Clinical implications and management of drug-drug interactions between antiretroviral agents and psychotropic medications
Medications used in the treatment of human immunodeficiency virus (HIV) often have drug-drug interactions which complicate treatment of psychiatric illnesses in HIV-infected patients. Protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the two classes of HIV medications most likely to be involved with interactions, with the majority occurring via the cytochrome P450 (CYP450) system. These interactions can result in either increased or decreased exposure to psychotropic and antiretroviral medications, often requiring dosage adjustments and increased monitoring. This article reviews some of the major drug interactions with antiretroviral agents.
Psychiatric illness has a significant impact on patients infected with human immunodeficiency virus (HIV), leading to decreased adherence rates, disease progression, and decreased quality of life.1–6 The prevalence of psychiatric illness is high among HIV-infected patients.78 Thus, many HIV-infected patients are taking psychotropic medications,9 with 27.2% HIV-positive patients receiving at least one psychotropic drug, including antidepressants being the most common agents used.10
Up to 40% of HIV-positive patients experience major depression.2 A meta-analysis completed by Ciesla and colleagues indicated that HIV-positive patients were almost two times more likely to have an episode of major depressive disorder compared to HIV-negative patients.11 In turn, literature also indicates that depression is a risk factor for patients acquiring HIV, with rates ranging from 3% to 23% in these patients, compared to 0.6% in the general population.212
Treatment of the underlying psychiatric illness in these patients is imperative, as there is evidence of increased antiretroviral adherence in depressed patients taking antidepressant therapy.813
The addition of psychotropic agents such as antidepressants to an HIV-infected patient's highly active antiretroviral therapy (HAART) is of particular concern as both medication classes are prone to drug interactions due to metabolism through the cytochrome P450 (CYP450) isoenzymes.1415–17 The major CYP450 isoenzymes affected include CYP3A4, CYP2D, and CYP2C9/2C19.16 Out of the six major classes of HAART medications, non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) have the highest potential for drug-drug interactions (Table 1). Of the PIs, ritonavir is the most potent inhibitor making it one of the biggest culprits of clinically significant drug interactions in this population;17 consequently, clinicians need to be aware of its inclusion in many HAART regimens and combination products such as Kaletra (lopinavir/ritonavir). The consequences of these interactions can range from subtherapeutic drug concentrations resulting in treatment failure or toxicities. However, if psychotropic agents are started appropriately and monitored closely, the benefit of increased adherence and quality of life outweighs the risks.
This review will discuss the clinical implications of utilizing psychotropic medications in the HIV-infected population, focusing on major drug interactions with antiretroviral agents.
ANTIDEPRESSANTS
Selective Serotonin Reuptake Inhibitors (SSRIs)
Selective serotonin reuptake inhibitors are one of the most frequently utilized classes of antidepressants in HIV-positive patients due to the relatively benign side effect profile compared to older antidepressant classes.14 The efficacy of various SSRIs has been demonstrated in HIV-infected patients.1819 However, as most of the medications in this class are substrates for and can inhibit or induce one or more CYP450 isoenzymes, the potential for drug interactions with all SSRIs exist.20 (Table 1).
Many SSRIs including fluoxetine, citalopram, paroxetine, and sertraline are metabolized via the CYP450 system.20 Thus, antiretroviral agents that inhibit CYP450 metabolism, such as ritonavir, may inhibit SSRI metabolism and increase concentrations.221 However, the most recent National Institute of Health (NIH) HIV guidelines state that the area under the curve (AUC) of paroxetine decreases by 39% and 55% when given concomitantly with the combination of darunavir/ritonavir or fosamprenavir/ritonavir, respectively and the AUC of sertraline appears to decrease by 49% when given in combination with darunavir/ritonavir and 39% with efavirenz.22 A case series reported by DeSilvaand colleagues describes the clinical significance of increased SSRI concentrations leading to toxicity resulting from this potential drug-drug interaction.23 A series of HIV-infected patients presented with signs and symptoms of serotonin syndrome after receiving antiretroviral therapy containing ritonavir, saquinavir, or efavirenz in combination with fluoxetine. All symptoms resolved in these patients with a decrease in fluoxetine dose or discontinuation of ritonavir. Although there is a potential for this to occur with all SSRIs, fluoxetine may be more susceptible due to its long half-life.
