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Nevirapine Concentrations in HIV-infected Ugandan Children on Adult Fixed-dose Combination Tablet ART, with and without Rifampicin-based Treatment for Active M. tuberculosis Infection
Linda Barlow-Mosha*1, P Musoke1,2, T Parsons3, P Ajuna1, M Lutajjumwa1, B Musoke1, D Bagenda1, M Mubiru1, M Mirochnick4, and MUJHU Intl Leadership Award (EGPAF) Team
1Makerere Univ-Johns Hopkins Univ Res Collaboration, Kampala, Uganda; 2Makerere Univ Mulago, Kampala, Uganda; 3Johns Hopkins Univ, Baltimore, MD, US; and 4Boston Univ Sch of Med, MA, US
Background: HIV-infected children have increasing
access to ART. In some resource-limited settings, adult fixed-dose combination
antiretroviral tablets are used to treat children, instead of costly syrup
formulations. An analysis was conducted to assess nevirapine (NVP) plasma
concentrations in HIV infected children dosed with adult fixed-dose combination,
Triomune 30/40.
Methods: HIV-infected children were initiated on
Triomune (stavudine [d4T]/lamivudine [3TC]/NVP) for ART. Plasma samples for NVP
assay were obtained from 20 children before the first dose and then at the end
of a dosing interval (trough) weekly for the first 4 weeks. Median time from
last NVP dose, median NVP concentration, and the relationship between per kg
NVP dose and age were calculated. In addition, possible confounding variables
including, age per kg dose, length of time between NVP administration and
sample collection, concomitant anti-tuberculosis therapy were analyzed.
Results: Median age at the first visit was 5.0 years
(range 1.2 to 11.3 years) with median weight 15.7 kg (range 9.3 to 38.3 kg). Median
per kg NVP dose administered was 5.3 mg/kg (range 4.0 to 7.8 mg/kg). Median
time from last NVP dose to sample collection was 12.8 hours (range 11.3 to 17.8
hours). NVP concentration was undetectable in all of the pre-dose samples
except 1, which was a child on NVP therapy using a different formulation at the
time of study entry. One sample was inadequate for assay, so excluding the
pre-dose samples there were 79 samples available for analysis from the 4 study
visits when the children were on study drug. The median trough NVP concentration
was 3555.9 ng/mL (range 833.8 to 15975.6 ng/mL; the standard NVP target used in
therapeutic drug monitoring studies and programs is a trough concentration of
3000 ng/mL. This target was exceeded by 51 of 79 (65%) of the samples assayed. Of
the 20 children, 7 were receiving concomitant anti-TB therapy including
rifampicin. Median NVP concentration was 4204 ng/mL (range 834 to 15976 ng/mL)
in the children not receiving anti-TB therapy compared to 2920 ng/mL (range
1668 to 9978 ng/mL) in those receiving anti-TB therapy.
Conclusions: HIV-infected children can achieve
target level of NVP when dosed with adult fixed-dose combination tablets. As
expected, concomitant use of anti-TB therapy and NVP-containing fixed-dose
combination tablets may lead to under-dosing of NVP, with only 43% of the
children on anti-TB therapy achieving adequate NVP trough levels.
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