Determinants of non-compliance with Antiretroviral ...

JBI Library of Systematic Reviews

JBL000630

2012; 10 (56) 3596-3648

Determinants of non-compliance with Antiretroviral Therapy among adults living with HIV/AIDS: A Systematic Review

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Desta Hiko Gemeda BSC, MPHE , Lakew Abebe Gebretsadik (BSc, MPH) Tariku Dejene (BSc, MSc)

3

Mirkuzie Wolde (MD, MPH) Morankar Sudhakar

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4

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1. Lecturer of Epidemiology, Department of Epidemiology, College of Public Health and Medical Science, Jimma University, The Ethiopian Malaria Alert Centre: a collaborating centre of the Joanna Briggs Institute , E-mail: [email protected]

or [email protected]

2. Assistant Professor, Department of Health Education and Behavioral Sciences, College of Public Health and Medical Science, Jimma University, The Ethiopian Malaria Alert Centre: a collaborating centre of the Joanna Briggs Institute Email: [email protected], or [email protected] 3. Lecturer, Department of Epidemiology, College of Public Health and Medical Sciences, Jimma University, Email: [email protected] 4. Associate Professor, Department of Health Services Management, College of Public Health and Medical Sciences, Jimma University, Email: [email protected] 5 .Professor, Department of Health Education and Behavioral Sciences, College of Public Health and Medical Sciences, Jimma University, Director,The Ethiopian Malaria Alert Centre: a collaborating centre

of

the

Joanna

Briggs

Institute

Email:

[email protected]

,

[email protected]

Corresponding author Desta Hiko Gemeda E-mail: [email protected]

or [email protected]

Gemeda et al. Determinants of non-compliance with Antiretroviral Therapy among adults living with HIV/AIDS: A Systematic Review © the authors 2012

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Executive summary Background Non-compliance with Antiretroviral Therapy is a major public health concern and further challenged by interaction of various social and clinical obstacles. So; near perfect pill taking is desirable in order to maximise its benefits. Objectives To systematically search, appraise and synthesise the best available evidence on determinants of non-compliance with Antiretroviral Therapy among adults living with HIV/AIDS and provide direction to future how to increase compliance with Antiretroviral Therapy. Inclusion criteria Types of participants The systematic review considered studies with 18 years and above year old adults living with HIV/AIDS. Focus of the review Determinants of non-compliance with Antiretroviral Therapy among adults living with HIV/AIDS. Types of studies Quantitative study designs were considered for inclusion. Types of outcomes Socio-economic, Health service, Psychosocial and behavioural and Clinical related outcomes. Search strategy English language articles published between January1997 and December 2011 were sought across major databases. Methodological quality Methodological quality was assessed using Joanna Briggs Institute Meta Analysis of Statistical Assessment and Review Instrument critical appraisal tools. Data collection Data were extracted from papers included in the review by using a standardized data extraction tool.


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Data synthesis Meta- analysis was conducted using fixed and random effects model with mantel Haenszel method using Revman5 software. Heterogeneity between the studies was assessed using χ2 test at a p-value of 47 kilometres from their home to health facilities; 12(57.14%) and 9(42.86%) of the adults living HIV/AIDS had at least one and did not have medication side respectively.

The study showed that regular clinic follow up was the only statistical factor affecting medication compliance (last week (p value < 0.005), last month (p value < 0.005), last six month (p value < 0.005) and lifetime (p value = 0.002). Positive trends for medication compliance were seen for increasing age, larger families, having previously had an AIDS defining illness, smaller pill burden and less medication side-effects experienced. Older adults living HIV/AIDS showed a tendency towards better medication compliance but this was not statistically significant (p value = 0.325). This may be related to older adults living HIV/AIDS' familiarity with medication usage and their increasing awareness of Gemeda et al. Determinants of non-compliance with Antiretroviral Therapy among adults living with HIV/AIDS: A Systematic Review © the authors 2012

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HIV as a disease that requires optimal adherence.

2012; 10 (56) 3596-3648

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It was those aged less than 40 years in this

study that showed the poorest levels of medication-compliance. Many other studies have also identified young age as a risk factor for poor medication-compliance especially in those less than 35 years.

50, 52

Gender was not associated with medication-compliance in this study as was supported in another descriptive study.

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Surprisingly neither living in a rural compared with an urban area nor travelling

long distances to the clinic showed trends against medication medication-compliance (p value = 0.479). It has been also shown in this study that attending for regular follow-up with a doctor showed significance association with better medication-compliance (p value = 0.002). Surprisingly literacy was not significantly associated with lower medication-compliance (p = 0.089). This has also been shown by Cheng et al in a 2006 publication.

