African animal trypanocide resistance: A systematic review and meta-analysis

Abstract

Background: African animal trypanocide resistance (AATr) continues to undermine global efforts to eliminate the transmission of African trypanosomiasis in endemic communities. The continued lack of new trypanocides has precipitated drug misuse and overuse, thus contributing to the development of the AATr phenotype. In this study, we investigated the threat associated with AATr by using the major globally available chemotherapeutical agents.

Methods: A total of seven electronic databases were screened for an article on trypanocide resistance in AATr by using keywords on preclinical and clinical trials with the number of animals with treatment relapse, days taken to relapse, and resistant gene markers using the PRISMA checklist. Data were cleaned using the SR deduplicator and covidence and analyzed using Cochrane RevMan®. Dichotomous outputs were presented using risk ratio (RR), while continuous data were presented using the standardized mean difference (SMD) at a 95% confidence interval.

Results: A total of eight publications in which diminazene aceturate (DA), isometamidium chloride (ISM), and homidium chloride/bromide (HB) were identified as the major trypanocides were used. In all preclinical studies, the development of resistance was in the order of HB > ISM > DA. DA vs. ISM (SMD = 0.15, 95% CI: -0.54, 0.83; I ² = 46%, P = 0.05), DA vs. HB (SMD = 0.96, 95% CI: 0.47, 1.45; I ² = 0%, P = 0.86), and HB vs. ISM (SMD = -0.41, 95% CI: -0.96, 0.14; I ² = 5%, P = 0.38) showed multiple cross-resistance. Clinical studies also showed evidence of multi-drug resistance on DA and ISM (RR = 1.01, 95% CI: 0.71-1.43; I ² = 46%, P = 0.16). To address resistance, most preclinical studies increased the dosage and the treatment time, and this failed to improve the patient's prognosis. Major markers of resistance explored include TbAT1, P1/P2 transporters, folate transporters, such as F-I, F-II, F-III, and polyamine biosynthesis inhibitors. In addition, immunosuppressed hosts favor the development of AATr.

Conclusion: AATr is a threat that requires a shift in the current disease control strategies in most developing nations due to inter-species transmission. Multi-drug cross-resistance against the only accessible trypanocides is a major public health risk, justifying the need to revise the policy in developing countries to promote control of African trypanosomiasis.

Keywords: African animal trypanosomiasis; T. congolense; T. evansi; T. vivax; Trypanosoma brucei brucei; bovine trypanosomiasis; drug resistance; trypanocide resistance.

Figure 1

PRISMA checklist showing searched databases, registries, google search directories, and publications included in the study.

Figure 2

AATr, African animal trypanocide resistance. (A) This provides the global perspective showing that emphasis on AATr is in Africa and Europe. (B) Field surveys are only taking place in Africa globally demonstrating why AATr continues to be a neglected tropical disease. Biomedical experiments have generally been spearheaded by collaborative institutions in Europe while Africa continues to lag in this field due to the low number of active experimental studies on the African continent on AATr (A). This has subsequently translated to a continued lack of commitment by local African institutions to routinely conduct surveillance activities to monitor the development of drug resistance in their countries (B). It is important to note that West and East African countries are more prepared on AATr than their African neighbors in Central and Southern Africa, which all lie within the endemic regions of the continent.

Figure 3

Mean relapse time in preclinical trials with diminazene aceturate and isometamidium chloride.

Figure 4

Mean relapse time in preclinical trials with diminazene aceturate and homidium bromide.

Figure 5

Mean relapse time in preclinical trials with homidium bromide and isometamidium chloride.

Figure 6

Clinical studies on African trypanocide resistance showing the number of animals that relapsed after 14 days.

Figure 7

Trypanocide activity is favored by a healthy phenotype (A). (1) Gene expression leading to production of TbAT1/P2. Trypanocides (2) move into the cell to exert their effects leading to cell death (3). Resistant phenotype (B). This arises following DNA damage (4), transcription errors, and subsequent loss of P1/P2 transporters. This subsequently disrupts trypanocide absorption into the parasite, leading to the establishment of a resistant phenotype (5).