Nigeria’s Bet on Beating Drug-Resistant Malaria

Inside an emergency ward at Ikorodu’s general hospital on the outskirts of Lagos, 19 year-old Rafiat, dressed in a pale yellow headscarf, cradles her newborn daughter. A doctor and two nurses crowd over her tiny, motionless body, administering finger compressions and pumping air through a bag into her lungs. A day old and not yet named, the baby has tested positive for malaria and is dangerously hypoglycemic, a common and potentially fatal complication.

Across the room, another woman paces, mumbling urgent prayers through tears. Her newborn has the same symptoms. Dr. Akeem Ismail rushes between the two for 15 minutes until they’re finally stable. “Hallelujah,” he exhales.

Every day, Ismail sees up to five potentially fatal cases of malaria in infants and toddlers. His daily ledger is peppered with notes of his clinical diagnosis: severe malaria. The newborns he treated that day received a single shot of the drug artemisinin which should start clearing their bodies of the malaria parasites within hours—the difference between life and death in some cases. But in Africa’s most populous country, with the heaviest burden of malaria worldwide, the world’s frontline antimalarial is at risk.

Dr. Akeem Ismail
Dr. Akeem Ismail tends to a young patient who tested positive for malaria in Ikorodu’s general hospital on the outskirts of Lagos.

Artemisinin was discovered in the 1970s by Chinese scientist Tu Youyou, who recently won a Nobel Prize. The drug gained favor as resistance to chloroquine, once the leading antimalarial, began to spread and cause a resurgence in malaria deaths.

Scientists were once adamant that malaria parasites could never build resistance to artemisinin, but resistance now has spread through four countries in South East Asia. “It’s serious,” Ismail says. If resistance builds in Nigeria he is concerned there could be a resurgence of malaria. He believes that the ample availability of substandard antimalarial drugs, whether due to low standard production or poor storage, and the continued use of monotherapies is endangering the efficacy of even the artemisinin combination treatments.

Monotherapies—the practice of using only one drug to fight malaria—are still widely used despite the fact that artemisinin-based combination therapy (ACT) was introduced in 2000. By matching fast-acting artemisinin with other longer-acting antimalarial drugs, this two-pronged approach more effectively clears the parasites. ACT cocktails have halved malaria deaths ever since.

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Dried roots on sale at a traditional herbalist in the Lagos slum of Makoko.

While all public hospitals in Nigeria are supposed to provide antimalarial medication for free, many people prefer—or feel their only affordable option is—to go to the local markets and self medicate. They often choose monotherapies over ACTs. Even Ismail, who only gives his patients government-approved ACTs, often self-medicates with chloroquine, despite knowing that the drug has a high rate of resistance and is no longer a recommended treatment in Nigeria. Having grown up exposed to malaria, he feels that even resistant malaria is likely not a huge risk to him. But if resistant parasites linger in his bloodstream, just one mosquito bite could put his more vulnerable patients—especially young children and pregnant women—at risk.

When Rafiat developed severe malaria just before falling pregnant, she came to the hospital and received an injection of artemisinin, which should have then been followed with the recommended dosage of ACT. Despite being prescribed ACT, she didn’t take the medicine after returning home, instead choosing to visit a traditional healer for an herbal remedy. Since she had felt better right away, she kept the medicine for another time. It was a decision that could compromise the efficacy of artemesinin, the same drug that was now saving her baby’s life.

Spreading Mutations

Ismail’s hospital in Ikorodu, just a short ride away from Lagos, Africa’s fastest growing city, is in the center of a hotspot for malaria. Here and elsewhere in Nigeria, researchers like Christian Happi are studying how to prevent antimalarial resistance. Using samples collected from patients infected with malaria, Happi is identifying and geographically mapping where genetic indicators of resistance appear so that he can create an early warning system for the country. While resistance to artemisinin, either as a monotherapy or combination therapy, has yet to appear in Nigerian patients, it is already lurking in the genes of Plasmodium falciparum, the most deadly malaria species.

For Happi and his team, their work is personal. While growing up in Cameroon, he suffered malaria so many times that he promised his mother that, when he grew up, he would find a cure. His colleague, Onikepe Folarin, knows too many people who have lost loved ones to malaria.

Happi’s lab is housed on the grounds of a mega church the size of a small town just outside Lagos State. It was here, last year, that he diagnosed the first case of Ebola in Nigeria. The peeling yellow exterior of the lab building belies the clinically clean research facility within. Equipped with the latest in genomic sequencing equipment, it may be the most advanced lab of its kind in the country and possibly, on the continent.

Christian-Happi-lab
Christian Happi, one of Nigeria's most prominent malaria researchers, walks up to his laboratory on the campus of Redeemer's University outside of Lagos.

His team is working with more than 2,500 blood samples collected from all over Nigeria. Their lab is littered with brown envelopes full of thin tabs of paper, each with a round spot of malaria-infected blood from a pricked thumb. Each sample is reconstituted, diluted, and filtered before they can decode the parasites’ genomes.

