Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Adherence to Antiretroviral Therapy in Children and Adolescents Living with HIV
Last Updated: April 27, 2017; Last Reviewed: April 27, 2017
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 Suboptimal adherence may include missed or late doses, treatment interruptions and discontinuations, as well as sub-therapeutic or partial dosing.2,3 Poor adherence will result in sub-therapeutic plasma antiretroviral (ARV) drug concentrations, facilitating development of drug resistance to 1 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.4 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 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 and behavioral characteristics of children and caregivers—have been associated with nonadherence. However, no consistent predictors of either good or poor adherence in children have been consistently identified.5 Furthermore, several studies have demonstrated that adherence is not static and can vary with time on treatment.6 These findings illustrate the difficulty of maintaining high levels of adherence and underscore the need to work in partnership 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 patient-provider relationship.7 The limited availability of once-daily and single-tablet regimens and palatable formulations for infants and young children is especially problematic.8 Furthermore, infants and children are dependent on others for medication administration: barriers faced by adult caregivers that can contribute to nonadherence in children include forgetting doses, changes in routine, being too busy, and child refusal.9,10 Some caregivers may place too much responsibility for managing medications on older children and adolescents before they are developmentally able to undertake such tasks.11 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, involvement with the criminal justice system, limited social support).12
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 assess social and behavioral factors that may influence adherence by children and their families and should 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 potential adverse effects of ARV drugs (e.g., nausea, headaches, abdominal discomfort), how they can be managed and the importance of informing the clinical team if they should 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.13-15 Viral load monitoring is the most useful indicator of adherence and is a routine component of monitoring individuals 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.16 Use of at least one other method in addition to monitoring viral load to assess adherence is recommended.15,17 Table 13 includes commonly employed approaches to monitoring medication adherence.
Strategies to Improve and Support Adherence
Intensive follow-up is required, particularly during the first few months after therapy is initiated or changed. 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.11,18,19 The evidence is mixed as to the efficacy of programs designed for the administration of directly observed therapy (DOT) to improve adherence, but DOT may still be a useful strategy for some patients.18,20-24 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 offers a web-based toolkit (consisting of 4 evidence-based HIV medication adherence strategies) to HIV care providers (located at http://www.effectiveinterventions.org/en/HighImpactPrevention/BiomedicalInterventions/MedicationAdherence.aspx).25
ARV drug regimens for children often require taking multiple pills or unpalatable liquids, each with potential adverse effects (AEs) 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 AEs.26 Efforts should be made to reduce the pill burden and to prescribe once-daily ARV drug regimens and single-tablet 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, including some medications now available in small pill size, 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 and with single tablet formulations compared with multiple-tablet regimens.8,27
When nonadherence 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).28 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.29 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 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.30 Availability of mental health services and the treatment of mental health disorders (such as depression) may facilitate adherence to complex ARV drug regimens.31 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.32 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; 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 adherence33-37 and a recent study in poorly adherent HIV-positive adolescents and young adults demonstrated that 2-way personalized daily text messaging improved self-reported adherence.38 It should be noted, however, that the evidence base for effective adherence interventions in adolescents and young adults taking daily ART is limited.39-41
Health Care Provider-Related Strategies
To improve and support adherence, providers should maintain a nonjudgmental attitude, establish trust with patients/caregivers, and identify mutually acceptable goals for care. 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.42 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.43 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 quantitative self-report of missed doses.||Ask patient and/or caregiver about the number of missed doses over defined period (1, 3, or 7 days).|
|Elicit description of medication regimen.||Ask patient and/or caregiver about the name/appearance, number, frequency of medications.|
|Assess barriers to medication administration.||Engage the patient and caregiver in dialogue around facilitators and challenges to adherence.|
|Monitor pharmacy refills.||Approaches include 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 clinic, home visits, or referral to community health nursing.|
|Targeted Approaches to Monitor Adherence in Special Circumstances||Description|
|Implement directly observed therapy.||Include brief hospitalization if indicated.|
|Measure plasma drug concentration.||Can be considered for particular drugs.b|
|Approaches to Monitor Medication Adherence in Research Settings||Description|
|Measure drug concentrations in hair.||Good measure of adherence over time.c|
|Use electronic monitoring devices.||Medication Event Monitoring System [MEMS] caps, Wisepill|
|Use mobile phone-based technologies.||Interactive voice response, SMS text messaging|
|aSee Clinical and Laboratory Monitoring After Initiation of Combination Antiretroviral Therapy (or After a Change in Combination Antiretroviral Therapy) regarding the frequency of adherence assessment after initiating or changing therapy.
