Primaquine Administration after Falciparum Malaria Treatment in Malaria Hypoendemic Areas with High Incidence of Falciparum and Vivax Mixed Infection: Pros and Cons

In malaria endemic areas, e.g. Thailand, where both Plasmodium falciparum and Plasmodium vivax [1] have caused approximately equal numbers of malaria cases for many years until recently, the prevalence of both species are nearly up to 50% each [2]. Both diseases may cause severe and fatal diseases. P. vivax relapses after curative treatment of P. falciparum, or subsequent appearance of P. vivax after P. falciparum clearance, occurs in up to 30% of cases during 2 months follow-up in hospitals [3], and approximately 10% with vivax malaria during 28 days in hospital have developed subsequent falciparum malaria [4-7]. Re-infection by other Plasmodium species after admission with initial falciparum or vivax malaria presentations in those studies was not possible since all patients were monitored in hospitals in Bangkok where no malaria transmission occurs and none of them received blood transfusion during hospitalization.

The diagnosis of mixed infections even by expert microscopists is rather difficult since P. falciparum suppresses P. vivax [8] and the converse may also occur [9]. Drug treatment of P. vivax also suppresses P. falciparum parasitemia. Mixed infections with P. falciparum and P. vivax are clinically unpredictable. Vivax patients with cryptic P. falciparum infection had a significantly lower mean hematocrit than those with P. vivax alone [7]. In many malaria endemic areas, P. falciparum is highly chloroquine-resistant and not suppressed by conventional vivax treatment. The conventional P. falciparum treatment, e.g. artemisinin combination therapy (ACT) or quinine plus doxycycline or clindamycin, with or without single dose of primaquine (30-45 mg base for adults and 0.5-0.75 mg base/kg in children to kill P. falciparum gametocytes) can kill both asexual forms of P. falciparum and P. vivax but can not eradicate P. vivax hypnozoites, if the patients have.

With microscopy, it has been hardly possible to identify mixed infections with submicroscopic P. falciparum in patients diagnosed with acute vivax malaria. However, PfHRP-2 test was sensitive and 99% specific in predicting mixed infections with subpatent P. falciparum parasitemia at presentation since asexual and immature sexual P. falciparum secrete PfHRP-2 in the patient's circulation for 3-4 weeks. Pf HRP-2 may be useful adjunct to microscopy in areas where mixed infections are common. However, PfHRP-2 has limitation to detect P. falciparum in mixed infections if P. falciparum parasitemia is too low. If subpatent P. falciaprum in patients who present with vivax malaria can be screened it may be useful.

Nested PCR and real-time PCR could detect mixed infections of P. falciparum and P. vivax. PCR assay surpass microscopy and also offer clear advantage in detection of mixed infections [10, 11]. PCR is more sensitive to detect both malaria species than PfHRP-2 for detection of P. falciparum. However, there is no study using pLDH adjunct to microscopy to detect P. falciparum and P. vivax mixed infections.

It was suggested by Mayxay et al. [7] that screening of every patient with vivax malaria at presentation with both microscopy and PfHRP-2 in areas where mixed infections were high should be weighted with the cost of the test, the risks, and cost of managing the subsequent falciparum malaria. However, in many endemic areas, PfHRP-2 or other rapid diagnostic test or PCR are not available or affordable. The cost of PfHRP-2 test with good quality is high (~US$3.00) and the cost of microscopic diagnosis of malaria is low (~US$0.50). Adjunct using PfHRP-2 and microscopy (which costs ~US$3.50) is rather expensive in many endemic countries and may not be practical.

Treatment of P. falciparum with blood schizontocides and concurrent chloroquine (10 mg base/kg start followed by 5 mg base/kg at 12, 24, and 36 hr; or 10 mg base/kg at 24 hr, 5 mg base/kg at 48 hr) and primaquine 15-30 mg base (0.25-0.5 mg/kg base) for 14 days for eradication of hypnozoites may be justified and possibly cost-effective in mixed infections. The incidence of P. vivax reappearance after P. falciparum treatment is high (~30%) in Thailand where nearly equal incidence of both malaria species (~50%) occurs. A 14 day primaquine administration concurrently with treatment of asexual forms of P. vivax is recommended in hypoendemic areas, e.g. Thailand. Concurrent chloroquine and primaquine administration reduces the period that the patient is infective to mosquitoes by about 4 days. Chloroquine and primaquine concurrent treatment may enhance the activity of chloroquine against blood-stage parasites and enhance the primaquine effects against the liver stage of the parasite [12]. While this may not be significant in a hospital setting in non-transmission areas, e.g., Bangkok, where no anopheles mosquitoes are found due to polluted water, in rural areas where patients are released to bed rest at their home, they will continue to infect mosquitoes.