It’s thanks to that surveillance that, a few years ago, Happi’s team discovered mutations within P. falciparum which suggested artemisinin resistance was already building within malaria parasites in Nigeria, raising the threat of resistance to virtually all known antimalarial drugs. Worldwide, the World Health Organization (WHO) has identified dozens of mutations of the K13 gene, now the marker for tracking artemisinin resistance, but no one knows which of them represents the biggest threat.

When I ask if they have found K13 mutations in many of the clinical samples from Nigeria, he almost laughs. “Oh yeah,” he says. “We’ve found it a whole lot.” Out of the samples collected, 80–90% have at least one mutation.

Now Happi and his research team are focusing on how to prevent resistance from spreading to patients. “Once you see it clinically, it means that it’s already a done deal,” Happi says. “Usually when it starts accumulating in the parasites, you have an opportunity to prevent it. But when you start to have clinical cases, it means that the parasites have already reached a level of resistance where you can’t eliminate it.”

Lagos is the perfect “melting pot” for resistance to spread, Happi says. As a transit hub for the region, resistant parasites could be transported into the country by infected travellers and spread out to the region. There is little in the way of cross border surveillance for resistance, which would be costly and require greater collaboration. Still, Happi’s map is a small step in the right direction. Similar initiatives across West Africa led by African researchers and scientists show promise, including one project that tracks the parasite’s migratory patterns and genetic mutations.

But as Happi has been learning, it seems inevitable that artemisinin resistance will spread. “They get used to it,” Happi says of the parasites. “With gradual exposure, there’s a process of adaptation which takes place, and when you bring in the full dose, they’re like, we’re ready for you!”

Antimalarial drugs are available without a prescription in Nigeria—part of the effort to make genuine, high-quality treatments more accessible to the entire population. But even if quality drugs are available for a mother to treat her sick child, she may not give him the entire course. Once he starts feeling better, she’ll keep the rest for another time. Other Nigerians may not be able to afford the whole pack so they buy half the pack or just a few tablets. When only part of the dosage is taken, not all of the parasites are killed off. The survivors are more likely to contain mutations for resistance.

Yet none of that has stopped the proliferation drugs, including banned and substandard formulations as well as counterfeits, in Nigeria’s open drug market. I show Happi a photo of four different types of antimalarial medication I found for sale in an upscale neighborhood pharmacy on Victoria Island. “You’re going to see 20 times more than this is the markets,” he laughs. “You’ll be shocked at what you can buy.”

Market Chaos

Lagos’s wholesale drug traders ply their trade at the vibrant melee of Idumota market, the biggest in Nigeria. The streets are lined with bustling stalls, piles of colorful bras, and mountains of sandals. Today, a woman in a bright yellow print dress is weaving her way through the crowd, deftly balancing a flat screen TV on her head. On the side, a man is selling bibles from a wheelbarrow. The sweet smell of dough balls frying in hot oil hangs thickly in the air.

Down a cramped passageway, just over a rivulet of greyish water, a busy pharmacy sells a plethora of mainly imported medicines. A 25 year-old trader named Chidieberre, a member of the Igbo ethnic group, stands behind a desk in his neatly stocked stall, serving customers as cartoons buzz on a small television screen hanging in the corner. People flit in and out, carrying the stubs of medicine packets they’ve used before or ordering new ones by brand name. Many of Chidieberre’s customers are retailers who will buy bulk boxes and resell the individual packets.

In one corner of his stall, the walls are stacked with antimalarial drugs. Those visible are ACTs, but he can quickly produce boxes of different types and brands of monotherapies, including older drugs such as a chloroquine syrup for children and artesunate, a form of artemisinin that the WHO strongly advises against selling on its own.

Chidieberre-market
Chidieberre, a 25 year-old trader, stands in his stall stacked with medicines, including monotherapy antimalarials, at Idumota market in Lagos.

“I buy them direct from the distributor,” he tells me. “There are a lot of distributors; these are Mekophar products from Vietnam.” A single pack of Artesunat-brand artesunate costs just over 100 naira, not even one U.S. dollar. Chidieberre tells me this is one of the fastest selling drugs he has. He estimates that he moves one to two boxes of it on a good day.

The rapid sales of Vietnamese artesunate in Idumota is emblematic of how globalized pharmaceutical markets have become. It’s a growing headache for public health officials. “The problem is, we cannot do much,” says Pascal Ringwald, who leads the Drug Efficacy and Response unit of the WHO’s Global Malaria Program. “We cannot force a country to stop importation and marketing of monotherapies. We cannot play policemen.”

Artemisinin resistance, he says, is “emerging everywhere in the world.” To delay the inevitable, the WHO has advised countries since 2005 to ban the use of artemisinin as a monotherapy. But while the biggest manufacturers of monotherapies, such as pharmaceutical giant Sanofi-Aventis and the Shanghai-based Guilin Pharmaceuticals, agreed to cease production, smaller companies have filled the gap. “There are really small companies doing exchange with countries and entering a market that is, in theory, forbidden,” Ringwald says. “It’s extremely complicated.”

Banned monotherapies aren’t the only problem. Substandard medications also fuel drug resistance by providing only a tiny amount of the active ingredient. It’s usually enough to make patients feel a little better, but not enough to kill off the parasites. Outright fakes are exacerbating the problem, too.