Due to the inhibition capabilities of fluoxetine and paroxetine on CYP2D6, and fluvoxamine on CYP1A2,20 concurrent administration with HAART may increase plasma concentrations of antiretroviral agents metabolized by these CYP450 isoenzymes, possibly resulting in toxicity. Although pharmacokinetic studies have described these interactions, the clinical significance is unclear. Significant increases in ritonavir AUC were demonstrated when given concurrently with fluoxetine; however, the authors concluded that these results were likely not clinically significant.24 Additionally, delavirdine package insert recommendations indicate an increase in delavirdine trough plasma concentrations from concomitant administration of fluoxetine. The manufacturer recommends decreasing the dose of delavirdine by 0%-50%.25 Although there were no dose adjustment recommendations for ritonavir and dosage adjustments for delavirdine were not well defined,24 there is a potential for increased side effects of these antiretrovirals when given in combination with SSRIs that inhibit CYP3A4 isoenzymes.
While all SSRIs are metabolized via the CYP450 system, sertraline, citalopram, and escitalopram, appear to have a less significant effect on the major CYP450 isoenzymes, decreasing the potential for alterations in the pharmacokinetics of antiretroviral agents.1420 A study by Gutierrez and colleagues found no significant changes in the pharmacokinetics of escitalopram and ritonavir when administered concurrently.26 Furthermore, there appears to be no significant effect between paroxetine and NNRTIs such as efavirenz and etravirine.22 As the risk for drug-drug interactions appears to be lower with these agents, they may be preferred among HIV-infected patients. When initiating SSRI therapy with concomitant antiretroviral therapy, a low dose should be initiated and slowly titrated based on therapeutic response with close monitoring of signs and symptoms of toxicity of the SSRI and the antiretroviral agent.22227
Tricyclic Antidepressants (TCA)
Several studies have demonstrated the effectiveness of TCAs for the treatment of depression in HIV-infected patients,2728 but their use has decreased with the arrival of newer classes of antidepressants with fewer side effects.1419
As with other antidepressants, TCAs utilize the CYP450 system for metabolism, specifically isoenzyme CYP2D6.29 Due to the potent inhibition of CYP2D6 by ritonavir, when used concurrently with TCAs, systemic concentrations of TCAs can rise 1.5 to 3 fold, increasing the likelihood of adverse events.2129 Patients receiving a TCA and ritonavir concomitantly should be monitored for worsening of common TCA adverse effects such as sedation, postural hypotension, dry mouth, blurred vision, constipation, and urinary retention.29 Due to the significant increases in TCA systemic concentrations, patients should be started on a low dose and titrated up to a therapeutic response with monitoring for symptoms of TCA toxicity.22 As cardiac arrhythmias, seizures, and death may occur with TCA toxicity,29 therapeutic drug monitoring of TCAs is also suggested when used in combination with inhibitors of CYP2D6 such as ritonavir.
Bupropion
Bupropion is a monocyclic antidepressant with norepinephrine and dopamine reuptake inhibition. Bupropion may be used less frequently in the HIV-positive patient population due to drug interactions which could potentially further increase the risk of seizures. However, in an open label study, sustained release bupropion was found effective for the treatment of depression and well-tolerated among HIV-infected patients.30 This study was done in a small population and concurrent antiretroviral therapy was not known. The seizure risk should not deter clinicians from prescribing bupropion to HIV-positive patients without a seizure history or risk.
