Psychiatric Care During Hepatitis C Treatment: The Changing Role of Psychiatrists in the Era of Direct-Acting Antivirals

Case Presentation

“Mr. K,” a 52-year-old single Caucasian man, was diagnosed with hepatitis C virus (HCV) infection nearly two decades ago after routine testing revealed an elevated alanine transaminase (ALT) level. Additional blood work identified an HCV genotype 1 infection with a viral load of 5.2×10⁶ IU/mL. While liver biopsy demonstrated cirrhosis, esophagogastroduodenoscopy showed no varices, and ultrasonography of the liver showed nodularity but no hepatocellular carcinoma. The patient’s only risk factor for HCV infection was a 1-month period of injection drug use (cocaine) 15 years earlier. Mr. K's psychiatric history was significant for a major depressive episode with psychotic features requiring hospitalization, 6 years before the HCV diagnosis. He had a history of alcohol dependence, consuming up to 75 drinks/week episodically over the 20 years preceding the HCV diagnosis. At the time of his admission for depression, he had not used alcohol for 3 months. For the next 6 years, he was treated with an antidepressant, at times in combination with an antipsychotic. After his diagnosis of HCV infection, he achieved abstinence from alcohol and was treated with citalopram (30 mg/day).

Three years after the HCV diagnosis, Mr. K started weekly pegylated interferon alfa-2B (IFN-α2B) injections and daily oral ribavirin for HCV infection. After the initial IFN-α injection, he experienced significant side effects, including excessive fatigue, nausea, fevers, and worsening mood symptoms. He decided to take his ribavirin every other day without notifying his care team. At week 6, his HCV therapy was stopped because of delirium caused by the interferon. After a brief hospital admission, his mental status returned to baseline and he was discharged, without modification of his psychiatric medication.

For the next 10 years, Mr. K was followed regularly for HCV infection by a hepatologist. Treatment was deferred because of the hepatologist's concerns about psychiatric side effects. After 10 years, Mr. K developed mild ascites, which was controlled with diuretics. At that time, his liver enzymes remained elevated and his liver function had declined. After attending a collaborative-care hepatology and psychiatry clinic, he was reassessed for interferon-based therapy. The clinic psychiatrist monitored Mr. K closely as IFN-α was initiated. Mr. K was started on boceprevir, pegylated IFN-α2A, and ribavirin, with the aim of completing 48 weeks of treatment. At week 2, he complained of fatigue and poor sleep, and mirtazapine (15 mg/day) was used to augment the citalopram. Despite attempts to further optimize the citalopram and mirtazapine dosages, Mr. K’s fatigue worsened. At week 22, he developed liver failure and presented to the emergency department with hepatic encephalopathy. HCV therapy was stopped and the patient’s mental status soon returned to baseline and his liver function improved.

For the next 3 years, Mr. K remained stable with early liver failure. Then, on the evening news, he heard about new treatments for HCV infection that do not require IFN-α, and he asked his psychiatrist and hepatologist about them. Simeprevir/sofosbuvir therapy was started, with a planned treatment duration of 12 weeks. Mr. K experienced mild nausea but no other side effects. He was followed weekly to monitor and encourage adherence to this once-daily two-pill regimen. He completed the full course and was confirmed to have sustained virological response. No adjustments to his psychiatric medications were needed, and his depressive symptoms remained stable throughout his treatment.

Discussion

Approximately 185 million people worldwide have chronic hepatitis C virus (HCV) infection (1), and persons with severe mental illness are a high-prevalence population (2). HCV is among the leading causes of hepatocellular cancer and need for liver transplant. Historically, the backbone of HCV treatment has been IFN-α and ribavirin, which are nonspecific immune boosters. The recent arrival of a new class of agents, direct-acting antivirals, has revolutionized HCV treatment. Direct-acting antivirals increase the likelihood of cure (referred to as “sustained virological response”) with a shorter duration of treatment and better side effect profile compared with previous HCV medications.

