because of a known interaction between the drug and rifampicin (which the patient was taking as prophylaxis against MAI).
After four days of therapy, the 14 hour blood concentration of efavirenz was monitored. Efavirenz levels were undetectable. Levels of efavirenz were measured again on day 14 and once again found to be undetectable. The patient had a viral load of 12,400 copies/ml at this time.
Physicians took the decision to discontinue therapy with phenytoin and replace it with levetiracetam and lamotrigine. The dose of efavirenz was decreased to the standard 600 mg daily two weeks after this treatment change.
Approximately 30 days after antiretroviral therapy was initiated, the patient’s viral load had fallen to 921 copies/ml.
Efavirenz, rifampicin and phenytoin are all metabolised using the P450 pathway in the liver. Rifampicin can reduce efavirenz levels by up to 30%, but it was expected that phenytoin would have a much smaller interaction. However, the investigators note that there can be wide variations in efavirenz concentrations between patients.
“Our patient experienced a dramatic reduction in efavirenz plasma concentrations with concurrent phenytoin administration”, comment the investigators. They add, “although previous reports disclose success with co-administration of efavirenz and phenytoin, close monitoring of both efavirenz plasma levels and virologic response would be prudent given the potential for significant variability of the drug-drug interaction.”
Spak CW et al. Clinical interaction between efavirenz and phenytoin. AIDS 22: 164 – 165, 2008.