Malaria mutations show new data that may be building a foothold in Africa

The new data provide the first clinical evidence that drug resistance mutations in the Plasmodium falciparum Plasmodium falciparum may have gained a foothold in Africa. The study conducted in Rwanda Lancet infection For the first time, we discovered that mutations were associated with delayed parasite clearance, as first shown in Southeast Asia, where artemisinin resistance began to emerge.

The study also found that mutations were more prevalent than previously reported, suggesting the potential for transmission of mutations and raising concerns about the further geographical spread of resistance.

There are an estimated 229 million malaria outbreaks worldwide, with 409,000 deaths from malaria in 2019, of which 274,000 (67%) were children under the age of five. With 94% of all malaria cases and deaths occurring in Africa, experts have long been concerned about the potential emergence of drug resistance across the African continent.

on the other hand Effectiveness of Current treatments remain high, and the authors are calling for more intensive monitoring in Rwanda and neighboring countries to monitor the spread of mutations and inform public health activities.

Mutations can appear spontaneously, and previous studies have pointed to isolated cases of resistance. However, our new study shows that resistant isolates are beginning to become more common and, most importantly, are associated with clinical effects (delayed parasite clearance). “

Dr. Aline Uwimana, Principal Writer, Rwanda Biomedical Center, Kigali, Rwanda

Co-author Dr. Naomi Lucki, CDC Resident Advisor to the US President’s Malaria Initiative, adds:

Introduced in the early 2000s, artemisinin-based combination therapy (ACT) is currently the most effective and widely used treatment for malaria caused by Plasmodium falciparum. ACT is a combination of an artemisinin component that removes most parasites from the patient’s body within 3 days and a long-acting partner drug that removes the remaining parasites.

Resistance to the artemisinin component of ACT is suspected if the presence of the parasite remains after 3 days of treatment (called delayed parasite removal). This drug resistance is associated with parasites that have a mutation in the Plasmodium falciparum Kerch 13 gene (pfk13).

Currently, 10 mutations in pfk13 have been identified as markers of partial artemisinin resistance (including R561H, P574L, C580Y) and several other mutations (called candidate markers) may be associated with resistance. Has been identified.

Partial artemisinin resistance was first identified in Cambodia in 2008. Currently, the C580Y mutation is well documented in many Southeast Asian countries where it is common. Evidence from the Mekong region shows that widespread artemisinin resistance often leads to continued resistance to partner drugs, leading to failure of ACT treatment.

In 2006, Rwanda introduced artemether-lumefantrine (ACT, and the most widely used antimalarial drug) as a first-line treatment for malaria.

The World Health Organization recommends studies of therapeutic effects at least every two years to monitor the efficacy of ACT and track resistance via molecular markers. If ACT is found to be less than 90% effective, it is recommended to replace it with an effective antimalarial drug.

One such study was conducted in Rwanda from 2013 to 2015 in children aged 1 to 14 years in Rwanda and Masaka. The R561H mutation was observed in 7.4% of Plasmodium falciparum collected in Masaka, and the low prevalence of the P574L mutation was found in isolates collected in Masaka and Rufuha from 2013 to 2015 and in Hue in 2015. It was reported.

However, the presence of these mutations was not found to be associated with delayed parasite clearance, confirming the therapeutic effect of ACT in more than 97% of both sites.

In 2018, another therapeutic effect study was conducted and the results are reported in this new article. The pfk13 R561H and P574L mutations were present in 12.8% (28/218) and 0.9% (2/218) of the pretreated samples, respectively.

This study showed for the first time that the pfk13R561H mutation was associated with delayed parasite clearance, although the efficacy of artemether-lumefantrine remained high. Genetic analysis of the pfk13 R561H mutant has shown their common ancestral and regional origin in Rwanda.

The survey was conducted at three sites in Rwanda (Masaka, Lucara and Bugarama). 224 children aged 6 months to 5 years infected with Plasmodium falciparum were treated with a 3-day course of artemether-lumefantrine, monitored for 28 days, and blood was drawn weekly. According to WHO criteria for partial resistance, 8/51 (15.7%) participants in Masaka and 12/82 (14.6%) participants in Lucara have detectable parasites 3 days after treatment. I did. The therapeutic effect was estimated to be 94-97%.

In a linked comment, Professor Philip Rosenthal of the University of California, San Francisco, USA, who was not involved in the study, said: “Recent data suggest that Africa is at risk of clinically meaningful artemisinin resistance. In Southeast Asia more than a decade ago. Resistance genotypes have emerged and strong drug pressure continues. Therefore, it may be expected that resistance selection will continue.

Loss of artemisinin activity threatens ACT partner drugs. The loss of efficacy of the major ACTs, especially the most widely used antimalarial drug artemether-lumefantrine, was disastrous when chloroquine resistance significantly increased malaria mortality in the second half of the 20th century. It can bring results. Although it is not possible to predict the rate of drug resistance progression in Africa, many are provided by close monitoring of genotype and phenotypic evidence of artemisinin and partner drug resistance and rapid replacement of failed regimens. You can save your life. “