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Study of Adherence to Medication in Pediatric Liver Diseases (“SAMPLD” Study) in Indian Children

Published:October 17, 2022DOI:https://doi.org/10.1016/j.jceh.2022.10.006

      Background/objectives

      Adherence to medication(s) is an essential component of holistic management in any chronic disease including in post liver transplant (LT) patients. Thus, this study aimed to assess adherence to medications in Indian pediatric liver disease patients (including post LT recipients) and to identify variables affecting its occurrence.

      Methods

      A cross-sectional study was conducted among pediatric (<18 years of age) subjects with Wilson disease (WD) and autoimmune liver disease (AILD) along with post LT recipients from May 2021 to October 2021. Structured tools using prevalidated questionnaires (Medication adherence measure and the Child & Adolescent Adherence to Medication Questionnaire) were used to collect data related to nonadherence prevalence (based on missed and late doses) and factors influencing the adherence.

      Results

      A total of 152 children were included in the study (WD 39.5%, AILD 32.9%, and post LT 27.6%). Prevalence of missed and late dose nonadherence (at a cut-off of ≥20%) was 12.5% and 16.4%, respectively. Older age (odd's ratio/O.R 1.185), stay in a rural area (O.R 5.08), and barriers like bad taste of medication (O.R 4.728) and hard to remember the medication (O.R 7.180) were independently associated with nonadherence (P < 0.05).

      Conclusions

      Overall, nonadherence was seen in 12–16%, i.e., around one-sixth of the patients, with least nonadherence seen in post LT recipients (0–2.4%). Older age of the patient, rural place of stay and personal barriers like hard to remember/forgetfulness and bad medication taste were identified as factors independently leading to nonadherence.

      Keywords

      Abbreviations:

      AILD (Autoimmune liver disease), CAAMQ (The Child & Adolescent Adherence to Medication Questionnaire), LT (liver transplant), WD (Wilson disease)
      Adherence is defined as “the extent to which a person's behavior–taking medication, following a diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a health care provider.”
      • Sabaté E.
      Adherence to Long-Term Therapies: Evidence for Action.
      Adherence to medications is a critical aspect in the overall management and outcomes of any chronic disease
      • Al-Hassany L.
      • Kloosterboer S.M.
      • Dierckx B.
      • Koch B.C.
      Assessing methods of measuring medication adherence in chronically ill children-a narrative review.
      ,
      • Boswell K.A.
      • Cook C.L.
      • Burch S.
      • Eaddy M.
      • Cantrell C.
      Associating medication adherence with improved outcomes: a systematic literature review.
      . Poor adherence attenuates optimum clinical benefits and therefore reduces the overall effectiveness of health systems.
      • Sabaté E.
      Adherence to Long-Term Therapies: Evidence for Action.
      • Al-Hassany L.
      • Kloosterboer S.M.
      • Dierckx B.
      • Koch B.C.
      Assessing methods of measuring medication adherence in chronically ill children-a narrative review.
      • Boswell K.A.
      • Cook C.L.
      • Burch S.
      • Eaddy M.
      • Cantrell C.
      Associating medication adherence with improved outcomes: a systematic literature review.
      Medication nonadherence is a common problem across all pediatric chronic disease etiological groups with rates varying from 22 to 88% across chronic illnesses and from 3 to 78% amongst organ transplant population.
      • Jacquelet E.
      • Poujois A.
      • Pheulpin M.C.
      • et al.
      Adherence to treatment, a challenge even in treatable metabolic rare diseases: a cross sectional study of Wilson’s disease.
      • Basharat S.
      • Jabeen U.
      • Zeeshan F.
      • Bano I.
      • Bari A.
      • Rathore A.W.
      Adherence to asthma treatment and their association with asthma control in children.
      • Vasylyeva T.L.
      • Singh R.
      • Sheehan C.
      • Chennasamudram S.P.
      • Hernandez A.P.
      Self-reported adherence to medications in a pediatric renal clinic: psychological aspects.
      • LeLeiko N.S.
      • Lobato D.
      • Hagin S.
      • et al.
      Rates and predictors of oral medication adherence in pediatric patients with IBD.
      • McGrady M.E.
      • Hommel K.A.
      Medication adherence and health care utilization in pediatric chronic illness: a systematic review.
      • Zelikovsky N.
      • Schast A.P.
      • Palmer J.
      • Meyers K.E.
      Perceived barriers to adherence among adolescent renal transplant candidates.
      • Hoegy D.
      • Bleyzac N.
      • Robinson P.
      • Bertrand Y.
      • Dussart C.
      • Janoly-Dumenil A.
      Medication adherence in pediatric transplantation and assessment methods: a systematic review.
      • Meng X.
      • Gao W.
      • Wang K.
      • Han C.
      • Zhang W.
      • Sun C.
      Adherence to medical regimen after pediatric liver transplantation: a systematic review and meta-analysis.
      This has been further negatively impacted by the recent corona virus disease 2019 (COVID-19) pandemic.
      • Subathra G.N.
      • Rajendrababu S.R.
      • Senthilkumar V.A.
      • Mani I.
      • Udayakumar B.
      Impact of COVID-19 on follow-up and medication adherence in patients with glaucoma in a tertiary eye care centre in south India.
      • Clement J.
      • Jacobi M.
      • Greenwood B.N.
      Patient access to chronic medications during the Covid-19 pandemic: evidence from a comprehensive dataset of US insurance claims.
      • Shimels T.
      • Asrat Kassu R.
      • Bogale G.
      • et al.
      Magnitude and associated factors of poor medication adherence among diabetic and hypertensive patients visiting public health facilities in Ethiopia during the COVID-19 pandemic.
      • Zhao C.
      • Batio S.
      • Lovett R.
      • Pack A.P.
      • Wolf M.S.
      • Bailey S.C.
      The relationship between COVID-19 related stress and medication adherence among high-risk adults during the acceleration phase of the US outbreak.
      The assessment of medication adherence thus becomes an important parameter to assess during follow up of all patients. Due to a lack of similar data from the Indian population in pediatric liver diseases and post liver transplant (LT) subjects, this study thus attempted to assess adherence to medications and to identify variables affecting it in pediatric liver disease patients including post LT recipients. The knowledge about the nonadherence rates and the factors influencing the adherence in the local population would likely help to design the remedial interventions.

