Care for HIV-infected individuals has dramatically improved since 1996 by the use of highly active antiretroviral therapy (HAART). Nevertheless, virologic failure occurs and is often associated with the development of drug resistance.1 Adherence is a major factor determining the degree of viral suppression that is achieved in response to HAART and the emergence of resistant mutations.2-4 Problems of adherence occur frequently in children.4-6 Among the 2.2 million children who were HIV infected in 2004, 90% live in sub-Saharan Africa and are just beginning to benefit from access to antiretroviral medications on a large scale. However, little is known about adherence in African HIV-infected children. To improve knowledge in this field, we studied an existing observational cohort of HIV-infected children in Côte d'Ivoire. The objective was to assess their adherence to HAART and to examine its associated factors.
We conducted a cross-sectional analysis of clinical records and caregivers' and children's interviews between February and April 2004 in Abidjan, Côte d'Ivoire.
Participants were recruited from the ANRS (Agence Nationale De Recherches Sur Le SIDA) 1244 observational open cohort of 282 HIV-infected children enrolled between October 2000-December 2003. Details of enrollment and follow-up procedures in the cohort have been described elsewhere.7 All patients receiving HAART were eligible for the adherence study.
Subjects had to attend the day hospital provided by the research program with a caregiver who knew about their HIV infection and the treatment that the child was undertaking and who consented to participate in the study.
Measurement of Adherence and Associated Factors
Sociodemographic and clinical characteristics and the record of adherence difficulties were obtained through clinical records of the day hospital. In addition, a questionnaire regarding the child's age was administered to the caregiver or the child when they came to the day hospital. They were asked if the treatment had been interrupted at least once in the month prior to the study visit (Box 1). They were then asked about the reasons that could account for the interruption of the treatment.
Viral Load Measurement
All viral load levels were measured by a real-time polymerase chain reaction assay.8
The χ2 test or the Fisher test was used for qualitative variables, and the Kruskal-Wallis test was used for quantitative variables to compare data from clinical records between respondents and nonrespondents and to analyze the effect of different factors on adherence. Adherence for a given patient was defined as full adherence when no doses of any HAART drugs were missed in the month prior to the visit. Non-full adherence was defined as missing at least 1 dose of a HAART drug in the month prior to the visit. Logistic regression models were used to perform multivariate analysis and to study the relative effect of each factor expressed as prevalence odds ratio. The effect of adherence in the prior month in response to treatment (defined as achieving HIV-1 RNA <2.5 log10 copies/mL) was assessed when a measure of viral load was available in the same period. All P values were 2-tailed and the threshold of significance was set at 0.05. All statistical analyses were conducted with SAS software (Raleigh, NC).
Among the 143 children receiving HAART at the time of the study, 112 met the selection criteria for this adherence substudy (78% of response rate, nobody refusing to take part in the study). When comparing these 112 respondents with the 31 patients who were excluded from the study because they did not attend the day hospital with an appropriate caregiver during the study period, no significant difference was found for characteristics such as gender, parent status, or age. A significantly higher proportion of individuals living in Abidjan and the suburbs were found among respondents to the recruitment.
Adherence Rate and Associated Factors
In our cross-sectional survey, 37 children (33%) reported less than full adherence in the prior month. There were direct reported reasons accounting for non-full adherence: children forgetting to take the treatment (40.5%), drug stock exhaustion at the central level (48.7%), children refusing to take the treatment (8.1%), and delay in getting a new prescription (2.7%). When comparing patients with non-full adherence due to drug stock exhaustion and patients with non-full adherence due to other issues, no significant difference was found for characteristics such as gender (P = 0.236), parent status (P = 0.095), median age at study period (P = 0.162), home place (P = 0.230), and medications taken during the study period: zidovudine (P = 0.072), stavudine (P = 0.072), didanosine (P = 0.902), lamivudine (P = 0.902), efavirenz (P = 0.413), and nevirapine (P = 0.413). Nonadherent children were older at the time of interview (P = 0.012) and at the beginning of HAART (P = 0.007) and were more likely to be receiving an efavirenz-containing regimen (P = 0.015) (Table 1). In multivariate analysis, being 13 years or older at the time of the study and receiving efavirenz were still associated with non-full adherence (adjusted prevalence odds ratio 3.2, 95% CI 1.0-9.5, P = 0.04; and 2.5, 95% CI 1.0-5.8, P = 0.04, respectively). In children receiving efavirenz, the main reasons for reporting non-full adherence were forgetting to take the treatment (47.3%) and shortage of drugs (42.1%).
Relationship Between Adherence and Viral Load
An HIV-1 RNA plasma viral load in the prior month was available for only 24 children. Among them, 4 reported non-full adherence, all because of forgetting doses. An undetectable viral load (<2.4 log10 copies/mL) was obtained for 55% of the patients with full adherence but for none of the patients with non-full adherence (P = 0.098).
To our knowledge, this is the first assessment of adherence to HAART among a group of children living in West Africa. It shows that one-third of the children reported less than full adherence in the month prior to the study visit. These results compare well with studies conducted in developed countries.5-6,9 However, the adherence rate was likely to be enhanced by the close follow-up proposed in the context of a research program as well as by the method of adherence assessment itself and its lack of anonymity. Indeed, considering the literacy rate of 50% in Côte d'Ivoire in 2003, we used face-to-face interviews to assess children's adherence. This overestimation could have been compensated by the memory bias introduced by the month recall, which is a long delay.
We decided to include in our analysis children with reported adherence problems due to “drug stock exhaustion at the central level,” even though the patients and caretakers were not responsible for them, because we considered this issue would have the same consequences in terms of health as other issues and therefore warranted to be studied. Shortage of drugs was the leading determinant of nonadherence, a finding that public health authorities should note with regard to their preparedness to provide sufficient material supply in the current national antiretroviral program.10
Because of the small subset of children from whom a blood sample was taken in the same period as the interview, no association between low viral load and full adherence could be demonstrated, even though trends confirmed those found in other studies.4,5
An important factor associated with non-full adherence was the child's age, as described in other recent studies.6,11 Attention should therefore be paid to the period when the responsibility for taking and giving drugs is shared between the child and the caregiver so that appropriate support may be defined for adherence at each age.6,12 Nonadherent children were more likely to be receiving efavirenz, even though this drug is usually easy to take (only once daily). In fact, efavirenz is more likely to be prescribed to older children because the pills are large and to children known to be nonadherent to reduce the burden of pills per day.
This study demonstrates a lower adherence rate than those reported in clinical records (84%). This underscores the importance of developing a cheap, high-performance, easy-to-use tool to measure adherence specifically in African children in routine clinical settings. Standard tools do not meet all this criteria.13 A promising avenue is the visual analogue scale14 in which participants tick how much of each drug they think they have taken in the preceding 3 or 4 weeks. Although it has been validated in marginally housed, indigent HIV-infected patients in the United States and in adults from Uganda, further research is needed to know whether it could be used with children in the African context.15
We would like to thank the Programme Enfant Yopougon team for their dedication and to express our gratitude towards the children and the families who participated. We also thank Mathilde Arrivé, Dominique Marchand, Susan Birch and Ray Cooke for assistance in writing this article and Dr. Freddy Perez (ISPED) for comments and proofreading the manuscript.
1. Tanuri A, Caridea E, Dantas MC, et al. Prevalence of mutations related to HIV
-1 antiretroviral resistance in Brazilian patients failing HAART. J Clin Virol
2. Paterson DL, Swindells S, Mohr J, et al. Adherence
to protease inhibitor therapy and outcomes in patients with HIV
infection. Ann Intern Med
3. Sethi AK, Celentano DD, Gange SJ, et al. Association between adherence
to antiretroviral therapy and HIV
drug resistance. Clin Infect Dis
4. Van Dyke RB, Lee S, Johnson GM, et al. Reported adherence
as a determinant of response to highly active antiretroviral therapy
who have human immunodeficiency virus infection. Pediatrics
5. Reddington C, Cohen J, Baldillo A, et al. Adherence
to medication regimens among children
with human immunodeficiency virus infection. Pediatr Infect Dis J
6. Mellins CA, Brackis-Cott E, Dolezal C, et al. The role of psychosocial and family factors in adherence
to antiretroviral treatment in human immunodeficiency virus-infected children
. Pediatr Infect Dis J
7. Fassinou P, Elenga N, Rouet F, et al. Highly active antiretroviral therapies among HIV
in Abidjan, Côte d'Ivoire. AIDS
8. Rouet F, Msellati P, Coulibaly N, et al. Antiretroviral treatment monitoring of children
with plasma HIV
-1 RNA quantitative real-time PCR assay: a very attractive alternative in resource-poor settings. Abstract 1093. Paper presented at: Second International AIDS Society Conference on HIV
Pathogenesis and treat ment; July 13-17, 2003; Paris.
9. Eley B, Nuttall J, Davies MA, et al. Initial experience of a public sector antiretroviral treatment programme for HIV
and their infected parents. S Afr Med J
10. Zeguela B. M édicaments antirétroviraux: rupture de deux molécules, les VIH+ menacent. Fraternité Matin June 2003. Available at: http://www.essentialdrugs.org/emed/archive/200306/msg00068.php
. Accessed April 2005.
11. Farley J, Gona P, Crain M, et al. Prevalence of elevated cholesterol and associated risk factors among perinatally HIV
(4-19 years old) in Pediatric AIDS Clinical Trials Group 219C. J Acquir Immune Defic Syndr
12. Kalyebara J, Barigye H. Children
[P315]. Paper presented at: Sixth International Congress on Drug Therapy in HIV
Infection; November 17-21, 2002; Glasgow, UK.
13. Farley J, Hines S, Musk A, et al. Assessment of adherence
to antiviral therapy in HIV
using the Medication Event Monitoring System, pharmacy refill, provider assessment, caregiver self-report, and appointment keeping. J Acquir Immune Defic Syndr
14. Giordano TP, Guzman D, Clark R, et al. Measuring adherence
to antiretroviral therapy in a diverse population using a visual analogue scale. HIV Clin Trials
15. Oyugi JH, Byakika-Tusiime J, Charlebois ED, et al. Multiple validated measures of adherence
indicate high levels of adherence
to generic HIV
antiretroviral therapy in a resource-limited setting. J Acquir Immune Defic Syndr