Battle of the species: It’s man vs mosquito

It’s 5pm. Loud screams of babies relentlessly cut through the air at Ruhuha Health Centre in Kigali,  Rwanda.

Inside the compound, an elderly woman is seated at a corner in a small Catholic chapel. She is deeply lost in thoughts. Her right hand firmly clasps onto a rosary as tears race down her sullen cheeks.

She is fixedly staring at the statue of Jesus erected at the front of the church, perhaps waiting for a miracle.

 “My name is Ernestine Bizimana. I have been here four times in the last three months. My grandson is unwell. The medications are not working. I am almost giving up,” she tells Healthy Nation. 

Trouble started  five months ago, according to the grand mother of six. 

One Monday evening, her youngest grandson, Claude Bizimana, 8, complained of a headache at night. “He also had high fever and so I put him on my back and went to see a community health promoter(CHP) in our village.”

The CHP would diagnose him with malaria and put him on Coartem/Riamet dispersible tablets.

“I ensured my grandchild took the drugs religiously as per the prescription I was given,” says Ernestine, 50.

She admits that she has not always been keen when it comes to protecting her loved ones from malaria and that she knows too little about the disease.

“I live next to a river and I spend most of my time working on the farm so that I can sell foodstuffs in the market. Closing my windows by 6pm is something I am not keen on because mosquitoes around here bite even during the day when the sun is up there,” she says.

Two weeks later after the night visit to the CHP, the boys’ high fever accompanied by a severe headache resurfaced.

After another round of tests, the CHP concluded that the boy had severe malaria. He prescribed more drugs for Claude.

A few weeks later, the boy would yet again come down with malaria for the third consecutive time.

“This time round the CHP referred us to Ruhuha Health Centre and again laboratory test results showed that Claude was suffering from nothing else but malaria,”Ernestine tells Healthy Nation.

Nurses at Ruhuha advised a change in the boy’s medication as the coartem tablets that he had been put him on seemed ineffective.

Even though Claude’s treatment was guaranteed and free under President Paul Kagame’s community-based health insurance scheme, not being able to understand why her grandson did not respond to treatment as expected kept Ernestine awake for days.

Her fingers remained crossed as doctors took a different approach, citing that Claude was at the time the 50th patient in a sequence of partial coartem resistance cases they had noted in the country.

A 10-minute drive from the health facility that is run by Catholic nuns gets us to the home of a CHP who villagers here depend on.

“I have been trained and certified by entities like Rwanda Biomedical Centre (RBC) and GCP (Good Clinical Practices) to do this job, which started as a passion to help others.

“ I have seen what malaria has done to my loved ones and would not want it to happen to someone else,” Pascal Mbanzagukeba tells Healthy Nation.

He explains that it is the villagers who decide who gets to be a CHP.

“The government furnishes me with a medical kit for first aid to measure temperatures, pressure and weight as well as medication to treat some illnesses.”

He also conducts HIV tests  and assesses babies’ nutritional status. Pascal says once he realises that a situation is dire, he recommends patients to go to the health centre, where the case can be further escalated to a Level two hospital.

The CHP points out that in the last few years, he has observed many cases of partial resistance while treating malaria.

“I always escalate them,” he says, adding: “I have also noticed that many locals do not know that washing mosquito nets with detergent/soap makes them ineffective.”

From the village, the Healthy Nation team heads to one of the most important buildings in Rwanda’s capital where mosquitoes are dissected.

 As we arrive at the entomology laboratory, there is pin-drop despite the place being a bee-hive of activity that is expected to revolutionise malaria treatment not only on the continent but also globally.  The centre is run by the Rwanda Biomedical Centre.

Dr Dunia Munyakanage, the vector control supervisor, lets us in on a dirty little secret.

“Did you know that we largely depend on very smelly socks, especially of men, to trap mosquitoes? There’s something about the human scent in your feet that they just can’t resist.”

He notes that some individuals are more attractive to mosquitoes than others.

