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

Introduction

The development of an effective therapy using direct-acting antiviral agents to cure infection by the hepatitis C virus has made it even more important to assure adherence to treatment¹1 Campos Fernández de Sevilla MÁ, Gallego Úbeda M, Tovar Pozo M, García-Cabrera E, Monje García B, Tutau Gómez F, Delgado Téllez de Cepeda L, Iglesias-Peinado I. Measure of adherence to direct-acting antivirals as a predictor of the effectiveness of hepatitis C treatment. Int J Clin Pharm 2019; 41:1545-1554.. Prevalence of hepatitis C worldwide is approximately 1%, affecting more than 71 million individuals²2 Polaris Observatory HCV Collaborators. Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study. Lancet 2017; 2(3):161-176. and accounting for 400,000 deaths annually as a result of its two main complications: hepatic cirrhosis and hepatocellular carcinoma³3 Westbrook RH, Dusheiko G. Natural history of hepatitis C. J Hepatol 2014; 61:S58-S68..

Treatment of hepatitis C with second-generation direct-acting antiviral agents, including sofosbuvir, simeprevir, ledipasvir/sofosbuvir, velpatasvir/sofosbuvir, ombitasvir/paritraprevir/ritonavir and glecaprevir/pibrentasvir with or without ribavirin (RBV), began to be available in 2014, replacing the existing treatment for hepatitis C, which involved using pegylated interferon (PEG-IFN) in association with ribavirin (PEG-IFN+RBV) in a variety of regimes depending on the virus genotype⁴4 Brasil. Ministério da Saúde (MS). Secretaria de Ciência, Tecnologia e Insumos Estratégicos. Protocolo Clínico e Diretrizes Terapêuticas para Hepatite C e Coinfecções. Brasília: MS; 2018.

5 Douglass CH, Pedrana A, Lazarus JV, 't Hoen EFM, Hammad R, Leite RB, Hill A, Hellard M. Pathways to ensure universal and affordable access to hepatitis C treatment. BMC Med 2018; 16(1):175.^-66 Rosenthal ES, Graham CS. Price and affordability of direct-acting antiviral regimens for hepatitis C virus in the United States. Infect Agents Cancer 2016; 11:24..

In Brazil, treatment with direct-acting antiviral agents has been available in the national health system (Sistema Único de Saúde, SUS) since 2015. In many countries and regions, however, the high cost of the medicines is a barrier to access, which is also conditional on certain criteria⁵5 Douglass CH, Pedrana A, Lazarus JV, 't Hoen EFM, Hammad R, Leite RB, Hill A, Hellard M. Pathways to ensure universal and affordable access to hepatitis C treatment. BMC Med 2018; 16(1):175.^,66 Rosenthal ES, Graham CS. Price and affordability of direct-acting antiviral regimens for hepatitis C virus in the United States. Infect Agents Cancer 2016; 11:24..

The regime for this new treatment consists in one or two tablets by mouth in contrast to the previous treatment, which involved the patient needing weekly subcutaneous injections of pegylated interferon, as well as taking tablets of ribavirin. In addition to the changes in medications and their administration, the current treatment period is shorter - 8 to 24 weeks, as compared with 72 weeks in previous regimes - and there is less likelihood of adverse events.

With this new treatment, the sustained virological response (SVR) rate, which means that infection by the hepatitis C virus is cured, is 90-95%⁴4 Brasil. Ministério da Saúde (MS). Secretaria de Ciência, Tecnologia e Insumos Estratégicos. Protocolo Clínico e Diretrizes Terapêuticas para Hepatite C e Coinfecções. Brasília: MS; 2018.^,77 Ferreira VL, Pontarolo R. Contextualização e avanços no tratamento da hepatite C: uma revisão da literatura. Visao Academica 2017; 18(1):78-96.. Buti and Esteban⁸8 Buti M, Esteban R. Management of direct antiviral agent failures. Clin Mol Hepatol 2016; 22(4):432-438. and Campos Fernández de Sevilla et al.¹1 Campos Fernández de Sevilla MÁ, Gallego Úbeda M, Tovar Pozo M, García-Cabrera E, Monje García B, Tutau Gómez F, Delgado Téllez de Cepeda L, Iglesias-Peinado I. Measure of adherence to direct-acting antivirals as a predictor of the effectiveness of hepatitis C treatment. Int J Clin Pharm 2019; 41:1545-1554. note that the treatment’s efficacy can vary with several factors, such as the virus genotype, the severity of the disease and adherence to the treatment. Studies of these new medications suggest that high levels of adherence are necessary in order to achieve sustained virological response and reduce the development of drug resistance, which would prejudice possible future treatments⁹9 Sarpel D. Non-adherence is the most important risk factor for ledipasvir/sofosbuvir HCV treatment failure in the real world [Internet]. In: Paper presented at the American Association for the Study of Liver Disease Meeting; 2016 [cited 2018 mar 18]. Available from: http://www.natap.org/2016/AASLD/AASLD_75.htm.
http://www.natap.org/2016/AASLD/AASLD_75... ^,1010 European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2018. J Hepatol 2018; 69(2):461-511..

It is thus important to bear in mind that treatment adherence is a dynamic, multi-factor process¹¹11 Organização Mundial da Saúde (OMS). Adherence to long-term therapies. Evidence for action. Geneva: WHO; 2003. which needs to be examined, evaluated and understood, so as to be stimulated in hepatitis C treatment with direct-acting antiviral agents.

