P. vivax, the second major human malaria species, constitutes about 41% of malaria cases worldwide (1, 2) and is the dominant species of malaria in many areas outside Africa. It is prevalent in the Middle East, Asia, the Western Pacific and Central and South America. It is rarer in Africa and almost absent from West Africa (2). In most areas where P. vivax is prevalent, malaria transmission rates are low and, therefore, the affected populations achieve little immunity to this parasite. Consequently, people of all ages, adults and children alike are at risk of acquiring P. vivax infections (2). Where both P. falciparum and P. vivax prevail, the incidence rates of P. vivax tend to peak in people of a younger age than those of P. falciparum (3). The other two human malaria parasite species, P. malariae and P. ovale , are generally much less prevalent worldwide.
Among the four species of Plasmodium that affect humans, only P. vivax and P. ovale have the ability to form hypnozoites, parasite stages in the liver that can result in relapse infections weeks to months after the primary infection. P. vivax preferentially invades reticulocytes and this may lead to anaemia. Repeated infections lead to a chronic anaemia that can affect personal well-being, thereby impairing human and economic development in affected populations. The residual malaria burden of P. vivax is likely to be underestimated, and is increasing in some regions of the world (2). Appropriate case management of P. vivax malaria will help to minimize the global malaria burden.
Although P. vivax is known to be benign malaria, it causes a severe and debilitating febrile illness. Vivax malaria can also occasionally result in severe disease with life-threatening end-organ involvement, similar to severe disease in falciparum malaria. Severe vivax malaria manifestations can present with cerebral malaria (4), severe anaemia (5), jaundice (5), acute respiratory distress syndrome (6), splenic rupture (7), acute renal failure (8-10), severe thrombo-cytopenia (7, 11) and pancytopenia (5). The underlying mechanisms of severe manifestations are not well understood, and may be of an inflammatory pathology similar to that seen in falciparum malaria. During pregnancy, infection with P. vivax, as with P. falciparum, reduces birth weight. In primegravidae, the reduction is approximately two-thirds that associated with P. falciparum (110 g compared to 170 g), but the effect does not decline with successive pregnancies, indeed in the one large series in which this was studied, it increased (12). Chronic anaemia, sequestration and pro-inflammatory cytokines in the placenta lead to lower birth weights (12, 14), increasing the risk of low birth weight (<2500 g) and thus the risk of neonatal death.
Diagnosis of vivax malaria is based on microscopy. RDTs based on immuno-chromatographic methods are available for the detection of non-falciparum malaria. However, their sensitivities for detecting parasitaemias of ≤500/µl are low (15-21). The relatively high cost of these tests is a further impediment to their widespread use in endemic areas. Molecular markers for genotyping P. vivax parasites are available for the dhfr gene, and those for chloroquine resistance are under development.
The objectives of treatment of vivax malaria are to cure the acute infection and also to clear hypnozoites from the liver to prevent future relapses. This is known as radical cure.
There are relatively few studies on the treatment of P. vivax. Only 11% of the 435 published antimalarial drug trials have been on P. vivax malaria (22).
A10.3.1 Standard oral regimen
Chloroquine monotherapy (25 mg base/kg bw over 3 days) is recommended as the standard treatment for vivax malaria because the parasite remains sensitive to chloroquine in much of the world. Primaquine (0.25 or 0.5 mg base/kg bw in a single daily dose for 14 days) is used as a supplement to the standard treatment for the purpose of eradicating dormant parasites in the liver and preventing relapses. The optimal dose of primaquine differs in geographical areas depending on the relapsing nature of the infecting strain, and it remains unclear in patients of heavy body weight (23). This combination of chloroquine and primaquine constitutes treatment to achieve radical cure of vivax malaria.
Primaquine also has weak activity against blood stage parasites. The radical cure regimen of vivax malaria with chloroquine and primaquine therefore conforms to the definition of a combination therapy. The combination of any antimalarial against P. vivax infections with primaquine has improved cure rates (24, 28) and is therefore useful in the treatment of chloroquine-resistant P. vivax infections.