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One may assume that those of a higher social status and income are more compliant to their ART. This was not supported by this study as neither a patient's individual income (p = 0.786) nor their total family income (p value = 0.9) showed statistical significance association with compliance. A study undertaken in Chennai, India found that almost all the participants discussed the cost of ART as a barrier, with many reporting drug holidays, turning to family and/or friends or taking drastic measures (i.e. selling family jewels, property) for financial assistance.

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Poorer medication-compliance was also

seen in those living alone (p value = 0.407). It may therefore be argued that increased acceptance and understanding of the disease, thus reducing social stigma, and knowledge of the disease treatments may improve medication adherence.

Being on Antiretroviral Therapy for less than 6 months or for greater than 10 years was associated with the largest number of missed medications, in this study. This finding was supported by Andreo et al who found that duration of treatment greater than two years was associated with increased noncompliance with Antiretroviral Therapy.

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Tablet and schedule burdens can often, understandably, be

assumed to affect any medication adherence. In this Indian, cohort trend towards increased 100% medication adherence in those on less than five tablets per day (p value = 0.054) was seen. The number of times per day that tablets were taken was also analysed but this yielded no associations. This may be because most adults living HIV/AIDS (37 out of 53) are taking once or twice a day regimens as they have started their ART since the advent of HAART.

Older studies of medication-compliance showed that once daily or twice daily dosing would give 95% medication-compliance while three times per day scheduling reduced it to 60%.

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Food restrictions (p

value = 0.157), time restrictions (p value = 0.259) and temperature restrictions (p value = 0.374) seemed to decrease medication-compliance as was seen in other studies.

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Study by Li Li et al

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2007

This was a cross-sectional study that used the baseline data from a randomized controlled family intervention trial designed to improve the quality of life of adults living HIV/AIDS in the northern and northeastern regions of Thailand. These data were collected in 2007 from four district hospitals in the two regions. The adults living HIV/AIDS were recruited when they sought medical care from the study hospitals. Participation in the study was on voluntary bases and written informed consent was obtained from each HIV patient. Following informed consent, a trained interviewer administered the baseline survey to adults living HIV/AIDS by using a computer assisted personal interview The approval of the study was obtained from the Institutional Review Board of the University of California, Los Angeles, USA and the Ministry of Public Health‟s Ethical Review Committee for Research in Human Subjects, Bangkok, Thailand. Among the 507 adults living HIV/AIDS that were enrolled in the intervention trial, 386(76%) adults living HIV/AIDS who were on ART at the time of the assessment were included in this study.

The aim of the study was to assess barriers to compliance to ART in northern and northeastern regions of Thailand. The ART compliance status was the outcome variable while age, sex, annual income, educational status, and questions about their perceived stigma, social support, access to care, depressive symptoms, HIV disclosure status, internalized shame, social support, physical health, and family functioning were the independent variables. All the analyses were carried out by using SAS statistical software, version 9.1 (SAS Institute, Cary, NC, USA). Descriptive statistics were used to describe the ART compliance of adults living HIV/AIDS by using socio-demographic variables followed by calculating Pearson‟s correlation coefficients to examine the relationships between ART compliance. The multivariable logistic regression model was carried out to identify the independent predictors of ART compliance after controlling the effects other independent variables. A p-value of less than 0.05 was used to show statistical significance between outcome and independent variables. Adjusted odds ratios (AOR) and their 95% CI were used to look into the strength of association between the dependent and independent variables The study indicated that the adults living HIV/AIDS‟ age ranged from 18–64 years with a mean age of 38.0 years (SD± 6.4 years). Two hundred fifty nine (67.3%) and 126(32.7%) were female and male adults living HIV/AIDS respectively. One hundred twenty (31.41%) of the adults living HIV/AIDS did not comply with ART out of which 85(70.83%) and 36(29.17%) were 18-40 and 41 and above years; 14(11.57%) and 107(88.43%) were unemployed and employed; 11(10.00%) and 99(90.00%) were illiterate and literate; 45(37.19%) and 76(62.81%) were divorced/widowed/single and married respectively.