There is a great deal of diversity in the study of treatment adherence, because of a lack of uniformity in the literature as to the concept, the terminology used and the different measurements used to evaluate adherence¹¹11 Organização Mundial da Saúde (OMS). Adherence to long-term therapies. Evidence for action. Geneva: WHO; 2003.^,1212 Vrijens B, Geest S, Hughes DA, Przemyslaw K, Demonceau J, Ruppar T, Dobbels F, Fargher E, Morrison V, Lewek P, Matyjaszczyk M, Mshelia C, Clyne W, Aronson JK, Urquhart J; ABC Project Team. A new taxonomy for describing and defining adherence to medications. Br J Clin Pharmacol 2012; 73(5):691-705.. This lack of standardisation has prevented comparisons between research findings and limited the implementation of effective procedures and measures to increase adherence to health-related behaviours¹¹11 Organização Mundial da Saúde (OMS). Adherence to long-term therapies. Evidence for action. Geneva: WHO; 2003.^,1212 Vrijens B, Geest S, Hughes DA, Przemyslaw K, Demonceau J, Ruppar T, Dobbels F, Fargher E, Morrison V, Lewek P, Matyjaszczyk M, Mshelia C, Clyne W, Aronson JK, Urquhart J; ABC Project Team. A new taxonomy for describing and defining adherence to medications. Br J Clin Pharmacol 2012; 73(5):691-705..

In this study, adherence was defined as “the extent to which a person’s behaviour - taking medication following the recommended diet and/or implementing lifestyle changes - corresponds to the recommendations made by a health professional”¹¹11 Organização Mundial da Saúde (OMS). Adherence to long-term therapies. Evidence for action. Geneva: WHO; 2003.(p.3).

The complexity of this phenomenon stems from the fact that adherence behaviour results from the interaction of factors of different kinds, which can be grouped as: a) individual factors; b) socioeconomic factors; c) factors connected with health services and health personnel; d) factors connected with the disease; and e) factors connected with the treatment itself¹¹11 Organização Mundial da Saúde (OMS). Adherence to long-term therapies. Evidence for action. Geneva: WHO; 2003.^,1313 Polejack L, Seidl EMF. Monitoramento e avaliação da adesão ao tratamento antirretroviral para HIV/aids: desafios e possibilidades. Cien Saude Colet 2010; 15(Supl. 1):1201-1208.

14 Obreli-Neto PR, Baldoni AO, Guidoni CM, Bergamini D, Hernandes KC, Luz RT, Silva FB, Silva RO, Pereira LRL, Cuman RKN. Métodos de avaliação de adesão à farmacoterapia. Rev Bras Farm 2012; 93(4):403-410.^-1515 Martin LR, Williams SL, Haskard KB, Dimatteo MR. The challenge of patient adherence. Ther Clin Risk Manag 2005; 1(3):189-199..

In the clinical context, as well as in the research context, there are discussions and divergences as to the best way to assess adherence, given that no method can be considered to be the gold standard¹⁴14 Obreli-Neto PR, Baldoni AO, Guidoni CM, Bergamini D, Hernandes KC, Luz RT, Silva FB, Silva RO, Pereira LRL, Cuman RKN. Métodos de avaliação de adesão à farmacoterapia. Rev Bras Farm 2012; 93(4):403-410.^,1616 Leite SN, Vasconcellos MPC. Adesão à terapêutica medicamentosa: elementos para a discussão de conceitos e pressupostos adotados na literatura. Cien Saude Colet 2003; 8(3):775-782.. The main methods are known as direct and indirect methods. Self-reporting, pill counts, pharmacy records and patient records, electronic devices and the patient diary are considered to be indirect measurements for assessing treatment adherence. The direct measurements are: detecting the medication in the blood and therapeutic serum level¹¹11 Organização Mundial da Saúde (OMS). Adherence to long-term therapies. Evidence for action. Geneva: WHO; 2003.^,1313 Polejack L, Seidl EMF. Monitoramento e avaliação da adesão ao tratamento antirretroviral para HIV/aids: desafios e possibilidades. Cien Saude Colet 2010; 15(Supl. 1):1201-1208.

14 Obreli-Neto PR, Baldoni AO, Guidoni CM, Bergamini D, Hernandes KC, Luz RT, Silva FB, Silva RO, Pereira LRL, Cuman RKN. Métodos de avaliação de adesão à farmacoterapia. Rev Bras Farm 2012; 93(4):403-410.

15 Martin LR, Williams SL, Haskard KB, Dimatteo MR. The challenge of patient adherence. Ther Clin Risk Manag 2005; 1(3):189-199.^-1616 Leite SN, Vasconcellos MPC. Adesão à terapêutica medicamentosa: elementos para a discussão de conceitos e pressupostos adotados na literatura. Cien Saude Colet 2003; 8(3):775-782.. One option for refining assessment of adherence has been to use combined methods¹⁴14 Obreli-Neto PR, Baldoni AO, Guidoni CM, Bergamini D, Hernandes KC, Luz RT, Silva FB, Silva RO, Pereira LRL, Cuman RKN. Métodos de avaliação de adesão à farmacoterapia. Rev Bras Farm 2012; 93(4):403-410.^,1515 Martin LR, Williams SL, Haskard KB, Dimatteo MR. The challenge of patient adherence. Ther Clin Risk Manag 2005; 1(3):189-199..

