Safety and tolerability of artemether-lumefantrine versus dihydroartemisinin-piperaquine for malaria in young HIV-infected and uninfected children

Katrak, Shereen; Gasasira, Anne; Arinaitwe, Emmanuel; Kakuru, Abel; Wanzira, Humphrey; Bigira, Victor; Sandison, Taylor; Homsy, Jaco; Tappero, Jordan W.; Kamya, Moses R.; Dorsey, Grant

doi:10.1186/1475-2875-8-272

Cited by 26 publications

(21 citation statements)

References 23 publications

(27 reference statements)

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“…Thus, although our in vitro findings support only a moderate role for CYP3A4 in PQ metabolism, we feel that further investigation into whether these findings translate into meaningful in vivo interactions is warranted. We and others have recently demonstrated that several antiretrovirals, notably CYP3A4 inhibiting protease inhibitors, and CYP3A4-inducing non-nucleoside reverse transcriptase inhibitors can have potent effects on CYP3A4-mediated antimalarial metabolism (Slutsker & Marston 2007; German et al 2009; Katrak et al 2009). It will be prudent to investigate whether or not PQ will be subject to similar effects to these and other coadministered medications.…”

Section: Discussionmentioning

confidence: 99%

In vitrometabolism of piperaquine is primarily mediated by CYP3A4

et al. 2012

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Piperaquine (PQ) is part of a first-line treatment regimen for Plasmodium falciparum malaria recommended by the World Health Organization (WHO). We aimed to determine the major metabolic pathway(s) of PQ in vitro. A reliable, validated tandem mass spectrometry method was developed. Concentrations of PQ were measured after incubation with both human liver microsomes (HLMs) and expressed cytochrome P450 enzymes (P450s). In pooled HLMs, incubations with an initial PQ concentration of 0.3 µM resulted in a 34.8 ± 4.9% loss of substrate over 60 min, corresponding to a turnover rate of 0.009 min−1 (r2 = 0.9223). Miconazole, at nonspecific P450 inhibitory concentrations, resulted in almost complete inhibition of PQ metabolism. The greatest inhibition was demonstrated with selective CYP3A4 (100%) and CYP2C8 (66%) inhibitors. Using a mixture of recombinant P450 enzymes, turnover for PQ metabolism was estimated as 0.0099 min−1; recombinant CYP3A4 had a higher metabolic rate (0.017 min−1) than recombinant CYP2C8 (p < .0001). Inhibition of CYP3A4-mediated PQ loss was greatest using the selective inhibitor ketoconazole (9.1 ± 3.5% loss with ketoconazole vs 60.7 ± 5.9% with no inhibitor, p < .0001). In summary, the extent of inhibition of in vitro metabolism with ketoconazole (83%) denotes that PQ appears to be primarily catalyzed by CYP3A4. Further studies to support these findings through the identification and characterization of PQ metabolites are planned.

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Section: Discussionmentioning

confidence: 99%

In vitrometabolism of piperaquine is primarily mediated by CYP3A4

et al. 2012

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“…Details of this cohort have been described elsewhere, and the sub-study described in this report includes only HIV-uninfected children born to HIV-uninfected mothers [20], [84]–[87]. Briefly, children in the TCC were enrolled at infancy (median 5.5 months of age) and followed for all medical problems at a dedicated study clinic open seven days a week.…”

