Adherence to isoniazid prophylaxis among HIV-infected children: a randomized controlled trial comparing two dosing schedules

BMC Medicine, Nov 2009

Background Tuberculosis contributes significantly to morbidity and mortality among HIV-infected children in sub-Saharan Africa. Isoniazid prophylaxis can reduce tuberculosis incidence in this population. However, for the treatment to be effective, adherence to the medication must be optimized. We investigated adherence to isoniazid prophylaxis administered daily, compared to three times a week, and predictors of adherence amongst HIV-infected children. Methods We investigated adherence to study medication in a two centre, randomized trial comparing daily to three times a week dosing of isoniazid. The study was conducted at two tertiary paediatric care centres in Cape Town, South Africa. Over a 5 year period, we followed 324 HIV-infected children aged ≥ 8 weeks. Adherence information based on pill counts was available for 276 children. Percentage adherence was calculated by counting the number of pills returned. Adherence ≥ 90% was considered to be optimal. Analysis was done using summary and repeated measures, comparing adherence to the two dosing schedules. Mean percentage adherence (per child during follow-up time) was used to compare the mean of each group as well as the proportion of children achieving an adherence of ≥ 90% in each group. For repeated measures, percentage adherence (per child per visit) was dichotomized at 90%. A logistic regression model with generalized estimating equations, to account for within-individual correlation, was used to evaluate the impact of the dosing schedule. Adjustments were made for potential confounders and we assessed potential baseline and time-varying adherence determinants. Results The overall adherence to isoniazid was excellent, with a mean adherence of 94.7% (95% confidence interval [CI] 93.5-95.9); similar mean adherence was achieved by the group taking daily medication (93.8%; 95% CI 92.1-95.6) and by the three times a week group (95.5%; 95% CI 93.8-97.2). Two-hundred and seventeen (78.6%) children achieved a mean adherence of ≥ 90%. Adherence was similar for daily and three times a week dosing schedules in univariate (odds ratio [OR] 0.88; 95% CI 0.66-1.17; P = 0.38) and multivariate (adjusted OR 0.85; 95% CI 0.64-1.11; P = 0.23) models. Children from overcrowded homes were less adherent (adjusted OR 0.71; 95% CI 0.54-0.95; P = 0.02). Age at study visit was predictive of adherence, with better adherence achieved in children older than 4 years (adjusted OR 1.96; 95% CI 1.16-3.32; P = 0.01). Conclusion Adherence to isoniazid was excellent regardless of the dosing schedule used. Intermittent dosing of isoniazid prophylaxis can be considered as an alternative to daily dosing, without compromising adherence or efficacy. Trial registration Clinical Trials NCT00330304

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Adherence to isoniazid prophylaxis among HIV-infected children: a randomized controlled trial comparing two dosing schedules

Stanzi M le Roux 2 Mark F Cotton 1 Jonathan E Golub 0 David M le Roux 2 Lesley Workman 2 Heather J Zar 2 0 Department of Epidemiology, Johns Hopkins School of Medicine & Bloomberg School of Public Health , USA 1 Department of Paediatrics and Child Health , Stellenbosch , South Africa 2 School of Child and Adolescent Health, University of Cape Town , South Africa Background: Tuberculosis contributes significantly to morbidity and mortality among HIV-infected children in subSaharan Africa. Isoniazid prophylaxis can reduce tuberculosis incidence in this population. However, for the treatment to be effective, adherence to the medication must be optimized. We investigated adherence to isoniazid prophylaxis administered daily, compared to three times a week, and predictors of adherence amongst HIV-infected children. Methods: We investigated adherence to study medication in a two centre, randomized trial comparing daily to three times a week dosing of isoniazid. The study was conducted at two tertiary paediatric care centres in Cape Town, South Africa. Over a 5 year period, we followed 324 HIV-infected children aged 8 weeks. Adherence information based on pill counts was available for 276 children. Percentage adherence was calculated by counting the number of pills returned. Adherence 90% was considered to be optimal. Analysis was done using summary and repeated measures, comparing adherence to the two dosing schedules. Mean percentage adherence (per child during follow-up time) was used to compare the mean of each group as well as the proportion of children achieving an adherence of 90% in each group. For repeated measures, percentage adherence (per child per visit) was dichotomized at 90%. A logistic regression model with generalized estimating equations, to account for within-individual correlation, was used to evaluate the impact of the dosing schedule. Adjustments were made for potential confounders and we assessed potential baseline and timevarying adherence determinants. Results: The overall adherence to isoniazid was excellent, with a mean adherence of 94.7% (95% confidence interval [CI] 93.5-95.9); similar mean adherence was achieved by the group taking daily medication (93.8%; 95% CI 92.1-95.6) and by the three times a week group (95.5%; 95% CI 93.8-97.2). Two-hundred and seventeen (78.6%) children achieved a mean adherence of 90%. Adherence was similar for daily and three times a week dosing schedules in univariate (odds ratio [OR] 0.88; 95% CI 0.66-1.17; P = 0.38) and multivariate (adjusted OR 0.85; 95% CI 0.64-1.11; P = 0.23) models. Children from overcrowded homes were less adherent (adjusted OR 0.71; 95% CI 0.54-0.95; P = 0.02). Age at study visit was predictive of adherence, with better adherence achieved in children older than 4 years (adjusted OR 1.96; 95% CI 1.16-3.32; P = 0.01). Conclusion: Adherence to isoniazid was excellent regardless of the dosing schedule used. Intermittent dosing of isoniazid prophylaxis can be considered as an alternative to daily dosing, without compromising adherence or efficacy. Trial registration: Clinical Trials NCT00330304 - Background In 2007, 90% of the estimated 2.0 million HIV-infected children worldwide lived in sub-Saharan Africa, a reflection of the HIV epidemic in adults of the same region [1]. Opportunistic infections, especially tuberculosis (TB), are a major cause of morbidity and mortality amongst these children [2,3]. Internationally, significant progress has been made to minimize morbidity and mortality amongst people living with HIV/AIDS. The benefits of highly active antiretroviral therapy (HAART), trimethoprim-sulphamethoxazole (TMP-SMX) prophylaxis and, more recently, isoniazid (INH) prophylaxis for preventing TB, have been proven in adults and children in various settings [4-8]. However, in resource-limited settings these benefits are rarely realized. Obstacles include cost, interrupted drug supplies and suboptimal adherence [1,9,10]. To enable all those infected by HIV to benefit from these life-saving interventions, it is imperative that cost-effectiveness and barriers to adherence be urgently and innovatively addressed. Common barriers to adherence include complex dosing schedules, toxicity, pill burden and, in many resource-limited settings, financial cost to the patient [11,12]. Intermittent dosing schedules can potentially address these adherence barriers and may prove cost-saving. Intermittent dosing for the treatment and prevention of TB has been successfully used for adults and efficacy has been proven in children [8,13-15]. Even if the efficacy of a treatment is similar for different dosing schedules, it is possible that subtle adherence differences may impact on the feasibility and effectiveness when the treatment is rolled out on a large scale. To our knowledge, there have been no randomized controlled trials evaluating the impact of dosing schedule on adherence to INH prophylaxis in HIV-infected children. In a recent pl (...truncated)


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Stanzi M le Roux, Mark F Cotton, Jonathan E Golub, David M le Roux, Lesley Workman, Heather J Zar. Adherence to isoniazid prophylaxis among HIV-infected children: a randomized controlled trial comparing two dosing schedules, BMC Medicine, 2009, pp. 67, 7, DOI: 10.1186/1741-7015-7-67