      Material and methods

      This cross-sectional study was conducted over a period of 6 months (May to October 2021) and included patients below 18 years of age attending the Pediatric Hepatology Department at a tertiary care institute after obtaining ethical committee approval [IEC/2021/86/MA05]. Inclusion criteria included (1) patients below 18 years of age with primary diagnosis (as per standard criteria) being Wilson disease (WD),
      European Association for Study of Liver
      EASL clinical practice guidelines: wilson's disease.
      autoimmune liver disease (AILD),
      • Sood V.
      • Lal B.B.
      • Rawat D.
      • et al.
      Spectrum of pediatric autoimmune liver disease and validation of its diagnostic scores in Indian children.
      and post LT recipients (more than 3 months after transplant), (2) taking 2 or more drugs (as defined later), and (3) taking medications for at least 3-month duration.

      Sample Size Estimation

      Based on estimated baseline population size (under follow-up at the institute currently as per etiology and expected hospital visits during the study period, i.e., around 250 subjects), average prevalence of medication nonadherence in previous pediatric studies in world literature (i.e. 40 ± 5%) and confidence limits as % of 100 (absolute +/− %) (d) as 5%, we calculated the sample size of around 150.
      Questionnaires [for details, see Supplementary Material/SM-1]
      • o
        Prevalidated questionnaires were administered by the principal investigators (first author/AS and second author/AA) during physical consultation.
        • Overall, the questionnaire consisted of three parts: part 1 involved basic questions about demographic and clinical details, part 2 involved the medication module of the “Medication adherence measure” (MAM),
          • Zelikovsky N.
          • Schast A.P.
          • Palmer J.
          • Meyers K.E.
          Perceived barriers to adherence among adolescent renal transplant candidates.
          and part 3 included the “The Child and Adolescent Adherence to Medication Questionnaire” (CAAMQ).
          • Vasylyeva T.L.
          • Singh R.
          • Sheehan C.
          • Chennasamudram S.P.
          • Hernandez A.P.
          Self-reported adherence to medications in a pediatric renal clinic: psychological aspects.
          In addition, part 2 included three questions specifically addressed to assess the effect of COVID-19 pandemic on the medication adherence.
      • o
        For children <12 years of age, only parents were requested to fill up the questionnaire and for children ≥12 years of age, both the child and one of the parent were requested to fill up the questionnaire (in the same visit but in different physical settings).

      Statistical Analysis

      For baseline descriptive analysis, normally distributed continuous study variables were expressed as mean (± standard deviation or SD), and the study variables with skewed distribution were expressed as median (interquartile range or IQR). Individual medications and overall adherence rates were calculated as per mentioned formula (see SM-1). Medication nonadherence (both missed and late) was defined as a patient taking less than 80% of the prescribed medication.
      • Al-Hassany L.
      • Kloosterboer S.M.
      • Dierckx B.
      • Koch B.C.
      Assessing methods of measuring medication adherence in chronically ill children-a narrative review.
      ,
      • Loiselle K.A.
      • Gutierrez-Colina A.M.
      • Eaton C.K.
      • et al.
      Longitudinal stability of medication adherence among adolescent solid organ transplant recipients.
      ,
      • Hommel K.A.
      • Greenley R.N.
      • Maddux M.H.
      • Gray W.N.
      • Mackner L.M.
      Self-management in pediatric inflammatory bowel disease: a clinical report of the North American society for pediatric gastroenterology, Hepatology, and nutrition.
      Two-tailed Spearman rank correlations were used to examine whether the total number of barriers reported and ability to recall medications associated with higher rates of nonadherence. Agreement analysis (using Kappa value and intraclass correlation coefficient [ICC]) was done for assessing differences between responses given by children ≥12 years age versus their parents.
      For comparing risk factors for medical nonadherence, the mean differences between the groups were tested by using nonparametric tests (Mann–Whitney U test for upto two groups and Kruskal–Wallis H test for >two groups) because of the skewed distribution of adherence rates, while the chi square (or Fisher's exact) test was for categorical variables. Binary logistic regression analysis was then attempted for assessing independent risk factors. Significance was defined as two-tailed P value of less than 0.05. For part 3 of the questionnaire, a one-sample t-test between proportions was performed to assess the preference over one option or the other. Data were analyzed by using the Statistical Package for the Social Sciences version 22 (IBM corp Ltd.; Armonk NY, USA).

      Results

      Demographic and Clinical Profile [Table 1]

      A total of 152 patients were included in the study. Of these, 60 (39.5%) patients were in the WD group (predominantly hepatic form), 50 (32.9%) were in the AILD group, and 42 (27.6%) were in the post LT group. Mean age of the patients was 11.6 ± 4.5 years with 81 patients aged ≥12 years. Almost three-fourths (73.8%) of the post LT patients had duration of medication intake were between 1 and 5 years after LT. There was a male preponderance (91 males: 61 females) which was seen across all etiological groups except AILD [male (%) - WD: 70%, AILD: 38% and post LT: 71.4%] (SM-2). Majority (72.2%) of the families stayed in the urban areas with almost equal proportions having joint (50.3%) versus nuclear (49.7%) family setup. One-fourth (25%) of the families were dependent on external support for managing the finances related to the medical bills.
      Table 1Basic Demographic and Clinical Profile of Patients.
      Demographic variablesFrequency (f)Percentage (%)
      Age at enrollment
      • <12 Years
      • ≥12 Years
      71

      81
      46.7

      53.3
      Gender
      • Male
      • Female
      91

      61
      59.9

      40.1
      Family type
      • Nuclear
      • Joint
      74

      77
      49.7

      50.3
      Place of stay
      • Rural
      • Urban
      42

      109
      27.8

      72.2
      Educational qualification of the patients
      • Not yet enrolled in school
      • Primary educational level
      • Secondary educational level
      • Senior secondary education level
      • Dropped out of school
      14

