UC Berkeley

Malaria and malnutrition are major causes of morbidity and mortality in children worldwide. Malnourished children may be at higher risk of malaria due to impaired immune response. Malnutrition and young age may alter the pharmacokinetics (PK) of antimalarial treatment thus potentially impacting treatment efficacy. Though malaria and malnutrition frequently coexist, results from previous studies that have investigated the association between these two co-morbidities are conflicting. No previous studies have evaluated the effect of malnutrition on response to treatment with artemisinin-based combination therapies (ACTs). Moreover, there are no other studies that have evaluated the effect of malnutrition on the PK of ACT regimens. This dissertation examines the following: 1) the magnitude of the difference between efficacy estimates derived from 3 analytical methods and discusses the optimal statistical approach for monitoring in vivo efficacy (chapter 2); 2) the effect of nutritional status on the response to treatment with artemisinin-combination therapy (ACT) in young Ugandan children with malaria (Chapter 3); and 3) the effect of nutritional status on the pharmacokinetics (PK) of two ACT treatment regimens (chapter 4).

Chapter 2 utilizes data from 29 clinical trials conducted in Africa and Thailand to compare the risk estimates of treatment failure, adjusted and unadjusted by genotyping, derived by 3 analytical methods; intention to treat (ITT), modified intention to treat (mITT) and per protocol (PP) analysis. Estimates of treatment failure were consistently higher when derived from the ITT or PP analyses compared to the mITT approach in both unadjusted and adjusted analyses. Poor patient adherence to follow-up, higher incidence of P. vivax relapse and high incidence of P. falciparum new infections were all factors contributing to differences in failure estimates. Because estimates of antimalarial clinical efficacy vary significantly depending on the analytical methodology from which they are derived, standardized analytical tools should be used to monitor temporal and spatial trends in antimalarial efficacy. Survival analysis is the preferred approach to monitor in vivo efficacy of malaria treatment.

Chapter 3 and 4 utilize data from the Tororo Child Cohort (TCC) Study conducted in Tororo, Uganda. In chapter 3, children aged 4 to 12 months diagnosed with uncomplicated malaria were randomized to either dihydroartemisinin-piperaquine (DP) or artemether-lumefantrine (AL) and followed for up to 2 years for repeated episodes of malaria. The primary exposure variables of interest were height-for-age (HAZ score) and weight-for-age (WAZ score) z-scores and outcomes included parasite clearance at day 2 and 3 and risk of recurrent parasitemia after 42 days of follow-up. HAZ and WAZ scores were not associated with a positive blood smear two days following treatment with DP or AL. In children treated with DP not on trimethoprim-sulfamethoxazole (TS) prophylaxis, a decreasing HAZ score was independently associated with a higher risk of recurrent parasitemia. However, statistical significance was reached only when comparing HAZ scores <-1 with those > 0 (HAZ ¡Ý -2 - <-1: HR=2.89, p=0.039; HAZ <-2: HR=3.18, p=0.022). Overall, DP and AL are effective antimalarial therapies in chronically malnourished children in a high transmission setting however, children taking DP with signs of mild to moderate chronic malnutrition not taking TS prophylaxis are at higher risk of recurrent parasitemia.

In chapter 4, PK samples were collected from a subset of patients ages 6 months to 2 years who were randomized to DP or AL and followed prospectively for multiple episodes of malaria providing a total of 214 treatments for DP and 243 treatments for AL for PK analysis. Primary exposure variables included stunting and underweight, (HAZ score of <-2 and WAZ score of <-2, respectively). Chronic malnutrition appeared to be associated with day 3 piperaquine concentrations in adjusted analyses with stunted children having lower concentrations than non-stunted children (OR=0.78, p=0.007). Stunting was associated with apparent clearance (CL/fpip) (OR=1.32, p=0.001) with stunted children having higher CL/fpip than non-stunted children which may be the consequence of a lower overall exposure to drug and is consistent with the lower piperaquine concentrations measured on day 3. Chronic malnutrition does not have an effect of piperaquine or lumefantrine concentrations at day 7 ¨C an important determinant for treatment response.

Overall, our results indicate that DP and AL are effective antimalarial treatments in very young chronically malnourished children. This is supported by the finding that chronic malnutrition does not have an effect on of piperaquine or lumefantrine day 7 concentrations, an indicator for treatment response. However, children taking DP not on TS prophylaxis may be at higher risk of recurrent parasitemia. Further studies should be conducted to justify these results and provide a definitive understanding of the causal relationship between malnutrition and malaria.