Braz J Psychiatry. 2020 Jan-Feb;42(1):72-76 doi:10.1590/1516-4446-2018-0336 Brazilian Psychiatric Association 0 0 0 0 -0 02-7316-1 85 BRIEF COMMUNICATION Incidence of depression in patients with hepatitis C treated with direct-acting antivirals Elfi Egmond,1,2 Zoe Mariño,3 Ricard Navines,1,4 Giovanni Oriolo,1,4 Anna Pla,3 Concepció Bartres,3 Sabela Lens,3 Xavier Forns,3 Rocio Martin-Santos1,4,50 0 -0 03-4150-4726 1 Servei de Psiquiatria i Psicologia, Hospital Clı́nic de Barcelona, Institut d’Investigacions Biomèdicas August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain. 2Departament de Psicologia Clı́nica i de la Salut, Facultat de Psicologia, Universitat Autònoma de Barcelona, Barcelona, Spain. 3Servei d’Hepatologia, Hospital Clı́nic de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Universitat de Barcelona, Barcelona, Spain. 4Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain. 5Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT- TM), Conselho Nacional de Desenvolvimento Cientı́fico e Tecnológico (CNPq), Ribeirão Preto, Brazil. Objective: Depression has been associated with hepatitis C, as well as with its treatment with proinflammatory cytokines (i.e., interferon). The new direct-acting antiviral agents (DAAs) have minimal adverse effects and high potency, with a direct inhibitory effect on non-structural viral proteins. We studied the incidence and associated factors of depression in a real-life prospective cohort of chronic hepatitis C patients treated with the new DAAs. Methods: The sample was recruited from a cohort of 91 patients with hepatitis C, of both sexes, with advanced level of fibrosis and no HIV coinfection, consecutively enrolled during a 6-month period for DAA treatment; those euthymic at baseline (n=54) were selected. All were evaluated through the depression module of the Patient Health Questionnaire (PHQ-9-DSM-IV), at three time points: baseline, 4 weeks, and end-of-treatment. Results: The cumulative incidence (95%CI) of major depression and any depressive disorder during DAA treatment was 13% (6.4-24.4) and 46.3% (33.7-59.4), respectively. No differences were observed between those patients with and without cirrhosis or ribavirin treatment (p 4 0.05). Risk factors for incident major depression during DAA treatment included family depression (relative risk 9.1 [1.62-51.1]), substance use disorder (11.0 [1.7-73.5]), and baseline PHQ-9 score (2.1 [1.1-3.1]). Conclusions: The findings of this study highlight the importance of screening for new depression among patients receiving new DAAs, and identify potential associated risk factors. Keywords: Depression; direct-acting antivirals; DAA; hepatitis C; PHQ-9 Introduction Interactions of these factors with several neurobiological pathways, neurotransmission, and neurotrophic mechan- Depression is a common mental illness1 and a leading isms may account for the pathogenesis of neuropsychiatric cause of disability worldwide. Chronic exposure to symptoms in CHC.8,9 hepatitis C virus (HCV) and previous antiviral treatment Until a few years ago, antiviral treatment for CHC with interferon alpha has been associated with major involved a weekly injection of pegylated interferon-alpha depression.2,3 HCV infection leads to chronic hepatitis C (IFNa), a proinflammatory cytokine, together with daily (CHC) in around 80% of cases, and, if untreated, pro- weight-based doses of ribavirin (RBV) for 24 to 48 weeks. gresses to liver cirrhosis in one in five patients within 20 This regimen was known to cause major depression in to 50 years after initial infection; of these, 5 to 10% will around 30% of patients,3 beside a wide range of other develop hepatocellular carcinoma or decompensated liver adverse events (AEs), with a high rate of treatment disease.4 CHC has been recognized as a systemic discontinuation10 and additional effects on physical and disease with many extrahepatic manifestations, including mental health-related quality of life.11 Increased under- feelings of depression, anhedonia, fatigue, irritability, standing of the HCV viral