Abstract
Background Current treatment combinations for chronic hepatitis C virus infection still include pegylated interferon and ribavirin despite the new therapeutic options available. Interferon-based treatments are associated with a high incidence of adverse effects. Central nervous system events are among the most frequent adverse drug reactions and their influence on treatment adherence and effectiveness is controversial. Objective The aim of the study was to evaluate neuropsychiatric adverse effects of interferon-based treatment for chronic hepatitis C in standard multidisciplinary clinical practice. Risk factors for these adverse effects and their impact on adherence and sustained viral response were also evaluated. Setting Ambulatory care pharmacy in coordination with the liver unit and the infectious diseases unit at a 650-bed tertiary university hospital. Methods We included all consecutive patients with chronic hepatitis C who completed treatment with pegylated interferon and ribavirin between 2005 and 2013. All patients underwent a multidisciplinary follow-up during treatment. Main outcome measures Neuropsychiatric adverse effects were evaluated in relation to severity, management and outcome. The presence of anxiety and depression was evaluated by means of specific tests. Results A total of 717 treatments in 679 patients were included. During treatment, we detected 1679 neuropsychiatric adverse effects in 618 patients (86.2 %), generating 1737 clinical interventions. Fifty-seven (3.3 %) neuropsychiatric adverse effects were severe and 2 (0.1 %) were life-threatening (suicidal attempts). Most neuropsychiatric adverse effects (1555 events, 92.6 %) resolved without sequelae. Psychiatric medication was required in 289 patients (40.3 %). Sustained viral response was achieved in 400 cases (55.8 %) and was associated with adherence (OR = 1.942, 95 % CI = 1.235–3.052, p = 0.004). A multivariate analysis did not show any relationship between neuropsychiatric adverse effects and treatment adherence or sustained viral response. A psychiatric history was a strong risk factor for depression, anxiety and other psychiatric disorders during treatment. Conclusion Neuropsychiatric adverse effects during interferon-based treatments in patients with chronic hepatitis C were common but mostly mild or moderate. Early detection and accurate multidisciplinary management avoided treatment discontinuation, ensuring adherence and attaining sustained viral response. The identified risk factors could be used to determine patients eligible for interferon-free combinations, thus optimizing health system economics.
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Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013;57:1333–42.
Manns MP, Pockros PJ, Norkrans G, Smith CI, Morgan TR, Haussinger D, et al. Long-term clearance of hepatitis C virus following interferon alpha-2b or peginterferon alpha-2b, alone or in combination with ribavirin. J Viral Hepat. 2013;20:524–9.
Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology. 2002;36:S237–44.
European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2015. J Hepatol. 2015;63:199–236.
European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatitis C virus infection. J Hepatol. 2014;60:392–420.
Rein DB, Wittenborn JS, Smith BD, Liffmann DK, Ward JW. The cost-effectiveness, health benefits, and financial costs of new antiviral treatments for hepatitis C virus. Clin Infect Dis. 2015;61:157–68.
Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–82.
Direcció General de Regulació, Planificació i Recursos Sanitaris. Departament de Salut. Generalitat de Catalunya. Criteris d’indicació del tractament de les hepatitis víriques. [Indication criteria for the treatment of viral hepatitis]. Available at: http://canalsalut.gencat.cat/web/.content/home_canal_salut/professionals/participacio/grups_de_treball/consells_assessors_sobre_lus_racional_dels_medicaments/consell_assessor_sobre_el_tractament_farmacologic_de_les_hepatitis_viriques/documents/arxius/crit_indica.pdf. Accessed 22 June 2015.
European Medicines Agency. Pegasys: EPAR—Product Information. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000395/WC500039195.pdf. Accessed 22 June 2015.
National Cancer Institute (U.S.). Common terminology criteria for adverse events (CTCAE). Rev. ed. Bethesda: U.S. Dept. of Health and Human Services, National Institutes of Health, National Cancer Institute; 2009.
Schaefer M, Capuron L, Friebe A, Diez-Quevedo C, Robaeys G, Neri S, et al. Hepatitis C infection, antiviral treatment and mental health: a European expert consensus statement. J Hepatol. 2012;57:1379–90.
Herrero MJ, Blanch J, Peri JM, De Pablo J, Pintor L, Bulbena A. A validation study of the hospital anxiety and depression scale (HADS) in a Spanish population. Gen Hosp Psychiatry. 2003;25:277–83.
Lobo A, Perez-Echeverria MJ, Artal J. Validity of the scaled version of the General Health Questionnaire (GHQ-28) in a Spanish population. Psychol Med. 1986;16:135–40.
Haynes RB, Taylor DW, Sackett DL, Gibson ES, Bernholz CD, Mukherjee J. Can simple clinical measurements detect patient noncompliance? Hypertension. 1980;2:757–64.
Constant A, Castera L, Dantzer R, Couzigou P, de Ledinghen V, Demotes-Mainard J, et al. Mood alterations during interferon-alfa therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms. J Clin Psychiatry. 2005;66:1050–7.
Schaefer M, Hinzpeter A, Mohmand A, Janssen G, Pich M, Schwaiger M, et al. Hepatitis C treatment in “difficult-to-treat” psychiatric patients with pegylated interferon-alpha and ribavirin: response and psychiatric side effects. Hepatology. 2007;46:991–8.
Martin-Santos R, Diez-Quevedo C, Castellvi P, Navines R, Miquel M, Masnou H, et al. De novo depression and anxiety disorders and influence on adherence during peginterferon-alpha-2a and ribavirin treatment in patients with hepatitis C. Aliment Pharmacol Ther. 2008;27:257–65.
Evon DM, Verma A, Simpson K, Galanko JA, Dougherty KA, Fried MW. Psychiatric symptoms during interferon treatment for hepatitis C: experiences from a tertiary care hepatology centre. Aliment Pharmacol Ther. 2008;27:1071–80.
