Psychiatric Treatment Considerations With DAAs in HCV
Psychiatric Treatment Considerations With DAAs in HCV
Data on neuropsychiatric adverse effects of DAAs is limited and predominantly derived from landmark clinical trials for boceprevir and telaprevir (see Table 1). Across trials, there was no significant difference in neuropsychiatric side effects between DAAs and treatment with peg- IFNα and ribavirin alone. It should be noted that the rates of neuropsychiatric sequalae from DAAs may be an underestimate, as patients with significant psychiatric illness were excluded from these studies and detection of psychiatric side effects did not utilize formal psycho-diagnostic tools. Only one study published data on anxiety during triple therapy and found a comparable reported rate of anxiety in patients treated with triple therapy (10%) versus standard therapy alone (12%). Although studies focusing specifically on psychiatric complications of DAAs are lacking, this preliminary data suggests that DAAs confer a minimal risk of additional neuropsychiatric side effects.
Antidepressants are used primarily in the treatment of depression and anxiety in both untreated HCV patients and patients undergoing IFNα therapy for HCV. Studies have explored the use of antidepressants in HCV as both prophylactic (i.e. antidepressant pre-treatment) and symptomatic treatment for IFNα-D. Two recent guidelines have specifically identified management of IFNα-D and provided recommendations for antidepressant therapy in HCV-infected patients (see Table 2). Based upon these guidelines and previous reviews, only escitalopram currently has Level 1 evidence for treating or preventing depression emerging during HCV treatment.
Anxiety secondary to IFNα can also be treated with antidepressants, which are a first line treatment based upon the limited available literature (Level 4). Escitalopram and citalopram may be beneficial options in treating anxiety disorders in HCV based upon the anecdotal reports of safety in HCV and extrapolation of evidence from non-HCV anxiety treatment guidelines. Clinicians should be aware of the potential risk of dose-related QT prolongation with citalopram and escitalopram. The maximum recommended dose is citalopram 20 mg per day in patients with hepatic impairment, those 65 years of age or older, patients who are CYP2C19 poor metabolizers, or patients who are taking concomitant cimetidine or another CYP2C19 inhibitor. In some countries, such as Canada, the maximum recommended dose for escitalopram in patients with hepatic impairment is 10 mg per day due to QT prolongation concerns.
Drug interactions between DAAs and some antidepressants, specifically those affected by CYP 450 interactions of PIs, may lead to clinically significant adverse effects which impact tolerability to therapy for HCV. For example, SSRIs and Selective Noradrenergic Reuptake Inhibitors (SNRIs) can be associated with nausea, gastrointestinal upset, sweating and sexual dysfunction, which could emerge with PI related drug interactions.
Specific drug interactions with antidepressants and DAAs are summarized in Table 2. In a single study involving telaprevir, escitalopram area under the curve (AUC) was reduced by 35%, suggesting the need for clinicians to monitor the need for dose optimization on triple therapy. No significant DDI has been observed between escitalopram and boceprevir. Specific antidepressants, for example trazodone, that have a high sedative potential and potential for DDIs with DAAs can lead to increased sedation and may impact overall tolerability and compliance to both agents. Therefore, the selection of antidepressant agents during HCV therapy should include consideration of potential DDIs, in order to avoid possible adverse effects, which may negatively affect HCV antiviral treatment adherence. Clinicians should also be aware that St. John's Wort is a potent inducer of CYP3A4 and P-gp, and is contraindicated with DAAs due to the potential risk for significant reductions in boceprevir or telaprevir concentrations.
Benzodiazepines may be a treatment option for anxiety symptoms in the context of HCV or secondary to IFNα; however, no large trials have examined the efficacy of anxiolytics in HCV. Anecdotally, benzodiazepines have also been used short-term for insomnia in HCV-infected patients. Furthermore, the prevalence of substance dependence in HCV patients has cautioned the use of benzodiazepines in this patient population. In general, short-acting benzodiazepines should be avoided due to potential rebound effect on anxiety and long-term benzodiazepine use may lead to tolerance and dependence.
