Suboptimal Cotrimoxazole prophylactic concentrations in HIV-infected children according to the WHO guidelines

Abstract

Aims

A clinical study was conduct in HIV-infected children to evaluate the prophylactic doses of cotrimoxazole (sulfamethoxazole (SMX) and trimethoprim (TMP)) advised by WHO.

Methods

Children received lopinavir-based antiretroviral therapy with cotrimoxazole prophylaxis (200 mg of SMX/ 40 mg of TMP once daily). Nonlinear mixed effects modelling approach was used to analyze plasma concentrations. Factors that could impact the pharmacokinetic profile were investigate. The model was subsequently used to simulate individual exposure and evaluate different administration schemes.

Results

The cohort counted 136 children (average age: 1.9 years (range: [0.7-4]), average weight: 9.5 kg (range: [6-16.3]). A dose per kg was justified by the significant influence of implementing an allometrically scaled body size covariate on SMX and TMP pharmacokinetic. SMX and TPM clearance were estimated at 0.49 L/h/9.5 kg and 3.06 L/h/9.5 kg respectively. The simulated exposures obtained after administration of oral dosing recommended by WHO for children from 10 to 15 kg were significantly lower than in adult for SMX and TMP. This could induce a reduction of effectiveness of cotrimoxazole. Simulations show that regimens of 30 mg/kg of SMX and 6 mg/kg of TMP in the group of 5 to 10 kg and 25 mg/kg of SMX and 5mg/kg of TMP in the group of 10 to 15 are more pertinent doses

Conclusions

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 adult a dosing scheme per kg was proposed.

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