bSee Role of Therapeutic Drug Monitoring in Management of Pediatric HIV Infection regarding indications for therapeutic drug monitoring.
cSource: Olds PK, Kiwanuka JP, Nansera D, et al. Assessment of HIV antiretroviral therapy adherence by measuring drug concentrations in hair among children in rural Uganda. AIDS Care. 2015;27(3):327-332. Available at https://www.ncbi.nlm.nih.gov/pubmed/25483955.44
|Initial Intervention Strategies|
|Follow-Up Intervention Strategies|
|Key to Acronyms: ARV = antiretroviral; AE = adverse effect; DOT = directly observed therapy|
- Chadwick EG, Rodman JH, Britto P, et al. Ritonavir-based highly active antiretroviral therapy in human immunodeficiency virus type 1-infected infants younger than 24 months of age. Pediatr Infect Dis J. 2005;24(9):793-800. Available at http://www.ncbi.nlm.nih.gov/pubmed/16148846.
- Vreeman RC, Nyandiko WM, Liu H, et al. Measuring adherence to antiretroviral therapy in children and adolescents in western Kenya. J Int AIDS Soc. 2014;17:19227. Available at http://www.ncbi.nlm.nih.gov/pubmed/25427633.
- Hawkins A, Evangeli M, Sturgeon K, Le Prevost M, Judd A, Committee AS. 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.
- MacDonell KK, Jacques-Tiura AJ, Naar S, Fernandez MI, Team ATNP. Predictors of Self-Reported Adherence to Antiretroviral Medication in a Multisite Study of Ethnic and Racial Minority HIV-Positive Youth. J Pediatr Psychol. 2016;41(4):419-428. Available at http://www.ncbi.nlm.nih.gov/pubmed/26498724.
- 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.
- Haberer J, Mellins C. Pediatric adherence to HIV antiretroviral therapy. Curr HIV/AIDS Rep. 2009;6(4):194-200. Available at http://www.ncbi.nlm.nih.gov/pubmed/19849962.
- Clay PG, Nag S, Graham CM, Narayanan S. Meta-Analysis of Studies Comparing Single and Multi-Tablet Fixed Dose Combination HIV Treatment Regimens. Medicine (Baltimore). 2015;94(42):e1677. Available at http://www.ncbi.nlm.nih.gov/pubmed/26496277.
- Marhefka SL, Koenig LJ, Allison S, et al. Family experiences with pediatric antiretroviral therapy: responsibilities, barriers, and strategies for remembering medications. AIDS Patient Care STDS. 2008;22(8):637-647. Available at http://www.ncbi.nlm.nih.gov/pubmed/18627275.
- Skovdal M, Campbell C, Madanhire C, Nyamukapa C, Gregson S. Challenges faced by elderly guardians in sustaining the adherence to antiretroviral therapy in HIV-infected children in Zimbabwe. AIDS Care. 2011;23(8):957-964. Available at http://www.ncbi.nlm.nih.gov/pubmed/21400306.
- Naar-King S, Montepiedra G, Nichols S, et al. Allocation of family responsibility for illness management in pediatric HIV. J Pediatr Psychol. 2009;34(2):187-194. Available at http://www.ncbi.nlm.nih.gov/pubmed/18586756.
- Cluver LD, Hodes RJ, Toska E, et al. 'HIV is like a tsotsi. ARVs are your guns': associations between HIV-disclosure and adherence to antiretroviral treatment among adolescents in South Africa. AIDS. 2015;29 Suppl 1:S57-65. Available at http://www.ncbi.nlm.nih.gov/pubmed/26049539.
- Farley JJ, Montepiedra G, Storm D, et al. Assessment of adherence to antiretroviral therapy in perinatally HIV-infected children and youth using self-report measures and pill count. J Dev Behav Pediatr. 2008;29(5):377-384. Available at http://www.ncbi.nlm.nih.gov/pubmed/18714204.
- Khan M, Song X, Williams K, Bright K, Sill A, Rakhmanina N. Evaluating adherence to medication in children and adolescents with HIV. Arch Dis Child. 2009;94(12):970-973. Available at http://www.ncbi.nlm.nih.gov/pubmed/19723637.