      47

      38

      45

      08
      9.2

      30.9

      25

      29.6

      5.3
      Educational qualification of father
      • No formal education
      • Primary educational level
      • Secondary or Higher secondary level
      • Graduate or above
      7

      5

      67

      72
      4.6

      3.3

      44.4

      47.7
      Educational qualification of the mother
      • No formal education
      • Primary educational level
      • Secondary or Higher secondary level
      • Graduate or above
      15

      13

      64

      60
      9.9

      7.9

      42.4

      39.8
      Occupation of father
      • Employed
      • Unemployed
      152

      0
      100

      0
      Occupation of mother
      • Employed
      • Homemaker
      23

      123
      15.2

      84.8
      Family support
      • Living with both parents
      • With either of parents
      • Other (Family members etc)
      141

      10

      01
      92.8

      6.6

      0.7
      Family income (per month)
      • Rs <10,000
      • Rs 10,001–20,000
      • Rs 20,001–50,000
      • Rs > 50,000
      • Below Poverty Line/Economically Weaker Section (EWS)
      09

      35

      54

      31

      23
      5.9

      23

      35.5

      20.4

      15.1
      Financial support for monthly drug bill
      • Self
      • Family or relatives
      • NGO
      • Government support
      114

      17

      02

      19
      75.0

      11.2

      1.3

      12.5
      Distance from the institute
      • Within Delhi NCR region
      • Outside Delhi NCR region
      62

      90
      40.8

      59.2
      Post liver transplant group
      Duration post-transplant
      • 3 months to < 1 year
      • 1 to < 5 years
      • ≥ 5 Years
      4

      31

      7
      09.5

      73.8

      16.7
      Donor type
      • Living donor liver transplant
      • Deceased donor liver transplant
      41

      1
      97.6

      2.4
      Relation with donor
      • Father
      • Mother
      • Siblings
      • Relatives
      12

      24

      3

      3
      29.3

      56.1

      7.3

      7.3
      History of rejection
      • Yes
      • No
      13

      29
      31.7

      68.3
      NGO: Non-Governmental Organization; NCR: National Capital Region (NCR) of India.
      The most common system used to organize or keep the medications at home was the common plastic bag or box (73.9%), while the pill box (daily or weekly) was used by only 3.3% of the families (P > 0.05). Majority of the families considered the morning hours (48%) as the most difficult time of the day for medication intake followed by dinner hours (18%) (P > 0.05). For <12-year-old patient, parents primarily (78.9%) took the responsibility for giving the medications, while in those ≥12 years age, it was the patients (42%) who were the primary person responsible for taking medications (see SM-3). Patient reported side-effects are mentioned in SM-4.
      The overall median duration of medication intake was 36 months (IQR 22–48 months) which was similar across all groups (WD: 41 months/AILD: 35 months/post LT: 35.5 months) (P > 0.05). The overall median monthly cost of the medications was 1557.5 INR (or ₹) (IQR 1128.3 to 2853.8) which was lower for the AILD group (680 INR, IQR 400 to 2502.5) compared to the other two groups (WD: INR 1500, IQR 1307.5 to 2000 and post LT: INR 3111.5, IQR 1800 to 4260) (χ2 (2) = 32.3, P < 0.001; AILD vs. WD: P 0.004, AILD vs. post LT: P < 0.001, and WD vs. post LT: P < 0.001) (SM-5).

      Agreement Analysis

      On agreement analysis, high levels of agreement between the responses given by the subjects in ≥12 year age-group and their parents. The ICC between patient and parents’ responses indicated >70% agreement with respect to the response to number of barriers to medication intake (ICC values 0.799 [95% C.I 0.686 to 0.872]) and the drug recall percentage (ICC values 0.730 [95% C.I 0.577 to 0.828]) suggestive of good and moderate reliability respectively (see the Bland–Altman plots in Figure 1) (See Figure 2 also ).
      Figure 1
      Figure 1The Bland–Altman plots for the agreement (reliability) analysis between responses given by the subjects in ≥12 year age-group and their parents using the intraclass correlation coefficient (ICC): with respect to the response to number of barriers to medication intake (a) and the drug recall percentage (b).
      Figure 2
      Figure 2Perceived barriers to drug adherence.
      Similarly, with respect to drug adherence as per missed and late doses, there was good agreement in their responses (for missed doses ≥20%, Cohen's kappa value was 0.827 [95% C.I 0.659 to 0.995] suggestive of near perfect agreement, and for late doses ≥20%, Cohen's kappa value was 0.765 [95% C.I was 0.585–0.945] suggestive of substantial agreement).

      Medication nonadherence

      The majority (93.2%) of subjects were using only two of the medications as per the etiology (as mentioned earlier). Defining nonadherence as a missed dose percentage more than 20%, the nonadherence rate was 12.5% in our cohort. Using same cutoff, nonadherence to timing of drug was seen in 16.4%. Using a cutoff of ≥10%, these proportions increased to 17.8% and 32.2%, respectively.
      On comparing etiology-wise nonadherence, there was significant difference for both missed and late doses suggesting adherence varying as per the etiology with lower rates of nonadherence in the posttransplant group compared to others (see Figure 3). For missed doses, WD group had higher nonadherence compared to post LT group (overall χ2 (2) = 6.2, P < 0.047; for WD vs. post LT: χ2 (1) = 5.8, P 0.016, mean ranks 56.8 vs. 43.9; AILD vs. WD: P 0.108, and AILD vs. post LT: P 0.586).
      Figure 3
      Figure 3Etiology-wise medication nonadherence •Abbreviations: AILD: autoimmune liver disease, LT: liver transplantation.
      For late doses, AILD group took more late doses compared to both WD and post LT group (overall χ2 (2) = 10.5, P 0.005; for AILD vs. WD: χ2 (1) = 6.5, P 0.011, mean ranks 63.8 vs. 48.6; for AILD vs. post LT: χ2 (1) = 9.2, P 0.002, mean ranks 54.1 vs. 37.5; and WD vs. post LT P 0.736).

