# Non-adherence and non-persistence with antiretroviral treatment in Belgium: A real-world evaluation using a pharmacy database, 2018–2021

Dieudonné Ilboudo, Patricia Mbouche, Agnès Sommet, Philippe van Wilder, Fati Kirakoya-samadoulougou

► To cite this version:

Dieudonné Ilboudo, Patricia Mbouche, Agnès Sommet, Philippe van Wilder, Fati Kirakoya-samadoulougou. Non-adherence and non-persistence with antiretroviral treatment in Belgium: A real-world evaluation using a pharmacy database, 2018–2021. Pharmacoepidemiology and Drug Safety, 2024, 33 (5), pp.e5804. 10.1002/pds.5804. hal-04964201

HAL Id: hal-04964201

https://ut3-toulouseinp.hal.science/hal-04964201v1

Submitted on 24 Feb 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
<figure><img src="image_2.png" /></figure>

ORIGINAL ARTICLE

<figure><img src="image_3.png" /></figure>

# Non-adherence and non-persistence with antiretroviral treatment in Belgium: A real-world evaluation using a pharmacy database, 2018–2021

Dieudonné Ilboudo<fnref n="1" />,<fnref n="2" /> ID

<figure><img src="image_4.png" /></figure>

Patricia Mbouche<fnref n="1" /> ID

<figure><img src="image_5.png" /></figure>

Agnès Sommet<fnref n="3" /> ID

<figure><img src="image_6.png" /></figure>

Philippe Van Wilder<fnref n="4" /> ID

<figure><img src="image_7.png" /></figure>

Fati Kirakoya-Samadoulougou<fnref n="1" />,<fnref n="5" /> ID

<figure><img src="image_8.png" /></figure>

Correspondence

Fati Kirakoya-Samadoulougou, Centre de recherche Epidémiologie, Biostatistique et Recherche Clinique, Ecole de Santé Publique, Université libre de Bruxelles (U.L.B.), Route de Lennik 808, CP 596, Bruxelles 1070, Belgium.

Email: fati.kirakoya@ulb.be

Abstract

**Purpose:** To evaluate the real-world rates of non-adherence and non-persistence to antiretroviral therapy (ART) among treatment-naïve adult patients with HIV after a 12-month follow-up period in Belgium.

**Methods:** A retrospective analysis of longitudinal pharmacy claims was conducted using the Pharmanet database from January 1, 2018, to December 31, 2021. Non-adherence was assessed over 12 months and reported as the proportion of days covered below the 80% threshold. Non-persistence was defined as the first 90-day gap in treatment between the two types of ART dispensed. Poisson regression with robust standard error and Cox proportional hazard models were used to assess the factors associated with non-adherence and non-persistence, respectively.

**Results:** Overall, 2999 patients were initiated on ART between 2018 and 2021. After a 12-month follow-up, the proportions of non-adherence and non-persistence were 35.6% and 15.9%, respectively in 2018, and decreased to 18.7% and 6.8%, respectively in 2021. Non-adherence was higher among women, Brussels residents, and those receiving multiple-tablet regimens (MTRs). Similarly, the prevalence of non-persistence was higher among women and MTR recipients.

**Conclusion:** Among treatment-naïve adults with HIV in Belgium, non-adherence, and non-persistence to ART showed improvement over the study period but remained at high levels. Disparities were observed by sex and between geographical regions. Prioritizing strategies targeting women in Brussels and facilitating the transition from MTRs to single-tablet regimens should be emphasized to optimize adherence to ART in Belgium.

KEYWORDS

antiretroviral therapy, Belgium, non-adherence, non-persistence, treatment-naïve patients with HIV

<footnote n="1">¹Centre de recherche Epidémiologie, Biostatistique et Recherche Clinique, Ecole de santé publique, Université libre de Bruxelles (U.L.B.), Bruxelles, Belgium</footnote>

<footnote n="2">²District Sanitaire de Banfora, Direction Régionale de la Santé des Cascades, Banfora, Burkina Faso</footnote>

<footnote n="3">³Pharmacologie Médicale, Faculté de Médecine, Université de Toulouse III, Inserm CERPOP, CHU, Toulouse, France</footnote>

<footnote n="4">⁴Centre de recherche en Economie de la Santé, Gestion des Institutions de Soins et Sciences Infirmières, Ecole de Santé Publique, Université Libre de Bruxelles (ULB), Bruxelles, Belgium</footnote>

<footnote n="5">⁵Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA</footnote>
## Key Points

* This study, utilizing pharmacy claims data, presents for the first time the rate of non-adherence and non-persistence of ART in treatment-naïve patients at the population level in Belgium.

* Variations in the non-adherence and non-persistence proportions were observed by sex, geographical region and therapeutic regimen (MTR/STR).

* The study provides real-world insights into non-adherence and non-persistence to prescribed ART, suggesting potential opportunities for targeted interventions during ART dispensing in pharmacies.

* Recommendations that involve prioritizing strategies for women in Brussels and supporting the transition from multiple-tablet to single-tablet regimens should be emphasized.

## Plain Language Summary

In this study, we looked at data from the Pharmanet database over a 3-year period to understand how well adults with HIV in Belgium adhered to their prescribed antiretroviral treatment and how often they stopped taking their medication (non-persistence) following the first year of treatment commencement. Among the 2999 patients who started ART, we observed a decline in non-adherence rates from 2018 to 2021 with one in three individuals experiencing non-adherence and one in six, non-persistence after 12 months of follow-up. Non-adherence was notably higher among women, residents of Brussels, and recipients of multiple-tablet regimens (MTRs). Similarly, non-persistence was more frequent among women and MTR recipients. To enhance adherence to ART in Belgium, targeted interventions tailored for women in Brussels and facilitating the transition from MTRs to single-tablet regimens are recommended.

# 1 | INTRODUCTION

In 2021, an estimated 17 622 people were living with human immunodeficiency virus (HIV) in Belgium, 84% of whom received medical treatment. In that same year, 781 newly diagnosed cases of HIV infection were reported. Despite a 17% decline in the estimated annual number of HIV infections in 2019, the burden on patients remains a public health concern.¹

Antiretroviral therapy (ART) is the cornerstone of HIV treatment as it prevents disease progression and transmission and improves the life expectancy and quality of life of people living with HIV (PLWH).² The European AIDS Clinical Society (EACS) guidelines for HIV treatment recommend immediate life-long ART initiation in all PLWH, regardless of the disease stage.³ In treatment-naïve patients, these guidelines recommend a regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTIs), along with a third drug, preferably an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or boosted protease inhibitors (PI) as alternatives to INSTI.⁴ ART is dispensed either as single-tablet regimens (STRs) or multiple-tablet regimens (MTRs), requiring single or multiple dosing units per day, respectively.³,⁵,⁶

Adherence and persistence with ART are key factors in maintaining viral suppression and reducing resistance, disease progression, and mortality.⁵,⁷⁻¹⁰ Non-adherence may result from factors related to the patient, patient-care provider-health system relationships, ART, or disease symptoms.¹¹,¹² Prior research suggests that the prevalence of non-adherence and non-persistence is higher among women, those with neurocognitive complaints, younger individuals, patients treated

with MTRs compared with those treated with STRs,⁹,¹³,¹⁴ and those who experience adverse drug reactions.¹⁵,¹⁶ Recently, with the advent of new treatment options that are more effective and tolerable and the EACS recommendations to switch from MTRs to STRs, the main predictors of non-adherence and non-persistence have not yet been fully investigated in Belgium. Moreover, the few studies that assessed non-adherence to ART in Belgium were based on self-reported questionnaires, had varying results, and were not representative of the entire population.¹³,¹⁷ For example, when adherence was measured using the Center for Adherence Support Evaluation (CASE) questionnaire, a proportion of 93.5% was reported compared with a proportion of 78.5% when the simplified medication adherence questionnaire (SMAQ) was used.¹³ Analysis of pharmacy claims data is an alternative method for measuring ART adherence, which is simple, less costly, and widely validated.¹⁸ Thus, the use of pharmacy databases can provide real-world evidence on adherence and persistence with prescribed ART.

In Belgium, ART has been reimbursed for all people with HIV, regardless of their CD4 count, since December 2016. Pharmanet is a database of pharmaceutical services provided by public pharmacies and reimbursed by compulsory healthcare insurance. Considering this, it is necessary to update current evidence regarding non-adherence and non-persistence with ART among PLWH in Belgium using data representative of the entire population, with methods suited for the exploitation of pharmaceutical data. Hence, this study aimed to assess non-adherence and non-persistence with ART and identify pharmacy-based predictors among treatment-naïve patients in Belgium, using the Pharmanet database.
## 2 | METHODS

### 2.1 | Data source

This retrospective real-world study used pharmaceutical data from the Belgian Pharmanet database, covering the period from January 1, 2018, to August 31, 2022. Pharmanet, a database of patients under compulsory healthcare insurance, consolidates medical, surgical, and prescription claims from 5240 pharmacies in Belgium. It includes details, such as medication identification, Anatomical Therapeutic and Chemical (ATC) code, commercial name, packaging, issue date, quantity issued, and a beneficiary identifier. The database also contains outpatient service prescription claims and long-term care records. Standard demographic variables such as age, sex, and region were available. The database lacks information on nationality, migration status, drugs dispensed by hospital pharmacies, and those not reimbursed by public pharmacies.¹⁹ However, although migration status and nationality can influence ART adherence,²⁰ these factors were not considered in the analysis.

In 2018, Belgium, with 4841 pharmacies, served 11 million inhabitants at a rate of nearly 1 pharmacy per every 2500 residents.²¹

### 2.2 | Study population

The study focused on adult patients aged ≥18 years who initiated ART between July 1, 2018, and August 31, 2022. The index date was determined as the date of the first adjudicated ART claim for STRs or, for MTRs, the date of the first claim of the last drug in the regimen. Patient characteristics, treatment attributes, and selected co-medications were measured from the index date until December 31, 2021, with a 12-month follow-up period.

We assumed that dispensing two or three antiretroviral (ARV) agents indicated HIV treatment, whereas dispensing only one agent (tenofovir or lamivudine) suggested hepatitis B treatment. We also assumed that dispensing tenofovir and emtricitabine alone indicated pre-exposure prophylaxis (PrEP). Therefore, patients who received only tenofovir, lamivudine, or a combination of tenofovir and emtricitabine at their first drug delivery during the study period were excluded at the time of data extraction. Our cohort was restricted to patients receiving dispensed ART regimens, defined as receiving at least two ARVs in a 30-day window. Table 1 summarizes the full list of the ART dispensed in this study.

Patients aged ≥18 years from the index date who had at least two ART prescription claims on at least two separate dates during the study period were included in this study (Figure 1). In total, 17 604 patients had at least one ART prescription dispensed during the study period. Of these, 4478 started ART on the index date, and 3916 had at least two ART prescriptions filled during the study period. Patients over the age of 18 year on the index date were 3882 and 2999 had more than 12 months of ART follow-ups (Figure 1).

### 2.3 | Outcome measures

The outcome variables were non-adherence and non-persistence with ART during the follow-up period. Adherence to ART was measured using the proportion of days covered (PDC), which was defined as the number of days for which a patient received the drug divided by the number of days in a specified time period.²²,²³ For patients receiving triple therapy, non-covered days were defined as days when a patient received ≤2 ARVs, and for patients receiving dual therapy non-covered days were defined as days when a patient received ≤1 ARV agents. We calculated the PDC over the 12-month follow-up period and classified the patients by the type of regimen dispensed (STR or MTR). Non-adherence was considered if the PDC was <80%.²⁴

Persistence was defined as the time from therapy initiation to discontinuation. Patients were considered to have discontinued first-line therapy if a gap ≥90 days between filling prescriptions was observed.²⁵ For MTRs, non-persistence was considered for a gap ≥90 days between filling prescriptions and at least one medicine claim. Additionally, patients who restarted therapy after a ≥ 90-day gap were classified as “non-persistence” because restarts were not included in the analysis.¹⁴ Switching treatment regimens (MTR to STR and/or triple therapy to dual therapy) during the first year following ART initiation was considered treatment discontinuation.²⁶ This is because we wanted to assess adherence to first-line ART during the first year of follow-up among PLWH.²⁶

### 2.4 | Demographic and baseline clinical characteristics

Patient demographics including age (18–34, 35–49, 50–64, and ≥65 years), sex (male or female), region (Flemish region, Brussels-Capital region, Walloon region), and co-medication were assessed. Co-medications were coded as 1 or 0 based on the presence or absence of treatment of any HIV comorbidity based on the ATC codes of the prescribed drugs. Medications for mental and neurological disorders (ATC codes: N03, N04, N05, and N06), antihypertensives (ATC code: C02), antidiabetic drugs (ATC code: A10), cardiovascular drugs (ATC codes: C01, C03, C09, C10, and B01), and drugs for chronic respiratory disease (ATC code: R03) were considered. ART was described according to the therapeutic regimen type (STR or MTR) and the therapeutic classes of drugs used. The year of treatment initiation (2018, 2019, 2020, or 2021) was also considered as an adjustment variable.

### 2.5 | Statistical analysis

Data were summarized using descriptive statistics and presented as proportions for categorical variables.

To assess the factors associated with non-adherence according to participants' characteristics (age, sex, region of residence, co-medication, and therapeutic regimen), we employed modified Poisson
<table><caption>TABLE 1 Description of antiretroviral treatment regimens using in Belgium during study period and year of introduction in European AIDS Clinical Society guidelines.</caption><thead><tr><th>Antiretroviral therapy combinations</th><th>Therapeutic regimen</th><th>Therapeutic class</th><th>Year of introduction<sup>b</sup></th></tr></thead><tbody><tr><td>ABC<sup>d</sup>/3TC/DTG 600/300/50 mg</td><td>MTR/STR</td><td>2 NRTIs + INSTI</td><td>2017</td></tr><tr><td>TAF/FTC 25/200 mg + DTG<sup>g</sup> 50 mg</td><td>MTR<sup>n</sup></td><td></td><td></td></tr><tr><td>TDF/FTC 300/200 mg + DTG 50 mg</td><td>MTR</td><td></td><td></td></tr><tr><td>TAF/FTC/EVG/c<sup>a</sup> 10/200/150/150 mg</td><td>MTR/STR</td><td></td><td></td></tr><tr><td>TDF/FTC/EVG/c 300/200/150/150 mg</td><td>MTR/STR</td><td></td><td></td></tr><tr><td>TAF/FTC 25/200 mg + RAL 400 mg</td><td>MTR</td><td></td><td></td></tr><tr><td>TDF/FTC 300/200 mg + RAL 400 mg</td><td>MTR</td><td></td><td></td></tr><tr><td>TAF/FTC/BIC<sup>e</sup> 25/200/50 mg</td><td>MTR/STR</td><td></td><td>2018</td></tr><tr><td>TAF/3TC + RAL<sup>i</sup></td><td>MTR</td><td></td><td>2020</td></tr><tr><td>TDF/XTC + RAL</td><td>MTR</td><td></td><td>2021</td></tr><tr><td>TDF/XTC + DTG</td><td>MTR</td><td></td><td></td></tr><tr><td>TAF/FTC<sup>m</sup>/RPV 25/200/25 mg</td><td>MTR/STR</td><td>2 NRTIs +1 NNRTI</td><td>2017</td></tr><tr><td>TDF/FTC/RPV 300/200/25 mg</td><td>MTR/STR</td><td></td><td></td></tr><tr><td>TDF/3TC<sup>l</sup> + RPV<sup>c</sup> 25 mg</td><td>MTR/STR</td><td></td><td>2019</td></tr><tr><td>TDF/3TC/DOR 300/300/mg</td><td>MTR/STR</td><td></td><td></td></tr><tr><td>TAF<sup>f</sup>/FTC + DOR</td><td>MTR</td><td></td><td></td></tr><tr><td>TDF<sup>k</sup>/FTC + DOR</td><td>MTR</td><td></td><td></td></tr><tr><td>TDF/XTC + DOR<sup>g</sup></td><td>MTR</td><td></td><td>2021</td></tr><tr><td>TAF/FTC 10/200 mg + DRV/c 800/150 mg, ou + DRV/r<sup>h</sup></td><td>MTR/STR</td><td>2 NRTIs + PI/r ou PI/c</td><td>2017</td></tr><tr><td>TDF/FTC 300/200 mg + DRV/c 800/150 mg ou + DRV/r</td><td>MTR</td><td></td><td></td></tr><tr><td>TDF/3TC 300/200 mg + DRV/c 800/150 mg ou + DRV/r</td><td>MTR</td><td></td><td>2019</td></tr><tr><td>DTG + 3TC</td><td>STR<sup>o</sup></td><td>1 NRTI +1 INSTI</td><td>2019</td></tr><tr><td>XTC + DTG</td><td>MTR/STR</td><td></td><td>2021</td></tr><tr><td>DRV/RAL</td><td>MTR</td><td>PI + II</td><td>2019</td></tr></tbody></table>

regression models based on Generalized Estimating Equations (GEE). Estimates for crude and adjusted prevalence ratios (cPR and aPR, respectively) and their 95% confidence interval (95%CI) were obtained. The GEE approach was constructed with unstructured matrices of correlation to account for correlated observations. Also, a linear regression model was used to assess the trend of non-

adherence between 2018 and 2021 and the estimates were adjusted for sex, age, and region.

A Poisson regression with robust standard error model was also performed to evaluate the factors associated with non-adherence according to the participants' characteristics, and the prevalence ratios and 95% CIs were presented. The trend in non-adherence between

<footnote><sup>a</sup>EVG/c: Not recommended as first line after 2017.</footnote>

<footnote><sup>b</sup>Year of introduction by European AIDS Clinical Society (EACS) guidelines.</footnote>

<footnote><sup>c</sup>RPV and DOR: Not recommended as first line after 2020.</footnote>

<footnote><sup>d</sup>ABC, abacavir.</footnote>

<footnote><sup>e</sup>BIC, bictegravir.</footnote>

<footnote><sup>f</sup>DOR, doravirine.</footnote>

<footnote><sup>g</sup>DTG, dolutegravir.</footnote>

<footnote><sup>h</sup>DRV/r ou DRV/c, darunavir + ritonavir ou cobicistat; EFV, efavirenz; EVG/c, elvitegravir + cobicistat.</footnote>

<footnote><sup>i</sup>RAL, raltegravir.</footnote>

<footnote><sup>j</sup>TAF, tenofovir alafenamide.</footnote>

<footnote><sup>k</sup>TDF, tenofovir disoproxil fumarate.</footnote>

<footnote><sup>l</sup>3TC: lamivudine.</footnote>

<footnote><sup>m</sup>FTC: emtricitabine.</footnote>

<footnote><sup>n</sup>MTR, multiple tablets regimen.</footnote>

<footnote><sup>o</sup>STR, single tablets regimen.</footnote>
<figure><img src="image_9.png" /><figcaption>**FIGURE 1** Flow diagram describing the process of selecting the study population.</figcaption></figure>

2018 and 2021 was assessed using a linear regression model adjusted for sex, age, and region.

Kaplan-Meier curves were used to assess the overall time to discontinuation of first-line ART for both STRs and MTRs. A multivariable Cox proportional hazards regression model was constructed to identify the factors associated with the risk of non-persistence for each regimen, initially unadjusted, and subsequently adjusted for demographic and clinical variables to estimate hazard ratios (HRs) with their 95% confidence intervals (CIs). The proportionality of the risks was verified for each predictor, and collinearity between the independent variables was evaluated. All analyses were performed using Stata (Stata Corp, College Station, TX, USA) and R (The R

Foundation for Statistical Computing) software, and statistical significance was set at *p* < 0.05.

## 2.6 | Ethical approval

This study used administrative health information routinely collected by Institut national d'assurance maladie-invalidité (INAMI) in Belgium. To reduce the risk of patient identification, the age variable was categorized, and an anonymous number was assigned to each patient before data extraction. The Security Committee of Information approved the release of the data (approval number: 22/306).²⁷
## 3 | RESULTS

### 3.1 | Patient characteristics and therapeutics regimens

Overall, 2999 patients initiated ART during the study period, with >12 months of follow-up. Table 2 summarizes the baseline sociodemographic and clinical characteristics of the patients. More than two-thirds of the participants were men and received STRs. Almost half the patients were aged 35-49 years and Flanders residents, and almost 20% of the patients had one co-medication (Table 2).

Treatment combinations based on 2 NRTIs + INSTI drug classes were the most dispensed drugs, comprising 62.5% of all ARTs dispensed, followed by 2 NRTIs +1 NNRTI. The most frequently used ARV combinations were emtricitabine/tenofovir alafenamide

<table><caption>TABLE 2 Baseline socio-demographic and therapeutic characteristics of patients initiating ART from 2018 to 2021 in Belgium.</caption><thead><tr><th>Demographics and clinical characteristics</th><th>Total (n = 2999)</th><th>Percentage (%)</th></tr></thead><tbody><tr><td>Sex</td><td></td><td></td></tr><tr><td>Male</td><td>1965</td><td>65.5</td></tr><tr><td>Female</td><td>1034</td><td>34.5</td></tr><tr><td>Age (years)</td><td></td><td></td></tr><tr><td>18-34</td><td>866</td><td>28.9</td></tr><tr><td>35-49</td><td>1312</td><td>43.7</td></tr><tr><td>50-64</td><td>705</td><td>23.5</td></tr><tr><td>≥65</td><td>116</td><td>3.9</td></tr><tr><td>Region</td><td></td><td></td></tr><tr><td>Flanders</td><td>1316</td><td>43.9</td></tr><tr><td>Brussels-Capital</td><td>929</td><td>31.0</td></tr><tr><td>Wallonia</td><td>754</td><td>25.1</td></tr><tr><td>Co-medications</td><td></td><td></td></tr><tr><td>Chronic respiratory disease medicines</td><td>288</td><td>9.6</td></tr><tr><td>Antihypertensives</td><td>24</td><td>0.8</td></tr><tr><td>Cardiovascular medicines</td><td>603</td><td>20.1</td></tr><tr><td>Neurological disorders medicines</td><td>403</td><td>13.4</td></tr><tr><td>Antidiabetics</td><td>144</td><td>4.8</td></tr><tr><td>Therapeutic regimen</td><td></td><td></td></tr><tr><td>STR<sup>b</sup></td><td>2275</td><td>75.9</td></tr><tr><td>MTR<sup>a</sup></td><td>724</td><td>24.1</td></tr><tr><td>Year of ART initiation</td><td></td><td></td></tr><tr><td>2018</td><td>1006</td><td>33.5</td></tr><tr><td>2019</td><td>971</td><td>32.4</td></tr><tr><td>2020</td><td>701</td><td>23.4</td></tr><tr><td>2021</td><td>321</td><td>10.7</td></tr></tbody></table>

fumarate/bictegravir sodium (FTC/TAF/BIC) (26.4%), emtricitabine/tenofovir alafenamide fumarate/elvitegravir/cobicistat FTC/TAF/EVG/c (15.5%), and emtricitabine/tenofovir alafenamide fumarate/rilpivirine (FTC/TAF/RPV) (15.5%). Approximately 5% of the patients received dual therapy (Table 3). The proportion of patients receiving STRs increased significantly from 63.6% in 2018 to 90.3% in 2021 after adjusting for age, sex, and region of residence ($p_{trend} < 0.001$).

### 3.2 | Non-adherence to antiretroviral therapy and associated factors in Belgium

The proportion of non-adherence was 35.6% after 12 months of follow-up. As shown in Table 4, the prevalence of non-adherence decreased from 46.6% in 2018 to 18.7% in 2021 after adjusting for age, sex, and region of residence ($p_{trend} < 0.001$).

In univariate analysis, non-adherence was associated with MTRs (prevalence ratio [PR]: 3.16, 95% CI: 2.90-3.45, *p* < 0.001), compared three-tablet with two-tablet regimens (PR: 1.97, 95% CI: 1.39-2.78, *p* < 0.001), and therapeutic class (2 NRTIs + PI, PR: 1.71, 95% CI: 1.53-1.92; 2 NRTIs + NNRTI, PR: 1.32, 95% CI: 1.17-1.50, *p* < 0.001). We did not find an association between non-adherence and the alternative regimen (PR: 1.00, 95% CI: 0.89-1.12, *p* = 0.98). Table 5 shows non-adherence according to treatment characteristics.

In multivariate analysis, after 12 months follow-up 35.6% (95% CI: 33.9-37.3) of the patients were non-adherent (PDC <80%). Non-adherence was higher among women (adjusted prevalence ratio [aPR]: 1.64, 95% CI: 1.49-1.80), people living in the Brussels-Capital region (aPR: 1.13, 95% CI: 1.03-1.25), and those who received MTRs (aPR: 2.72, 95% CI: 2.33-3.17). Co-medication was not significantly associated with an increased risk of non-adherence (Table 6).

### 3.3 | Non-persistence with antiretroviral therapy and associated factors in Belgium

Overall, 15.9% (95% CI: 14.6-17.3) of patients were non-persistent to ART after one year of follow-up. The prevalence of non-persistence decreased from 23.8% in 2018 to 6.8% in 2021 ($p_{trend} < 0.001$). Figure 2 shows the proportion of non-persistence in PLWH according to their sociodemographic characteristics.

Non-persistence was higher among women (adjusted hazard ratio [aHR]: 2.09, 95% CI: 1.66-2.64) and those receiving MTRs (aHR: 10.02, 95% CI: 6.58-15.25). We did not find any variation in the risk of non-persistence according to age, region, and co-medication use (Table 7).

## 4 | DISCUSSION

The primary objective of this study was to assess the real-world rates of non-adherence and non-persistence to ART among treatment-

<footnote><sup>a</sup>MTR, multiple tablet regimens.</footnote>

<footnote><sup>b</sup>STR, single tablet regimens.</footnote>
<table><caption>TABLE 3 The 12 most commonly used antiretroviral combinations among newly treated patients in Belgium (n = 2999).</caption><thead><tr><th>Therapeutic class</th><th>Antiretroviral therapy combinations</th><th>Total (n = 2999)</th><th>Percentage (%)</th></tr></thead><tbody><tr><td rowspan="4">2 NRTIs + INSTI</td><td>FTC/TAF/BIC<sup>d</sup></td><td>791</td><td>26.4</td></tr><tr><td>FTC/TAF<sup>f</sup>/EVG/c<sup>a</sup></td><td>466</td><td>15.5</td></tr><tr><td>3TC/ABC<sup>c</sup>/DTG<sup>f</sup></td><td>404</td><td>13.5</td></tr><tr><td>TDF<sup>k</sup>/3TC + DTG</td><td>214</td><td>7.1</td></tr><tr><td rowspan="4">2 NRTIs + 1 NNRTI</td><td>FTC/TAF/RPV<sup>b</sup></td><td>466</td><td>15.5</td></tr><tr><td>FTC/TDF/RPV</td><td>257</td><td>8.6</td></tr><tr><td>FTC/TDF/EFV<sup>h</sup></td><td>110</td><td>3.7</td></tr><tr><td>3TC<sup>l</sup>/TDF/DOR<sup>e</sup></td><td>28</td><td>0.9</td></tr><tr><td rowspan="2">2 NRTIs + PI/r ou PI/c</td><td>FTC<sup>m</sup>/TAF/DRV/c<sup>g</sup></td><td>423</td><td>14.1</td></tr><tr><td>ABC/3TC + ATV/c</td><td>67</td><td>2.2</td></tr><tr><td>1 NRTI + 1 INSTI</td><td>3TC/DTG</td><td>112</td><td>3.7</td></tr><tr><td rowspan="2">1 PI + 1 II<sup>n</sup></td><td>RAL<sup>i</sup> + DRV/c or DRV/r</td><td>31</td><td>1.0</td></tr><tr><td>Others combinations</td><td>96</td><td>3.2</td></tr></tbody></table>

<table><caption>TABLE 4 Evolution of non-adherence, non-persistence and antiretroviral therapeutic regimen during the study period among newly treated patient in Belgium.</caption><thead><tr><th rowspan="3"></th><th colspan="4">Year of introduction</th><th rowspan="3">p trend</th></tr><tr><th>2018</th><th>2019</th><th>2020</th><th>2021</th></tr><tr><th>n = 1006 (%)</th><th>n = 971 (%)</th><th>n = 701 (%)</th><th>n = 321 (%)</th></tr></thead><tbody><tr><td>Non-adherence</td><td></td><td></td><td></td><td></td><td>&lt;0.001*</td></tr><tr><td>No (PDC ≥ 80)</td><td>537 (53.4)</td><td>620 (63.8)</td><td>513 (73.2)</td><td>261 (81.3)</td><td></td></tr><tr><td>Yes (PDC &lt; 80)</td><td>469 (46.6)</td><td>351 (36.2)</td><td>188 (26.8)</td><td>60 (18.7)</td><td></td></tr><tr><td>Non-persistence</td><td></td><td></td><td></td><td></td><td>&lt;0.001**</td></tr><tr><td>No (gap &lt; 90 days)</td><td>767 (76.2)</td><td>818 (84.2)</td><td>638 (91.0)</td><td>299 (93.2)</td><td></td></tr><tr><td>Yes (gap ≥ 90 days)</td><td>239 (23.8)</td><td>153 (15.8)</td><td>63 (9.0)</td><td>22 (6.8)</td><td></td></tr><tr><td>Therapeutic regimen</td><td></td><td></td><td></td><td></td><td>&lt;0.001***</td></tr><tr><td>STR</td><td>640 (63.6)</td><td>749 (77.1)</td><td>596 (85.0)</td><td>290 (90.3)</td><td></td></tr><tr><td>MTR</td><td>366 (36.4)</td><td>222 (22.9)</td><td>105 (14.9)</td><td>31 (9.7)</td><td></td></tr></tbody></table>

naïve adults with HIV following a 12-month follow-up period. In this real-world investigation, we observed that 35.6% and 15.9% of newly treated PLWH on ART were non-adherent and non-persistent to treatment, respectively, after 12 months of follow-up. Additionally,

our findings indicated a significantly higher prevalence of non-adherence among women, residents of Brussels, and patients receiving MTRs. Similarly, the proportion of non-persistence was significantly higher in women and patients receiving MTRs. Between 2018

<footnote><sup>a</sup>EVG/c (Elvitegravir + cobicistat): Not recommended as first line after 2017.</footnote>

<footnote><sup>b</sup>RPV and DOR: Not recommended as first line after 2020.</footnote>

<footnote><sup>c</sup>ABC: Abacavir.</footnote>

<footnote><sup>d</sup>BIC: Bictegravir.</footnote>

<footnote><sup>e</sup>DOR: Doravirine.</footnote>

<footnote><sup>f</sup>DTG: Dolutegravir.</footnote>

<footnote><sup>g</sup>DRV/r ou DRV/c: Darunavir + ritonavir ou cobicistat.</footnote>

<footnote><sup>h</sup>EFV: Efavirenz.</footnote>

<footnote><sup>i</sup>RAL: Raltegravir.</footnote>

<footnote><sup>j</sup>TAF: Tenofovir alafenamide.</footnote>

<footnote><sup>k</sup>TDF: Tenofovir Disoproxil fumarate.</footnote>

<footnote><sup>l</sup>3TC: Lamivudine.</footnote>

<footnote><sup>m</sup>FTC: Emtricitabine.</footnote>

<footnote><sup>n</sup>II: Integrase Inhibitor.</footnote>

<footnote>*p trend of non-adherence after adjusted on age, sex and region of residence.</footnote>

<footnote>**p trend of non-persistence after adjusted on age, sex and region of residence.</footnote>

<footnote>***p trend of therapeutic regimen after adjusted on age, sex and region of residence.</footnote>
<table><caption>TABLE 5 Treatment characteristics and non-adherence to antiretroviral therapy among newly treated patients in Belgium.</caption><thead><tr><th>Treatment characteristics</th><th>Total (n = 2999)</th><th>Percentage of non-adherence (%)</th><th>Crude PR (95%CI)</th><th>p value</th></tr></thead><tbody><tr><td>Therapy regimen</td><td></td><td></td><td></td><td><strong>&lt;0.001<sup>a</sup></strong></td></tr><tr><td>STR</td><td>2275</td><td>23.4</td><td>1</td><td></td></tr><tr><td>MTR</td><td>724</td><td>74.0</td><td>3.16 (2.90-3.45)</td><td></td></tr><tr><td>Therapy type</td><td></td><td></td><td></td><td></td></tr><tr><td>Bitherapy</td><td>146</td><td>18.5</td><td>1</td><td><strong>&lt;0.001<sup>a</sup></strong></td></tr><tr><td>Tritherapy</td><td>2853</td><td>36.5</td><td>1.97 (1.39-2.78)</td><td></td></tr><tr><td>Therapeutic class</td><td></td><td></td><td></td><td><strong>&lt;0.001<sup>a</sup></strong></td></tr><tr><td>2 NRTIs + PI</td><td>490</td><td>50.8</td><td>1.71 (1.53-1.92)</td><td></td></tr><tr><td>2 NRTIs + INSTI</td><td>1675</td><td>29.6</td><td>1</td><td></td></tr><tr><td>2 NRTIs + NNRTI</td><td>595</td><td>39.3</td><td>1.32 (1.17-1.50)</td><td></td></tr><tr><td>Others combinations</td><td>239</td><td>37.2</td><td>1.25 (1.05-1.51)</td><td></td></tr><tr><td>Regimen</td><td></td><td></td><td></td><td>0.98<sup>a</sup></td></tr><tr><td>Recommended regimen (2018)</td><td>2289</td><td>35.6</td><td>1</td><td></td></tr><tr><td>Alternative regimen</td><td>710</td><td>35.6</td><td>1.00 (0.89-1.12)</td><td></td></tr><tr><td>Co-prescription</td><td></td><td></td><td></td><td>0.16<sup>a</sup></td></tr><tr><td>No</td><td>1911</td><td>34.7</td><td>1</td><td></td></tr><tr><td>Yes</td><td>1088</td><td>37.2</td><td>1.07 (0.97-1.18)</td><td></td></tr></tbody></table>

Abbreviations: CI, confidence interval; MTR, multiple tablets regimen; PR, prevalence ratio; STR, single tablet regimen.

<table><caption>TABLE 6 Factors associated to ART non-adherence in first year after initiation treatment between 2018 and 2021 in Belgium.</caption><thead><tr><th rowspan="2"></th><th rowspan="2">n</th><th rowspan="2">%</th><th colspan="3">Low adherence (PDC &lt; 80%)</th><th colspan="3">Low adherence (PDC &lt; 80%)</th></tr><tr><th>Crude PR<sup>**</sup></th><th>(95%CI)</th><th>p</th><th>Adjusted PR</th><th>(95%CI)</th><th>p</th></tr></thead><tbody><tr><td></td><td>2999</td><td>35.6</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Sex</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Male</td><td>1965</td><td>29.2</td><td>1</td><td></td><td><strong>&lt;0.001<sup>a</sup></strong></td><td>1</td><td></td><td><strong>&lt;0.001<sup>b</sup></strong></td></tr><tr><td>Female</td><td>1034</td><td>47.8</td><td>1.64</td><td>(1.49;1.80)</td><td></td><td>1.38</td><td>(1.26;1.51)</td><td></td></tr><tr><td>Age (years)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>18-34</td><td>866</td><td>34.6</td><td>1.06</td><td>(0.80;1.39)</td><td>0.78<sup>a</sup></td><td>1.28</td><td>(0.98;1.68)</td><td>0.28<sup>b</sup></td></tr><tr><td>35-49</td><td>1312</td><td>36.1</td><td>1.10</td><td>(0.84;1.44)</td><td></td><td>1.25</td><td>(0.96;1.63)</td><td></td></tr><tr><td>50-64</td><td>705</td><td>36.3</td><td>1.11</td><td>(0.84;1.46)</td><td></td><td>1.20</td><td>(0.92;1.57)</td><td></td></tr><tr><td>≥65</td><td>116</td><td>32.7</td><td>1</td><td></td><td></td><td>1</td><td></td><td></td></tr><tr><td>Region</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Flanders</td><td>1316</td><td>34.2</td><td>1</td><td></td><td>0.53<sup>a</sup></td><td>1</td><td></td><td><strong>0.03<sup>b</sup></strong></td></tr><tr><td>Brussels-Capital</td><td>929</td><td>36.5</td><td>1.07</td><td>(0.95;1.19)</td><td></td><td>1.15</td><td>(1.03;1.27)</td><td></td></tr><tr><td>Wallonia</td><td>754</td><td>35.0</td><td>1.02</td><td>(0.88;1.19)</td><td></td><td>1.07</td><td>(0.96;1.19)</td><td></td></tr><tr><td>Co-medication</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>1911</td><td>34.7</td><td>1</td><td></td><td>0.16<sup>a</sup></td><td>1</td><td></td><td>0.94<sup>b</sup></td></tr><tr><td>Yes</td><td>1088</td><td>37.2</td><td>1.07</td><td>(0.97;1.18)</td><td></td><td>1.00</td><td>(0.91;1.10)</td><td></td></tr><tr><td>Therapeutic regimen</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>STR</td><td>2275</td><td>23.4</td><td>1</td><td></td><td><strong>&lt;0.001<sup>a</sup></strong></td><td>1</td><td></td><td><strong>&lt;0.001<sup>b</sup></strong></td></tr><tr><td>MTR</td><td>724</td><td>74.0</td><td>3.16</td><td>(2.91;3.45)</td><td></td><td>3.05</td><td>(2.79;3.33)</td><td></td></tr></tbody></table>

Abbreviations: CI, confidence interval; MTR, multiple tablets regimen; PDC, proportion of days covered; PR, prevalence ratio; STR, single tablet regimen.

<footnote><sup>a</sup>Unadjusted *p* value; bold value presented significant *p* value.</footnote>

<footnote><sup>a</sup>Unadjusted *p* value.</footnote>

<footnote><sup>b</sup>Adjusted *p* value; bold value presented significant *p* value.</footnote>
<figure><img src="image_10.png" /><figcaption>**TABLE 7** Demographics and therapeutics characteristics associated with non-persistence level to ART among newly treated patients in Belgium.</figcaption></figure>

<table><thead><tr><th colspan="8">Patients with a gap ≥ 90 days between fills</th></tr><tr><th></th><th>n</th><th>Crude HR</th><th>(95%CI)</th><th>p</th><th>Adjusted HR</th><th>(95%CI)</th><th>p</th></tr></thead><tbody><tr><td>Total</td><td>2999</td><td></td><td>(14.6;17.3)</td><td></td><td></td><td></td><td></td></tr><tr><td>Sex</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Male</td><td>1965</td><td>1</td><td></td><td>&lt;0.001</td><td>1</td><td></td><td>&lt;0.001</td></tr><tr><td>Female</td><td>1034</td><td>2.07</td><td>(1.64;2.61)</td><td></td><td>2.09</td><td>(1.66;2.64)</td><td></td></tr><tr><td>Age (years)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>18-34</td><td>866</td><td>1.17</td><td>(0.83;1.63)</td><td>0.19</td><td>1.27</td><td>(0.89;1.82)</td><td>0.39</td></tr><tr><td>35-49</td><td>1312</td><td>1.31</td><td>(0.95;1.79)</td><td></td><td>1.31</td><td>(0.95;1.79)</td><td></td></tr><tr><td>50-64</td><td>705</td><td>1</td><td></td><td></td><td>1</td><td></td><td></td></tr><tr><td>≥65</td><td>116</td><td>1.13</td><td>(0.56;2.29)</td><td></td><td>1.03</td><td>(0.51;2.11)</td><td></td></tr><tr><td>Region</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Flanders</td><td>1316</td><td>1.13</td><td>(0.77;1.65)</td><td>0.82<sup>a</sup></td><td>1</td><td></td><td>0.48<sup>b</sup></td></tr><tr><td>Brussels-Capital</td><td>929</td><td>1.39</td><td>(0.95;2.04)</td><td></td><td>1.17</td><td>(0.89;1.53)</td><td></td></tr><tr><td>Wallonia</td><td>754</td><td>1</td><td></td><td></td><td>1.03</td><td>(0.76;1.39)</td><td></td></tr><tr><td>Co-medication</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>1911</td><td>1</td><td></td><td>0.59</td><td>1</td><td></td><td>0.88<sup>b</sup></td></tr><tr><td>Yes</td><td>1088</td><td>1.07</td><td>(0.83;1.36)</td><td></td><td>1.02</td><td>(0.79;1.32)</td><td></td></tr><tr><td>Therapeutic regimen</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>STR</td><td>2275</td><td>1</td><td></td><td>&lt;0.001<sup>a</sup></td><td>1</td><td></td><td>&lt;0.001<sup>b</sup></td></tr><tr><td>MTR</td><td>724</td><td>9.85</td><td>(6.53;14.86)</td><td></td><td>10.02</td><td>(6.58;15.25)</td><td></td></tr></tbody></table>

Abbreviations: CI, confidence interval; HR, hazards ratios; MTR, multiple tablet regimens; STR, single tablet regimens.

and 2021, there was a significant decrease in the proportions of non-adherence and non-persistence to ART in Belgium.

Non-adherence and non-persistence with ART are associated with virological failure, an increased risk of HIV transmission,

emergence of ART-resistant viral strains, disease progression, and increased mortality.⁹ Therefore, optimal adherence is necessary to achieve the UNAIDS third goal, which is for 95% of all patients on ART having an undetectable viral load.²

<footnote><sup>a</sup>Unadjusted *p* value.</footnote>

<footnote><sup>b</sup>Adjusted *p* value; bold value presented significant *p* value.</footnote>
In our study, the population starting ART was predominantly male and aged 35-49 years. We found that the proportion of patients who started ART and had at least a 12-month follow-up period, was highest in Brussels (0.8%), followed by Wallonia (0.2%). However, the number of patients initiating treatment decreased in 2020 and 2021 compared with 2018 and 2019. This decline could be attributed to the impact of the coronavirus (COVID-19) pandemic, which was first reported in Belgium on February 4, 2020.²⁸ In response to the pandemic, government health measures, such as lockdowns and transportation restrictions limited access to healthcare and services, affecting the detection of HIV cases, initiation of ART, and drug delivery.²⁸

Our study revealed that approximately one in three patients on ART were non-adherent over a 12-month follow-up period. Another study that used the SMAQ and CASE questionnaire to assess adherence in 218 patients at the AIDS reference center of Ghent University Hospital in Belgium¹³ found that 78.5% and 93.5% of patients adhered to ART using the SMAQ and CASE questionnaire, respectively.¹³ Our study found that 6 months after ART initiation, non-adherence to ART was 31.7%, and that it tended to increase between 6 and 12 months after initiating ART. This could be attributed to the general tendency of patients undergoing chronic treatment to forget to take drugs over time.²⁹ Long-term treatment can interfere with patients' social habits; for example, fear of the combined toxicity of drugs and alcohol may lead patients to avoid using drugs when consuming alcohol.²⁹ Additionally, asymptomatic individuals may believe that ART worsens their health due to adverse drug reactions, contributing to poor adherence over time.³⁰ However, the proportion of non-adherent patients decreased between 2018 and 2021, reflecting an improvement in adherence, which may be related to an increase in the proportion of patients receiving STRs. The proportion of non-adherent patients at 6 months of follow-up also represents the proportion of people at risk of presenting an uncontrolled viral load by the end of this follow-up period. These results contrast with national surveillance data, which showed in 2022 that the proportion of PLWH on ART has reached optimal coverage of 97% since 2016.³¹ Among people on treatment for at least 6 months, 97% had a controlled viral load.³¹ Indeed, these results pertain to all people with HIV in care, not just initiators.

However, results pertain to all people with HIV in care, and are not limited to those who initiated ART within the past year.

Our study identified a higher risk of non-adherence among women residing in Brussels, which is consistent with the findings of previous studies. One study found that in Belgium smoking, neurocognitive complaints, and being a woman were independent predictors of non-adherence.¹³ Similar associations have been reported in several other studies.¹²,³²⁻³⁴ Among women, ART adherence has been shown to decrease over the course of HIV infection, possibly linked to the higher number of adverse reactions experienced by women.³⁴⁻³⁶ Morphological alterations such as lipoatrophy and lipohypertrophy, dyslipidemia, lactic acidosis, and hypersensitivity reactions are more prevalent in women and contribute to a higher incidence of ART side effects. This may be attributed to higher ARV

concentrations in females, as evidenced by recent pharmacokinetic studies in plasma and cellular reservoirs.³⁷,³⁸ Moreover, a substantial proportion of women receiving HIV care in Belgium are of Sub-Saharan African origin. For example, in 2020, women represented 70% of HIV diagnoses among heterosexual adults in Sub-Saharan Africa and 32% among heterosexual adults of Belgian nationality.³⁹ Migration and geographic mobility, which are particularly prevalent in this demographic, have been associated with an increased risk of HIV infection and may influence engagement in HIV care and adherence to ART.²⁰ Consequently, strategies need to be developed to promote adherence among women living with HIV during the dispensing of ARVs in pharmacies.

MTRs are associated with an increased risk of non-adherence to ART. A cohort study conducted in France using the National Health-care Insurance database found a significant benefit in terms of adherence to STRs compared with MTRs in patients taking medication more than once a day.⁸ In a study of Medicaid patients with HIV conducted in South Carolina in the United States found that STRs achieved viral suppression with adherence levels ≥80%, whereas MTRs required adherence levels ≥90% to achieve viral suppression.⁴⁰ According to the World Health Organization, treatment adherence decreases as the complexity of the medication regimen increases, including the number of pills per dose, and doses per day.⁴¹ Therefore, it is necessary to favor STRs when initiating ART in newly diagnosed patients, and to facilitate the transition from MTRs to STRs among patients already taking ART. The significant decrease in the proportion of non-adherence and non-persistence during the study period might be attributable to the change from MTRs to STRs. For example, we noted that the proportion of patients receiving STRs increased considerably over the study period (from 63.6% in 2018 to 90.3% in 2021).

Treatment interruptions were noted in 15.9% of the patients at least once during the 12-month follow-up. The risk of treatment discontinuation was higher in women and patients receiving MTRs. The Pharmanet database lacks detailed information on sociodemographic factors such as nationality, migration status, socioeconomic level, and clinical-biological data such as HIV stage, CD4 count, and viral load. Therefore, these factors, which may influence persistence with ART were not considered in the analyses. Historical studies have associated HIV care interruption with factors such as non-Belgian nationality, injecting drug use, being male, and CD4 count <350 cells/µL.⁴ In the United States, women and those with comorbidities are at higher risk of discontinuing the initial ART regimen. Real-world data on adherence and persistence with newly prescribed HIV treatment among Medicaid beneficiaries in the United States indicated that patients initiated on MTRs were at a greater risk of treatment discontinuation than those initiated on STRs.²⁵ In 2014, the median persistence duration was 45.0 months for STRs versus 15.2 months for MTRs (p < 0.001).¹⁴ Treatment discontinuation is primarily attributed to poor tolerability, adherence, or treatment complexity.⁸ Enhancing adherence and persistence is crucial for the long-term treatment of PLWH.
## 4.1 | Strengths and limitations

Several limitations to our study warrant mention. Our sole reliance on medico-administrative data made it challenging to verify actual medication consumption among HIV patients. Moreover, the absence of hospitalization data might have led to an overestimation of treatment gaps or an underestimated adherence among hospitalized individuals. However, studies have demonstrated a high correlation between prescriptions claims data and direct measures of adherence.42,43 Additionally, the impact of hospitalization is likely to be significant mainly for long-term admissions and minimal for shorter stays.44 Furthermore, the lack of information regarding migration status hindered our ability to consider its effect on adherence, and the use of the PDC measure might not have fully captured the dynamic nature of non-adherence over time. Nevertheless, these limitations do not diminish the practical value of our real-world findings. We were able to provide novel insights into non-adherence and non-persistence to prescribed ART, along with potential opportunities for targeted interventions in HIV reference centers with the support of general physicians and pharmacists. Future studies should consider employing a multi-method approach integrating pharmacy claims data with hospital data and including measures that capture the dynamic nature of non-adherence over time (such as longitudinal assessments). This approach would contribute to a more comprehensive understanding of non-adherence patterns among PLWH in Belgium.

## 5 | CONCLUSION

Our study revealed high rates of non-adherence, with one in three individuals experiencing non-adherence and one in six likely to discontinue treatment at least once during the 12-month follow-up period. Notably, both the non-adherence and non-persistence proportions significantly decreased between 2018 and 2021. To achieve the maximum impact in reducing non-adherence, strategies should prioritize optimizing therapeutic education, particularly tailored to specific target groups. Additionally, facilitating the transition from MTRs to STRs should be a priority. Further research on the dynamic nature of adherence over time and the factors influencing its evolution is necessary to improve patient management.

### AUTHOR CONTRIBUTIONS

**Dieudonné Ilboudo:** Conceptualization, Formal analysis, Methodology, Original draft writing, Review writing and editing. **Patricia Mbouche:** Conceptualization, Methodology. **Agnès Sommet** and **Philippe Van Wilder:** Validation, Visualization, Review writing and editing. **Fati Kirakoya-Samadoulougou:** Conceptualization, Methodology, Supervision, Original draft writing, Review writing and editing, Funding acquisition.

### ACKNOWLEDGEMENTS

We thank Marc De Falleur from the "Institut national d'assurance maladie-invalidité (INAMI)" for providing the Pharmanet data.

### FUNDING INFORMATION

DI received a fellowship from the Commission de la Coopération au Développement (CDD) from the Académie de Recherche et d'Enseignement Supérieur (ARES).

### CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

### ETHICS STATEMENT

This study used administrative health information routinely collected in Belgium by Institut National d'assurance maladie-invalidité (INAMI). The Security Committee of Information (SCI) gave its approval (deliberation N°22/306) before the data was transmitted by the INAMI. This was a study using anonymous administrative databases in Belgium. Informed consent could therefore not be obtained in this context.

### ORCID

Dieudonné Ilboudo https://orcid.org/0009-0008-7004-1461

Patricia Mbouche https://orcid.org/0009-0002-7649-6201

Agnès Sommet https://orcid.org/0000-0001-7980-5650

Philippe Van Wilder https://orcid.org/0000-0001-8433-9340

Fati Kirakoya-Samadoulougou https://orcid.org/0000-0002-9584-6329

### REFERENCES

1. Deblonde. Epidémiologie du sida et de l'infection à VIH en Belgique. Situation au 31 décembre 2021. *sciensano.be*. Published 2022. Accessed January 4, 2024. https://www.sciensano.be/en/biblio/epidemiologie-du-sida-et-de-l-infection-a-vih-en-belgique-situation-au-31-decembre-2021

2. UNAIDS. HIV treatment. Accessed January 5, 2023. https://www.unaids.org/en/topic/treatment

3. EACS Guidelines. EACSociety. Accessed February 2, 2023. https://www.eacsociety.org/guidelines/eacs-guidelines/

4. Van Beckhoven D, Florence E, De Wit S, et al. Incidence rate, predictors and outcomes of interruption of HIV care: nationwide results from the Belgian HIV cohort. *HIV Med*. 2020;21(9):557-566. doi:10.1111/hiv.12901

5. Cohen CJ, Meyers JL, Davis KL. Association between daily antiretroviral pill burden and treatment adherence, hospitalisation risk, and other healthcare utilisation and costs in a US medicaid population with HIV. *BMJ Open*. 2013;3(8):e003028. doi:10.1136/bmjopen-2013-003028

6. Tarrier L, Kegg S. Who gets single tablet regimens (STR), and why? *J Int AIDS Soc*. 2014;17(4S3):19777. doi:10.7448/IAS.17.4.19777

7. Cramer J, Roy A, Burrell A, et al. Medication compliance and persistence: terminology and definitions. *Value Health*. 2008;11(1):44-47. doi:10.1111/j.1524-4733.2007.00213.x

8. Raffi F, Yazdanpanah Y, Fagnani F, Laurendeau C, Lafuma A, Gourmelen J. Persistence and adherence to single-tablet regimens in HIV treatment: a cohort study from the French National Healthcare Insurance Database. *J Antimicrob Chemother*. 2015;70(7):2121-2128. doi:10.1093/jac/dkv083

9. Altice F, Evuarherhe O, Shina S, Carter G, Beaubrun AC. Adherence to HIV treatment regimens: systematic literature review and meta-analysis. *Patient Prefer Adherence*. 2019;13:475-490. doi:10.2147/PPA.S192735
10. Yu Y, Luo D, Chen X, Huang Z, Wang M, Xiao S. Medication adherence to antiretroviral therapy among newly treated people living with HIV. BMC Public Health. 2018;18(1):825. doi:10.1186/s12889-018-5731-z

11. Goujard C, Bernard N, Sohier N, et al. Impact of a patient education program on adherence to HIV medication: a randomized clinical trial. JAIDS J Acquir Immune Defic Syndr. 2003;34(2):191-194. doi:10.1097/00126334-200310010-00009

12. Bastakoti S, Khanal S, Dahal B, Pun NT. Adherence and non-adherence to treatments: focus on pharmacy practice in Nepal. J Clin Diagn Res JCDR. 2013;7(4):754-757. doi:10.7860/JCDR/2013/4872.2905

13. Degroote S, Vogelaers D, Vermeir P, et al. Determinants of adherence in a cohort of Belgian HIV patients: a pilot study. Acta Clin Belg. 2014; 69(2):111-115. doi:10.1179/0001551214Z.000000000035

14. Sweet D, Song J, Zhong Y, Signorovitch J. Real-world medication persistence with single versus multiple tablet regimens for HIV-1 treatment. J Int AIDS Soc. 2014;17(4 Suppl 3):19537. doi:10.7448/IAS.17.4.19537

15. Kim MJ, Kim SW, Chang HH. Comparison of antiretroviral regimens: adverse effects and tolerability failure that cause regimen switching. Infect Chemother. 2015;47(4):231-238. doi:10.3947/ic.2015.47.4.231

16. Davy-Mendez T, Erron JJ, Zakharova O, Wohl DA, Napravnik S. Increased persistence of initial treatment for HIV infection with modern antiretroviral therapy. J Acquir Immune Defic Syndr. 2017;76(2):111-115. doi:10.1097/QAI.0000000000001481

17. Degroote S, Vogelaers DP, Vermeir P, et al. Socio-economic, behavioural, (neuro)psychological and clinical determinants of HRQoL in people living with HIV in Belgium: a pilot study. J Int AIDS Soc. 2013; 16(1):18643. doi:10.7448/IAS.16.1.18643

18. McMahon JH, Jordan MR, Kelley K, et al. Pharmacy adherence measures to assess adherence to antiretroviral therapy: review of the literature and implications for treatment monitoring. Clin Infect Dis. 2011;52(4):493-506. doi:10.1093/cid/ciq167

19. INAMI. Statistiques sur les médicaments délivrés en pharmacies publiques (Pharmanet)—INAMI. Accessed January 5, 2023. https://www.inami.fgov.be/fr/statistiques/medicament/Pages/statistiques-medicaments-pharmacies-pharmanet.aspx

20. Taylor BS, Reyes E, Levine EA, et al. Patterns of geographic mobility predict barriers to engagement in HIV care and antiretroviral treatment adherence. AIDS Patient Care STDs. 2014;28(6):284-295. doi: 10.1089/apc.2014.0028

21. Association Pharmaceutique Belge. Nombre de Pharmacie en Belgique. Accessed June 11, 2023. https://www.apb.be/fr/corp/santepublique/La-pharmacie/Nombre-de-pharmacies/Pages/default.aspx

22. Linden A. Assessing medication adherence using Stata. Stata J Promot Commun Stat Stata. 2019;19:820-831. doi:10.1177/1536867X19893625

23. Yildirim C, Garvie PA, Chernoff M, et al. The role of pharmacy refill measures in assessing adherence and predicting HIV disease markers in youth with perinatally-acquired HIV (PHIV). AIDS Behav. 2019;23(8):2109-2120. doi:10.1007/s10461-019-02468-x

24. De Oliveira CJ, Schaffer AL, Medland NA, et al. Adherence to antiretroviral regimens in Australia: a Nationwide cohort study. AIDS Patient Care STDs. 2020;34(2):81-91. doi:10.1089/apc.2019.0278

25. Cohen J, Beaubrun A, Bashyal R, Huang A, Li J, Baser O. Real-world adherence and persistence for newly-prescribed HIV treatment: single versus multiple tablet regimen comparison among US medicaid beneficiaries. AIDS Res Ther. 2020;17(1):12. doi:10.1186/s12981-020-00268-1

26. Hines DM, Ding Y, Wade RL, Beaubrun A, Cohen JP. Treatment adherence and persistence among HIV-1 patients newly starting treatment. Patient Prefer Adherence. 2019;13:1927-1939. doi:10.2147/PPA.S207908

27. Comité de Sécurité de l'Information. Délibération n°22/306 du 06 décembre 2022. Délibérations. Accessed January 8, 2024. https://www.ehealth.fgov.be/ehealthplatform/file/view/AYU5KMLSuwVJMA nC0FX1?filename=22-306-f506-VIH-PHARMANET-ULB.pdf

28. Van Beckhoven D, Serrien B, Montourcy M, et al. Impact of COVID-19 on the Belgian HIV epidemic: slowdown of HIV transmission and testing and adaptation of care. BMC Infect Dis. 2022;22(1):901. doi: 10.1186/s12879-022-07879-1

29. Liekens S, Mémoire de fin d'études - Groupe observance thérapeutique, Hulshagen L, Dethier M, Laekeman G, Foulon V. Adherence to chronic medication: also a frequent problem in Belgium! J Pharm Belg. 2013;(4):18-27.

30. Ahmed A, Dujaili JA, Jabeen M, et al. Barriers and enablers for adherence to antiretroviral therapy among people living with HIV/AIDS in the era of COVID-19: a qualitative study from Pakistan. Front Pharmacol. 2022;12:807446. Accessed January 5, 2023;12. doi:10.3389/fphar.2021.807446

31. Deblonde. Epidémiologie du VIH en Belgique. Situation au 31 décembre 2022. sciensano.be. Published November 28, 2023. Accessed January 4, 2024. https://www.sciensano.be/fr/biblio/epidemiologie-du-vih-en-belgique-situation-au-31-decembre-2022

32. Ghidei L, Simone M, Salow M, et al. Aging, antiretrovirals, and adherence: a meta analysis of adherence among older HIV-infected individuals. Drugs Aging. 2013;30(10):809-819. doi:10.1007/s40266-013-0107-7

33. Chakraborty A, Qato DM, Awadalla SS, Hershow RC, Dworkin MS. Antiretroviral therapy adherence among treatment-naïve HIV-infected patients. AIDS Lond Engl. 2020;34(1):127-137. doi:10.1097/QAD.0000000000002384

34. Nicastri E, Leone S, Angeletti C, et al. Sex issues in HIV-1-infected persons during highly active antiretroviral therapy: a systematic review. J Antimicrob Chemother. 2007;60(4):724-732. doi:10.1093/jac/dkm302

35. Turner BJ, Laine C, Cosler L, Hauck WW. Relationship of gender, depression, and health care delivery with antiretroviral adherence in HIV-infected drug users. J Gen Intern Med. 2003;18(4):248-257. doi: 10.1046/j.1525-1497.2003.20122.x

36. Sayles JN, Wong MD, Cunningham WE. The inability to take medications openly at home: does it help explain gender disparities in HAART use? J Women's Health 2002. 2006;15(2):173-181. doi:10.1089/jwh.2006.15.173

37. Umeh OC, Currier JS. Sex differences in pharmacokinetics and toxicity of antiretroviral therapy. Expert Opin Drug Metab Toxicol. 2006;2(2):273-283. doi:10.1517/17425255.2.2.273

38. Cressey TR, Lallemant M. Pharmacogenetics of antiretroviral drugs for the treatment of HIV-infected patients: an update. Infect Genet Evol J Mol Epidemiol Evol Genet Infect Dis. 2007;7(2):333-342. doi:10.1016/j.meegid.2006.08.004

39. Geyter DD, Martin T, Vuylsteke B. AUTEURS DEBLONDE J. DE ROUCK M, MONTOURCY M. SERRIEN B. VAN BECKHOVEN D.

40. Sutton SS, Magagnoli J, Hardin JW. Odds of viral suppression by single-tablet regimens, multiple-tablet regimens, and adherence level in HIV/AIDS patients receiving antiretroviral therapy. Pharmacother J Hum Pharmacol Drug Ther. 2017;37(2):204-213. doi:10.1002/phar.1889

41. Tarquinio C, Tarquinio P. L'observance thérapeutique: déterminants et modèles théoriques. Prat Psychol. 2007;13:1-19. doi:10.1016/j.prps.2006.09.005

42. Komandt M, Canfield S, Lengel M, Gilmore V, Kilcrease C. Correlation between medication adherence using proportion of days covered and achieving viral suppression in patients living with HIV. J Manag Care Spec Pharm. 2023;29(10):1129-1137. doi:10.18553/jmcp.2023.29.10.1129
43. Saberi P, Chakravarty D, Ming K, et al. Moving antiretroviral adherence assessments to the modern era: correlations among three novel measures of adherence. *AIDS Behav*. 2020;24(1):284-290. doi:10.1007/s10461-019-02744-w

44. Rein SM, Lampe FC, Ingle SM, et al. All-cause hospitalisation among people living with HIV according to gender, mode of HIV acquisition, ethnicity, and geographical origin in Europe and North America: findings from the ART-CC cohort collaboration. *Lancet Public Health*. 2023;8(10):e776-e787. doi:10.1016/S2468-2667(23)00178-0

**How to cite this article:** Ilboudo D, Mbouche P, Sommet A, Van Wilder P, Kirakoya-Samadoulougou F. Non-adherence and non-persistence with antiretroviral treatment in Belgium: A real-world evaluation using a pharmacy database, 2018–2021. *Pharmacoepidemiol Drug Saf*. 2024;33(5):e5804. doi:10.1002/pds.5804