Categorizing factors of adherence to parenteral treatment in growth hormone deficiencies and hemophilia: What should be the targets for future research?

Figures & data

Table 1 Taxonomy of factors of adherence identified in diabetes research and expected to be found in growth hormone–treated conditions and hemophilia

Domains	Factors or predictors
Demographic and clinical context (non-modifiable)	Diagnosis, illness severity, symptoms, treatment outcomes Illness duration Age, maturity, pubertal status, or adolescent phase Injector/infuser (parent vs child, confounded with age)
Injector or infuser (patients or parents)	Knowledge, understanding (disease, treatment) Know-how (treatment skills) Feeling capable, controllability, self-efficacy Positive beliefs: treatment necessity, expected benefits Negative beliefs: treatment concern, expected side effects, negative consequences Psychological barriers: psychological issues, negative effects, distress
Social environment	Child–parent relationship quality Parental monitoring and supervision Parental involvement Promoting transition to self-care Social norms Social and peer support Social stigma
Practical issues	Barriers such as issues in treatment availability, tight schedule, etc. Delivery device: burden, complexity, convenience Financial cost to the family
Health care	Trust with health care provider Good relationship with provider Transition program Type of care: rural vs urban, country specificities

Table 2 Data extraction from eleven studies on factors of adherence to rhGH treatment (2011–2017)