      Barriers to Drug Adherence

      On analysis of the barriers related to nonadherence, 41.9% of subjects had more than one barrier. Most common barriers were do not want to take medication/refusal (28.8%), hate the taste of medication (24.8%), and ran out of medications (15.7%). Bad taste as a barrier was more commonly reported in <12 years old while refusal to take medications was more commonly seen in ≥12 years age (Figure 2).

      Factors Affecting Medication Adherence

      Average missed dose percentage directly correlated with the total number of barriers (r = 0.31, P < 0.001, weak to moderate relationship) and inversely correlated with the ability to recall the medications (r = −0.28, P 0.001; weak to moderate relationship). Similarly, average late dose percentage directly correlated with the total number of barriers (r = 0.17, P 0.037; weak relationship).
      For missed dose nonadherence (≥20%), on multivariate analysis, rural place of stay (odd's ratio/O.R 5.08), older current age (O.R 1.185), and barriers like bad taste of medication (O.R 4.728) and hard to remember the medication (O.R 7.180) were independently associated with nonadherence (P < 0.05) with no relation to duration of medication intake, primary responsibility over medication, difficult time of day, or system used to organize medication (Table 2). For late dose nonadherence (≥20%), only bad taste of medication (z −2.2, mean ranks 89.9 vs. 72, P 0.025) was significantly associated with nonadherence.
      Table 2Factors Affecting Medication Adherence.
      Univariate analysis
      ParametersNonadherent vs. AdherentEffect Size
      z value, mean ranks for comparison of means, OR/95% CI for comparison of proportions, ∗∗ P-value < 0.05 as significant.
      P value∗∗
      Place of stay (%)Rural (23.8%) vs. Urban (8.2%)0.29, (0.11–0.78)0.014
      Hard to remember (%)33.3 vs. 9.74.6, (1.5–14.5)0.012
      Bad Taste (%)26.3 vs. 7.94.2, (1.5–11.2)0.008
      Side effects (%)42.3 vs. 116, (1.2–29.5)0.042
      Current Age (years)14.1 ± 2.4 vs. 11.3 ± 4.6−2.6, 100.6 vs. 73.10.011
      Age at diagnosis (years)10.7 ± 2.1 vs. 8.5 ± 3.9−2.7, 94.8 vs. 67.30.006
      Multivariate analysis
      Parametersβ coefficientAdjusted OR (95% C.I)P value
      Place of stay (%)1.6275.08 (1.578–16.397)0.006
      Hard to remember (%)1.9717.180 (1.824–28.2590.005
      Bad taste (%)1.5544.728 (1.543–14.493)0.007
      Current age in (Years)0.1701.185 (1.015–1.385)0.032
      a z value, mean ranks for comparison of means, OR/95% CI for comparison of proportions, ∗∗ P-value < 0.05 as significant.
      The Child and Adolescent Adherence to Medication Questionnaire (CAAMQ) (Part 3): Prednisolone was cited as the most disliked medication (36%) followed by zinc (28%) (see SM-7). Almost three-fourths (72.5% and 73.2% respectively) of the respondents confirmed that it did bother them to take their medications daily, and that they did “feel upset about taking medicines” (P < 0.05). But majority (83.7%) of them mentioned that their medications did not interfere with their daily activities (P < 0.05). One-third (31.4% and 30.1% respectively) of them felt that an alarm system or a pill box would help them to remember taking their daily medications in a better way (P < 0.05). Also, almost half (47.7%) agreed that a better tasting medicine would help them remember to take their medicine. Please see SM-6 for further details.

      Effect of COVID-19 Pandemic

      Majority (90%) of the participants did not discontinue their medication during the pandemic. The most common reasons behind discontinuation (if any) were unavailability of medication during lockdown (35.7%), financial issues (21.4%) and actually suffered from Covid-19 infection/fear of immunosuppressive effect of medications (14.3%). Almost one-third (28.9%) of the subjects did not turn up for their routine outpatient department consultation (see SM-7).

