Psychiatric Treatment Considerations With Direct Acting Antivirals in Hepatitis C

Sanjeev Sockalingam; Alice Tseng; Pierre Giguere; David Wong


BMC Gastroenterol. 2013;13(86) 

In This Article


Treatment of hepatitis C virus (HCV), a virus infecting over 170 million worldwide,[1] has evolved over the last two decades and moved from interferon-alpha monotherapy to pegylated interferon-alpha (IFNα) in combination with ribavirin therapy. HCV therapy with IFNα and ribavirin has yielded overall sustained virological response (SVR) rates of approximately 54% to 56% with SVR rates for genotype 1 approximating 45% to 50%.[2,3] The next generation of HCV therapeutic agents is direct acting antivirals (DAAs) that still require the use of interferon-ribavirin combination therapy. Protease inhibitors, specifically telaprevir or boceprevir, in combination with IFNα and ribavirin (i.e. triple therapy) have improved SVR rates to 70% to 75% in HCV genotype 1 patients.[4,5]

Despite these enhanced SVR rates, psychiatric illness remains a barrier to widespread HCV treatment uptake due to the neuropsychiatric risks associated with IFNα. It is estimated that up to 50% of patients with untreated chronic HCV suffer from psychiatric illness when substance abuse and dependence is excluded.[6,7] Lifetime rates of mood, anxiety and personality disorders in untreated HCV-infected patients have each ranged from approximately 20% to 40%.[6,7] Treatment with pegylated interferon-alpha (IFNα) therapy can induce a myriad of neuropsychiatric side effects including depression in approximately 25% to 30% of patients undergoing IFNα therapy for HCV.[8–11] In addition, HCV-infected patients with pre-existing psychiatric disorders may experience an exacerbation of psychopathology secondary to IFNα.

Poorly managed psychiatric illness can lead to treatment discontinuation, poor adherence to treatment and serious psychiatric sequalae, such as suicide.[12,13] The onset of suicidal ideation and suicide on HCV therapy coincides with the onset of IFNα-induced depression (IFNα-D) and requires prompt recognition and treatment to prevent these serious psychiatric sequelae.[12,14] Integrated Hepatology-Psychiatric care models have demonstrated the capacity to mitigate neuropsychiatric risks associated with HCV therapy through improved access to psychiatric and psychological interventions.[15,16]

In the era of DAAs, adherence is paramount to treatment success given the strict dosing regimen of first generation HCV protease inhibitors (PIs). First generation DAAs have high pill burdens and frequent dosing intervals. Active depression has been associated with poor antiviral therapy (ART) in patients infected with human immunodeficiency virus (HIV).[17] Therefore, it is possible that poorly controlled psychiatric illness may compromise adherence to PI dosing schedules and as a result, reduce HCV treatment efficacy. Similar to the advent of HIV ART, first generation DAAs have also presented concerns regarding drug-drug interactions (DDIs) with medications including several psychotropic medications. Given the high prevalence of psychiatric illness in HCV-infected patients and need for psychotropic treatments for IFNα-induced neuropsychiatric side effects, an understanding of salient DDIs involving psychotropic medications is essential to the clinical care of patients treated for HCV.

With respect to DDIs, both boceprevir and telaprevir are substrates and inhibitors of CYP3A4.[18,19] Both agents also inhibit p-glycoprotein[18,19] and telaprevir may inhibit renal transporters.[20] Approximately 50% to 60% of available prescription medications are metabolized via CYP3A4 pathway.[21,22] Moreover, preliminary HCV data suggests that in clinical practice, 72% of patients had at least one DDI and 50% had at least two DDIs related to DAAs.[23] Therefore, there is a high potential for DDIs with HCV protease inhibitors, particularly if treatment for other comorbid conditions is necessary.

Interactions may be pharmacokinetic or pharmacodynamic in nature. Pharmacodynamic interactions impact drug efficacy or toxicity in an additive, synergistic or antagonistic manner. For instance, pegylated interferon and ribavirin have CNS effects that overlap with those of the antiretroviral regimens involving efavirenz; co-administration may theoretically contribute to adverse effects including depression, mood changes, and suicidality. Clinicians may therefore wish to avoid this combination if possible, particularly in patients with a history of significant mental illness.

Pharmacokinetic interactions may result in altered concentrations of one or more interacting drugs. Negative two-way interactions have been observed between both boceprevir and telaprevir and ritonavir-boosted HIV protease inhibitors, with significant reductions in exposures of HCV agents and HIV protease inhibitors; therefore, telaprevir should not be coadministered with ritonavir-boosted darunavir, fosamprenavir, or lopinavir[18] and boceprevir is not recommended for use with any boosted protease inhibitor.[24]

Negative consequences of drug interactions may include viral breakthrough and development of resistance, sub-optimal disease/symptom management, or drug toxicity and possible non-adherence.[25] These interactions highlight the challenges of managing multiple comorbidities in patients with HCV infection.

The purpose of this review was to evaluate the current evidence on: (i) the neuropsychiatric adverse effects of DAAs, and (ii) the DDIs between DAAs and psychotropic agents when used in HCV patients.