A10.3.2 Treatment of drug-resistant P. vivax
Therapeutic efficacy data available to date indicate that P. vivax remains sensitive to chloroquine throughout most of the world (26, 29-43). Indonesia is exceptional in that high therapeutic failure rates ranging from 5% to 84% have been reported on day 28 of follow-up (25, 26, 44-49). There are reports of chloroquine failure as both treatment and prophylaxis against P. vivax malaria from several countries and regions where the species is endemic (50-53). Some of these studies did not measure chloroquine drug concentrations, so that it is questionable whether these findings represented strictly defined chloroquine resistance (34, 38, 39, 41, 43, 54-57).
Antimalarials that are effective against P. falciparum are generally effective against the other human malarias. The exception to this is sulfadoxine-pyrimethamine to which P. vivax is commonly resistant. Owing to the high prevalence of dhfr mutations (pvdhfr) in P. vivax, resistance to sulfadoxine-pyrimethamine develops faster in this parasite than in P. falciparum, and resistant P. vivax become prevalent in areas where this drug is used for the treatment of falciparum malaria (37, 58-66).
The recommended treatment for chloroquine-resistant P. vivax is quinine (10 mg salt/kg bw three times a day for 7 days) (67). However, it is not an ideal treatment because of the toxicity of quinine and the poor adherence to this regimen. A study in Thailand has found that treatment of vivax malaria with quinine leads to early relapses. This may be because quinine has a short half-life, and no antihypnozoite activity (37).
Other treatments that have been tested for the treatment of P. vivax malaria with varying degrees of efficacy include the following drugs.
Amodiaquine (25-30 mg base/kg bw given over 3 days) has been used effectively for the treatment of chloroquine-resistant vivax malaria (67) and has been well tolerated (68-70). Primaquine must be added for radical cure. Mild nausea, vomiting and abdominal pain are the commonly reported adverse reactions (70).
Mefloquine (15 mg base/kg bw as a single dose) has been found to be highly effective with a treatment success of 100% (37).
Halofantrine (24 mg base/kg bw over 12 hours in three divided doses) has shown varied efficacy in vivax malaria (24, 25, 36, 37) but is not recommended because of its known cardiotoxicity.
Doxycycline alone (100 mg twice a day for 7 days) is not recommended for the treatment of vivax malaria because of its poor efficacy (46).
Artemisinin derivatives as monotherapy for 3-7 days have shown poor efficacy in vivax malaria, with day 28 cure rates of 47-77% (27, 37, 55). The addition of primaquine to these regimes improved the day 28 cure rates to 100% (27, 71).
Combinations of chloroquine (25 mg base/kg bw given in divided doses over 3 days) and sulfadoxine-pyrimethamine (based on a pyrimethamine dosage of 1.25 mg/kg bw as a single dose) or chloroquine (25 mg base/kg bw in divided doses over 3 days) and doxycycline (100 mg twice a day for 7 days) have shown modest efficacy (71-82%) and have not shown significant improvements in cure rate compared with chloroquine alone (46, 70).
Other combinations of artesunate (4 mg/kg bw, single daily dose for 3 days) and sulfadoxine-pyrimethamine (based on a pyrimethamine dosage of 1.25 mg/kg bw, single dose), when used in areas of high chloroquine-resistant P. vivax (west Papua), produced 28-day cure rates of less than 90% (64).
Artemether-lumefantrine (the latter formerly known as benflumetol) (16 tablets for 3 days or 20 tablets for 5 days given twice a day in divided doses) has shown significantly shorter parasite clearance times than in the standard regimen of chloroquine + primaquine. However, these regimens were associated with higher relapse rates than with chloroquine + primaquine in the nine months of follow up (72). In another evaluation of the efficacy of artemether-lumefantrine against P. falciparum the population studied included patients who were also infected with P. vivax. Although high rates of P. vivax parasite clearance were noted within 42 h, in 6/16 patients parasites reappeared before 28 days (73).
The best combinations for the treatment of P. vivax are those containing primaquine when given at antihypnozoite doses (24, 29, 37, 39, 56, 70, 74, 75). The addition of primaquine at the standard dose of 0.25 mg/kg bw, once daily for 14 days to chloroquine has improved the cure rates in chloroquine-resistant vivax malaria (25, 39, 54, 56). Further, at higher doses (0.5-0.6 mg/kg, once daily for 14 days), primaquine appears to be effective in areas where there are presumed primaquine-resistant hypnozoite infections (27, 76).
