A new mathematical model of how malaria is transmitted from person to person suggests that the disease could be eliminated in many parts of the world if 80 to 85 percent of people who would not otherwise receive treatment were promptly treated with current first-line antimalarial drug therapies, artemisinin-based combination therapies (ACTs).
But adding the drug primaquine—a strategy currently being considered internationally —does not significantly improve the benefit of increasing treatment coverage, according to the model.
As the WHO and the Bill & and Melinda Gates Foundation plan to ramp up the introduction of primaquine in an effort to reduce the spread of malaria, the study suggests that the focus of elimination efforts should be on increasing coverage with current combination therapies.
“Our modeling study predicts that primaquine is not a game changer,” said one of the study’s principal investigators, David Fidock, PhD, professor of microbiology and immunology at Columbia University Medical Center. “If we are able to achieve full coverage of infected individuals with ACTs within five days of fever, we can achieve a far greater benefit than by adding primaquine.”
ACTs are the current first-line therapy for malaria worldwide. The rationale for adding primaquine to ACTs is based on studies reporting that primaquine reduces the number of gametocytes (the sexual stages of the parasite) in an infected person’s blood and limits the infectivity of the remaining gametocytes to the mosquito. Transmission of the parasite to additional people is impossible unless the sexual stage is passed from an infected person to a mosquito where the parasite reproduces.
Currently available ACTs rapidly reduce the numbers of circulating asexual blood-stage forms that cause disease. They also act upon immature gametocytes, as well as mosquito stages in some cases. The modeling study shows that these drugs are effective enough that they are essentially transmission-blocking if used correctly; therefore the addition of primaquine to the drug armamentarium would be of only very limited benefit.
“Clinical studies have reported an added benefit of primaquine; however, our modeling exercise finds that this benefit is modest in the context of population-wide transmission,” said co-author Geoffrey Johnston, PhD, who developed the model while a graduate student in the sustainable development program in Columbia’s School of International and Public Affairs.
The model produces a more realistic picture of transmission, as it considers many additional parameters, including how the drugs are absorbed in the body, immune responses, patient variability in response to the drugs, and how the drugs affect different parasitic stages in the infected person and inside the mosquito.
“We find that although primaquine reduces the number of sexual-stage parasites and the infectivity of those parasites to the mosquito, the bulk of parasite transmission comes from weeks to months of asexual-stage reproduction in the infected person,” Dr. Johnston said. “With ACTs, you stop producing asexual stages, so there are not many left to create the transmissible sexual forms. Some ACTs are also effective at killing the sexual and mosquito stages; if used correctly they already are the magic bullet we have been seeking with primaquine.”
The authors note that their model assumes that the effectiveness of the current ACTs is not compromised by the emergence of parasite resistance and that patients comply with treatment. “If one assumes that patients receive only a partial dose of ACTs or are malnourished so that the drugs do not work as well, there is room for a single-dose of primaquine to provide a benefit,” Dr. Johnston said. “It is also possible that primaquine could help new ACT combinations that are not as effective as the therapies modeled in our work. These alternative scenarios need to be investigated.”
By increasing the use of ACTs to cover most infected people, the authors say, it is possible to reduce the number of sexual and mosquito stages to such a low level that the parasite population becomes unstable and shrinks toward extinction.
Drs. Johnston and Fidock also worked with colleagues David Smith of Johns Hopkins University, as well as Peter Gething and Simon Hay of Oxford University, to apply their modeling results to maps of current malaria prevalence and locate areas of the world where malaria could conceivably be eliminated through achievable reductions in parasite transmission.These maps used parasite surveys to calculate the worldwide prevalence of malaria in 2010, including the levels of control that had been achieved to that point.
The authors found that increasing ACT coverage to promptly treat 93 to 98 percent of people with malaria symptoms above these current levels of control could eventually drive malaria to elimination in many areas of Southeast Asia and India, as well as parts of East and Southern Africa. (The model was not designed to look at sub-Saharan Africa, where malaria is so rampant that it evokes a substantial immune response.)
“We need to drastically increase the percentage of symptomatic people getting treatment,” Dr. Johnston said. “We cannot eliminate malaria now because many infected people are not getting treatment. They live in rural areas far from health clinics, or in refugee camps; or they are too poor. Because untreated individuals are so much more infectious than treated individuals, even a few untreated individuals in a population drastically reduce the effectiveness of any eradication effort.”
Drs. Fidock and Johnston are concerned that putting the focus on deploying primaquine will undermine efforts to increase use of ACTs. “The help that primaquine can provide appears in many cases to be minor, yet the problem is vast,” Dr. Johnston said.
“It’s like proposing to add a small thruster to a rocket to achieve a one percent increase in speed. The problem is that we haven’t built the rocket yet. A more realistic means of achieving a substantial reduction in the burden of malaria, based on our findings, is to facilitate prompt treatment with ACTs for essentially all symptomatic infections. Delivering effective medicines throughout endemic regions, many of which are very resource-poor, represents a major challenge and has the greatest potential impact on transmission.”
The study, published in the January 2014 issue of PLoS Computational Biology, was supported by grants from the Bill & Melinda Gates Foundation, Wellcome Trust, National Science Foundation, Department of Homeland Security, Fogarty International Center, Bloomberg Family Foundation, the UK Medical Research Council, and the NIH (AI079709).
The views expressed are those of the study authors alone and do not necessarily reflect the views of the funding agencies or any other outside organizations.