Researchers in Rwanda identify strain of the parasite that causes drug-resistant malaria

*This case was adapted from a real case for illustration purposes.

Specific mutation of the parasite, resistant to artemisinin, was found in 19 of 257 (or 7.4%) of the patients in one of the monitored health centers

A study published in early August in the journal Nature, entitled “Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda” revealed that the parasites that cause malaria were able to resist treatment with artemisinin, a frontline medicine in the fight against the disease. In the article, scientists elegantly detail the molecular mechanisms of drug resistance, one of the main problems in controlling malaria. They examined the peptide transport system and medications of the Plasmodium falciparum digestive vacuole and provide grounds for developing strategies to combat malaria parasites, avoiding the millions of additional deaths of African children. The disease is commonly treated with a combination of two drugs: artemisinin and piperaquine.

Asked about the repercussions of this work for the treatment and control of malaria, one of the authors of the research, Dr. Aimable Mbituyumuremyi, from the Division of Malaria and Other Parasitic Diseases in Rwanda, explained that the results show that the artemisinin treatment used in Rwanda (Arthemeter-Lumefantrina) is still effective against the parasite, with a cure rate above 95%, recommended by the World Health Organization (WHO), despite the appearance of these mutant parasites. This does not imply any change in our treatment guidelines, but we need to closely monitor the effectiveness of this combination to detect any need for changes in advance, he points out.

Dr. Didier Menard, from the Malaria Genetics and Resistance laboratory, at the Department Of Parasites And Insect Vectors at Pasteur Institute, France, and also one of the authors of the research, adds: “From my point of view and as it was expressed in the manuscript, the emergence and spread of in vitro artemisinin resistant R561H have currently no impact on the recommended ACT treatment in Rwanda, until the partner drugs (lumefantrine or piperaquine) are fully effective”, he stresses. To him, the main issue is to know for how long the partner drug will remain 100% effective, since an increasing number of parasites is now exposed to the partner drugs and the probability to select resistant parasites to both drugs (artemisinin and partner drug) is higher. “The most important action to reinforce the monitoring of the drug susceptibility of the parasites in Rwanda and the neighbor countries”, he observes

The WHO fears that 769 thousand people could die of malaria in sub-Saharan Africa this year, the number is double of that recorded in 2018. According to the World Malaria Report 2019, Sub-Saharan Africa was responsible for almost 93% of all cases worldwide and 94% of all deaths from the disease in 2018. More than two thirds of these deaths corresponded to children under 5 years of age.

To learn more about malaria, the Communication Office of the Brazilian Society of Tropical Medicine (BSTM), interviewed Dr. Virgilio do Rosário, researcher and retired professor at the Institute of Hygiene and Tropical Medicine, Universidade Nova de Lisboa (IHMT).

Find the full interview below:

SBMT: Why does resistance occur? Is the problem of drug resistance endless?

Dr. Virgilio do Rosário: In this world of drugs (or medications) the target is, in the case of malaria, the parasite. The issue is complex, often associated with poverty, social difficulties and wars and requires international cooperation to be resolved. There are no boundaries for the mobility of the transmitting insects.

In the case of malaria, treatment is antiparasitic. It requires an efficient diagnosis and treatment must be administered rigorously. The problem of resistance concerns, above all, infections with Plasmodium falciparum and P. vivax, the most relevant of the 4 species that cause human malaria.

Whether in therapy or in prophylaxis, the drug must be ingested, metabolized and act on the parasite and, as such, the drug ingested must be of quality and taken in the correct dosage.

Resistance occurs for several reasons. The drug should never cause the transformation (mutation) of the parasite from sensitive to resistant. Unicellular organisms, parasites of humans or animals, change naturally and are selected in suitable environments. In the laboratory, it is confirmed that under the presence of low doses of drugs, these parasites are selected that have gained one or more mutations linked to resistance. In certain cases, even high doses can select these parasites. It depends on the drug and its mechanism of action and laboratory experiments carried out with various animal models prove that the so-called parasitic mutations of resistance are associated with the mechanisms of these resistances.

Laboratory tests allow the study of resistant parasites by subjecting them to a range of dosages while molecular biology helps in the identification of genes that have undergone changes (mutations).

There are several experimental models where these studies are carried out.

In the various antimalarial drugs available, there are several examples of single mutations, or accumulated or even crossed mutations, and in this case, resistance to drug A is extensible to drug B.

Therefore, the resistance problem is due to the existence of parasites that carry mutations for resistance, selected by the environment in which they live. The drug eliminates those sensitive and allows the resistant to survive, who will now become the predominant population.

If in the life cycle of the parasite within the erythrocyte circulation, we enter the gametocyte production phase, and we are in the presence of a transmitting mosquito, this population begins to spread within the human population.

The problem has several components, as the cycle includes mankind (human malaria), the vector or transmitting mosquito and the environment in which it develops.

In Europe or North America and several countries in Asia this situation has been controlled, but Africa remains martyred.

SBMT: Does the discovery mark a setback in the fight against malaria?

