Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.
Adherence to Antiretroviral Therapy in Children and Adolescents Living with HIV
Last Updated: April 14, 2020; Last Reviewed: April 14, 2020
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. Suboptimal adherence may include missed or late doses, treatment interruptions and discontinuations, and subtherapeutic or partial dosing.1,2 Poor adherence will result in subtherapeutic plasma antiretroviral (ARV) drug concentrations, facilitating the development of resistance to one or more drugs in a given regimen and possible 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.3 In addition to compromising the efficacy of the current regimen, suboptimal adherence can limit the options for future effective drug regimens in patients who develop multidrug-resistant HIV; it can also increase the risk of secondary transmission of drug-resistant virus.
Poor adherence to ARV drugs is commonly encountered in the treatment of children and adolescents living with HIV. 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, behavioral, and sociodemographic characteristics of children and caregivers—have been associated with nonadherence. However, no consistent predictors of either good or poor adherence in children have been identified.4-6 Several studies have demonstrated that adherence is not static and can vary with time on treatment.7 More recently, findings from the U.S. Pediatric HIV/AIDS Cohort Study (PHACS) demonstrated that the prevalence of nonadherence increased with age. Among 381 children and adolescents with perinatal HIV infection, the prevalence of nonadherence increased from 31% to 50% (P < 0.001) and the prevalence of unsuppressed viral loads increased from 16% to 40% (P < 0.001) between pre-adolescence and late adolescence/young adulthood.8 These findings illustrate the difficulty of maintaining high levels of adherence and underscore the need to work with patients and their 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 the patient-provider relationship.9,10 Despite improvements over the last several years, the limited availability of once-daily and single-tablet regimens and palatable formulations for infants and young children remains especially problematic.11 Furthermore, infants and children are dependent on others for medication administration; adult caregivers may face barriers that contribute to nonadherence in children, including forgetting doses, changes in routine, being too busy, and child refusal.12,13 Some caregivers may place too much responsibility for managing medications on older children and adolescents before they are developmentally able to undertake such tasks.14 Adherence may also be jeopardized by social and health issues within a family (e.g., substance abuse, poor physical or mental health, unstable housing, poverty, violence, involvement with the criminal justice system, limited social support).15,16
Adherence Assessment and Monitoring
Clinicians should begin assessing potential barriers to adherence and discussing the importance of adherence with patients before initiating or changing an ARV regimen. Evaluations should assess social and behavioral factors that may influence adherence and should identify individual needs for intervention. Clinicians should ask patients about their experience with taking medications, as well as concerns and expectations about treatment. Before beginning treatment, it is important that the patient explicitly agrees to the treatment plan, which should include strategies to support adherence. It is also important to alert patients to potential adverse effects of ARV drugs (e.g., nausea, headaches, abdominal discomfort, sleep disturbances), explain how they can be managed, and emphasize the importance of informing the clinical team if they occur.
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.17-19 Viral load monitoring is the most useful indicator of adherence and is a routine component of monitoring individuals who are on ART (see Plasma HIV-1 RNA [Viral Load] and CD4 Count Monitoring in the Adult and Adolescent Antiretroviral Guidelines). In addition, it can be used as positive reinforcement to encourage continued adherence.20 Clinicians should use at least one other method to assess adherence in addition to monitoring viral load.18 Table 13 includes common approaches to monitoring medication adherence.
Strategies to Improve and Support Adherence
When there are concerns about adherence, a patient should be seen and/or contacted frequently (by phone, text messaging, email, and social networking, as allowed within the context of local legal and regulatory requirements) to assess adherence and to determine the need for strategies that can improve and support adherence. During the first month of treatment (or a regimen change), a patient can be contacted weekly, or even daily, if necessary.