cycle in the last decade led to anxiety, insomnia, and increased sensitivity to pain.5 the development of direct-acting antiviral agents (DAA) that There is some evidence of direct neuroinvasion by HCV,6 have minimal AEs and high potency, with a direct inhibitory as well as of a chronic, systemic immune activation.7 effect on non-structural viral proteins.12 The sustained Correspondence: Rocio Martin-Santos, Servei de Psiquiatria i Psico- How to cite this article: Egmond E, Mariño Z, Navines R, Oriolo G, logia, Hospital Clı́nic, University of Barcelona, IDIBAPS, CIBERSAM, Pla A, Bartres C, et al. Incidence of depression in patients with C/ Villarroel, 170, 08036, Barcelona, Spain. hepatitis C treated with direct-acting antivirals. Braz J Psychiatry. E-mail: rmsantos@clinic.cat 2020;42:72-76. http://dx.doi.org/10.1590/1516-4446-2018-0336 Submitted Nov 15 2018, accepted Apr 18 2019, Epub Jul 15 2019. Depression in hepatitis C treated with direct-acting antivirals 73 virological response rate with DAA therapy is over 95% in correspond to the symptom criteria for depressive dis- most patients. With the use of all-oral DAA combinations, orders as outlined in the DSM-IV.15 The depression the short- and long-term prognosis for HCV-infected module (PHQ-9) comprises nine items rated from 0 to patients has improved significantly.13 3 (not at all, several days, more than 50% of days, and The aims of this study were to evaluate the incidence nearly every day). Major depression is diagnosed if of and risk factors associated with depressive disorders patients score 2 or 3 on five or more symptom criteria in during DAA treatment in a real-life, prospective cohort of the past 2 weeks, and if one of the symptoms is depres- patients with CHC with advanced liver disease. sed mood or anhedonia. Other depression is diagnosed if two, three, or four depressive symptoms have been Methods present in the last 2 weeks and if one of the symptoms is depressed mood or anhedonia. This questionnaire Patients has shown good psychometric properties.14 The PHQ-9 was administered before each medical visit and blinded All consecutive patients with HCV monoinfection starting to virological results. all-oral DAA therapy at the Liver Unit of Hospital Clı́nic de Patients with depressive disorders were referred to an Barcelona (Spain), University of Barcelona, from June to independent senior psychiatrist and treated as necessary. December 2015 were considered for the study. Patients with HIV coinfection were not considered for this study, Statistical analysis as they are treated at the Infectious Diseases Unit. From this initial cohort of patients, we selected those who were The baseline characteristics of patients in the sample are euthymic at baseline to evaluate the incidence of depres- presented as mean (standard deviation) for numerical sion during DAA treatment. variables and as absolute and relative frequencies for All patients provided written informed consent for parti- categorical variables. The cumulative incidence of major cipation. The study protocol was approved by the institu- depression and any depression disorder (i.e., both major tional research ethics committee. depression and other depressive disorder) during DAA Demographic, clinical, and virological data at baseline, treatment was estimated and 95% confidence intervals were collected. Family and personal history of depression (95%CI) were calculated. Logistic binomial regression and alcohol/drug use disorder (SUD) were also recorded. models were fitted to study possible risk factors for the All participants were clinically assessed at three points: incidence of major depression and any depression. An baseline, at 4 weeks (4W) of DAA therapy, and at the end effect-size measure of these models, relative risk (RR), of treatment (EOT). was estimated with 95%CIs. Liver fibrosis was assessed at baseline by means of Statistical analyses were carried out using the R free transient elastography (TE). Liver stiffness p 7.8 kilo- software environment for statistical computing (The R pascals (kPa) was defined as F0-1; 7.8-9.4 kPa, as F2; Foundation for Statistical Computing; Vienna, Austria), 9.5-13.9 kPa, as F3; and X 14 kPa, as F4 or cirrhosis. version 3.4.2. Statistical significance was set at p = 0.05. Cirrhosis could also be diagnosed by other methods: liver biopsy, clinical evidence (i.e., gastroesophageal varices), Results and/or the presence of ultrasonographic criteria. Patients with cirrhosis were screened for hepatocellular carcinoma Sample selection every 6 months as per clinical practice. During the 6-month study period (June to December Antiviral treatment 2015), 93 subjects were selected before starting antiviral therapy, all of whom agreed to participate. One patient DAA regimen, duration of therapy (12 or 24 weeks), and did not start antiviral treatment, and another patient use of concomitant ribavirin (RBV) were planned at the did not complete the clinical assessment; thus, neither discretion of the treating physician, in accordance with was included. Of the 91 patients starting DAA treat- national and international recommendations at that time.12 ment, 54 (59.3%) were euthymic at baseline and thus At the time of the study, access to all-oral IFN-free DAA eligible for inclusion. Table 1 shows their baseline char- therapy in Spain was restricted to patients with advanced acteristics. liver disease (F3 or cirrhosis) or those with mild liver Of the 54 patients who were euthymic at baseline, 46 disease (F0-2) but concomitant extrahepatic manifesta- (85.2%) received DAA treatment (sofosbuvir; ledipasvir; tions. Viral eradication or sustained virological response 2D/3D paritaprevir/ombitasvir/ritonavir with or without (SVR) was defined as undetectable viremia (HCV-RNA) dasabuvir; or daclatasvir) for 12 weeks, and 8 (14.8%) at 12 weeks after the end of treatment (12AT). were treated for 24 weeks. Thirty-nine (72%) received concomitant treatment with RBV. All patients achieved Clinical assessment SVR (100%) after DAA treatment, confirmed at 12AT. All enrolled patients were screened for the presence of Incidence of depression current depressive symptoms by means of the Spanish- validated version of the self-administered PHQ-9 ques- Figure 1 shows the cumulative incidence of depression tionnaire for CHC patients.14 The items on the PHQ-9 measured by PHQ-9 during antiviral treatment (at 4 weeks Braz J Psychiatry. 2020;42(1) 74 E Egmond et al. Table 1 Characteristics of the euthymic cohort (n=54) of hepatitis C patients before DAA treatment All sample Euthymic during Incident depression (any)* Incident major depressionw (n=54) DAA (n=29) during DAA (n=25) during DAA (n=7) Sociodemographic and HCV variables Age, years 61.1 (12) 60.5 (12.1) 61.3 (12.2) 57.0 (16.2) Gender (male) 28 (51.9) 13 (46.9) 15 (57.7) 4 (57.1) HCV genotype 1a 12 (22.2) 6 (20.7) 6 (24) 2 (28.6) 1b 37 (68.5) 22 (75.9) 15 (60) 3 (42.9) 2 1 (1.9) 0 (0) 1 (4) 0 (0) 3 3 (5.6) 1 (3.5) 2 (8) 1 (14.3) 4 1 (1.9) 0 (0) 1 (4) 1 (14.3) Previous non-responders to PegIFN/RBV 28 (51.9) 16 (55.2) 14 (56) 1 (14.3) therapy Liver stiffness X 21 kPa (n=51) 14 ( 27.5) 7 (25.9)w 7 (29.2)y 2 (28.6)|| Fibrosis stage by TE F0-1 4 (7.4) 2 (6.9) 2 (8) 0 (0) F2 1 (1.9) 1 (3.5) 0 (0) 0 (0) F3 11 (20.4) 6 (21.7) 5 (20) 3 (42.9) F4 38 (70.4) 20 (68.9) 18 (72) 4 (57.1) Previous decompensation of cirrhosis 10 (26.3) 6 (31.6) 4 (21.1) 1 (25.0) Child-Pugh Score in cirrhosis (n=37) A (%) 29 (78.4) 13 (68.4) 16 (88.9) 4 (100) B (%) 8 (21.6) 6 (31.6) 2 (11.1) 0 (0) MELD score (n=32) o 10 20 (62.5) 9 (52.9) 11 (73.3) 3 (100) X 10 12 (37.5) 8 (47.1) 4 (26.7) 0 (0) Albumin (g/dL) 41.4 (4.7) 41.0 (4.8) 41.4 (5.0) 44.3 (1.9) Platelets (109/mL) 127.9 (68.1) 128.9 (63.1) 124.7 (71.2) 147.4 (59.9) Relevant comorbidityz 54 (100) 29 (100) 25 (100) 7 (100) Psychiatric variables Family history of depression 10 (18.5) 6 (21.4) 4 (15.4) 4 (57.1)** Family history of SUD 6 (11.1) 3 (10.7) 3 (11.5) 3 (42.9)** Personal history of depression 13 (24.1) 9 (32.1) 4 (15.4) 2 (28.6) Personal history of SUD 5 (9.3) 3 (10.7) 2 (7.7) 2 (28.6) PHQ-9 total score (0 to 27) 1.3 (1.4) 1.4 (1.4) 1.2 (1.4) 2.6 (1.4)** Treatment variables DAA with RBV 39 (72.2) 20 (71.4) 19 (76.0) 6 (85.7) DAA without RBV 15 (27.8) 9 (28.6) 6 (24.0) 1 (14.3) Numerical variables given as mean (SD); categorical variables, as n (%). DAA = direct-acting antivirals; F = fibrosis score; HCV = hepatitis C virus; IFN = interferon; kPa = kilopascals; MELD = model for end-stage liver disease; PHQ-9 = Patient Health Questionnaire, depression module; RBV = ribavirin; SD = standard deviation; SUD = substance use disorder; TE = transient elastography. * Any depression is the sum of ‘‘other depression’’ (diagnosed if two, three, or four depressive symptoms have been present in the last 2 weeks and if one of the symptoms is depressed mood or anhedonia) and ‘‘major depression.’’ w ‘‘Major depression’’ is diagnosed if the patient has scored 2 (more than 50% of days) or 3 (nearly every day) on five or more DSM-IV symptom criteria in the past 2 weeks, and if one of the symptoms is depressed mood or anhedonia. w n=27; y n=24; || n=7. z Ischemic cardiovascular events and arrhythmias, current or previous history of neoplastic disease, cryoglobulinemic vasculitis, chronic obstructive pulmonary disorder (COPD), or any disease potentially impacting activities of daily living. **p o 0.05. and at end-of-treatment) among patients euthymic at Risk factors associated with depression during direct- baseline (n=54). The cumulative incidence was 12.9% acting antiviral treatment (95%CI 6.4-24.4) (n=7) for major depression, and 46.3% (95%CI 33.7-59.4) (n=25) for any depression. Regarding major depression, univariate logistic binomial Concerning cirrhosis and use of RBV during DAA treat- regression indicated a statistically significant association ment, the differences between groups for both major with family history of depression (RR = 9.1, 95%CI 1.6- depression and any depression were not significant 51.1), family history of substance use disorder (RR = (p 4 0.05). 11.0, 95%CI 1.7-73.5), and higher PHQ-9 baseline score Braz J Psychiatry. 2020;42(1) Depression in hepatitis C treated with direct-acting antivirals 75 Figure 1 Cumulative incidence (95%CI) of major depression (red line) and any depression (blue line) during DAA treat- ment in patients euthymic at baseline (n=54). 95%CI = 95% confidence interval; PHQ-9 = Patient Health Questionnaire 9; PHQ-9 4 10 = major depression; PHQ-9 4 5 = any depressive disorder; 4W = 4 weeks of treatment; EOT = end of treatment (12 or 24 weeks). (RR = 2.1, 95%CI 1.1-3.9, for every one-point increase factors seem to be associated with a high relative risk of in baseline score). No multivariate models were fitted for major depression during DAA treatment. the incidence of depression because of the number of Second, CHC patients with a family history of depres- incident cases throughout the study (n=7/54). Concerning sion before starting antiviral treatment had a more than the development of any depression during DAA, no base- fourfold increased risk of developing depression during line characteristic was identified as a risk factor on DAA treatment. Moreover, every one-point increase in univariate analysis. baseline PHQ-9 score was associated with a twofold risk (RR = 2.1) of incident depression during DAA treatment. Neither these factors nor others were associated with the incidence of mild depressive symptoms during DAA Discussion treatment. In the context of allostatic load, the subgroup Several important findings were revealed in the present of HCV patients with these risk factors may be more study. First, 13% of patients who were euthymic at base- vulnerable to major depression.20 Large naturalistic cohort line developed major depression during DAA treatment, studies would be needed to confirm these results. and up to 40% developed depressive symptoms. Dual This study is not free from limitations. Due to the antiviral treatment based on IFN-a with RBV was asso- sample size, the advanced stage of liver disease in the ciated with a high incidence of major depression (25- patients, their relevant comorbidities, and the absence