Reference	Sample	Objectives	Data collection and analysis design	Adherence measure and level	Factors of higher adherence	Factors unrelated
Bagnasco et al (2017)^Citation18 Endocrine Practice Italy (support: Novo Nordisk)	1,007 children 6–16 years Mixed conditions treated with rhGH % GHD: NA Mean age (estimated): 11–12 years % pubertal: NA % male: NA % self-injection: 22%	1. Evaluate the prevalence of non-adherence to rhGH therapy 2. Assess treatment and patient-level correlates of poor adherence using a questionnaire	Cross-sectional survey (self-reported) Multivariate logistic regression to predict adherence	Injection missed over a typical week in the last 12 months of rhGH treatment (self-report, parents, and child) High: No injection missed (72.1%) Low: ≥ 1 injection missed (24.4%)	Level of education (parents). Very low level associated with lower adherence Shorter duration of therapy, using current device Parent injected. Adolescence period associated with lower adherence Easy parent–child relations over treatment Injection less painful. High reported pain associated with lower adherence Understanding the consequences of non-adherence Treatment satisfaction, convenience of the device, satisfaction with the device Satisfaction with the health care team	Who prepares injection Device that covers the needle during injection Degree of knowledge of the disease
Gau and Takasawa (2017)^Citation19 Journal of Pediatric Endocrinology and Metabolism Japan (support: N/A)	46 children % GHD: 100% Mean age: 7.6 years % pubertal: NA % male: 52% % self-injection: 74%–80%	1. Examine the influence of PC on adherence to GH therapy 2. Examine therapeutic effects of GH therapy	Retrospective, single-center, comparative study Associations with adherence tested with 2×2 Fisher test	Number of missed injections per week (charts) Low: ≥ 1 injection missed per week (33% in non-PC, 7% in PC)	Being able to choose device or aspects of therapy	Age Sex Device type
Auer et al (2016)^Citation20 Clinical Endocrinology Germany (support: Pfizer)	179 adults % GHD: 100% % Adult onset: 79% Mean age: 35–64 years % male: 50%	1. Assess long-term adherence in adult patients with GHD 2. Identify markers of long-term adherence	Retrospective, single-center, cohort study Associations with adherence tested in bivariate analyses (ANOVA, t-tests, correlations) and multivariate regression for selected variables	Prescription filled/recommended dose • Prescription filled: prescribed GH dose filled by patients during period • Recommended GH dose: calculated retrospectively according to patient files Mean overall adherence: 74%±28.2% High: 81%–100% (53%) Low: 0%–60% (29%)	Shorter duration of therapy, especially at the start of therapy Adult-onset higher adherent than child-onset, higher age associated with adherence	Sex Device type
de Pedro et al (2016)^Citation21 Growth Hormone & IGF Research Spain (support: Pfizer)	158 children 4–16 years Mixed conditions treated with rhGH % GHD: 77% Mean age: 11 years % pubertal: 52% % male: 64% % self-injection: NA	1. Identify patients non-adherent to GH therapy 2. Assess the effect that adherence has on treatment outcome 3. Analyze serum IGF-I measurements as a biomarker for adherence 4. Analyze the possible influence of socioeconomic factors on therapeutic adherence	Retrospective, single-cohort, study–chart, and patient survey Associations with adherence tested in bivariate analyses (t-tests, chi-squared, 2×2 Fisher test). Multivariate logistic model to predict adherence levels	Prescription filled/recommended dose • Prescription filled: doses annually picked up by the patient • Recommended doses: available from the pharmacist High: not missing at least 92% of the prescribed doses (66.5%) Medium: <92% and ≥ 85% (at least 2 doses missed in 1 month) (12.5%) Low: <85% (at least 1 dose missed per week) (21%)	Younger age Shorter duration of treatment Higher education level of mothers	Pubertal status Ethnicity Education level of fathers
Kappelgaard et al (2015)^Citation22 Expert Review of Medical Devices France, Germany, Italy, USA (support: Novo Nordisk)	103 children 3–13 years 48 self-described, others Caregivers Mixed conditions treated with rhGH % GHD: 76% Mean age (estimated): 8–9 years % pubertal: NA % male: 61% % self-injection: NA	1. Examine the functional and emotional impact (including adherence) of storage-flexible GH products in young patients compared with refrigeration-only products	Cross-sectional patient survey (online) Differences between adherence groups tested by t -test	Injections missed each month (self-reported) Storage-flexible: 76% missed 0 injection, 22% missed 1–3 injections, 0.58 missed/month Refrigeration-only: 57% missed 0, 38% missed 1–3 injections, 0.88 missed/month	Storage-flexible product (as compared to a refrigeration-only product) is positively associated with high adherence and negatively associated with low adherence
