Drug resistance markers within an evolving efficacy of anti-malarial drugs in Cameroon: a systematic review and meta-analysis (1998-2020)

Abstract

Background: Malaria remains highly endemic in Cameroon. The rapid emergence and spread of drug resistance was responsible for the change from monotherapies to artemisinin-based combinations. This systematic review and meta-analysis aimed to determine the prevalence and distribution of Plasmodium falciparum drug resistance markers within an evolving efficacy of anti-malarial drugs in Cameroon from January 1998 to August 2020.

Methods: The PRISMA-P and PRISMA statements were adopted in the inclusion of studies on single nucleotide polymorphisms (SNPs) of P. falciparum anti-malarial drug resistance genes (Pfcrt, Pfmdr1, Pfdhfr, Pfdhps, Pfatp6, Pfcytb and Pfk13). The heterogeneity of the included studies was evaluated using the Cochran's Q and I² statistics. The random effects model was used as standard in the determination of heterogeneity between studies.

Results: Out of the 902 records screened, 48 studies were included in this aggregated meta-analysis of molecular data. A total of 18,706 SNPs of the anti-malarial drug resistance genes were genotyped from 47,382 samples which yielded a pooled prevalence of 35.4% (95% CI 29.1-42.3%). Between 1998 and 2020, there was significant decline (P < 0.0001 for all) in key mutants including Pfcrt 76 T (79.9%-43.0%), Pfmdr1 86Y (82.7%-30.5%), Pfdhfr 51I (72.2%-66.9%), Pfdhfr 59R (76.5%-67.8%), Pfdhfr 108 N (80.8%-67.6%). The only exception was Pfdhps 437G which increased over time (30.4%-46.9%, P < 0.0001) and Pfdhps 540E that remained largely unchanged (0.0%-0.4%, P = 0.201). Exploring mutant haplotypes, the study observed a significant increase in the prevalence of Pfcrt CVIET mixed quintuple haplotype from 57.1% in 1998 to 57.9% in 2020 (P < 0.0001). In addition, within the same study period, there was no significant change in the triple Pfdhfr IRN mutant haplotype (66.2% to 67.3%, P = 0.427). The Pfk13 amino acid polymorphisms associated with artemisinin resistance were not detected.

Conclusions: This review reported an overall decline in the prevalence of P. falciparum gene mutations conferring resistance to 4-aminoquinolines and amino alcohols for a period over two decades. Resistance to artemisinins measured by the presence of SNPs in the Pfk13 gene does not seem to be a problem in Cameroon. Systematic review registration PROSPERO CRD42020162620.

Keywords: Anti-malarial drug; Cameroon; Efficacy; Malaria; Mutations; Plasmodium falciparum; Resistance; Systematic review.

Fig. 1

Flow chart for studies included in the systematic review and meta-analysis on anti-malarial drug resistance markers in Cameroon from 1998–2020

Fig. 2

Pooled prevalence of Plasmodium falciparum anti-malarial drug resistance mutations from 1998–2020

Fig. 3

a Subgroup analysis for pooled prevalence of Pfcrt K76T mutation from 1998 to 2020. b Subgroup analysis for pooled prevalence of Pfcrt CVIET haplotype mutations from 1998–2020. c Subgroup analysis for pooled prevalence of Pfmdr1 N86Y haplotype mutations from 1998 to 2020. d Subgroup analysis for pooled prevalence of Pfdhfr IRN haplotype mutations from 1998 to 2020. e Subgroup analysis for pooled prevalence of Pfdhfr-Pfdhps IRNG haplotype mutations from 1998 to 2020. f Subgroup analysis for pooled prevalence of Pfk13 mutations from 1998 to 2020

Fig. 3

a Subgroup analysis for pooled prevalence of Pfcrt K76T mutation from 1998 to 2020. b Subgroup analysis for pooled prevalence of Pfcrt CVIET haplotype mutations from 1998–2020. c Subgroup analysis for pooled prevalence of Pfmdr1 N86Y haplotype mutations from 1998 to 2020. d Subgroup analysis for pooled prevalence of Pfdhfr IRN haplotype mutations from 1998 to 2020. e Subgroup analysis for pooled prevalence of Pfdhfr-Pfdhps IRNG haplotype mutations from 1998 to 2020. f Subgroup analysis for pooled prevalence of Pfk13 mutations from 1998 to 2020

Fig. 4

Pfdhfr and Pfdhps haplotype distribution in three major towns of Cameroon. Efficacy of ACTs (AL and ASAQ) and prevalence of Pfcrt 76 T and Pfmdr1 86Y mutants over time

Fig. 5

Efficacy of AL/ASAQ and prevalence of Pfcrt 76 T and Pfmdr1 86Y mutant alleles from 2008 to 2019. AL, Artemether–lumefantrine, ASAQ, Artesunate-amodiaquine, Pfcrt, Plasmodium falciparum chloroquine resistance transporter gene, Pfmdr1, Plasmodium falciparum multidrug resistance 1 gene

Fig. 6

a Proportion of ASAQ and AL deployed in Cameroon versus prevalence of Pfcrt 76 T and Pfmdr1 86Y mutants from 2006 to 2017. ASAQ: Artesunate-amodiaquine, AL, Artemether–lumefantrine; Pfcrt, Plasmodium falciparum chloroquine resistance transporter gene; Pfmdr1, Plasmodium falciparum, multidrug resistance 1 gene. b Proportion of SP deployed in Cameroon versus prevalence of Pfdhfr IRN mutant haplotype from 2006 to 2017. SP, Sulfadoxine–pyrimethamine, Pfcrt, Plasmodium falciparum chloroquine resistance transporter gene, Pfmdr1, Plasmodium falciparum multidrug resistance 1 gene