Carbamazepine-Indinavir Interaction Causes Antiretroviral Therapy Failure
Carbamazepine-Indinavir Interaction Causes Antiretroviral Therapy Failure
Abstract & commentary
Synopsis: Viral resistance, plasma drug concentration data, and the chronology of events are highly indicative of antiretroviral treatment failure due to the interaction between CBZ and indinavir.
Source: Hugen PW, et al. Carbamazepine-indinavir interaction causes antiretroviral therapy failure. Ann Pharmacother 2000;34:465-470.
Hugen and associates report the case of a 48-year-old HIV-positive white male who had been treated with three antiretroviral agents: indinavir (Crixivan), zidovudine (Retrovir, also known as AZT), and lamivudine (Epivir, also known as 3TC). The patient’s viral load (HIV-RNA) became undetectable (< 400 copies/mL) less than two months after this therapy was initiated. Following a course of famciclovir (Famvir) therapy for herpes zoster, the patient was treated with tramadol for post-herpetic neuralgia, but this was subsequently changed to carbamazepine (CBZ) due to insufficient analgesic effect.
Indinavir plasma concentrations decreased substantially within a short period after the initiation of CBZ therapy. CBZ was stopped after two and a half months and two weeks later the HIV-RNA was detectable (6 × 103 copies/mL). Resistance to the triple antiretroviral therapy was demonstrated. Several months later, the viral load continued to increase (300 × 103 copies/mL), necessitating a switch to a new antiretroviral regimen containing nevirapine (Viramune), didanosine (Videx), and stavudine (Zerit). Hugen et al conclude that the viral resistance, plasma drug concentration data, and the chronology of events are highly indicative of antiretroviral treatment failure due to the interaction between CBZ and indinavir.
Comment by Michael F. Barber, PharmD
Given the susceptibility of HIV-infected patients to seizures and psychiatric disorders, as well as the role of CBZ in the treatment of these conditions, the likelihood of patients being treated with both indinavir and CBZ is clinically significant. Further, the possibility of increased HIV replication by CBZ’s induction of indinavir metabolism makes this drug interaction important. This case supports the notion that a drug interaction that reduces the serum concentration of an antiretroviral (in this case, indinavir) can ultimately lead to resistance, much in the same way that that can occur if patients are nonadherent to their medication regimen. Since the time of onset of CBZ’s induction effects on hepatic enzymes vary between patients (usually 2-3 weeks); this drug interaction is extremely difficult to manage. It seems most reasonable to avoid the use of CBZ in patients who are receiving protease inhibitors for HIV disease. Alternative choices include valproic acid and lithium, as well as gabapentin, lamotrigine, and olanzapine.
In summary, the introduction of the protease inhibitors has certainly represented a major advance in the treatment of HIV; however, as substrates of the CYP3A4 enzyme, there are several psychotropic medications that can cause clinically important drug interactions. St. John’s wort has also been documented to lower serum levels of protease inhibitors and should be avoided. (Dr. Barber is Assistant Professor of Clinical Sciences and Administration, University of Houston, College of Pharmacy, Houston, Tex.)
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