Treating uncomplicated P. vivax, P. ovale, P. malariae or P. knowlesi malaria
Blood stage infection
If the malaria species is not known with certainty, treat as for uncomplicated P. falciparum malaria.
Good practice statement
In areas with chloroquine-susceptible infections, treat adults and children with uncomplicated P. vivax, P. ovale, P. malariae or P. knowlesi malaria with either an ACT (except pregnant women in their first trimester) or chloroquine.
Strong recommendation, high-quality evidence
In areas with chloroquine-resistant infections, treat adults and children with uncomplicated P. vivax, P. ovale, P. malariae or P. knowlesi malaria (except pregnant women in their first trimester) with an ACT.
Strong recommendation, high-quality evidence
Treat pregnant women in their first trimester who have chloroquine-resistant P. vivax malaria with quinine.
Strong recommendation, very low-quality evidence
Preventing relapse in P. vivax or P. ovale malaria
The G6PD status of patients should be used to guide administration of primaquine for preventing relapse.
Good practice statement
To prevent relapse, treat P. vivax or P. ovale malaria in children and adults (except pregnant women, infants aged < 6 months, women breastfeeding infants aged < 6 months, women breastfeeding older infants unless they are known no to be G6PD deficient, and people with G6PD deficiency) with a 14-day course of primaquine in all transmission settings.
Strong recommendation, high-quality evidence
In people with G6PD deficiency, consider preventing relapse by giving primaquine base at 0.75 mg/kg bw once a week for 8 weeks, with close medical supervision for potential primaquine-induced adverse haematological effects.
Conditional recommendation, very low-quality evidence
When the G6PD status is unknown and G6PD testing is not available, a decision to prescribe primaquine must be based on an assessment of the risks and benefits of adding primaquine.
Good practice statement
Pregnant and breast feeding women
In women who are pregnant or breastfeeding, consider weekly chemoprophylaxis with chloroquine until delivery and breastfeeding are completed, then, on the basis of G6PD status, treat with primaquine to prevent future relapse.
Conditional recommendation, moderate-quality evidence
P. vivax is the second most important causative agent of human malaria. Approximately 35% of the world's population is at risk. P. vivax accounts for approximately 9%8 of malaria cases worldwide and is the dominant malaria species outside Africa. P. vivax is prevalent in endemic areas in Asia, Central and South America, the Middle East and Oceania. In Africa, P. vivax is relatively uncommon, except in the Horn of Africa. In West Africa, P. vivax is rare except in Mauritania and Mali. In most areas in which P. vivax is prevalent, malaria transmission rates are low, and the affected populations therefore achieve little immunity. Consequently, people of all ages are at risk. The exception is the island of New Guinea, where transmission in some parts is intense. The other human malaria parasite species P. malariae and P. ovale (two sympatric species) are generally less prevalent, but they are distributed worldwide, especially in the tropical areas of Africa. During the past decade, there have been many reported human infections with P. knowlesi, a simian parasite in the forested areas of South-East Asia. In parts of the island of Borneo, this is now the main species causing malaria. Further information is provided in Annex 6.
Of the species of Plasmodium that affect humans, only P. vivax and P. ovale form hypnozoites, which are dormant parasite stages in the liver that cause relapses of infection weeks to years after the primary infection. Thus, a single mosquito inoculation may result in repeated bouts of illness. P. vivax exists in two general forms: the more prevalent tropical form, which causes malaria that relapses at frequent intervals (typically every 3 weeks unless slowly eliminated antimalarial drugs are given, in which case the interval is 5–7 weeks) and tends to be less susceptible to primaquine; and a temperate form, in which there may be a long (∼9-month) incubation period or a similarly long interval between primary illness and relapse. The temperate form of P. vivax is more sensitive to primaquine. Infection with P. vivax during pregnancy reduces the birth weight of the infant, as does P. falciparum. In primigravidae, the birth weight reduction is approximately two thirds of that associated with P. falciparum (110 g compared with 170 g), but this adverse effect does not decrease with successive pregnancies, unlike in P. falciparum infections. P. knowlesi infections in humans are potentially dangerous; the patient may deteriorate rapidly because this parasite has a 24-h asexual cycle (quotidian) and so the parasite burden may expand rapidly, resulting in severe and sometimes fatal illness.