Sarkar S, Jiang Z, Evon DM, Wahed AS, Hoofnagle JH. Fatigue before, during and after antiviral therapy of chronic hepatitis C: results from the Virahep-C study. J Hepatol. 2012;57:946–52.
Sockalingam S, Abbey SE, Alosaimi F, Novak M. A review of sleep disturbance in hepatitis C. J Clin Gastroenterol. 2010;44:38–45.
Sockalingam S, Blank D, Al Jarad A, Alosaimi F, Hirschfield G, Abbey SE. A comparison of depression screening instruments in hepatitis C and the impact of depression on somatic symptoms. Psychosomatics. 2011;52:433–40.
Raison CL, Borisov AS, Broadwell SD, Capuron L, Woolwine BJ, Jacobson IM, et al. Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction. J Clin Psychiatry. 2005;66:41–8.
Ogawa E, Furusyo N, Kajiwara E, Takahashi K, Nomura H, Tanabe Y, et al. Evaluation of the adverse effect of premature discontinuation of pegylated interferon alpha-2b and ribavirin treatment for chronic hepatitis C virus infection: results from Kyushu University Liver Disease Study. J Gastroenterol Hepatol. 2012;27:1233–40.
Carrion JA, Gonzalez-Colominas E, Garcia-Retortillo M, Canete N, Cirera I, Coll S, et al. A multidisciplinary support programme increases the efficiency of pegylated interferon alfa-2a and ribavirin in hepatitis C. J Hepatol. 2013;59:926–33.
Smith JP. Treatment options for patients with hepatitis C: role of pharmacists in optimizing treatment response and managing adverse events. Pharmacotherapy. 2008;28:1151–61.
Schmidt F, Janssen G, Martin G, Lorenz R, Loeschke K, Soyka M, et al. Factors influencing long-term changes in mental health after interferon-alpha treatment of chronic hepatitis C. Aliment Pharmacol Ther. 2009;30:1049–59.
Udina M, Hidalgo D, Navines R, Forns X, Sola R, Farre M, et al. Prophylactic antidepressant treatment of interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis. J Clin Psychiatry. 2014;75:e1113–21.
Hou XJ, Xu JH, Wang J, Yu YY. Can antidepressants prevent pegylated interferon-alpha/ribavirin-associated depression in patients with chronic hepatitis C: meta-analysis of randomized, double-blind, placebo-controlled trials? PLoS One. 2013;8:e76799.
Klein MB, Lee T, Brouillette MJ, Sheehan NL, Walmsley S, Wong DK, et al. Citalopram for the prevention of depression and its consequences in HIV-hepatitis C coinfected individuals initiating pegylated interferon/ribavirin therapy: a multicenter randomized double-blind placebo-controlled trial. HIV Clin Trials. 2014;15:161–75.
Mulder RT, Ang M, Chapman B, Ross A, Stevens IF, Edgar C. Interferon treatment is not associated with a worsening of psychiatric symptoms in patients with hepatitis C. J Gastroenterol Hepatol. 2000;15:300–3.
Sarkar S, Sarkar R, Berg T, Schaefer M. Sadness and mild cognitive impairment as predictors for interferon-alpha-induced depression in patients with hepatitis C. Br J Psychiatry. 2015;206:45–51.
Wu JY, Shadbolt B, Teoh N, Blunn A, To C, Rodriguez-Morales I, et al. Influence of psychiatric diagnosis on treatment uptake and interferon side effects in patients with hepatitis C. J Gastroenterol Hepatol. 2014;29:1258–64.
Preau M, Marcellin F, Spire B, Ravaux I, Dellamonica P, Blanc D, et al. Impaired anger control as an underappreciated side effect of treatments for chronic HCV infection in HIV–HCV coinfected patients. J Clin Gastroenterol. 2008;42:92–6.
Raison CL, Broadwell SD, Borisov AS, Manatunga AK, Capuron L, Woolwine BJ, et al. Depressive symptoms and viral clearance in patients receiving interferon-alpha and ribavirin for hepatitis C. Brain Behav Immun. 2005;19:23–7.
Fontana RJ, Kronfol Z, Lindsay KL, Bieliauskas LA, Padmanabhan L, Back-Madruga C, et al. Changes in mood states and biomarkers during peginterferon and ribavirin treatment of chronic hepatitis C. Am J Gastroenterol. 2008;103:2766–75.
Castera L, Constant A, Henry C, Champbenoit P, Bernard PH, De Ledinghen V, et al. Impact on adherence and sustained virological response of psychiatric side effects during peginterferon and ribavirin therapy for chronic hepatitis C. Aliment Pharmacol Ther. 2006;24:1223–30.
Cabre Serres M, Rudi Sola N, Pontes Garcia C, Vergara Gomez M, Parra Uribe I, Gorgas Torner MQ. [Multidisciplinary approach as a model for detection and monitoring of psychiatric morbidity in patients treated with interferon and ribavirin]. Farm Hosp. 2014;38:162–8.
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–45.
Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. 2000;356:1255–9.
Nguyen TM, La Caze A, Cottrell N. What are validated self-report adherence scales really measuring?: a systematic review. Br J Clin Pharmacol. 2014;77:427–45.
Acknowledgments
The authors thank J. Cadafalch for his help during the study, Carolyn Newey for assistance revising the English, and I. Gich for supporting statistical analysis.
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Masip, M., Tuneu, L., Pagès, N. et al. Prevalence and detection of neuropsychiatric adverse effects during hepatitis C treatment. Int J Clin Pharm 37, 1143–1151 (2015). https://doi.org/10.1007/s11096-015-0177-1
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DOI: https://doi.org/10.1007/s11096-015-0177-1