In addition to different forms of monitoring, quantitative studies apply different standards in considering someone to be adhering or not to treatment¹³13 Polejack L, Seidl EMF. Monitoramento e avaliação da adesão ao tratamento antirretroviral para HIV/aids: desafios e possibilidades. Cien Saude Colet 2010; 15(Supl. 1):1201-1208.^,1616 Leite SN, Vasconcellos MPC. Adesão à terapêutica medicamentosa: elementos para a discussão de conceitos e pressupostos adotados na literatura. Cien Saude Colet 2003; 8(3):775-782.. Qualitative studies on this issue are also important and will be included in this review, because they permit greater understanding of adherence-related phenomena from the patient’s standpoint, considering social, cultural, psychological, health service- and treatment-related factors and those relating to the relationship between patient and health personnel¹⁶16 Leite SN, Vasconcellos MPC. Adesão à terapêutica medicamentosa: elementos para a discussão de conceitos e pressupostos adotados na literatura. Cien Saude Colet 2003; 8(3):775-782..

There is insufficient systematised knowledge on factors that favour hepatitis C treatment adherence behaviour, understanding such behaviour is inherently complex and it is fundamental to the success of treatment with direct-acting antiviral agents. Accordingly, it is important to locate and examine studies designed to identify variables associated with hepatitis C treatment adherence. This is crucial, because of the severity of the disease, the complexity and cost of treatment, the requirement of complete adherence in order to obtain SVR and the personal and social impact of the disease and its treatment, which make it a public health problem.

In view of the foregoing, the objectives of this integrative review were to identify, describe and analyse factors associated with adherence to hepatitis C treatment in studies published from January 2000 to October 2019.

Method

To achieve these objectives, an integrative review was conducted¹⁷17 Ganong LH. Integrative Reviews of Nursing Research. Res Nurs Health 1987; 10(1):1-11.^,1818 Mendes KDS, Silveira RCCP, Galvão CM. Revisão integrativa: método de pesquisa para a incorporação de evidências na saúde e na enfermagem. Texto Contexto Enferm 2008; 17(4):758-764., so that studies with different methodological designs (observational studies, cross-sectional studies and qualitative design studies) could be included in the analysis, thus making it possible to identify and analyse the multiple factors that can be associated with treatment adherence behaviour.

An integrative review requires six steps: (1) selecting the topic and developing the research question; (2) establishing the criteria for including studies from the literature; (3) specifying the information to be extracted from the studies selected; (4) evaluating the studies; (5) interpreting the results; and (6) presenting the review¹⁷17 Ganong LH. Integrative Reviews of Nursing Research. Res Nurs Health 1987; 10(1):1-11.^,1818 Mendes KDS, Silveira RCCP, Galvão CM. Revisão integrativa: método de pesquisa para a incorporação de evidências na saúde e na enfermagem. Texto Contexto Enferm 2008; 17(4):758-764..

The guiding question for this integrative review was: “What factors are associated with adherence to hepatitis C treatment?”. In order to conduct this review, the Health Sciences Descriptors (Descritores em Ciências da Saúde, DeCS) and Medical Subject Headings (MeSH) were used. Unindexed keywords were also used with a view to encompassing more publications in the search based on three groups of keywords combined using the Boolean method OR and AND: ((“hepatitis C” [MeSH Terms] OR “hep C”[Title/Abstract] OR HCV[Title/Abstract] OR “hepatitis c, chronic”[MeSH Terms]) AND Adherence[Title/Abstract] OR “medication adherence”[MeSH Terms] OR “treatment adherence”[All Fields] OR “treatment compliance”[All Fields] OR nonadherence[Title/Abstract] OR nonadherent[Title/Abstract] OR Compliance[Title/Abstract] OR “patient compliance”[MeSH Terms] OR noncompliance[Title/Abstract] OR noncompliant [Title/Abstract]) AND (“psychological factor”[TIAB] OR “psychological predictor”[TIAB] OR “psychological influence”[TIAB] OR “facilitators”[TIAB] OR “psychological barriers”[TIAB] OR “psychosocial factors”[All Fields] OR “psychosocial barriers”[All Fields] OR “psychosocial influence”[All Fields] OR “socioeconomic factors”[MeSH Terms] OR barriers [All Fields])).

The data search was performed in October 2019 and articles were selected from the electronic data bases Medical Literature Analysis and Retrieval System (Medline), Latin American and Caribbean Health Sciences Literature (Lilacs), PsycINFO, Web of Science, Scopus and Cumulative Index to Nursing and Allied Health Literature (CINAHL).

The inclusion criteria used in this study accepted articles on the subject of hepatitis C treatment adherence in adult patients, published between January 2000 and October 2019, in Portuguese, English or Spanish. The criteria excluded theses, articles arising from reviews, intervention studies and duplicate articles. Publications indexed in more than one database were extracted from the base in which they were first identified, thus eliminating duplicate occurrences.

In order to specify the information to be extracted from the studies selected, the authors developed a data collection instrument, with which they systematised the articles by year of publication, authorship, journal, design, sample size, country of origin of the article, study objective, treatment medication type, method used to assess adherence and significant findings.

The first stage of this study (locating the references) was performed by the first reviewer by reading the titles of the articles encountered in the data bases. In the second stage, the article abstracts were read. In the third and final stage, the articles were read in full to confirm that they met all the study criteria. In the second and third stages, the articles were read and analysed by two researchers independently, so as to avoid selection bias. Disagreements were discussed and evaluated jointly.

The studies were grouped by five factors that could be associated with adherence behaviour¹¹11 Organização Mundial da Saúde (OMS). Adherence to long-term therapies. Evidence for action. Geneva: WHO; 2003.^,1212 Vrijens B, Geest S, Hughes DA, Przemyslaw K, Demonceau J, Ruppar T, Dobbels F, Fargher E, Morrison V, Lewek P, Matyjaszczyk M, Mshelia C, Clyne W, Aronson JK, Urquhart J; ABC Project Team. A new taxonomy for describing and defining adherence to medications. Br J Clin Pharmacol 2012; 73(5):691-705.: Individual factors - lifestyle changes, psychological symptoms, abuse of alcohol and other substances and the presence of psychiatric disorders; Socioeconomic factors - age, sex, ethnicity, level of schooling, employment status, marital status, housing conditions, social support and stigma; Factors relating to the health service and health personnel - relationship and communication between patient and health professional, limitations of the health service, access to services and medications; Factors relating to the disease - genotype, symptomatology, comorbidity; Factors relating to the treatment - number of tablets to be taken daily, treatment type, prior treatments and adverse events.