If benzodiazepines are used, lorazepam, oxazepam or temazepam are preferred due to the reliance on glucuronidation, a process that is relatively preserved in patients with significant liver disease. Furthermore, these three agents are the least susceptible to pharmacokinetic interactions with DAAs since they are not metabolized through the cytochrome P450 system. Most other benzodiazepine agents undergo metabolism solely or partially through CYP3A4, and thus concentrations may be increased by DAAs via CYP3A4 inhibition. Triazolam and oral midazolam are contraindicated with boceprevir and telaprevir, due to hypothesized or documented significant interactions. When administered orally, midazolam exposures were increased 430% in the presence of boceprevir and almost 9-fold in the presence of telaprevir. Intravenous midazolam concentrations increased 3.4-fold when co-administered with telaprevir. Thus, while intravenous midazolam is not absolutely contraindicated with PIs, it is recommended that this combination be administered with caution in a setting which allows for close clinical monitoring for prolonged sedation and/or respiratory depression, and that dose adjustment of intravenous midazolam should be considered.
Zolpidem is metabolized through a variety of CYP450 isozymes, including CYP3A, 2C9, 1A2, 2D6, and 2C19. In the presence of steady-state telaprevir, zolpidem exposures were unexpectedly reduced by 47%. Close monitoring and dose titration of zolpidem is recommended if this agent is coadministered with telaprevir. Zopiclone is also metabolized predominantly by CYP3A4 and to a lesser degree by CYP2C8 and CYP2C9. Zopiclone concentrations may theoretically be increased by DAAs and require close monitoring. Most other benzodiazepines should be used cautiously in patients on DAAs. Clinicians may consider starting with a decreased benzodiazepine dose and monitoring for benzodiazepine-related toxicity, or selecting an alternate agent such as lorazepam, oxazepam or temazepam. Dose reductions are also recommended in patients with severe liver impairment as per product monographs.
Anticonvulsants can be used as mood stabilizers for new onset or de-stabilized bipolar disorder during IFNα therapy for HCV. Studies on the efficacy of anticonvulsants as moodstabilizers in HCV are limited to case reports and as a result, treatment often follows non-HCV bipolar treatment guidelines.
Lithium is a preferred moodstabilizer due its renal excretion and minimal dose adjustment in patients with HCV except in patients with shifting fluid balance resulting from decompensated cirrhosis. Lithium has no known drug interactions with DAAs. Valproic acid has no significant DDIs with DAAs; however, valproic acid use in HCV has been limited by its purported risk of hepatotoxicity. Nonetheless, in a study of patients with less severe HCV disease, elevations in alanine aminotransferase (ALT) were comparable between valproic acid and other psychotropic agents.
Amongst the remaining moodstabilizers, carbamazepine is contraindicated due to induction of cytochrome P450 3A4 and potential for decreasing boceprevir or telaprevir levels (see Table 3). Lamotrigine undergoes extensive metabolism by UDP-glucuronosyltransferase (UGT) 1A4. This metabolic pathway is not inhibited or induced by boceprevir or telaprevir. Lamotrigine has been associated with severe rash, including Steven's Johnson rash. Given that DAAs, particularly telaprevir, have also been associated with severe rashes, it is recommended to use extra precautions if coadministration is required. Gabapentin and pregabalin are not effective moodstabilizers for bipolar disorder in monotherapy; however, based upon data from non-HCV populations pregabalin and gabapentin can be efficacious in treating co-morbid generalized anxiety disorder (GAD) in HCV. Both pregabalin and gabapentin have no significant drug interactions with HCV triple therapy involving DAAs as they are both predominantly renally excreted. Table 3 provides a summary of anticonvulsant drug interactions with DAAs.
Antipsychotic medications can be used during HCV therapy to stabilize pre-existing mood or psychotic disorders in patients or to treat IFNα-induced mood or psychotic symptoms secondary. Patients with severe mental illness, such as schizophrenia and bipolar disorder have been shown to have higher rates of HCV compared to the general population and thus, it may not be uncommon to treat patients with HCV who are already treated with antipsychotic medications for severe mental illness. Albeit rare, antipsychotic medications may be used to treat de novo secondary to IFNα. In addition, atypical antipsychotics can be used for mood stabilization and irritability emerging during HCV therapy.
Several DDIs and side effects should be considered when prescribing antipsychotic medication in the context of HCV triple therapy (see Table 4). Telaprevir and boceprevir may interact with antipsychotics prone to corrected QT (QTc) interval prolongation and elevations in plasma levels could increase QTc prolongation risk. As a result, pimozide, a conventional antipsychotic with a high propensity for QTc prolongation, is contraindicated when treating patients with boceprevir and telaprevir. Amongst the atypical antipsychotics, ziprasidone, which is metabolized by CYP 3A4, is associated with an increased QTc prolongation risk amongst novel antipsychotics. Initiation of ziprasidone should include a baseline electrocardiogram (ECG) and this may need to be reassessed on triple therapy for HCV due to DDI.
