Direct-acting antiviral treatment in real world patients with hepatitis C not associated with psychiatric side effects: a prospective observational study

Direct-acting antiviral treatment in real world patients with hepatitis C not associated with... Background: Treatment of Hepatitis C virus (HCV) infection has evolved from interferon (IFN)-based treatments to direct-acting antivirals (DAAs). Patients with HCV have an elevated psychiatric morbidity (including substance abuse) and patients with such comorbidity have often been excluded from treatment with IFN. To date, little is known about psychiatric adverse effects of DAA-based regimens. We therefore aimed to study the psychiatric side effects of new IFN-free treatment for HCV (including depressive symptoms and sleep) in real world patients also including those with a history of psychiatric diagnosis, substance abuse or drug dependence. Methods: Consecutive patients were monitored during treatment with three of the latest DAA agents (sofosbuvir, simeprevir and daclatasvir). Repeated expert psychiatric assessments from baseline to 12 weeks post-treatment were performed with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) clinical version and the self-report versions of the Montgomery Åsberg Depression Rating Scale (MADRS-S) and the Pittsburgh Sleep Quality Index (PSQI). Friedman’s test was performed to calculate differences in the MADRS-S and PSQI over time. In a post-hoc analysis Wilcoxon’s test was used to compare baseline depressive symptoms with those at post-treatment. Spearman’srank correlation test was conducted in another post-hoc analysis to evaluate the correlation between symptoms of depression and HCV viral load at baseline. Results: At baseline, 15/17 patients (88%) had a history of any psychiatric diagnosis; 11 (65%) had a history of substance abuse or dependence; and 11 (65%) had previously been treatedwithIFN andsix of thosehad experiencedpsychiatric side effects. There was no correlation between depressive symptoms and HCV viral load at baseline. Symptoms of depression did not increase during DAA treatment and were lower 12 weeks post-treatment compared with baseline: MADRS-S10.7vs. 8.3(p = 0.01). This observation held when excluding patients taking antidepressant medication. Sleep quality did not significantly change during treatment. Adherence to treatment was estimated to 95% and sustained virological response was 88%. Conclusions: Despite high psychiatric morbidity, including previous substance abuse, patients successfully completed DAA treatment without increasing depressive symptoms or sleep disturbance. Symptoms of depression were significantly reduced 12 weeks after DAA treatment. Keywords: Hepatitis C virus, Direct-acting antiviral, Depression, Sleep, Side effects * Correspondence: isak.sundberg@neuro.uu.se Department of Neuroscience, Psychiatry, Uppsala University Hospital, Entrance 10, Floor 3B, 751 85 Uppsala, Sweden Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sundberg et al. BMC Psychiatry (2018) 18:157 Page 2 of 9 Background that excluded patients with substance abuse and prior Hepatitis C virus (HCV) infection is an important cause IFN-based treatment found that symptoms of depres- of chronic liver disease worldwide with an estimated 185 sion decreased after treatment with DAA. This study million people infected. Moreover, it is among the lead- also reported equal adherence and SVR rates in pa- ing causes of end-stage hepatic disease and is associated tients with indications of mental disease compared with the development of hepatocellular cancer [1]. Until with those without [31]. More data are needed to 2011, the gold standard of care for HCV treatment was assess PROs and treatment adherence of patients with the combination of pegylated interferon alpha HCV in clinical practice [22, 28, 32]. (PEG-IFN-α) and ribavirin (RBV), which are nonspecific Against this background, it is essential to study side ef- immune boosters [2, 3]. A major disadvantage of this fects, adherence and efficacy in a real-world patient therapy has been frequent side effects that are largely at- population, where psychiatric comorbidity (including tributed to IFN-α. Psychiatric side effects during IFN-α substance abuse) is common. Therefore, this study seeks treatment include depressive symptoms in 30–70%, mild to identify psychiatric side effects in HCV patients to moderate depression in 45–60% and major depression receiving DAAs (DCV, SOF and SIM), with repeated in 15–45% of treated individuals [4]. IFN-α triggers a observations from baseline to 12 weeks post-treatment. series of hypothalamic-pituitary-adrenal axis abnorma- To our knowledge, this is the first study to specifically lities and immune responses, resulting in depressive monitor psychiatric side effects in DAA treatment in symptoms [5]. Sleep disturbance is common in chronic real-world patients with psychiatric morbidity including HCV infection and treatment with IFN-α confers an past substance abuse. additional risk of sleep disturbance of about 20% [6]. Psychiatric morbidity in patients with HCV infection is elevated and otherwise eligible patients have frequently not Methods received treatment because of the fear of an exacerbation of Subjects psychiatric symptoms [4, 7–9]. A few studies suggest psy- This study was initiated in 2013, shortly before new chiatric comorbidity and drug abuse to be risk factors for DAA treatments were introduced, with the aim to study non-adherence and not attaining sustained viral response the longitudinal relationship between psychiatric symp- (SVR) [10–12], whereas several other studies have demon- toms and HCV treatment. Patients were recruited from strated similar rates of adherence and SVR in patients with a group of patients treated by a specialist in infectious HCV infection and psychiatric comorbidity (including drug disease (AL) at the Department of Infectious Diseases, abuse) [13–17]. In a recent study the prevalence of drug Uppsala University Hospital. The eligible patients for use in the past year was 65% (201/309) in patients consider- DAA treatment were those without malignancy. Patients ing HCV treatment [18]. In the same material the preva- with advanced liver fibrosis and cirrhosis, extrahepatic lence of a lifetime psychiatric diagnosis was 88% and the diseases, as well as those with strong psychosocial prevalence of a current psychiatric diagnosis was 54% [19]. reasons for treatment were prioritised for inclusion. HCV infection per se may contribute to psychiatric symp- Exclusion criteria were inability to read or write Swedish toms by inflammatory routes, direct brain neurotoxicity, and low cognitive or intellectual ability. These criteria metabolic and neurotransmitter pathway derangement and were considered incompatible with completing an exten- immune-mediated responses [20, 21]. sive research protocol and undergoing an in-depth inquiry The arrival of direct-acting antiviral agents (DAAs) has with recurrent interviews. Sixty-three consecutive patients drastically changed HCV treatment by increasing the were considered for participation in this study between likelihood of cure (referred to as SVR) and shortening the June 2014 and April 2015. Eleven were excluded because duration of treatment [22, 23]. The current generation of of a lack of Swedish language skills or low cognitive or in- DAAs (e.g., daclatasvir [DCV], sofosbuvir [SOF], sime- tellectual functioning. This selection was made by the previr [SIM] and ledipasvir [LDV]) is used without IFN treating specialist (AL) at the Department of Infectious [24, 25]. Because DAAs are not inflammatory cytokines, Diseases, Uppsala University Hospital, based on clinical they should not share the same side effects as IFN-α and judgement of the patient’s ability to understand and RBV of inducing flu-like symptoms, depression or suici- complete the study protocol with repeated assessments in dality. The side effect profile of DAAs compared with pre- the Swedish language. Of the 52 eligible patients, 19 (37%) vious HCV medications is reported to be less severe [26] accepted and were included in the study. Two of and patient-reported outcomes (PROs) improved [27, 28]. those patients declined to start the study before the Although there are efficacy studies with DAAs that in- first visit. Thus, the final sample was composed of clude patients with psychiatric comorbidity, [29, 30], few 17/52 patients (33%). The patients represented the studies have specifically addressed psychiatric symptoms spectrum of individuals considered suitable for treat- in DAA treatment [7, 13]. A recent retrospective study ment of HCV. None of the patients had HBV-HCV Sundberg et al. BMC Psychiatry (2018) 18:157 Page 3 of 9 or HIV-HCV co-infection. A flow chart of the patient the HCV RNA results at the time of completion of the inclusion process is provided in Fig. 1. questionnaires, but not blinded to the HCV RNA results from earlier time points in the study. Design The study was a prospective observational study. The Psychiatric assessment choice of treatment regimen was based on actual Swedish At baseline, patients were assessed for past and current national recommendations by The Swedish Medical Prod- psychiatric morbidity by a trained psychiatrist (IS) using ucts Agency at the time of treatment [33]. The prescrip- the Structured Clinical Interview for DSM-IV Axis I tion was combined with a treatment schedule that was Disorders (SCID-I) clinical version. Previous HCV treat- carefully supervised by research nurses at the outpatient ment and psychiatric side effects were also addressed in ward. Before treatment start, the physician reviewed la- the interview. In following visits (including the 12-week boratory data, liver elasticity, biopsy data and concomitant