Dr. Virgilio do Rosário: There will always be a problem of drug resistance. For some drugs, the emergence of resistance was rapid, as in the case of pyrimethamines and, in others, slower and even associated with geographical factors. For chloroquine, resistance first arose in Southwest Asia and Latin America and later in Africa. This motivated a great scientific discussion about a) parasitic diversity, b) use of chloroquinated salt, as a prophylactic and accidentally as a selective agent, c) excessive use of drugs in irregular dosages, d) absence of post-treatment surveillance, e) absence of personnel qualified in technical-laboratory teams, and f) the possible role of immunity in the selection of resistant parasites.

SBMT: Do you believe that this represents a threat to public health on the continent? Why?

Dr. Virgilio do Rosário: Without a doubt, resistance is a huge problem for public health and the economy. The pharmaceutical industry must have drugs that are effective and affordable. Resistance disables the use of drugs and requires national and international public health rules and studies on new drugs.

SBMT: In the article, scientists warned that parasites that developed resistance to previous drugs are suspected of having contributed to millions of additional malaria deaths in African children in the 1980s. Do you also believe in this possibility? Why?

Dr. Virgilio do Rosário: I do.

The African continent is the scene of enormous problems. There are problems of poverty, diversions of funds that could improve the health of the peoples, a huge inclusion of outside interests whose work in health care that, once finished, throws the populations back into poverty, due to the lack of continuity of these programs.

In Europe, success had to do with strong funding, with strong support from the USA at the time, and well-designed and applied programs, with permanent surveillance. These programs acted on the three most relevant points, humans, the vector mosquito, the environment in which it develops (with land drainage and elimination of mosquito breeding sites).

Thus, the transmission cycle should be interrupted and the parasite eliminated whenever possible. At the time, there was still no resistance to drugs or insecticides, both used in programs with good medical and technical teams.

In Africa, not all countries have properly applied the aid they received for these control actions. There is poverty, housing difficulties, unhealthiness and new diseases.

SBMT: You were one of the pioneers in Plasmodium cultures, which allowed for drug resistance testing. Could you tell us the story of your work on drug resistance to malaria, including in Brazil?

Dr. Virgilio do Rosário: The culture of P. falciparum had its origin in two scientists, Trager and Jensen, in the USA. The WHO organized various training courses and so at the Evandro Chagas Institute of the Sesp Foundation, work began on cultivating the parasite P. falciparum. The Institute had an excellent policy for disseminating the technique to any other interested institution. These cultures made it possible to carry out well-standardized drug resistance tests. They would later make it possible to produce gametocytes and to infect mosquitoes in the laboratory, in case of access to colonies of these vectors.

It also made it possible to isolate parasites from a patient and verify that the patient had different populations of parasites, and, in case of resistance, we could find parasites with different levels of resistance.

Molecular biology no longer requires cultures, as it would be concentrated on nucleic acids, namely DNA through techniques such as PCR and which require less infected blood.

Brazil has had and has several well-known research centers in the area of drugs, medicinal plants, applied molecular biology or entomology, and clinical trials, among others.

SBMT: Can we conclude that malaria is becoming more difficult to treat? What to expect in relation to drug resistance?

Dr. Virgilio do Rosário: Yes. Drug use policy is a topic of discussion. Researching new drugs, or traditional medicine, looking for medicinal plants that can serve as a basis for new drugs. The still highly valued use of Quinine or Artemisinin and its derivatives, both centuries-old and originated from plants, makes us believe in the importance of traditional medicine and plants.

The pharmaceutical industry is crucial in making decisions on this topic.

There have been and are dozens of studies on antimalarial vaccines, but bear in mind that an adequate immune response requires a population that has the capacity to establish an adequate immune response, and that hunger or other illnesses such as HIV/AIDS interfere negatively.

I believe that for any drug there will be resistance.

SBMT: What are the main events that contributed to the containment and eradication of malaria?

Dr. Virgilio do Rosário: Adequate funding and a well-designed, long-term program. Quality technical teams.

Knowledge about the region, from the species of parasites and vectors, a controlled distribution of drugs and insecticides, their correct use and continued surveillance. The use of mosquito nets can be essential, but without an adequate budget, little can be expected.

Successful programs are not always economically viable.

SBMT: Regarding research and the malaria vaccine, what would you highlight?

Dr. Virgilio do Rosário: Vaccine and new antimalarial research programs are always welcome. However, the parasite is extremely diverse and has a very visible morphological plasticity. Vaccine targets must be universal. Vaccination implies good health centers and records.

And little is studied about the role of human immunity, in certain circumstances, as a favorable agent for the parasite. It was questioned whether antimalarial antibodies could, when ingested by the mosquito, have an unexpected role in inducing a greater production of sporozoites, which are the causative agent of new infections.

In science, questioning is fundamental. Then laboratory methods are sought, the best possible, to search for answers. And basic biology is relevant to understand the behavior of parasites in their various facets.

SBMT: Would you like to add something that you consider relevant?

Dr. Virgilio do Rosário: The scientist does not like to mention social issues as negative factors in solving the malaria problem. The destruction of forests and the creation of breeding grounds for mosquitoes, the misuse or diversion of financial resources are factors that the malariologist witnesses, but it is not part of his study to research. Hence teams must be diverse and include teams with technical-scientific and social objectives.

The new diseases divert attention from the malaria problem, among others.