Despite advances in pediatric HIV treatment and prevention , the global burden of pediatric HIV infection remains great. With infrastructure to support timely diagnosis and antiretroviral medications for pregnant HIV-infected mothers and HIV-exposed infants, mother-to-child HIV transmission rates may be reduced from greater than 25% to less than 5% [2,3]. In 2010, however, an estimated 390 000 new pediatric infections occurred nonetheless, 98% in low and middle-income countries (LMICs) . In 2011, UNAIDS framed an initiative to reduce new pediatric HIV infections by 90%, to provide combination antiretroviral therapy (cART) for all HIV-infected children, and to reduce AIDS-related infant deaths by more than 50% by 2015 . Optimized medication regimens, improved access to maternal  and early infant [6–9] diagnostic testing, better retention in services [10–12], and increased antiretroviral adherence [13–15] are vital for improving both prevention of mother-to-child HIV transmission (PMTCT) and pediatric HIV treatment effectiveness. Yet these are not sufficient for ensuring favorable outcomes; adult caregivers must also be able to accurately administer cART to the HIV-infected children.
Caregiver errors in administering liquid medications to children are frequent in the United States [16–19] with as many as 30–70% of caregivers measuring or administering liquid over-the-counter medications incorrectly [17–20]. Factors that contribute to dosing errors are incompletely understood, but include medication formulations, communication skills of the healthcare provider, and caregiver characteristics. Health literacy, defined as ‘the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions’ , may influence dosing accuracy . We postulate that health literacy is particularly important in settings in which limited literacy is prevalent . In sub-Saharan Africa, characteristics that contribute to pediatric dosing errors, such as low health literacy, are common among caregivers .
Little is known about caregiver dosing accuracy for liquid medications in LMICs. Erroneous dosing of pediatric ARV medications such as zidovudine, commonly used in both prophylactic  and treatment regimens , may have serious adverse consequences. We hypothesized that in a population of adults in sub-Saharan Africa who were receiving cART for their own HIV infections, lower HIV health literacy would be associated with dosing errors for liquid zidovudine using two common standardized dosing instruments.
From August to November 2012, we enrolled a convenience sample of adults receiving cART for HIV infection in Maputo Province, Mozambique to participate in a primary study designed to validate a novel measure of HIV health literacy (the HIV Literacy Test or HIV-LT). The study took place at two public clinics: Polana Caniço, an urban facility located near the Maputo city center, and Marracuene, a rural facility located approximately 40 km from the center of Maputo city. Our cross-sectional assessment of dosing ability was nested within this primary study.
Both clinics were staffed by Clinical Officers assigned by the Ministry of Health and offered adult and pediatric HIV care and treatment services, antenatal care, PMTCT, tuberculosis care, and other services. At the time of the study, Mozambican national guidelines  recommended ‘opt-out’ PMTCT services and zidovudine/nevirapine dual therapy (or cART) for the exposed infant. Caregivers of HIV-exposed/infected infants and children receive written prescriptions from the healthcare provider for the child. Typically, full bottles of liquid antiretrovirals are dispensed by the onsite pharmacy. Although dosing cups or syringes are dispensed when available, no single standardized dosing instrument is offered routinely. Typically, caregivers receive brief dosing instructions at the pharmacy, but no formal counseling is provided systematically.
HIV-infected Portuguese-speaking adults aged 18–49 years presenting to either health center for HIV-related care and treatment were eligible if they had been receiving cART for at least 3 months. Participants were excluded if they were unable to communicate in basic Portuguese or did not pass vision screening.
Data included interview and observational measures. All study communications were conducted in Portuguese, the official language of Mozambique and the language most commonly used in these two health centers . The primary outcome variable was dosing accuracy. Primary predictor variables were dosing instrument type and HIV health literacy. Sociodemographic data were collected by standardized interview.
Each participant was administered the HIV-LT, a 16-item scale designed to measure literacy and numeracy skills applied to HIV self-management. The HIV-LT was designed to assess common tasks that adults with HIV infection must perform in order to participate in care. These tasks include the ability to dose oral medications, determine the timing of follow-up appointments, and understand the risk of HIV transmission and treatment side-effects. Scores were calculated as the number of items answered correctly and ranged from 0 to 16 with higher scores indicating greater literacy. The HIV-LT was validated as part of the primary study , and the internal reliability was excellent (Kuder–Richardson 20 coefficient = 0.87).
A standard dosing cup (10 ml) and a standard dosing syringe (10 ml) were used that were obtained from Mozambican clinics. The plastic cup had clear etched calibration markings at every 2.5 ml interval. The syringe had black calibration markings printed numerically at each ml interval, with hash marks every 0.2 ml.
Participants were shown a prescription card and were instructed using a script to measure a hypothetical pediatric dose of zidovudine suspension [2.5 ml (25 mg)] using both the cup and syringe. The measured dose was weighed using a digital prescription scale accurate to 0.05 g (Zieis, Apple Valley, Minnesota, USA). For both instruments, the magnitude of error was calculated by comparing the weight of the measured dose to a reference weight . The average weight of 2.5 ml of zidovudine as measured by five pediatricians was used as the reference weight for both the cup and the syringe. No zidovudine was administered to study participants or their children.