Lass and Reinehr (2015)^Citation23 Hormone Research in Paediatrics Germany (support: Merck Serono)	103 children 8–12 years Mixed conditions treated with rhGH % GHD: 72% Mean age: 10 years % prepubertal: 64% % pubertal: NA % male: 65% % self-injection: 35%	1. Identify factors that influence treatment adherence	Retrospective chart review Associations with adherence tested in bivariate analyses (chi-squared, t-tests, correlations) and multivariate regression for selected variables	Prescription refill rates during last year (charts) High: <1 missed dose per week (>85.7% adherence) =51% Medium: 1–3 missed doses per week (57.1%–85.7% adherence) =23% Low: >3 missed doses per week (<57.1% adherence) =26%	Prepubertal children (as compared to pubertal children) Younger age Parent-injected Shorter treatment duration in younger children	Device type (easypod vs other) Treatment success (height gain during observation period)
Spoudeas et al (2014)^Citation24 Patient Preference and Adherence UK (support: Ferring Pharma)	4,093 children Mixed conditions treated with rhGH % GHD: NA Mean age: 10 years % male: 58% % self-injection: NA	1. Investigate how the use of a jet-delivery device (ZomaJet) impacts persistence and adherence compared to needle-based devices	Retrospective cohort study (charts from UK nationwide database of GH home-delivery schedules) Comparison of persistence between ZomaJet and needle-based devices: Mantel–Cox log-rank and chi-squared tests Association with adherence tested with independent t-tests	PDC = number of days with access to viable heads/number of days receiving treatment PDC score >0.8: highly adherent (58% using ZomaJet) Persistence (data not shown): time interval between a patient’s first and last delivery of GH for each GH brand		Sex Age (children vs teenage) Service type (full health care at home vs stores only)
Aydın et al (2014)^Citation25 Endocrine Practice Turkey (support: Pfizer)	217 children Mixed conditions treated with rhGHD % GHD: 85% Mean age: 11 years >10 years: 67% % pubertal: NA % male: 53% % self-injection: 28%	1. Evaluate the adherence to GH therapy 2. Identify influencing factors and outcomes	Prospective follow-up (4 time points, survey, and charts) Association with adherence tested with Mann–Whitney U test, chi-squared test, Fisher’s exact test, and correlations	Percent of doses omitted at each evaluation period (M3–M6–M12 of therapy, charts) Excellent: 0 doses missed (87.6%, 84.8%, and 77.9%) Good: 5% of doses missed (8.3%, 7.4%, and 12.9%) Fair: 5%–10% of doses missed (1.4%, 2.8%, and 1.8%) Poor: >10% of doses missed (2.8%, 5.1%, and 7.4%)	Shorter duration of treatment Boys (vs girls) had higher adherence rates	Age Diagnostic type Socioeconomic status Who injects treatment Injection device GH product used
Hartmann et al (2013)^Citation26 Hormone Research in Paediatrics Germany (support: Merck Serono)	75 children Mixed conditions treated with rhGH % GHD: 64% Mean age: 12 years % pubertal: 55% % male: 61% % self-injection: NA	1. Evaluate rhGH therapy adherence in children and adolescents with different growth disorders	Cross-sectional online survey with electronic device recording Associations with adherence explored with t-tests	Actual injection/prescribed dose Actual injection = injected rhGH recorded by electronic device (easypod) High: missed ≤1 dose a week on average (85.7%–100% proportion injected) (78.7%) Medium: missed 1–3 doses/week (57.1%–85.7% proportion injected) (18.7%) Low: missed ≥ 3 doses/week (<57.1% proportion injected) (2.7%)	Prepubertal age (vs pubertal)	Sex Diagnosis
Bozzola et al (2011)^Citation27 BMC Endocrine Disorders 15 countries including Argentina, France, Italy (support: Merck Serono)	824 children 1–18 years Mixed conditions treated with rhGH % GHD: 66% Mean age: 11 years % pubertal: NA % male: 56% % self-injection: 39%	1. Assess adherence to rhGH treatment as a function of use of electronic auto-injector 2. Compare adherence patterns in treatment-naïve and treatment-experienced children 3. Assess the acceptability of the device	Cross-sectional online survey with electronic device recording Association with adherence tested with Fisher’s exact test	Actual injection/prescribed dose (recorded by electronic device) (measure 1) Injection missed each month (self-reported)/injection prescribed (measure 2) High: if >92% (missed a maximum of 2 daily injections per month or 6 daily injections for the 3-month period)	Shorter duration of treatment (treatment naive vs treatment experienced). In almost all countries was related to higher adherence Living in Spain (vs living in Argentina)	Who injects the treatment
Cutfield et al (2011)^Citation28 PLoS ONE New Zealand (support: NZ ministry of health)	150 children Mixed conditions treated with rhGH % GHD: 57% Mean age: 12 years % pubertal: NA % male: 48% % self-injection: NA	1. Assess adherence to GH treatment 2. Examine the effects of age, sex, ethnicity, area of residence, and diagnosis on GH treatment adherence	Cross-sectional survey and chart review (nationwide New Zealand) Association with adherence assessed with binary logistic linear regression	Self-reported % of GH vials required/number of vials prescribed (Measure 1) and chart-recorded % GH returned/number of vials prescribed (Measure 2) High: ≤1 dose a week on average (27.3%) Medium: missed 2 doses/week (46.4%) Low: missed ≥ 3 doses/week (26.4%)	Self-report measure GHreq yields higher adherence rates Other ethnicity than Maori associated with higher adherence	Age Sex Diagnosis Area of residence

