The purpose of this study was to determine the reliability of screening for medication adherence in HIV-infected children. The results suggest that caregivers who are unable to describe the medication regimen or who are nonadherent with appointments are unlikely to adhere to the medication regimen. Adherence with at least 90% of medication doses was associated with a virologic response.
Antiretroviral treatment of HIV infection in children has been advanced by using combinations of agents for maximal suppression of viral replication. 1–3 A high level of adherence to these complex regimens is critical for virologic efficacy and to hinder development of viral resistance. 4–6 Children living with HIV have an especially complex set of factors that may contribute to nonadherence, including reliance on others for medication administration, problems scheduling medications around meals and drug palatability. Social issues such as concerns about disclosure, caregiver perception and denial and guilt may also increase the possibility of nonadherence. 1, 2, 7–9
Objective methods to assess adherence are needed because patients and caregivers tend to overestimate their level of adherence. 10, 11 The purpose of this study was to determine the reliability of screening for adherence by assessment of attendance at medical appointments and assessing the ability of the caregiver to describe the medication regimen. We also investigated the relationship between virologic response and medication adherence as measured by prescription refill history.
Study population. From a multidisciplinary clinic population of 70, a convenience sample of 34 HIV-infected children (35 caregivers) was selected for study during the calendar year 1999. One child was in the care of his mother and a foster parent at different times during the year, and the information from both caregivers was included in the analysis. Patients were included in the study if they were patients of the clinic during the calendar year 1999, if they received their medications at a commercial pharmacy and if the caregiver consented to the release of pharmacy information. Patients participating in clinical trials of HIV medications were excluded. The study was reviewed and approved by the Institutional Review Board for Research with Human Subjects of the Medical University of South Carolina.
Medication adherence. A list of all medications dispensed was obtained from each patient’s pharmacy for the year 1999. For each medication the proportion of days of medication dispensed to days of medication prescribed was converted to a percentage and defined as medication adherence. Previous studies in HIV-infected adults have found that >90% adherence with antiretroviral medications is required for prolonged viral suppression. 11 This level of adherence was selected as the minimal desired level of adherence.
Ability to verbalize medications. At each clinic visit the primary caregiver was asked to either name or describe the patient’s medications, the quantity administered and the dosing frequency of each. Those caregivers who complied with all aspects of this request were defined as able to verbalize medications.
Adherence with appointments. Adherence with appointments was defined as the proportion of appointments kept divided by the total number of appointments scheduled during the year. Good adherence was defined as missing no appointments without notifying staff before the appointment time.
Virologic response. Virologic response was defined as a decrease in viral load of at least 100.75 RNA copies/ml from the baseline for patients with baseline RNA >2000 copies/ml, or an undetectable (<400 copies/ml) viral load in patients with baseline RNA <2000 copies/ml. This is modified from the definition used by the Pediatric AIDS Clinical Trials Group for assessment of virologic response in HIV treatment trials in children. 12 The assessment of virologic response was based on viral load measurements immediately before and the first available viral load after the medication change. A medication change was defined as changing at least two drugs from the previous regimen.
Statistical analysis. Statistical analyses were done using commercially available software (GraphPad Prism, 2.01; GraphPad Software, Inc., San Diego, CA). Comparisons between proportions were assessed with the Fisher exact test. Comparisons between continuous variables were analyzed by the Mann-Whitney U test.
Medication adherence, as assessed by pharmacy report, ranged from 22 to 100%. Twelve (34%) of the 35 caregivers gave at least 90% of the prescribed medications. The only significant difference in demographic or disease characteristics of patients who had at least 90% adherence was in the proportion of patients for whom the biologic mother was the primary caregiver (Table 1). A virologic response to the change in antiretroviral therapy occurred in 6 (50%) of the 12 patients who had at least 90% medication adherence compared with 3 (13%) of the 23 patients who did not achieve this level of adherence (P = 0.039).
Nineteen (54%) of the 35 caregivers could describe the child’s medication regimen. Twelve (63%) of these 19 caregivers had at least 90% adherence compared with none of the 16 caregivers who could not describe the medications (P < 0.001; 95% confidence interval for positive prediction, 42 to 84%). Thus although inability to describe the medication regimen identified caregivers who gave <90% of the medications, a substantial proportion of those who could name the medications also failed to achieve this desired level of adherence.
Twenty-five caregivers (71%) had perfect adherence with clinic appointments, but adherence with appointments was not a useful predictor of medication adherence. Ten of the 25 caregivers with perfect appointment adherence had at least 90% medication adherence (95% confidence interval for positive prediction, 21 to 59%) compared with 2 of 10 caregivers who had missed appointments (P = 0.43)
The results of this study suggest that caregivers who are unable to describe the medication regimen or who are nonadherent with appointments are unlikely to adhere to the medication regimen. In contrast the ability to describe the medications or adherence with appointments were poor positive predictors for identification of caregivers who were adherent to the medication regimen. Although the number of caregivers in this study was relatively small, the 95% confidence intervals for positive prediction of 90% adherence suggest that a larger study would be unlikely to identify either of these observations as a clinically useful predictor of adherence.
The record of medications dispensed by pharmacies was used as the standard for medication adherence in this study. In a previous study involving children with asthma, there was good correlation between pharmacy reports and records of Medicaid reimbursement for medications. 13 A study of antiretroviral therapy adherence in HIV-infected children demonstrated an association between adherence as assessed by the pharmacy report and virologic response. 14 Although this method appears to be useful as a general measure of adherence, the fact that the medications were obtained appropriately is at best a surrogate marker for appropriate administration of the medications. A recent preliminary report suggests that the pharmacy report may actually overestimate medication adherence. 10
Viral response results in this study are consistent with previous observations suggesting that even modest deviations from perfect adherence with antiretroviral therapy are associated with a decreased virologic response. 9, 11, 14–16 Studies in HIV-infected adults have found that >90% adherence with antiretroviral medications is required for prolonged viral suppression. 11 Our results are consistent with these observations. In contrast Watson and Farley, 14 in a study of HIV-infected children, found that 75% adherence was associated with prolonged viral suppression.
The overall rate of virologic response, 26%, to antiretroviral treatment in the patients included in this report was quite low. Other studies of the effectiveness of current antiretroviral regimens in children have reported undetectable viral loads in 35 to 44% of patients. 9, 14, 17 The response rate increases to ∼50% in those patients who are adherent to the medication regimen, 9, 14 a rate comparable with the response rate we found in medication-adherent patients. Even in those patients who do not demonstrate a virologic response, adherence to antiretroviral treatments may be associated with an improvement in immunologic status. 18, 19
The availability of effective antiretroviral drugs provides the potential for successful treatment of HIV. It is clear that evaluation of treatment failures must take into account the high probability of nonadherence. It is less clear, however, what intervention can, or should, be provided when nonadherence is identified as a possible contributor to treatment failure. Studies of adult patients have reported that intravenous drug users, younger patients and those with depression or who perceive lack of social support have poorer medication adherence. 8, 11, 20, 21 The complexity of the medication regimen also affects the level of adherence in these studies. 8, 11, 20, 21 Similar factors affecting adherence in children have also been identified. 9 Future studies directed at accurate assessment of medication adherence, identification of the barriers to adherence in pediatric patients and development of appropriate interventions to overcome these barriers are essential to the care of these patients.
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