Africa’s race against time to stop malaria drug resistance

Deep in the lush, green rolling hills of Rwanda’s Bugesera district, Esther Urimubenshi reflects often on how her life has improved. Until recently, the 50-year-old farmer would watch stormy clouds gathering to mark the start of the rainy season with unease, knowing it would herald the deadly threat of malaria. In fact, back in 2016, Esther fell ill with malaria three times in just two months.

“The fever, chills and weakness left me bedridden and unable to care of my family or tend to my crops. It was a dark time,” she told the World Health Organization (WHO).

But Rwanda’s dedicated efforts to combat the disease through prevention, early diagnosis and treatment and surveillance, have meant that she hasn’t contracted malaria in years.

As soon as 2030, however, there is a chance that Esther’s fortunes could be reversed. The parasites that cause malaria are becoming resistant to drugs, and that resistance is now racing across the continent.

Experts predict that, if left unchecked, as many as 30% of malaria infections in countries like Rwanda, Uganda and Kenya could be untreatable by the end of this decade.   

Since Africa is home to 95% of the world’s malaria cases and deaths, this would be catastrophic. While an arsenal of tools to fight malaria, including bed-nets, insecticide-spraying and antimalarials are available, access is still a challenge for many in the highest-burden countries, as is the medical care needed when they are infected.

Malaria-carrying mosquitoes are increasingly able to reproduce faster at the exact time that methods to control them are becoming less effective.

Waging endless war

Malaria has always been a powerful foe, and humanity’s fight against it has been a long-running battle with victories on both sides.

Significant progress was made at the start of the 21st Century, with malaria deaths halving from 839,000 in 2000 to 438,000 in 2015. However the number of people succumbing to the disease since then has steadily risen. In 2022, over 600,000 people died from the disease, according to WHO.

For years, mosquito control was possible by deploying insecticides that were either sprayed where the Plasmodium falciparum mosquitoes clustered or infused into bed-nets. However, mosquitoes are developing widespread resistance to the insecticides, making it urgent to find new ways to control them.

This is increasingly challenging, given that climate change is fuelling the spread of malaria-carrying mosquitoes by making parts of the world hotter and wetter – the perfect breeding conditions for these insects. Malaria-carrying mosquitoes are increasingly able to reproduce faster at the exact time that methods to control them are becoming less effective.

And then there is the immense threat of drug resistance.

For decades, every time a winning drug was rolled out – chloroquine, sulfadoxine, pyrimethamine – the malaria parasite evolved to evade it. Just as the use of antibiotics applies an evolutionary pressure on bacteria to develop the ability to resist them, it is inevitable that decades of antimalarial drugs would lead to the malaria parasite developing resistance.

The artemisia plant had been known in China since the 1960s, but the effectiveness of its extract, artemisinin, in tackling malaria was first proved in Vietnam in the early 1990s, when it was shown to be so effective it was considered a wonder drug.

Alert to lessons learned through the experience with other anti-malarial drugs, in 2005 WHO recommended artemisinin should only be given in combination with other drugs as a tactic to slow the development of resistance.

But parasites are starting to develop resistance to artemisinin in several countries in Africa that carry the highest burden of disease.

If artemisinin drug resistance spreads out of control, the consequences would be catastrophic. in 2022, the WHO African Region had an estimated 233 million cases, accounting for about 94% of cases globally. There are few new antimalarial drugs in the pipeline.

“By 2030, if resistant malaria parasites are left unchecked, they could dominate infections in countries like Rwanda. Five years is plenty of time for them to go from 5% prevalence to 90%,” Maciej Boni, an evolutionary epidemiologist at Temple University’s Institute for Genomics and Evolutionary Medicine, Philadelphia, USA, told VaccinesWork.

Ticking time bomb

Parasites that can resist artemisinin were first documented in Rwanda in 2014, and then separately in Uganda and Eritrea. Now, the resistant parasites have spread across borders into Ethiopia, Kenya and Tanzania, with about 10% of malaria cases in these five countries being caused by resistant parasites. In some areas this number is as high as 20%.

What’s worrying scientists like Abdoulaye Djimdé, senior malaria researcher and head of the drug resistance unit at the Malaria Research and Training Centre University in Bamako, Mali, is that resistance has been spreading much faster than expected.

“Given the high level of transmission, we were hoping that the level of immunity and the diversity of parasites in the population would lead to resistance later than it has,” he told VaccinesWork.