Unlike P. falciparum, P. vivax cannot be cultured continuously in vitro, so that it is more difficult to determine the in vitro sensitivity of P. vivax to antimalarials. In vivo assessment of the therapeutic efficacy of drugs against P. vivax malaria is also compounded by difficulties in distinguishing recrudescences due to drug-resistant infections from relapses. The interval between the primary and repeat infection can serve as a general guide. If the recurrence appears within 16 days of starting treatment of the primary infection it is almost certainly a recrudescence due to therapeutic failure. A recurrence between days 17 and
28 may be either a recrudescence by chloroquine-resistant parasites or a relapse. Beyond day 28 any recurrence probably represents a relapse in an infection of chloroquine-sensitive P. vivax (77, 78). A recurrent vivax parasitaemia in the presence of chloroquine blood levels exceeding 100 ng/ml, and a parasite genotype identical with the primary infection as detected by PCR are more suggestive of chloroquine resistance of the primary infection than a relapse infection.
A10.3.3 Preventive therapy for relapses
Primaquine is the only available and marketed drug that can eliminate the latent hypnozoite reservoirs of P. vivax and P. ovale that cause relapses. There is no evidence that treatment courses shorter than 14 days are effective in preventing relapses (39, 56, 79, 80). Relapse rates and primaquine sensitivity vary geographically. The reported incidences of relapses range from 11-26.7% in India (56, 81) to 49-51% in Afghanistan (79). Relapses may occur one to four times after initiation of radical treatment (80, 82). In patients treated with chloroquine, the first relapse is often suppressed by pharmacologically active concentrations of chloroquine and therefore does not manifest clinically or parasitologically. The first clinically manifested relapse has been reported any time after day 16 and up to four years following the primary infection (83, 85). Host immunity is also considered to be a major contributor to the therapeutic response against relapses (86). Risk factors associated with relapses are female sex, higher parasitaemia at baseline, shorter number of days with symptoms prior to baseline, and a lower dose of primaquine (83).
Hypnozoites of many strains of P. vivax are susceptible to a total dose of 210 mg of primaquine (24, 37, 54, 75, 79, 83, 87). Infections with the Chesson strain or primaquine-resistant strains prevalent in southern regions of SouthEast Asia and Oceania require a higher dosage of primaquine (22.5 mg or 30 mg per day for 14 days for a total dose of 315 mg or 420 mg, respectively) to prevent relapses (56, 74, 76). Primaquine is contraindicated in patients with severe variants of the inherited enzyme deficiency, G6PD (88, 89) (see section below on adverse effects).
Although, the long 14-day course of primaquine is a clear disadvantage, it has been shown that poor adherence to unsupervised 14-day primaquine therapy can be overcome effectively through patient education (90). The lengthy treatment courses and follow-up periods make the assessment of primaquine efficacy difficult. Thus, the identification of P. vivax strains that are resistant to chloroquine and/or to primaquine presents major challenges.
Alternative drugs are much needed for the radical treatment of P. vivax malaria resistant to chloroquine and/or primaquine. A new drug, tafenoquine, is currently being evaluated as an alternative to primaquine in the prevention of relapses (91). However, this too has haemolytic potential in G6PD-deficient individuals.
A10.3.4 Treatment of severe and complicated vivax malaria
Prompt and effective management should be the same as for severe and complicated falciparum malaria (set out in section 8 of the main document).
A10.3.5 Treatment of malaria caused by P. ovale and P. malariae
Resistance of P. ovale and P. malariae to antimalarials is not well characterized and these infections are considered to be generally sensitive to chloroquine. Only a single study in Indonesia has reported P. malariae resistant to chloro-quine (63). The recommended treatment for radical cure of P. ovale , another relapsing malaria, is the same as that for P. vivax, i.e. with chloroquine and primaquine. The high prevalence of G6PD-deficiency status in areas endemic for P. ovale calls for the same caution in the use of primaquine as stated in section A10.3.3. P. malariae forms no hypnozoites and so does not require radical cure with primaquine.