Patients with severe comorbid psychiatric illness, such as Mr. K, have historically been considered high risk for HCV treatment because of the significant neuropsychiatric side effects associated with IFN-α. Rates of IFN-α-induced depression range from 25% to 30%, and additional IFN-α-induced neuropsychiatric sequelae, such as anger or irritability, anxiety, mania or hypomania, psychosis, and suicidal ideation, pose additional concerns (3, 4). Mr. K is among the 50% of patients with HCV infection who have a history of psychiatric illness and the nearly 90% of patients who have a history of substance use disorders (5). Patients with psychiatric illness and substance use disorders have higher rates of not being treated for HCV infection (odds ratio for psychiatric illness, 9.45; odds ratio for a substance use disorder, 17.68) (6), despite the fact that their rates of treatment completion and sustained virological response are similar to those of patients without these comorbidities. As highlighted in this case, Mr. K experienced a delay in his HCV retreatment because of psychiatric concerns in the absence of integrated hepatology and mental health services.

Studies have demonstrated that collaborative models of care increase treatment access for marginalized patient populations with comorbid psychiatric disorders, including substance use disorders. These models have been configured with on-site infectious disease or hepatology support integrated with psychosocial supports, such as peer groups (7), psychiatrists (8), and mental health nurses (9). Patients with HCV who are injection drug users or are actively using other substances have shown higher rates of initiation of HCV treatment (up to 28%) and comparable rates of sustained virological response in these primary care settings with interdisciplinary support (7, 10). In these studies, HCV infection was treated with IFN-α, which clearly demonstrates that comorbid psychiatric illness is not a contraindication to IFN-α therapy. Although the introduction of direct-acting antivirals has decreased the psychiatric risks of treatment, the need for strict adherence has redefined the role of psychiatrists in collaborative care models in HCV care (see Table 1).

Impact of Direct-Acting Antivirals on Psychiatric Risk Evaluation

Direct-acting antivirals have substantially increased HCV treatment response rates and decreased the duration of exposure to IFN-α therapy or eliminated it entirely (response rates are summarized in Table 2) (11). The increasing proliferation of direct-acting antivirals for HCV treatment will require psychiatrists caring for these patients to consider these improved response rates in the risk-benefit stratification of individual patients.

Although studies specifically examining neuropsychiatric complications of treatment with direct-acting antivirals for HCV are lacking, few psychiatric side effects have been reported in clinical trials, and when these agents are used in combination with IFN-α therapy, no increase in depression or anxiety has been noted (12–15). Trials of simeprevir and sofosbuvir demonstrate lower rates of insomnia and fatigue as compared with rates from boceprevir and telaprevir (first-generation HCV protease inhibitors) and suggest that these new agents may be better tolerated (12–17). Compared with placebo, clinical trials for simeprevir did not show any significant difference in depression ratings during the course of clinical trials (12, 13). Moreover, an analysis of clinical trials of sofosbuvir showed a reduction in health-related quality of life during combination treatment with sofosbuvir, ribavirin, and pegylated IFN-α; however, data from a study of sofosbuvir without IFN-α showed that it was associated with significantly less impairment in health-related quality of life, comparable to placebo (18). Additionally, that study demonstrated that depression, fatigue, and insomnia were significant predictors of impairment of health-related quality of life both during and after HCV treatment. These results suggest that IFN-α-free HCV treatment regimens may be associated with reduced neuropsychiatric adverse effects, but pre-existing psychiatric issues may still affect tolerability of therapy, meaning that psychiatrists may move from being “gatekeepers” of HCV treatment to focusing more on engagement and supporting treatment adherence. Mr. K’s advancing liver disease and the potential benefits of HCV therapy seem to outweigh potential psychiatric risks.

Drug-Drug Interactions With Direct-Acting Antivirals

Psychiatrists involved in the care of HCV patients will need to have knowledge about potential drug-drug interactions based on the pharmacokinetic profile of direct-acting antivirals. The risk of drug-drug interactions will increase with the use of multiple agents, and particularly with the use of the class of agents that inhibit the viral protease (protease inhibitors) because they inhibit cytochrome P450 3A4. Comparable psychopharmacological challenges have been seen in HIV psychiatry with antiretroviral therapies.