“By 2030, if resistant malaria parasites are left unchecked, they could dominate infections in countries like Rwanda. Five years is plenty of time for them to go from 5% prevalence to 90%.”

– Maciej Boni, an evolutionary epidemiologist at Temple University’s Institute for Genomics and Evolutionary Medicine, Philadelphia, USA

The tell-tale genetic marker of artemisinin resistance in P. falciparum malaria parasites are mutations in the Kelch13gene (PfK13). A paper published in Science in July 2024, co-authored by Nicholas White, who played a key role in documenting drug resistance in South-East Asia, explains that in Eritrea PfK13 mutations jumped from 8% of cases in 2016 to 21% in 2019.

Between 2017 and 2022, the prevalence of this mutation increased across three regions of Ethiopia and by 2022 similar mutations had spread across Uganda, reaching a prevalence of more than 20% in many districts.

“We are seeing independent markers of resistance, which suggests that containment and control measures will need to be multifaceted,” says Djimdé.

These mutations tend to manifest clinically as delayed parasite clearance, which means treating the infection takes longer. This is challenging because if the parasite fails to clear from the bloodstream within two days, it can lead to treatment failure and drive drug resistance even further. So far, delayed parasite clearance isn’t leading to treatment failure in Africa – yet.

A 2016 study by researchers at Imperial College London estimated that if 54% of infected individuals experiencing delayed parasite clearance and there was high partner-drug resistance (45% of treated individuals re-developing disease) there would be an additional 16 million cases and 80,000 deaths per year. They predicted that would cost Africa an extra US$ 1 billion.

History repeating itself?

This pattern of resistance has already played out in another continent, that once had high rates of malaria incidence – South-East Asia.

P. falciparum resistance to artemisinin first emerged in Cambodia in the 1990s but wasn’t reported until 2008, by which time it was followed rapidly by resistance in Thailand, Vietnam, Myanmar and Laos. By 2013, health workers were seeing complete treatment failure first in Cambodia, then Thailand and Vietnam.

Kim Lindblade, malaria epidemiologist at PATH, says the region “tried several approaches to contain resistance, and concluded that only by eliminating transmission of malaria could multi-drug resistance be defeated”.

Lindblade says that, with the guidance of WHO and funding from the Global Fund and the Gates Foundation, the ministries of health of the six countries in the region (Cambodia, China, Lao PDR, Myanmar, Thailand and Viet Nam) began coordinating their malaria elimination strategies and sharing data to improve communication and effective action.

Djimdé says that the response to spiralling drug resistance in South-East Asia was “a concerted effort that including mass roll-out of bed-nets, prompt diagnosis, follow-up on efficacy of the treatment and an adjustment of treatment policies when necessary, and a sharp increase of funding.” 

And it worked. By 2018, the WHO South-East Asia Region had 8 million cases and 11,600 malaria deaths – a massive 70% reduction from 2010. In the Greater Mekong Subregion specifically, there was a 94% reduction in P. falciparum cases.

Djimdé would like to see this formula applied to sub-Saharan Africa, but is worried that the threat of resistance in Africa is not triggering quite the same global response as it did in South-East Asia.

The challenge in Africa, says Djimdé, is that resistance is still not very obvious at the clinical level and infections are still able to be treated. According to a WHO strategy on tackling antimalarial drug resistance in Africa, resistance to drugs that are used to partner with artemisinin has not been detected “despite some worrying signals”.

Nevertheless, says Boni, there are still “fresh memories of how disastrous chloroquine resistance was for 20 years across Africa, and how many people died as a result”.

“The African malaria community is taking this threat extremely seriously and is coordinating to strengthen surveillance for early indicators of resistance and treatment failures, working to limit drug pressure by improving the use of diagnostics and therapeutics and decreasing use of mono-therapies such as injectable artesunate, and investigating potential containment strategies such as multiple first-line therapies and triple ACTs.”

– Kim Lindblade, malaria epidemiologist at PATH

Number-crunching against resistance  

All may not be lost yet – modelling research that Boni began years before artemisinin resistance emerged in Africa could give countries an advantage against the parasite. 

Boni leads one of just a handful of laboratories around the world undertaking the kind of extremely specialised disease modelling that could help African countries work out strategies to reduce the development of antimalarial resistance.

“We look at variables like how often do people get bitten by mosquitoes? Do children get bitten more often than adults? What drugs are used in the country? What genotypes are circulating in a country?” says Boni.