- Burack G, Gaur S, Marone R, Petrova A. Adherence to antiretroviral therapy in pediatric patients with human immunodeficiency virus (HIV-1). J Pediatr Nurs. 2010;25(6):500-504. Available at http://www.ncbi.nlm.nih.gov/pubmed/21035017.
- Bonner K, Mezochow A, Roberts T, Ford N, Cohn J. Viral load monitoring as a tool to reinforce adherence: a systematic review. J Acquir Immune Defic Syndr. 2013;64(1):74-78. Available at http://www.ncbi.nlm.nih.gov/pubmed/23774877.
- Muller AD, Jaspan HB, Myer L, et al. Standard measures are inadequate to monitor pediatric adherence in a resource-limited setting. AIDS Behav. 2011;15(2):422-431. Available at http://www.ncbi.nlm.nih.gov/pubmed/20953692.
- Simoni JM, Amico KR, Pearson CR, Malow R. Strategies for promoting adherence to antiretroviral therapy: a review of the literature. Curr Infect Dis Rep. 2008;10(6):515-521. Available at http://www.ncbi.nlm.nih.gov/pubmed/18945394.
- Barnighausen T, Chaiyachati K, Chimbindi N, Peoples A, Haberer J, Newell ML. Interventions to increase antiretroviral adherence in sub-Saharan Africa: a systematic review of evaluation studies. Lancet Infect Dis. 2011;11(12):942-951. Available at http://www.ncbi.nlm.nih.gov/pubmed/22030332.
- Williams AB, Fennie KP, Bova CA, Burgess JD, Danvers KA, Dieckhaus KD. Home visits to improve adherence to highly active antiretroviral therapy: a randomized controlled trial. J Acquir Immune Defic Syndr. 2006;42(3):314-321. Available at http://www.ncbi.nlm.nih.gov/pubmed/16770291.
- Bain-Brickley D, Butler LM, Kennedy GE, Rutherford GW. Interventions to improve adherence to antiretroviral therapy in children with HIV infection. Cochrane Database Syst Rev. 2011;12(12):CD009513. Available at http://www.ncbi.nlm.nih.gov/pubmed/22161452.
- Gaur AH, Belzer M, Britto P, et al. Directly observed therapy (DOT) for nonadherent HIV-infected youth: lessons learned, challenges ahead. AIDS Res Hum Retroviruses. 2010;26(9):947-953. Available at http://www.ncbi.nlm.nih.gov/pubmed/20707731.
- Ford N, Nachega JB, Engel ME, Mills EJ. Directly observed antiretroviral therapy: a systematic review and meta-analysis of randomised clinical trials. Lancet. 2009;374(9707):2064-2071. Available at http://www.ncbi.nlm.nih.gov/pubmed/19954833.
- Hart JE, Jeon CY, Ivers LC, et al. Effect of directly observed therapy for highly active antiretroviral therapy on virologic, immunologic, and adherence outcomes: a meta-analysis and systematic review. J Acquir Immune Defic Syndr. 2010;54(2):167-179. Available at http://www.ncbi.nlm.nih.gov/pubmed/20375848.
- Centers for Disease Control and Prevention. Medication Adherence. 2014. Available at http://www.effectiveinterventions.org/en/HighImpactPrevention/BiomedicalInterventions/MedicationAdherence.aspx.
- Pham PA. Antiretroviral adherence and pharmacokinetics: review of their roles in sustained virologic suppression. AIDS Patient Care STDS. 2009;23(10):803-807. Available at http://www.ncbi.nlm.nih.gov/pubmed/19795999.
- Nachega JB, Parienti JJ, Uthman OA, et al. Lower pill burden and once-daily antiretroviral treatment regimens for HIV infection: A meta-analysis of randomized controlled trials. Clin Infect Dis. 2014;58(9):1297-1307. Available at http://www.ncbi.nlm.nih.gov/pubmed/24457345.
- Czyzewski D, Runyan D, Lopez M, al e. Teaching and maintaining pill swallowing in HIV-infected children. The AIDS Reader. 2000;10(2):88-94.
- Garvie PA, Lensing S, Rai SN. Efficacy of a pill-swallowing training intervention to improve antiretroviral medication adherence in pediatric patients with HIV/AIDS. Pediatrics. 2007;119(4):e893-899. Available at http://www.ncbi.nlm.nih.gov/pubmed/17353298.
- Foster C, McDonald S, Frize G, Ayers S, Fidler S. "Payment by Results"--financial incentives and motivational interviewing, adherence interventions in young adults with perinatally acquired HIV-1 infection: a pilot program. AIDS Patient Care STDS. 2014;28(1):28-32. Available at http://www.ncbi.nlm.nih.gov/pubmed/24428797.