There are some definite factors that explain why you might just be more susceptible to getting bitten — from your skin microbiota and carbon dioxide emitted in your breath to the colour of clothing you're wearing (with colours like red, orange and black being the most attractive to mosquitoes).

But in the end, according to the expert, much of the variation in mosquito preference comes down to two factors: our natural body odour and genetics.

“A few years ago, a Dutch medical entomologist discovered the insects’ strange affinity to foot odour by standing naked in a room full of mosquitoes to see where they bit him,” he adds.

Only female mosquitoes bite humans and they do it to get a ‘blood meal’, deriving proteins from human blood to produce their eggs.

They use their antennae and palps, the organs between their antennae, to detect carbon dioxide and odour.

 “That means people who have a high metabolic rate and emit more carbon dioxide, including those who are pregnant, working out, or drinking alcohol, tend to be more attractive to mosquitoes,” highlights Dr Dunia.

He then cites the emergence of antimalarial drug resistance.

“Around 2012, a CHP in Kigali alerted us that he had treated three patients using Coartem®/Riamet®, a fixed-dose combination of artemether-lumefantrine, but two weeks later, they experienced malaria-reinfection.

“At the moment, we have noted partial resistance to the drug that is now at 20 per cent,” the vector control supervisor says.

This is why Rwanda went ahead to contact WHO as coartem is on its Model List of Essential Medicines, and Novartis, the Swedish drug maker that in 1999 came up with the drug, to let them know of the lurking danger.

Further tests in the laboratory would show that there was an emergence of artemisinin-resistant malaria as the Anopheles stephensi mosquito had found a way to resist artemisinin, a vital component of coartem.

This, according to Dr Dunia, was heartbreaking for Rwanda considering the fact that coartem is the main drug for treating malaria on its essential drugs list after quinine suffered a similar fate many years ago.

Dr Dunia notes that An. stephensi is a mosquito species capable of transmitting both Plasmodium falciparum and P. vivax malaria parasites.

The mosquito species was traditionally confined to South-East Asia and the Arabian Peninsula.

Ever since it was first found in Djibouti in 2012, the predominantly urban vector has rapidly expanded its geographical scope due to climate change.
“This is why it was recently spotted in Kenya by scientists at the Kenya Medical Research Institute(Kemri),” Dr Dunia says.

The An. stephensi usually travels by road in containers and in recent years, it has traversed Ethiopia (2016), Sudan (2016), Sri Lanka (2017), which was declared malaria-free a few years ago, Somalia (2019), Nigeria (2020), Yemen (2021), Kenya and Ghana (2022).

Its remarkable adaptability to urban environments and resistance to various insecticides pose unique challenges to malaria control efforts, notes the expert.

“Warmer temperatures and changing rainfall patterns create new suitable habitats for the An. stephensi. For every degree increase, the mosquitoes  increase by 23 per cent. Temperatures in Rwanda have increased by four degrees due to climate change in the last few years,” he tells Healthy Nation.

“This means that scientists have to now go back to the drawing board before what happened few years ago happens again,” Dr Dunia notes.

“The evolution of widespread resistance to chloroquine and sulfadoxine-pyrimethamine forced scientists to develop new therapies like artemether and lumefantrine that are now under-siege.”

The three cases of resistance compelled RBC to carry out a comprehensive study in 2018 that found evidence of delayed parasite clearance. This can be a sign of partial resistance to the artemisinin component of artemisinin combination therapy. The study also identified mutations in P falciparum genes that have been associated with delayed parasite clearance and artemisinin resistance.

During the study, Children aged six to 59 months with P falciparum monoinfection and fever were treated at three sites—Masaka, Rukara and Bugarama. This was done together with a three-day course of artemether-lumefantrine.

Researchers then monitored treatment response for 28 days using weekly microscopy screenings of blood samples for P falciparum.