6.1. THERAPEUTIC OBJECTIVE
The objective of treating malaria caused by P. vivax and P. ovale is to cure both blood-stage and liver-stage infections (called radical cure), thereby preventing recrudescence and relapse, respectively.
6.2. DIAGNOSIS
The clinical features of uncomplicated malaria are non-specific, and diagnosis of malaria requires blood testing. Malaria species are usually differentiated by microscopy. Young ring forms of all species look similar, but older stages and gametocytes have species-specific characteristics, except for the two forms of P. ovale, which appear identical. P. knowlesi malaria is frequently misdiagnosed as P. malariae, so any case of high parasitaemia with “P. malariae-like” parasites in or near an area where long- or pig-tailed macaque monkeys live should be treated as P. knowlesi until proved otherwise. P. knowlesi infections require confirmation by PCR. RDTs based on lateral flow immunochromatography are available for the detection of P. vivax, and their performance has improved in recent years, although their sensitivity for the other non-falciparum malarias is low. Molecular genotyping of P. vivax parasites is less useful in studies of therapeutic efficacy than in falciparum malaria as relapses may be due to either the same genotype that caused the initial illness or a different one.
6.3. SUSCEPTIBILITY OF P. VIVAX, P. OVALE, P. MALARIAE AND P. KNOWLESI TO ANTIMALARIAL DRUGS
Few recent data are available on the susceptibility of P. ovale, P. malariae and P. knowlesi to antimalarial agents in vivo. These species are all regarded as sensitive to chloroquine, although chloroquine resistance was reported recently in P. malariae. Experience indicates that P. ovale and P. malariae are also susceptible to amodiaquine, mefloquine and the artemisinin derivatives and to ACT. Their susceptibility to antifolate antimalarial drugs, such as SP, is less certain. P. knowlesi is also sensitive to quinine, mefloquine, atovaquone – proguanil and artemether + lumefantrine and severe knowlesi malaria responds well to artesunate.
The susceptibility of P. vivax has been studied extensively, and, now that short-term culture methods have been standardized, the results of clinical studies are supported by in vitro observations. P. vivax is generally still sensitive to chloroquine, but resistance is increasing. High-level resistance to chloroquine is prevalent throughout the island of New Guinea, in Oceania and in parts of Indonesia. Lower-level resistance is found in other parts of South-East Asia and parts of South America. On the Indian subcontinent where most of the world's P. vivax malaria occurs, the parasites are mainly sensitive to chloroquine. Resistance to pyrimethamine has increased rapidly in some areas, rendering SP ineffective. There are insufficient data on current susceptibility to proguanil, although resistance to proguanil was selected rapidly when it was first used in areas endemic for P. vivax malaria.
In general, P. vivax is sensitive to all the other antimalarial drugs. In contrast to P. falciparum, asexual stages of P. vivax are also susceptible to primaquine. Thus, chloroquine + primaquine can be considered as a combination treatment for blood-stage infections, in addition to providing radical cure. The only drugs with significant activity against the hypnozoites are the 8-aminoquinolines (primaquine, bulaquine, tafenoquine). There is no standardized in vitro method for assessing the hypnozoiticidal activity of antimalarial drugs. In vivo assessments suggests that tolerance of P. vivax to primaquine is greater in eastern Asia and Oceania than elsewhere.