post-treatment visit), patients were interviewed by the medication. A visit was scheduled every four weeks during principal author, using module A of the SCID-I to assess treatment. After the treatment was completed, follow-up the presence of depressive episodes according to visits were performed at 12 and 24 weeks. At each time DSM-IV. point, research nurses asked the participants about adher- ence to medication (taking DAA medication as prescribed Self-assessment or not), which was then noted in the medical records. Symptoms of depression were measured using the Psychiatric assessment and patient self-report measures self-rating version of the Montgomery Åsberg Depres- were employed at baseline, after 4 weeks of treatment, sion Rating Scale (MADRS-S). It has been shown to be a after 8 weeks of treatment, at the end of treatment and reliable and sensitive self-report tool for depressive 12 weeks post-treatment. symptoms [34] and thus suitable to follow patients with Information was gathered on sociodemographic data, depressive symptoms over time. Scores on the medical history and treatment from the patients and MADRS-S range from 0 to 54, with higher scores indi- medical records. Patients and providers were blinded to cating a greater severity of depression [35]. Sleep quality Fig. 1 Patient inclusion. Sixty-three consecutive patients were considered for this study. Eleven were excluded because they could not speak or write fluently in Swedish or had low cognitive/intellectual ability. Of the 52 eligible patients, 19 accepted and were included in the study. Two patients declined to participate before study start. One patient was diagnosed with lung cancer and had to discontinue treatment at week 11. Sixteen of 17 patients completed the study Sundberg et al. BMC Psychiatry (2018) 18:157 Page 4 of 9 was measured with the Pittsburgh Sleep Quality Index with lung cancer during the treatment; this individual (PSQI), a validated self-rated questionnaire assessing had a negative HCV test (< 15 IU/mL) at 4 and 8 weeks sleep quality and disturbances over a one month period of treatment and discontinued treatment at week 11. [36]. The PSQI measures several aspects of sleep (e.g., One patient attained SVR but developed hepatocellular sleep latency, sleep duration, habitual sleep efficiency cancer shortly after completing DAA treatment. Ultra- and sleep disturbances). This tool includes seven compo- sound of the liver and computer tomography of the nent scores (range 0–3), as well as a composite global upper abdomen was performed before DAA treatment score (range 0–21). At each visit, patients filled in the for this patient showing no indication of malignancy. MADRS-S and PSQI questionnaires. To screen for alco- hol and drug use, the Alcohol Use Disorders Identifica- Psychiatric morbidity at baseline tion Test (AUDIT) [37] and Drug Use Disorders According to the SCID-I, 15/17 patients (88%) had any Identification Test (DUDIT) [38] were completed at lifetime DSM IV psychiatric diagnosis. At baseline, 6/17 baseline, after 12 weeks of treatment and 12 weeks patients (35%) had an ongoing DSM IV psychiatric diag- post-treatment. The AUDIT is a 10-item screening nosis. The number of lifetime psychiatric diagnoses instrument to assess alcohol consumption, drinking be- ranged from 0 to 7 (median 2). Eleven of 17 patients havior and problems related to alcohol consumption. (65%) had previous abuse or dependence of drugs or alco- The DUDIT serves as a parallel tool to the AUDIT to hol. Eleven of 17 patients (65%) were previously treated identify persons with drug-related problems. with IFN for HCV but the treatment had not been successful because of relapse (n = 3), intolerance (n = 3), Laboratory tests partial response (n = 3) and viral breakthrough (n = 2). HCV RNA was obtained from blood samples and Retrospectively, at least two of the previously treated analysed at each time point. All analyses were conducted patients had developed a depressive episode during treat- at the Department of Clinical Chemistry at Uppsala ment (according to the psychiatric assessment with University Hospital. A negative test for HCV RNA (de- SCID-I) while another four had developed depressive tection limit of ˂15 IU/mL) at both 12 and 24 weeks symptoms. One patient had developed diabetes, which is a post-treatment was considered as a SVR. The rate of the reported side effect of IFN/RBV treatment [39–41]. SVR was calculated on an “intention to treat” basis – i.e. all the patients who started treatment. Relationship between depressive symptoms and HCV viral load at baseline Statistics There was no significant correlation between baseline Non-parametric tests were used to calculate differences symptoms of depression and HCV viral load at baseline in MADRS-S, PSQI, AUDIT and DUDIT over time (Spearman’s rho: r = 0.17, p = 0.55). (Friedman’s test) and between depressive symptoms and HCV viral load at baseline (Spearman’s rank correlation Depressive symptoms during DAA treatment test). In a post-hoc analysis Wilcoxon’s test was applied MADRS-S scores for each visit were available for 15/17 to compare baseline depressive symptoms with patients (one patient was lost to follow-up because of post-treatment depressive symptoms. All statistical ana- lung cancer and one missed filling in the MADRS-S at lyses were conducted with the Statistical Package for the one of the assessment visits). For these 15 remaining pa- Social Sciences version 2 (SPSS Inc., Chicago, IL, USA). tients, the mean MADRS-S score was 10.7 (range 1–30, Reported p-values are two-sided with statistical signifi- SD 7.9) at baseline, 7.2 (range 0–26, SD 7.1) after cance set at p < 0.05. 4 weeks, 7.3 (range 0–19, SD 5.7) after 8 weeks, 8.0 (range 0–25, SD 7.4) at the end of treatment and 8.3 Results (range 0–30, SD 8.3) at 12 weeks post-treatment (Fig. 2). Patient characteristics are presented in Table 1. All No statistical difference in MADRS-S levels was found DAA-treated patients (17/17) received treatment with when comparing all test points (Friedman test Χ = 4.03, SOF combined with either SIM 9/17 (53%), DCV 7/17 p = 0.40), indicating that depressive symptoms did not (41%) or LDV 1/17 (6%). Additionally, 2/17 (12%) increase during treatment. We observed a significant patients received RBV. difference when comparing baseline MADRS-S with 12-week post-treatment (Wilcoxon p = 0.01), i.e. there Treatment adherence and response were less depressive symptoms post-treatment. At 95% of the visits, patients reported taking their DAA Reanalysis, omitting those three patients taking medication as prescribed. Fifteen of 17 (88%) patients antidepressant medication again found no statistical reached SVR at both 12 and 24 weeks. One male patient difference in MADRS-S levels when comparing all had a virological relapse. A female patient was diagnosed test points (Friedman test Χ =4.6, p = 0.33) and a Sundberg et al. BMC Psychiatry (2018) 18:157 Page 5 of 9 Table 1 Baseline characteristics and psychiatric morbidity MADRS-S score increased from 8 at baseline to 15 after four weeks and then decreased to 11, 9 and 8 Age, mean (range) 58 (44–67) during the rest of the study. Male sex, n (%) 9 (53) Three patients were depressed at baseline (based on BMI, mean (range) 27.2 (17.5–35.6) the psychiatric assessment with the SCID-I). Two 6 5 HCV RNA IE/mL, median (range) 2.6 × 10 (2.8 × 10 - 6 patients developed depression during DAA treatment. 16 × 10 ) Of the two patients who developed depression, one de- HCV genotype, n (%) scribed a subthreshold depressive episode at baseline 1a 7 (41) (days with depressed mood but not during two weeks) 1b 3 (18) and the other experienced family psychosocial problems 3a 5 (29) during the treatment period. The latter patient also had a history of recurrent depressive episodes. One patient 1a/1b/1× 2 (12) was depressed 12 weeks after treatment concluded. Descent European 16 (94) Middle Eastern 1 (6) Sleep quality during DAA treatment Mean total PSQI scores were 7.7 (range 2–19, SD 4.8) at Previous IFN treatment, n (%) 11 (65) baseline, 7.6 (range 2–18, SD 4.7) after 4 weeks, 7.7 Psychiatric side effects during IFN treatment, n 6 (range 2–19, SD 4.9) after 8 weeks, 7.2 (range 2–19, SD Liver cirrhosis, n (%) 10 (59) 4.7) at the end of treatment and 7.6 (range 3–18, SD 4.9) Child-Pugh A 9 12 weeks after treatment ended (Fig. 2). No significant Child-Pugh B 1 variation in total PSQI was noted (Χ = 3.4, p = 0.49). For Current psychiatric morbidity, n (%) 6 (35) PSQI component scores, post-hoc analysis of these measures revealed no significant variation during DAA Any mood disorder 4 (24) a treatment for sleep duration (Χ = 2.4, p = 0.66), sleep Any substance abuse or dependence 2 (12) 2 2 disturbances (Χ = 1.8, p = 0.77), sleep latency (Χ = 2.7, Any anxiety disorder 1 (6) p = 0.61), day dysfunction (Χ = 5.5, p = 0.24), habitual ADHD 2 (12) 2 sleep efficiency (Χ = 2.4, p = 0.67), and overall sleep Lifetime psychiatric morbidity, n (%) 15 (88) quality (Χ = 3.4, p = 0.50) (Fig. 3). Any mood disorder 10 (59) Any psychotic disorder 1 (6) AUDIT during DAA treatment Any substance abuse or dependence 11 (65) Mean AUDIT scores were 1.9 (range 0–7, SD 2.2) at Any anxiety disorder 6 (35) baseline, 1.5 (range 0–12, SD 3.0) 12 weeks of treat- Any eating disorder 2 (12) ment and 1.9 (range 0–9, SD 2.5) 12 weeks post-treatment. There was no significant variation ADHD 2 (12) during treatment (Χ =1.15, p = 0.59). Psychotropic medication Any psychotropic medication 8 (47) Antidepressants 3 (18) DUDIT during DAA treatment Mean DUDIT scores were 2.8 (range 0–41, SD 10.0) at Benzodiazepines 3 (18) baseline, 2.3 (range 0–28, SD 7.0) after 12 weeks of treat- Benzodiazepine-like agents for sleep 3 (18) ment and 0.6 (range 0–7, SD 2.0) 12 weeks after treat- Central