The factors associated with hepatitis C treatment adherence were analysed in detail and critically, exploring the relations among the issues and seeking explanations for the differing or conflicting findings in different studies. The articles were classified by level of evidence, following the proposal of Melnyk and Fineout-Overholt¹⁹19 Melnyk BM, Fineout-Overholt E. Making the case for evidence-based practice. In: Melnyk BM, Fineout-Overholt E. Evidence-based practice in nursing & healthcare. A guide to best practice. Philadelphia: Lippincot Williams & Wilkins; 2005. p. 3-24..

Results and discussion

The database search found 540 articles and, in the first stage, from reading the titles, 80 articles were selected for their abstracts to be read. Articles on other subjects were excluded. After reading and discussing the abstracts together, the two reviewers excluded any articles that did not assess factors associated with adherence, intervention studies and review articles. From that procedure, 48 studies were selected to be read in full. Once read in full by both reviewers, 24 more studies were excluded for not investigating factors associated with adherence (16) and another (8) for being intervention studies (Figure 1).

As shown in Chart 1, the study corpus consisted of 22 articles, with the following characteristics: they were written in English, published from 2001 to 2019, about studies conducted in the United States (54%), Australia (18%) and on the European continent (in Spain, Germany and France) (18%), as well as one study in Pakistan (5%) and another in Brazil (5%). The fact that only one study in South America was found seems to indicate that studies of factors associated with adherence to hepatitis C treatment are rare in Latin American countries.

The articles were encountered in 18 journals, as shown in Chart 2. The journals European Journal of Gastroenterology & Hepatology, Digestive Diseases and Sciences and Journal of Clinical Gastroenterology accounted for the largest portion (32%) of the articles included in this review.

As regards the studies’ distribution over time, 46% had been published in the previous five years, three in 2019, two in 2018, two in 2017 and three in 2015; another three dated from 2013, four from 2011 and one each from 2014, 2010, 2008, 2007 and 2001. From the studies’ publication dates, it can be seen that research into factors associated with treatment adherence are relatively recent in the literature.

In their methodological design, seven (32%) of the studies were qualitative and 15 (68%) were quantitative, the latter being predominantly observational cohort-type studies (87%) - three retrospective cohorts - and two cross-sectional studies (13%). Sample size varied in the quantitative studies, ranging from 71 to 5706 participants, and five were multicentre studies¹³13 Polejack L, Seidl EMF. Monitoramento e avaliação da adesão ao tratamento antirretroviral para HIV/aids: desafios e possibilidades. Cien Saude Colet 2010; 15(Supl. 1):1201-1208.

14 Obreli-Neto PR, Baldoni AO, Guidoni CM, Bergamini D, Hernandes KC, Luz RT, Silva FB, Silva RO, Pereira LRL, Cuman RKN. Métodos de avaliação de adesão à farmacoterapia. Rev Bras Farm 2012; 93(4):403-410.

15 Martin LR, Williams SL, Haskard KB, Dimatteo MR. The challenge of patient adherence. Ther Clin Risk Manag 2005; 1(3):189-199.

16 Leite SN, Vasconcellos MPC. Adesão à terapêutica medicamentosa: elementos para a discussão de conceitos e pressupostos adotados na literatura. Cien Saude Colet 2003; 8(3):775-782.^-1717 Ganong LH. Integrative Reviews of Nursing Research. Res Nurs Health 1987; 10(1):1-11..

Evaluation of findings as regards treatment adherence in the studies selected

The criterion used to assess adherence, in most of the studies included in this review, was doses taken as a percentage of doses prescribed. Percentage non-adherence to treatment, on the criteria established in the studies analysed here, ranged from 12% to 32%.

Self-reporting was used in 23% of the studies²⁰20 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.

21 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.

22 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.

23 Batool S, Kausar R. Health Related Behaviors and Medication Adherence in Patients with Hepatitis C. J Behav Sci 2015; 25(1):172-186.^-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., 14% used pharmacy records²⁵25 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.

26 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.^-2727 Vieira-Castro ACM, Oliveira LCM. Impact of alcohol consumption among patients in hepatitis C virus treatment. Arq Gastroenterol 2017; 54(3):232-237., 14% combined methods²⁸28 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.

29 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.^-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., 9% electronic monitoring³¹31 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.^,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., 4% used nursing records of weekly administration of PEG-IFN injections³³33 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., 4% used patient record data (attendance to start treatment, attendance at medical referral, absence of relapse in use of injected drugs or alcohol and absence of treatment dropout)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., 9% used the treatment conclusion annotation in the patient record³⁵35 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.^,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. and 23% (the qualitative studies)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.

38 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.

39 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.

40 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.^-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. did not measure adherence objectively.

The criteria used for satisfactory adherence also differed, ranging from 80% to 100% of appropriate use of prescribed medication. Accordingly, the studies’ use of different standards, and forms of monitoring, for adherence made it difficult to compare their findings.