Strategies should include simplifying the drug regimen, developing treatment plans that integrate medication administration into daily routines (e.g., associating medication administration with daily activities such as brushing teeth), and optimizing the 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 may be more effective than one specific intervention. Table 14 summarizes some of the strategies that can be used to support and improve adherence to ARV medications. The Centers for Disease Control and Prevention (CDC) offers a web-based toolkit (consisting of four evidence-based HIV medication adherence strategies) to HIV care providers.21
ARV regimens for infants and young children often require taking multiple daily doses of multiple pills or liquids, some of which are unpalatable and each of which has the potential for adverse effects (AEs) and drug interactions. To the extent possible, regimens should be simplified with respect to the number of pills or volume of liquid prescribed, as well as the number of daily doses, and drugs in the regimen should be chosen to minimize drug interactions and AEs.22 Efforts should be made to reduce the pill burden and pill size and to prescribe once-daily ARV regimens and single-tablet regimens whenever feasible (see Table 16 in Management of Children Receiving Antiretroviral Therapy). With the introduction of new drug classes and a wider array of once-daily formulations, including some medications that are now available in a small pill size, there are now more options for less toxic, simplified regimens, particularly for older children and adolescents. Several studies in adults have demonstrated better adherence with once-daily ARV regimens than with twice-daily regimens, and better adherence with single-tablet formulations than with multiple-tablet regimens.11,23-26 Appendix A, Table 1 shows which ARV drugs are available in fixed-dose combination (FDC) tablets, and Appendix A, Table 2 provides information about minimum body weight requirements and other considerations when using FDC tablets in children.
When nonadherence is related to the poor palatability of a liquid formulation or crushed pills, the offending taste can sometimes be masked with a small amount of flavoring syrup or food if simultaneous administration of food is not contraindicated (see Appendix A: Pediatric Antiretroviral Drug Information).27 Unfortunately, the taste of lopinavir/ritonavir cannot be masked with flavoring syrup. A small study of children and youth aged 4 years to 21 years found that training children to swallow pills was associated with improved adherence at 6 months post-training.28 Finally, if drug-specific toxicities are thought to be contributing to nonadherence, efforts should be made to alleviate the AEs by changing the particular drug (or, if necessary, the drug regimen) when feasible.
Patient and caregiver education is an essential component of establishing good medication adherence in children. Educating families about adherence should begin before initiating or changing ARV medications and should include a discussion of the goals of therapy, the importance of optimizing adherence, 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. Additionally, it may be helpful to assess the medication adherence of the caregiver or other household members who currently take ARV drugs or other chronic medications.
Several behavioral tools can be used to integrate taking medications into a 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.29 Treating mental health disorders (e.g., depression) may facilitate adherence to complex ARV regimens.30,31
In situations where the child has not been informed of their HIV status, HIV disclosure should be discussed with the caregivers. In a recent review that explored the relationship between ART adherence and disclosure, five studies linked disclosure to improved adherence, four studies found that disclosure led to worse adherence among study participants, and five studies found no association.32 Therefore, the decision to disclose HIV status should not necessarily be expected to improve adherence. The decision should instead be based on a comprehensive assessment of the psychosocial milieu and the needs of the child and family.
In poorly adherent children who are at risk of disease progression and who have severe and persistent aversion to taking medications, the use of a gastrostomy tube may be considered.33 If adequate resources are available, home-nursing interventions or directly observed therapy (DOT) may also be beneficial. The evidence is mixed as to the efficacy of programs that are designed to improve adherence through DOT, but DOT may still be a useful strategy for some patients.34-36
Other strategies to support adherence include using mobile applications (apps) that remind patients to take medications; setting patients’ cell phone alarms to go off at medication times; sending text-message reminders; conducting motivational interviews; providing pill boxes, blister packaging, and other adherence support tools; and delivering medications to the home. The CDC has an adherence toolbox, which includes a free mobile app (CDC’s Every Dose Every Day mobile app) that is available through their website.