nervous system stimulants 1 (6) ment. One person with previous methamphetamine Buprenorphine 2 (12) abuse was taken into a substance abuse treatment centre Patients were in an opiate substitution treatment programme just before start of the study (and start of treatment). Substance-induced psychotic disorder This patient’s DUDIT scores were 41 at baseline, 28 after ADHD, attention-deficit/hyperactivity disorder based on patient diagnosis in medical records 12 weeks of treatment and 7 12 weeks post-treatment. She did not report drug abuse during the study, but be- significant difference was still seen when comparing cause the questions in DUDIT refer to “during the last baseline MADRS-S with 12 weeks after treatment year”, high scores can be obtained without ongoing (Wilcoxon p =0.02). abuse. One patient had slightly increasing DUDÌT scores In one patient adjunctive RBV treatment was dis- (0 at baseline, 4 after 12 weeks of treatment and 7 at continued after four weeks because of affected blood 12 weeks post-treatment). No significant variation was count (from 146 to 115 g/L). For this patient, the found during the treatment (Χ = 1.2, p = 0.55). Sundberg et al. BMC Psychiatry (2018) 18:157 Page 6 of 9 Fig. 2 Mean scores for depressive symptoms (MADRS-S) and sleep quality (Total PSQI) from baseline to post-treatment. Depressive symptoms were lower 12 weeks post-treatment. Total PSQI did not significantly change during DAA treatment. Abbreviations: MADRS-S, self-rating version of the Montgomery Åsberg Depression Rating Scale; PSQI, Pittsburgh Sleep Quality Index; 4WTx, 4 weeks of treatment; 8WTx, 8 weeks of treatment; EOT, end of treatment; 12WpostTx, twelve weeks post-treatment Discussion adherence in this group was high (> 95%) as was treat- To our knowledge, this prospective study is the first to ment response (88%) [26]. specifically examine psychiatric symptoms during DAA In this study, the MADRS-S score was significantly treatment in real-world patients with substantial psychi- lower 12 weeks after the conclusion of treatment atric morbidity (including a history of substance abuse). compared with baseline. This finding is in agreement In this small but clinically relevant population of HCV with research showing that mental health parame- patients with significant psychiatric comorbidity DAA ters, neurocognitive function and fatigue are signifi- treatment did not increase depressive symptoms or in- cantly improved [42–44]. Moreover, a reduction in fluence sleep quality. In line with previous results Beck Depression Inventory scores was seen after Fig. 3 Mean component scores of the PSQI from baseline to post-treatment. There was no significant change in the component scores of the PSQI during DAA treatment. Abbreviations: PSQI, Pittsburgh Sleep Quality Index; 4WTx, four weeks of treatment; 8WTx, eight weeks of treatment; EOT, end of treatment; 12WpostTx, twelve weeks post-treatment Sundberg et al. BMC Psychiatry (2018) 18:157 Page 7 of 9 treatment with SOF [31]. In addition to the psy- Conclusions chological aspect of wellbeing in the virus-free pa- Although a majority of patients in this study had a his- tient [45], pretreatment viral load may contribute tory of affective disorder, drug abuse or neuropsychiatric directly to inflammation in the central nervous sys- disorder and previous IFN-based treatment, they were tem [20, 21, 45, 46] and to depressive symptoms. able to complete DAA treatment without substantial The eradication of HCV with anti-viral treatment psychiatric side effects. Depressive symptoms were re- may lower inflammation levels, resulting in less psy- duced after DAA treatment. Our study confirms findings chiatric symptoms [46–48]. In our sample, however, showing that HCV patients with psychiatric comorbidity there was no correlation at baseline between viral can be treated with DAAs with good efficacy and load and depressive symptoms. without psychiatric side effects, which is an important Two patients, who received RBV in addition to finding for HCV patients previously excluded from HCV DAA, reported increased depressive symptoms during treatment. Further studies with larger patient samples treatment (4–7-point increase in the MADRS-S are needed to add strength to these findings. score). There is no clear evidence linking RBV treat- Abbreviations ment to depressive symptoms [4]. However, previous AUDIT: Alcohol Use Disorders Identification Test; DAA: Direct-acting antiviral; studies have mainly focused on IFN-α.The depressive DCV: daclatasvir; DUDIT: Drug Use Disorders Identification Test.; HCV: Hepatitis C virus; IFN-α: Interferon alpha; IU/mL: International units per effects of IFN-α might have overshadowed smaller milliliter; MADRS-S: The self-rating version of the Montgomery Åsberg De- psychiatric side effects of RBV. pression Rating Scale; PSQI: Pittsburgh Sleep Quality Index; RBV: Ribavirin; One strength of this study is its well-characterised pa- SIM: Simeprevir; SOF: Sofosbuvir tient sample. Another strength is that patients were Acknowledgements assessed with gold standard psychiatric evaluation and The authors thank all patients for their participation, the staff at the open followed prospectively for 9–12 months with repeated as- ward at the Department of Infectious Diseases, Uppsala University Hospital sessments, self-reported measures and clinical, biochem- who collected the data, Hans Arinell for excellent assistance in the statistical analysis and Lisa Ekselius for fruitful discussions concerning study design and ical and virological monitoring. The sample also reflects data analysis. Sample management has been in collaboration with Uppsala real world patients, which increases the generalisability of Biobank. the findings. In contrast to many studies, our study in- cludes patients with a history of substance abuse and Funding This work was funded by Medical Training and Research Agreement (ALF) IFN-based treatment. Funds from Uppsala University Hospital, the Märta och Nicke Nasvells fund, One major limitation of this study is its small sample the Erik, Karin and Gösta Selanders Stiftelse, the Fredrik and Ingrid Thurings size. The relatively low inclusion rate was in part due to Stiftelse and The Swedish Society of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation other ongoing studies at the clinic and may have pro- of the manuscript. duced a differential selection effect. A second limitation is that the assessment of language skills and cognitive Availability of data and materials functioning was based on subjective clinical judgement The datasets used or analysed during the current study are available from the corresponding author on reasonable request. and was not operationalised formally. The results, such as the high adherence in this study, may therefore not Authors’ contributions be generalisable to populations with poor language skills IS, AL, MR and JC designed the study; IS and AL contributed to data acquisition; IS, AL, MR and JC analysed the data; IS wrote the first draft; AL, and lower cognitive functioning. Yet, the study patients MR and JC revised and approved the final version of the article. All authors represent a selection of chronic HCV patients regarding read and approved the final manuscript. psychiatric comorbidity and liver disease typical for our practice and with similar rates of psychiatric comorbidity Ethics approval and consent to participate The study was approved by the Regional Ethics Committee in Uppsala (Dnr. as in other studies characterising psychiatric comorbidity 2013/219). All patients received oral and written information and signed a in chronic HCV patients [18]. Patients’ use of psycho- written consent. tropic medication including antidepressants may have mitigated symptoms of depression and thus influenced Competing interests The authors declare that they have no competing interests. outcome. This possibility is reflective of a real-life setting, however. There is evidence that patients with intravenous Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in substance abuse may be at a higher risk of reinfec- published maps and institutional affiliations. tion, but that this risk can be lowered by properly ad- dressing this comorbidity during and after HCV cure Author details Department of Neuroscience, Psychiatry, Uppsala University Hospital, [49–51]. A coherent and comprehensive approach to Entrance 10, Floor 3B, 751 85 Uppsala, Sweden. Department of Medical deal with mental health and substance abuse is likely Sciences, Section of Infectious Diseases, Uppsala University Hospital, Entrance important to prevent reinfection of HCV. 34, Floor 2, 751 85 Uppsala, Sweden. Sundberg et al. BMC Psychiatry (2018) 18:157 Page 8 of 9 Received: 26 September 2017 Accepted: 11 May 2018 23. Gutierrez JA, Lawitz EJ, Poordad F. Interferon-free, direct-acting antiviral therapy for chronic hepatitis C. J Viral Hepat. 2015;22(11):861–70. 24. Coppola N, Zampino R, Bellini G, Stanzione M, Capoluongo N, Marrone A, et al. The impact of the CB2-63 polymorphism on the histological presentation of References chronic hepatitis B. Clin Microbiol Infect. 2015;21(6):609 e601–4. 1. Saeed Sadiq Hamid, et al. Guidelines for the screening care and treatment 25. Lawitz E, Sulkowski MS, Ghalib R, Rodriguez-Torres M, Younossi ZM, of persons with chronic hepatitis C infection: updated version. Geneva: Corregidor A, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to WHO Press; 2016. treat chronic infection with hepatitis C virus genotype 1 in non-responders 2. European Association for the Study of the L. EASL clinical practice guidelines: to pegylated interferon and ribavirin and treatment-naive patients: the management of hepatitis C virus infection. J Hepatol. 2011;55(2):245–64. COSMOS randomised study. Lancet. 