The correlation analysis revealed that ART compliance was significantly associated with internalized shame, access to care, depressive symptoms, and family communication. The multivariable logistic Gemeda et al. Determinants of non-compliance with Antiretroviral Therapy among adults living with HIV/AIDS: A Systematic Review © the authors 2012

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regression analysis showed depressive symptoms, access to care, HIV disclosure, and family communication were predictors of ART compliance. Having depressive symptoms remains a significant barrier to adherence, while access to care, HIV disclosure, and family communication play important positive roles. Significant negative correlations were observed between ART compliance and internalized shame (r = -0.12, p value < 0.05) and depression (r = -0.15, p value 2 doses, individuals on a non-boosted PI regimen (Adjusted OR =1.53, 95% CI: 1.15- 2.04) were more likely to non-comply with ART, whereas individuals with reported fat loss (Adjusted OR=0.76; 95% CI: 0.60 to 0.95) were less likely to noncomply with ART. Multivariate analysis indicated, non-compliance defined as taking < 95% of doses, individuals with a basic education (Adjusted OR=1.42; 95%CI: 1.04-1.94), current intravenous drug users (Adjusted OR=1.67; 95% CI: 1.12 - 2.51), and those on a non-boosted PI regimen (Adjusted OR= 1.70; 95% CI: 1.12 - 2.57) or a triple-nucleoside regimen (Adjusted OR=2.03; 95% CI: 1.33 3.11) were more likely to non-comply to therapy whereas individuals of white race (Adjusted OR=0.66; 95% CI: 0.46 - 0.95) and with reported fat loss (Adjusted OR=0.63; 95%CI: 0.45- 0.88) were less likely to non-comply with ART.

Study by Wakibi et al

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2008

This was a facility-based cross-sectional study that included 416 adults living HIV/AIDS aged 18 years or more on free HAART for three or more months between November 2008 and April 2009. The study was collected from systematically selected adults living HIV/AIDS as they visited the three purposively selected health facilities and the adults living HIV/AIDS were interviewed about their health beliefs, health system interaction, ARV therapy uptake and reasons for non-compliance. This study was conducted at HIV/AIDS treatment centre in the Kenyatta National Hospital, Kenya Medical Research Institute (KEMRI) and Riruta Health centre in Nairobi, Kenya. The aim of the study was to assess compliance to ART and to identify determinants of noncompliance in Nairobi. The compliance status with ART was the dependent variable while sociodemographic characteristics, ability to fit therapy in own daily schedule, social support status, period on therapy, distance of health facility, time spent per visit were the independent variables. Data were processed prior to data analysis and analysed using SPSS to generate frequencies and crosstabulations. Chi-square test and multivariate logistic regression was used to determine the determinants of non-compliance with ART. A p-value of less than 0.05 was used to show statistical significance between outcome and independent variables. Adjusted odds ratios (AOR) and their 95% CI were used to look into the strength of association between the dependent and independent variables

The study found that the mean age of the study adults living HIV/AIDS was 39.7 years, ranging from 18 to 64 years. Out of the 416 adults living HIV/AIDS interviewed, 403 answered all compliance questions. The study indicated that 72(17.87%) of the adults living HIV/AIDS did not comply with ART from which 47(65.28%) and 25(34.72%) female and male; 1(1.41%) and 70(98.59%) were illiterate Gemeda et al. Determinants of non-compliance with Antiretroviral Therapy among adults living with HIV/AIDS: A Systematic Review © the authors 2012

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and literate; 32(44.44%) and 40(55.56%) were divorced/widowed/single and married; 13(18.31%) and 58(81.69%) had ≤200lm/cell and >200ml/cell had base line CD4 count adults living HIV/AIDS respectively

The study reported compliance with ART among respondents differed significantly at p-value < 0.05 by age (p-value = 0.017), difficulty fitting therapy in own daily schedule (p = 0.006), social support (pvalue =0.015), period on therapy (p-value = 0.002), self report missed therapy (p-value = 0.001), proximity to clinic where respondents refilled (p-value = 0.003) and time spent at clinic per visit (pvalue = 0.001) on bivariate analysis. However, only having difficult fitting therapy in own schedule (Adjusted OR = 2.310; 95%CI: 1.211-4.408, p value =0.011) and proximity to clinic where respondents refilled (Adjusted OR = 2.387; 95%CI: = 1.155-4.931, p-value = 0.019) predicted noncompliance with ART.

Study by Harris et al

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2004

This was a cross-sectional study conducted by enrolling 300 adults living HIV/AIDS who were 18 and above years of age receiving HAART between June 2004 and December 2005 in two clinics in the Dominican Republic. Sixty two percent and 38% of adults living HIV/AIDS participated from Puerto Plata and Santo Domingo respectively. Informed consent and interviews were conducted in Spanish. The study was approved by the University of Pennsylvania Committee on studies involving human beings and the local ethics boards in the Dominican Republic. Barriers to compliance were assessed by self-report using the standard Spanish language Adult AIDS Clinical Trials Group (ACTG) barriers to compliance questionnaire.