A recent systematic review of studies that evaluated the use of mobile phone technologies to improve ART adherence concluded that the use of mobile short message service (SMS) interventions improved adherence to ART compared with control conditions. A recent systematic review of studies that evaluated the use of mobile phone technologies to improve ART adherence reported mixed results; the efficacy of short SMS interventions varied depending on the specific SMS intervention tested.37 Another recent systematic review of the effectiveness of using mobile phone interventions to improve adherence to ART also reported mixed results; effectiveness varied depending on the measured outcomes and the specific intervention (e.g., whether the study evaluated the use of texts or the use of phone calls).38 It should be noted, however, that the evidence base for effective adherence interventions in adolescents and young adults who are taking daily ART is limited.39-44
Health Care Provider-Related Strategies
To improve and support adherence, providers should maintain a nonjudgmental attitude, establish trust with patients and caregivers, and identify mutually acceptable goals for care. Providers can 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. Provider characteristics that have been associated with improved patient adherence in adults include consistency, willingness to give information and ask 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. Immigrant children and families may face unique social and cultural issues; it is important to recognize these issues and facilitate establishing links to community resources, particularly for families who are recent immigrants. 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.
|Routine Assessment of Medication Adherence in Clinical Carea||Description|
|Monitor viral load.||Viral load monitoring should be done more frequently after initiating or changing medications.a|
|Assess a quantitative self-report of missed doses.||Ask the patient and/or caregiver about the number of missed doses over a defined period (1, 3, or 7 days).|
|Request a description of the medication regimen.||Ask the patient and/or caregiver about the name, appearance, and number of medications, and how often the medications are taken.|
|Assess barriers to medication administration.||Engage the patient and caregiver in a dialogue about potential barriers to adherence and strategies to overcome them.|
|Monitor pharmacy refills.||Approaches include a pharmacy-based or clinic-based assessment of on-time medication refills.|
|Conduct announced and unannounced pill counts.||Approaches include asking patients to bring medications to the clinic, home visits, or referral to community health nursing.|
|Targeted Approaches to Monitoring Adherence in Special Circumstances||Description|
|Implement DOT.||Include a brief period of hospitalization if indicated.|
|Measure drug concentration in plasma or DBS.||Measuring drug concentrations can be considered for particular drugs.|
|Approaches to Monitoring Medication Adherence in Research Settings||Description|
|Measure drug concentrations in hair.||Measuring hair drug concentrations can be considered for particular drugs; it provides a good measure of adherence over time.17,45,46|
|Use electronic monitoring devices.||Approaches include MEMS caps and Wisepill.|
|Use cell phone-based technologies.||Approaches include interactive voice response, text messaging, and mobile apps.|
|a See Clinical and Laboratory Monitoring of Pediatric HIV Infection regarding the frequency of adherence assessment after initiating or changing therapy.
Key: apps = applications; DBS = dried blood spots; DOT = directly observed therapy; MEMS = Medication Event Monitoring System
|Initial Intervention Strategies|
|Follow-up Intervention Strategies|
|Key: apps = applications; ARV = antiretroviral; AE = adverse effect; CDC = Centers for Disease Control and Prevention; DOT = directly observed therapy|
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- Hawkins A, Evangeli M, Sturgeon K, Le Prevost M, Judd A, Aalphi Steering Committee. Episodic medication adherence in adolescents and young adults with perinatally acquired HIV: a within-participants approach. AIDS Care. 2016;28 Suppl 1:68-75. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26886514.
- Gardner EM, Burman WJ, Steiner JF, Anderson PL, Bangsberg DR. Antiretroviral medication adherence and the development of class-specific antiretroviral resistance. AIDS. 2009;23(9):1035-1046. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19381075.
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- Schlatter AF, Deathe AR, Vreeman RC. The need for pediatric formulations to treat children with HIV. AIDS Res Treat. 2016;2016:1654938. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27413548.
- Giannattasio A, Albano F, Giacomet V, Guarino A. The changing pattern of adherence to antiretroviral therapy assessed at two time points, 12 months apart, in a cohort of HIV-infected children. Expert Opin Pharmacother. 2009;10(17):2773-2778. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19929700.
- Kacanek D, Huo Y, Malee K, et al. Nonadherence and unsuppressed viral load across adolescence among US youth with perinatally acquired HIV. AIDS. 2019. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31274538.
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- Pintye J, Bacchetti P, Teeraananchai S, et al. Brief report: lopinavir hair concentrations are the strongest predictor of viremia in HIV-infected Asian children and adolescents on second-line antiretroviral therapy. J Acquir Immune Defic Syndr. 2017. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28825944.
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