Abbreviations: GH, growth hormone; GHD, growth hormone deficiency; PC, patient choice; PDC, proportion of days covered; GHreq, required GH treatment; rhGH, recombinent human GH; NA, not available.

Table 3 Domains of factors of adherence to rhGH studied in 11 reports (2011–2017)

Reference	Descriptive factors	Individual factors	Social factors	Practical factors	Health care factors	No domains	Factors suggested in the discussion section of the articles
Bagnasco et al (2017)^Citation18 Endocrine Practice	x	x	x	x	x	5
Gau and Takasawa (2017)^Citation19 Journal of Pediatric Endocrinology and Metabolism	x			x		2	Socioeconomic factors (eg, mother’s education level) Type of device Pubertal stage
Auer et al (2016)^Citation20 Clinical Endocrinology	x			x		2	Forgetfulness Side effects of treatment Perceived treatment benefits Physician–patient relationship Patient education
de Pedro et al (2016)^Citation21 Growth Hormone & IGF Research	x					1
Kappelgaard et al (2015)^Citation22 Expert Review of Medical Devices				x		1	Choice of device Easy-to-use device
Lass and Reinehr (2015)^Citation23 Hormone Research in Paediatrics	x			x		2	Education level Psychological and emotional problems Social issues Technical handling issues Misconceptions about consequences of missed doses Discomfort with injections Dissatisfaction with results Inadequate contact with HCPs
Spoudeas et al (2014)^Citation24 Patient Preference and Adherence	x				x	2	Lack of choice of delivery device Person who administers the dose Injection discomfort or anxiety Patient support (injection training and contact with HCP) Too much involvement in treatment decisions
Aydın et al (2014)^Citation25 Endocrine Practice	x			x		2	Neglecting to renew the prescription Forgetting to administer the drug Vacation/break from taking the medication Problems with the delivery device
Hartmann et al (2013)^Citation26 Hormone Research in Paediatrics	x					1	Education Psychological, emotional, and social problems Delivery device Support for adolescents and their families
Bozzola et al (2011)^Citation27 BMC Endocrine Disorders	x				x	2	Duration of treatment (participants become less enthusiastic and motivated) Misperceptions about the consequences of missed GH doses Discomfort with injections Dissatisfaction with treatment results Inadequate contact with HCP Patient not involved in treatment decisions Choice of the delivery device Use of complicated delivery devices Experience with the delivery device
Cutfield et al (2011)^Citation28 PLoS One	x					1	Injection frequency Type of device Lack of perceived benefits Lack of perceived risks of noncompliance Culture and socioeconomic factors

Abbreviations: GH, growth hormone; HCP, Health Care Professionals; rhGH, recombinent human GH.

Table 4 Data extraction from 16 studies on factors of adherence to prophylaxis treatment in hemophilia (2011–2017)

