Factors associated with hepatitis C treatment adherence: an integrative review

Côco, Layla Tatiane; Silva, Giovanni Faria; Romeiro, Fernando Gomes; Cerqueira, Ana Teresa de Abreu Ramos

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REVIEW • Ciênc. saúde coletiva 27 (04) • Apr 2022 • https://doi.org/10.1590/1413-81232022274.06942021 copy

Factors associated with hepatitis C treatment adherence: an integrative review

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

This integrative review examined factors associated with hepatitis C treatment adherence. The articles included were published in English, Spanish and Portuguese in the Lilacs, Medline, PsycINFO, Web of Science, Scopus and CINAHL databases, between 2000 and 2019. Initially, 540 publications were found and, after applying the study inclusion criteria, 22 articles were selected. Percentage non-adherence to treatment ranged from 12% to 32%. The variables identified as facilitating adherence were: receiving treatment for psychiatric disorders identified during treatment; knowing about medications and disease; receiving less complex treatment with greater likelihood of cure; fewer adverse events; social support; doctor-patient communication; and/or being in relationships. Barriers to adherence identified were: presence of depressive symptoms and other mental disorders; abuse of alcohol and psychoactive substances; education; age; ethnicity; unemployment; not having a steady partner; stigma; distance from health services; and the complexity and adverse effects of treatment. This review identified gaps in research on adherence.