of 40%) in the past, mainly due to its IFN-a pro-inflamma- patients with HIV coinfection, any generalization of our tory properties.3,16 As DAA works instead by direct results should be approached with caution. Because of inhibition of the various steps of HCV replication, a direct the naturalistic cohort design, the study lacked a control neuropsychiatric effect was not expected. Thus, other group, and patients were included consecutively. mechanisms might explain the incidence of depression In conclusion, direct-acting antiviral treatment for chro- observed. First, four in five patients included in our study nic hepatitis C was associated with a lower incidence of received RBV, an antiviral co-agent with an unclear major depressive episode than previous classical treat- mechanism of action that is known to have negative effects ment with interferon-alpha. However, the results of this on mental health.17 Nevertheless, it was not identified as a study highlight the importance of screening for depres- confounding factor when a specific analysis was per- sion, and its associated risk factors, over the course of formed. Second, the incidence of depression may be DAA treatment. related to the advanced liver disease and medical com- Acknowledgements orbidity of this cohort, as these patients often experi- ence more symptoms related to cirrhosis.18,19 However, XF was funded by ISCIII – Subdirección General de when we controlled for the presence of cirrhosis, no statis- Evaluación, grant PI15/00151, integrated in Plan Nacional tically significant differences were found. Importantly, some I+D+I, and cofounded by Fondo Europeo de Desarrollo Braz J Psychiatry. 2020;42(1) 76 E Egmond et al. Regional (FEDER-‘‘una manera de Hacer Europa’’), from 6 Wilkinson J, Radkowski M, Laskus T. Hepatitis C virus neuroinvasion: the Spanish Health Ministry (Plan Estratégico Nacional identification of infected cells. J Virol. 2009;83:1312-9. 7 Liu CS, Adibfar A, Herrmann N, Gallagher D, Lanctôt KL. Evidence contra la Hepatitis C), and by Secretaria d’Universitats i for inflammation-associated depression. In: Dantzer R, Capuron L, Recerca del Departament d’Economia i Coneixement, editors. Inflammation-associated depression: evidence, mechanisms Grups consolidats de recerca, grant 2014-SGR-605, and and implications, current topics in behavioral neurosciences. Cham: 2017-SGR-1753. XF was also supported by CERCA Springer; 2016. Vol. 31, p.3-30. Programme/Generalitat de Catalunya. RM-S is grateful to 8 Yarlot L, Heald E, Forton D. Hepatitis C virus infection, and neu- rological and psychiatric disorders - a review. J Adv Res. 2017;8: the support of the Instituto de Salud Carlos III, Spanish 139-48. Ministry of Economy and Competiveness, Centro para la 9 Oriolo G, Egmond E, Mariño Z, Cavero M, Navines R, Zamarrenho L, Investigación Biomédica en Red de Salud Mental et al. Systematic review with meta-analysis: neuroimaging in hepatitis (CIBERSAM); the Secretaria d’Universitats I Recerca C chronic infection. 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Disclosure Hepatitis B and C Public Policy Association Newsletter. 2015 Oct [cited 2019 May 8]. doi: www.hepbcppa.org/wp-content/uploads/ ZM has served as advisor for Gilead and has received 2015/09/3056-HBC-Oct15b.pdf speaker fees from AbbVie, Gilead, Jansen, and MSD. SL 13 Flisiak R, Pogorzelska J, Flisiak-Jackiewicz M. Hepatitis C: efficacy has served as advisor for Gilead, AbbVie, and MSD, and and safety in real life. Liver Int. 2017;37:S26-32. 14 Navinés R, Castellvi P, Moreno-Espana J, Gimenez D, Udina M, has received speaker fees from AbbVie, Gilead, Jansen, Cañizares S, et al. Depressive and anxiety disorders in chronic and MSD. XF has received unrestricted grant support hepatitis C patients: reliability and validity of the Patient Health from AbbVie and Gilead, and has served as advisor for Questionnaire. J Affect Disord. 2012;138:343-51. AbbVie and Gilead. The other authors report no conflicts 15 Kroenke K, Spitzer Rl, Williams JB. 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