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“We really have the perfect conditions for resistance to develop”: an interview with Dr Marian Warsame


Saturday November 19, 2022

As part of WHO’s launch of a new antimalarial drug resistance strategy for Africa, we spoke with Dr Marian Warsame, an expert on this topic. A medical doctor by training, Dr Warsame wrote her PhD’s thesis on antimalarial drug resistance in Somalia, worked for many years on malaria treatment and drug resistance trials in the United Republic of Tanzania, and, while with WHO’s Global Malaria Programme, helped countries in Africa and the Eastern Mediterranean implement better studies to monitor changes in drug and treatment efficacy. This conversation has been edited for concision and clarity.

First from a broad perspective, can you explain why this issue demands attention?

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Antimalarial drug resistance is very much an increasing concern in Africa. More than 90% of the global malaria burden – cases and deaths – occurs in Africa, and most of these cases involve Plasmodium falciparum, the parasite that is quickly developing resistance to current drugs. This is especially troubling because we only have a limited number of antimalarial drugs today – called artemisinin-based combination therapies (ACTs) – that can treat uncomplicated malaria. So, if we lose those, we don’t have any other options and malaria could become uncontrollable.

What is causing this drug resistance to spread in Africa?

Unfortunately, several factors are facilitating a conducive environment for growing drug resistance in Africa today. These include the use of sub-optimal dosages and fake drugs, as well as the inappropriate use of current antimalarial drugs. The best treatment for uncomplicated malaria is an ACT, which combines artemisinin and a partner drug. Monotherapy – taking only an artemisinin-derivative injectable for the treatment of uncomplicated falciparum infection – has in fact been banned. But even though there are guidelines in place against it, monotherapy is still very commonly practiced in malaria-endemic countries. This leads to drug pressure, which is the major contributing factor to the development of drug resistance.

So, on the ground in Africa, we really have the perfect conditions for resistance to develop. As the genetics of the malaria parasite changes, drug-resistant mutations are produced that have a survival advantage in the presence of the drug over the sensitive parasites. These new mutations are thus more likely to be transmitted and spread, particularly when you factor in population movement both within countries and across borders. It’s a perfect recipe for the spread of antimalarial drug resistance, especially in places suffering from political or climate instability, or where many people are being displaced.

So where are we seeing this spread today?

Globally, resistance to artemisinin and to some of the partner drugs has been seen in South-East Asia in the Mekong region and in many places in Africa. Based on validated molecular markers that help us find and predict drug resistance, we have seen hotspots of confirmed partial artemisinin resistance in Eritrea, Rwanda and Uganda, but that doesn’t mean it doesn’t exist in other areas as well. Usually, studies are done at selected central sites, so the full scope of what we can see is limited and the geographical extent of the spread is not yet clear.

Can you tell us about the role surveillance played in detecting the emergence and spread of drug resistance in these countries?

As part of WHO recommendations in place for malaria-endemic countries in the Horn of Africa, sentinel sites were established to regularly monitor the use of ACTs as first- and second-line treatments and to look for the known molecular markers associated with antimalarial drug resistance.

In addition, a network called HANMAT – the Horn of Africa Network for Monitoring Antimalarial Treatment – was created in 2004 that included Djibouti, Saudi Arabia, Somalia, Sudan, and Yemen from the EMRO [Eastern Mediterranean] region and Eritrea, Ethiopia, and South Sudan of the AFRO [African] countries. Through this network, member countries have been supported on protocol development, technical support on data validation, data analysis, and report writing. Every year, HANMAT meets to plan the next round of surveillance studies, and WHO provides up-to-date technical information if there is a new tool that needs to be covered or new molecular markers to be assessed.

A decade ago, this system allowed for the timely detection of growing drug resistance to AS-SP [Artesunate + sulfadoxine–pyrimethamine], which was then the first-line treatment for malaria in Somalia. We saw high rates of treatment failure with this combination due to, as we discovered from molecular markers, resistance to SP. This led to a change in Somalia’s treatment policy in 2016 and the replacement of AS-SP with another combination of drugs, AL [artemether + lumefantrine]. We were also able to identify a new second-line treatment, which was DHA+PPQ [dihydroartemisinin + piperaquine].