      Discussion

      The current study is the largest study from the Indian subcontinent (and the first report from India) on the status of medication adherence in liver diseases (including post LT cases) in pediatric population. Its strengths further include a comparatively larger sample size, use of previously validated pediatric adherence measures, and also inclusion of both the parents and patients (in ≥12 years age group) in the study.
      It is a well known fact that adherence to medications is a critical aspect in achieving optimum outcomes in any chronic disease.
      • Al-Hassany L.
      • Kloosterboer S.M.
      • Dierckx B.
      • Koch B.C.
      Assessing methods of measuring medication adherence in chronically ill children-a narrative review.
      ,
      • Boswell K.A.
      • Cook C.L.
      • Burch S.
      • Eaddy M.
      • Cantrell C.
      Associating medication adherence with improved outcomes: a systematic literature review.
      This becomes especially important in the pediatric age group since they may have to take medications either lifelong or for decades altogether. Similarly, in post-transplant patients, graft survival is dependent on lifelong immunosuppression. As discussed previously, nonadherence is a common problem across the entire disease spectrum with rates varying from 22 to 88% [4–11; also see SM-9]. In the current study, we found lower (12–16%) rates of nonadherence as compared to other studies (as shown in SM-8). But these adherence rates were comparable with other studies where cutoffs of ≥10% or ≥20% have been used for missed or late doses (for missed doses: 12.5–17.8% in current study, 21.8–38.2%
      • Zelikovsky N.
      • Schast A.P.
      • Palmer J.
      • Meyers K.E.
      Perceived barriers to adherence among adolescent renal transplant candidates.
      and 4.2%
      • McCormick King M.L.
      • Mee L.L.
      • Gutiérrez-Colina A.M.
      • Eaton C.K.
      • Lee J.L.
      • Blount R.L.
      Emotional functioning, barriers, and medication adherence in pediatric transplant recipients.
      ; for late doses: 16.4–32.2% in current study, 10.9–23.6%
      • Zelikovsky N.
      • Schast A.P.
      • Palmer J.
      • Meyers K.E.
      Perceived barriers to adherence among adolescent renal transplant candidates.
      and 11.4%
      • McCormick King M.L.
      • Mee L.L.
      • Gutiérrez-Colina A.M.
      • Eaton C.K.
      • Lee J.L.
      • Blount R.L.
      Emotional functioning, barriers, and medication adherence in pediatric transplant recipients.
      ; for missed or late doses >10%: 18.2–33.3%
      • Loiselle K.A.
      • Gutierrez-Colina A.M.
      • Eaton C.K.
      • et al.
      Longitudinal stability of medication adherence among adolescent solid organ transplant recipients.
      ). In the present study, better adherence rates were seen in post-transplant patients versus the other two groups. Although no statistically validated differences were found in the barriers to adherence between these two groups, the most plausible explanation is the extra attention and repeated counseling the post-transplant patients usually receive from multiple caregivers (including the surgeons, physicians, nurses, and transplant coordinators).
      Although there is no actual “gold standard” to assess adherence, self-reporting by patients (including the use of questionnaires) is still the most commonly used method in clinical practice.
      • Al-Hassany L.
      • Kloosterboer S.M.
      • Dierckx B.
      • Koch B.C.
      Assessing methods of measuring medication adherence in chronically ill children-a narrative review.
      ,
      • LeLeiko N.S.
      • Lobato D.
      • Hagin S.
      • et al.
      Rates and predictors of oral medication adherence in pediatric patients with IBD.
      ,
      • McCormick King M.L.
      • Mee L.L.
      • Gutiérrez-Colina A.M.
      • Eaton C.K.
      • Lee J.L.
      • Blount R.L.
      Emotional functioning, barriers, and medication adherence in pediatric transplant recipients.
      • Loiselle K.A.
      • Gutierrez-Colina A.M.
      • Eaton C.K.
      • et al.
      Longitudinal stability of medication adherence among adolescent solid organ transplant recipients.
      • Hommel K.A.
      • Greenley R.N.
      • Maddux M.H.
      • Gray W.N.
      • Mackner L.M.
      Self-management in pediatric inflammatory bowel disease: a clinical report of the North American society for pediatric gastroenterology, Hepatology, and nutrition.
      • Kluthe C.
      • Tsui J.
      • Spady D.
      • Carroll M.
      • Wine E.
      • Huynh H.Q.
      The frequency of clinic visits was not associated with medication adherence or outcome in children with inflammatory bowel diseases.
      • Hommel K.A.
      • Denson L.A.
      • Baldassano R.N.
      Oral medication adherence and disease severity in pediatric inflammatory bowel disease.
      • Pai A.L.
      • Rausch J.
      • Tackett A.
      • Marsolo K.
      • Drotar D.
      • Goebel J.
      System for integrated adherence monitoring: real-time non-adherence risk assessment in pediatric kidney transplantation.
      • Ingerski L.M.
      • Baldassano R.N.
      • Denson L.A.
      • Hommel K.A.
      Barriers to oral medication adherence for adolescents with inflammatory bowel disease.
      • Simons L.E.
      • McCormick M.L.
      • Devine K.
      • Blount R.L.
      Medication barriers predict adolescent transplant recipients' adherence and clinical outcomes at 18-month follow-up.
      • Simons L.E.
      • McCormick M.L.
      • Mee L.L.
      • Blount R.L.
      Parent and patient perspectives on barriers to medication adherence in adolescent transplant recipients.
      Some inherent shortcomings of questionnaire based approach including conscious manipulation of the responses by the respondents may have affected the nonadherence rates in current study. We did try to decrease the overall error by ensuring investigator-administered (in the native language) questionnaire approach so as to address various limitations like incomplete answers, unanswered questions, wrong understanding or interpretation of questions, illegibility, and so on. Also, in those patients >12 years of age, the questionnaires were administered to the patient and parent in separate settings so as to allow nonbiased recording of their individual responses. This we also documented by doing the agreement analysis (see Figure 1) where high levels of agreement between the responses given by the subjects in ≥12 year age-group and their respective parents.
      The study identified older age of the patient as one of the independent factors predicting nonadherence. This pattern of nonadherence in the adolescent period has been documented in the previous literature with younger age of the patient associated with better adherence.
      • Zelikovsky N.
      • Schast A.P.
      • Palmer J.
      • Meyers K.E.
      Perceived barriers to adherence among adolescent renal transplant candidates.
      ,
      • Simons L.E.
      • McCormick M.L.
      • Mee L.L.
      • Blount R.L.
      Parent and patient perspectives on barriers to medication adherence in adolescent transplant recipients.
      • Ellis D.A.
      • Podolski C.L.
      • Frey M.
      • Naar-King S.
      • Wang B.
      • Moltz K.
      The role of parental monitoring in adolescent health outcomes: impact on regimen adherence in youth with type 1 diabetes.
      • Koster E.S.
      • Raaijmakers J.A.
      • Vijverberg S.J.
      • Maitland-van der Zee A.H.
      Inhaled corticosteroid adherence in paediatric patients: the PACMAN cohort study.
      • Chan A.H.
      • Stewart A.W.
      • Foster J.M.
      • Mitchell E.A.
      • Camargo Jr., C.A.
      • Harrison J.
      Factors associated with medication adherence in school-aged children with asthma.
      This was also reflected in the pattern of responsibility over medication intake where as the age of the patient increased, they more likely became responsible for medication intake (SM-3) (P > 0.05). Similar results were found in the previous studies where adolescents took primary responsibility (12–75%) for their medication intake (42% in the current study).
      • Zelikovsky N.
      • Schast A.P.
      • Palmer J.
      • Meyers K.E.
      Perceived barriers to adherence among adolescent renal transplant candidates.
      ,
      • Simons L.E.
      • McCormick M.L.
      • Mee L.L.
      • Blount R.L.