The aim of the study was to assess barriers to compliance to ART in Dominican Republic. The compliance status with ART was the dependent variable while age, gender, race, and CD4 count educational level, employment status, alcohol use, illicit drug use, route of acquisition, number of children and the perceived stress were the independent variables. Data was analysed by using SPSS to generate frequencies and cross-tabulations. Chi-square test and multivariate logistic regression was used to determine the determinants of non-compliance with ART. A p-value of less than 0.05 was used to show statistical significance association between outcome and independent variables. Adjusted odds ratios (AOR) and their 95% CI were used to look into the strength of association between the dependent and independent variables. Risk of confounding and effect modification was assessed by adding suspected confounder and interaction terms to logistic regression model. Presence of confounding was declared if the point estimate (AOR) of the association between the exposure variable and compliance differed by 15% or more from the unadjusted analyses (COR).

The study indicated that sub-optimal compliance with ART was reported by 72(24%) adults living HIV/AIDS out of which 43(59.72%) and 29(40.28%) were females and males respectively. Risk Gemeda et al. Determinants of non-compliance with Antiretroviral Therapy among adults living with HIV/AIDS: A Systematic Review © the authors 2012

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factors related with non-compliance with ART included heavy alcohol use (Adjusted OR=2.5; 95% CI: 1.4-4.5, p value < 0.001), having children (Adjusted OR=2.2; 95% CI: 1.1-4.9, p value=0.03) and perceptions of less social support (Adjusted OR =2.0; 95% CI: 1.1-3.6, p value=0.01), lack of perceived family support (Adjusted OR=1.7; 95%CI:0.8-3.7,p value=0.12), age200ml/cell base line CD4 count respectively. Twenty four(18.89%) ,22(17.32%),


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20(15.75%), 10(7.87%) of the cases stopped ARV medications because of work commitment, thought completed the study, side effect of medication, relocated far away to keep appointments respectively.

Multivariable logistic regression was fit for income (p value>0.05), educational status (p value>0.05), time to get clinic (p value>0.05) and gender (p value47 kilometres from their home to health facilities; 72(98.63%) and 1(1.37%) of the adults living HIV/AIDS were depressed and not depressed respectively. Eleven(3.78%), 66(22.68%) and 5(1.7%) of the adults living HIV/AIDS reported active substance use, claimed had no social support and were found to be depressed respectively.

Results of bivariate logistic regression analyses showed that medication adverse effect (Crude OR= 6.85; 95% CI 2.65, 17.72), distance (Crude OR =2.19; 95% CI: 1.44, 5.25), compliance knowledge (Crude OR= 2.17; 95% CI 1.26, 3.77), satisfaction with social support (Crude OR=1.87; 95%CI:1.033.40), and schedule fitting to daily routine (Crude OR= 3.94; 95% CI: 1.03-15.07) showed statistical significant association with compliance with ART at p- value < 0.05. Gemeda et al. Determinants of non-compliance with Antiretroviral Therapy among adults living with HIV/AIDS: A Systematic Review © the authors 2012

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Results of multivariate logistic regression indicated that medication adverse effect, distance of ART clinic from residence and presence of dependents were independent predictors of compliance with ART. Those with medication adverse effect were over six times more likely to be non-compliant with ART than those without medication adverse effect (Adjusted OR=6.41; 95%CI=2.42-17.18, p value < 0.05). Those who lived ≥ 47 Km distance of ART clinic from residence were nearly 2.5 times more likely to be non-compliant with ART than those who lived in > 47 Km distance of ART clinic from residence (Adjusted OR=2.48; 95%CI=1.24-4.98, p value < 0.05) and those with dependents (with children) were 1.95 times more likely to be non-compliant with ART than those without dependents (Adjusted OR=1.95; 95%CI=1.06- 3.57, p value < 0.05).

Results of Meta synthesis/analysis of quantitative research findings The purpose of this meta-analysis was to identify the determinants of non-compliance with ART among adults living HIV/AID by using proportions, not specific estimates, of the risk factors for the outcome variable measured in primary studies

58-66

to calculate the pooled effect sizes. Random 2

effects meta-analysis model was used for studies having moderate heterogeneity level (when I test is 41%-85%)

67

when combined. This heterogeneity( differences) between studies might be explained by

differences between the studies regarding setting, time of outcome measurement, small sample sizes of individual studies (chance), different methods of exposure assessment (measurement errors), different statistical analyses and different data collection methods. model was used for studies with 0%-40% heterogeneity level.

