Changing Antimalarial Drug Sensitivities in Uganda

Abstract

Dihydroartemisinin-piperaquine (DP) has demonstrated excellent efficacy for the treatment and prevention of malaria in Uganda. However, resistance to both components of this regimen has emerged in Southeast Asia. The efficacy of artemether-lumefantrine, the first-line regimen to treat malaria in Uganda, has also been excellent, but continued pressure may select for parasites with decreased sensitivity to lumefantrine. To gain insight into current drug sensitivity patterns, ex vivo sensitivities were assessed and genotypes previously associated with altered drug sensitivity were characterized for 58 isolates collected in Tororo, Uganda, from subjects presenting in 2016 with malaria from the community or as part of a clinical trial comparing DP chemoprevention regimens. Compared to community isolates, those from trial subjects had lower sensitivities to the aminoquinolines chloroquine, monodesethyl amodiaquine, and piperaquine and greater sensitivities to lumefantrine and mefloquine, an observation consistent with DP selection pressure. Compared to results for isolates from 2010 to 2013, the sensitivities of 2016 community isolates to chloroquine, amodiaquine, and piperaquine improved (geometric mean 50% inhibitory concentrations [IC 50 ] ϭ 248, 76.9, and 19.1 nM in 2010 to 2013 and 33.4, 14.9, and 7.5 nM in 2016, respectively [P Ͻ 0.001 for all comparisons]), the sensitivity to lumefantrine decreased (IC 50 ϭ 3.0 nM in 2010 to 2013 and 5.4 nM in 2016 [P Ͻ 0.001]), and the sensitivity to dihydroartemisinin was unchanged (IC 50 ϭ 1.4 nM). These changes were accompanied by decreased prevalence of transporter mutations associated with aminoquinoline resistance and low prevalence of polymorphisms recently associated with resistance to artemisinins or piperaquine. Antimalarial drug sensitivities are changing in Uganda, but novel genotypes associated with DP treatment failure in Asia are not prevalent.

Recovery and stable persistence of chloroquine sensitivity in Plasmodium falciparum parasites after its discontinued use in Northern Uganda

“…Taken together, these results strongly suggest that neither back mutation nor additional mutations in pfcrt was associated with the observed recovery of chloroquine sensitivity in the study area. It is of note that recovery of chloroquine sensitivity after its withdrawal occurred much earlier in Gulu than in other regions in Uganda [9,[22][23][24]41]. In 2013, as much as 65% of parasites displayed ex vivo chloroquine resistance [24] and 60-80% carried K76T allele in Tororo, Eastern Uganda [42].…”

“…However, with widespread discontinued use, numerous molecular-epidemiological studies showed that there was return of chloroquine susceptibility in P. falciparum field isolates [4]. This is supported by ex vivo [5][6][7][8][9][10][11][12][13][14][15][16] and in vivo drug-susceptibility studies [5,17,18]. Findings suggest that chloroquine might be re-used in the future as an option for the treatment and/or chemoprophylaxis on the condition that chloroquine sensitivity is maintained in the area.…”

High proportion of multiple copies of Plasmodium falciparum Plasmepsin-2 gene in African isolates: Is piperaquine resistance emerging in Africa?

“…Unexpectedly, in African isolates, amplification of Pfpm2 gene was shown to occur at a much higher frequency (~27% on average across clinical sites in Africa, reaching 30.5% in Burkina Faso and 33.9% in Uganda) than was recently described (from 11.1% to 13.8% in Uganda and 1.1% in Mozambique) (27, 41). Considering the geographical extent and the diversity of the clinical sites in Africa, the high frequency reported at sites distant to each other suggests that amplification of Pfpm2 gene occurred independently in each site.…”

“…An evaluation is currently ongoing to see whether, and if so to what extent, these markers of artemisinin and PPQ resistance affected the parasite clearance half-life (PCT1/2) and PCR-adjusted 28 days follow up in patients treated with artefenomel/PPQ (study MMV OZ439 13 003). However, it was recently reported that compared to drug sensitivities measured on Ugandan isolates from 2010 to 2013 (from the same site, namely Tororo), those measured in 2016 to chloroquine, amodiaquine, and PPQ were increased by 7.4, 5.2 and 2.5-fold respectively (41). This longitudinal study showed that rather than drug resistance developing to these three antimalarial drugs, an increase in sensitivity was observed that was correlated with low prevalence of the polymorphisms recently associated with resistance to artemisinins or PPQ.…”

“…Although, we cannot exclude the possibility that parasites showing amplification of Pfpm2 observed in the current study are resistant to PPQ without confirmation of in vitro or ex vivo phenotypes, data reported by Rasmussen et al . (41) suggest that significant occurrence of clinical resistance to PPQ is unlikely. In other words, in Africa it is unclear whether the amplification of Pfpm2 is necessary and/or sufficient for the development of resistance to PPQ.…”