Terlouw, D. J. | bioRxiv Science

bioRxiv2018

Resolving within-host malaria parasite diversity using single-cell sequencing

Malaria patients can carry one or more clonal lineage of the parasite, Plasmodium falciparum, but the composition of these infections cannot be directly inferred from bulk sequence data. Well-defined, complete haplotypes at single-cell resolution are ideal for describing within-host population structure and unambiguously determining parasite diversity, transmission dynamics and recent ancestry but have not been analyzed on a large scale. We generated 485 near-complete single-cell genome sequences isolated from fifteen P. falciparum patients from Chikhwawa, Malawi, an area of intense malaria transmission. Matched single-cell and bulk genomic analyses revealed patients harbored up to seventeen unique lineages. Estimation of parasite relatedness within patients suggests superinfection by repeated mosquito bites is rarer than co-transmission of parasites from a single mosquito. Our single-cell analysis indicates strong barriers to establishment of new infections in malaria-infected patients and allows high resolution dissection of intra-host variation in malaria parasites.

genetics↗

bioRxiv2018

Impact of efavirenz, ritonavir-boosted lopinavir and nevirapine based antiretroviral regimens on the pharmacokinetics of lumefantrine and safety of artemether-lumefantrine in falciparum-negative HIV-infected Malawian adults stabilized on antiretroviral therapy

There is conflicting evidence of the impact of commonly used antiretroviral therapies (ARTs) on the pharmacokinetics of lumefantrine and safety profile of artemether-lumefantrine. We compared the area under the concentration-time curve (AUC0-14 days) of lumefantrine and safety profile of artemether-lumefantrine in malaria-negative human immunodeficiency virus (HIV) infected adults in two steps. In step 1, a half-dose adult course of artemether-lumefantrine was administered as a safety check in four groups (n = 6/group): (i) antiretroviral-naive, (ii) on nevirapine-based ART, (iii) on efavirenz-based ART and (iv) on ritonavir-boosted lopinavir-based ART. In step 2, a standard-dose adult course of artemether-lumefantrine was administered to a different cohort in three groups (n = 10-15/group): (i) antiretroviral-naive, (ii) on efavirenz-based ART and (iii) on ritonavir-boosted lopinavir-based ART. In step 1, lumefantrines AUC0-14 days was 53% [95% CI: 0.27-0.82] lower in the efavirenz-based ART group than the ART-naive group and was 2.4 [95% CI: 1.58-3.62] and 2.9 [95% CI: 1.75-4.72] times higher in the nevirapine and ritonavir-boosted lopinavir groups, respectively. In step 2, lumefantrines AUC0-14 days was 1.9 [95% CI: 1.26-3.00] times higher in the ritonavir-boosted lopinavir group and not significantly different between the efavirenz-and ART-naive groups (0.99 [95% CI: 0.63-1.57]). Frequent cases of haematological abnormalities (thrombocytopenia and neutropenia) were observed in the nevirapine group in step 1, leading to a recommendation from the data and safety monitoring board not to include a nevirapine group in step 2. Artemether-lumefantrine was well tolerated in the other groups. The therapeutic implications of these findings need to be evaluated among HIV-malaria co-infected adults.

pharmacology and toxicology↗