It can thus be concluded that the standards applied in order to evaluate adherence and the ways it is measured need to be improved. To date, there is no method that can be considered the “gold standard” for assessing adherence behaviour¹⁴14 Obreli-Neto PR, Baldoni AO, Guidoni CM, Bergamini D, Hernandes KC, Luz RT, Silva FB, Silva RO, Pereira LRL, Cuman RKN. Métodos de avaliação de adesão à farmacoterapia. Rev Bras Farm 2012; 93(4):403-410.^,1515 Martin LR, Williams SL, Haskard KB, Dimatteo MR. The challenge of patient adherence. Ther Clin Risk Manag 2005; 1(3):189-199.. Self-reporting is still the method most used, because it is quick, inexpensive, flexible and easy to apply, but its limitations must be noted: as it is subjective, it may lend itself to patients’ overestimating adherence¹²12 Vrijens B, Geest S, Hughes DA, Przemyslaw K, Demonceau J, Ruppar T, Dobbels F, Fargher E, Morrison V, Lewek P, Matyjaszczyk M, Mshelia C, Clyne W, Aronson JK, Urquhart J; ABC Project Team. A new taxonomy for describing and defining adherence to medications. Br J Clin Pharmacol 2012; 73(5):691-705.^,1515 Martin LR, Williams SL, Haskard KB, Dimatteo MR. The challenge of patient adherence. Ther Clin Risk Manag 2005; 1(3):189-199..

Adherence and treatment-related factors

Thirteen studies (59%) evaluated adherence to treatment with interferon in association with ribavirin, another five (23%) evaluated adherence to direct-acting antiviral agents and one study (4%) evaluated adherence among patients in treatment with interferon in association with ribavirin or patients participating in a phase II clinical trial to assess the combination of direct-acting antivirals with ribavirin and interferon. Three (13%) did not specify the treatment given.

The studies that evaluated factors associated with adherence to the treatment regime with interferon and ribavirin noted that the complexity of the treatment, the weekly injections and oral ingestion of large numbers of tablets at different times, which called for changes of routine and were long-duration treatments, were considered variables that constituted barriers to adherence³⁷37 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.

38 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.^-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.. Lesser adherence to treatment with PEG-IFN+RBV was also associated with the adverse events - extreme fatigue, nausea, irritability, hair loss, skin eruptions and insomnia - caused by using those medications³⁰30 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.^,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.^,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.. Also, the knowledge that this complex, difficult treatment might possibly be completed without achieving the hoped-for outcome was also considered a barrier to adherence³⁷37 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.. Another study showed that being in treatment for the first time was associated with greater adherence (p=0.02)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..

Of the studies included in this review, the more recent, investigating variables associated with adherence to treatment with direct-acting antiviral agents, showed that the change in treatment could facilitate adherence in its multiple dimensions, by virtue of its being a less complex treatment and occurring in a shorter time²⁴24 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.^,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.^,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.. Adverse personal experiences with prior treatments using interferon and ribavirin were also found to facilitate adherence to the treatment prescribed currently and examined here²⁴24 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.^,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.^,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..

In addition to these factors, knowing that there is a greater likelihood of cure with treatment using direct-acting antiviral agents, given their greater efficacy, facilitates adherence to the treatment²⁴24 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.^,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.^,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., while treatments using interferon in association with ribavirin returned low efficacy, with sustained virological response rates of around 50%³3 Westbrook RH, Dusheiko G. Natural history of hepatitis C. J Hepatol 2014; 61:S58-S68.^,77 Ferreira VL, Pontarolo R. Contextualização e avanços no tratamento da hepatite C: uma revisão da literatura. Visao Academica 2017; 18(1):78-96..

Adherence and individual factors

Twelve studies examined individual factors associated with treatment adherence. Nine (41%) of the 22 studies investigated the association of mental disorder and/or depressive and anxiety symptoms with adherence, four (44%) finding statistically significant associations (p<0.04³⁵35 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.; p=0.01³⁴34 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.; p=0.04²⁹29 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.; p=0.04²²22 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.). However, 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. found that starting psychiatric treatment while depressive or anxiety symptomatology was present was associated with increased adherence. Three of these studies used validated scales for symptom screening: Symptom Checklist-90 Revised (SCL-90-R)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., Hospital Anxiety and Depression Scale (HADS)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., Beck Depression Inventory³⁵35 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. and Patient Health Questionnaire (PHQ)²⁹29 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.. Another study in the United States obtained information about diagnosis of depression or other psychiatric disorder from patient records²²22 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..

Presenting with a mental disorder prior to and during treatment was the variable most investigated in the studies reviewed. This interest in assessing the influence of psychiatric problems on treatment adherence can be assumed to respond to the high prevalence of depressive symptoms in this population⁴²42 Adinolfi LE, Nevola R, Rinaldi L, Romano C, Giornado M. Chronic Hepatitis C Virus Infection and Depression. Clinics in Liver Disease 2017; 21(3):517-534., especially those receiving regimes (PEG-IFN+RBV) with significant psychiatric side-effects⁴²42 Adinolfi LE, Nevola R, Rinaldi L, Romano C, Giornado M. Chronic Hepatitis C Virus Infection and Depression. Clinics in Liver Disease 2017; 21(3):517-534.^,4343 Medeiros LPJ, Kayo M, Medeiros RBV, Lima MBC, Mello CEB. Interferon-induced depression in patients with hepatitis C: an epidemiologic study. Rev Assoc Med Bras 2014; 60(1):35-39.. It is also motivated by the association between psychiatric symptoms and non-adherence to treatment of other chronic diseases, as already evidenced in a meta-analysis with more than 18,000 participants regarding depression and adherence to medication in treatment of chronic diseases in the United States. In that study, the likelihood of a depressed patient being non-adherent was estimated to be 1.76 times greater than for a non-depressed patient⁴⁴44 Grenard J, Ewing B, Adams JL, Booth M, Maglione MA, McGlynn EA, Gellad WF. Depression and Medication Adherence in the Treatment of Chronic Diseases in the United States. A Meta-Analysis. J Gen Intern Med 2011; 26(10):1175-1182..