Previously, bupropion was contraindicated for concomitant use with ritonavir.29 As newer data became available indicating that bupropion is largely metabolized by CYP2B6 rather than 3A4, this contraindication was lifted. In vitro data suggests that antiretroviral agents including ritonavir, efavirenz, and nelfinavir have substantial CYP2B6 inhibition possibly resulting in increased bupropion concentrations,31 but this has not been demonstrated clinically. In a small case series where bupropion was administered in combination with ritonavir, efavirenz, and nelfinavir, no seizures were seen.32 Although in vitro studies suggest the administration of bupropion with ritonavir should result in increased concentrations of bupropion, a study by Hogelandand colleagues demonstrated decreased exposure to bupropion and its active metabolite when given with ritonavir.33 According to HIV guidelines, the AUC of bupropion decreases by 57% and 46% when given with the ritonavir combinations such as lopinavir/ritonavir and tipranavir, respectively. This is may be due to ritonavir induction of UPD-glucuronosyltransferase (UGT) and CYP2B6. The AUC of bupropion also decreases by 55% when given in combination with efavirenz. When bupropion is used in combination with antiretroviral therapy, close monitoring and bupropion dose adjustments based on clinical response are recommended.22
Mirtazapine
Mirtazapine is a noradrenergic and specific serotonergic antidepressant. It is frequently used in patients who are depressed and are experiencing insomnia and/or decreased appetite with weight loss, which can be a common presentation of HIV-infected patients. In a previous study, mirtazapine was found to be effective in treating depression in HIV-infected patients.34 As mirtazapine is metabolized via the CYP450 system,35 drug interactions may occur with potent inhibitors of CYP3A4 and CYP2D6 such as ritonavir. Currently, the clinical implications of this interaction have not been currently demonstrated and therefore it is unknown how clinically significant this potential interaction is. When mirtazapine is used in combination with these medications, the lowest effective dose of mirtazapine should be considered with close monitoring for increased risk of side effects.
Trazodone/Nefazodone
Trazodone is a triazolopyridine derivative that acts through a combination of postsynaptic 5-HT2 antagonism with 5-HT reuptake inhibition.36 Although there is no clinical data supporting the efficacy of trazodone in the HIV-positive patient population, nefazodone, a chemically similar antidepressant, was found to be effective in the treatment of depression in the HIV-infected population.37 It has been reported that nefazodone can elevate levels of PIs and NNRTIs and in turn, concentrations of nefazodone can be affected by both PIs and NNRTIs;38 however, nefazodone is infrequently used due to its risk of liver failure.
Trazodone is metabolized via the CYP450 system, primarily through CYP3A with additional CYP2D6 involvement. Coadministration of trazodone with antiretroviral agents that induce or inhibit CYP3A are likely to result in altered concentrations of trazodone. The HIV guidelines state ritonavir given as 200 mg twice daily for 2 days in combination with various PIs, resulted in a 240% increase in trazodone AUC.22 In a study evaluating the interaction of ritonavir with trazodone, short term exposure of ritonavir resulted in significant prolongation of the half-life of trazodone. When trazodone was administered with ritonavir, increased sedation, fatigue, and performance impairment were more common compared to the group receiving trazodone with placebo.36 Although saquinavir is a PI which is infrequently used, it should be noted that the combination of saquinavir/ritonavir and trazodone is contraindicated due to the risk of cardiac arrhythmias.22 If trazodone is indicated in a patient who is currently taking an antiretroviral agent with CYP3A activity such as ritonavir, trazodone should be initiated at a low dose then adjusted to a therapeutic response with close monitoring for adverse effects.
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)
Venlafaxine, desvenlafaxine, and duloxetine are newer antidepressant agents which selectively inhibit the reuptake of serotonin and norepinephrine. As with other antidepressants these agents are metabolized via the CYP450 system, resulting in potential for drug-drug interactions.
Both venlafaxine and duloxetine are metabolized by CYP2D6 with additional venlafaxine metabolism including CYP3A4, CYP2C9/19, and additional duloxetine metabolism via CYP1A2.39–41 Desvenlafaxine is primarily metabolized via conjugation and to a minor extent, CYP3A4.42 Theoretically, when given concomitantly with a potent CYP2D6 inhibitor such as ritonavir, an increase in levels of venlafaxine and duloxetine could result, leading to an increased risk of side effects. In a study evaluating the potential for venlafaxine to affect the metabolism of other substrates in theCYP450 system, a small effect on CYP450 activity was demonstrated, suggesting a low potential for interactions. To support this, a pharmacokinetic study found no change in indinavir disposition when administered with extended release venlafaxine and extended release desvenlafaxine.43 However, Levin and colleagues found that plasma concentrations of indinavir were decreased when given concurrently with immediate release venlafaxine.44 As venlafaxine and desvenlafaxine are unlikely to interact with indinavir via the CYP450 system, it has been hypothesized that this reaction occurs at the time of absorption in the gastrointestinal tract via PGP induction.43 If venlafaxine, desvenlafaxine, or duloxetine are selected as antidepressants in HIV-infected patients on antiretroviral agents, doses should be initiated low and titrated to therapeutic response with close monitoring of side effects.
