IFN-free regimens
With the arrival of the DAAs, the potential now exists to use IFN-free treatment regimens,10 which could eliminate concerns about IFN-induced depression.
Clinical trials of the DAAs and real-world use so far do not indicate an elevated risk for neuropsychiatric symptoms, including depression.11 As a result, more patients with severe psychiatric illness likely will be eligible to receive treatment for HCV. However, as clinical experience builds with these new agents, it is important to monitor the experience of patients with psychiatric comorbidity. Current treatment guidelines for HCV genotype 1, which is most common in the United States, do not include IFN-based regimens.10 Treatment of genotype 3, which affects 6% of the U.S. population, still includes IFN. Therefore, the risk of IFN-induced depression still exists for some patients with HCV. Table 310 describes current treatment regimens in use for HCV without cirrhosis (see Related Resources for treating HCV with cirrhosis).
Evolving role of the psychiatrist
The availability of shorter, better-tolerated regimens means that the psychiatric contraindications to HCV treatment will be eased. With the emergence of non-IFN treatment regimens, the role of mental health providers could shift toward assisting with treatment adherence, monitoring drug–drug interactions, and managing comorbid substance use disorders.10
The psychiatrist’s role might shift away from the psychosocial assessment of factors affecting treatment eligibility, such as IFN-associated depressive symptoms. Clinical focus will likely shift to supporting adherence to HCV treatment regimens.23 Because depression and substance use disorders are risk factors for non-adherence, mental health providers may be called upon to optimize treatment of these conditions before beginning DAA regimens. A multi-dose regimen might be complicated for those with severe mental illness, and increased psychiatric and community support could be needed in these patients.23 Furthermore, models of care that integrate an HCV specialist with psychiatric care have demonstrated benefits.6,23 Long-term follow-up with a mental health provider will be key to provide ongoing psychiatric support, especially for those who do not achieve SVR.
Psychotropic drug–drug interactions with DAAs
Both sofosbuvir and ledipasvir are substrates of P-glycoprotein and not metabolized by cytochrome P450 (CYP) enzymes.24 Therefore, there are no known contraindications with psychotropic medications. However, co-administration of P-glycoprotein inducers, such as St. John’s wort, could reduce sofosbuvir and ledipasvir levels leading to reduced therapeutic efficacy.
Because it has been used for many years as an HIV treatment, drug interactions with ritonavir have been well-described. This agent is a “pan-inhibitor” and inhibits the CYP3A4, 2D6, 2C9, and 2C19 enzymes and could increase levels of any psychotropic metabolized by these enzymes.25 After several weeks of treatment, it also could induce CYP3A4, which could lead to reduced efficacy of oral contraceptives because ethinylestradiol is metabolized by CYP3A4. Ritonavir is primarily metabolized by CYP3A4 (and CYP2D6 to a smaller degree). Carbamazepine induces CYP3A4, which may lead to decreased levels of ritonavir.23 This, in turn, could reduce the likelihood of attaining SVR and successful treatment of HCV.
Boceprevir, telaprevir, and simeprevir inhibit CYP3A4 to varying degrees and therefore could affect psychotropic medications metabolized by this enzyme.23,26,27 These DAAs are metabolized by CYP3A4; therefore CYP3A4 inducers, such as carbamazepine, could lower DAA blood levels, increasing risk of HCV treatment failure and viral resistance.
Daclatasvir is a substrate of CYP3A4 and an inhibitor of P-glycoprotein.28 Concomitant buprenorphine or buprenorphine/naloxone levels may be increased, although the manufacturer does not recommend dosage adjustment. Elbasvir and grazoprevir are metabolized by CYP3A4.29 Drug–drug interactions therefore may result when administered with either CYP3A4 inducers or inhibitors.
CASE Conclusion
Ms. S sees her new hepatologist, Dr. Smith. She decides to try a 12-week course of ledipasvir/sofosbuvir. Dr. Smith collaborates frequently with Ms. S’s psychiatrist to discuss her case and to help monitor her psychiatric symptoms. She follows up closely with her psychiatrist for symptom monitoring and to help ensure treatment compliance. Ms. S does well with the IFN-free treatment regimen and experiences no worsening of her psychiatric symptoms during treatment.