Reference	Sample	Objectives	Data collection and analysis design	Adherence measure and level	Factors of higher adherence	Factors unrelated
Tran et al (2017)^Citation29 Haemophilia USA (support: Bayer)	99 adults: 33±18 years Hemophilia A: 91% Severe: 78% Prophylaxis: 49% Caucasian: 69%	1. Determine the association between demographic, socioeconomic, psychosocial, and health literacy with adherence	Cross-sectional survey (self-reported) Multivariate regression analysis to predict adherence	VERITAS-Pro: 45±18, 80% adherent (score ≤57) VERITAS-Prn: 51±15, % adherent: NA	Physician trust Higher QoL No history of depression	Age Ethnicity Condition type or severity Socioeconomic factors Health literacy
van Os et al (2017)^Citation30 PLoS ONE UK (support: Bayer)	91 young adults: 19±4 years Hemophilia A: NA Severe: 100% Prophylaxis: 100% Caucasian: NA	1. Assess self-reported adherence among young people with hemophilia 2. Provide evidence of psychosocial predictors of adherence	Cross-sectional survey and chart review Multivariate regression analysis to predict adherence	VERITAS-Pro: 82% adherent, overall mean score =42	Better log-timing planning and skipping Higher necessity beliefs Lower concern beliefs Negative emotions associated with disease (fear, anger, distress) Self-efficacy Positive expectation of treatment Social support Understanding of hemophilia (coherence)	Age
Lock et al (2016)^Citation31 Haemophilia the Netherlands (support: Bayer)	46 children: 9.4±4.2 years Parental report: 100% Self-report: 48% Hemophilia A: 78% Severe: 91% Prophylaxis: 100% Caucasian: NA	1. To investigate the effect of home visits on adherence to treatment, health-related QoL, behavioral scores, self- efficacy, total clotting factor consumption, and number of joint bleeds	Multicenter pre-post intervention study Bivariate comparison of parametric outcome before and after the intervention	Infusion logs: percentage of weeks/year the patient respected 1) frequency (median 86 baseline vs 87 postintervention, P=0.55), 2) timing (median 91 baseline vs 85 postintervention, P=0.07), 3) total factor consumption (median 100 baseline vs 100 postintervention, P=0.24) VERITAS-Pro (parental report: score of 36 baseline, and 35 postintervention, P=0.78) Adolescent report (score of 44 baseline, and 41 postintervention, P=0.25)	New type of health care delivery (home visits) associated with better communication scores (VERITAS)	New type of health care delivery (home visits) not associated with improved adherence
Mclaughlin et al (2016)^Citation32 Racial and Ethnic Health Disparities USA (support: Pfizer)	80 adolescents and young: 13–25 years (estimated mean 18 years) Hemophilia A: 91% Severe: 91% Prophylaxis: 86% Caucasian: 76% Self-infusion: NA	1. To evaluate racial/ethnic differences in adherence, chronic pain, and QoL among AYA with moderate or severe hemophilia	Cross-sectional survey (online) Multivariable logistic regression predicting the odds of non-adherence	VERITAS-Pro (median non-white 47.5 vs white 48.0, P=0.87) VERITAS-Prn (median non-white 43.0 vs white 52.0, P=0.41)		Ethnic group
Miesbach and Kalnins (2016)^Citation33 Haemophilia Germany (support: NA)	397 children and adults: mean =29 years including 28% children: <15 years, and 52% adults: 20–59 years Hemophilia A: 86% Severe: 93% Prophylaxis: 100% Caucasian: NA Self-infusion: 73.8%	1. To analyze the influence of potential factors on adherence	Cross-sectional self-reported survey Multivariate regression analysis to explain adherence variance	VERITAS-Pro, mean =37 0–14 years: 100% adherent 15–19 years: 100% 20–59 years: 88.1% ≥60 years: 93.9%	Being younger or older associated with adherence Treatment site in subsample ≥20 years	Severity Self-infusion Pain Comorbidity HIV, HCV
Schrijvers et al (2016)^Citation34 British Journal of Haematology the Netherlands (support: Baxter)	241 children and adults: mean =23 years including 30% children: 2–11 years, and 70% adolescents and adults: 12–77 years Hemophilia A: 82% Severe: 95% Prophylaxis: 100% Caucasian: NA Self-infusion in children: 0% Self-infusion in ado/ adults: 70%	1. To assess patient adherence to prophylactic treatment and its association with age, bleeding events, and clotting factor consumption	Prospective multicenter study Bivariate frequency comparison and ANOVA	Infusion logs Adherent: missing <15% infusions,<10% dose changes, and <30% deviation in time (66% of parents, 43% of patients) Suboptimally adherent: missing 15%–25% infusions, <25% dose changes or >30% deviation in time (29% of parents, 37% of patients) Non-adherent: missing >25% infusions or >25% dose changes (5% of parents, 20% of patients)	Parent-infusion yielded higher frequency of adherence than self-infusion (66% vs 43%, P<0.01)