St. John's Wort
St. John's Wort is an herbal medication that is commonly used to reduce symptoms of depression; however, it is a potent inducer of CYP3A4 and PGP, resulting in many clinically significant drug interactions.45 The PIs and NNRTIs are primarily metabolized via CYP3A4; therefore, coadministration with St. John's Wort will likely result in a decrease in antiretroviral concentrations,22 potentially leading to virologic failure. The NIH guidelines recommend that St. John's Wort be avoided with any NNRTIs or PIs.22
ANTIPSYCHOTICS
Fifteen percent of HIV-infected patients can experience new-onset psychosis, and up to 7% of HIV-infected patients have pre-existing psychiatric illness such as schizophrenia.46 The majority of drug-drug interactions between antipsychotic medications and HIV antiretrovirals involve PIs. Atypical antipsychotics including aripiprazole, quetiapine and risperidone are all substrates of CYP3A4 and the concurrent administration of these agents with potent CYP3A4 inhibitors, such as ritonavir, can cause antipsychotic accumulation and toxicity. Depending on the adverse effects of the antipsychotic agent, toxicity can include increased metabolic side effects such as weight gain, QT prolongation causing increased risk of torsades de pointes, or CNS toxicity including somnolence, dizziness and confusion.14 Several case reports have illustrated the clinical importance of these drug-drug interactions.
Aripiprazole is a substrate of both CYP3A4 and CYP2D6; therefore, combination with inhibitors of either enzyme may lead to increased risk for adverse effects due to aripiprazole accumulation.47 This occurred in an HIV-infected patient taking a ritonavir and darunavir containing HAART regimen. After the initiation of aripiprazole 50 mg daily, the patient presented with supratherapeutic levels of aripiprazole 5 times higher than the predicted therapeutic range. The patient experienced no signs of neurotoxicity, but did experience tachycardia, stiffness, headache and blurred vision, which were attributed to the aripiprazole toxicity. No further aripiprazole concentrations were determined because the patient left the health system shortly after the toxicity was identified.48 It is recommended to decrease the dose of aripiprazole by half when starting a potent inhibitor of CYP3A4. Furthermore, patients taking a potent CYP3A4 inhibitor who are also poor metabolizers of CYP2D6 should decrease the aripiprazole by one-fourth of the original dose. Likewise, a patient taking aripiprazole with a potent inhibitor of CYP3A4 and CYP2D6 should decrease the original dose by one-fourth.47
Quetiapine is another atypical antipsychotic extensively metabolized by CYP3A4; therefore, caution is advised when coadministered with a potent CYP3A4 inhibitor.49 This interaction was demonstrated in a patient who experienced 50-pound weight gain when quetiapine was added to the pre-existing ritonavir containing HIV regimen. The patient's weight returned to normal approximately 5 months after ritonavir and quetiapine were discontinued. Another case illustrates quetiapine CNS toxicity including mental confusion and increased sedation when atazanavir-ritonavir was added. After cessation of quetiapine, the patient's somnolence and mental status changes resolved.50 When possible, clinicians should avoid using quetiapine with potent inhibitors of CYP3A4. When benefits outweigh risks, quetiapine doses should be reduced upon initiating potent inhibitors of CYP3A4 and patients should be monitored for signs of quetiapine toxicity, including somnolence, altered mental status, and hypotension.49
Risperidone, a substrate for both CYP3A4 and CYP2D6, is known to accumulate when coadministered with PIs.51 Kelly and colleagues document a case of an HIV-infected patient who developed dystonia and neuroleptic-induced Parkinson's when ritonavir/indinavir was coadministered with risperidone. After starting ritonavir/indinavir, the patient experienced increased tremors, difficulty breathing and swallowing, jerky movements of his hands, arms, and legs with a resting tremor. The patient's symptoms improved three days after discontinuing the risperidone.52 Caution is advised when using risperidone with ritonavir-boosted HIV regimens or other potent inhibitors of risperidone.51
Alternatively, reduced efficacy can occur when olanzapine is taken with ritonavir. Olanzapine is metabolized by CYP1A2 and glucuronsyltransferases which are both induced by ritonavir therapy. In an open-label pharmacokinetic study, the AUC of olanzapine decreased by 53% and the half-life of olanzapine decreased by 50% when co-administered with ritonavir. Overall, the clearance of olanzapine increased 115% when administered with ritonavir, placing patients at risk for decreased efficacy of olanzapine when taken with ritonavir.53 Special care should be taken when initiating ritonavir in a patient taking olanzapine. The patient should be closely monitored for increased psychiatric symptoms upon initiation of ritonavir.