Another aspect investigated as possibly relevant to adherence or non-adherence was psychoactive substance use. Three studies included in this review reported statistically significant associations between the regular use of psychoactive substances (heroin, stimulants, amphetamine, cocaine) and lower adherence rates (p<0.01²⁰20 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.; p=0.03²⁹29 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.; p=0.023²⁸28 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.). These studies found lower adherence to treatment in persons who used injected drugs in the month prior to starting treatment and among those using during treatment. Another study showed an association of lower adherence in heroin users undergoing methadone treatment, also showing an association between a higher adherence rate and SVR²⁵25 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..

The only study in Brazil included in this review indicated that alcohol use was also associated with higher rates of treatment dropout. That study found higher percentage treatment dropout in the group of patients who used >60 g/day of alcohol (32%) and an even higher percentage among patients who drank during treatment (66.7%, as against 21.4% in those who were abstinent) as well as among those who had not abstained from drinking for at least the prior 6 months (72.7%, as against 15.4% among those who had abstained). That study also found that persons co-infected with HIV and whose adherence was <80% failed to achieve SVR²⁷27 Vieira-Castro ACM, Oliveira LCM. Impact of alcohol consumption among patients in hepatitis C virus treatment. Arq Gastroenterol 2017; 54(3):232-237.. Given the high prevalence of psychoactive substance use among persons with hepatitis C, this population is cause for major concern, because injected drug use is currently the main risk factor for infection with the hepatitis C virus in most of the developed countries¹⁰10 European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2018. J Hepatol 2018; 69(2):461-511..

A cross-sectional study of a sample of 100 individuals in Pakistan²³23 Batool S, Kausar R. Health Related Behaviors and Medication Adherence in Patients with Hepatitis C. J Behav Sci 2015; 25(1):172-186. evaluated health care-related behaviour before and after a diagnosis of hepatitis C, as well as its possible relations to adherence as measured on the Morisky scale. The findings indicated that health-related behaviour improved significantly after the disease was diagnosed and that there was a significant association between good adherence rates and healthy diet (p<0.01) and modifying eating behaviour (p<0.01), while lower adherence rates were associated with fatigue (p<0.05).

Other studies have found that barriers to treatment were often related to missing doses and unintentional lateness. Being busy, forgetful, worried about family or work responsibilities or changing routine were signalled as unintentional barriers connected with non-adherence³⁸38 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.^,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..

Adherence and socioeconomic factors

The association between socioeconomic factors and treatment adherence was investigated in 13 of the studies reviewed here. Investigations in the United States identified lower adherence associated with age, one of the studies showing lower adherence to use of PEG-IFN among younger individuals (OR=0.76 (0.66, 0.88), p=0.003) and even lower rates of adherence to RBV in the first 24 weeks of treatment. A five-year reduction in age was associated with 20% greater likelihood of missing doses (OR=0.80 (0.72, 0.88), p<0.001)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.. One study of treatment with direct-acting antiviral agents found higher rates of adherence in older persons (p=0.0001) and women (p=0.05)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..

A cohort study in Australia found lower adherence to treatment among persons with less schooling (without higher education) (p=0.02)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.. A study in the United States indicated lower adherence rates among Afro-Americans (OR=2.22 (1.51, 3.27), p<0.001) than among Caucasians, among the unemployed (OR=2.57 (1.68, 3.92), p<0.001) than among the employed, and among those who were not in a conjugal relationship (OR=2.00 (1.23, 3.28), p=0.029)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..

Note that there is still controversy as to the influence of sociodemographic and economic conditions on adherence to treatment of other chronic diseases, and independent predictors of adherence were not found consistently among these conditions¹¹11 Organização Mundial da Saúde (OMS). Adherence to long-term therapies. Evidence for action. Geneva: WHO; 2003..

Patients in treatment for hepatitis C considered having social support to be important in facilitating adherence, which suggests the importance of being able to rely on people to fortify themselves and continue with the treatment at difficult times³⁷37 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.

38 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.

39 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.

40 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.^-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., which included those experienced from the side-effects of treatment with interferon and ribavirin. These findings corroborate those of other studies in the literature on adherence that point to perceived family support as the variable with the most significant associations with both adherence and mental health⁴⁵45 Camargo LA, Capitão CG, Filipe EMV. Saúde mental, suporte familiar e adesão ao tratamento: associações no contexto HIV/Aids. Psico-USF 2014; 19(2):221-232.^,4646 Dimatteo MR. Social Support and Patient Adherence to Medical Treatment: A Meta-Analysis. Health Psychol 2004; 23(2):207-218..

Patients also identified stigma, a socially-constructed condition⁴⁷47 Butt G, Paterson BL, Mcguinness LK. Living With the Stigma of Hepatitis C. West J Nurs Res 2008; 30(2):204-221.^,4848 Stewart BJ, Mikocka-Walusab AA, Harley H, Andrews JM. Help-seeking and coping with the psychosocial burden of chronic hepatitis C: A qualitative study of patient, hepatologist, and counsellor perspectives. Int J Nurs Stud 2012; 49(5):560-569., as a barrier to treatment and as a hindrance to obtaining social support³⁷37 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.^,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.^,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.. Some studies showed that patients in treatment for hepatitis C did not have to experience stigma in order to feel its effects: the fear of stigma was sufficient. They avoided talking about their illness and treatment for feat of discrimination in the workplace, which made it even more difficult to maintain regular dosage regimes and to refrigerate the medications (the complexity of the treatment with PEG-IFN+RBV entailed weekly injections and large numbers of tablets). Fear also prevented patients from socialising and broadening their support networks³⁷37 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.^,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..