Witkop et al (2016)^Citation35 Haemophilia USA (support: Pfizer)	73 adolescents and adults: mean 17 years (estimated) 56% adolescents: 13–17 years 44% adults: 18–25 years Hemophilia A: 88% Severe: 90% Prophylaxis: 100% Caucasian: 78% Self-infusion: NA	1. To determine factors associated with better adherence	Cross-sectional survey (online) Multivariate regression analysis to explain adherence variance	VERITAS-Pro Sample median: 48, min–max (25–78) Non-adherent: 30% (score ≥57)	Adolescence associated with higher adherence in comparison with young adulthood Mothers’ education	Ethnicity Bleeding disorder type
García-Dasí et al (2015)^Citation36 Haemophilia Spain (support: Bayer)	78 children and adolescents: 12±4 years 50% children: <12 years 50% adolescents: ≥12 years Hemophilia A: 100% Severe: 100% Prophylaxis: 100% Caucasian: NA Self-infusion: 44%	1. Evaluate adherence 2. Identify and compare the characteristics associated with adherence	Cross-sectional observational study Bivariate comparisons: Student’s t-test, one-factor ANOVA, chi-squared test	Infusion logs AI: (units administered)/ (units prescribed) ×100 AAI: Difference between AI and the perfect percentage of adhesion (100%) Adherence: administered exactly as prescribed (52.6%) Infra adherence: administered less than prescribed (33.3%) Over adherents: administered more than prescribed (14.1%)	QoL Primary prophylaxis Fewer negative emotions Self-image not affected by the disease Less overprotection by family No missed school days Sport practices similar to other children Satisfaction with the health care team	Age Self- or other-infusion
Mingot-Castellano et al (2015)^Citation37 Blood Coagulation and Fibrinolysis Spain (support: NA)	18 adults: >18 years Hemophilia A: 100% Severe: 100% Prophylaxis: 100% Caucasian: NA	1. Describe patient profiles, reasons to indicate prophylaxis, type of prophylaxis, and the protocol to individualize the prophylaxis scheme 2. Adherence and adverse events were also analyzed	Prospective case series study Bivariate comparisons: Student’s t-test, one-factor ANOVA	Infusion logs Adherence: number of weeks/year with the correct number of prophylaxis infusion Median adherence: 84% (69%–96%)	Patients qualitatively reported that poor adherence is favored by active working lives and irregular work schedules	Type of prophylaxis (primary, secondary, or tertiary)
Schrijvers et al (2015)^Citation38 Haemophilia the Netherlands (support: Baxter)	21 adults: 39 years (19–64 years) Hemophilia A: NA Severe: 100% Prophylaxis: 100% Caucasian: 100%	1. Clarify the process underlying adherence to prophylaxis in severe hemophilia from patients’ perspective	Qualitative study	Infusion logs Adherent: followed the prescribed regimen for at least 80%–100% of the time (47.6%) Non-adherent: following the prescribed regimen for <80% of the time (42.9%) Over treating: >100% of the prescribed dose, treated double during bleed (9.5%)	Acceptance of the disease Experience of bleeding Understanding hemophilia and prophylaxis Planning skills, prophylaxis ascribed into routine
Lamiani et al (2015)^Citation39 Haemophilia Italy (support: Bayer)	50 adolescents and adults: 40±13 years 24%: 13–30 years 44%: 31–44 years 32%: 45+ years Hemophilia A: 100% Severe: 68% Prophylaxis: 50% Caucasian: 96%	1. Assess the impact of patients’ health status and demographic characteristics on their illness representations and perceived adherence 2. Explore the relationship between illness representations and perceived adherence	Cross-sectional survey (self-report) Bivariate comparisons (t-tests, one-way ANOVA) Multivariate regression analysis to explain adherence variance by illness representation subscales	Perceived adherence to treatment (Morisky) Medication adherence scale (MMAS-4) Non-adherent: scores ≤2, 24%	Being in couple Perceived chronicity Negative emotions	Treatment type Severity Presence of inhibitors Education level Age
Ho et al (2014)^Citation40 Haemophilia BC, Canada (support: Baxter)	31 adults: 29 years (18–56 years) Hemophilia A: 100% Severe: 100% Prophylaxis: 100% Caucasian: NA	1. Determine the accuracy of infusion logs 2. Identify the effects of age, comorbidities, duration of prophylaxis, and the presence of joints affected by hemophilic arthropathy, on adherence levels	Retrospective study (chart review) Multivariate regression models predicting adherence	Adherence based on differences in dosage and frequency per week Adherence to dosage: proportion of weeks with accurate dosage. Median: 93%, min–max (73%–97%) Adherence to frequency: Each week is coded 0, 1, 2 with 2=perfect adherence, 1=one difference detected, 0=more than one difference. Final % is total score/ maximum possible. Median: 76%, 67%–85%	Longer exposure to prophylaxis	Age Comorbidities Number of bleeds Number of joints affected