In a study published in May, researchers at the London School of Hygiene & Tropical Medicine found that of more than 3,000 ACT antimalarials purchased from pharmacies, vendors and public hospitals in south eastern Nigeria, 9.3% were of poor quality, either fakes, degraded, or substandard. Given what I saw in Idumota, that number may be conservative.

Antimalarial drugs from stalls like Chidieberre’s diffuse to neighborhoods throughout the city, including Makoko, a slum home to hundreds of thousands of people reaching out on stilted shacks into the murky coastal waters.

children-in-makoko-slum
Children play in the floating maze of Makoko, one of the biggest slums in Lagos.

On a bustling main street, customers come in and out of Makoko’s oldest pharmacy, a neighborhood stalwart for around 30 years. Behind the counter, sharp-eyed Chinyere, the owner’s wife, displays the antimalarials she has in stock on request, including two forms of the monotherapy Artseunat—one in tablet form for adults, the other an injection for children. She says they are very popular with customers, as is the chloroquine, which she also sells in syrup form for children.

Despite a campaign launched by the Nigerian government to crack down on the open drug market in July, Falabi says it is almost be impossible to close since, by his estimates, it’s worth around 30 billion naira. Too many people, like the young trader in Idumota, depend on it not only for access to affordable drugs but also for their livelihoods.

Keeping Watch

Without a ban on resistance-inducing drugs, Nigerian health officials have to watch for potential clinical resistance to the two ACTs currently used in the country—artemether-lumefantrine and artemether-amodiaquine.

Every two years, the country surveys the efficacy of the government issued antimalarial medicine. The 2014 test, delayed due to Ebola, is still in process, but so far the results show ACTs remain effective, according to Godswill Okara, head of case management for the National Malaria Elimination Program. At the same time, Okara still remembers when independent researchers first started publishing on chloroquine resistance in Nigeria in 2002. They contradicted government-led reports that said the drug was still effective. “The country was foot-dragging,” he says. “Nobody was too keen to say, ‘Let’s change.’ ”

Nigeria decided to change to ACTs after a WHO-sponsored study conducted in the early 2000s showed that chloroquine resistance was present in more than 60% of cases, according to Okara. But the fact that chloroquine is popular and still available more than a decade later shows how difficult it is to change practice.

The national program also has tried to remove monotherapies from the market. Suppliers such as hospitals can only receive government-subsidized medicine if they don’t stock monotherapies. “If we go to your facility and we see monotherapy, we stop you from getting our product,” Okara says.

On the wall of the Ikorodu hospital pharmacy, there is a big sign reminding customers that antimalarials are free in public hospitals. But while this improves accessibility for those at need, it can lead to irresponsible use.

“Antimalarial medicines in public hospitals are free, and it’s the only thing you get for free,” Okara says. Many patients who have made a long journey are hesitant to go home empty handed. Okara remembers a woman coming to a clinic and testing negative for malaria but asking for the medicine to take home anyway to keep for another time. “It’s like, ‘I’ve taken transport from my home to the hospital, and I need to get something at least.’ ”

Risk of Resistance

With six different ACTs available worldwide, it is unlikely that total resistance will build in the near future, Ringwald says. But no one wants to take any chances. The pipeline for new antimalarial drugs is running dry, and Ringwald says that, if disease modelers are correct, total resistance to ACTs would increase fatality rates to 60%.

Though six combination therapies are available, in reality, not all of them may be useful in a given country. In Nigeria, for example, malaria is resistant to one of the longer-acting drugs and patients had bad reactions to another, so only four ACTs are recommended. Three will soon have been in widespread use. If resistance to them rises, there is only one fall back option.

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A researcher in Christian Happi's lab retrieves blood samples from malaria infected patients from a freezer.

But even those may not be safe. A study published this month in the journal Emerging Infectious Diseases discovered that general artemisinin resistance can lead to multi-drug resistance and jeopardize combination therapies. Researchers who dosed P. falciparum parasites with artemisinin treatments for five years found that the survivors’ offspring not only developed artemisinin resistance, but also tolerated ten other antimalarial drugs, many of which are common combination drugs used in ACTs.

Just over a year ago, the Nigerian government established the Malaria Parasite Sentinel Surveillance Sites, which collect monthly data on malaria treatment and recovery. Happi and his team’s mapping efforts will be a key contribution. Together, they hope to catch any red flags, such as if a medication doesn’t quickly or effectively clear malaria parasites from a patient. Happi hopes this national system can forestall antimalarial drug resistance in Nigeria. “If we catch it early, we can find out what’s going on,” he said.

The nationwide surveillance system may turn into a crucial line of defense for ACTs, but its success depends on continued investment in maintenance, training, and technology. Happi worries that, just like with Ebola, there won’t be any urgency until there is a crisis.

“It becomes a priority when they see people dying of it and they see the resurgence of malaria. Then they will start running helter-skelter like headless chicken,” Happi says. “Right now, when there are no clinical cases reported, you scream but nobody listens.”

This article is part of the “Next Outbreak” series, a collaboration between NOVA Next and The GroundTruth Project in association with WGBH Boston.