Key words:
Treatment adherence; Hepatitis C; Review

Year	Authors	Design	N	Country	Objective	Treatment type	Measurement used to assess adherence	Findings
2001	Kraus et al.³⁴34 Kraus MR, Schafer A, Csef H, Faller H, Mork H, Scheurlen M. Compliance with Therapy in Patients with Chronic Hepatitis C. Associations with Psychiatric Symptoms, Interpersonal Problems, and Mode of Acquisition. Dig Dis Sci 2001; 46(10):2060-2065.	Cohort	74	Germany	To investigate psychiatric symptoms, interpersonal problems, different manners of contracting hepatitis C and sociodemographic factors as variables possibly associated with adherence	Interferon (IFN)-a-2b with or without Ribavirin	Attending to start treatment; attending follow-up; maintaining abstinence and not dropping out of treatment	Predictors of non-adherence: phobic anxiety (p=0.04); depression (p=0.01); hostility (p<0.01); intrusiveness (p=0.01).
2007	Sylvestre and Clements²⁹29 Sylvestre DL, Clements BJ. Adherence to Hepatitis C treatment in recovering heroin users maintained on methadone. Eur J Gastroenterol Hepatol 2007; 19(9):741-747.	Cohort	71	United States	To evaluate hepatitis C treatment of heroin users in maintenance treatment with methadone	Interferon (IFN)-a-2b + Ribavirin	Combined method: self-reporting + medication dispensation records	Predictors of non-adherence: regular substance use (p=0.03); pre-existing psychiatric disorder (p=0.04). Predictor of adherence: Starting psychiatric medication during treatment (p=0.02). Significant association between adherence and SVR
2008	Martín-Santos et al.³⁵35 Martin-Santos R, Diez-Quevedo C, Castellvi P, Navinés R, Miquel M, Masnou H, Soler A, Ardevol M, Garcia F, Galeras JA, Planas R, Sola R. 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; 27:257-265.	Cohort	176	Spain	To investigate incidence of anxiety and depression, treatment of their symptoms and association with adherence to hepatitis C treatment	Interferon (IFN)-a-2b + Ribavirin	Took > 80% of the medication	36% incidence of depressive and anxiety disorder; greater in first four weeks of treatment. Immigrants showed greater incidence of depressive and anxiety disorder than non-immigrants (p=0.005). Predictor of non-adherence: Depressive and anxiety disorder (p<0.04).
2010	Melin et al.²¹21 Melin P, Choustermanc M, Fontangesd T, Ouzane D, Rotilyf M, Lang JP, Marcellin P, Cacoub P; CheObs Study Group. Effectiveness of chronic hepatitis C treatment in drug users in outine clinical practice: results of a prospective cohort study. Eur J Gastroenterol Hepatol 2010; 22(9):1050-1057.	Multi-centre cohort	1,860	France	To investigate SVR, adherence and quality of life in chemical dependents and in patients with no history of dependence	Interferon (IFN)-a-2b + Ribavirin	Self-reporting	Adherence, SVR and quality of life were similar in dependent and non-dependent patients.
2011	Grebely et al.³³33 Grebely J, Matthews GV, Hellard M, Shaw D, Beek IV, Petoumenos K, Alavi M, Yeung B, Haber PS, Lloyd AR, Kaldor JM, Dore GJ. Adherence to treatment for recently acquired hepatitis C virus (HCV) infection among injecting drug users. J Hepatol 2011; 55(1):76-85.	Multi-centre cohort	163	Australia	To evaluate adherence to treatment in persons with a recent diagnosis of hepatitis C	Interferon (IFN)-a-2b with or without Ribavirin	PEG-IFN administration records	Predictor of adherence: Schooling (having higher education) (p=0.02).
2011	Marcellin et al.²⁰20 Marcellin P, Chousterman M, Fontanges T, Ouzan D, Rotily M, Varastet M, Lang J-P, Melin P, Cacoub P. Adherence to treatment and quality of life during hepatitis C therapy: a prospective, real-life, observational study. Liver Int 2011; 31(4):516-524.	Multi-centre cohort	1,860	France	To evaluate adherence to treatment, identify factors associated with, and coherence between, adherence reported by patient and doctor	Interferon (IFN)-a-2b + Ribavirin	Self-reporting by patient + self-reporting by doctor	Self-reporting by patient and doctor disagreed, with doctors overestimating adherence by 20% to 30%. Predictors of adherence: virus genotype 3 (p=0.02); co-infection with HIV (p=0.003); first treatment (p=0.03); distance to referral centre (p=0.024); and abstinence during treatment (p<0.01).
