Higher chloroquine dose, add-on primaquine reduces parasitaemia recurrence in vivax malaria
Recurrence of Plasmodium vivax malaria following chloroquine treatment may be due to frequent under-dosing, according to a recent meta-analysis, which reports that add-on primaquine effectively prevents early recurrence.
“Increasing the target dose of chloroquine from 25–30 mg/kg could significantly reduce the risk of P. vivax recurrence within 42 days in children younger than 5 years who are not given primaquine,” said researchers.
Pooled analysis of 37 studies involving 5,240 patients showed that more than half (57.1 percent; n=2,990) were treated with chloroquine alone while 34.2 percent (n=1,790) received additional early primaquine. In those who were given chloroquine alone, the median dose was 25.4 mg/kg and more than a third (34.8 percent; n=1,041) received less than the recommended target dose of 25 mg/kg. [Lancet Infect Dis 2018;doi:10.1016/S1473-3099(18)30348-7]
Recurrence of parasitaemia between days 7 and 42 was reported in 505 patients who were given chloroquine alone. The cumulative risks of recurrence by days 28 and 42 were 10.4 percent and 32.4 percent, respectively.
Each 5-mg/kg increase in the dose of chloroquine led to a significantly reduced rate of recurrence between days 7 and 42 (adjusted hazard ratio [HR], 0.82; 95 percent CI, 0.69–0.97; p=0.021). This trend was significant even when adjusted for parasitaemia, sex and age.
Notably, the effect of increasing dosages was most pronounced in children <5 years of age (adjusted HR for each 5-mg/kg increase, 0.59; 0.41–0.86; p=0.0058).
In patients ≥5 years of age, higher chloroquine doses had no significant effect on the risk of recurrence up to day 21 but yielded reduced risks between days 22 and 42: 5 to <15 years (adjusted HR, 0.66; 0.45–0.96; p=0.030) and ≥15 years (adjusted HR, 0.83; 0.61–1.15; p=0.27).
In patients cotreated with early primaquine, 51.2 percent (n=917) were given doses between 3.5 and <5.0 mg/kg, while 48.8 percent (n=873) received ≥5 mg/kg; the median primaquine dose was 4.7 mg/kg. The cumulative risks of recurrent parasitaemia by days 28 and 42 were 1.4 percent and 4.9 percent, respectively, noticeably lower than those treated with chloroquine alone.
The result was confirmed in the Cox regression model, which showed a strong reduction in the risk of parasitaemia recurrence following addition of primaquine treatment (adjusted HR, 0.10; 0.05–0.17; p<0.0001). Moreover, no significant variation with time was observed. Primaquine significantly suppressed the rate of recurrence up to day 21 (adjusted HR, 0.07; 0.03–0.18; p<0.0001) and between days 22 and 42 (adjusted HR, 0.10; 0.06–0.18; p<0.0001).
While the addition of primaquine strongly improves treatment efficacy where resistance to chloroquine is high, the results of the present meta-analysis “suggest that in the absence of primaquine, an increased dose of chloroquine would also decrease P. vivax recurrence substantially in children younger than 5 years,” said researchers.
For the present meta-analysis, researchers accessed the databases of Cochrane, Web of Science, Embase and Medline. Studies that assessed the efficacy of chloroquine alone or in combination with primaquine for P vivax monoinfection were eligible for inclusion. Cox regression analyses were performed to investigate the effect of chloroquine dosage and primaquine inclusion on the rate of parasitaemia recurrence.
“[H]ealthcare providers should be encouraged to provide adjunctive primaquine radical therapy to reduce the risk of both recrudescent and relapsing infections,” said researchers, noting that this is especially relevant given the increasing reports of chloroquine failure for P. vivax malaria.
“Alternatively, a universal policy of [artemisinin combination therapy] for uncomplicated malaria, with additional primaquine for vivax malaria, should be considered in regions where there is a high risk of recurrent P. vivax after chloroquine treatment,” they added.