Early this month, two studies were published in Science and The Lancet, each with evidence of artemisinin-resistance along the Thailand-Myanmar border. If this strain of drug resistant malaria proves to be the same strain previously found in Cambodia, it would suggest that drug resistant malaria is spreading and, in the process, thwarting our efforts to control this devastating disease.
Artemisinins are extremely important antimalarial drugs. Developed by the Chinese in the 1970s and used worldwide since the 1990s, artemisinin-based combination therapies (ACT) have been recommended by the WHO as first-line treatment for Plasmodium falciparum, the deadliest of malaria species. Combination therapy is treatment using different drugs in tandem to combat disease. In this case, artemisinin compounds are used with other drugs to kill malaria parasites, and where they falter, a partner drug will succeed. However, it is feasible that a drastic increase in resistance could occur, rendering artemisinins, and thus some combination therapies, ineffective.
While there is some speculation around the global burden of malaria, the death toll is undeniably high. The World Health Organization (WHO) reports an approximate 650,000 deaths each year, but the Institute for Health Metrics and Evaluation claims that 1.2 million deaths were recorded in 2010 alone.
There are four species of malaria parasites that infect humans: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae. In recent years there have been a few human cases of a fifth type, a monkey malaria known as Plasmodium knowlesi.
The life of malaria parasites depends on human hosts and the female Anopheles mosquito. There are approximately 3,500 mosquito species, organized into 41 different groups (one of which is the Anopheles). Somewhere between 30 and 40 species of mosquitoes are able to transmit malaria.
Different species of malaria thrive in different regions. For example, P. falciparum, which kills approximately 1 million people each year, is found predominantly in Africa. P. vivax, far more prevalent than P. falciparum, lives mostly in Asia and Latin America.
An infected mosquito transmits malaria parasites to humans while taking a blood meal. Parasites grow in human liver cells and, when they reach a certain stage of growth, they burst the infected liver cells and move to red blood cells. Here they asexually multiply and destroy other red blood cells. Humans show signs of infection when the malaria parasites are in the blood cells.
Uncomplicated malaria presents with fever, chills, nausea, vomiting, and general discomfort. These attacks can last between six and ten hours, and may reoccur, depending on the species of malaria. Complicated malaria, usually called severe malaria, can cause seizures, coma, severe anemia, acute respiratory distress, or acute kidney failure.
There is no vaccine for malaria, so efforts focus on control and treatment. Malaria can be controlled with insecticides, treated mosquito nets, proper clothing, repellents and prophylaxis. Drug treatments include: atovaquone-proguanil (brand name: Malarone), chloroquine, doxycycline, mefloquine (brand name: Lariam), and quinine. However, some of these drugs are no longer effective in certain areas, due to resistance.
Drug resistance is a man made problem. It is also, as Bryan Walsh points out in Time’s Healthland, inevitable: “the more a treatment is used, the faster resistance will often develop, and the fact is that there are some 250 million cases of malaria a year.”
Resistance develops faster, though, when drugs are misused, or regimens are not followed (which could be caused by a myriad of social, political, or economic factors). Symptoms of malaria are not specific and can be indicative of other conditions. Definitive malaria diagnoses can only be made with microscopy (analyzing the patient’s blood under a microscope) or with rapid diagnostic tests. Definitive diagnoses may not always be feasible as they depend on technical resources and experience. Because malaria needs to be treated quickly, there is the chance that people without malaria are given malaria medication, thus contributing to drug resistance.
Drug Resistance in Asia
And now we’ve come full circle: back to the spread of resistant malaria in WHO Western Pacific and South East Asian regions. Hints of artemisinin resistance began in 2002, when failure rates of the artesunate (a class of artemisinins) and mefloquine combination therapy began to rise in Cambodia. In 2009, a study published in the New England Journal of Medicine investigated the efficacy of artemisinin-based combination therapy and artesunate monotherapy (monotherapy is treatment with one drug only) in western Cambodia compared to northwestern Thailand. The study found that western Cambodian P. falciparum parasites had significantly reduced susceptibility to artesunate, meaning that these dangerous parasites were surviving longer against the effects of the drug. The authors of the study point out that artemisinins have been used in Cambodia for over 30 years. Prior to artemisinin, Cambodians used chloroquine. They had to stop when P. falciparum developed chloroquine resistance. That resistance has since spread across Asia and to Africa. Could history be repeating itself?
Thailand borders Cambodia from the northwest. Myanmar lies northwest of Thailand. The studies published this month show drug resistant malaria on the Thai-Myanmar border. In the Lancet, scientists examined over 3,000 patients and found that it took significantly longer for malaria parasites to be killed during treatment with artemisinin therapies than it had in 2001. These new instances of drug resistance are found 800km away from the 2009 cases of antimalarial resistance. Researchers are currently testing if these two strains of resistant malaria are the same.
Frank Smithuis, director of Medical Action Myanmar, and Nick White, Professor of tropical medicine at Mahidol Oxford Tropical Medicine Research Unit, summarize the urgency of this issue in a New York Times opinion piece. Myanmar, they suggest, is the place to stop drug resistant malaria. They posit that this drug resistance threatens the control of malaria world wide, as no drugs can “satisfactorily” replace artemisinins. If Myanmar fails to control resistant malaria, it will spread to India and Sub Saharan Africa. They say Myanmar has a plan, but not the money, and “the world cannot afford to lose this battle.” According to White and Smithius, artemisinin resistance in Africa could cost between 10,000 and 200,000 children’s lives per year.
“Immediate and large scale action in Myanmar is needed to prevent further spread of these artemisinin-resistant malaria parasites. Myanmar needs substantial financial support to prevent a looming malaria catastrophe. The tropical world will be the beneficiary.”