Several antipsychotics are metabolized via CYP3A4/5, which are inhibited by current DAAs. Sedating antipsychotics that are metabolized by CYP3A4, such as quetiapine, may be increased via DDIs secondary to DAAs and could result in more pronounced sedation that could hinder compliance with multiple daily dosing regimens of DAAs. Clozapine is also metabolized in part by CYP3A4 and clozapine levels should be monitored closely during HCV triple therapy as higher doses of clozapine have been associated with an increased adverse effects including seizures. Treatment with clozapine is further complicated during HCV therapy due to additive theoretical risks of agranulocytosis and neutropenia related specifically to IFNα effects. Therefore, clozapine monitoring protocols may need to be adjusted due to this risk and vigilant follow-up monitoring for signs of infection is recommended.
Lastly, DAAs are known inhibitors of P-gp and many second generation antipsychotics are substrates of P-gp. In theory, inhibition of P-gp may lead to increased exposure of the antipsychotic in the CSF, and may be associated with enhanced effectiveness or toxicity. Despite the absence of documented metabolic drug interactions, caution is to be exercised with known substrates of P-gp (quetiapine, risperidone, olanzapine) and DAAs.
Given the higher rates of substance dependence in HCV-infected patient populations compared to the general population, treatment of concurrent substance use disorders, either through harm reduction or abstinence based models, is an important component of pre-HCV therapy stabilization. To date, no studies have determined if the addition of DAAs to HCV treatment increased the risk of substance use relapse.
In some HCV-infected populations, methadone treatment is a core component of HCV treatment stabilization in patients at risk of opioid and polysubstance dependence. Methadone is metabolized by CYP2C19 and 3A4. The coadministration of methadone and telaprevir was shown to result in a 21% decrease of the active enantiomer R-methadone exposure. However, free concentrations of R-methadone were unaffected and therefore no dosage adjustment is necessary. Buprenorphine pharmacokinetics are not affected by telaprevir and is safe for coadministration. Boceprevir was studied with methadone, buprenorphine and naloxone. Similar to telaprevir, boceprevir led to a 15% decrease of R-methadone exposure. No free methadone concentrations were performed. Boceprevir was also associated with an increase of naloxone and buprenorphine exposure by 19 and 33% respectively, which is considered to be clinically non-significant.
Results
Neuropsychiatric Side Effects of DAAs
Data on neuropsychiatric adverse effects of DAAs is limited and predominantly derived from landmark clinical trials for boceprevir and telaprevir (see Table 1). Across trials, there was no significant difference in neuropsychiatric side effects between DAAs and treatment with peg- IFNα and ribavirin alone. It should be noted that the rates of neuropsychiatric sequalae from DAAs may be an underestimate, as patients with significant psychiatric illness were excluded from these studies and detection of psychiatric side effects did not utilize formal psycho-diagnostic tools. Only one study published data on anxiety during triple therapy and found a comparable reported rate of anxiety in patients treated with triple therapy (10%) versus standard therapy alone (12%). Although studies focusing specifically on psychiatric complications of DAAs are lacking, this preliminary data suggests that DAAs confer a minimal risk of additional neuropsychiatric side effects.
Antidepressant Use With DAAs
Antidepressants are used primarily in the treatment of depression and anxiety in both untreated HCV patients and patients undergoing IFNα therapy for HCV. Studies have explored the use of antidepressants in HCV as both prophylactic (i.e. antidepressant pre-treatment) and symptomatic treatment for IFNα-D. Two recent guidelines have specifically identified management of IFNα-D and provided recommendations for antidepressant therapy in HCV-infected patients (see Table 2). Based upon these guidelines and previous reviews, only escitalopram currently has Level 1 evidence for treating or preventing depression emerging during HCV treatment.
Anxiety secondary to IFNα can also be treated with antidepressants, which are a first line treatment based upon the limited available literature (Level 4). Escitalopram and citalopram may be beneficial options in treating anxiety disorders in HCV based upon the anecdotal reports of safety in HCV and extrapolation of evidence from non-HCV anxiety treatment guidelines. Clinicians should be aware of the potential risk of dose-related QT prolongation with citalopram and escitalopram. The maximum recommended dose is citalopram 20 mg per day in patients with hepatic impairment, those 65 years of age or older, patients who are CYP2C19 poor metabolizers, or patients who are taking concomitant cimetidine or another CYP2C19 inhibitor. In some countries, such as Canada, the maximum recommended dose for escitalopram in patients with hepatic impairment is 10 mg per day due to QT prolongation concerns.
