New HCV protease inhibitors interact with a wide range of drugs used in treatment of psychiatric conditions

Recently licensed direct-acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) infection do not pose a significant risk of psychiatric side-effects but have several important interactions with drugs used to treat mental health problems, an article published in BMC Gastroenterology shows.

A review of data from clinical trials indicated that the anti-HCV protease inhibitors telaprevir (Incivek or Incivo) and boceprevir (Victrelis) did not add to the psychiatric adverse-event profile of existing HCV therapy. However, the investigators identified several significant interactions between the protease inhibitors and a number of antidepressants, benzodiazepines, anticonvulsants and antipsychotics. 

“DAAs do not appear to confer additional neuropsychiatric risks to patients undergoing HCV triple therapy,” write the authors. “The potential for clinically significant and complex interactions between DAAs and psychotropic drug classes is high.”

Telaprevir and boceprevir were recently approved for the treatment of HCV infection in combination with pegylated interferon and ribavirin after clinical trials showed they increased the proportion of people achieving a sustained virological response (SVR). However, pegylated interferon remains a mainstay of HCV therapy and is associated with significant neuropsychiatric side-effects, especially depression. This can lead to treatment discontinuation, poor adherence and serious psychiatric outcomes.

A team of Canadian investigators therefore wished to see if the new DAAs caused additional psychiatric complications.

The investigators also noted that both telaprevir and boceprevir are metabolised via the cytochrome P450 enzyme, a pathway used by approximately 50 to 60% of prescription medications. They therefore wished to identify possible interactions between the new DAAs and commonly used psychotropic medications.

Data concerning potential side-effects and interactions were obtained from published studies, conference abstracts and the drugs’ manufacturers.

There were limited data concerning the neuropsychiatric side-effects of DAAs. However, results from the registration trials showed that there were no significant differences in rates of neuropsychiatric adverse events between people treated with DAAs plus standard therapy and people taking pegylated interferon/ribavirin alone.

However, the authors note “rates of neuropsychiatric sequalae from DAAs may be an underestimated” due to the exclusion of people with significant psychiatric illnesses from clinical trials.

Nevertheless, they believe that preliminary data “suggests that DAAs confer a minimal risk of additional neuropsychiatric side effects.”

Potential interactions were identified with drugs in all the major classes of psychotropic medications.

The investigators recommended that, due to the risk of interactions, the use of duloxetine, nefazodone and St John’s wort should be avoided.

Caution and monitoring are recommended for sertraline, mirtazapine, venlafaxine and tricyclic antidepressants. Monitoring and possible dose adjustments are recommended for escitalopram, citalopram, bupropion, desvenlafaxine and nortriptyline.

“Selection of antidepressant agents during HCV therapy should include consideration of potential [drug interactions], in order to avoid possible adverse effects, which may negatively affect HCV antiviral treatment adherence,” comment the investigators.

If drugs in this class are used, the investigators recommend lorazepam, oxazepam and temazepam. These agents are safe for the liver and “are least susceptible to pharmacokinetic interactions with DAAs since they are not metabolised through the cytochrome P450 system.”

Lithium is the preferred mood stabiliser because it is secreted via the kidneys rather than the liver. Moreover, the drug has no known interactions with DAAs. Similarly, valproic acid has no significant interactions with DAAs, but its use in the context of HCV infection is limited because of its purported liver toxicity.

Carbamazepine is contradicted because it is processed using the P450 pathway.

Lamotrigine therapy is not recommended because of its association with rash, a known side-effect of DAAs.

Pregabalin and gabapentin are used as mood stabilisers and have no known interactions with DAAs.

Caution, careful baseline assessment, enhanced clinical monitoring and possible dose adjustment are recommended for most drugs in this class.

“Studies utilizing more detailed psychiatric assessment tools during HCV treatment with DAAs are needed to increase our understanding of DAA related psychiatric complications,” conclude the authors. “Additional drug interaction studies between DAAs and commonly used psychotropic agents are urgently needed.”