Measuring adherence to antiretroviral therapy in children and adolescents in western Kenya

Introduction

High levels of adherence to antiretroviral therapy (ART) are central to HIV management. The objective of this study was to compare multiple measures of adherence and investigate factors associated with adherence among HIV-infected children in western Kenya.

Methods

We evaluated ART adherence prospectively for six months among HIV-infected children aged ≤14 years attending a large outpatient HIV clinic in Kenya. Adherence was reported using caregiver report, plasma drug concentrations and Medication Event Monitoring Systems (MEMS^®). Kappa statistics were used to compare adherence estimates with MEMS^®. Logistic regression analyses were performed to assess the association between child, caregiver and household characteristics with dichotomized adherence (MEMS^® adherence ≥90% vs. <90%) and MEMS^® treatment interruptions of ≥48 hours. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.

Results

Among 191 children, mean age at baseline was 8.2 years and 55% were female. Median adherence by MEMS^® was 96.3% and improved over the course of follow-up (p<0.01), although 49.5% of children had at least one MEMS^® treatment interruption of ≥48 hours. Adherence estimates were highest by caregiver report, and there was poor agreement between MEMS^® and other adherence measures (Kappa statistics 0.04–0.37). In multivariable logistic regression, only caregiver-reported missed doses in the past 30 days (OR 1.25, 95% CI 1.14–1.39), late doses in the past seven days (OR 1.14, 95% CI 1.05–1.22) and caregiver-reported problems with getting the child to take ART (OR 1.10, 95% CI 1.01–1.20) were significantly associated with dichotomized MEMS^® adherence. The caregivers reporting that ART made the child sick (OR 1.12, 95% CI 1.01–1.25) and reporting difficulties in the community that made giving ART more difficult (e.g. stigma) (OR 1.14, 95% CI 1.02–1.27) were significantly associated with MEMS^® treatment interruptions in multivariable logistic regression.

Conclusions

Non-adherence in the form of missed and late doses, treatment interruptions of more than 48 hours and sub-therapeutic drug levels were common in this cohort. Adherence varied significantly by adherence measure, suggesting that additional validation of adherence measures is needed. Few factors were consistently associated with non-adherence or treatment interruptions.     

Universal test and treat is not associated with sub‐optimal antiretroviral therapy adherence in rural South Africa: the ANRS 12249 TasP trial

Introduction

HIV treatment guidelines now recommend antiretroviral therapy (ART) initiation regardless of CD4 count to maximize benefit both for the individual and society. It is unknown whether the initiation of ART at higher CD4 counts would affect adherence levels. We investigated whether initiating ART at higher CD4 counts was associated with sub‐optimal adherence (<95%) during the first 12 months of ART.

Methods

A prospective cohort study nested within a two‐arm cluster‐randomized trial of universal test and treat was implemented from March 2012 to June 2016 to measure the impact of ART on HIV incidence in rural KwaZulu‐Natal. ART was initiated regardless of CD4 count in the intervention arm and according to national guidelines in the control arm. ART adherence was measured monthly using a visual analogue scale (VAS) and pill counts (PC). HIV viral load was measured at ART initiation, three and six months, and six‐monthly thereafter. We pooled data from participants in both arms and used random‐effects logistic regression models to examine the association between CD4 count at ART initiation and sub‐optimal adherence, and assessed if adherence levels were associated with virological suppression.

Results

Among 900 individuals who initiated ART ≥12 months before study end, median (IQR) CD4 at ART initiation was 350 cells/mm³ (234, 503); median age was 34.6 years (IQR 27.4 to 46.4) and 71.7% were female. Adherence was sub‐optimal in 14.7% of visits as measured by VAS and 20.7% by PC. In both the crude analyses and after adjusting for potential confounders, adherence was not significantly associated with CD4 count at ART initiation (adjusted OR for linear trend in sub‐optimal adherence with every 100 cells/mm³ increase in CD4 count: 1.00, 95% CI 0.95 to 1.05, for VAS, and 1.03, 95% CI 0.99 to 1.07, for PC). Virological suppression at 12 months was 97%. Optimal adherence by both measures was significantly associated with virological suppression (p < 0.001 for VAS; p = 0.006 for PC).

Conclusions

We found no evidence that higher CD4 counts at ART initiation were associated with sub‐optimal ART adherence in the first 12 months. Our findings should alleviate concerns about adherence in individuals initiating ART at higher CD4 counts, however long‐term outcomes are needed. ClinicalTrials.gov NCT01509508.

     

Adherence to antiretroviral therapy for HIV in sub‐Saharan Africa and Asia: a comparative analysis of two regional cohorts

Introduction : Our understanding of how to achieve optimal long‐term adherence to antiretroviral therapy (ART) in settings where the burden of HIV disease is highest remains limited. We compared levels and determinants of adherence over time between HIV‐positive persons receiving ART who were enrolled in a bi‐regional cohort in sub‐Saharan Africa and Asia. Methods : This multicentre prospective study of adults starting first‐line ART assessed patient‐reported adherence at follow‐up clinic visits using a 30‐day visual analogue scale. Determinants of suboptimal adherence (<95%) were assessed for six‐month intervals, using generalized estimating equations multivariable logistic regression with multiple imputations. Region of residence (Africa vs. Asia) was assessed as a potential effect modifier. Results : Of 13,001 adherence assessments in 3934 participants during the first 24 months of ART, 6.4% (837) were suboptimal, with 7.3% (619/8484) in the African cohort versus 4.8% (218/4517) in the Asian cohort (p < 0.001). In the African cohort, determinants of suboptimal adherence were male sex (odds ratio (OR) 1.27, 95% confidence interval (CI) 1.06–1.53; p = 0.009), younger age (OR 0.8 per 10 year increase; 0.8–0.9; p = 0.003), use of concomitant medication (OR 1.8, 1.0–3.2; p = 0.044) and attending a public facility (OR 1.3, 95% CI 1.1–1.7; p = 0.004). In the Asian cohort, adherence was higher in men who have sex with men (OR for suboptimal adherence 0.6, 95% CI 0.4–0.9; p = 0.029) and lower in injecting drug users (OR for suboptimal adherence 1.6, 95% CI 0.9–2.6; p = 0.075), compared to heterosexuals. Risk of suboptimal adherence decreased with longer ART duration in both regions. Participants in low‐ and lower‐middle‐income countries had a higher risk of suboptimal adherence (OR 1.6, 1.3–2.0; p < 0.001), compared to those in upper‐middle or high‐income countries. Suboptimal adherence was strongly associated with virological failure, in Africa (OR 5.8, 95% CI 4.3–7.7; p < 0.001) and Asia (OR 9.0, 95% CI 5.0–16.2; p < 0.001). Patient‐reported adherence barriers among African participants included scheduling demands, drug stockouts, forgetfulness, sickness or adverse events, stigma or depression, regimen complexity and pill burden. Conclusions : Psychosocial factors and health system resources may explain regional differences. Adherence‐enhancing interventions should address patient‐reported barriers tailored to local settings, prioritizing the first years of ART.     

Frequency and factors associated with adherence to and completion of combination antiretroviral therapy for prevention of mother to child transmission in western Kenya

Introduction

The objective of this analysis was to identify points of disruption within the prevention of mother-to-child transmission (PMTCT) continuum from combination antiretroviral therapy (CART) initiation until delivery.

Methods

To address this objective, the electronic medical records of all antiretroviral-naïve adult pregnant women who were initiating CART for PMTCT between January 2006 and February 2009 within the Academic Model Providing Access To Healthcare (AMPATH), western Kenya, were reviewed. Outcomes of interest were clinician-initiated change or stop in regimen, disengagement from programme (any, early, late) and self-reported medication adherence. Disengagement was categorized as early disengagement (any interval of greater than 30 days between visits but returning to care prior to delivery) or late disengagement (no visit within 30 days prior to the date of delivery). The association between covariates and the outcomes of interest were assessed using bivariate (Kruskal-Wallis test for continuous variables and the Chi-square test for categorical variables) and multivariate logistic regression analysis.

Results

A total of 4284 antiretroviral-naïve pregnant women initiated CART between January 2006 and February 2009. The majority of women (89%) reported taking all of their medication at every visit. There were 18 (0.4%) deaths reported. Clinicians discontinued CART in 10 patients (0.7%) while 1367 (31.9%) women disengaged from care. Of those disengaging, 404 (29.6%) disengaged early and 963 (70.4%) late. In the multivariate model, the odds of disengagement decreased with increasing age (odds ratio [OR] 0.982; confidence interval [CI] 0.966–0.998) and increasing gestational age at CART initiation (OR 0.925; CI 0.909–0.941). Women receiving care at a district hospital (OR 0.794; CI 0.644–0.980) or tuberculosis medication (OR 0.457; CI 0.202–0.935) were less likely to disengage. The odds of disengagement were higher in married women (OR 1.277; CI 1.034–1.584). The odds of early disengagement decreased with increasing age at CART initiation (OR 0.902; CI 0.881–0.924). The odds of late disengagement decreased with increasing age at CART initiation (OR 0.936; CI 0.917–0.956). While they increased with higher CD4 counts at CART-initiation (OR 1.001; CI 1.000–1001) and in married women (OR 1.297; CI 1.000–1.695)

Conclusions

In a PMTCT programme embedded in an antiretroviral treatment programme with an active outreach department, the majority (67.4%) of women remained engaged and received uninterrupted prenatal CART.     

High self‐reported non‐adherence to antiretroviral therapy amongst adolescents living with HIV in Malawi: barriers and associated factors

Introduction : Globally adolescents and young adults account for more than 40% of new HIV infections, and HIV‐related deaths amongst adolescents increased by 50% from 2005 to 2012. Adherence to antiretroviral therapy (ART) is critical to control viral replication and preserve health; however, there is a paucity of research on adherence amongst the growing population of adolescents living with HIV/AIDS (ALHIV) in Southern Africa. We examined levels of self‐reported ART adherence, barriers to adherence, and factors associated with non‐adherence amongst ALHIV in Malawi. Methods : Cross‐sectional study of 519 ALHIV (12–18 years) attending two large HIV clinics in central and south‐eastern Malawi. Participants self‐reported missed doses (past week/month), barriers to adherence, and completed questionnaires on past traumatic events/stressors, disclosure, depression, substance use, treatment self‐efficacy, and social support. Biomedical data were retrieved from existing medical records. Multivariate logistic regression was performed to identify factors independently associated with self‐reported ART adherence (7 day recall). Results : The mean age of participants (SD) was 14.5 (2) years and 290 (56%) were female. Of the 519 participants, 153 (30%) reported having missed ART doses within the past week, and 234 (45%) in the past month. Commonly reported barriers to adherence included forgetting (39%), travel from home (14%), busy with other things (11%), feeling depressed/overwhelmed (6%), feeling stigmatized by people outside (5%) and within the home (3%). Factors found to be independently associated with missing a dose in the past week were drinking alcohol in the past month (OR 4.96, 95% CI [1.41–17.4]), missed clinic appointment in the past 6 months (OR 2.23, 95% CI [1.43–3.49]), witnessed or experienced violence in the home (OR 1.86, 95% CI [1.08–3.21]), and poor treatment self‐efficacy (OR 1.55 95% CI [1.02–2.34]). Sex and age were not associated with adherence. Conclusions : In our study, nearly half of all ALHIV reported non‐adherence to ART in the past month. Violence in the home or alcohol use in the past year as well as poor treatment self‐efficacy were associated with worse adherence. Sub‐optimal adherence is a major issue for ALHIV and compromise treatment outcomes. Programmes specifically tailored to address those challenges most pertinent to ALHIV may help improve adherence to ART.     

Trends of CD4 cell count levels at the initiation of antiretroviral therapy over time and factors associated with late initiation of antiretroviral therapy among Asian HIV-positive patients

Introduction

Although antiretroviral therapy (ART) has been rapidly scaled up in Asia, most HIV-positive patients in the region still present with late-stage HIV disease. We aimed to determine trends of pre-ART CD4 levels over time in Asian HIV-positive patients and to determine factors associated with late ART initiation.

Methods

Data from two regional cohort observational databases were analyzed for trends in median CD4 cell counts at ART initiation and the proportion of late ART initiation (CD4 cell counts <200 cells/mm³ or prior AIDS diagnosis). Predictors for late ART initiation and mortality were determined.

Results

A total of 2737 HIV-positive ART-naïve patients from 22 sites in 13 Asian countries and territories were eligible. The overall median (IQR) CD4 cell count at ART initiation was 150 (46–241) cells/mm³. Median CD4 cell counts at ART initiation increased over time, from a low point of 115 cells/mm³ in 2008 to a peak of 302 cells/mm³ after 2011 (p for trend 0.002). The proportion of patients with late ART initiation significantly decreased over time from 79.1% before 2007 to 36.3% after 2011 (p for trend <0.001). Factors associated with late ART initiation were year of ART initiation (e.g. 2010 vs. before 2007; OR 0.40, 95% CI 0.27–0.59; p<0.001), sex (male vs. female; OR 1.51, 95% CI 1.18–1.93; p=0.001) and HIV exposure risk (heterosexual vs. homosexual; OR 1.66, 95% CI 1.24–2.23; p=0.001 and intravenous drug use vs. homosexual; OR 3.03, 95% CI 1.77–5.21; p<0.001). Factors associated with mortality after ART initiation were late ART initiation (HR 2.13, 95% CI 1.19–3.79; p=0.010), sex (male vs. female; HR 2.12, 95% CI 1.31–3.43; p=0.002), age (≥51 vs. ≤30 years; HR 3.91, 95% CI 2.18–7.04; p<0.001) and hepatitis C serostatus (positive vs. negative; HR 2.48, 95% CI 1.−4.36; p=0.035).

Conclusions

Median CD4 cell count at ART initiation among Asian patients significantly increases over time but the proportion of patients with late ART initiation is still significant. ART initiation at higher CD4 cell counts remains a challenge. Strategic interventions to increase earlier diagnosis of HIV infection and prompt more rapid linkage to ART must be implemented.     

持续随访提高艾滋病患者抗病毒治疗的耐受性及依从性

目的探讨持续随访提高艾滋病患者抗病毒治疗耐受性及依从性的效果。方法将460例艾滋病患者按抗病毒治疗编号顺序随机分为对照组和干预组各230例,对照组仅给予常规的用药指导、依从性教育及复查时间;干预组实施持续随访管理:根据随访时间表,由专职人员通过电话、短信、微信等方式对患者实施持续随访,内容包括服药情况、机体适应性、依从性教育、不良反应的应对以及心理支持等。结果实施持续随访管理后,干预组患者抗病毒治疗的耐受性和依从性显著高于对照组(P0.05,P0.01)。结论持续随访可显著提高艾滋病患者抗病毒治疗的耐受性和依从性,从而保证抗病毒治疗的顺利进行。     

持续随访提高艾滋病患者抗病毒治疗的耐受性及依从性

目的 探讨持续随访提高艾滋病患者抗病毒治疗耐受性及依从性的效果.方法 将460例艾滋病患者按抗病毒治疗编号顺序随机分为对照组和干预组各230例,对照组仅给予常规的用药指导、依从性教育及复查时间;干预组实施持续随访管理：根据随访时间表,由专职人员通过电话、短信、微信等方式对患者实施持续随访,内容包括服药情况、机体适应性、依从性教育、不良反应的应对以及心理支持等.结果 实施持续随访管理后,干预组患者抗病毒治疗的耐受性和依从性显著高于对照组（P＜0.05,P＜0.01）.结论 持续随访可显著提高艾滋病患者抗病毒治疗的耐受性和依从性,从而保证抗病毒治疗的顺利进行.     

Factors of adherence to treatment with trospium in employees

AimTo conduct a comprehensive study of adverse factors and decreasing patients’ adherence during treatment with trospium.Materials and methodsDuring 12 months, 977 patients receiving trospium were studied regarding demographic, socioeconomic, and medical parameters by studying employer’s records, extracts from income tax returns, questionnaires OABq-SF, MOS SF-36, ICIQ-SF, and questionnaires concerning demographic and social status, voiding diaries, and uroflowmetry.ResultsIn total, 54.4% and 35.5% of patients preserved adherence to treatment with trospium during 6 months and 12 months, respectively. The average time of reaching a 30-day break in trospium administration was 182 days. Patients diagnosed with urge urinary incontinence and overactive bladder OAB (56.1%; 40.7%), having severe incontinence symptoms (56.1%), showing objectively high treatment efficacy (25.3%), and individuals subjectively satisfied with treatment outcome (57.5%) prevail among adherent patients, a significant minority is heavy coffee drinkers (14.5%).Individuals who are healthcare and education employees having annual and monthly income significantly higher than the mean income of patients receiving trospium also prevail among adherent patients (25.0%; 32.5%). Adherent patients are significantly older (56.3) than patients less adherent to the treatment.ConclusionThis experiment allowed for the first time the determination of the complexity of heterogeneous medical, socioeconomic, and demographic factors affecting patients’ adherence in treatment with trospium.     

A review of adherence to drug therapy in patients with overactive bladder

Drug therapy for overactive bladder (OAB) is associated with improvements in symptoms and quality of life, but the short- and long-term adherence and persistence is suboptimal. In this review we outline methods of measuring, and factors affecting, adherence to pharmacotherapy in patients with OAB. Clinical practice suggests that adherence rates reported in clinical trials are much greater than in real practice. Factors affecting adherence include psychological and social variables that might alter patients' perception of the benefits of taking medication, and the effect of comorbidity and polypharmacy. Whilst there is some evidence that lack of efficacy and side-effects are contributory, these additional factors are also important.     

Population prevalence of antiretroviral therapy sharing and its association with HIV viremia in rural Uganda: a cross-sectional population-based study

Introduction

Antiretroviral treatment (ART) sharing has been reported among fishermen and sex workers in Uganda and South Africa. However, no population-based studies have documented ART diversion prevalence (including sharing [giving/receiving], buying and selling) or its relationship with viremia among men and women living with HIV in Africa.

Methods

In 2018–2020, we surveyed people living with HIV aged 15–49 years in 41 communities in the Rakai Community Cohort Study, a population-based cohort in south-central Uganda. We assessed the prevalence and correlates of self-reported lifetime and past-year ART diversion, stratifying by age and gender and documenting sources of diverted drugs. We used log-binomial regression to quantify the relationship between diversion patterns and viremia (viral load >40 copies/ml), reported as unadjusted and adjusted prevalence ratios (aPR) with 95% confidence intervals (CI).

Results

Of 2852 people living with HIV and self-reporting current ART use, 266 (9.3%) reported lifetime ART diversion. Giving/receiving drugs were most common; few participants reported buying, and none reported selling. Men (12.9%) were more likely to report lifetime diversion than women (7.4%), with men aged 25–34 reporting high levels of sharing (18.9%). Friends were the most common sources of shared drugs, followed by spouses/sexual partners. Patterns of lifetime and past-year diversion were similar. Among participants with viral load results, 8.6% were viraemic. In adjusted analyses, people who reported only giving ART were nearly twice as likely to be viraemic than those who reported no diversion (aPR: 1.94, 95% CI: 1.10−3.44), and those reporting only receiving ART were less likely to exhibit viremia (aPR: 0.46, 95% CI: 0.12−1.79), although the latter was not statistically significant. Reporting both giving and receiving ART was not associated with viremia (aPR: 0.79, 95% CI: 0.43−1.46). Reporting buying ART, though rare, was also correlated with higher rates of viremia, but this relationship was not statistically significant (aPR: 1.98, 95% CI: 0.72−5.45).

Conclusions

ART sharing is common among persons reporting ART use in rural Uganda, particularly among men. Sharing ART was associated with viremia, and receiving ART may facilitate viral suppression. HIV programmes may benefit from considering ART sharing in counselling messages.     

Monitoring adherence to antiretroviral therapy among adolescents in Southern Uganda: comparing Wisepill to Self‐report in predicting viral suppression in a cluster‐randomized trial

IntroductionOptimal antiretroviral therapy (ART) adherence is crucial for improved patient outcomes; however, ART adherence among adolescents living with HIV (ALHIV) is low. Also, the performance of various adherence measures among ALHIV is under contention. We monitored ART adherence and compared Self‐report (SR) and Wisepill electronic monitoring (EM) performance in measuring ART adherence and predicting HIV viral suppression among ALHIV.MethodsBetween January 2014 and December 2015, we recruited 702 ALHIV aged 10–16 years into our cluster‐randomized controlled trial (2012–2018) in 39 clinics in Uganda. The intervention included a long‐term savings child development account, four micro‐enterprise workshops and 12 mentorship sessions. Using the entire sample, we performed multilevel logistic regression to predict monthly ART adherence trends for the first year of follow‐up. Since it is possible that the intervention had different effects on SR and EM adherence, we used participants in the control arm only to compare adherence using SR and EM and to calculate their sensitivity and specificity in predicting viral suppression.ResultsThere was a significant decline in adherence for each month throughout the entire follow‐up period regardless of the group assigned. Good ART adherence was measured at 79.2% (75.2–82.6%) and 97.0% (95.4–98.1%) using EM and SR, respectively. Overall, 64.3% (60.6–67.9%) had suppressed viral loads. The specificities for EM and SR in predicting viral non‐suppression were 80.4% (73.6–85.7%) and 96.7% (93.3–98.4%), while the sensitivities were 22.9% (15.0–33.3%) and 1.8% (0.4–6.9%), respectively. The area under the curve was low for both EM and SR, at 53.6% (45.7–61.5%) and 56.2% (53.2–59.3%), respectively. There was high agreement (78%) between SR and EM in monitoring adherence.ConclusionsOur findings highlighted the need for strategies for sustained optimal adherence. SR and EM measure adherence with a considerable agreement; however, neither is an accurate predictor of virological outcome. There is still a need for an acceptable, feasible and affordable method that predicts viral suppression among ALHIV.     

Pharmacokinetics‐based adherence measures for antiretroviral therapy in HIV‐infected Kenyan children

Background : Traditional medication adherence measures do not account for the pharmacokinetic (PK) properties of the drugs, potentially misrepresenting true therapeutic exposure. Methods : In a population of HIV‐infected Kenyan children on antiretroviral therapy including nevirapine (NVP), we used a one‐compartment model with previously established PK parameters and Medication Event Monitoring Systems (MEMS®)‐recorded dosing times to estimate the mean plasma concentration of NVP (Cp) in individual patients during 1 month of follow‐up. Intended NVP concentration (Cp’) was calculated under a perfectly followed dosing regimen and frequency. The ratio between the two (R = Cp/Cp’) characterized the patient's NVP exposure as compared to intended level. Smaller R values indicated poorer adherence. We validated R by evaluating its association with MEMS®‐defined adherence, CD4%, and spot‐check NVP plasma concentrations assessed at 1 month. Results : In data from 152 children (82 female), children were mean age 7.7 years (range 1.5–14.9) and on NVP an average of 2.2 years. Mean MEMS® adherence was 79%. The mean value of R was 1.11 (SD 0.37). R was positively associated with MEMS® adherence (p < 0.0001), and lower‐than‐median R values were significantly associated with lower NVP drug concentrations (p = 0.0018) and lower CD4% (p = 0.0178), confirming a smaller R value showed poorer adherence. Conclusion : The proposed adherence measures, R, captured patient drug‐taking behaviours and PK properties.