      Parent and patient perspectives on barriers to medication adherence in adolescent transplant recipients.
      ,
      • Orrell-Valente J.K.
      • Jarlsberg L.G.
      • Hill L.G.
      • Cabana M.D.
      At what age do children start taking daily asthma medicines on their own?.
      This is compounded by the erratic and defiant behavior more commonly seen in adolescence with increasing risk of refusal to take medications due to various social and physiological factors. For this group, disease specific support/self help groups would encourage them and alleviate their fears. Realizing this shortcoming, we have initiated support groups for Wilson and autoimmune liver disease patients and post LT recipients which have been well received by the patients, especially adolescents.
      Similarly, rural place of residence was identified as one of the risk factors of nonadherence. These patients may have faced issues with local medication procurement and regular follow-up visits secondary to the prevailing pandemic. This may have been compounded with the financial constraints secondary to loss of jobs in this period. Previous studies have shown conflicting results with respect to relation of residence and adherence rates.
      • Kluthe C.
      • Tsui J.
      • Spady D.
      • Carroll M.
      • Wine E.
      • Huynh H.Q.
      The frequency of clinic visits was not associated with medication adherence or outcome in children with inflammatory bowel diseases.
      ,
      • Murphy G.K.
      • McAlister F.A.
      • Weir D.L.
      • Tjosvold L.
      • Eurich D.T.
      Cardiovascular medication utilization and adherence among adults living in rural and urban areas: a systematic review and meta-analysis.
      Barriers like hard to remember/forgetfulness and bad medication taste were identified as independent factors leading to nonadherence in current study, as also seen in previous studies.
      • Zelikovsky N.
      • Schast A.P.
      • Palmer J.
      • Meyers K.E.
      Perceived barriers to adherence among adolescent renal transplant candidates.
      ,
      • Hommel K.A.
      • Greenley R.N.
      • Maddux M.H.
      • Gray W.N.
      • Mackner L.M.
      Self-management in pediatric inflammatory bowel disease: a clinical report of the North American society for pediatric gastroenterology, Hepatology, and nutrition.
      ,
      • Ingerski L.M.
      • Baldassano R.N.
      • Denson L.A.
      • Hommel K.A.
      Barriers to oral medication adherence for adolescents with inflammatory bowel disease.
      ,
      • Simons L.E.
      • McCormick M.L.
      • Mee L.L.
      • Blount R.L.
      Parent and patient perspectives on barriers to medication adherence in adolescent transplant recipients.
      ,
      • Claes A.
      • Decorte A.
      • Levtchenko E.
      • Knops N.
      • Dobbels F.
      Facilitators and barriers of medication adherence in pediatric liver and kidney transplant recipients: a mixed-methods study.
      ,
      • Dehghani S.M.
      • Shamsaeefar A.
      • Kazemi A.
      • et al.
      Medication non-adherence prevalence and determinants in children and adolescents with chronic liver diseases.
      It is imperative to address these issues at the earliest since many of them are amenable to a significant improvement if intensive counseling is done and simple changes are made to the daily routine of the patient. These may include use of daily medication reminders (including alarm system), taste maskers (for bad taste), rewards/incentives for timely adherence, and decrease in overall medication burden (number as well as frequency, e.g., once daily dosage using long acting formulations) among others.
      • Zelikovsky N.
      • Schast A.P.
      • Palmer J.
      • Meyers K.E.
      Perceived barriers to adherence among adolescent renal transplant candidates.
      ,
      • Simons L.E.
      • McCormick M.L.
      • Mee L.L.
      • Blount R.L.
      Parent and patient perspectives on barriers to medication adherence in adolescent transplant recipients.
      ,
      • Davies G.
      • Koenig L.J.
      • Stratford D.
      • et al.
      Overview and implementation of an intervention to prevent adherence failure among HIV-infected adults initiating antiretroviral therapy: lessons learned from Project HEART.
      • Roberts K.J.
      Barriers to antiretroviral medication adherence in young HIV-infected children.
      • Chisholm M.A.
      Identification of medication-adherence barriers and strategies to increase adherence in recipients of renal transplants.
      • Penza-Clyve S.M.
      • Mansell C.
      • McQuaid E.L.
      Why don't children take their asthma medications? A qualitative analysis of children's perspectives on adherence.
      • Burgess S.W.
      • Sly P.D.
      • Morawska A.
      • Devadason S.G.
      Assessing adherence and factors associated with adherence in young children with asthma.
      • Modi A.C.
      • Quittner A.L.
      Barriers to treatment adherence for children with cystic fibrosis and asthma: what gets in the way?.
      • Boutopoulou B.
      • Koumpagioti D.
      • Matziou V.
      • Priftis K.N.
      • Douros K.
      Interventions on adherence to treatment in children with severe asthma: a systematic review.
      Almost one-third of the subjects actually felt that an alarm system or a pill box would better help them to remember taking their daily medications. A practical tool to overcome the “forgetfulness” barrier would be a “disease specific customized pill box” which could be given to the patients after detailed explanation. Thus, these simple remedial measures may actually help take care of some of these common personal barriers.
      • Wadhwani S.I.
      • Nichols M.
      • Klosterkemper J.
      • et al.
      Implementing a process to systematically identify and address poor medication adherence in pediatric liver transplant recipients.
      The recent COVID-19 pandemic has had a negative overall impact on medication adherence.
      • Subathra G.N.
      • Rajendrababu S.R.
      • Senthilkumar V.A.
      • Mani I.
      • Udayakumar B.
      Impact of COVID-19 on follow-up and medication adherence in patients with glaucoma in a tertiary eye care centre in south India.
      • Clement J.
      • Jacobi M.
      • Greenwood B.N.
      Patient access to chronic medications during the Covid-19 pandemic: evidence from a comprehensive dataset of US insurance claims.
      • Shimels T.
      • Asrat Kassu R.
      • Bogale G.
      • et al.
      Magnitude and associated factors of poor medication adherence among diabetic and hypertensive patients visiting public health facilities in Ethiopia during the COVID-19 pandemic.
      • Zhao C.
      • Batio S.
      • Lovett R.
      • Pack A.P.
      • Wolf M.S.
      • Bailey S.C.
      The relationship between COVID-19 related stress and medication adherence among high-risk adults during the acceleration phase of the US outbreak.
      Despite the fact that the current study was conducted during the peak of the pandemic phase in the region, the nonadherence rates were surprisingly low in the study. This may be secondary to a probable selection bias because the subjects (parents and the children), who followed up for their routine physical visits/consultations even during the pandemic period, are the ones who are likely more compliant with the medications.
      Apart from being a single center study, the current study was limited by use of the investigator-driven questionnaire-based methodology with its inherent shortcomings and a likely chance of selection bias as mentioned earlier. We assessed adherence only for main disease-related drugs and not for the whole prescribed regimen (e.g., nutritional supplements). It was a cross-sectional study, so we could not assess adherence over a period of time after the pandemic was actually over. We did not attempt subgroup analysis to assess etiology-specific predictive factors for nonadherence due to limited number of subjects.
      To conclude, medication nonadherence is likely an underestimated problem in Indian children with liver diseases. This may adversely affect long-term disease outcomes, and thus, further larger and multicentric studies are mandated in this study population to identify potentially modifiable factors to allow effective interventions to manage nonadherence. If such factors can be identified, simple remedial measures can be instituted to decrease overall nonadherence.