This system has had other successes as well. It’s really very useful to have a regional surveillance system in place with technical and financial support to capture the emergence of problems like treatment failure and drug resistance wherever they arise.

What are some of the challenges that these countries face in terms of surveillance?

While these countries have a surveillance system in place, they need WHO to help them keep up to date on evolving resources and information about antimalarial drug efficacy, new molecular markers discovered, and new tools developed. So, it’s good to have a platform to help keep countries informed and to encourage adherence to WHO protocols.

Sometimes, countries do a study without any treatment supervision. For example, one malaria treatment involves a twice-daily dose, and usually, doctors give the first treatment under supervision and then give the second for the patient to take at home. But studies show that, under this system of unsupervised treatment, the second dose isn’t taken, or taken correctly, leading to treatment failure. This is a separate problem from drug resistance, and there are many confounding factors, many of which can be mitigated by supervised treatment. That’s why it’s important to keep countries aware of the best protocols through the regional network.

Countries also sometimes need critical support in gathering, managing, and storing data, through proper data entry and analysis, platform software, and other tools, so that it can be cross-checked and everyone can be sure scientific studies are being done appropriately and effectively. Countries do their best, but it’s always good to ensure standard protocols are being followed.

Countries face many other challenges too. Political instability in countries like Somalia, Sudan, or Yemen can lead to studies being postponed or even sites being abandoned. Some sites in Somalia, for example, are no longer accessible because of insecurity. Funding is another constant issue – studies are often delayed or redesigned because of lack of money, since most of a country’s malaria budget usually goes to case management, drugs, spraying, and the like.

Local capacity can be another bottleneck, especially in places when there is a high turnover of health workers. Formal training is needed to execute these studies well, especially in areas like malarial microscopy. I would encourage not just training packages for each round of a clinical study but refresher training to help keep health workers up-to-date and give them the knowledge and tools to be effective at tracking malaria resistance.

How worried should people be that malaria treatments are going to stop working?

I don't think people should worry about losing ACT treatments in the very near future, because partial resistance to artemisinin does not impact the efficacy of the combination treatment so long as the partner drug remains effective. This is well established, even in areas with high rates of artemisinin resistance and delayed parasite clearance. So, it's important to avoid unnecessary panic that increasing drug resistance will mean immediate and widespread treatment failure. But it is a growing problem that needs to be managed and hopefully contained before it gets worse.

Is there anything else you think our readers should know about this topic?

I have a few important points that I want to underscore, yes.

First, to avoid panic and confusion among health professionals and the public in general, the situation on drug resistance and treatment efficacy should be properly communicated at the country level, through media platforms like TV, radio, and local newspapers. Otherwise, bad information will create chaos. People will hear rumors or reports about failing drugs and may make decisions that lead to bad outcomes, like using unnecessary injectable monotherapies that accelerate the development of drug resistance. So, I think messaging is critical, and there needs to be good educational material available for all.

Second, countries need to actually administer the bans on oral monotherapy for the treatment of uncomplicated malaria and encourage the rational use of antimalarial medicines. These bans exist but they are often not enforced, which is also speeding up the spread of resistance.

Along the same lines, I hope countries can work to strengthen surveillance of therapeutic efficacy. Because while molecular markers are very useful, ensuring treatment is supervised and monitored is critical for understanding how resistance is evolving over time, and there is no substitute for high-quality data at the country level for understanding resistance’s spread.

Finally, I would urge global malaria partners to recognize the importance of these surveillance efforts and help us accomplish this work. If countries don’t have the funds at the national level, we will need help from organizations like WHO, USAID/PMI, and the Global Fund to support the monitoring of drug resistance and help ensure countries have the evidence to enact treatment policy changes when needed.



 





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