Drug interactions between DAAs and some antidepressants, specifically those affected by CYP 450 interactions of PIs, may lead to clinically significant adverse effects which impact tolerability to therapy for HCV. For example, SSRIs and Selective Noradrenergic Reuptake Inhibitors (SNRIs) can be associated with nausea, gastrointestinal upset, sweating and sexual dysfunction, which could emerge with PI related drug interactions.
Specific drug interactions with antidepressants and DAAs are summarized in Table 2. In a single study involving telaprevir, escitalopram area under the curve (AUC) was reduced by 35%, suggesting the need for clinicians to monitor the need for dose optimization on triple therapy. No significant DDI has been observed between escitalopram and boceprevir. Specific antidepressants, for example trazodone, that have a high sedative potential and potential for DDIs with DAAs can lead to increased sedation and may impact overall tolerability and compliance to both agents. Therefore, the selection of antidepressant agents during HCV therapy should include consideration of potential DDIs, in order to avoid possible adverse effects, which may negatively affect HCV antiviral treatment adherence. Clinicians should also be aware that St. John's Wort is a potent inducer of CYP3A4 and P-gp, and is contraindicated with DAAs due to the potential risk for significant reductions in boceprevir or telaprevir concentrations.
Benzodiazepine and Hypnotic Use With DAAs
Benzodiazepines may be a treatment option for anxiety symptoms in the context of HCV or secondary to IFNα; however, no large trials have examined the efficacy of anxiolytics in HCV. Anecdotally, benzodiazepines have also been used short-term for insomnia in HCV-infected patients. Furthermore, the prevalence of substance dependence in HCV patients has cautioned the use of benzodiazepines in this patient population. In general, short-acting benzodiazepines should be avoided due to potential rebound effect on anxiety and long-term benzodiazepine use may lead to tolerance and dependence.
If benzodiazepines are used, lorazepam, oxazepam or temazepam are preferred due to the reliance on glucuronidation, a process that is relatively preserved in patients with significant liver disease. Furthermore, these three agents are the least susceptible to pharmacokinetic interactions with DAAs since they are not metabolized through the cytochrome P450 system. Most other benzodiazepine agents undergo metabolism solely or partially through CYP3A4, and thus concentrations may be increased by DAAs via CYP3A4 inhibition. Triazolam and oral midazolam are contraindicated with boceprevir and telaprevir, due to hypothesized or documented significant interactions. When administered orally, midazolam exposures were increased 430% in the presence of boceprevir and almost 9-fold in the presence of telaprevir. Intravenous midazolam concentrations increased 3.4-fold when co-administered with telaprevir. Thus, while intravenous midazolam is not absolutely contraindicated with PIs, it is recommended that this combination be administered with caution in a setting which allows for close clinical monitoring for prolonged sedation and/or respiratory depression, and that dose adjustment of intravenous midazolam should be considered.
Zolpidem is metabolized through a variety of CYP450 isozymes, including CYP3A, 2C9, 1A2, 2D6, and 2C19. In the presence of steady-state telaprevir, zolpidem exposures were unexpectedly reduced by 47%. Close monitoring and dose titration of zolpidem is recommended if this agent is coadministered with telaprevir. Zopiclone is also metabolized predominantly by CYP3A4 and to a lesser degree by CYP2C8 and CYP2C9. Zopiclone concentrations may theoretically be increased by DAAs and require close monitoring. Most other benzodiazepines should be used cautiously in patients on DAAs. Clinicians may consider starting with a decreased benzodiazepine dose and monitoring for benzodiazepine-related toxicity, or selecting an alternate agent such as lorazepam, oxazepam or temazepam. Dose reductions are also recommended in patients with severe liver impairment as per product monographs.
Anticonvulsant Use With DAAs
Anticonvulsants can be used as mood stabilizers for new onset or de-stabilized bipolar disorder during IFNα therapy for HCV. Studies on the efficacy of anticonvulsants as moodstabilizers in HCV are limited to case reports and as a result, treatment often follows non-HCV bipolar treatment guidelines.
Lithium is a preferred moodstabilizer due its renal excretion and minimal dose adjustment in patients with HCV except in patients with shifting fluid balance resulting from decompensated cirrhosis. Lithium has no known drug interactions with DAAs. Valproic acid has no significant DDIs with DAAs; however, valproic acid use in HCV has been limited by its purported risk of hepatotoxicity. Nonetheless, in a study of patients with less severe HCV disease, elevations in alanine aminotransferase (ALT) were comparable between valproic acid and other psychotropic agents.
Amongst the remaining moodstabilizers, carbamazepine is contraindicated due to induction of cytochrome P450 3A4 and potential for decreasing boceprevir or telaprevir levels (see Table 3). Lamotrigine undergoes extensive metabolism by UDP-glucuronosyltransferase (UGT) 1A4. This metabolic pathway is not inhibited or induced by boceprevir or telaprevir. Lamotrigine has been associated with severe rash, including Steven's Johnson rash. Given that DAAs, particularly telaprevir, have also been associated with severe rashes, it is recommended to use extra precautions if coadministration is required. Gabapentin and pregabalin are not effective moodstabilizers for bipolar disorder in monotherapy; however, based upon data from non-HCV populations pregabalin and gabapentin can be efficacious in treating co-morbid generalized anxiety disorder (GAD) in HCV. Both pregabalin and gabapentin have no significant drug interactions with HCV triple therapy involving DAAs as they are both predominantly renally excreted. Table 3 provides a summary of anticonvulsant drug interactions with DAAs.
Antipsychotic Use With DAAs
Antipsychotic medications can be used during HCV therapy to stabilize pre-existing mood or psychotic disorders in patients or to treat IFNα-induced mood or psychotic symptoms secondary. Patients with severe mental illness, such as schizophrenia and bipolar disorder have been shown to have higher rates of HCV compared to the general population and thus, it may not be uncommon to treat patients with HCV who are already treated with antipsychotic medications for severe mental illness. Albeit rare, antipsychotic medications may be used to treat de novo secondary to IFNα. In addition, atypical antipsychotics can be used for mood stabilization and irritability emerging during HCV therapy.
Several DDIs and side effects should be considered when prescribing antipsychotic medication in the context of HCV triple therapy (see Table 4). Telaprevir and boceprevir may interact with antipsychotics prone to corrected QT (QTc) interval prolongation and elevations in plasma levels could increase QTc prolongation risk. As a result, pimozide, a conventional antipsychotic with a high propensity for QTc prolongation, is contraindicated when treating patients with boceprevir and telaprevir. Amongst the atypical antipsychotics, ziprasidone, which is metabolized by CYP 3A4, is associated with an increased QTc prolongation risk amongst novel antipsychotics. Initiation of ziprasidone should include a baseline electrocardiogram (ECG) and this may need to be reassessed on triple therapy for HCV due to DDI.
Several antipsychotics are metabolized via CYP3A4/5, which are inhibited by current DAAs. Sedating antipsychotics that are metabolized by CYP3A4, such as quetiapine, may be increased via DDIs secondary to DAAs and could result in more pronounced sedation that could hinder compliance with multiple daily dosing regimens of DAAs. Clozapine is also metabolized in part by CYP3A4 and clozapine levels should be monitored closely during HCV triple therapy as higher doses of clozapine have been associated with an increased adverse effects including seizures. Treatment with clozapine is further complicated during HCV therapy due to additive theoretical risks of agranulocytosis and neutropenia related specifically to IFNα effects. Therefore, clozapine monitoring protocols may need to be adjusted due to this risk and vigilant follow-up monitoring for signs of infection is recommended.
Lastly, DAAs are known inhibitors of P-gp and many second generation antipsychotics are substrates of P-gp. In theory, inhibition of P-gp may lead to increased exposure of the antipsychotic in the CSF, and may be associated with enhanced effectiveness or toxicity. Despite the absence of documented metabolic drug interactions, caution is to be exercised with known substrates of P-gp (quetiapine, risperidone, olanzapine) and DAAs.
Addictions Agents With DAAs
Given the higher rates of substance dependence in HCV-infected patient populations compared to the general population, treatment of concurrent substance use disorders, either through harm reduction or abstinence based models, is an important component of pre-HCV therapy stabilization. To date, no studies have determined if the addition of DAAs to HCV treatment increased the risk of substance use relapse.
In some HCV-infected populations, methadone treatment is a core component of HCV treatment stabilization in patients at risk of opioid and polysubstance dependence. Methadone is metabolized by CYP2C19 and 3A4. The coadministration of methadone and telaprevir was shown to result in a 21% decrease of the active enantiomer R-methadone exposure. However, free concentrations of R-methadone were unaffected and therefore no dosage adjustment is necessary. Buprenorphine pharmacokinetics are not affected by telaprevir and is safe for coadministration. Boceprevir was studied with methadone, buprenorphine and naloxone. Similar to telaprevir, boceprevir led to a 15% decrease of R-methadone exposure. No free methadone concentrations were performed. Boceprevir was also associated with an increase of naloxone and buprenorphine exposure by 19 and 33% respectively, which is considered to be clinically non-significant.