2011	Re et al.²⁶26 Re VL, Teal V, Localio AR, Amorosa VK, Kaplan DE, Gross R. Relationship between adherence to hepatitis C virus therapy and virologic outcomes: a cohort study. Ann Med Intern Fenn Suppl 2011; 155(6):353-360.	Retrospective cohort	5,706	United States	To evaluate the relationship between adherence and early virological response, changes in adherence in the course of treatment and risk factors for non-adherence	Interferon (IFN)-a-2b + Ribavirin	Medication dispensation records	Early virological response was greater in patients with higher treatment adherence rates. Sustained virological response was greater in those with higher levels of adherence to interferon and ribavirin during the second, third and fourth adherence evaluation intervals for patients with genotypes 1 and 4.
2011	Wagner et al.²²22 Wagner G, Osilla KC, Garnett J, Ghosh-Dastidar B, Bhatti L, Goetz MB, Witt M. Patient Characteristics Associated with HCV Treatment Adherence, Treatment Completion, and Sustained Virologic Response in HIV Coinfected Patients. AIDS Res Treat 2011; 2011:903480.	Cohort	72	United States	To evaluate HIV co-infected patients’ characteristics associated with adherence, conclusion of treatment and SVR	Interferon (IFN)-a-2b + Ribavirin	Self-reporting (analogical visual scale)	Predictor of non-adherence: Psychiatric disorder (p=0.04).
2015	Bonner et al.³¹31 Bonner JE, Esserman DA, Golin CE, Evon DM. Self-Efficacy and Adherence to Antiviral Treatment for Chronic Hepatitis C. J Clin Gastroenterol 2015; 49:76-83.	Multi-centre cohort	401	United States	To identify associations between patient characteristics and self-efficacy expectations, before and during treatment, and association between self-efficacy expectations and adherence to treatment	Interferon (IFN)-a-2b + Ribavirin	Electronic monitoring	Self-efficacy expectations were associated with having a relationship, schooling, health insurance and being less depressed. More communication in week 24 reduced the risk of missing doses during weeks 24 to 48 of treatment.
2013	Evon et al.³²32 Evon DM, Esserman DA, Bonner JE, Rao T, Fried MW, Golin CE. Adherence to PEG/Ribavirin Treatment for Chronic Hepatitis C: Prevalence, Patterns, and Predictors of Missed Doses and Nonpersistence. J Viral Hepat 2013; 20(8):536-549.	Cohort	48	United States	To identify patient characteristics associated with prevalence, missed doses and stopping treatment	Interferon (IFN)-a-2b + Ribavirin	Electronic monitoring	Predictors of non-adherence: Age (being younger) (p<0.001); ethnicity (Afro-American) (p<0.001); unemployed (p<0.001); not being in a marital relationship (p=0.029).
2013	Re et al.²⁵25 Re VL, Teal V, Localio AR, Amorosa VK, Kaplan DE, Gross R. Adherence to Hepatitis C Virus Therapy in HIV/Hepatitis C Coinfected Patients. AIDS Behav 2013; 17(1):94-103.	Retrospective cohort	333	United States	To examine for the presence of depressive disorder, bipolar disorder, schizophrenia and methadone maintenance treatment for chemical dependency as possible barriers to adherence in patients co-infected with HIV	Interferon (IFN)-a-2b + Ribavirin	Medication dispensation records	Predictor of non-adherence: Methadone treatment for dependency (p=0.04).
2015	Batool and Kausar²³23 Batool S, Kausar R. Health Related Behaviors and Medication Adherence in Patients with Hepatitis C. J Behav Sci 2015; 25(1):172-186.	Cross-sectional	100	Pakistan	To examine changes in health-related behaviour before and after diagnosis and the relationship between these behaviours and adherence	Not stated	Self-reporting (Morisky scale)	Predictors of adherence: healthy diet, change in eating behaviour (p<0.01). Predictor of non-adherence: fatigue (p<0.05).
2017	Vieira-Castro and Oliveira²⁷27 Vieira-Castro ACM, Oliveira LCM. Impact of alcohol consumption among patients in hepatitis C virus treatment. Arq Gastroenterol 2017; 54(3):232-237.	Cross-sectional	121	Brazil	To evaluate the impact of alcohol consumption in patients in treatment for hepatitis C	Interferon (IFN)-a-2b + Ribavirin	Medication dispensation records	Predictor of non-adherence: Discontinuance of treatment was greater among patients who consumed alcohol during treatment (66.7% vs. 21.4%) and among those who were not abstinent for at least 6 months (72.7% vs. 15.4%).
2018	Cunningham et al.²⁸28 Cunningham EB, Amina J, Feldc JJ, Bruneaud J, Dalgarde O, Powis J, Hellard M, Cooper C, Read P, Conway B, Dunlop AJ, Norton B, Litwin AH, Hajarizadeh B, Thurnheer MC, Dillon JF, Weltman M, Shaw D, Bruggmann P, Gane E, Fraser C, Marks P, Applegate TL, Quiene S, Siriragavan S, Matthews GV, Dore GJ, Grebely J, SIMPLIFY study group. Adherence to sofosbuvir and velpatasvir among people with chronic HCV infection and recent injection drug use: The SIMPLIFY study. Int J Drug Policy 2018; 62:14-23.	Multi-centre cohort	103	Australia	To study the association between adherence to treatment and recent use of injected drugs	Sofosbuvir and velpatasvir	Combined method: electronic monitoring + pill count + self-reporting	Predictor of non-adherence at baseline: Use of injected drugs (cocaine and amphetamines) in prior month (p=0.019). Predictors of non-adherence during treatment: non-abstinent (p=0.023); deviation from administration schedule (p<0.001).
