Strategies for Improving Adherence in Patients with HIV/AIDS

Human Immunodeficiency Virus (HIV)-1 is the cause of Acquired Immunodeficiency Syndrome (AIDS). Due to advances in clinical management, HIV/AIDS is now regarded a chronic disease instead of terminal disease. However, non-adherence is a challenge in effective management of HIV/AIDS. Non-adherence is classified into intentional and unintentional non-adherence Interactive toxicity belief is now one of the main factors that promotes non-adherence among HIV patients. Detecting non-adherence is an essential component of managing this phenomenon. A number measures has been proposed on how to manage non-adherence Optimum non-adherence-preventing measures should be holistic that involve different strategies. This review suggest MIB+ model for tackling non-adherence among HIV/AIDS patients. We also need to have more understanding on how stigma implicates non-adherence.

Human Immunodeficiency Virus (HIV) was first described in the 1980s and it is divided into HIV-1 and HIV-2. It belongs to the members of Lentiviruses [1]. In 2022, approximately 39 million were living with the virus and 1.3 million new cases were reported [2]. During the early phase of the pandemic, acquiring the virus is like been given a certificate of death but it is now regarded as chronic disease. The introduction of Antiretroviral Therapy (ART) also referred to as Highly Active Antiretroviral Therapy (HAART) or Combined Antiretroviral Therapy (cART) resulted in better management of HIV/AIDS. By the end of 2022, approximately 29.8 million people were on ART around the globe [2]. HAART is the key foundation of managing HIV/ AIDS and consist of regimens that block the key steps in the replication cycle of the virus via several mechanisms [3]. The primary aim of HAART is reducing the transmission of the virus, for e.g. among pregnant patients, HAART is associated with significant prevention of mother-to-child transmission of the virus. AIDS-related mortality has reduced since the introduction of HAART; however, remains about five times more in patients with AIDS when compared to those without AIDS. Risk factors associated with the high mortality rate include high viral load, CD4 count less than 200 cells/mL, and cytomegalovirus retinitis [4].

Currently, the HAART regimens consist of Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Non-Nucleoside Transcriptase Inhibitors (NNRTIs), Protease Inhibitors (PIs) such as, Integrase Inhibitors (INSTIs), Fusion Inhibitors (FIs), Chemokine Receptor Antagonist (CCR5 antagonists), early inhibitors (CD4- directed post attachment inhibitors), and Capsid Inhibitors (CIs). Although these agents are useful in delaying the onset of AIDS, their clinical utilization is limited by antiviral drug resistance, non-adherence, and toxicity [5].

According to the World Health Organization, adherence is a patient’s ability to abide by a scheduled treatment plan, take drugs at a specified time and frequencies as well as following any restriction on food and other medications [6]. Adherence to HAART regimen is one of the most essential factors that predicts the patient’s ability to achieve and maintain viral suppression below the detection threshold and is a very important factor for success of HAART. Factors such as socioeconomic status, the structure of the family, medication regimen, disclosure, hospitalization, and HIV-related stigmatization are associated with non-adherence. [7-11] Non-adherence to HAART is associated with AIDS and AIDS-associated mortality, treatment failure, and development of antiviral drug resistance [12]. Lack of adherence also negatively impact HIV/AIDS patients with chronic conditions such as diabetes and hypertension [13]. The results of non-adherence include extra cost, clinical complications, and treatment failure. The clinical complications of HIV/AIDS are also driven by non-adherence especially in HIV-associated dementia [14]. Complex antiretroviral agent schedules, drug toxicity, and drug interactions have been implicated in non-adherence among HIV/AIDS patients [15] while in sub-Saharan Africa, the cost of transportation is a factor for non-adherence and elsewhere. However, data on this is limited therefore required more evaluation [16]. The economic cost of non-adherence is high. Barnett et al found in their study aimed at characterizing the cost of HIV care including cART reported that the total cost of non-adherence in HIV/AIDS was $30 523 while Pruitt et al also reported that the cost of non-adherence among Medicaid patients was $30 527 [17,18]. In sub-Saharan Africa, although the data on economic costs is limited, it can be suggested that the due to overstressed health system, non-adherence have negative impact on the continent. The success of ART is therefore dependent on adherence to the ART regimens.

Taking into consideration that there are large data on this topic, this review intends to provide current update on non-adherence among HIV/AIDS patients. It also provides novel strategies for addressing non-adherence among HIV/AIDS patients.

Non-adherence to drugs is a common phenomenon in patients with chronic diseases in which the multiple drug regimens are needed. Adherence to ART is not due to single factor but several factors have been implicated in this phenomenon. Non-adherence can be grouped into two: intentional non-adherence and unintentional non-adherence.

This occurs when patients decides not to take the recommended therapy. It is caused by factors such as denying that the patient is HIV positive, not trusting the medications and the healthcare provider, fear of stigmatization, and inability to integrate the prescriptions schedule into one’s daily routine. Intentional non-adherence is therefore an active decision by a patient which is based on the intuitive barriers like personal judgement that the medication was not necessary or any concern about consuming the medications [19]. One important factor in intentional non-adherence due to use of illicit drugs or alcohol as patients holds the belief that consuming either alcohol or illicit drugs could lead to toxicity (refer to as interactive toxicity). Although toxicity have been described in co-morbid liver diseases such as hepatitis C viral infection on ART, interactive toxicity beliefs are common in patients who have not been diagnosed with co-morbid liver disease [20]. Current evidence supports that interactive toxicity belief due to illicit drugs are associated with intentional non-adherence A study in the US involving HIV clinics reported that 77% of the study participants held the belief that ART is harmful when used with heroin while 61% believed that use of ART with methadone can be harmful [21]. Another study found that 35% of the study participants acknowledged that they intentionally did not adhere to ART when using drugs [22]. Drinking alcohol has also been associated with non-adherence in which patients held the belief that interactive toxicity was linked to consuming alcohol. A review study by El-Krab and Kalichman involving seventeen published articles reported that alcohol and belief in interactive toxicity when using ART was more prevalent and this was directly linked to intentional nondherence to ART and incomplete suppression of HIV [23]. This was consistent with previous studies that suggested that patients on ART who consume alcohol intentionally skip taking their medications [20,24]. Kalichman SC, et al. [25] reported that among young people living with HIV (N = 406), majority of the subjects reported that they intentionally did not adhere to their schedule, with subjects with unsuppressed HIV associating non-adherence to interactive toxicity beliefs. This means among young adult living with HIV, the belief in interactive toxicity is common and such individuals would have poorer adherence and high treatment failure rates.

Multi-ethnicity can also be a factor for non-adherence as reported by study Castelan A, et al. [19]. Reported that among people living with IV who visited the Amsterdam University Medical Centre’s HIV clinic, intentional non-adherence was linked with migrants from Surinam or Netherlands Antilles. Because of stigmatization, intentional non-adherence can also be more common among Africans and Afro-Caribbean’s individuals. However, this suggestion is not consistent with the study carried by Castelan A, et al. [19] who found non-adherence to ART was lower in migrants from Surinam and Netherlands Antilles. Large cohort studies are required to establish association between these communities and non-adherence to ART.

Mental disorders s such as posttraumatic stress disorder can also play a role in intentional non-adherence as this affects the psychological status and worsens the quality of life of HIV patients [26]. However more cohort studies are needed to find association between mental disorder and intentional non-adherence in HIV infection.

Finally, adverse events has also been implicated in non-adherence among people living with HIV. A study in British Columbia found that 11% (N = 638) subjects intentionally refused to adhere to their medication due to therapy-associated side effects [27].

Unintentional non-adherence is when HIV patients are not able to unintentionally keep to their treatment schedule due to reasons beyond their control. This occurs un subconsiously with the patients having no input into the decision not to adhere to their treatment schedule. Factors such as lack of resources, ability, and skills have been implicated. Unintentional non-adherence have been associated with need for medication, concern for such medications, and belief about the efficacy of the medication but these need to be elucidated in HIV patients [28-31]. Furthermore, it must be added that unintentional non-adherence is not random but predicted by drugs, belief in chronic diseases and sociodemographic features [32]. As found in intentional non-adherence, interactive toxicity belief is also associated with non-adherence among people living with HIV. In a study, Kalichman SC, et al. [25]. Reported that among their study participants (N-178), 51% reported of not adhering to their antiviral treatmen which was linked to their belief that mixing alcohol and medication could cause interactive toxicity [33]. Similar findings were reported in South Africa and Uganda [34]. Family members, friends, non-drinkers HIV patients, and healthcare provider were the source of this information.

There is no gold standard for measuring non-adherence among HIV patients. Healthcare providers’ require a monitoring method that can quickly assist them to identify poor adherence to ART. Such method should be inexpensive, simple to perform, and reliable [35]. While measuring non-adherence, the measuring technique should be able to identify reason for non-adherence to enable healthcare providers devise specific methodologies for specific patients [36]. A variety of non-adherence measuring tools including self-reporting, pharmacy refill recording, laboratory monitoring (e.g. monitoring the blood level of ART), electronic monitoring device, and pill counts have been introduced with each addressing certain characteristics but not all [37].

Self-reporting is one of the commonly utilized measuring methods for adherence and has been shown to be associated with viral suppression [38]. Self-reporting tool is easy to use, cheap, and flexible as different characteristics can be integrated in the data. In addition, it can also differentiate intentional non-adherence from unintentional non-adherence [39]. However, self-reporting is limited by the fact that it can be overestimated and provide information for short term adherence [40]. Furthermore, self-reporting is better suited for patients on less complex ART regimens. This is linked to the fact that when the patients’ understanding increases, the regimen dosing reduces while the complexity increases [41]. The sensitivity and specificity of this tool need to be established.

Visual Analog Scale (VAS), Likert item, pill identification test and medication possession rate are tools used for measuring adherence among HIV patients and associated with HIV viral suppression. They are inexpensive and can be used easily. It must be noted that reliable and simple measuring tools used for adherence are important component of evaluating ART progress especially in Sub-Saharan Africa and other resource-limited countries [42,44]. These measuring tools can be used as valid techniques to measure adherence. However, they need to be validated and adjusted before to implementation so that factors such as local culture and logistics can be taken into account. A study in Namibia reported that adherence was high when all the measuring tools were utilized; however Medication Possession Ratio (MPR) was associated with short-term virologic response. This suggests that of its cross-culture utilization for early confirmation of patients who are at high risk for virologic failure [42]. This finding was consistent with previous studies in other countries [45]. MPR can be useful in detecting in patients who are at risk of early virology failure therefore MPR can be an important tool in resource-limited settings where the potential of treatment interruption because of lack access to HIV medications is high. Other measuring tools such as Computer-Assisted Self-Administered (CASA), pharmacy refill, and electronic pill monitoring can be used to measure adherence [42,45]. While considering these adherence-measuring tools, it must be noted that each has its limitation and advantage; for e.g. pharmacy refill cannot be utilized when ART are submitted outside the pharmacies or without any track record while self-reporting can be used to elucidate reasons for non-adherence [37]. Healthcare providers should in agreement with the patients identify the best computerized adherence-measuring tool based on the patient’s characteristics and demographic features.

Laboratory tests are essential tool for analysing adherence as the viral load is the optimum biomarker and excellent indicator of adherence. However, it is expensive and not easily available in resource-limited settings such as sub-Saharan Africa [46]. Therefore in such settings, affordable and easily available laboratory markers needs to be identified and validated. CD4+ cell count is a common marker in ART patients with approximately 95% adherence; it cannot be used in adherence measurement because it is a poor indicator of treatment failure [47,48]. Therefore other markers of treatment failure such as HIV proviral load, viral RNA, p24 antigen, and immunological markers should be evaluated as potential laboratory markers in HIV adherence measurement [49-52]. Developing novel low cost laboratory markers of adherence among HIV patients is a must and should be analysed for routine use in clinical setting. Integrating different measuring tools would be the ideal strategy for evaluating adherence among HIV patients. In addition, in resource-limited settings, optimum measuring tools for adherence are needed for efficient management of HIV/AIDS since lack of access to antiviral medications are drivers of treatment failure.

After developing the optimum adherence-measuring tool, the next question is the frequency needed to measure for adherence. Most available data suggested that adherence measurement should be performed in monthly [53]. In its recommendation, the World Health Organization suggested that adherence measurement can commence after initiating therapy but it didn’t specify any method or duration [54]. However, the frequency of measurement should be a crucial component of any measurement strategy by safe guarding first-line treatment since treatment failure is associated with frequency of HIV mutation [55]. A study suggested that HIV patients should be switched to another regimen within 8 weeks after virologic failure to ensure better clinical outcome and continuous virologic suppression [56]. Sensitivity and specificity of any adherence-measuring tool should be factored when measuring adherence.

Non-adherence is influenced by several factors therefore no single strategy can address the problem of non-adherence A misconception held regarding adherence is that it is a single behaviour that can predicts a patient’s behaviour and only the clinician can address adherence in patients. An effective adherence program would require a number of factors that are influenced by the environment, the individual, and social indices that must be broadly oriented instead of targeting only an individual. Several models have been proposed for addressing adherence among HIV patient. One such model is the Information-Motivation-Behavioral skills (IMB) model [57,58]. This model suggested that sub-optimal adherence is due to deficiency in adherence-associated information, motivation, and behavioral skills. This model can be upgraded to IMB+ in order to include some important aspect of strategies.

Factual information is also important adherence-association interventions. As reported in studies related to interactive toxicity beliefs, HIV patients are given information that is not factual. Therefore adherence-associated information needs to be factual such as having knowledge on potential drug interactions and the possible side effects of the drugs. In addition, misinformation that would discourage HIV patients from taking their medications should be addressed; for e.g. the idea that ARV are given to patients by governments so that people continue to be sick and the belief that the pharmaceutical industry continue to make profit out of a diseases that is not true. Furthermore, one of the predictors of ART non-adherence is the use of alcohol which is believed to be associated with interactive toxicity. In alcohol-related adherence, alcohol use is a significant predictor of ART non-adherence. As found in Uganda, 24% of HIV patients in HIV care services approves the beliefs that ART need to be stopped while drinking while 15% reported that they themselves decided to stop ART when they are about to start drinking alcohol [34]. In Sub-Saharan Africa, almost 13% and 29% of adults and adolescent take alcohol, respectively [59] with the consumption of alcohol linked with increased risk of ART non-adherence [60]. This belief is having negative implication in addressing adherence to ART as most of HIV patients on ART will prefer to skip ART to enable them initiates drinking alcohol which they associated with interactive toxicity. In order to address this, healthcare providers must develop an effective and efficient strategy that would disprove the alcohol-ART interactive toxicity without unintentionally increasing the utilization of alcohol [25]. Information provided by healthcare providers must be accurate and consistent. A study reported that their participants revealed that during their adherence-counselling, the healthcare providers initially recommended that they cannot simultaneously use alcohol with their medications but later the same healthcare providers advised that they can combined alcohol with their medications [61]. This type of message is confusing which will negatively impact the adherence-strategies. More research is needed to evaluate the communication methods used by healthcare providers and the impact on alcohol and substance-ART non-adherence

The motivation of HIV patients is another essential intervention as some patients can decide to ‘take a break’ from their ART regimen. Those who decided not to report such ‘breaking’ to their healthcare providers were classified as intentional non adherent while those who decided to report ‘breaking’ were classified as unintentional adherents [62]. Such adherence-associated motivation should consist of personal motivation like attitude of the patients towards keeping to the regimen schedule and also taking the medications and social motivation, for e.g. support provided to patients in taking their medications [57,58].

Behavioural intervention is an essential in intentional and unintentional non-adherence has been associated with certain beliefs therefore HIV patients beliefs on medications need to be addressed for both intentional and unintentional non-adherence Behavioral intervention is also multifactorial; it is therefore recommended that integrative behavioral strategies should be adopted. For example in depression associated non-adherence, cognitive behavioral therapy can be integrated into behavioral intervention since majority of HIV patients are mostly depressed [63]. An integration behaviour intervention called Act Healthy analysed substance use, depressive symptoms, and health outcomes reported that there was improvement in depressive symptoms, commencement of and adherence to ARV, respectively [64]. Act Healthy is example of Behaviour Activation [BA], a form of intervention in which certain behaviours are deliberately manipulated with the aim of activating better emotional state of the individual. It is used for treating depression by the functional evaluation of depression.

Patients-centred adherence interventions are needed. This is based on patients engaged in their care. Engaging patients in their care will facilitate patients adhering to their medications. The patient-centred approach should involve using data that patient-generated data and adopting the measure in the report which is a better reflection of the patient. A number of patient-centred outcome measures have been developed over the course of time but most focus on the status of the patient. These reports were developed in consultation with the patients’ reports but the outcomes were not developed with patient-centred approach. To improve the standard of care for HIV patients, their care plan should be based on evidence-based and multifactorial approach. Self-reporting should therefore be should consist of baseline and follow-up questions. Baseline questions should address missed doses, substance use, psychosocial risk factors and demography while follow-up questions should include tackling medication recall and dosing practice. However, self-reporting can be overestimated therefore care should be taking when synthesising data of self-reporting. Finally, adding education to HIV patients care plan will aid in adhering to their medication regimens. Adherence-associated knowledge gap between clinicians and HIV patients should therefore be addressed and narrowed.

Non-adherence is a major factor in negatively impacting HIV/AIDS management, this review attempts to address some knowledge gaps by providing update to data on classification of non-adherence, evaluating non-adherence and providing strategies on addressing non-adherence. Finally, it provides recommendation on how to close knowledge associated with non-adherence.

Non-adherence to ART is a continuous problem in the global effort to tackle HIV/AIDS which is difficult to address, Adherence varies from culture to culture and from program to program therefore adherence-preventing measures should take into consideration. Such measures should be simple, valid, and efficient in detecting prevalence of and reason for non-adherence because viral suppression is associated with adherence, it is important that healthcare providers rigorously included in any adherence-promoting measures in care program. Healthcare providers should consider involving families to any care plan. Better adherence can be improved by social support with a model suggesting that barriers to ART adherence can be overcome through support of family and other individuals in the community. Economic and logistic support should be factored in when planning and implementing adherence-prevention measures. Multiple adverse-measuring tools should be utilized to estimate adherence behaviour. The “excellent” strategies to address non-adherence in HIV patients should be a holistic approach that involve multi-approach. This review proposes MIB+ model consisting of motivation, information provision, behaviour and patient-centred activities. Future research should focus on having better understanding of key factors that influence adherence which will ultimately improve adherence. In addition, although there has been increased advance in the global understanding of stigma, we still need to understand how stigma compromises RT adherence.

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