Studies of hepatitis C and stigma, by Butt et al.⁴⁷47 Butt G, Paterson BL, Mcguinness LK. Living With the Stigma of Hepatitis C. West J Nurs Res 2008; 30(2):204-221. and Stewart et al.⁴⁸48 Stewart BJ, Mikocka-Walusab AA, Harley H, Andrews JM. Help-seeking and coping with the psychosocial burden of chronic hepatitis C: A qualitative study of patient, hepatologist, and counsellor perspectives. Int J Nurs Stud 2012; 49(5):560-569., argue that persons with hepatitis C experienced stigma for a variety of reasons, prominent among which were misunderstandings as to the cause and transmission of the disease and its association with illicit drug use, Such stigma can undermine the ability to obtain social support, prejudicing relationships in the workplace and also influencing early treatment dropout⁴⁷47 Butt G, Paterson BL, Mcguinness LK. Living With the Stigma of Hepatitis C. West J Nurs Res 2008; 30(2):204-221.^,4848 Stewart BJ, Mikocka-Walusab AA, Harley H, Andrews JM. Help-seeking and coping with the psychosocial burden of chronic hepatitis C: A qualitative study of patient, hepatologist, and counsellor perspectives. Int J Nurs Stud 2012; 49(5):560-569..

Adherence and factors relating to the health service and health personnel

Issues connected with the health service and health personnel were discussed in nine of the 22 studies examined here and were associated with both the treatment with interferon and ribavirin and the current treatment. Higher adherence rates were found among persons undergoing treatment in hepatitis C referral services with specific treatment protocols (p<0.001)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.. The analysis of the articles selected also found a significant association reported between greater adherence and distance between place of residence and health service (OR=1.003 (1.000-1.006), p=0.024)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..

One qualitative study observed that having to miss work in order to wait a long time for a doctor’s appointment was an important barrier for employed patients and this circumstance was considered a limitation of the health service³⁹39 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.^,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..

The quality of the relationship between health personnel and patient has been associated with high levels of motivation and facilitation in adhering to treatment. Good bonding and trust in the health professional show the importance of establishing clear, honest communication and receiving appropriate information on disease and treatment; in the studies reviewed here, these are the factors considered facilitators of adhesion to the treatment process²⁴24 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.^,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.^,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.

38 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.

39 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.

40 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.^-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..

The main characteristics of communication identified by patients in treatment for hepatitis C and by health personnel in Australia were appointment time, use of medical jargon, the quality and quantity of information provided and whether or not personalised clinical feedback was provided³⁹39 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.^,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.. Authors also concluded that receiving detailed clinical information during treatment, coupled with a visualisation of the effects of the treatment, gave patients a better perspective on their health and helped them feel better informed and in control of the treatment⁴⁰40 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.. Corroborating these findings on the importance of communication and the doctor-patient relationship to treating patients with hepatitis C, studies have highlighted the importance of trust, of the health professional’s being sensitive to the experience the patient is going through, with a view to establishing a relationship of empathy in which it is possible to listen to patients and share in finding strategies that will help them adapt to the lifestyle demanded by the disease¹¹11 Organização Mundial da Saúde (OMS). Adherence to long-term therapies. Evidence for action. Geneva: WHO; 2003.^,1313 Polejack L, Seidl EMF. Monitoramento e avaliação da adesão ao tratamento antirretroviral para HIV/aids: desafios e possibilidades. Cien Saude Colet 2010; 15(Supl. 1):1201-1208.^,4949 Caprara A, Franco ALS. A Relação paciente-médico: para uma humanização da prática médica. Cad Saude Publica 1999; 15(3):647-654.^,5050 Caprara A, Rodrigues J. A relação assimétrica médico-paciente: repensando o vínculo terapêutico. Cien Saude Colet 2004; 9(1):139-146..

Adherence and disease-related factors

Three studies addressed factors relating to the disease and two of them found significant associations with treatment adherence. One study pointed to a relationship between co-infection with HIV (p=0.003), the presence of the genotype 3 virus (p=0.01) and greater treatment adherence²⁰20 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.. Its authors argued that the association between co-infection with HIV and greater hepatitis C treatment adherence may possibly also be related to adherence to treatment for HIV, which is routinely emphasised in patient care and may thus have contributed to greater adherence to treatment for hepatitis C as well²⁰20 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.. There is a long history of studies, discussions and interventions directed to increasing HIV treatment adherence, which posed a challenge for individual and public health, and these are advancing in understanding and addressing the process of non-adherence⁵¹51 Bonolo PF, Gomes RRFM, Guimarães MDC. Adesão à terapia anti-retroviral (HIV/aids): fatores associados e medidas da adesão. Epidemiol Serv Saude 2007; 16(4):261-278.^,5252 Brasil. Ministério da Saúde (MS). Manual de adesão ao tratamento para pessoas vivendo com HIV e aids. Brasília: MS; 2008..