- Sin NL, DiMatteo MR. Depression treatment enhances adherence to antiretroviral therapy: a meta-analysis. Annals of Behavioral Medicine : A Publication of the Society of Behavioral Medicine. 2014;47(3):259-269. Available at http://www.ncbi.nlm.nih.gov/pubmed/24234601.
- Shingadia D, Viani RM, Yogev R, et al. Gastrostomy tube insertion for improvement of adherence to highly active antiretroviral therapy in pediatric patients with human immunodeficiency virus. Pediatrics. 2000;105(6):E80. Available at http://www.ncbi.nlm.nih.gov/pubmed/10835093.
- Lester RT, Ritvo P, Mills EJ, et al. Effects of a mobile phone short message service on antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial. Lancet. 2010;376(9755):1838-1845. Available at http://www.ncbi.nlm.nih.gov/pubmed/21071074.
- Horvath T, Azman H, Kennedy GE, Rutherford GW. Mobile phone text messaging for promoting adherence to antiretroviral therapy in patients with HIV infection. Cochrane Database Syst Rev. 2012;3:CD009756. Available at http://www.ncbi.nlm.nih.gov/pubmed/22419345.
- Pop-Eleches C, Thirumurthy H, Habyarimana JP, et al. Mobile phone technologies improve adherence to antiretroviral treatment in a resource-limited setting: a randomized controlled trial of text message reminders. AIDS. 2011;25(6):825-834. Available at http://www.ncbi.nlm.nih.gov/pubmed/21252632.
- Finitsis DJ, Pellowski JA, Johnson BT. Text message intervention designs to promote adherence to antiretroviral therapy (ART): a meta-analysis of randomized controlled trials. PLoS One. 2014;9(2):e88166. Available at http://www.ncbi.nlm.nih.gov/pubmed/24505411.
- Simoni JM, Huh D, Frick PA, et al. Peer support and pager messaging to promote antiretroviral modifying therapy in Seattle: a randomized controlled trial. J Acquir Immune Defic Syndr. 2009;52(4):465-473. Available at http://www.ncbi.nlm.nih.gov/pubmed/19911481.
- Garofalo R, Kuhns LM, Hotton A, Johnson A, Muldoon A, Rice D. A randomized controlled trial of personalized text message reminders to promote medication adherence among HIV-positive adolescents and young adults. AIDS Behav. 2016;20(5):1049-1059. Available at http://www.ncbi.nlm.nih.gov/pubmed/26362167.
- Shaw S, Amico KR. Antiretroviral therapy adherence enhancing interventions for adolescents and young adults 13–24 years of age: a review of the evidence base. J Acquir Immune Defic Syndr. 2016;72(4):387-399. Available at http://www.ncbi.nlm.nih.gov/pubmed/26959190.
- Judd A, Sohn AH, Collins IJ. Interventions to improve treatment, retention and survival outcomes for adolescents with perinatal HIV-1 transitioning to adult care: moving on up. Curr Opin HIV AIDS. 2016;11(5):477-486. Available at http://www.ncbi.nlm.nih.gov/pubmed/27272537.
- MacPherson P, Munthali C, Ferguson J, et al. Service delivery interventions to improve adolescents' linkage, retention and adherence to antiretroviral therapy and HIV care. Trop Med Int Health. 2015;20(8):1015-1032. Available at https://www.ncbi.nlm.nih.gov/pubmed/25877007.
- Molassiotis A, Morris K, Trueman I. The importance of the patient-clinician relationship in adherence to antiretroviral medication. Int J Nurs Pract. 2007;13(6):370-376. Available at http://www.ncbi.nlm.nih.gov/pubmed/18021166.
- Van Winghem J, Telfer B, Reid T, et al. Implementation of a comprehensive program including psycho-social and treatment literacy activities to improve adherence to HIV care and treatment for a pediatric population in Kenya. BMC Pediatr. 2008;8:52. Available at http://www.ncbi.nlm.nih.gov/pubmed/19025581.
- Olds PK, Kiwanuka JP, Nansera D, et al. Assessment of HIV antiretroviral therapy adherence by measuring drug concentrations in hair among children in rural Uganda. AIDS Care. 2015;27(3):327-332. Available at https://www.ncbi.nlm.nih.gov/pubmed/25483955.