      Credit authorship contribution statement

      VS, BBL, RK, and SA conceptualized the research paper; AS, AA, and VS did the acquisition, analysis, and interpretation of data for the work; GK did the statistical analysis; and VS, AS, and AA prepared the first draft. All authors reviewed the manuscript, provided critical inputs, and approved the final version.

      Conflicts of interest

      All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

      Funding

      The authors did not receive support from any organization for the submitted work.

      Appendix A. Supplementary data

      The following are the supplementary data to this article:

      References

        • Sabaté E.
        Adherence to Long-Term Therapies: Evidence for Action.
        World Health Organization, Geneva2003
        • Al-Hassany L.
        • Kloosterboer S.M.
        • Dierckx B.
        • Koch B.C.
        Assessing methods of measuring medication adherence in chronically ill children-a narrative review.
        Patient Prefer Adherence. 2019 Jul 22; 13: 1175-1189
        • Boswell K.A.
        • Cook C.L.
        • Burch S.
        • Eaddy M.
        • Cantrell C.
        Associating medication adherence with improved outcomes: a systematic literature review.
        American J Pharmacy Benefits. 2012; 4: e97-e108
        • Jacquelet E.
        • Poujois A.
        • Pheulpin M.C.
        • et al.
        Adherence to treatment, a challenge even in treatable metabolic rare diseases: a cross sectional study of Wilson’s disease.
        J Inherit Metab Dis. 2021 Nov; 44: 1481-1488
        • Basharat S.
        • Jabeen U.
        • Zeeshan F.
        • Bano I.
        • Bari A.
        • Rathore A.W.
        Adherence to asthma treatment and their association with asthma control in children.
        J Pak Med Assoc. 2018 May; 68: 725-728
        • Vasylyeva T.L.
        • Singh R.
        • Sheehan C.
        • Chennasamudram S.P.
        • Hernandez A.P.
        Self-reported adherence to medications in a pediatric renal clinic: psychological aspects.
        PLoS One. 2013 Jul 18; 8
        • LeLeiko N.S.
        • Lobato D.
        • Hagin S.
        • et al.
        Rates and predictors of oral medication adherence in pediatric patients with IBD.
        Inflamm Bowel Dis. 2013 Mar-Apr; 19: 832-839
        • McGrady M.E.
        • Hommel K.A.
        Medication adherence and health care utilization in pediatric chronic illness: a systematic review.
        Pediatrics. 2013 Oct; 132: 730-740
        • Zelikovsky N.
        • Schast A.P.
        • Palmer J.
        • Meyers K.E.
        Perceived barriers to adherence among adolescent renal transplant candidates.
        Pediatr Transplant. 2008 May; 12: 300-308
        • Hoegy D.
        • Bleyzac N.
        • Robinson P.
        • Bertrand Y.
        • Dussart C.
        • Janoly-Dumenil A.
        Medication adherence in pediatric transplantation and assessment methods: a systematic review.
        Patient Prefer Adherence. 2019 May 7; 13: 705-719
        • Meng X.
        • Gao W.
        • Wang K.
        • Han C.
        • Zhang W.
        • Sun C.
        Adherence to medical regimen after pediatric liver transplantation: a systematic review and meta-analysis.
        Patient Prefer Adherence. 2018 Dec 17; 13: 1-8
        • Subathra G.N.
        • Rajendrababu S.R.
        • Senthilkumar V.A.
        • Mani I.
        • Udayakumar B.
        Impact of COVID-19 on follow-up and medication adherence in patients with glaucoma in a tertiary eye care centre in south India.
        Indian J Ophthalmol. 2021; 69: 1264-1270
        • Clement J.
        • Jacobi M.
        • Greenwood B.N.
        Patient access to chronic medications during the Covid-19 pandemic: evidence from a comprehensive dataset of US insurance claims.
        PLoS One. 2021 Apr 1; 16e0249453
        • Shimels T.
        • Asrat Kassu R.
        • Bogale G.
        • et al.
        Magnitude and associated factors of poor medication adherence among diabetic and hypertensive patients visiting public health facilities in Ethiopia during the COVID-19 pandemic.
        PLoS One. 2021 Apr 6; 16e0249222
        • Zhao C.
        • Batio S.
        • Lovett R.
        • Pack A.P.
        • Wolf M.S.
        • Bailey S.C.
        The relationship between COVID-19 related stress and medication adherence among high-risk adults during the acceleration phase of the US outbreak.
        Patient Prefer Adherence. 2021; 15: 1895-1902
        • European Association for Study of Liver
        EASL clinical practice guidelines: wilson's disease.
        J Hepatol. 2012 Mar; 56: 671-685
        • Sood V.
        • Lal B.B.
        • Rawat D.
        • et al.
        Spectrum of pediatric autoimmune liver disease and validation of its diagnostic scores in Indian children.
        J Pediatr Gastroenterol Nutr. 2018 Oct; 67: e65-e72
        • McCormick King M.L.
        • Mee L.L.
        • Gutiérrez-Colina A.M.
        • Eaton C.K.
        • Lee J.L.
        • Blount R.L.
        Emotional functioning, barriers, and medication adherence in pediatric transplant recipients.
        J Pediatr Psychol. 2014; 39: 283-293
        • Loiselle K.A.
        • Gutierrez-Colina A.M.
        • Eaton C.K.
        • et al.
        Longitudinal stability of medication adherence among adolescent solid organ transplant recipients.
        Pediatr Transplant. 2015 Jun; 19: 428-435
        • Hommel K.A.
        • Greenley R.N.
        • Maddux M.H.
        • Gray W.N.
        • Mackner L.M.