2014;384(9956):1756–65. 3. Rehermann B, Bertoletti A. Immunological aspects of antiviral therapy of 26. Sulkowski MS, Vargas HE, Di Bisceglie AM, Kuo A, Reddy KR, Lim JK, et al. chronic hepatitis B virus and hepatitis C virus infections. Hepatology. 2015; Effectiveness of Simeprevir plus Sofosbuvir, with or without ribavirin, in real- 61(2):712–21. world patients with HCV genotype 1 infection. Gastroenterology. 2016; 4. Schaefer M, Capuron L, Friebe A, Diez-Quevedo C, Robaeys G, Neri S, et al. 150(2):419–29. Hepatitis C infection, antiviral treatment and mental health: a European 27. Younossi ZM, Stepanova M, Marcellin P, Afdhal N, Kowdley KV, Zeuzem S, expert consensus statement. J Hepatol. 2012;57(6):1379–90. Hunt SL. Treatment with ledipasvir and sofosbuvir improves patient- 5. Hoyo-Becerra C, Schlaak JF, Hermann DM. Insights from interferon-alpha- reported outcomes: results from the ION-1, −2, and −3 clinical trials. related depression for the pathogenesis of depression associated with Hepatology. 2015;61(6):1798–808. inflammation. Brain Behav Immun. 2014;42:222–31. 28. Younossi ZM, Stepanova M, Jacobson IM, Asselah T, Gane EJ, Lawitz E, et al. 6. Sockalingam S, Abbey SE, Alosaimi F, Novak M. A review of sleep Sofosbuvir and velpatasvir with or without voxilaprevir in direct-acting disturbance in hepatitis C. J Clin Gastroenterol. 2010;44(1):38–45. antiviral-naive chronic hepatitis C: patient-reported outcomes from POLARIS 7. Rowan PJ. What psychiatric screening and monitoring might be needed with 2 and 3. Aliment Pharmacol Ther. 2018;47(2):259–67. the new generation of hepatitis C treatments? World J Virol. 2015;4(1):13–6. 29. Ho SB, Monto A, Peyton A, Kaplan DE, Byrne S, Moon S, et al. Efficacy of 8. Carta MG, Hardoy MC, Garofalo A, Pisano E, Nonnoi V, Intilla G, et al. Sofosbuvir plus ribavirin in veterans with hepatitis C virus genotype 2 Association of chronic hepatitis C with major depressive disorders: irrespective infection, compensated cirrhosis. and Multiple Comorbidities Clin of interferon-alpha therapy. Clin Pract Epidemiol Ment Health. 2007;3:22. Gastroenterol Hepatol. 2016; 9. el-Serag HB, Kunik M, Richardson P, Rabeneck L. Psychiatric disorders 30. Ioannou GN, Beste LA, Chang MF, Green PK, Lowy E, Tsui JI, Su F, Berry K. among veterans with hepatitis C infection. Gastroenterology. 2002; Effectiveness of Sofosbuvir, Ledipasvir/Sofosbuvir, or Paritaprevir/ritonavir/ 123(2):476–82. Ombitasvir and Dasabuvir regimens for treatment of patients with hepatitis 10. Niederau C, Mauss S, Schober A, Stoehr A, Zimmermann T, Waizmann M, et C in the veterans affairs National Health Care System. Gastroenterology. al. Predictive factors for sustained virological response after treatment with 2016;151(3):457–71. e455 pegylated interferon alpha-2a and ribavirin in patients infected with HCV 31. Tang LSY, Masur J, Sims Z, Nelson A, Osinusi A, Kohli A, Kattakuzhy S, Polis genotypes 2 and 3. PLoS One. 2014;9(9):e107592. M, Kottilil S. Safe and effective sofosbuvir-based therapy in patients with 11. Younossi Z, Henry L. Systematic review: patient-reported outcomes in mental health disease on hepatitis C virus treatment. World J Hepatol. 2016; chronic hepatitis C–the impact of liver disease and new treatment 8(31):1318–26. regimens. Aliment Pharmacol Ther. 2015;41(6):497–520. 32. Jafri SM, Gordon SC. The safety of daclatasvir for the treatment of hepatitis 12. Mathes T, Antoine SL, Pieper D. Factors influencing adherence in hepatitis-C C. Expert Opin Drug Saf. 2015;14(11):1787–97. infected patients: a systematic review. BMC Infect Dis. 2014;14:203. 33. Läkemedelsbehandling av hepatit C- virusinfektion hos vuxna och barn.– 13. Sockalingam S, Sheehan K, Feld JJ, Shah H. Psychiatric care during hepatitis kunskapsunderlag [http://docplayer.se/6964210-Lakemedelsbehandling-av- C treatment: the changing role of psychiatrists in the era of direct-acting hepatit-c-virusinfektion-hos-vuxna-och-barn-kunskapsunderlag.html]. antivirals. Am J Psychiatry. 2015;172(6):512–6. 34. Fantino B, Moore N. The self-reported Montgomery-Åsberg depression 14. Elsherif O, Bannan C, Keating S, McKiernan S, Bergin C, Norris S. Outcomes rating scale is a useful evaluative tool in major depressive disorder. BMC from a large 10 year hepatitis C treatment programme in people who inject Psychiatry. 2009;9:26. drugs: no effect of recent or former injecting drug use on treatment 35. Cunningham JL, Wernroth L, von Knorring L, Berglund L, Ekselius L. adherence or therapeutic response. PLoS One. 2017;12(6):e0178398. Agreement between physicians' and patients' ratings on the Montgomery- 15. Hauser P, Morasco BJ, Linke A, Bjornson D, Ruimy S, Matthews A, Rifai A, Åsberg depression rating scale. J Affect Disord. 2011;135(1–3):148–53. Indest DW, Loftis JM. Antiviral completion rates and sustained viral response 36. Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh in hepatitis C patients with and without preexisting major depressive sleep quality index: a new instrument for psychiatric practice and research. disorder. Psychosomatics. 2009;50(5):500–5. Psychiatry Res. 1989;28(2):193–213. 16. Schäfer A, Scheurlen M, Weissbrich B, Schöttker K, Kraus MR. Sustained 37. Allen JP, Litten RZ, Fertig JB, Babor T. A review of research on the alcohol use virological response in the antiviral therapy of chronic hepatitis C: is there a disorders identification test (AUDIT). Alcohol Clin Exp Res. 1997;21(4):613–9. predictive value of interferon-induced depression? Chemotherapy. 2007; 38. Hildebrand M. The psychometric properties of the drug use disorders 53(4):292–9. identification test (DUDIT): a review of recent research. J Subst Abus Treat. 17. Dieperink E, Ho SB, Thuras P, Willenbring ML. A prospective study of 2015;53:52–9. neuropsychiatric symptoms associated with interferon-alpha-2b and 39. Alsabbagh ME, Eisa N, Alraiyes AH, Alraies MC, Chronic h C. Therapy: a rare ribavirin therapy for patients with chronic hepatitis C. Psychosomatics. 2003; complication revisited. BMJ Case Rep. 2013;2013 44(2):104–12. 40. Cozzolongo R, Betterle C, Fabris P, Paola Albergoni M, Lanzilotta E, Manghisi 18. Sims OT, Pollio DE, Hong BA, Jain MK, Brown GR, North CS. An assessment OG. Onset of type 1 diabetes mellitus during peginterferon alpha-2b plus of concurrent drug and alcohol use among patients seeking treatment for ribavirin treatment for chronic hepatitis C. Eur J Gastroenterol Hepatol. 2006; hepatitis C. Ann Clin Psychiatry. 2016;28(1):31–6. 18(6):689–92. 19. North CS, Sims O, Hong BA, Jain MK, Brown G, Lisker-Melman M, Pollio DE. 41. Eibl N, Gschwantler M, Ferenci P, Eibl MM, Weiss W, Schernthaner G. An empirical study of alcohol consumption by patients considering HCV Development of insulin-dependent diabetes mellitus in a patient with treatment. Am J Drug Alcohol Abuse. 2014;40(6):484–9. chronic hepatitis C during therapy with interferon-alpha. Eur J Gastroenterol 20. Tully DC, Hjerrild S, Leutscher PD, Renvillard SG, Ogilvie CB, Bean DJ, et al. Hepatol. 2001;13(3):295–8. Deep sequencing of hepatitis C virus reveals genetic compartmentalization in cerebrospinal fluid from cognitively impaired patients. Liver Int. 2016; 42. Younossi ZM, Stepanova M, Zeuzem S, Dusheiko G, Esteban R, Hezode 21. Forton DM, Allsop JM, Main J, Foster GR, Thomas HC, Taylor-Robinson SD. C, et al. Patient-reported outcomes assessment in chronic hepatitis C Evidence for a cerebral effect of the hepatitis C virus. Lancet. 2001; treated with sofosbuvir and ribavirin: the VALENCE study. J Hepatol. 358(9275):38–9. 2014;61(2):228–34. 22. Banerjee D, Reddy KR. Review article: safety and tolerability of direct-acting 43. Cacoub P, Ratziu V, Myers RP, Ghillani P, Piette JC, Moussalli J, Poynard T, anti-viral agents in the new era of hepatitis C therapy. Aliment Pharmacol Multivirc G. Impact of treatment on extra hepatic manifestations in patients Ther. 2016;43(6):674–96. with chronic hepatitis C. J Hepatol. 2002;36(6):812–8. Sundberg et al. BMC Psychiatry (2018) 18:157 Page 9 of 9 44. Kraus MR, Schafer A, Teuber G, Porst H, Sprinzl K, Wollschlager S, Keicher C, Scheurlen M. Improvement of neurocognitive function in responders to an antiviral therapy for chronic hepatitis C. Hepatology. 2013;58(2):497–504. 45. Zampino R, Boemio A, Sagnelli C, Alessio L, Adinolfi LE, Sagnelli E, Coppola N. Hepatitis B virus burden in developing countries. World J Gastroenterol. 2015;21(42):11941–53. 46. Kuhn T, Sayegh P, Jones JD, Smith J, Sarma MK, Ragin A, et al. Improvements in brain and behavior following eradication of hepatitis C. J Neuro-Oncol. 2017;23(4):593–602. 47. Byrnes V, Miller A, Lowry D, Hill E, Weinstein C, Alsop D, Lenkinski R, Afdhal NH. Effects of anti-viral therapy and HCV clearance on cerebral metabolism and cognition. J Hepatol. 2012;56(3):549–56. 48. Negro F, Forton D, Craxi A, Sulkowski MS, Feld JJ, Manns MP. Extrahepatic morbidity and mortality of chronic hepatitis C. Gastroenterology. 2015; 149(6):1345–60. 49. Midgard H, Weir A, Palmateer N, Lo Re V 3rd, Pineda JA, Macias J, Dalgard O. HCV epidemiology in high-risk groups and the risk of reinfection. J Hepatol. 2016;65(1 Suppl):S33–45. 50. Islam N, Krajden M, Shoveller J, Gustafson P, Gilbert M, Buxton JA, et al. Incidence, risk factors, and prevention of hepatitis C reinfection: a population-based cohort study. Lancet Gastroenterol Hepatol. 2017;2(3):200–10. 51. Midgard H, Bjoro B, Maeland A, Konopski Z, Kileng H, Damas JK, et al. Hepatitis C reinfection after sustained virological response. J Hepatol. 2016;64(5):1020–6. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Psychiatry Springer Journals

Direct-acting antiviral treatment in real world patients with hepatitis C not associated with psychiatric side effects: a prospective observational study

Free
9 pages
Loading next page...
