New data provide the first clinical evidence that drug-resistant mutations in the malaria parasite Plasmodium falciparum could gain a foothold in Africa. The study carried out in Rwanda is published in The Lancet Infectious Diseases Journal and notes for the first time that the mutations are associated with delayed parasite clearance, as was first shown in Southeast Asia when artemisinin resistance emerged.
The study also notes that the mutations are more common than reported in previous studies, suggesting a likely transmission of the mutations and raising concerns about further geographic spread of resistance.
There are an estimated 229 million cases of malaria worldwide and there were 409,000 deaths from malaria in 2019 – of which 274,000 (67%) were in children under the age of 5. 94% of all malaria cases and deaths occur in Africa, and experts have long been concerned about the possible emergence of drug resistance across the continent.
While the effectiveness of current therapies remains high, the authors call for more intensive surveillance in Rwanda and neighboring countries to monitor the spread of mutations and inform public health measures.
Mutations can occur spontaneously and previous studies have indicated isolated cases of resistance. However, our new study shows that resistant isolates are becoming more common and, above all, associated with clinical effects (delayed parasite clearance). “
Dr. Aline Uwimana, Study Director, Rwanda Biomedical Center, Kigali, Rwanda
The co-author Dr. Naomi Lucchi, CDC Resident Advisor for the US President’s Malaria Initiative, added: “Our study showed that the treatment of malaria in Rwanda is still 94% effective, but new studies and ongoing monitoring are urgently needed. “
Artemisinin-based combination therapies (ACTs), introduced in the early 2000s, are currently the most effective and widely used treatments for malaria caused by Plasmodium falciparum. ACTs combine an artemisinin component, which removes most parasites from the patient’s body within three days, and a long-acting partner drug, which eliminates the remaining parasites.
Resistance to the artemisinin component of ACT is suspected if the presence of the parasite persists after the third day of treatment (known as delayed parasite clearance). This drug resistance is associated with parasites that carry mutations in the Plasmodium falciparum cup 13 gene (pfk13).
To date, ten mutations in pfk13 have been confirmed as markers of partial artemisinin resistance (including R561H, P574L, and C580Y), and several other mutations (called candidate markers) have been identified as potentially associated with resistance.
Partial artemisinin resistance was first detected in Cambodia in 2008. It is now well documented in many Southeast Asian countries where the C580Y mutation is common. Evidence from the Mekong region has shown that after the onset of artemisinin resistance, resistance to the partner drug often occurs, which leads to failure of ACT treatment.
In 2006, Rwanda introduced artemether-lumefantrine (an ACT and the most widely used antimalarial drug) as the first-line treatment for malaria.
The World Health Organization recommends therapeutic efficacy studies at least every two years to monitor the effectiveness of ACTs and track resistance through molecular markers. If ACT effectiveness is confirmed to be less than 90%, replacement with an effective antimalarial drug is recommended.
One such study was carried out in Rwanda in children aged 1 to 14 years in Ruhuha and Masaka from 2013 to 2015. The R561H mutation was seen in 7.4% of P. falciparum parasites collected in Masaka, and a low prevalence of the P574L mutation was reported in isolates collected in Masaka and Ruhuha in 2013-2015 and in Huye in 2015.
However, the presence of these mutations was not found to be associated with delayed parasite clearance, and the therapeutic efficacy of ACT has been confirmed at over 97% in both sites.
Another therapeutic efficacy study was conducted in 2018, the results of which 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 pretreatment samples, respectively.
For the first time, this study shows that the pfk13 R561H mutation was associated with delayed parasite clearance, although the efficacy of artemether-lumefantrine remained high. Genetic analysis of pfk13 R561H mutants revealed their common ancestry and local ancestry in Rwanda.
The study was carried out at three locations in Rwanda (Masaka, Rukara and Bugarama). 224 children between 6 months and 5 years of age with P. falciparum infection were treated with artemether-lumefantrine for 3 days and monitored with weekly blood samples for 28 days. 8/51 (15.7%) participants in Masaka and 12/82 (14.6%) in Rukara had detectable parasites according to WHO criteria for partial resistance three days after treatment. The therapeutic effectiveness was estimated to be 94-97%.
Professor Philip Rosenthal of the University of California at San Francisco, USA (who was not involved in the study) writes in a linked comment: “Recent data suggests that in Africa we are on the verge of clinically meaningful artemisinin resistance in Southeast Asia over a decade ago, and given the emergence of resistant genotypes and persistent heavy drug pressure, we can expect a wider range of resistances.
Loss of artemisinin activity will, in turn, threaten ACT partner drugs. The loss of the effectiveness of key ACTs, particularly artemether-lumefantrine, the most widely used anti-malarial drug, can have dire consequences, such as occurred when chloroquine resistance led to a huge increase in malaria deaths in the late 20th century. While it is impossible to predict the pace of drug resistance progression in Africa, close monitoring for genotypic and phenotypic evidence of artemisinin and partner drug resistance with prompt replacement of failed therapies can save many lives. “
Uwimana, A., et al. (2021) Association of Plasmodium falciparum kelch13 Delayed Parasite Clearance R561H Genotypes in Rwanda: An Open-label, Single-Arm, Multi-Center, Therapeutic Efficacy Study. The Lancet Infectious Diseases. doi.org/10.1016/S1473-3099(21)00142-0.