6.4. TREATMENT OF BLOOD-STAGE INFECTION
Treating uncomplicated P. vivax, P. ovale, P. malariae or P. knowlesi malaria
In areas with chloroquine-susceptible infections, treat adults and children with uncomplicated P. vivax, P. ovale, P. malariae or P. knowlesi malaria with either an ACT (except pregnant women in their first trimester) or chloroquine.
Strong recommendation, high-quality evidence
In areas with chloroquine-resistant infections, treat adults and children with uncomplicated P. vivax, P. ovale, P. malariae or P. knowlesi malaria (except pregnant women in their first trimester) with an ACT.
Strong recommendation, high-quality evidence
In a systematic review of ACTs for the treatment of P. vivax malaria, five trials were conducted in Afghanistan, Cambodia, India, Indonesia and Thailand between 2002 and 2011 with a total of 1622 participants which compared ACTs directly with chloroquine. In comparison with chloroquine:
ACTs cleared parasites from the peripheral blood more quickly (parasitaemia after 24 h of treatment: RR, 0.42; 95% CI, 0.36–0.50, four trials, 1652 participants, high-quality evidence); and
ACTs were at least as effective in preventing recurrent parasitaemia before day 28 (RR, 0.58; 95% CI, 0.18–1.90, five trials, 1622 participants, high-quality evidence).
In four of these trials, few cases of recurrent parasitaemia were seen before day 28 with both chloroquine and ACTs. In the fifth trial, in Thailand in 2011, increased recurrent parasitaemia was seen after treatment with chloroquine (9%), but was infrequent after ACT (2%) (RR, 0.25; 95% CI, 0.09–0.66, one trial, 437 participants).
ACT combinations with long half-lives provided a longer prophylactic effect after treatment, with significantly fewer cases of recurrent parasitaemia between day 28 and day 42 or day 63 (RR, 0.57; 95% CI, 0.40–0.82, three trials, 1066 participants, moderate-quality evidence).
Other considerations
The guideline development group recognized that, in the few settings in which P. vivax is the only endemic species and where chloroquine resistance remains low, the increased cost of ACT may not be worth the small additional benefits. Countries where chloroquine is used for treatment of vivax malaria should monitor for chloroquine resistance and change to ACT when the treatment failure rate is > 10% at day 28.
Gogtay N, Kannan S, Thatte UM, Olliaro PL, Sinclair D. Artemisinin-based combination therapy for treating uncomplicated Plasmodium vivax malaria. Cochrane Database Systemat Rev. 2013;10 CD008492. [PMC free article: PMC6532731] [PubMed: 24163021] [CrossRef].
6.4.1. UNCOMPLICATED P. VIVAX MALARIA
In areas with chloroquine-sensitive P. vivax
For chloroquine-sensitive vivax malaria, oral chloroquine at a total dose of 25 mg base/kg bw is effective and well tolerated. Lower total doses are not recommended, as these encourage the emergence of resistance. Chloroquine is given at an initial dose of 10 mg base/kg bw, followed by 10 mg/kg bw on the second day and 5 mg/kg bw on the third day. In the past, the initial 10-mg/kg bw dose was followed by 5 mg/kg bw at 6 h, 24 h and 48 h. As residual chloroquine suppresses the first relapse of tropical P. vivax (which emerges about 3 weeks after onset of the primary illness), relapses begin to occur 5–7 weeks after treatment if radical curative treatment with primaquine is not given.
ACTs are highly effective in the treatment of vivax malaria, allowing simplification (unification) of malaria treatment; i.e. all malaria infections can be treated with an ACT. The exception is artesunate + SP, where resistance significantly compromises its efficacy. Although good efficacy of artesunate + SP was reported in one study in Afghanistan, in several other areas (such as South-East Asia) P. vivax has become resistant to SP more rapidly than P. falciparum. The initial response to all ACTs is rapid in vivax malaria, reflecting the high sensitivity to artemisinin derivatives, but, unless primaquine is given, relapses commonly follow. The subsequent recurrence patterns differ, reflecting the elimination kinetics of the partner drugs. