Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Adherence to Antiretroviral Therapy in HIV-Infected Children and Adolescents
Last Updated: March 1, 2016; Last Reviewed: March 1, 2016
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints; I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical outcomes with accompanying data in children† from one or more similar nonrandomized trials or cohort studies with clinical outcome data; III = Expert opinion
† Studies that include children or children/adolescents, but not studies limited to post-pubertal adolescents
Adherence to antiretroviral therapy (ART) is a principal determinant of virologic suppression.1-3 Prospective adult and pediatric studies have established a direct correlation between risk of virologic failure and the proportion of missed doses of antiretroviral (ARV) drugs.4 Suboptimal adherence may include missed or late doses, treatment interruptions and discontinuations, as well as sub-therapeutic or partial dosing.5 Poor adherence will result in sub-therapeutic plasma ARV drug concentrations, facilitating development of drug resistance to one or more drugs in a given regimen, and possibly cross-resistance to other drugs in the same class. Multiple factors (including regimen potency, pharmacokinetics, drug interactions, viral fitness, and the genetic barrier to ARV resistance) influence the adherence-resistance relationship.6 In addition to compromising the efficacy of the current regimen, suboptimal adherence has implications for limiting future effective drug regimens in patients who develop multidrug-resistant HIV and for increasing the risk of secondary transmission.
Poor adherence to ARV drugs is commonly encountered in the treatment of HIV-infected children and adolescents. A variety of factors—including medication formulation, frequency of dosing, drug toxicities and side effects, child’s age and developmental stage, as well as psychosocial and behavioral characteristics of children and parents—have been associated with non-adherence. However, no consistent predictors of either good or poor adherence in children have been consistently identified.7-9 Furthermore, several studies have demonstrated that adherence is not static and can vary with time on treatment.10 These findings illustrate the difficulty of maintaining high levels of adherence and underscore the need to work in partnership with families to ensure that adherence education, support, and assessment are integral components of care.
Specific Adherence Issues in Children
Adherence is a complex health behavior that is influenced by the drug regimen, patient and family factors, and patient-provider relationship.8 The limited availability of palatable formulations and once-daily regimens for infants and young children is especially problematic.4 Furthermore, infants and children are dependent on others for medication administration; thus, assessment of the capacity for adherence to a complex, multidrug regimen requires evaluation of the caregivers and their environments, as well as the ability and willingness of a child to take the drug. Barriers faced by adult caregivers that can contribute to non-adherence in children include forgetting doses, changes in routine, being too busy, and child refusal.11,12 Some caregivers may place too much responsibility for managing medications on older children and adolescents before they are developmentally able to undertake such tasks,13 whereas others themselves face health and adherence challenges related to HIV infection, substance use, or mental health and other medical conditions. Other barriers to adherence include caregivers’ unwillingness to disclose HIV infection status to the child and/or others, reluctance of caregivers to fill prescriptions locally, hiding or relabeling of medications to maintain secrecy within the household, absence of social support, and a tendency for doses to be missed if the parent is unavailable. Adherence may also be jeopardized by social issues within a family (e.g., substance abuse, unstable housing, poverty, involvement with the criminal justice system).14
Adherence Assessment and Monitoring
The process of adherence preparation and assessment should begin before therapy is initiated or changed. A comprehensive assessment should be instituted for all children in whom ART initiation or change is considered. Evaluations should include nursing, social, and behavioral assessments of factors that may influence adherence by children and their families and can be used to identify individual needs for intervention. Specific, open-ended questions should be used to elicit information about past experience as well as concerns and expectations about treatment. When assessing readiness and preparing to begin treatment, it is important to obtain a patient’s explicit agreement with the treatment plan, including strategies to support adherence. It is also important to alert patients to minor adverse effects of ARV drugs (e.g., nausea, headaches, abdominal discomfort) that may recede over time or respond to change in diet or timing of medication administration.
A routine adherence assessment should be incorporated into every clinic visit. Adherence is difficult to assess accurately; different methods of assessment have yielded different results and each approach has limitations.15-17 Viral load monitoring is the most useful indicator of adherence and should be used routinely for all patients on ART (see Plasma HIV-1 RNA [Viral Load] and CD4 Count Monitoring in the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents). In addition, it can be used as positive reinforcement to encourage continued adherence.18 Use of at least one other method in addition to monitoring viral load to assess adherence is recommended.17,19 Other measures include quantitative self report of missed doses by caregivers and children or adolescents (i.e., focusing on missed doses during a recent 3-day or 1-week period), descriptions of the medication regimens, and reports of barriers to administration of medications. Patients, caregivers, and health care providers often overestimate adherence, but admission of missed doses or suboptimal adherence is highly correlated with poor therapeutic response.20 Targeted questions about stress, pill burden, and daily routine are recommended. A nonjudgmental attitude and trusting relationship foster open communication and facilitate assessment. Pharmacy refill checks and pill counts can identify adherence problems not evident from self-reports.21
Home visits can play an important role in assessing adherence. In some cases, suspected non-adherence is confirmed only when dramatic clinical responses to ART occur during hospitalizations or in other supervised settings. Preliminary studies suggest that monitoring plasma ARV drug concentrations or therapeutic drug monitoring may be useful measures in situations where non-adherence is suspected. Drug concentrations in hair are currently being studied as an alternative method to measure adherence but are primarily useful in research studies, as are22,23 electronic monitoring devices (e.g., Medication Event Monitoring System [MEMS] caps, Wisepill) that are equipped with a computer chip that records each opening of a medication bottle. Mobile phone-based and adherence device technologies (e.g., interactive voice response, SMS text messaging) are being investigated to quantify missed doses and provide real-time feedback to patients and caregivers, but studies in the pediatric population are in the pilot phase.24-26
Strategies to Improve and Support Adherence
Intensive follow-up is required, particularly during the first few months after therapy is initiated. This is particularly important if treatment must be started urgently. If there are particular concerns about adherence, patients should be seen and/or contacted (by phone, text messaging, email, and social networking, as allowed within the context of local legal and regulatory requirements) frequently—as often as weekly, or even more often, during the first month of treatment—to assess adherence and determine the need for strategies to improve and support adherence.
Strategies should include optimization of the drug regimen and the development of patient-focused treatment plans to accommodate specific patient needs, integration of medication administration into the daily routines of life (e.g., associating medication administration with daily activities such as brushing teeth), and use of social and community support services. Multifaceted approaches that include regimen-related strategies; educational, behavioral, and supportive strategies focused on children and families; and strategies that focus on health care providers—rather than one specific intervention—may be most effective.13,27,28 The evidence is mixed as to the efficacy of programs designed for administration of directly observed therapy (DOT) to improve adherence, but DOT may be a useful strategy for particular patients.27,29-33 Table 11 summarizes some of the strategies that can be used to support and improve adherence to ARV medications. The Centers for Disease Control and Prevention offers a web-based toolkit (consisting of four evidence-based HIV medication adherence strategies) to HIV care providers (located at http://www.effectiveinterventions.org/en/HighImpactPrevention/BiomedicalInterventions/MedicationAdherence.aspx).34
ARV drug regimens for children often require taking multiple pills or unpalatable liquids, each with potential adverse effects and drug interactions, in multiple daily doses. To the extent possible, regimens should be simplified with respect to the number of pills or volume of liquid prescribed, as well as frequency of therapy, and chosen to minimize drug interactions and adverse effects (AEs).35 Efforts should be made to reduce the pill burden and to prescribe a once-daily ARV drug regimens whenever feasible (see Management of Children Receiving Antiretroviral Therapy). With the introduction of new drug classes and a wider array of once-daily formulations, there are now more options to offer less toxic, simplified regimens particularly for older children and adolescents. Several studies in adults have demonstrated better adherence with once-daily versus twice-daily ARV drug regimens.36-39 When non-adherence is related to poor palatability of a liquid formulation or crushed pills and simultaneous administration of food is not contraindicated, the offending taste can sometimes be masked with a small amount of flavoring syrup or food (see Appendix A: Pediatric Antiretroviral Drug Information).40 Unfortunately, the taste of lopinavir/ritonavir cannot be masked with flavoring syrup. A small study of children aged 4 to 21 years found that training children to swallow pills has been associated with improved adherence at 6 months post-training.41 Finally, if drug-specific toxicities are thought to be contributing to nonadherence, efforts should be made to alleviate the AEs or change the particular drug (or, if necessary, drug regimen) when feasible.
The primary approach taken by the clinical team to promote medication adherence in children is patient and caregiver education. Educating families about adherence should begin before ARV medications are initiated or changed and should include a discussion of the goals of therapy, the reasons for making adherence a priority, and the specific plans for supporting and maintaining a child’s medication adherence. Caregiver adherence education strategies should include the provision of both information and adherence tools, such as written and visual materials; a daily schedule illustrating times and doses of medications; and demonstration of the use of syringes, medication cups, and pillboxes.
A number of behavioral tools can be used to integrate taking medications into an HIV-infected child’s daily routine. The use of behavior modification techniques, especially the application of positive reinforcements and the use of small incentives (including financial incentives) for taking medications, can be effective tools to promote adherence.42 Availability of mental health services and the treatment of mental health disorders (such as depression) may facilitate adherence to complex ARV drug regimens.43 A gastrostomy tube should be considered for nonadherent children who are at risk of disease progression and who have severe and persistent aversion to taking medications.44 If adequate resources are available, home-nursing interventions or DOT may also be beneficial.
Other strategies to support adherence include setting patients’ cell phone alarms to go off at medication times; using beepers or pagers as an alarm; sending SMS text-message reminders; conducting motivational interviews; providing pill boxes, blister packaging, and other adherence support tools; and delivering medications to the home. Randomized clinical trials in adults have demonstrated that text messaging is associated with improved adherence.45-49 Motivational interviews, including computer-based interventions, are currently being evaluated.42,50 A study evaluating the efficacy of a four-session, individual, clinic-based, motivational, interviewing intervention targeting multiple risk behaviors in HIV-infected youth demonstrated an association with lower viral load at 6 months in youth taking ART. However, reduction in viral load was not maintained at 9 months.51
Health Care Provider-Related Strategies
Providers have the ability to improve adherence through their relationships with patients’ families. This process begins early in a provider’s relationship with a family, when the clinician obtains explicit agreement about the medication and treatment plan and any further strategies to support adherence. Fostering a trusting relationship and engaging in open communication are particularly important.52 Provider characteristics that have been associated with improved patient adherence in adults include consistency, giving information, asking questions, technical expertise, and commitment to follow-up. Creating an environment in the health care setting that is child-centered and includes caregivers in adherence support also has been shown to improve treatment outcomes.53 Providing comprehensive multidisciplinary care (e.g., with nurses, case managers, pharmacists, social workers, psychiatric care providers) may also better serve more complex patient and family needs, including adherence.
|Initial Intervention Strategies|
|Follow-Up Intervention Strategies|
|Key to Acronyms: ARV = antiretroviral; AE = adverse effect; DOT = directly observed therapy|
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