Additional drug-drug interactions exist between antipsychotics known to carry a warning for QT prolongation when used with antiretrovirals that can also cause QT prolongation, such as saquinavir. Saquinavir prescribing information cautions the coadministration of saquinavir with phenothiazine antipsychotics including chlorpromazine, fluphenazine, thioridazone and other antipsychotics including haloperidol and droperidol.54 In general, saquinavir is rarely utilized in clinical practice and coadministration with phenothiazines should be avoided. However, when any of the antipsychotic agents listed above must be used in combinations with saquinavir, a pre-treatment EKG should be ordered to establish the patient's base-line QT interval. If the base-line interval is longer than 450 milliseconds, the antipsychotic should not be initiated. However, if the QT interval is shorter than 450 milliseconds, the antipsychotic can be initiated with a second EKG ordered 3 - 4 days afterwards. If the second EKG shows the QT interval is greater than 480 milliseconds or has increased by more than 20 milliseconds from baseline, the antipsychotic agent, saquinavir, or both should be discontinued to avoid arrhythmias including torsades de pointes.54
ANXIOLYTICS
Benzodiazepines
Benzodiazepines are commonly used for anxiety disorders and insomnia. Alprazolam, estazolam, midazolam, and triazolam are metabolized by CYP3A enzymes, lending to the potential for drug-drug interaction when used in HIV-positive patients currently on antiretroviral therapy. The NIH guidelines indicate the combination of diazepam and the NNRTI, etravirine, may result in increased diazepam concentrations; potentially requiring decreased diazepam doses.22 Furthermore, the NNRTI efavirenz increases the Cmax of lorazepam by 16%; however, dosage adjustments are not necessary.22
Several studies have evaluated the effects of CYP3A4 inhibition of PIs on the clearance of benzodiazepines. The NIH Guidelines recommend that midazolam and triazolam not be coadministered with HAART regimens containing PIs due to a significant increase in AUC (1114% and 2000%, respectively).22 This was also demonstrated in a pharmacokinetic study by Palkama and colleagues evaluating the effects of saquinavir on midazolam when given concurrently.55 This resulted in a significant increase in the Cmax and AUC of oral midazolam, with similar effects expected with intravenous midazolam. This interaction has been observed clinically in a patient taking a saquinavir containing HAART regimen concomitantly with midazolam prior to a procedure. This resulted in the patient experiencing prolonged over-sedation requiring flumazenil administration. At a prior procedure where the patient's HAART regimen did not include saquinavir, midazolam was administered with no complications.56 Additionally, the NIH guidelines indicate that alprazolam's pharmacokinetics may be significantly altered with a possible 222% increase in half-life and 248% increase in AUC.22 A study by Green and colleagues found that clearance of triazolam was reduced while the half-life was prolonged when administered with ritonavir.57 The authors also observed these effects in alprazolam to a lesser extent. However, when ritonavir was administered for 10 days, it did not impair clearance of alprazolam.58 Lorazepam, oxazepam, and temazepam may be used as alternatives, as they are not extensively metabolized by the CYP450 system.22 If benzodiazepines are administered to HIV-infected patients on antiretroviral therapy with CYP3A4 inhibition, a low dose should be initiated and increased side effects of benzodiazepines should be monitored closely.
Non-Benzodiazepines
Newer non-benzodiazepine anxiolytics including zolpidem, eszopiclone, zaleplon, and ramelteon may be used in this patient population as sleeping aids to avoid drug dependence that may result from benzodiazepine use. Zolpidem, eszopiclone, and zaleplon exert their activity through binding to benzodiazepine and GABA receptors. Ramelteon is a melatonin receptor agonist acting specifically on MT1 and MT2 receptors. The potential for drug interactions exist because all of these agents are extensively metabolized via the CYP450 system (Table 1).