Tang et al (2013)^Citation41 Haemophilia China (support: Bayer)	125 children: 8 years Hemophilia A: NA Severe: NA Prophylaxis: 100% Caucasian: 0% (100% Chinese)	1. To confirm that a similar short-term low-dose secondary prophylaxis for a similar hemophilia population remains feasible and beneficial when carried out at multiple centers in different areas of China	Pre-post intervention study Rank-test to determine the significance of data difference between the observation and prophylaxis period	Factor consumption Continuous prophylaxis treatment over 6 weeks (reported by treatment centers)	Comprehensive care team effective Specialized team to properly administer prophylaxis Necessity beliefs (reported by treatment centers)	Age
Duncan et al (2012)^Citation42 Haemophilia USA (support: Baxter)	117 children and adults: 25 years Pediatric: 45% Adult: 55% Hemophilia A: 100% Severe: 100% Prophylaxis: 60% Caucasian: 78% Self-infusion in children: 0% Self-infusion in adolescents: 76%	1. Assess lifetime treatment patterns among hemophilia A patients and determine whether these treatment patterns were associated with differences in HRQoL 2. Assess the level of treatment adherence among hemophilia patients in the USA and explore the potential factors	Cross-sectional survey (online) Bivariate analyses (student t-tests) to evaluate adherence differences across self-infusion status	VERITAS-Pro for only 70 patients (32.9% adults) Pediatric patients score 38 vs adults 45.8, P<0.05	Younger age favored recommended dose and better communication with the health care team Children <12 years old had better adherence compared to that of adolescents (12–18 years)	Parent-infusion (in children)
Thornburg et al (2012)^Citation43 Haemophilia USA (support: Bayer)	56 professionals in HTCs Age: NA Physician: 64% Nurse: 25% Nurse pract: 11% No other description	1. Determine whether the prescription of prophylaxis for children with hemophilia and perceptions of adherence to prophylaxis have changed since the publication of the JOS	Cross-sectional survey of HTCs Bivariate comparison of adherence levels and factors with original levels found by Thornburg	Reported average prescription as reported by professionals Excellent adherence: administering ≥80% of prescribed infusions. 42% of respondents reported that >75% of their patients have excellent adherence (≥80% of prescribed doses) with prophylaxis	Patient age: professionals report more frequently excellent adherence in the very young 1–5 years (70% of respondents) as compared to adolescents (22%)	Professional role Years of experience Size of treatment program Pediatric–adult facility
Zappa et al (2012)^Citation44 Haemophilia USA (support: Baxter)	71 HTCs Nurses responded on sample: 10,375 patients Children: 40% Hemophilia A: 74.1% Severe: 45.3% On-demand: 63.1%	1. To compare the treatment practices for hemophilia A with those for hemophilia B in relation to on-demand and prophylactic factor replacement therapy, adherence to treatment, optimal care, and approaches to inhibitor management	Cross-sectional survey of HTCs Documentation of adherence included nurses’ definitions of adherence, rates of adherence, and adherence barriers Nurses reported that influencing and tracking patient adherence is difficult because existing tools to track or influence adherence are unreliable (prescription refills, patient-reported adherence, treatment logs)	Patients deemed to follow recommended treatment Definition in high volume centers: having no breakthrough bleeding episodes, except for severe trauma in patients with hemophilia A; no breakthrough bleeding episodes except for severe trauma and no deterioration in joint health in hemophilia B. Definition in low volume centers: for hemophilia A and B, the patient followed the physician’s prescription Adherence rate: reported number of prophylactic doses per month/by the prescribed number of prophylactic doses per month. Mean rate reported by nurses for severe hemophilia B (78%) vs hemophilia A (80%)	Reported barriers to adherence 1. Inconvenience/ interference of treatment with the activities of living (94% of respondents) 2. Low perceived benefits: 79% of respondents 3. Low perceived negative consequences or vulnerability if non-adherent: 67% of respondents Age: adherence is greatest in patients ≤2 years (90%) and lowest in young adults 18–24 years (64%)	Type of hemophilia A or B except in senior patients. B: 87% vs A: 79%