 
/lp/springer_journal/direct-acting-antiviral-treatment-in-real-world-patients-with-o1kEinWFVK
Publisher
BioMed Central
Copyright
Copyright © 2018 by The Author(s).
Subject
Medicine & Public Health; Psychiatry; Psychotherapy
eISSN
1471-244X
D.O.I.
10.1186/s12888-018-1735-6
Publisher site
See Article on Publisher Site

Abstract

Background: Treatment of Hepatitis C virus (HCV) infection has evolved from interferon (IFN)-based treatments to direct-acting antivirals (DAAs). Patients with HCV have an elevated psychiatric morbidity (including substance abuse) and patients with such comorbidity have often been excluded from treatment with IFN. To date, little is known about psychiatric adverse effects of DAA-based regimens. We therefore aimed to study the psychiatric side effects of new IFN-free treatment for HCV (including depressive symptoms and sleep) in real world patients also including those with a history of psychiatric diagnosis, substance abuse or drug dependence. Methods: Consecutive patients were monitored during treatment with three of the latest DAA agents (sofosbuvir, simeprevir and daclatasvir). Repeated expert psychiatric assessments from baseline to 12 weeks post-treatment were performed with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) clinical version and the self-report versions of the Montgomery Åsberg Depression Rating Scale (MADRS-S) and the Pittsburgh Sleep Quality Index (PSQI). Friedman’s test was performed to calculate differences in the MADRS-S and PSQI over time. In a post-hoc analysis Wilcoxon’s test was used to compare baseline depressive symptoms with those at post-treatment. Spearman’srank correlation test was conducted in another post-hoc analysis to evaluate the correlation between symptoms of depression and HCV viral load at baseline. Results: At baseline, 15/17 patients (88%) had a history of any psychiatric diagnosis; 11 (65%) had a history of substance abuse or dependence; and 11 (65%) had previously been treatedwithIFN andsix of thosehad experiencedpsychiatric side effects. There was no correlation between depressive symptoms and HCV viral load at baseline. Symptoms of depression did not increase during DAA treatment and were lower 12 weeks post-treatment compared with baseline: MADRS-S10.7vs. 8.3(p = 0.01). This observation held when excluding patients taking antidepressant medication. Sleep quality did not significantly change during treatment. Adherence to treatment was estimated to 95% and sustained virological response was 88%. Conclusions: Despite high psychiatric morbidity, including previous substance abuse, patients successfully completed DAA treatment without increasing depressive symptoms or sleep disturbance. Symptoms of depression were significantly reduced 12 weeks after DAA treatment. Keywords: Hepatitis C virus, Direct-acting antiviral, Depression, Sleep, Side effects * Correspondence: isak.sundberg@neuro.uu.se Department of Neuroscience, Psychiatry, Uppsala University Hospital, Entrance 10, Floor 3B, 751 85 Uppsala, Sweden Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sundberg et al. BMC Psychiatry (2018) 18:157 Page 2 of 9 Background that excluded patients with substance abuse and prior Hepatitis C virus (HCV) infection is an important cause IFN-based treatment found that symptoms of depres- of chronic liver disease worldwide with an estimated 185 sion decreased after treatment with DAA. This study million people infected. Moreover, it is among the lead- also reported equal adherence and SVR rates in pa- ing causes of end-stage hepatic disease and is associated tients with indications of mental disease compared with the development of hepatocellular cancer [1]. Until with those without [31]. More data are needed to 2011, the gold standard of care for HCV treatment was assess PROs and treatment adherence of patients with the combination of pegylated interferon alpha HCV in clinical practice [22, 28, 32]. (PEG-IFN-α) and ribavirin (RBV), which are nonspecific Against this background, it is essential to study side ef- immune boosters [2, 3]. A major disadvantage of this fects, adherence and efficacy in a real-world patient therapy has been frequent side effects that are largely at- population, where psychiatric comorbidity (including tributed to IFN-α. Psychiatric side effects during IFN-α substance abuse) is common. Therefore, this study seeks treatment include depressive symptoms in 30–70%, mild to identify psychiatric side effects in HCV patients to moderate depression in 45–60% and major depression receiving DAAs (DCV, SOF and SIM), with repeated in 15–45% of treated individuals [4]. IFN-α triggers a observations from baseline to 12 weeks post-treatment. series of hypothalamic-pituitary-adrenal axis abnorma- To our knowledge, this is the first study to specifically lities and immune responses, resulting in depressive monitor psychiatric side effects in DAA treatment in symptoms [5]. Sleep disturbance is common in chronic real-world patients with psychiatric morbidity including HCV infection and treatment with IFN-α confers an past substance abuse. additional risk of sleep disturbance of about 20% [6]. Psychiatric morbidity in patients with HCV infection is elevated and otherwise eligible patients have frequently not Methods received treatment because of the fear of an exacerbation of Subjects psychiatric symptoms [4, 7–9]. A few studies suggest psy- This study was initiated in 2013, shortly before new chiatric comorbidity and drug abuse to be risk factors for DAA treatments were introduced, with the aim to study non-adherence and not attaining sustained viral response the longitudinal relationship between psychiatric symp- (SVR) [10–12], whereas several other studies have demon- toms and HCV treatment. Patients were recruited from strated similar rates of adherence and SVR in patients with a group of patients treated by a specialist in infectious HCV infection and psychiatric comorbidity (including drug disease (AL) at the Department of Infectious Diseases, abuse) [13–17]. In a recent study the prevalence of drug Uppsala University Hospital. The eligible patients for use in the past year was 65% (201/309) in patients consider- DAA treatment were those without malignancy. Patients ing HCV treatment [18]. In the same material the preva- with advanced liver fibrosis and cirrhosis, extrahepatic lence of a lifetime psychiatric diagnosis was 88% and the diseases, as well as those with strong psychosocial prevalence of a current psychiatric diagnosis was 54% [19]. reasons for treatment were prioritised for inclusion. HCV infection per se may contribute to psychiatric symp- Exclusion criteria were inability to read or write Swedish toms by inflammatory routes, direct brain neurotoxicity, and low cognitive or intellectual ability. These criteria metabolic and neurotransmitter pathway derangement and were considered incompatible with completing an exten- immune-mediated responses [20, 21]. sive research protocol and undergoing an in-depth inquiry The arrival of direct-acting antiviral agents (DAAs) has with recurrent interviews. Sixty-three consecutive patients drastically changed HCV treatment by increasing the were considered for participation in this study between likelihood of cure (referred to as SVR) and shortening the June 2014 and April 2015. Eleven were excluded because duration of treatment [22, 23]. The current generation of of a lack of Swedish language skills or low cognitive or in- DAAs (e.g., daclatasvir [DCV], sofosbuvir [SOF], sime- tellectual functioning. This selection was made by the previr [SIM] and ledipasvir [LDV]) is used without IFN treating specialist (AL) at the Department of Infectious [24, 25]. Because DAAs are not inflammatory cytokines, Diseases, Uppsala University Hospital, based on clinical they should not share the same side effects as IFN-α and judgement of the patient’s ability to understand and RBV of inducing flu-like symptoms, depression or suici- complete the study protocol with repeated assessments in dality. The side effect profile of DAAs compared with pre- the Swedish language. Of the 52 eligible patients, 19 (37%) vious HCV medications is reported to be less severe [26] accepted and were included in the study. Two of and patient-reported outcomes (PROs) improved [27, 28]. those patients declined to start the study before the Although there are efficacy studies with DAAs that in- first visit. Thus, the final sample was composed of clude patients with psychiatric comorbidity, [29, 30], few 17/52 patients (33%). The patients represented the studies have specifically addressed psychiatric symptoms spectrum of individuals considered suitable for treat- in DAA treatment [7, 13]. A recent retrospective study ment of HCV. None of the patients had HBV-HCV Sundberg et al. BMC Psychiatry (2018) 18:157 Page 3 of 9 or HIV-HCV co-infection. A flow chart of the patient the HCV RNA results at the time of completion of the inclusion process is provided in Fig. 1. questionnaires, but not blinded to the HCV RNA results from earlier time points in the study. Design The study was a prospective observational study. The Psychiatric assessment choice of treatment regimen was based on actual Swedish At baseline, patients were assessed for past and current national recommendations by The Swedish Medical Prod- psychiatric morbidity by a trained psychiatrist (IS) using ucts Agency at the time of treatment [33]. The prescrip- the Structured Clinical Interview for DSM-IV Axis I tion was combined with a treatment schedule that was Disorders (SCID-I) clinical version. Previous HCV treat- carefully supervised by research nurses at the outpatient ment and psychiatric side effects were also addressed in ward. Before treatment start, the physician reviewed la- the interview. In