2019	Chehl et al.³⁶36 Chehl N, Maheshwari A, Yoo H, Cook C, Zhang T, Brown S, Thuluvath PJ. HCV compliance and treatment success rates are higher with DAAs in structured HCV clinics compared to general hepatology clinics. Medicine (Baltimore) 2019; 98(28):e16242.	Retrospective cohort	1,328	United States	To ascertain whether adherence to treatment was greater among patients treated in an outpatient facility structured for hepatitis C than among those treated in a general hepatology clinic.	Sofosbuvir, sofosbuvir/daclatasvir, sofosbuvir/ ledipasvir, sofosbuvir/velpatasvir, sofosbuvir/simeprevir, elbasvir/grazoprevir or dasabuvir/ombitasvir/paritaprevir/ritonavir with or without ribavirin	Show SVR	Predictors of adherence: Patients in treatment in a service structured for hepatitis C displayed greater adherence to treatment than those in treatment in a general hepatology service (p<0001). Other findings: age (being older) (p=0.0001); being female (p=0.05).
2014	North et al.³⁷37 North CS, Devereaux R, Pollio DE, Hong BA, Jain MK. Patient perspectives on hepatitis C and its treatment. Eur J Gastroenterol Hepatol 2014; 26(1):74-81.	Qualitative	48	United States	To examine barriers and facilitators to hepatitis C treatment as perceived by patients	Not stated	Did not evaluate adherence	Facilitators to treatment: Social support. Barriers to treatment: Stigma; not receiving appropriate information; problems communicating with the doctor; financial difficulties; logistical difficulties; the asymptomatic course of the disease; and undergoing difficult treatment with the possibility of not achieving the hoped-for response.
2015	Evon et al.³⁸38 Evon DM. Adherence During Antiviral Treatment Regimens forChronic Hepatitis C. A Qualitative Study of Patient-reported Facilitators and Barriers. J Clin Gastroenterol 2015; 49(5):41-50.	Qualitative	21	United States	Perceptions of persons with hepatitis C about factors that facilitated or hindered adherence to treatment	Interferon (IFN)-a-2b + Ribavirin or direct-acting antivirals with Interferon (IFN)-a-2b and Ribavirin	Did not evaluate adherence	Facilitators to adherence: More knowledge and information about the disease and the importance of adherence; internal locus of control; optimistic thinking; social motivators, particularly relationship with the doctor. Barriers to adherence: being busy at medication time; family responsibilities; work; changes in daily routine upset medication, particularly being far from home without the medications; time of going to sleep/waking up; adverse events, mostly nausea, led some intentionally to avoid taking the medication.
2015	Sublette et al.³⁹39 Sublette VA, Smith SK, George J, McCafferyd K, Douglas MW. The Hepatitis C treatment experience: patients' perceptions of the facilitators of and barriers to uptake, adherence and completion. Psychol Health 2015; 30(8):987-1004.	Qualitative	20	Australia	Patients’ perceptions of factors that influenced their decisions to start, adhere to and conclude treatment	Interferon (IFN)-a-2b + Ribavirin	Did not evaluate adherence	Starting treatment: Fear of death; stigma; shame. Facilitators to adherence: Social support; receiving personalised information and guidance with their neds and lifestyle. Barriers to adherence: Complexity of treatment; adverse events; lack of support social, stigma; limitations of health system.
2017	Sublette et al.⁴⁰40 Sublette VA, Smith SK, George J, McCaffery K, Douglas MW. Listening to both sides: A qualitative comparison between patients with hepatitis C and their healthcare professionals' perceptions of the facilitators and barriers to hepatitis C treatment adherence and completion. J Health Psychol 2017; 22(10):1300-1311.	Qualitative	40	Australia	To compare and contrast the views of patients and health personnel as to facilitators and barriers to treatment	Not stated	Did not evaluate adherence	Facilitators to adherence: Social support; communication between patient and health professional. Barriers to adherence: Stigma; difficulties in communicating between patient and health professional; limitations of health service.