Section: Methodsmentioning

confidence: 99%

IFNγ/IL-10 Co-producing Cells Dominate the CD4 Response to Malaria in Highly Exposed Children

et al. 2014

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Although evidence suggests that T cells are critical for immunity to malaria, reliable T cell correlates of exposure to and protection from malaria among children living in endemic areas are lacking. We used multiparameter flow cytometry to perform a detailed functional characterization of malaria-specific T cells in 78 four-year-old children enrolled in a longitudinal cohort study in Tororo, Uganda, a highly malaria-endemic region. More than 1800 episodes of malaria were observed in this cohort, with no cases of severe malaria. We quantified production of IFNγ, TNFα, and IL-10 (alone or in combination) by malaria-specific T cells, and analyzed the relationship of this response to past and future malaria incidence. CD4+ T cell responses were measurable in nearly all children, with the majority of children having CD4+ T cells producing both IFNγ and IL-10 in response to malaria-infected red blood cells. Frequencies of IFNγ/IL10 co-producing CD4+ T cells, which express the Th1 transcription factor T-bet, were significantly higher in children with ≥2 prior episodes/year compared to children with <2 episodes/year (P<0.001) and inversely correlated with duration since malaria (Rho = −0.39, P<0.001). Notably, frequencies of IFNγ/IL10 co-producing cells were not associated with protection from future malaria after controlling for prior malaria incidence. In contrast, children with <2 prior episodes/year were significantly more likely to exhibit antigen-specific production of TNFα without IL-10 (P = 0.003). While TNFα-producing CD4+ T cells were not independently associated with future protection, the absence of cells producing this inflammatory cytokine was associated with the phenotype of asymptomatic infection. Together these data indicate that the functional phenotype of the malaria-specific T cell response is heavily influenced by malaria exposure intensity, with IFNγ/IL10 co-producing CD4+ T cells dominating this response among highly exposed children. These CD4+ T cells may play important modulatory roles in the development of antimalarial immunity.

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“…Details of this study have been described elsewhere [17-20]. Briefly, convenience sampling was used to enroll children referred to a dedicated study clinic from an adjacent post-natal clinic at Tororo District Hospital.…”

Section: Methodsmentioning

confidence: 99%

Increasing incidence of malaria in children despite insecticide-treated bed nets and prompt anti-malarial therapy in Tororo, Uganda

Jagannathan

Muhindo

Kakuru

et al. 2012

Malar J

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BackgroundThe burden of malaria has decreased in parts of Africa following the scaling up of control interventions. However, similar data are limited from high transmission settings.MethodsA cohort of 100 children, aged six weeks to 10 months of age, were enrolled in an area of high malaria transmission intensity and followed through 48 months of age. Children were given a long-lasting insecticide-treated bed net (LLIN) at enrolment and received all care, including monthly blood smears and treatment with artemisinin-based combination therapy (ACT) for uncomplicated malaria, at a dedicated clinic. The incidence of malaria was estimated by passive surveillance and associations between malaria incidence and age, calendar time and season were measured using generalized estimating equations.ResultsReported compliance with LLINs was 98% based on monthly routine evaluations. A total of 1,633 episodes of malaria were observed, with a median incidence of 5.3 per person-year (PPY). There were only six cases of complicated malaria, all single convulsions. Malaria incidence peaked at 6.5 PPY at 23 months of age before declining to 3.5 PPY at 48 months. After adjusting for age and season, the risk of malaria increased by 52% from 2008 to 2011 (RR 1.52, 95% CI 1.10-2.09). Asymptomatic parasitaemia was uncommon (monthly prevalence <10%) and rarely observed prior to 24 months of age.ConclusionsIn Tororo, despite provision of LLINs and prompt treatment with ACT, the incidence of malaria is very high and appears to be rising. Additional malaria control interventions in high transmission settings are likely needed.Trial registrationCurrent Controlled Trials Identifier NCT00527800

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Safety and tolerability of artemether-lumefantrine versus dihydroartemisinin-piperaquine for malaria in young HIV-infected and uninfected children

Cited by 26 publications

References 23 publications

In vitrometabolism of piperaquine is primarily mediated by CYP3A4

In vitrometabolism of piperaquine is primarily mediated by CYP3A4

IFNγ/IL-10 Co-producing Cells Dominate the CD4 Response to Malaria in Highly Exposed Children

Increasing incidence of malaria in children despite insecticide-treated bed nets and prompt anti-malarial therapy in Tororo, Uganda

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