following visits (including the 12-week boratory data, liver elasticity, biopsy data and concomitant post-treatment visit), patients were interviewed by the medication. A visit was scheduled every four weeks during principal author, using module A of the SCID-I to assess treatment. After the treatment was completed, follow-up the presence of depressive episodes according to visits were performed at 12 and 24 weeks. At each time DSM-IV. point, research nurses asked the participants about adher- ence to medication (taking DAA medication as prescribed Self-assessment or not), which was then noted in the medical records. Symptoms of depression were measured using the Psychiatric assessment and patient self-report measures self-rating version of the Montgomery Åsberg Depres- were employed at baseline, after 4 weeks of treatment, sion Rating Scale (MADRS-S). It has been shown to be a after 8 weeks of treatment, at the end of treatment and reliable and sensitive self-report tool for depressive 12 weeks post-treatment. symptoms [34] and thus suitable to follow patients with Information was gathered on sociodemographic data, depressive symptoms over time. Scores on the medical history and treatment from the patients and MADRS-S range from 0 to 54, with higher scores indi- medical records. Patients and providers were blinded to cating a greater severity of depression [35]. Sleep quality Fig. 1 Patient inclusion. Sixty-three consecutive patients were considered for this study. Eleven were excluded because they could not speak or write fluently in Swedish or had low cognitive/intellectual ability. Of the 52 eligible patients, 19 accepted and were included in the study. Two patients declined to participate before study start. One patient was diagnosed with lung cancer and had to discontinue treatment at week 11. Sixteen of 17 patients completed the study Sundberg et al. BMC Psychiatry (2018) 18:157 Page 4 of 9 was measured with the Pittsburgh Sleep Quality Index with lung cancer during the treatment; this individual (PSQI), a validated self-rated questionnaire assessing had a negative HCV test (< 15 IU/mL) at 4 and 8 weeks sleep quality and disturbances over a one month period of treatment and discontinued treatment at week 11. [36]. The PSQI measures several aspects of sleep (e.g., One patient attained SVR but developed hepatocellular sleep latency, sleep duration, habitual sleep efficiency cancer shortly after completing DAA treatment. Ultra- and sleep disturbances). This tool includes seven compo- sound of the liver and computer tomography of the nent scores (range 0–3), as well as a composite global upper abdomen was performed before DAA treatment score (range 0–21). At each visit, patients filled in the for this patient showing no indication of malignancy. MADRS-S and PSQI questionnaires. To screen for alco- hol and drug use, the Alcohol Use Disorders Identifica- Psychiatric morbidity at baseline tion Test (AUDIT) [37] and Drug Use Disorders According to the SCID-I, 15/17 patients (88%) had any Identification Test (DUDIT) [38] were completed at lifetime DSM IV psychiatric diagnosis. At baseline, 6/17 baseline, after 12 weeks of treatment and 12 weeks patients (35%) had an ongoing DSM IV psychiatric diag- post-treatment. The AUDIT is a 10-item screening nosis. The number of lifetime psychiatric diagnoses instrument to assess alcohol consumption, drinking be- ranged from 0 to 7 (median 2). Eleven of 17 patients havior and problems related to alcohol consumption. (65%) had previous abuse or dependence of drugs or alco- The DUDIT serves as a parallel tool to the AUDIT to hol. Eleven of 17 patients (65%) were previously treated identify persons with drug-related problems. with IFN for HCV but the treatment had not been successful because of relapse (n = 3), intolerance (n = 3), Laboratory tests partial response (n = 3) and viral breakthrough (n = 2). HCV RNA was obtained from blood samples and Retrospectively, at least two of the previously treated analysed at each time point. All analyses were conducted patients had developed a depressive episode during treat- at the Department of Clinical Chemistry at Uppsala ment (according to the psychiatric assessment with University Hospital. A negative test for HCV RNA (de- SCID-I) while another four had developed depressive tection limit of ˂15 IU/mL) at both 12 and 24 weeks symptoms. One patient had developed diabetes, which is a post-treatment was considered as a SVR. The rate of the reported side effect of IFN/RBV treatment [39–41]. SVR was calculated on an “intention to treat” basis – i.e. all the patients who started treatment. Relationship between depressive symptoms and HCV viral load at baseline Statistics There was no significant correlation between baseline Non-parametric tests were used to calculate differences symptoms of depression and HCV viral load at baseline in MADRS-S, PSQI, AUDIT and DUDIT over time (Spearman’s rho: r = 0.17, p = 0.55). (Friedman’s test) and between depressive symptoms and HCV viral load at baseline (Spearman’s rank correlation Depressive symptoms during DAA treatment test). In a post-hoc analysis Wilcoxon’s test was applied MADRS-S scores for each visit were available for 15/17 to compare baseline depressive symptoms with patients (one patient was lost to follow-up because of post-treatment depressive symptoms. All statistical ana- lung cancer and one missed filling in the MADRS-S at lyses were conducted with the Statistical Package for the one of the assessment visits). For these 15 remaining pa- Social Sciences version 2 (SPSS Inc., Chicago, IL, USA). tients, the mean MADRS-S score was 10.7 (range 1–30, Reported p-values are two-sided with statistical signifi- SD 7.9) at baseline, 7.2 (range 0–26, SD 7.1) after cance set at p < 0.05. 4 weeks, 7.3 (range 0–19, SD 5.7) after 8 weeks, 8.0 (range 0–25, SD 7.4) at the end of treatment and 8.3 Results (range 0–30, SD 8.3) at 12 weeks post-treatment (Fig. 2). Patient characteristics are presented in Table 1. All No statistical difference in MADRS-S levels was found DAA-treated patients (17/17) received treatment with when comparing all test points (Friedman test Χ = 4.03, SOF combined with either SIM 9/17 (53%), DCV 7/17 p = 0.40), indicating that depressive symptoms did not (41%) or LDV 1/17 (6%). Additionally, 2/17 (12%) increase during treatment. We observed a significant patients received RBV. difference when comparing baseline MADRS-S with 12-week post-treatment (Wilcoxon p = 0.01), i.e. there Treatment adherence and response were less depressive symptoms post-treatment. At 95% of the visits, patients reported taking their DAA Reanalysis, omitting those three patients taking medication as prescribed. Fifteen of 17 (88%) patients antidepressant medication again found no statistical reached SVR at both 12 and 24 weeks. One male patient difference in MADRS-S levels when comparing all had a virological relapse. A female patient was diagnosed test points (Friedman test Χ =4.6, p = 0.33) and a Sundberg et al. BMC Psychiatry (2018) 18:157 Page 5 of 9 Table 1 Baseline characteristics and psychiatric morbidity MADRS-S score increased from 8 at baseline to 15 after four weeks and then decreased to 11, 9 and 8 Age, mean (range) 58 (44–67) during the rest of the study. Male sex, n (%) 9 (53) Three patients were depressed at baseline (based on BMI, mean (range) 27.2 (17.5–35.6) the psychiatric assessment with the SCID-I). Two 6 5 HCV RNA IE/mL, median (range) 2.6 × 10 (2.8 × 10 - 6 patients developed depression during DAA treatment. 16 × 10 ) Of the two patients who developed depression, one de- HCV genotype, n (%) scribed a subthreshold depressive episode at baseline 1a 7 (41) (days with depressed mood but not during two weeks) 1b 3 (18) and the other experienced family psychosocial problems 3a 5 (29) during the treatment period. The latter patient also had a history of recurrent depressive episodes. One patient 1a/1b/1× 2 (12) was depressed 12 weeks after treatment concluded. Descent European 16 (94) Middle Eastern 1 (6) Sleep quality during DAA treatment Mean total PSQI scores were 7.7 (range 2–19, SD 4.8) at Previous IFN treatment, n (%) 11 (65) baseline, 7.6 (range 2–18, SD 4.7) after 4 weeks, 7.7 Psychiatric side effects during IFN treatment, n 6 (range 2–19, SD 4.9) after 8 weeks, 7.2 (range 2–19, SD Liver cirrhosis, n (%) 10 (59) 4.7) at the end of treatment and 7.6 (range 3–18, SD 4.9) Child-Pugh A 9 12 weeks after treatment ended (Fig. 2). No significant Child-Pugh B 1 variation in total PSQI was noted (Χ = 3.4, p = 0.49). For Current psychiatric morbidity, n (%) 6 (35) PSQI component scores, post-hoc analysis of these measures revealed no significant variation during DAA Any mood disorder 4 (24) a treatment for sleep duration (Χ = 2.4, p = 0.66), sleep Any substance abuse or dependence 2 (12) 2 2 disturbances (Χ = 1.8, p = 0.77), sleep latency (Χ = 2.7, Any anxiety disorder 1 (6) p = 0.61), day dysfunction (Χ = 5.5, p = 0.24), habitual ADHD 2 (12) 2 sleep efficiency (Χ = 2.4, p = 0.67), and overall sleep Lifetime psychiatric morbidity, n (%) 15 (88) quality (Χ = 3.4, p = 0.50) (Fig. 3). Any mood disorder 10 (59) Any psychotic disorder 1 (6) AUDIT during DAA treatment Any substance abuse or dependence 11 (65) Mean AUDIT scores were 1.9 (range 0–7, SD 2.2) at Any anxiety disorder 6 (35) baseline, 1.5 (range 0–12, SD 3.0) 12 weeks of treat- Any eating disorder 2 (12) ment and 1.9 (range 0–9, SD 2.5) 12 weeks post-treatment. There was no significant variation ADHD 2 (12) during treatment (Χ =1.15, p = 0.59). Psychotropic medication Any psychotropic medication 8 (47) Antidepressants 3 (18) DUDIT during DAA treatment Mean DUDIT scores were 2.8 (range 0–41, SD 10.0) at Benzodiazepines 3 (18) baseline, 2.3 (range 0–28, SD 7.0) after 12 weeks of