Since G6PD deficiency status in Thailand is mild to moderate and all malaria clinics of Ministry of Public Health of Thailand do not routinely screen G6PD status of the patients as the national antimalarial program. Therefore, this management may be useful and possibly cost-effective (without taking into account of supplemental therapy or hospitalization costs or opportunity loss of work during illness) to treat both P. falciparum and P. vivax mixed infections when the patients present with P. falciparum malaria at only one visit at the clinic or hospital. Moreover, the risk of hemolysis from 14 day primaquine administration for vivax infection is very low in Thailand. The patients with mixed infections will be ill or lose work again with P. vivax if they are treated with only conventional treatment of P. falciparum without concurrent chloroquine and 14 days of primaquine administration. The cost of chloroquine treatment for a 60 kg adult is US$0.10 [13] and the cost of primaquine is also very cheap (US$0.30-0.60 for 14 tablets of 15-30 mg base primaquine). In some countries, like Indonesia, where P. vivax is chloroquine-resistant, ACTs with the exception of combinations containing sulfadoxine-pyrimethamine are the first-line of P. vivax treatment which will be beneficial to kill asexual forms of both P. vivax and subpatent P. falciparum mixed infections. However, if the patients given primaquine develop black urine or anemia due to hemolysis, they are advised to go to hospitals for further G6PD test and the cost of the test (NADH+ Spot test) is low (< US$1.00 per test) [14]. In the patients with mild to moderate G6PD deficiency, primaquine 0.75 mg base/kg body weight once a week for 8 weeks may be given. The cost of weekly 45 mg base of primaquine for 8 weeks is US$0.50.

Major drug interactions of chloroquine are very unusual. Theoretically, the risk of convulsions may be increased with mefloquine. Primaquine should be given after meal to avoid abdominal pain (an adverse effect if administered to an empty stomach). The disadvantage of the concurrent administration of ACT with chloroquine and primaquine is the amount of drugs, since the patients have to take many tablets for completing the treatment course.

In contrast, the incidence of P. falciparum appearance after P. vivax presentation is not high (~10%). Chloroquine given concurrently with 14 days of primaquine, which is the conventional treatment of P. vivax, cannot kill chloroquine-resistant P. falciparum. Conventional non-chloroquine treatment of P. falciparum, e.g., ACT, and concurrent administration of chloroquine and primaquine 14 days when the patients present with vivax malaria from the areas with chloroquine-sensitive P. vivax is expensive, not justified, and possibly not cost-effective although the patients may have mixed infections since the incidence of subsequent P. falciparum after P. vivax presentation is lower (~10%) than incidence of subsequent P. vivax after P. falciparum presentation (~30%) in mixed infections. The costs of antimalarial treatment for a 60 kg adult are US$2.50 for artesunate-mefloquine for 3 days, and US$2.00 for quinine plus doxycycline for 7 days [13]. Therefore, the cost of artesunate-mefloquine with concurrent chloroquine and 14 days of primaquine administration is US$2.90-3.20 which is not much higher than US$2.50 for the cost of artesunate-mefloquine alone. However, some clinicians do not prefer to treat malaria infection unless specific species is laboratory-confirmed, e.g., by microscopy. The national antimalarial program of many countries, including Thailand, recommended to treat certain malaria species according to laboratory confirmed diagnosis, even though the incidence of mixed P. falciparum and P. vivax infections is high and common when the patients present with P. falciparum malaria.

In conclusion, in malaria hypoendemic areas where mixed infections of P. falciparum and P. vivax is high when the patients present with P. falciparum malaria which is confirmed only by microscopy, conventional treatment of P. falciparum with concurrent chloroquine and 14 days of primaquine administration (for hypnozoite eradication, if there is subpatent P. vivax infection or even there is no mixed vivax infection at all) may be useful and possibly cost-effective. However, further studies to prove this hypothesis may be warranted in geographic regions where mixed infections are common and high and G6PD deficiency is mild or moderate. Whether the incidence of both falciparum and vivax malaria will decline in malaria endemic areas after this new treatment of falciparum malaria is interesting to follow.