Dosing accuracy was recorded as a categorical variable. Dosing errors were defined as either no error (within 20% of the reference weight), any error (any dosing error ≥20% deviation from the reference), or major error (≥40% deviation) .
Our participants were enrolled in a primary study designed to validate the HIV-LT; the design of the parent study formed the basis for sample size calculations for our substudy. We aimed to recruit 320 participants in the parent study in order to have adequate sample size to validate the HIV-LT [26–28].
Data were analyzed using Stata version 12.0 statistical software (StataCorp LP, College Station, Texas, USA). Continuous variables were compared between sites using the Student's t-test; categorical variables were compared between groups using the χ 2 test. The frequency of dosing errors was reported by calculating the proportion of participants who committed any dosing error (≥20% deviation from reference dose) and major dosing errors (≥40% deviation) for each dosing instrument in the total population; comparisons of dosing error frequency were made according to literacy level, sex, and the presence of a child less than 5 years of age in the household. The proportions of errors for each dosing instrument were compared in the total population, as well as in participants with children less than 5 years in the household and between the groups with below-average vs. above-average HIV-LT scores using the Wilcoxon signed-rank test. Multivariable logistic regression analysis was conducted to analyze the relationships between HIV-LT score and the occurrence of errors for each dosing instrument. These models adjusted for covariates that were specified a priori, including the adult's age, sex, clinic site, employment, income, years of education, duration of antiretroviral therapy, language spoken at home, and number of children less than 18 years of age in the household.
All study procedures were approved by the Institutional Review Boards at Vanderbilt University Medical Center (Nashville, Tennessee, USA) and Universidade Eduardo Mondlane (Maputo, Mozambique). All participants provided informed consent prior to study enrollment.
We approached 578 potential participants; 102 (17.6%) refused or could not communicate in basic Portuguese (Fig. 1). Refusals were primarily due to concerns about delaying appointments. Of 476 individuals who provided informed consent, 316 individuals (66.4%) were eligible and completed all study measures. The mean age of participants was 34.8 years (SD 6.7); 76% were women (Table 1). Nearly 90% of participants had at least one child 18 years or under in the household, and nearly half of all participants had at least one child less than 5 years of age in the household. The mean HIV-LT score in our sample was 6.7 (SD 4.1). As expected, HIV-LT scores were strongly correlated with general literacy (ρ = 0.8), general numeracy (ρ = 0.7), and education (ρ = 0.7; P <0.001). Sociodemographic characteristics were compared between participants with and without children less than 5 years of age in the household (data not shown). The group with children less than 5 were slightly younger [33.8 (6.7) vs. 35.7 (6.6); P = 0.02] and had more children in the household [3.5 (1.8) vs. 1.8 (1.4); P <0.0001] than the group without children less than 5 years in the household.
Dosing errors by instrument
Using the cup, 157 participants (49.7%) made an error, including 90 participants (28.4%) who committed a major dosing error (Table 2). Using the syringe, 151 participants (47.8%) committed an error, and 88 of these (27.9%) committing major errors. Nearly 90% of errors made using the cup were overdosing errors, whereas the majority of errors using the syringe were underdosed (58%). There were no significant differences in the proportion of dosing errors using the dosing cup compared with the dosing syringe (Fig. 2a). No significant differences existed in the proportion of dosing errors between participants with children less than 5 in the household compared with those without. Similarly, there were no differences in proportion of dosing errors by sex.
Dosing errors and HIV health literacy
Participants with below-average literacy were more likely to commit dosing errors than those with above-average literacy using both the cup and syringe (Fig. 2b and c). After adjustment for covariates, higher HIV-LT score remained significantly associated with reduced odds of committing any error and major errors for both instruments (Table 2), in both the total population and the subpopulation with at least one child less than 5 in the household. Participants with above-average literacy had significantly reduced odds of committing any error using both the dosing cup [adjusted odds ratio 0.52 (95% confidence interval 0.29–0.92), P = 0.03] and syringe [adjusted odds ratio 0.39 (95% confidence interval 0.19–0.80), P = 0.01]. Aside from HIV-LT score, in the adjusted model, only education was significantly associated with reduced major errors using both the cup (P = 0.021) and the syringe (P = 0.038).
To our knowledge, this study is the first to measure dosing accuracy for a pediatric antiretroviral medication. Dosing errors were exceedingly common and were associated significantly with lower HIV health literacy. Alongside efforts toward improving infant testing, treatment, and access, our study highlights serious concern as to an adult's ability to accurately dose infants for PMTCT or child cART, even adults who are receiving cART for their own care. Our findings suggest that targeted interventions to improve instructions about pediatric liquid antiretroviral dosing are needed to improve pediatric antiretroviral adherence, particularly in settings dependent on liquid formulations because tablet and/or dissolvable formulations are unavailable in appropriate dosages for infants and small children.