A10.3.6 Adverse effects and contraindications
Chloroquine is generally well tolerated. Common adverse effects include mild dizziness, nausea, vomiting, abdominal pain and itching (3, 67 86).
Primaquine can induce a life-threatening haemolysis in those who are deficient in the enzyme G6PD (see section A10.3.3). A full course of primaquine, given as a daily dose of 0.25 mg base/kg bw for 14 days, is reported to be safe in populations where G6PD deficiency is either absent or readily diagnosable but could induce a self-limiting haemolysis in those with mild G6PD deficiency (34, 54, 56). To reduce the risk of haemolysis in such individuals, an intermittent primaquine regimen of 0.75 mg base/kg weekly for 8 weeks can be given under medical supervision. This regimen is safe and effective (89). In non-G6PD deficient individuals, a high dose of primaquine (30 mg/day) has been shown to be safe and effective for Chesson strain P. vivax malaria in South-East Asia during a 28-day follow-up (27, 74, 76). In regions where prevalence of G6PD deficiency is relatively high, G6PD testing is required before administration of primaquine. Primaquine is not recommended during pregnancy and in infancy since limited safety data are available in these groups (67). Abdominal pain and/or cramps are commonly reported when primaquine is taken on an empty stomach. Gastrointestinal toxicity is dose-related and is improved by taking primaquine with food. Primaquine may cause weakness, uneasiness in the chest, haemolytic anaemia, methaemoglobinaemia (which occurs in non- haemolysed red cells), leukopenia, and suppression of myeloid series. Therefore, primaquine should not be given in conditions predisposing to granulocytopenia, including rheumatoid arthritis and lupus erythematosus.
A10.4 Monitoring therapeutic efficacy
There is a need to monitor the antimalarial sensitivity of P. vivax in order to improve the treatment of vivax malaria, in particular in view of its emerging resistance to chloroquine. An in vitro test system has been developed for assessing the parasite's sensitivity to antimalarials (92, 93). A modified version of the standard WHO in vitro microtest for determination of the antimalarial sensitivity of P. falciparum has been used successfully for assessing the antimalarial sensitivity of P. vivax populations and for screening the efficacy of new antimalarials by measuring minimal inhibitory concentration (MIC), and the concentrations providing 50% and 90% inhibition (IC50), and (IC90) (87, 89). WHO has also recently introduced a revised protocol for in vivo monitoring of the therapeutic efficacy of chloroquine in P. vivax malaria (95). The revised protocol includes measurement of blood chloroquine levels, PCR genotyping and the use of molecular markers (only available for the dhfr gene) to help clarify and complete the overall picture of drug resistance. A better understanding of the molecular mechanisms underlying drug resistance in P. vivax is needed to improve the monitoring of chloroquine resistance.
A10.5 Conclusions and recommendations
• The standard oral regimen of chloroquine of 25 mg base/kg bw given over 3 days + primaquine at either a low (0.25 mg base/kg bw per day for 14 days) or high (0.5-0.75 mg base/kg bw per day for 14 days) dose is effective and safe for the radical cure of chloroquine-sensitive P. vivax malaria in patients with no G6PD deficiency.
• Of the limited alternative treatments that have been evaluated, amodiaquine is a promising monotherapy and has been shown to be effective for the treatment of chloroquine-resistant P. vivax malaria (cure rate >90%).
• In areas where infections of drug-resistant P. falciparum and/or P. vivax are common, drug regimens to treat both species effectively must be used. An ACT that does not include sulfadoxine-pyrimethamine would be a good choice.
• The use of high-dose primaquine (0.5-0.75 mg base/kg bw per day for 14 days), with either chloroquine or another effective antimalarial, is essential for trying to prevent relapses of primaquine-resistant or primaquine-tolerant P. vivax.
• A primaquine regimen of 0.75 mg base/kg bw once per week for 8 weeks is recommended as antirelapse therapy for P. vivax and P. ovale malaria in patients with mild G6PD deficiency.
• Increased efforts are needed to evaluate alternative treatments for P. vivax strains that are resistant to chloroquine. Urgent needs include establishing in vitro culture of P. vivax to permit the assessment of drug susceptibility, research to improve understanding of the molecular mechanisms of drug resistance, and the development of better tools for genotyping P. vivax.
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