By Philip R. Fischer, MD, DTM&H

Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN

Dr. Fischer reports no financial relationships relevant to this field of study.

SYNOPSIS: In glucose-6-phosphate-dehydrogenase-sufficient individuals in Southeast Asia, combined treatment with chloroquine and primaquine provides much more lasting relief from vivax malaria than either chloroquine alone or artesunate.

SOURCE: Chu CS, Phyo AP, Lwin KM, et al. Comparison of the cumulative efficacy and safety of chloroquine, artesunate, and chloroquine-primaquine in Plasmodium vivax malaria. Clin Infect Dis 2018;67:1543-1549.

Vivax malaria is mostly a seasonal infection along the Thailand-Myanmar border. Nonetheless, it is associated with significant morbidity resulting from frequently relapsing bouts of illness. In the United States, the treatment standard for patients with Plasmodium vivax infection generally is the use of chloroquine to eradicate the blood phase of the pathogen, followed by primaquine (an alternative, tafenoquine, just received FDA approval) to eradicate the liver phase organisms (hypnozoites) that account for the relapses. However, in endemic countries, chloroquine alone often is used. Although chloroquine alone usually is able to achieve a cure without relapse, it has not been clear whether different medication regimens also might delay or prevent recurrent symptomatic malaria infection.

Thus, researchers prospectively studied 644 patients at least 6 months of age from May 2010 through October 2012. Glucose-6-phosphate-dehydrogenase (G6PD)-sufficient individuals were randomized to receive either artesunate or chloroquine or both chloroquine and primaquine; G6PD-deficient individuals received either artesunate or chloroquine.

Parasitemia was cleared more rapidly with artesunate than with the other treatment regimens. With artesunate, 70% had cleared their parasites within the first day of treatment, 22% did so with chloroquine alone, and 28% did so with chloroquine and primaquine.

However, recurrence of infection by 28 days after treatment initiation was more common with artesunate (50%) than with chloroquine (8%). Combined chloroquine and primaquine led to much fewer recurrences (0.5%) than did either of the other therapeutic regimens. The median time to first recurrence was 28 days in those treated with artesunate, 49 days in those treated with chloroquine, and 195 days in those treated with both chloroquine and primaquine. Using primaquine reduced total recurrences by 92%. In fact, only 3% of individuals treated with both chloroquine and primaquine experienced repeated malaria episodes during the 12 months following initial treatment.

The investigators screened patients for G6PD deficiency prior to inclusion in the study. However, they readily remarked that current G6PD screening tests do not identify G6PD-heterozygous individuals and that heterozygous females risk significant anemia with primaquine treatment. Thus, one risk of primaquine treatment would be anemia in G6PD-heterozygous females, who are not always identified by the current routine G6PD screening tests.

COMMENTARY

Five different species of Plasmodium cause malaria in humans (not just four, as some of us learned in medical school). P. falciparum is responsible for approximately 200 million bouts of malaria and most of the 445,000 malaria-caused deaths each year (mostly in children in sub-Saharan Africa).1,2 P. vivax, the subject of this current study, is emerging as the most common cause of malaria outside Africa. P. ovale occurs mostly in West Africa. P. malariae occurs at low levels in tropical settings. The most recently recognized cause of human malaria, P. knowlesi, acts like P. falciparum clinically (causing severe disease), yet looks morphologically most similar to P. malariae. P. knowlesi is seen in Asian-Pacific areas.

P. falciparum has been markedly resistant to treatment with chloroquine for decades, but resistance has developed more recently and much less extensively for P. vivax. P. vivax can persist in a dormant state in the liver for months or even years; thus, later recurrences of symptomatic illness from the original infection still are possible. Therefore, effective treatment of P. vivax malaria depends not just on immediate clearance of bloodstream pathogens, but also on long-term reduction of recurrent bouts of symptomatic infection. Thus, artesunate is limited in treatment because although it can clear the initial bloodstream infection rapidly, it does not reduce or suppress subsequent release of parasites from the liver. Chloroquine persists longer in the human body than artesunate and, therefore, provides longer suppression of malaria, as noted in this new study by Chu and colleagues. Primaquine effects “radical cure” by killing the otherwise dormant liver stages of malaria.

Based on these new data, the authors rightly advocated for more widespread use of primaquine as part of malaria treatment, at least in areas such as Southeast Asia where malaria transmission is mostly seasonal rather than maintained throughout the year.

Of course, details are important. Chu and colleagues also recently published a systematic review showing that increasing the dose of chloroquine from the current standard 25 mg/kg over three days to 30 mg/kg, at least in young children, would reduce the risk of recurrent disease substantially, even when primaquine is not given.3

The incidence of malaria worldwide had been decreasing for several years and then plateaued in 2015-2016.1 Ninety percent of malaria cases are in Africa.1,2 Still, elimination programs continue.2 Ninety-one countries still are endemic for malaria, and 10 of those are on track to eliminate malaria by 2020.2

Travelers still are at risk of malaria. There were 1,517 individuals diagnosed with malaria in the United States in 2015, the most recent year for which summary data are available; 11 of those patients died.4 More than two-thirds of those individuals had been traveling to visit friends and relatives, and only about one-fourth of U.S. residents who returned home with malaria had been taking chemoprophylaxis.4

Researchers at a medical center in Washington, DC, reviewed its experience with 100 adult cases of imported malaria during this century.5 There, 76% had P. falciparum, and 94% had been traveling in sub-Saharan Africa.5 Twenty-one individuals had severe malaria (10 with cerebral malaria), but all survived (even though the pre-born child of one infected woman did not survive the infection).5 Clearly, pre-travel prescription of appropriate antimalarial prophylaxis, focusing especially on travelers going to visit friends and relatives, still is important.

REFERENCES

  1. World Health Organization. Malaria. Available at: http://www.who.int/malaria/en/. Accessed Nov. 3, 2018.
  2. World Health Organization. World Malaria Report 2017. Available at: http://www.who.int/malaria/publications/world-malaria-report-2017/en/. Accessed Nov. 3, 2018.
  3. Commons RJ, Simpson JA, Thriemer K, et al. The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence: A WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis. Lancet Infect Dis 2018;18:1025-1034.
  4. Mace KE, Arguin PM, Tan KR. Malaria surveillance — United States, 2015. MMWR Surveill Summ 2018;67:1-28.
  5. Akselrod H, Swierzbinski MJ, Zheng Z, et al. Characteristics and severity of disease among 100 cases of imported malaria seen at a U.S. university hospital, 2000-2017. Am J Trop Med Hyg 2018; doi: 10.4269/ajtmh.18-0608. [Epub ahead of print].