67

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Fixed effects meta-analysis

Gender and social support were

excluded from the meta-analysis as the studies reported these variables showed severe 2

heterogeneity (when I test is >84)

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after the two studies were combined (Appendix VIII).

Heterogeneity between the studies was measured using χ2 test at a statistically significant level of p 47 Km. This difference in non-compliance with ART between adults living HIV/AIDS who walked > 47 Km than who walked ≤ 47 Km adults living HIV/AIDS, however, didn‟t show statistical significance difference when they are pooled in metaanalysis as shown on the forest on Figure 7 (pooled OR=0.61; 95%CI=0.25, 5.53, p value=0.30). ≤47K.M Study or Subgroup

>47 K.M

Odds Ratio

Events Total Events Total Weight

Endrias Markos et al. Mary B Cauldbeck et al.

39

195

34

96

71.3%

0.46 [0.26, 0.79]

4

10

13

38

28.7%

1.28 [0.31, 5.37]

134 100.0%

0.61 [0.25, 1.53]

Total (95% CI)

205

Total events

M-H, Random, 95% CI

43

Odds Ratio M-H, Random, 95% CI

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Heterogeneity: Tau² = 0.23; Chi² = 1.75, df = 1 (P = 0.19); I² = 43% Test for overall effect: Z = 1.05 (P = 0.30)

0.01 0.1 1 10 100 Favours ≤47K.M Favours >47K.M

Figure 7. There was no significance difference in non-compliance with ART between adults living HIV/AIDS who reported walked > 47 Km and ≤ 47 Km

Psychosocial and behavioural related determinants of non-compliance with ART among adults living HIV/AIDS Two cross-sectional studies

65, 66

reported depression as a predictive variable related to non-

compliance with ART among Adults living with HIV/AIDS. Data from these two primary studies were 2

combined in meta-analysis. For this variable, the heterogeneity was found to be χ =0.06, p=0.80. For 2

this variable, no heterogeneity (I =0%) was found between the studies. None of the results of individual studies of these two studies suggested depression as predictor of the non-compliance with 65

ART. Gordilloa et al

individual study reported many non-depressed adults living HIV/AIDS were non66

compliant with ART than depressed Adults living HIV/AIDS. Markos et al

however, reported

depressed adults living HIV/AIDS were non-compliant with ART than non-depressed adults living HIV/AIDS. This difference in non-compliance with ART between depressed and non-depressed adults living HIV/AIDS showed statistical significant difference when they are pooled in meta-analysis as shown on the forest plot on Figure 8.


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Non-depressed adults living HIV/AIDS were 1.77 times more likely to non-comply with ART than depressed adults living HIV/AIDS (pooled OR=1.77; 95%CI=1.17, 2.69, p value=0.007).

Yes Study or Subgroup

No

Odds Ratio

Events Total Events Total Weight

Endrias Markos et al.

72

286

1

5

4.5%

1.35 [0.15, 12.24]

Victoria Gordilloa, et al

75

148

78

214

95.5%

1.79 [1.17, 2.74]

219 100.0%

1.77 [1.17, 2.69]

Total (95% CI)

434

Total events

147

Odds Ratio

M-H, Fixed, 95% CI

M-H, Fixed, 95% CI

79

Heterogeneity: Chi² = 0.06, df = 1 (P = 0.80); I² = 0%

0.01

Test for overall effect: Z = 2.68 (P = 0.007)

0.1 1 10 Favours yes Favours no

100

Figure 8. Non-depressed (labelled as No) adults living with HIV/AIDS were more likely to non-comply with ART than depressed (labelled as Yes) adults living with HIV/AIDS 61

One cohort study

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and one case-control study reported substance using as a predictive variable

related to non-compliance with ART among adults living HIV/AIDS. Data from these two primary studies were combined in meta-analysis. For the outcome, non-compliance with ART, the 2

2

heterogeneity was found to be χ =0.05, p=0.80. For this outcome, no heterogeneity (I =0%) was found between the studies. None of the results of individual studies of these four studies suggested substance using as predictor of the non-compliance with ART. In both studies, many substance user adults living HIV/AIDS were reported to be non-compliant with ART than substance non-users. This difference in non-compliance with ART between substance users and non-substance adults living HIV/AIDS, however, didn‟t show statistical significance difference when they are pooled in metaanalysis as shown on the forest plot on Figure 9. Substance non-user adults living HIV/AIDS were 2.04 times more likely to non-comply with ART than substance user adults living HIV/AIDS (pooled RR=2.04; 95%CI=1.51, 2.74, p value