        Self-management in pediatric inflammatory bowel disease: a clinical report of the North American society for pediatric gastroenterology, Hepatology, and nutrition.
        J Pediatr Gastroenterol Nutr. 2013 Aug; 57: 250-257
        • Kluthe C.
        • Tsui J.
        • Spady D.
        • Carroll M.
        • Wine E.
        • Huynh H.Q.
        The frequency of clinic visits was not associated with medication adherence or outcome in children with inflammatory bowel diseases.
        Can J Gastroenterol Hepatol. 2018 Feb 25; 20184687041
        • Hommel K.A.
        • Denson L.A.
        • Baldassano R.N.
        Oral medication adherence and disease severity in pediatric inflammatory bowel disease.
        Eur J Gastroenterol Hepatol. 2011 Mar; 23: 250-254
        • Pai A.L.
        • Rausch J.
        • Tackett A.
        • Marsolo K.
        • Drotar D.
        • Goebel J.
        System for integrated adherence monitoring: real-time non-adherence risk assessment in pediatric kidney transplantation.
        Pediatr Transplant. 2012; 16: 329-334
        • Ingerski L.M.
        • Baldassano R.N.
        • Denson L.A.
        • Hommel K.A.
        Barriers to oral medication adherence for adolescents with inflammatory bowel disease.
        J Pediatr Psychol. 2010 Jul; 35: 683-691
        • Simons L.E.
        • McCormick M.L.
        • Devine K.
        • Blount R.L.
        Medication barriers predict adolescent transplant recipients' adherence and clinical outcomes at 18-month follow-up.
        J Pediatr Psychol. 2010; 35: 1038-1048
        • Simons L.E.
        • McCormick M.L.
        • Mee L.L.
        • Blount R.L.
        Parent and patient perspectives on barriers to medication adherence in adolescent transplant recipients.
        Pediatr Transplant. 2009; 13: 338-347
        • Ellis D.A.
        • Podolski C.L.
        • Frey M.
        • Naar-King S.
        • Wang B.
        • Moltz K.
        The role of parental monitoring in adolescent health outcomes: impact on regimen adherence in youth with type 1 diabetes.
        J Pediatr Psychol. 2007 Sep; 32: 907-917
        • Koster E.S.
        • Raaijmakers J.A.
        • Vijverberg S.J.
        • Maitland-van der Zee A.H.
        Inhaled corticosteroid adherence in paediatric patients: the PACMAN cohort study.
        Pharmacoepidemiol Drug Saf. 2011 Oct; 20: 1064-1072
        • Chan A.H.
        • Stewart A.W.
        • Foster J.M.
        • Mitchell E.A.
        • Camargo Jr., C.A.
        • Harrison J.
        Factors associated with medication adherence in school-aged children with asthma.
        ERJ Open Res. 2016 Mar 31; 2 (00087-2015)
        • Orrell-Valente J.K.
        • Jarlsberg L.G.
        • Hill L.G.
        • Cabana M.D.
        At what age do children start taking daily asthma medicines on their own?.
        Pediatrics. 2008 Dec; 122: e1186-e1192
        • Murphy G.K.
        • McAlister F.A.
        • Weir D.L.
        • Tjosvold L.
        • Eurich D.T.
        Cardiovascular medication utilization and adherence among adults living in rural and urban areas: a systematic review and meta-analysis.
        BMC Publ Health. 2014 Jun 2; 14: 544
        • Claes A.
        • Decorte A.
        • Levtchenko E.
        • Knops N.
        • Dobbels F.
        Facilitators and barriers of medication adherence in pediatric liver and kidney transplant recipients: a mixed-methods study.
        Prog Transplant. 2014 Dec; 24: 311-321
        • Dehghani S.M.
        • Shamsaeefar A.
        • Kazemi A.
        • et al.
        Medication non-adherence prevalence and determinants in children and adolescents with chronic liver diseases.
        Iran J Pediatr. 2021; 31e112323
        • Davies G.
        • Koenig L.J.
        • Stratford D.
        • et al.
        Overview and implementation of an intervention to prevent adherence failure among HIV-infected adults initiating antiretroviral therapy: lessons learned from Project HEART.
        AIDS Care. 2006 Nov; 18: 895-903
        • Roberts K.J.
        Barriers to antiretroviral medication adherence in young HIV-infected children.
        Youth Soc. 2005; 37: 230-245
        • Chisholm M.A.
        Identification of medication-adherence barriers and strategies to increase adherence in recipients of renal transplants.
        Manage Care Interface. 2004; 17: 44-48
        • Penza-Clyve S.M.
        • Mansell C.
        • McQuaid E.L.
        Why don't children take their asthma medications? A qualitative analysis of children's perspectives on adherence.
        J Asthma. 2004; 41: 189-197
        • Burgess S.W.
        • Sly P.D.
        • Morawska A.
        • Devadason S.G.
        Assessing adherence and factors associated with adherence in young children with asthma.
        Respirology. 2008 Jun; 13: 559-563
        • Modi A.C.
        • Quittner A.L.
        Barriers to treatment adherence for children with cystic fibrosis and asthma: what gets in the way?.
        J Pediatr Psychol. 2006 Sep; 31: 846-858
        • Boutopoulou B.
        • Koumpagioti D.
        • Matziou V.
        • Priftis K.N.
        • Douros K.
        Interventions on adherence to treatment in children with severe asthma: a systematic review.
        Front Pediatr. 2018 Aug 21; 6: 232
        • Wadhwani S.I.
        • Nichols M.
        • Klosterkemper J.
        • et al.
        Implementing a process to systematically identify and address poor medication adherence in pediatric liver transplant recipients.
        Pediatr Qual Saf. 2020 May 13; 5: e296