treat- Benzodiazepine-like agents for sleep 3 (18) ment and 0.6 (range 0–7, SD 2.0) 12 weeks after treat- Central nervous system stimulants 1 (6) ment. One person with previous methamphetamine Buprenorphine 2 (12) abuse was taken into a substance abuse treatment centre Patients were in an opiate substitution treatment programme just before start of the study (and start of treatment). Substance-induced psychotic disorder This patient’s DUDIT scores were 41 at baseline, 28 after ADHD, attention-deficit/hyperactivity disorder based on patient diagnosis in medical records 12 weeks of treatment and 7 12 weeks post-treatment. She did not report drug abuse during the study, but be- significant difference was still seen when comparing cause the questions in DUDIT refer to “during the last baseline MADRS-S with 12 weeks after treatment year”, high scores can be obtained without ongoing (Wilcoxon p =0.02). abuse. One patient had slightly increasing DUDÌT scores In one patient adjunctive RBV treatment was dis- (0 at baseline, 4 after 12 weeks of treatment and 7 at continued after four weeks because of affected blood 12 weeks post-treatment). No significant variation was count (from 146 to 115 g/L). For this patient, the found during the treatment (Χ = 1.2, p = 0.55). Sundberg et al. BMC Psychiatry (2018) 18:157 Page 6 of 9 Fig. 2 Mean scores for depressive symptoms (MADRS-S) and sleep quality (Total PSQI) from baseline to post-treatment. Depressive symptoms were lower 12 weeks post-treatment. Total PSQI did not significantly change during DAA treatment. Abbreviations: MADRS-S, self-rating version of the Montgomery Åsberg Depression Rating Scale; PSQI, Pittsburgh Sleep Quality Index; 4WTx, 4 weeks of treatment; 8WTx, 8 weeks of treatment; EOT, end of treatment; 12WpostTx, twelve weeks post-treatment Discussion adherence in this group was high (> 95%) as was treat- To our knowledge, this prospective study is the first to ment response (88%) [26]. specifically examine psychiatric symptoms during DAA In this study, the MADRS-S score was significantly treatment in real-world patients with substantial psychi- lower 12 weeks after the conclusion of treatment atric morbidity (including a history of substance abuse). compared with baseline. This finding is in agreement In this small but clinically relevant population of HCV with research showing that mental health parame- patients with significant psychiatric comorbidity DAA ters, neurocognitive function and fatigue are signifi- treatment did not increase depressive symptoms or in- cantly improved [42–44]. Moreover, a reduction in fluence sleep quality. In line with previous results Beck Depression Inventory scores was seen after Fig. 3 Mean component scores of the PSQI from baseline to post-treatment. There was no significant change in the component scores of the PSQI during DAA treatment. Abbreviations: PSQI, Pittsburgh Sleep Quality Index; 4WTx, four weeks of treatment; 8WTx, eight weeks of treatment; EOT, end of treatment; 12WpostTx, twelve weeks post-treatment Sundberg et al. BMC Psychiatry (2018) 18:157 Page 7 of 9 treatment with SOF [31]. In addition to the psy- Conclusions chological aspect of wellbeing in the virus-free pa- Although a majority of patients in this study had a his- tient [45], pretreatment viral load may contribute tory of affective disorder, drug abuse or neuropsychiatric directly to inflammation in the central nervous sys- disorder and previous IFN-based treatment, they were tem [20, 21, 45, 46] and to depressive symptoms. able to complete DAA treatment without substantial The eradication of HCV with anti-viral treatment psychiatric side effects. Depressive symptoms were re- may lower inflammation levels, resulting in less psy- duced after DAA treatment. Our study confirms findings chiatric symptoms [46–48]. In our sample, however, showing that HCV patients with psychiatric comorbidity there was no correlation at baseline between viral can be treated with DAAs with good efficacy and load and depressive symptoms. without psychiatric side effects, which is an important Two patients, who received RBV in addition to finding for HCV patients previously excluded from HCV DAA, reported increased depressive symptoms during treatment. Further studies with larger patient samples treatment (4–7-point increase in the MADRS-S are needed to add strength to these findings. score). There is no clear evidence linking RBV treat- Abbreviations ment to depressive symptoms [4]. However, previous AUDIT: Alcohol Use Disorders Identification Test; DAA: Direct-acting antiviral; studies have mainly focused on IFN-α.The depressive DCV: daclatasvir; DUDIT: Drug Use Disorders Identification Test.; HCV: Hepatitis C virus; IFN-α: Interferon alpha; IU/mL: International units per effects of IFN-α might have overshadowed smaller milliliter; MADRS-S: The self-rating version of the Montgomery Åsberg De- psychiatric side effects of RBV. pression Rating Scale; PSQI: Pittsburgh Sleep Quality Index; RBV: Ribavirin; One strength of this study is its well-characterised pa- SIM: Simeprevir; SOF: Sofosbuvir tient sample. Another strength is that patients were Acknowledgements assessed with gold standard psychiatric evaluation and The authors thank all patients for their participation, the staff at the open followed prospectively for 9–12 months with repeated as- ward at the Department of Infectious Diseases, Uppsala University Hospital sessments, self-reported measures and clinical, biochem- who collected the data, Hans Arinell for excellent assistance in the statistical analysis and Lisa Ekselius for fruitful discussions concerning study design and ical and virological monitoring. The sample also reflects data analysis. Sample management has been in collaboration with Uppsala real world patients, which increases the generalisability of Biobank. the findings. In contrast to many studies, our study in- cludes patients with a history of substance abuse and Funding This work was funded by Medical Training and Research Agreement (ALF) IFN-based treatment. Funds from Uppsala University Hospital, the Märta och Nicke Nasvells fund, One major limitation of this study is its small sample the Erik, Karin and Gösta Selanders Stiftelse, the Fredrik and Ingrid Thurings size. The relatively low inclusion rate was in part due to Stiftelse and The Swedish Society of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation other ongoing studies at the clinic and may have pro- of the manuscript. duced a differential selection effect. A second limitation is that the assessment of language skills and cognitive Availability of data and materials functioning was based on subjective clinical judgement The datasets used or analysed during the current study are available from the corresponding author on reasonable request. and was not operationalised formally. The results, such as the high adherence in this study, may therefore not Authors’ contributions be generalisable to populations with poor language skills IS, AL, MR and JC designed the study; IS and AL contributed to data acquisition; IS, AL, MR and JC analysed the data; IS wrote the first draft; AL, and lower cognitive functioning. Yet, the study patients MR and JC revised and approved the final version of the article. All authors represent a selection of chronic HCV patients regarding read and approved the final manuscript. psychiatric comorbidity and liver disease typical for our practice and with similar rates of psychiatric comorbidity Ethics approval and consent to participate The study was approved by the Regional Ethics Committee in Uppsala (Dnr. as in other studies characterising psychiatric comorbidity 2013/219). All patients received oral and written information and signed a in chronic HCV patients [18]. Patients’ use of psycho- written consent. tropic medication including antidepressants may have mitigated symptoms of depression and thus influenced Competing interests The authors declare that they have no competing interests. outcome. This possibility is reflective of a real-life setting, however. There is evidence that patients with intravenous Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in substance abuse may be at a higher risk of reinfec- published maps and institutional affiliations. tion, but that this risk can be lowered by properly ad- dressing this comorbidity during and after HCV cure Author details Department of Neuroscience, Psychiatry, Uppsala University Hospital, [49–51]. A coherent and comprehensive approach to Entrance 10, Floor 3B, 751 85 Uppsala, Sweden. Department of Medical deal with mental health and substance abuse is likely Sciences, Section of Infectious Diseases, Uppsala University Hospital, Entrance important to prevent reinfection of HCV. 34, Floor 2, 751 85 Uppsala, Sweden. Sundberg et al. BMC Psychiatry (2018) 18:157 Page 8 of 9 Received: 26 September 2017 Accepted: 11 May 2018 23. Gutierrez JA, Lawitz EJ, Poordad F. Interferon-free, direct-acting antiviral therapy for chronic hepatitis C. J Viral Hepat. 2015;22(11):861–70. 24. Coppola N, Zampino R, Bellini G, Stanzione M, Capoluongo N, Marrone A, et al. The impact of the CB2-63 polymorphism on the histological presentation of References chronic hepatitis B. Clin Microbiol Infect. 2015;21(6):609 e601–4. 1. Saeed Sadiq Hamid, et al. Guidelines for the screening care and treatment 25. Lawitz E, Sulkowski MS, Ghalib R, Rodriguez-Torres M, Younossi ZM, of persons with chronic hepatitis C infection: updated version. Geneva: Corregidor A, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to WHO Press; 2016. treat chronic infection with hepatitis C virus genotype 1 in non-responders 2. European Association for the Study of the L. EASL clinical practice guidelines: to pegylated interferon and ribavirin and treatment-naive patients: the management of hepatitis C virus infection. J Hepatol. 