Stagnation in Malaria Elimination Efforts: The Rise of Drug Resistance and Diagnostic Challenges in Africa

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The battle against malaria, particularly Plasmodium falciparum, has reached a critical juncture. Despite intensified control efforts, recent years have witnessed a stagnation in progress towards malaria elimination. This is especially acute in Africa, which bears the brunt of this scourge, accounting for approximately 90% of global cases and deaths.

The World Health Organization (WHO) currently endorses artemisinin-combination therapies (ACTs), such as artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ), as first-line treatments for uncomplicated P. falciparum malaria. However, the landscape is rapidly changing due to the emergence and spread of drug-resistant strains of the malaria parasite.

This situation is further exacerbated by the spread of drug-resistant P. falciparum parasites. Initially identified in Southeast Asia around 2008, these strains have been observed to spread to neighboring regions. In Africa, where the bulk of malaria cases occur, there is growing concern over the reduced efficacy of artemisinin, evidenced by slower clearance times and increased cases of recrudescence. Genetic mutations, particularly in the kelch13 (K13) gene, have been linked to partial resistance to artemisinins, with such mutations identified in countries including Uganda, Tanzania, and Rwanda.

Compounding the challenge is the emergence of parasites that are undetectable by widely used rapid diagnostic tests (RDTs). This is due to deletion mutations in the histidine-rich proteins 2 and 3 (pfhrp2/3) genes, primarily reported in the Horn of Africa. In Ethiopia, where RDTs have been a mainstay in malaria diagnosis since 2004, these mutations present a significant obstacle, potentially rendering parasites resistant to both diagnosis and treatment.

Ethiopia, a country with a low overall incidence of malaria yet endemic in 75% of its territory, is a case study in these emerging challenges. The country has set an ambitious goal to eliminate malaria by 2030. Artemether-lumefantrine (AL) has been the first-line treatment here since 2004, and while it remains highly effective, the detection of potential artemisinin resistance mutations and high prevalence of residual submicroscopic parasitemia post-treatment are concerning signs. These issues are compounded by challenges in monitoring ACT usage and effectiveness, often hindered by empirical treatment practices and inconsistent adherence to treatment regimens.

In an effort to better understand these dynamics, a comparative genomic analysis was undertaken, focusing on drug resistance in pfhrp2/3-deleted and non-deleted parasites across Ethiopia. Using molecular inversion probe (MIP) sequencing, a method that allows for highly multiplexed targeted genotyping, researchers aimed to assess the prevalence of key drug-resistance mutations and their potential co-occurrence with pfhrp2/3 deletions.

The findings of this research are yet to be published, but they hold the promise of shedding light on the complex interplay between drug resistance and diagnostic challenges in the fight against malaria. This knowledge is critical for devising effective strategies to overcome the current stagnation in malaria elimination efforts, particularly in regions where the burden of the disease is heaviest. As the world grapples with these challenges, the lessons learned from Ethiopia and other affected regions will be crucial in informing global health strategies and interventions in the ongoing battle against malaria.

Discussion

The Dual Threat of Drug and Diagnostic Resistance in Malaria: Insights from Ethiopia

Recent genetic analyses have highlighted a significant concern in the fight against malaria, particularly in Ethiopia. The World Health Organization (WHO)-identified candidate artemisinin partial-resistance mutation, kelch 622I, is found to be prevalent in three Ethiopian regions, indicating a recent clonal spread. This finding aligns with earlier studies suggesting low polyclonality and moderate malaria transmission intensity in these areas. The primary concern here is the potential rapid expansion of artemisinin- and diagnostic-resistant parasites, driven by intensive test-and-treat strategies implemented in Ethiopia.

The widespread use of artemisinin-based combination therapies (ACTs) in Ethiopia for nearly two decades, along with other antimalarials such as primaquine and quinine, has placed significant selective pressure on P. falciparum populations. This pressure is believed to be a driving factor in the emergence of antimalarial drug resistance. The presence of the K13 622I mutation across all sampled districts in Ethiopia is a testament to this pressure and the ongoing evolution of the parasite to resist treatment. Studies have shown an increase in the prevalence of this mutation over time, raising alarms about its potential impact on malaria elimination efforts in the Horn of Africa.

A particularly troubling aspect of this mutation’s spread is its apparent origin and rapid expansion within the northern Ethiopian region or potentially from neighboring Eritrea. The lower frequency of 622I versus wild-type parasites in polyclonal infections suggests a decreased fitness within human hosts, a characteristic often associated with artemisinin partial-resistance mutations.

Another significant concern is the coexistence of parasites carrying both the K13 622I and pfhrp2/3-deletion mutations. While rare, the presence of these mutations in a single parasite could signify a dual threat, as these strains would be partially resistant to treatment and potentially undetectable by HRP2-based rapid diagnostic tests (RDTs). The spread of such parasites is particularly alarming in low transmission settings, where there is less inter-strain competition and fewer barriers to the expansion of resistant strains.

Ethiopia’s transition to alternative RDTs might reduce the selective pressures favoring pfhrp2/3-deleted strains. However, the presence of these deletions in regions where RDTs are less prevalent suggests that other factors may also contribute to their emergence. This situation underscores the need for ongoing surveillance and adaptation of malaria control strategies.

The study also reveals a high prevalence of mutations associated with resistance to other antimalarials, indicating the necessity for continuous monitoring of the efficacy of lumefantrine and other partner drugs. The observation of higher prevalence of the 622I mutation among pfhrp2/3 non-deleted compared to double-deleted parasites suggests a complex interaction between drug resistance and diagnostic failures.

The limitations of the study, including potential selection bias and the focus on regions with relatively higher transmission, suggest the need for broader research across Ethiopia and neighboring countries. This research would help to better understand the full extent of drug- and diagnostic-resistance mutations.

As Ethiopia and other African countries move closer to malaria elimination, the dual challenge of diagnostic and drug resistance becomes more pronounced. The integration of genomic surveillance with large-scale epidemiologic surveys is expected to become the norm, providing crucial insights into emerging drug resistance patterns. This comprehensive approach will be vital in shaping effective control and elimination strategies in the face of evolving challenges in the battle against malaria.


reference link : https://www.nature.com/articles/s41564-023-01461-4

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