Zolpidem is primarily metabolized by CYP3A4 with additional activity via CYP2C9, CYP1A2, CYP2D6, and CYP2C19.5960 In a study evaluating the change in clearance of zolpidem administered concomitantly with ritonavir, the combination resulted in a small decrease in clearance, slightly prolonged half-life, and increased Cmax of zolpidem. Although the changes in clearance and Cmax were statistically significant, they were not likely clinically relevant as zolpidem is metabolized by multiple CYP enzymes.59 If the decision is made to initiate zolpidem in an HIV-infected patient on antiretroviral therapy, dose reductions may be needed, particularly in patients receiving other psychotropic medications. Patients should be monitored closely for over sedation.
Eszopiclone and zaleplon are metabolized through the CYP450 system with involvement from CYP3A4.60 Therefore, inhibition of metabolism via CYP3A4 from PIs could lead to decreased metabolism and increased exposure to anxiolytic therapy. However, there are no reports in the literature of significant drug-drug interactions between HAART therapy and these agents. Due to this potential interaction, the lowest dose of eszopiclone (1 mg) should be started initially in patients concomitantly receiving CYP3A4 inhibitors.61 Doses may be increased as tolerated while monitoring for increased signs and symptoms for adverse events. However, since zaleplon is only a minor substrate of CYP3A4,62 this interaction is not likely to require any zaleplon dose adjustments. It is still recommended that patients be closely monitored for increased signs and symptoms for zaleplon adverse effects.
Ramelteon is extensively metabolized via CYP1A2. Other enzymes involved to a lesser extent include CYP2C19 and CYP3A4. Concomitant administration with strong CYP1A2 inhibitors could theoretically decrease metabolism of ramelteon.63 There are no reports in the literature of significant drug-drug interactions between HAART therapy and ramelteon. Given its relatively safe profile, initial dose adjustments may not be required, with close patient monitoring.
PSYCHOSTIMULANTS
Psychostimulants are commonly used for patients with narcolepsy, attention-deficit hyperactivity disorder, adjunct to depression, and chronic fatigue. Previously, psychostimulants including methylphenidate and dextroamphetamine have demonstrated improvements in depression, energy, and mood of HIV-infected patients.64–66
It appears that when utilizing these agents in combination with antiretroviral therapy, there is a potential for the occurrence of drug-drug interactions via the CYP450 system. Dextroamphetamine and atomoxetine utilize the CYP2D6 isoenzyme for metabolism.6768 This could theoretically result in increased exposure when used in combination with potent inhibitors such as ritonavir, potentially increasing the risk for psychostimulant adverse drug effects. However, this interaction has not been demonstrated clinically, and due to the many different enzymes involved in metabolism it is unlikely that this interaction would be clinically relevant.67 Additionally, in vitro studies indicate that atomoxetine may act as an inhibitor of CYP3A and CYP2D6 isoenzymes, possibly resulting in increased exposure to PIs and NNRTIs.69 Once again, this interaction has not been demonstrated clinically. Methylphenidate may be metabolized via the CYP450 system with possible inhibition of CYP2D6 and CYP2B6 to some extent, but this has not been well defined.2170 It appears that dexmethylphenidate and lisdexamphetamine do not utilize the CYP450 pathway for metabolism, suggesting a low risk for drug-drug interactions with HAART regimens.7172 Overall, metabolism pathways for psychostimulants are not well understood. If it is decided to initiate one of these agents in an HIV-infected patient, close monitoring should be recommended with a slower titration in those utilizing the CYP450 system.
MOOD STABILIZERS
Psychotropic agents including lithium, lamotrigine, valproic acid, and carbamazepine are effective mood stabilizers and approved for the treatment of bipolar disorder. The exact mechanisms of these agents are largely unknown. Of the four agents, carbamazepine has the greatest potential for drug interactions as it is a known substrate and inducer of CYP3A4 although some case reports of possible drug interactions have been documented with lamotrigine and valproic acid therapy.
