The changing landscape of malaria parasite P. vivax’s resistance to drugs

Anopheles gambiae is a known vector for the parasitic disease malaria. – Photo James Gathany CDC

Plasmodium vivas in Western Thailand has developed resistance to a few anti-malarial drugs. – Photo: James Gathany/CDC

The malaria parasite Plasmodium vivax found in South America and Asia evolves quickly in response to widely-used anti-malarial drugs, a genomic study published on June 27, 2016 in the journal Nature Genetics shows.

The results are based on 200 samples collected from Southeast Asia (Thailand, Cambodia, Vietnam, Laos, Myanmar, and Malaysia) Oceania (Papua Indonesia and Papua New Guinea) and from China, India, Sri Lanka, Brazil and Madagascar.

P. vivax parasites evolved differently in Thailand, Cambodia and Indonesia in response to different anti-malarial drugs used there to treat P. falciparum. It is important to note that the drug resistance seen in P. vivax is in response to drugs that are primarily used to treat malaria caused by P. falciparum. While the precise mechanism remains unknown, it is a “worrying sign that drug resistance can get deeply entrenched in the parasite population”.

P. vivax can remain dormant inside a person’s liver for years until it emerges causing a malaria relapse. Many samples studied had mixed infections of P.vivax and P. falciparum parasites. The presence of both parasites in a person provides an ideal environment for P. vivax parasites to get exposed to drugs used for killing P. falciparum and develop resistance against the drug.

Mefloquine drug

Scientists found genomic changes leading to duplication of pvmdr1, which was previously associated with resistance to mefloquine drug used for treating P. falciparum, was found in 19 per cent of samples collected from western Thailand but not from western Cambodia and Papua Indonesia.

Unlike in western Cambodia and Papua Indonesia, mefloquine drug is widely used in western Thailand as first-line treatment (either as monotherapy or in combination with artemisinin) for P. falciparum. This drug might have caused high selective pressure on relapsing P. vivax infections that occur frequently after P. falciparum infections.

Pyrimethamine and sulfadoxine

Similarly, P. vivax in western Thailand was found to contain genes that are resistant to two drugs — pyrimethamine and sulfadoxine — used for treating malaria caused by P. falciparum. Thailand introduced sulfadoxine-pyrimethamine as first-line treatment in 1973. The widespread use of these drugs in the private sector might have caused considerable selective pressure, as also the “high frequency” of P. vivax relapse after treatment for malaria caused by P. falciparum, they write.

The western Thailand and western Cambodia samples showed positive selection on chromosome 2; western Thailand samples also showed selection on chromosome 13. Chromosome 2 has four well known genes that have been implicated as drug resistance candidates. And the selection on chromosome 13 has been implicated in antibiotic resistance.

Duffy blood group

Earlier studies had shown that P. vivax had caused malaria even in people who did not express the Duffy blood group protein on their red blood cells.  People who did not express the Duffy-binding protein (or Duffy negative people) were historically thought to be resistant to the disease.

The latest study found that duplication of a part of chromosome 6 encompassing pvdbp, the gene that encodes for Duffy-binding protein, enables P. vivax to infect Duffy negative people and is common in people of Malagasy. “These findings show that similar duplications can also reach relatively high frequency in places where nearly all individuals are Duffy positive,” writes Richard D. Pearson, the first author of the paper from Wellcome Trust Sanger Institute, Cambridge.

Chloroquine is the main drug used for treating P. vivax malaria. However, in Papua, Indonesia, the resistance of P. vivax to chloroquine is now rampant, the study says. “High-grade chloroquine resistance of unknown cause is firmly established” in Papua Indonesia, they say.

In patients who were carrying multiple strains of parasite in their blood, the genomic data made it possible to determine how closely the different strains were related to one another.

Plasmodium vivax causes nearly 16 million cases each year across the world and over 2.5 billion people are at risk of infection. Yet, unlike P. falciparum, studying P. vivax has been challenging. Besides being able to stay dormant in a person’s liver for a long time and cause malaria relapse, it is extremely difficult to grow the parasite under lab conditions, and is present at low levels in the blood. But the use of population-level genome sequencing is helping scientists to look at the genetics of the parasite.

“Genomic signals of recent selection could help identify local emergences of resistance, both to the drugs used specifically to treat P. vivax and to those that are targeted at P. falciparum,” they write.

Global dispersal of P. vivax

Another paper published on June 27 in the journal Nature Genetics confirmed that P. vivax showed high diversity compared with P. falciparum and “regional populations of P. vivax exhibited greater diversity than the global P. falciparum population”.   Even the least genetically diverse P. vivax subpopulation was found to be more diverse than of the most the diverse P. falciparum population.

The researchers sequenced 182 samples collected from 11 countries and identified four distinct parasite populations which clustered into two distinct groups — parasites from New World countries (Brazil, Peru, Colombia and others) differed greatly from those of the Old World countries (Thailand, Myanmar, India and others). P. vivax samples from Papua New Guinea were genetically distinct from elsewhere in Asia, while strains from Mexico formed a fourth genetic grouping. The less genetic diversity seen in Mexico is primarily due to a sharp reduction in the P. vivax cases.

The great diversity of the P. vivax parasite highlights the need to deploy a wide variety of strategies to eliminate the parasite globally.