Efficacy and Tolerability of Antimalarials and Molecular Resistance Markers of Falciparum Malaria in Jimma Region, Ethiopia

Due to increasing drug resistance, artemisinin-based combination
chemotherapy (ACT) has become the first-line treatment of
falciparum malaria in many endemic countries. Ethiopia has also
adopted artemether/lumefantrine (AL) as first-line treatment in
2004 and its broad introduction was achieved in 2006. However,
irreversible ototoxicity associated with AL has been reported and
suggested to be a serious limitation in the use of ACT. The aim of
this study was to compare ototoxicity, tolerability, and efficacy
of ACT with that of quinine and atovaquone/proguanil in the
treatment of uncomplicated falciparum malaria. 97 patients in Jimma
area, Ethiopia with slide-confirmed malaria were randomly assigned
to receive either artemether/lumefantrine or quinine or
atovaquone/proguanil and followed-up on days 7, 28, and 90.
Comprehensive audio-vestibular testing by pure tone audiometry
(PTA), transitory evoked (TE) and distortion product (DP)
otoacoustic emissions (OAE) and brain stem evoked response
audiometry (BERA) was done before enrolment and on follow-up days.
PTA and DP-OAE levels revealed transient significant cochlear
hearing loss in patients treated with quinine but not in those
treated with artemether/lumefantrine or atovaquone/proguanil. There
was no evidence of drug-induced brain stem lesions by BERA
measurements. Hence, there was no detrimental effect of a standard
oral regimen of artemether/lumefantrine on peripheral hearing or
brainstem auditory pathways in patients with uncomplicated
falciparum malaria. In contrast, transient hearing loss was
evidenced with quinine therapy due to temporary outer hair cell
dysfunction. Reinfection and recrudescence were determined by RFLP
of msp-1 and msp-2 genes. Mutations associated with drug resistance
were characterized in Pfmdr1, Pfdhfr, Pfcytb, and Pfserca genes.
Single nucleotide polymorphisms (SNPs) previously reported to be
associated with resistance to the study drugs were identified in
both recrudescent and treatment sensitive isolates. A total of
seven recrudescences were obtained. The Pfmdr1 N86Y mutation was
found in 84.5% of isolates. The triple mutation 51I, 59R, 108N of
the Pfdhfr gene occurred in high frequency (83.3%) but no Pfcytb
mutation was detected. Sequencing showed a variety of previously
described and new mutations in the Pfserca gene. The prevalence of
high degree of mutations in Pfmdr1 and Pfdhfr is a reminiscent of
the impact of previously used drugs in the area, chloroquine and
sulfadoxine/pyrimethamine as first-line treatments. The broad
introduction of AL and the cessation of the former drug regimens
might probably change the current distribution of polymorphisms,
possibly leading to decreased sensitivity to AL in the future.
Continuous surveillance of molecular patterns in this region is,
therefore, recommended.