They went ahead to assess parasitemia on day three of treatment and then conducted molecular analysis on samples collected pre-treatment and during follow-up after which they characterised mutations in the pfkelch13 and P falciparum multidrug resistance-1 (pfmdr1) genes. The pfkelch13 gene is associated with artemisinin resistance, leading to artemisinin combination therapy treatment failure.

According to RBC, a total of 228 children with symptomatic uncomplicated P falciparum malaria were enrolled in the three sites: 88 in Rukara, 52 in Masaka, and 88 in Bugarama.

The per-protocol PCR-corrected drug efficacies were 93.8 per cent in Rukara, 97 per cent in Masaka, and 97.2 per cent in Bugarama.

The World Health Organization only recommends replacement of antimalarial therapy if efficacy falls below 90 per cent.

The pfkelch13 gene was successfully sequenced from 254 of 265 samples (218 pre-treatments and 36 post-treatment), and 38 (15 per cent) of the 254 samples had one of the mutations that have been validated as molecular markers for artemisinin partial resistance: 36 with a R561H mutation, and two with a P574L mutation. Thirty of those mutations were present in the pre-treatment samples.

“Efficacy rates from a therapeutic study conducted among children at three sites in Rwanda were above 90 per cent,” the peer reviewed study, which was recently published in The Lancet, highlights.

Dr Caroline Boulton, the head of drug development programme at Novartis, is responsible for making what she describes as ‘the next generation of antimalarial drugs’.

She highlights that apart from parasite resistance to front-line medicines such as artemisinin, An. stephensi is being aided by climate change, mosquito resistance to insecticides, genetic mutations that prevent diagnosis, the spread of zoonotic malaria and the rise of cartels dealing in counterfeit drugs in sub-Saharan Africa.

“We know there are cases of partial resistance that have been reported in Rwanda, Tanzania and Uganda; and soon we shall be setting up a clinical trial site in Kenya just as we have now done in the Democratic Republic of Congo (DRC).

“There is a whole history in malaria and that is of parasites evolving and evading the existing treatments. When that happens, there are more cases of malaria,” she says.

She points out that they have so far only noted ‘partial resistance’.

“At the moment, it’s that first phase that clears the parasite which appears to be at risk. The artemisinin component is not clearing parasites as quickly as it should, which puts a lot of pressure on the second drug in the combination to clear all the parasites.”

Previous studies in South Asia (where the partial resistance was first noted) on their combination therapy have shown that ‘partner drugs’ will fail when put under pressure.

“The good news is that the treatments which we have in sub-Saharan Africa that are artemether-lumefantrine-based seem to still be working at the moment, but what we have to do is to take the pressure off artemisinin and find an alternative,” Dr Caroline notes. 

By finding an alternative, they hope they can be able to treat all cases of malaria; whether patients are carrying the parasite with the resistant mutations or not.

Dr Caroline, however, points out that in sub-Saharan Africa, partial malaria resistance is not an ‘off and on’ switch.

“A lot of national malaria control programmes in the region have been tracking mutations, which are of concern for a long time, and what they are seeing, for example Rwanda from 2012 t0 2024, is that the prevalence of these mutations have grown.

The drug maker assures that they are working round the clock to ensure they have tools in place to fight new waves of malaria infection should their combination therapy end up experiencing full resistance.  “We have recently completed a clinical study of an optimised formulation and dosing regimen of our artemesinin-based combination therapy for infants weighing less than five kilogrammes with malaria,” the lead of malaria at Novartis tells Healthy Nation, adding that the current antimalarials are not fit for these infants and that they are currently being treated using tablets meant for children above five kilogrammes. “Yet these tiny patients handle drugs differently due to differences in metabolism compared to older patients, which may lead to an overdose and toxicity.”

The drug maker, which is currently in the third phase of clinical trials for new antimalarials in DRC and will soon be designing new study sites in countries like Kenya, says it is currently conducting global clinical trial programmes for three novel antimalarial drug candidates. “These three form a new class of medicines which target the malaria parasite differently from our current therapies,” says Dr Nekoye Otsyula, the global medical affairs, malaria director at Novartis.

[email protected]