Abbreviations: AI, adherence index; AAI, absolute adherence index; AYA, adolescents and young adults; HRQoL, health-related quality of life; HTC, hemophilia treatment center; JOS, Joint Outcome Study; QoL, quality of life; MMAS, Moritsky Medical-treatment Adherence Scale; NA, Not available.

Table 5 Domains of factors of adherence to prophylaxis treatment in hemophilia in 16 reports (2011–2017)

Reference	Descriptive factors	Individual factors	Social factors	Practical factors	Health care factors	No domains	Factors suggested in the discussion
Tran et al (2017)^Citation29 Haemophilia		x			x	2	Family support Social support Social stigma Necessity beliefs Concern beliefs Health-system factors: individual formularies, prior-authorization requirements, cost sharing
van Os et al (2017)^Citation30 PLoS ONE		x	x			2	Treatment cost
Lock et al (2016)^Citation31 Haemophilia					x	1	Communication between parents and the treatment center
Mclaughlin et al (2016)^Citation32 Racial and Ethnic Health Disparities						0	NA
Miesbach and Kalnins (2016)^Citation33 Haemophilia	x				x	2	Infusion timing Frequency of infusions Perceived benefits of treatment
Schrijvers et al (2016)^Citation34 British Journal of Haematology	x					1	Accepting the disease Self-management skills Infusion timing
Witkop et al (2016)^Citation35 Haemophilia	x					1	Attitudes toward prophylaxis treatment Parental support Motivation and encouragement Sense of normality (treatment is normal) Perceived benefits, experience of results
García-Dasí et al (2015)^Citation36 Haemophilia	x	x	x	x	x	5	Puberty Emotional aspects Accepting the disease Family attitude: watchfulness vs overprotection
Mingot-Castellano et al (2015)^Citation37 Blood Coagulation and Fibrinolysis				x		1	NA
Schrijvers et al (2015)^Citation38 Haemophilia	x	x		x		3	Perception of self-monitoring Self-management skills Age (position of hemophilia in adolescent patients)
Lamiani et al (2015)^Citation39 Haemophilia	x	x				2	NA
Ho et al (2014)^Citation40 Haemophilia	x					1	Intensity of treatment regimen Cost of treatment
Tang et al (2013)^Citation41 Haemophilia		x			x	2	Economic constraint Limitation in factor concentrate availability Education (potential benefits on the child’s well-being and quality of life)
Duncan et al (2012)^Citation42 Haemophilia	x					1	Transition points: shift from infused by family or nurse to self-infusion and switch from a prophylaxis regimen to on-demand treatment
Thornburg et al (2012)^Citation43 Haemophilia	x					1	Financial concerns Accessibility of treatment Self-infusion vs other-infusion Education Frequency of infusion
Zappa et al (2012)^Citation44 Haemophilia	x	x		x		3	NA

Abbreviation: NA, not available.

Figure S1 Flow diagram of retrieved studies in the review of factors of adherence in patients treated with recombinent human Growth Hormone (rhGH), 2011–2017.

Figure S2 Flow diagram of retrieved studies in the review of factors of adherence in hemophilia patients treated with prophylaxis, 2011–2017.

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