Suboptimal cotrimoxazole prophylactic concentrations in HIV‐infected children according to the WHO guidelines

Pressiat, Claire; Mea-Assande, Véronique; Yonaba, Caroline; Tréluyer, Jean‐Marc; Dahourou, Désiré Lucien; Amorissani‐Folquet, Madeleine; Blanche, Stéphane; Eboua, François Tanoh; Ye, Diarra; Lui, Gabrielle; Malateste, Karen; Zheng, Yi; Leroy, Valériane; Hirt, Déborah

doi:10.1111/bcp.13397

Cited by 3 publications

(3 citation statements)

References 38 publications

(56 reference statements)

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“… 3 , 4 Few prior studies have examined TMP–SMX levels in this context. 16 A recent study of 136 West African children on ARV and TMP–SMX prophylaxis suggested that overall TMP–SMX levels in children dosed according to WHO recommendations were lower than those achieved in adults, 17 although the relevance of this to preventing infections or driving drug resistance requires further study. Trimethoprim–sulfamethoxazole prophylaxis impact on the development of malaria-specific immunity in children requires further study.…”

Section: Discussionmentioning

confidence: 99%

Sulfamethoxazole Levels in HIV-Exposed Uninfected Ugandan Children

Kasule

Gabriel

Anok

et al. 2018

The American Journal of Tropical Medicine and Hygiene

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Abstract.Trimethoprim–sulfamethoxazole (TMP–SMX) prophylaxis in HIV-uninfected, exposed (HUE) children variably reduces clinical malaria burden despite antifolate resistance, but data regarding achieved serum levels and adherence are lacking. Serum samples from 70 HUE children aged 3–12 months from Rakai, Uganda, enrolled in an observational study were assayed for random SMX levels using a colorimetric assay. Adherence with TMP–SMX prophylaxis data (yes/no) was also collected. Of 148 visits with concurrent SMX levels available, 56% had self-reported adherence with TMP–SMX therapy. Among these 82 visits, mean (standard deviation) level was 19.78 (19.22) µg/mL, but 33% had SMX levels below half maximal inhibitory concentrations (IC50) for Plasmodium falciparum with some, but not all, of the reported antifolate resistance mutations reported in Uganda. With TMP–SMX prophylaxis, suboptimal adherence is concerning. Sulfamethoxazole levels below IC50s required to overcome malaria parasites with multiple antifolate resistance mutations may be significant. Further study of TMP–SMX in this context is needed.

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Section: Discussionmentioning

confidence: 99%

Sulfamethoxazole Levels in HIV-Exposed Uninfected Ugandan Children

Kasule

Gabriel

Anok

et al. 2018

The American Journal of Tropical Medicine and Hygiene

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“…Study design and procedures were already published. 7 For the MONOD non-inferiority trial, the statistical parameter of interest was the difference in viral success rate 12 months after the switch, defined as the rate in the LPV arm (control) minus the rate in the EFV arm, using a chi-square test. We aimed to obtain a viral success of at least 76% at 12 months post-switch.…”

Section: Methodsmentioning

confidence: 99%

“…Based on our anticipated enrolment of 146 children with 73 children per arm, we expected an 80% power to detect this difference. 7…”

Section: Methodsmentioning

confidence: 99%

Comparison of three galenic forms of lamivudine in young West African children living with Human Immunodeficiency Virus

et al. 2021

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Background Few pharmacokinetic data were reported on dispersible tablets despite their increasing use. One hundred fifty HIV-infected children receiving lamivudine were enrolled in the MONOD ANRS 12,206 trial. Three galenic forms were administered: liquid formulation, tablet form and dispersible scored tablet. Method HIV-infected children <4 years old were enrolled in the MONOD ANRS 12,206 trial designed to assess the simplification of a successful 12-months lopinavir-based antiretroviral treatment with efavirenz. Lamivudine plasma concentrations were analysed using nonlinear mixed effects modelling approach. Results One hundred and fifty children (age: 2.5 years (1.9–3.2), weight 11.1 (9.5–12.5) kg (median (IQR)) were included in this study. Over the study period, 79 received only the syrup form, 29 children switched from syrup form to tablet 3TC/AZT form, 36 from syrup to the orodispersible ABC/3TC form and two from the 3TC/AZT form to the orodispersible ABC/3TC form. The 630 lamivudine concentrations were best described by a two-compartment model allometrically scaled. Galenic form had no significant effect on 3TC pharmacokinetic. Conclusion This trial provided an opportunity to compare three galenic forms (liquid formulation, tablet form and dispersible scored tablet) of lamivudine in the target population of young HIV–1-infected children. Galenic form had no significant effect on lamivudine pharmacokinetics.

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External Evaluation of Two Pediatric Population Pharmacokinetics Models of Oral Trimethoprim and Sulfamethoxazole

Cohen‐Wolkowiez

Hornik

et al. 2021

Antimicrob Agents Chemother

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The antibiotic combination trimethoprim (TMP)-sulfamethoxazole (SMX) has a broad spectrum of activity and it is used for the treatment of numerous infections, but pediatric pharmacokinetic (PK) data are limited. We previously published population PK (popPK) models of oral TMP-SMX in pediatric patients based on sparse opportunistically collected data (POPS study, Antimicrob Agents Chemother 62:e01813-17, 2017, https://doi.org/10.1128/AAC.01813-17). We performed a separate PK study of oral TMP-SMX in infants and children with more traditional PK sample collection, and independently developed new popPK models of TMP-SMX using this external dataset. The POPS dataset and the External dataset were each used to evaluate both popPK models. The External TMP model had identical model and error structure as the POPS TMP model with typical values for PK parameters within 20%. The External SMX model did not identify the covariates in the POPS SMX model as significant. The External popPK models predicted higher exposures of TMP (median overprediction of 0.13 mg/L for the POPS dataset and 0.061 mg/L for the External dataset) and SMX (median overprediction of 1.7 mg/L and 0.90 mg/L) than the POPS TMP (median underprediction of 0.016 mg/L and 0.39 mg/L) and SMX (median underprediction of 1.2 mg/L and 14 mg/L) models. Nonetheless, both models supported TMP-SMX dose increases in infants and young children for more resistant pathogens with a minimum inhibitory concentration of 1 mg/L, although the required dose increase based on the External model is lower.

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Suboptimal cotrimoxazole prophylactic concentrations in HIV‐infected children according to the WHO guidelines

Abstract: In this context of high prevalence of opportunistic infections, a lower exposure to cotrimoxazole in children than adults was noted. To achieve comparable exposure to adults, a dosing scheme per kg was proposed.

Cited by 3 publications

References 38 publications

Sulfamethoxazole Levels in HIV-Exposed Uninfected Ugandan Children

Sulfamethoxazole Levels in HIV-Exposed Uninfected Ugandan Children

Comparison of three galenic forms of lamivudine in young West African children living with Human Immunodeficiency Virus

External Evaluation of Two Pediatric Population Pharmacokinetics Models of Oral Trimethoprim and Sulfamethoxazole

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