In the United States, the use of standardized dosing instruments for pediatric liquid medications has long been recommended [29–31]. To date, no such standard has been adopted in Mozambique. In 2008, Yin et al.  found that the use of the dosing syringe enhanced dosing accuracy for liquid acetaminophen compared with the cup in an urban US population. In contrast to these findings and others [27,30,32], syringe error rates in our population were comparatively high, possibly reflecting less familiarity with syringe dosing. Given that the advantage of the dosing syringe in reducing the proportion of dosing errors was not clearly established in our study population, additional studies are needed to determine whether recommendations for the use of dosing syringes in the United States also apply to resource-limited settings.
Strengths of our study include use of standard measuring approaches, precise calibration of errors, and a novel measure of HIV health literacy. Limitations include using a hypothetical dosing scenario that may not truly reflect the actual ability of caregivers to administer zidovudine doses to children that are relevant to PMTCT and cART of pediatric HIV infection. Because we designed the study to validate the HIV-LT in a general population of adults on treatment for HIV, participants were not necessarily caring for children receiving ARV medications, although nearly half of our study population had children under 5 in the home, and there were no differences in the dosing accuracy performance of this subpopulation. We included only individuals with basic Portuguese language skills, given that Portuguese is the language primarily used in health centers throughout Mozambique; however, Portuguese was not the primary language spoken in the homes of many participants, which may have influenced individuals’ abilities to understand study tools. Additionally, participants were provided 10 ml dosing instruments, allowing more opportunity to overdose than underdose. As no biologic outcomes were measured, it remains unclear whether the proportion and magnitude of dosing errors we identified translate into clinically relevant outcomes. Finally, the individuals captured in our cross-sectional study, HIV-infected individuals with experience in adult ARV dosing, likely represent those with the most consistent access to care and the greatest dosing abilities, and may underestimate the burden of liquid medication dosing errors in more remote areas in Mozambique, where lower literacy and numeracy abilities may be more prevalent .
We found that dosing errors for a liquid pediatric antiretroviral medication were very common among HIV-infected adults in Mozambique and were associated with lower HIV health literacy. The HIV-LT could be used in clinic settings to identify caregivers of HIV-exposed/infected children who may benefit from additional dosing instruction or counseling strategies. In addition to the many complex social and financial barriers that must be addressed, our findings suggest that caregiver dosing accuracy is a critical component of enhancing adherence to pediatric antiretroviral medications and should encourage programs to review their standard plans for giving medicines to young infants. Given the serious implications for successful PMTCT and pediatric HIV treatment outcomes, we urge development of targeted approaches to improving healthcare instructions and dosing skills for caregivers at the pediatric point of care.
L.M.H., J.A.T., and P.J.C. initiated the project, designed the study, developed the protocol, and designed the tools for collecting data. L.M.H., J.A.T., and S.G. participated in data collection. L.M.H., J.A.T., and P.J.C. cleaned and analyzed the data. L.M.H. drafted and made revisions to the article. J.A.T., S.G., M.S., R.L.R., S.H.V., and P.J.C. contributed to interpretation of the analysis and revision of the article. L.M.H. and P.J.C. are guarantors for the study. All authors had full access to all of the data, including statistical reports and tables, and can take responsibility for the integrity of the data and the accuracy of the data analysis.
Dr Kathryn Edwards critically reviewed the article.
Conflicts of interest
All authors declare that the research was conducted in accordance with the Declaration of Helsinki. Experiments were conducted with the understanding and the consent of each participant, and the responsible ethical committees have approved the experiments.
All authors declare that they have read and approved the article, that they met the criteria for authorship as established by the International Committee of Medical Journal Editors, that they believe that the article represents honest work, and that they are able to verify the validity of the results reported.
All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that L.M.H., J.A.T., S.G., M.S., R.L.R., S.H.V., and P.J.C. have no support from any company for the submitted work; L.M.H., J.A.T., S.G., M.S., R.L.R., S.H.V., and P.J.C. have no relationships to companies that might have an interest in the submitted work in the previous 3 years; their spouses, partners, or children have no financial relationships that may be relevant to the submitted work; and L.M.H., J.A.T., S.G., M.S., R.L.R., S.H.V., and P.J.C. have no nonfinancial interests that may be relevant to the submitted work. L.M.H. was funded by the Childhood Infections Research Program Training Grant #IT32AI095202-01. J.A.T. was funded by AIDS International Training and Research Program NIH grant #D43TW001035. Researchers were independent from funders, and funders had no role in study design, data collection, analysis, interpretation, decision to publish, or preparation of the article. The content is solely the responsibility of the authors.
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Keywords:© 2014 Lippincott Williams & Wilkins, Inc.
Africa; antiretroviral therapy; dosing errors; health literacy; HIV; prevention of mother-to-child HIV transmission