2018	Giordano et al.²⁴24 Giordano NM, Brinn AJ, Garcia-Tsao G, Martino S. Patient Perspectives on Adherence to the New Hepatitis C Antiviral Medications: 'A New Lease on Life'. The Quali Report 2018; 23(1):184-203.	Qualitative	12	United States	To explore the views of military veterans about facilitators to adherence to hepatitis C treatment	Direct-acting antivirals - not specified	Self-reporting (Morisky scale)	Facilitators to adherence: Knowing about the pros and cons of the new treatment as compared with the former treatment; the new treatment’s offering realistic hope of cure; easier treatment; integrating the treatment into existing daily routines; developing behavioural strategies to manage adverse events from the treatment and treatment time; greater ability to manage adverse events; availability of medications; negative experience with the previous treatment; clear, honest communication with the doctor; good bonding with health personnel; trusting health personnel; social support; knowledge of value of medication and structure of health service.
2019	Patel et al.³⁰30 Patel K, Zickmund SL, Jones H, Reid A, Calgaro L, Otero A, Coppler T, Rogal SS. Determinants of Hepatitis C Treatment Adherence and Treatment Completion Among Veterans in the Direct Acting Antiviral Era. Dig Dis Sci 2019; 64(10):3001-3012.	Qualitative	40	United States	To identify barriers and facilitators to adherence to treatment with direct-acting antivirals	Direct-acting antivirals - not specified	Combined method: self-reporting + pill count	Facilitators to adherence at pre-treatment interview: Possibility of incorporating the treatment into routine; high possibility of cure; trusting health personnel; feeling satisfied with the team; following guidance. Facilitators to adherence at post-treatment interview: Receiving positive results as to response to treatment and minimal adverse events. Barriers to adherence at pre-treatment interview: Unintentional forgetting; adverse events. Barriers to adherence at post-treatment interview: Difficulty in incorporating the treatment into routine; forgetting.
2019	Skolnik et al.⁴¹41 Skolnik AA, Noska A, Yakovchenko V, Tsai J, Jones N, Gifford AL, McInnes DK. Experiences with interferon-free hepatitis C therapies: addressing barriers to adherence and optimizing treatment outcomes. BMC Health Serv Res2019; 19(1):91.	Qualitative	48	United States	Health personnel’s and patients’ perceptions about factors that contribute to conclusion of treatment	Direct-acting antivirals - not specified	Did not evaluate adherence	Facilitators Perceptions of current treatments and their side-effects as compared with prior experience; perception of improvement in symptoms attributed to starting the treatment; optimism in relation to SVR and/or possibility of improved health or longevity, so that they felt motivated to conclude the treatment; trusting health personnel, empathy, length of appointments and support from health personnel contributed to patients’ concluding the treatment; descriptions of consistent curative habits and routines that contributed to the treatment, including social support, calendars and other strategies for adhering to medications and appointments. All facilitators reported by health personnel were reported by patients.

Journals	N
AIDS Behavior	1
AIDS Research and Treatment	1
Alimentary Pharmacology & Therapeutics	1
Annals of Internal Medicine	1
Arq Gastroenterol	1
BMC Health Services Research	1
Digestive Diseases and Sciences	2
European Journal of Gastroenterology &Hepatology	3
Journal of Clinical Gastroenterology	2
Journal of Behavioural Sciences	1
Journal of Health Psychology	1
Journal of Viral Hepatitis	1
Hepatology	1
Liver international: official journal of the International Association for the Study of the Liver	1
Medicine	1
Psychology & Health	1
International Journal of Drug Policy	1
The Qualitative Report	1
Total	22

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[1] Collaborations

LT Côco completed a Master’s Degree thesis in Public Health, which provided the basis for the article. She contributed with the research planning and data collection, as well as data analysis, and the writing of the manuscript. ATAR Cerqueira was the study advisor, participated in the interpretation and analysis of the obtained data and in the writing of the manuscript. GF Silva was the co-advisor of the study, contributed with the study planning, and supported the data analysis and writing of the manuscript. FG Romeiro contributed to the writing of the manuscript.