Lamotrigine
Lamotrigine is metabolized via glucuronidation through the UDP-glucuronosyl-transferase (UGT) system, specifically UGT1A4. Therefore, lamotrigine is not thought to have any significant DDIs with medications that are inducers or inhibitors of the CYP family of enzymes.73 Ritonavir, however, induces UGT and is known to decrease patient exposure to lamotrigine. In a pharmacokinetic study, the AUC of lamotrigine decreased by 32% and the elimination half-life decreased by 27% when taken with ritonavir/atazanavir. The concentration of lamotrigine did not differ significantly when taken with atazanavir alone.74 Additionally, the NIH guidelines state that ritonavir boosted-lopinavir can reduce lamotrigine AUC by 50% with no effect on lopinavir.22 The clinical significance of this interaction is unknown and clinicians are cautioned to carefully monitor the patient for manic episodes when starting ritonavir. Clinicians may also choose to monitor lamotrigine concentrations when starting or discontinuing ritonavir therapy.73
Valproic Acid
The metabolism of valproic acid is complex and thought to involve three phases including extensive UGT glucuronidation (UGT1A6, 1A9, 2B7), mitochondrial β-oxidation and minimal CYP metabolism.75–77 Therefore, medications known to inhibit or induce UGT enzymes can alter serum concentrations of valproic acid. Sheehan and colleagues report a case of a patient with mood disorder, hepatitis C and HIV. The patient was maintained on valproic acid for seven months following a manic episode. After initiating a HAART regimen including lamivudine, zidovudine, ritonavir and lopinavir, the patient became increasingly manic and was admitted to a psychiatric facility. The valproic acid level was found to be 48% lower than the previous concentrations, with no recent change in valproic acid dosing. The patient was treated with olanzapine through the manic episode and the valproic acid dose was increased to reach therapeutic range.77 Clinicians are cautioned to carefully monitor valproic acid serum concentrations upon starting or stopping an agent known to either induce or inhibit UGT metabolism. The NIH guidelines also note that lopinavir AUC is increased by approximately 75% with concomitant valproic acid. Therefore, patients should also be monitored for virologic response and signs of lopinavir related toxicity with coadministration.22
In addition to being a substrate of UGT metabolism, valproic acid also induces UGT2B7 and CYP2C9, which may interact with zidovudine as it is metabolized by UGT2B7.7879 Coadministration of zidovudine and valproic acid in a pharmacokinetic study, resulted in a two-fold increase in the zidovudine AUC. In addition, the amount of unconjugated zidovudine excreted in the urine increased approximately 50%.78 In a case report by Antoniou and colleagues, an HIV-infected patient was taking an HIV regimen including zidovudine as well as an anticonvulsant regimen including carbamazepine. After valproic acid was added, the patient presented to the emergency department after experiencing a seizure and had a hemoglobin/hematocrit of 2.2 g/dL and 6.3%, respectively. Prior to initiating the valproic acid, the patient's hemoglobin was 12.6 g/dL and his hematocrit was 30.6%. A thorough work-up did not identify a source of bleeding and no evidence of hemolysis. The patient was transfused with 4 units of blood and his HAART was discontinued. His hemoglobin returned to normal after four weeks and HAART was resumed with stavudine as opposed to lamivudine, as this agent does not undergo UGT glucuronidation. The authors conclude that the interaction between zidovudine and valproic acid resulted in increased patient exposure to zidovudine which increased the bone-marrow suppression side effects of zidovudine. As the authors conclude, stavudine may be a suitable alternative when valproic acid must be used with a nucleoside analogue.79
Carbamazepine
Carbamazepine is both a substrate and potent inducer of CYP3A4. The use of carbamazepine is generally contraindicated with antiretroviral agents that are substrates for CYP3A4, such as rilpivirine, delavirdine, etravirine, efavirenz, nevirapine and maraviroc due to the risk of decreased plasma concentrations of the antiretrovirals, increasing the risk of loss of virologic response and development of resistance to HIV therapy.80 When coadministration of maraviroc and carbamazepine is unavoidable, the NIH guidelines recommend increasing the maraviroc dose to 600 mg by mouth twice daily.22 The use of concomitant efavirenz and carbamazepine in particular is more complex as efavirenz is also an inducer of CYP3A4. In a pharmacokinetic, cross-over trial, 36 healthy adult participants took either efavirenz 600 mg daily for 14 days or carbamazepine 400 mg daily for 21 days. Those taking efavirenz also received increasing doses of carbamazepine on day 15 through 35, while patients taking carbamazepine took concomitant efavirenz starting day 22 to day 35. The addition of carbamazepine at efavirenz steady state reduced the AUC and Cmax of efavirenz. Likewise, the addition of efavirenz to steady state carbamazepine resulted in a reduction of the carbamazepine AUC and Cmax.81 NIH guidelines warn that the carbamazepine AUC is reduced by 27% and efavirenz AUC is reduced by 36% when the medications are coadministered. When the combination cannot be avoided, carbamazepine levels should be monitored frequently and patients should be monitored for signs of carbamazepine and efavirenz efficacy.22