A study using focal discussion groups suggested that hepatitis C’s being an asymptomatic disease may hinder adherence³⁷37 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.. The literature indicates that having a disease with no specific symptomatology¹¹11 Organização Mundial da Saúde (OMS). Adherence to long-term therapies. Evidence for action. Geneva: WHO; 2003.^,1313 Polejack L, Seidl EMF. Monitoramento e avaliação da adesão ao tratamento antirretroviral para HIV/aids: desafios e possibilidades. Cien Saude Colet 2010; 15(Supl. 1):1201-1208.^,5353 Oliboni LS, Castro MS. Adesão à farmacoterapia, que universo é esse? Uma revisão narrativa. Clin Biomed Res 2018; 38(2):178-195., such as arterial hypertension⁵⁴54 Manfroi A, Oliveira FA. Dificuldades de adesão ao tratamento na hipertensão arterial sistêmica: considerações a partir de um estudo qualitativo em uma unidade de Atenção Primária à Saúde. Rev Bras Med Fam Com 2016; 2(7):165-176.^,5555 Pierin AMG, Silva SSBE, Colósimo FC, Toma GA, Serafim TS, Meneghin P. Cronicidade e doença assintomática influenciam o controle dos hipertensos em tratamento na atenção básica. Rev Esc Enferm USP 2016; 50(5):764-771., can hinder adherence to treatment, as was found in this study.

Limitations of the study

One possible limitation of this study may have been that it did not include studies or other relevant material that failed to meet the inclusion criteria (only publications in Portuguese, English and Spanish and indexed in specific data bases), and the fact that it excluded dissertations, theses and official documents.

Final remarks

The articles reviewed were not always guided by the multidimensional view of adherence behaviour; rather the predominant perspective was that adherence is a particularly patient-centred difficulty. Adherence behaviour seems to result, in each case, from a singular interaction of multiple factors⁵³53 Oliboni LS, Castro MS. Adesão à farmacoterapia, que universo é esse? Uma revisão narrativa. Clin Biomed Res 2018; 38(2):178-195.. This broader view does not seem to have been contemplated yet, especially in the quantitative studies. Only where the study design was qualitative was it possible to identify important points, such as the characteristics of communication by health personnel with patients, interaction with the health team, and the conditions of the health service and the treatment.

It can also be concluded that the major differences in methodological approach among the articles reviewed here also frustrated the possibility of arrived at more objective and uniform conclusions about the variables that may have influenced low adherence, pointing to a need for further research in this area.

Most of the studies included in this integrative review evaluated factors associated with adherence to treatment with therapeutic regimes that still used interferon and ribavirin, which - from when they were discovered in 1989 until 2014 - were the only medications that existed to combat the hepatitis C virus. Treatment with these medications was lengthy, caused numerous adverse side effects and offered less efficacy that current medications. In this review, these problems were identified to be barriers associated with lower rates of adherence. Corroborating these factors’ importance, studies that have evaluated adherence to the new treatment with direct-acting antiviral agents have shown that the treatment’s lesser complexity is a significant facilitator of adherence.

In addition to the significant associations between adherence and factors connected with the complexity of treatment with interferon and ribavirin, other variables also proved important to the phenomenon of adherence to hepatitis C treatment with these medications. The following factors associated with non-adherence to hepatitis C treatment stood out and should be identified before and during treatment: the presence of psychiatric disorder and depressive symptoms and the use of alcohol and/or illicit drugs are factors that need to be explored further with the new treatment in order to receive attention, specialised treatment and guidance. Also associated with non-adherence were: schooling (not having higher education); age (being younger); ethnicity (Afro-Americans); being unemployed; marital status (not having a fixed partner); distance from the health service; lack of information about the disease and treatment; unintentional forgetting; the fact that the disease is asymptomatic; limitations of the health service; and the presence of stigma relating to the disease.

Adherence to treatment with interferon in association with ribavirin was favoured by: receiving treatment for psychiatric disorders identified during treatment; changing lifestyle; starting to eat healthily; having social support; gaining information and knowledge about the disease and treatment; good bonding between health personnel and patient; presenting with genotype 3 virus; being in treatment for the first time; and being in treatment for HIV.

This integrative review also identified factors associated with adherence to treatment with direct-acting antiviral agents. There was a significant association between greater adherence and being female; age (being older); social support; receiving treatment in a service set up and specialised to treat hepatitis C; receiving information about the disease and treatment; having information and knowledge about the treatment; and bonding between health personnel and patient. There was also a significant association between use of injected drugs and lesser adherence to direct-acting antiviral agents.

Further research is needed to contemplate the treatment currently indicated⁴4 Brasil. Ministério da Saúde (MS). Secretaria de Ciência, Tecnologia e Insumos Estratégicos. Protocolo Clínico e Diretrizes Terapêuticas para Hepatite C e Coinfecções. Brasília: MS; 2018.^,1010 European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2018. J Hepatol 2018; 69(2):461-511. - which constitutes an important milestone in treating hepatitis C, even though access still poses considerable challenges to treatment⁵5 Douglass CH, Pedrana A, Lazarus JV, 't Hoen EFM, Hammad R, Leite RB, Hill A, Hellard M. Pathways to ensure universal and affordable access to hepatitis C treatment. BMC Med 2018; 16(1):175.^,66 Rosenthal ES, Graham CS. Price and affordability of direct-acting antiviral regimens for hepatitis C virus in the United States. Infect Agents Cancer 2016; 11:24.^,77 Ferreira VL, Pontarolo R. Contextualização e avanços no tratamento da hepatite C: uma revisão da literatura. Visao Academica 2017; 18(1):78-96. - and all the variables that may influence adherence: those relating to the individual, to the disease, to the treatment, to family and community factors and to health personnel, as well as those reflecting aspects of health service organisation¹¹11 Organização Mundial da Saúde (OMS). Adherence to long-term therapies. Evidence for action. Geneva: WHO; 2003..

This integrative review underscores the importance of exploring our thinking about the meanings and complexity of hepatitis C treatment adherence behaviour in greater depth. Studies for that purpose, which are still so lacking in the literature, can contribute to the introduction of measures coordinated among researchers, health personnel, managers and policymakers to address the very important issue of adherence to treatment.

References

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