“Let’s say there are six or seven different drugs being used, and around 30 genotypes circulating in the country: you have to know what the treatment efficacy is of all these six or seven different therapies and all these 30 different genotypes of malaria that are circulating. So our model will have to calculate around 200 different treatment efficacies and know how this will affect the forward spread of drug-resistant genotypes.”

Boni’s team are working directly with African countries where resistance is emerging. This summer, with Boni’s guidance, Rwanda began implementation of a drug resistance mitigation strategy in six of the country’s 30 districts.

Instead of using one artemisinin combination therapy (ACT) year in and year out, the six districts are going to experiment with a rotation scheme, where they use a different ACT combination every year for three years. The idea behind this is mixing up drug use enough to keep the parasite guessing.

Tanzania, meanwhile, is switching to artesenuate-amodiaquine from artemether- lumefantrine first in the north-west of the country, where resistance is beginning to spread, and then the rest of the country. Boni says the country is preparing for this to be a temporary switch and will re-evaluate in two t four years, after which they can re-evaluate treatment options again. 

“This is an enormous leap in malaria drug resistance management at national levels,” he says. “Countries are not doing this as a policy change and just waiting around for 20 years. They’re viewing this as a continual iterative process with a robust monitor and surveillance approach so that they’re always on top of it.”

“It’s to the great credit of countries like Rwanda, Tanzania and Uganda, and especially their national malaria control programmes, that they are tackling this early,” adds Boni.

Lindblade adds: “The African malaria community is taking this threat extremely seriously and is coordinating to strengthen surveillance for early indicators of resistance and treatment failures, working to limit drug pressure by improving the use of diagnostics and therapeutics and decreasing use of mono-therapies such as injectable artesunate, and investigating potential containment strategies such as multiple first-line therapies and triple ACTs.”

Hiding in plain sight

Back in 2001, when the malaria parasite was developing resistance to chloroquine, Djimdé was one of the scientists who first showed how parasite gene mutations were linked to resistance. With his team, he is now hunting for molecular markers of resistance to artemisinin and partner drugs. “Genetic markers are the tool that allow us to be proactive rather than reactive because mapping the evolution of markers of resistance allows us to see changes happening before they materialise as increased burden of disease or a higher death toll,” he says.

Djimdé’s team are working with Mali’s National Malaria Control Programme on the largest molecular survey of markers of drug resistance in the country so far, and they are also going to be looking for markers of gene deletion. Around 95% of rapid detection tests for malaria look for the PfHRP2/3 gene. Parasites that evolve by deleting this gene are essentially undetectable by the most commonly used tests.

“African scientists should be in the forefront of this fight; we know firsthand what this can mean in terms of morbidity and mortality if the situation is left unchecked.”

– Abdoulaye Djimdé, senior malaria researcher and head of the drug resistance unit at the Malaria Research and Training Centre University in Bamako, Mali

WHO sets a maximum threshold of 5% of infections that a test can miss and still be considered effective. By determining the prevalence of this gene deletion, Djimdé and colleagues can determine whether the level of undetectable infections are past the WHO threshold and whether other tests need to be deployed instead.

In parts of the Horn of Africa, in Eritrea and Ethiopia, Djimdé says there is evidence that there is both artemisinin resistance and gene deletions that will render the parasite undetectable.

“This is a bombshell and means it is even more urgent to push to eliminate P. falciparum malaria from Africa,” says Djimdé.

The arrival of two malaria vaccines – RTS,S and R21 – has made scientists hopeful about the possibility of driving down infections and deaths. However, while the vaccines are already being rolled out in the most-affected countries, it may take time for these to be widely enough available to drive down infections significantly.

Alongside vaccine roll-out, the Science authors say that “an affordable, readily implementable, and sustainable approach to counter [resistance] is to combine an artemisinin derivative with two partner drugs instead of only one to create triple ACTs (TACTs)”. They also recommend investing in community health workers to ensure access to early diagnosis and treatment.

“Community health workers are the backbone of community health programmes and contribute immensely to managing diseases like malaria,” says Dr Jules Mugabo Semahore, Head of Malaria and Neglected Tropical Diseases at WHO Rwanda.

While a global effort is needed to fight this threat, Djimdé says, “African scientists should be in the forefront of this fight; we know firsthand what this can mean in terms of morbidity and mortality if the situation is left unchecked.”