Carbamazepine should also be avoided with concomitant PI therapy whenever possible, as carbamazepine may induce CYP3A4 enzymes causing increased PI exposure and pronounced adverse effects of these agents. Additionally, inhibition of CYP3A4 by PIs may potentially result in toxic carbamazepine concentrations. The potential for carbamazepine toxicity exists for all PIs, and carbamazepine concentrations should be monitored closely when any PI is added to a HAART regimen. Since ritonavir is the most potent inhibitor of CYP3A4, the magnitude of carbamazepine inhibition anticipated should be higher than moderate CYP3A4 inhibitors (indinavir and nelfinavir), or mild inhibitor (saquinavir).82
Carbamazepine toxicity with the coadministration of ritonavir is well documented,82–86 with the combination resulting in symptoms including vertigo, drowsiness, ataxia and vomiting. Bates and colleagues documented this drug interaction in a patient initiated on a HAART regimen including ritonavir who had previously been maintained on carbamazepine. The patient developed extreme drowsiness and elevated carbamazepine levels nine days after the initiation of ritonavir. The patient's carbamazepine dose was decreased from 400 mg three times daily to 400 mg twice daily. However, on day 12 of ritonavir-based HAART therapy, the patient presented to the hospital with extreme fatigue, difficulty swallowing and diffuse hemorrhagic lesions on extremities. Upon further examination, he was found to have pancytopenia with WBC 1.3 (103/mm3), hemoglobin 6.7 (g/dL) and platelets of 112 (103/mm3). As a result, the patient was switched to topiramate and HAART regimen changed to tenofovir, lamivudine, and nelfinavir. The patient's symptoms did not completely resolve until day 70.82 The authors concluded the patient experienced CNS toxicity, rash, and profound bone-marrow suppression due to ritonavir inhibition of carbamazepine metabolism. Based on this case report, the authors recommended a 25 – 50% carbamazepine dose reduction when starting a patient on a PI with careful carbamazepine serum concentration thereafter. Similar recommendations have been made by other case reports, although some clinicians chose to discontinue the use of carbamazepine completely.83–86
In general, the combination of carbamazepine and PI therapy should be avoided due to the risk of PI therapy failure secondary to carbamazepine induction of CYP3A4, as well as the risk of carbamazepine toxicity. When the combination of PI and carbamazepine therapy is unavoidable, monitoring plasma concentrations of both medications is recommended.22 Additionally, monitoring the patient for signs of virologic response and carbamazepine toxicity is encouraged. Of note, ritonavir-boosted darunavir seems to be least affected by carbamazepine therapy. Concomitant use with carbamazepine resulted in 45% increase in the carbamazepine concentrations with no significant change in darunavir concentrations.22 Likewise, clinicians may choose to boost atazanavir and fosamprenavir with ritonavir to overcome the PI reduction with concomitant carbamazepine use, but should carefully monitor the patient for carbamazepine toxicity.22 Finally, patients taking ritonavir-boosted lopinavir are not candidates for once daily dosing when taking concomitant carbamazepine because of the substantial decrease exhibited in the PI plasma concentrations.22
SUMMARY
Drug-drug interactions with HAART therapy often complicate treatment of psychiatric illnesses in HIV-infected patients. Of the antiretroviral agents used in the management of HIV, PIs and NNRTIs are most likely to be involved with interactions, with the majority occurring via the CYP450 system. These interactions can result in either increased or decreased exposure to psychotropic and antiretroviral medications, often warranting dosage adjustments and increased monitoring. In general, most psychotropic medications should be started at the lowest effective dose and titrated based on patient response. As psychotropic therapy has demonstrated increased quality of life and improved adherence in HIV-infected patients, it is imperative that these interactions are proactively sought out and prevented.