2011;55(2):245–64. COSMOS randomised study. Lancet. 2014;384(9956):1756–65. 3. Rehermann B, Bertoletti A. Immunological aspects of antiviral therapy of 26. Sulkowski MS, Vargas HE, Di Bisceglie AM, Kuo A, Reddy KR, Lim JK, et al. chronic hepatitis B virus and hepatitis C virus infections. Hepatology. 2015; Effectiveness of Simeprevir plus Sofosbuvir, with or without ribavirin, in real- 61(2):712–21. world patients with HCV genotype 1 infection. Gastroenterology. 2016; 4. Schaefer M, Capuron L, Friebe A, Diez-Quevedo C, Robaeys G, Neri S, et al. 150(2):419–29. Hepatitis C infection, antiviral treatment and mental health: a European 27. Younossi ZM, Stepanova M, Marcellin P, Afdhal N, Kowdley KV, Zeuzem S, expert consensus statement. J Hepatol. 2012;57(6):1379–90. Hunt SL. Treatment with ledipasvir and sofosbuvir improves patient- 5. Hoyo-Becerra C, Schlaak JF, Hermann DM. Insights from interferon-alpha- reported outcomes: results from the ION-1, −2, and −3 clinical trials. related depression for the pathogenesis of depression associated with Hepatology. 2015;61(6):1798–808. inflammation. Brain Behav Immun. 2014;42:222–31. 28. Younossi ZM, Stepanova M, Jacobson IM, Asselah T, Gane EJ, Lawitz E, et al. 6. Sockalingam S, Abbey SE, Alosaimi F, Novak M. A review of sleep Sofosbuvir and velpatasvir with or without voxilaprevir in direct-acting disturbance in hepatitis C. J Clin Gastroenterol. 2010;44(1):38–45. antiviral-naive chronic hepatitis C: patient-reported outcomes from POLARIS 7. Rowan PJ. What psychiatric screening and monitoring might be needed with 2 and 3. Aliment Pharmacol Ther. 2018;47(2):259–67. the new generation of hepatitis C treatments? World J Virol. 2015;4(1):13–6. 29. Ho SB, Monto A, Peyton A, Kaplan DE, Byrne S, Moon S, et al. Efficacy of 8. Carta MG, Hardoy MC, Garofalo A, Pisano E, Nonnoi V, Intilla G, et al. Sofosbuvir plus ribavirin in veterans with hepatitis C virus genotype 2 Association of chronic hepatitis C with major depressive disorders: irrespective infection, compensated cirrhosis. and Multiple Comorbidities Clin of interferon-alpha therapy. Clin Pract Epidemiol Ment Health. 2007;3:22. Gastroenterol Hepatol. 2016; 9. el-Serag HB, Kunik M, Richardson P, Rabeneck L. Psychiatric disorders 30. Ioannou GN, Beste LA, Chang MF, Green PK, Lowy E, Tsui JI, Su F, Berry K. among veterans with hepatitis C infection. Gastroenterology. 2002; Effectiveness of Sofosbuvir, Ledipasvir/Sofosbuvir, or Paritaprevir/ritonavir/ 123(2):476–82. Ombitasvir and Dasabuvir regimens for treatment of patients with hepatitis 10. Niederau C, Mauss S, Schober A, Stoehr A, Zimmermann T, Waizmann M, et C in the veterans affairs National Health Care System. Gastroenterology. al. Predictive factors for sustained virological response after treatment with 2016;151(3):457–71. e455 pegylated interferon alpha-2a and ribavirin in patients infected with HCV 31. Tang LSY, Masur J, Sims Z, Nelson A, Osinusi A, Kohli A, Kattakuzhy S, Polis genotypes 2 and 3. PLoS One. 2014;9(9):e107592. M, Kottilil S. Safe and effective sofosbuvir-based therapy in patients with 11. Younossi Z, Henry L. Systematic review: patient-reported outcomes in mental health disease on hepatitis C virus treatment. World J Hepatol. 2016; chronic hepatitis C–the impact of liver disease and new treatment 8(31):1318–26. regimens. Aliment Pharmacol Ther. 2015;41(6):497–520. 32. Jafri SM, Gordon SC. The safety of daclatasvir for the treatment of hepatitis 12. Mathes T, Antoine SL, Pieper D. Factors influencing adherence in hepatitis-C C. Expert Opin Drug Saf. 2015;14(11):1787–97. infected patients: a systematic review. BMC Infect Dis. 2014;14:203. 33. Läkemedelsbehandling av hepatit C- virusinfektion hos vuxna och barn.– 13. Sockalingam S, Sheehan K, Feld JJ, Shah H. Psychiatric care during hepatitis kunskapsunderlag [http://docplayer.se/6964210-Lakemedelsbehandling-av- C treatment: the changing role of psychiatrists in the era of direct-acting hepatit-c-virusinfektion-hos-vuxna-och-barn-kunskapsunderlag.html]. antivirals. Am J Psychiatry. 2015;172(6):512–6. 34. Fantino B, Moore N. The self-reported Montgomery-Åsberg depression 14. Elsherif O, Bannan C, Keating S, McKiernan S, Bergin C, Norris S. Outcomes rating scale is a useful evaluative tool in major depressive disorder. BMC from a large 10 year hepatitis C treatment programme in people who inject Psychiatry. 2009;9:26. drugs: no effect of recent or former injecting drug use on treatment 35. Cunningham JL, Wernroth L, von Knorring L, Berglund L, Ekselius L. adherence or therapeutic response. PLoS One. 2017;12(6):e0178398. Agreement between physicians' and patients' ratings on the Montgomery- 15. Hauser P, Morasco BJ, Linke A, Bjornson D, Ruimy S, Matthews A, Rifai A, Åsberg depression rating scale. J Affect Disord. 2011;135(1–3):148–53. Indest DW, Loftis JM. Antiviral completion rates and sustained viral response 36. Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh in hepatitis C patients with and without preexisting major depressive sleep quality index: a new instrument for psychiatric practice and research. disorder. Psychosomatics. 2009;50(5):500–5. Psychiatry Res. 1989;28(2):193–213. 16. Schäfer A, Scheurlen M, Weissbrich B, Schöttker K, Kraus MR. Sustained 37. Allen JP, Litten RZ, Fertig JB, Babor T. A review of research on the alcohol use virological response in the antiviral therapy of chronic hepatitis C: is there a disorders identification test (AUDIT). Alcohol Clin Exp Res. 1997;21(4):613–9. predictive value of interferon-induced depression? Chemotherapy. 2007; 38. Hildebrand M. The psychometric properties of the drug use disorders 53(4):292–9. identification test (DUDIT): a review of recent research. J Subst Abus Treat. 17. Dieperink E, Ho SB, Thuras P, Willenbring ML. A prospective study of 2015;53:52–9. neuropsychiatric symptoms associated with interferon-alpha-2b and 39. Alsabbagh ME, Eisa N, Alraiyes AH, Alraies MC, Chronic h C. Therapy: a rare ribavirin therapy for patients with chronic hepatitis C. Psychosomatics. 2003; complication revisited. BMJ Case Rep. 2013;2013 44(2):104–12. 40. Cozzolongo R, Betterle C, Fabris P, Paola Albergoni M, Lanzilotta E, Manghisi 18. Sims OT, Pollio DE, Hong BA, Jain MK, Brown GR, North CS. An assessment OG. Onset of type 1 diabetes mellitus during peginterferon alpha-2b plus of concurrent drug and alcohol use among patients seeking treatment for ribavirin treatment for chronic hepatitis C. Eur J Gastroenterol Hepatol. 2006; hepatitis C. Ann Clin Psychiatry. 2016;28(1):31–6. 18(6):689–92. 19. North CS, Sims O, Hong BA, Jain MK, Brown G, Lisker-Melman M, Pollio DE. 41. Eibl N, Gschwantler M, Ferenci P, Eibl MM, Weiss W, Schernthaner G. An empirical study of alcohol consumption by patients considering HCV Development of insulin-dependent diabetes mellitus in a patient with treatment. Am J Drug Alcohol Abuse. 2014;40(6):484–9. chronic hepatitis C during therapy with interferon-alpha. Eur J Gastroenterol 20. Tully DC, Hjerrild S, Leutscher PD, Renvillard SG, Ogilvie CB, Bean DJ, et al. Hepatol. 2001;13(3):295–8. Deep sequencing of hepatitis C virus reveals genetic compartmentalization in cerebrospinal fluid from cognitively impaired patients. Liver Int. 2016; 42. Younossi ZM, Stepanova M, Zeuzem S, Dusheiko G, Esteban R, Hezode 21. Forton DM, Allsop JM, Main J, Foster GR, Thomas HC, Taylor-Robinson SD. C, et al. Patient-reported outcomes assessment in chronic hepatitis C Evidence for a cerebral effect of the hepatitis C virus. Lancet. 2001; treated with sofosbuvir and ribavirin: the VALENCE study. J Hepatol. 358(9275):38–9. 2014;61(2):228–34. 22. Banerjee D, Reddy KR. Review article: safety and tolerability of direct-acting 43. Cacoub P, Ratziu V, Myers RP, Ghillani P, Piette JC, Moussalli J, Poynard T, anti-viral agents in the new era of hepatitis C therapy. Aliment Pharmacol Multivirc G. Impact of treatment on extra hepatic manifestations in patients Ther. 2016;43(6):674–96. with chronic hepatitis C. J Hepatol. 2002;36(6):812–8. Sundberg et al. BMC Psychiatry (2018) 18:157 Page 9 of 9 44. Kraus MR, Schafer A, Teuber G, Porst H, Sprinzl K, Wollschlager S, Keicher C, Scheurlen M. Improvement of neurocognitive function in responders to an antiviral therapy for chronic hepatitis C. Hepatology. 2013;58(2):497–504. 45. Zampino R, Boemio A, Sagnelli C, Alessio L, Adinolfi LE, Sagnelli E, Coppola N. Hepatitis B virus burden in developing countries. World J Gastroenterol. 2015;21(42):11941–53. 46. Kuhn T, Sayegh P, Jones JD, Smith J, Sarma MK, Ragin A, et al. Improvements in brain and behavior following eradication of hepatitis C. J Neuro-Oncol. 2017;23(4):593–602. 47. Byrnes V, Miller A, Lowry D, Hill E, Weinstein C, Alsop D, Lenkinski R, Afdhal NH. Effects of anti-viral therapy and HCV clearance on cerebral metabolism and cognition. J Hepatol. 2012;56(3):549–56. 48. Negro F, Forton D, Craxi A, Sulkowski MS, Feld JJ, Manns MP. Extrahepatic morbidity and mortality of chronic hepatitis C. Gastroenterology. 2015; 149(6):1345–60. 49. Midgard H, Weir A, Palmateer N, Lo Re V 3rd, Pineda JA, Macias J, Dalgard O. HCV epidemiology in high-risk groups and the risk of reinfection. J Hepatol. 2016;65(1 Suppl):S33–45. 50. Islam N, Krajden M, Shoveller J, Gustafson P, Gilbert M, Buxton JA, et al. Incidence, risk factors, and prevention of hepatitis C reinfection: a population-based cohort study. Lancet Gastroenterol Hepatol. 2017;2(3):200–10. 51. Midgard H, Bjoro B, Maeland A, Konopski Z, Kileng H, Damas JK, et al. Hepatitis C reinfection after sustained virological response. J Hepatol. 2016;64(5):1020–6.

Journal

BMC PsychiatrySpringer Journals

Published: May 29, 2018

References

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off