A summary of drug-drug interactions related to boceprevir and telaprevir was published recently (19). In general, protease inhibitors, such as telaprevir, boceprevir, and simeprevir, inhibit cytochrome P450 3A4 to varying degrees, which could increase levels of psychotropic agents metabolized by this isoenzyme, and thus the dosage may need to be reduced. Carbamazepine can decrease levels of boceprevir, telaprevir, simeprevir, and sofosbuvir, which may reduce efficacy and make selection of resistant virus more likely. The use of this medication for bipolar illness should be reassessed or avoided during therapy with the current direct-acting antivirals (19). Given that psychiatric comorbidity is the rule rather than the exception, ongoing reassessment of psychiatric medications will be needed, and psychiatrists will need to be knowledgeable about potential drug-drug interactions with increasing use of direct-acting antivirals in HCV therapy.

Interventions Focusing on Improving HCV Treatment Adherence

Adherence to treatment is critical to the success of HCV therapy. Treatment is extremely costly; sofosbuvir has been marketed in the United States at a price of $84,000 per 12-week course of therapy. Moreover, failed therapy may select for resistant variants, affecting future treatment options. Psychiatrists’ assistance in managing adherence will be instrumental for many patients (20). Depression is a potential cause for nonadherence to medical treatment regimens, and given the high prevalence of depression among patients with HCV, optimization of depression treatment in this population is warranted before HCV treatment is initiated, with continued monitoring during treatment (21). Patients with severe mental illness may have additional challenges with adherence because of multiple daily dosing regimens, potential cognitive deficits, and limited social supports. Therefore, increased community supports, optimization of psychiatric regimens, and integrated models of care are needed to enhance adherence to HCV treatment regimens with direct-acting antivirals. Interprofessional and peer support models of HCV care in collaborative care settings for marginalized patients with high rates of substance use have shown sustained virological response rates comparable to those reported for clinical trial populations (10, 22). These models used on-site psychiatric and HCV specialist care, group therapy, and peer support. Newer regimens with once-daily dosing will reduce pill burden, which will likely make treatment easier to tolerate and improve adherence (23).

Directly observed therapy has been utilized as a strategy for improving adherence rates and clinical outcomes in other chronic infections that require complex therapy regimens, such as HIV and tuberculosis (24, 25). To date, there has been limited investigation of directly observed therapy in HCV treatment (26–29), and none since the introduction of direct-acting antivirals. Previous trials of modified directly observed therapy models, which involved nurse-administered IFN-α and daily self-administered ribavirin, demonstrated rates of sustained virological response in community and drug-using populations comparable to those obtained in large randomized controlled trials (26, 27). While these studies showed no significant difference in rates of sustained virological response between modified directly observed therapy and self-administered IFN-α, the results suggest that modified directly observed therapy models may be most effective in improving rates of sustained virological response in difficult-to-treat groups, including those with comorbid psychiatric conditions (including substance use) (27, 28), as has been seen in HIV treatment (30, 31). Further investigation of directly observed therapy in the era of direct-acting antivirals is warranted, given the impact of treatment adherence on clinical outcome and prevention of drug resistance, as well as the shorter duration of required treatment. If directly observed therapy models prove to be effective for patients with comorbid psychiatric conditions, psychiatrists may play a role in the ongoing monitoring of treatment within these programs.

As demonstrated in Mr. K’s history, the evolution of HCV therapy will reshape psychiatrists’ role in HCV treatment. As HCV therapy moves to IFN-α-free regimens, more patients with severe mental illness and substance use diagnoses will likely receive HCV treatment, given the reduced neuropsychiatric sequelae of these treatments. Psychiatrists can play an important role in screening for HCV in at-risk populations, as over 50% of patients remain undiagnosed (11). In addition, informing patients of the dramatic changes in therapy to encourage those who may have avoided treatment in the past to reconsider treatment with direct-acting antivirals may improve treatment uptake. Psychiatrists will need to focus on promoting adherence and managing drug-drug interactions during treatment to maximize the likelihood of sustained virological response and minimize the risk of viral resistance. After treatment, psychiatrists need to remain an integral member of patients’ care teams to provide ongoing psychiatric support in this high-risk population (3). Continued psychiatric follow-up after treatment may be especially important for those patients who did not achieve sustained virological response, given the emotional impact of treatment failure. Therefore, psychiatrists’ role will continue to evolve with advances in HCV treatment to facilitate treatment engagement and adherence and to support patients during HCV treatment aftercare.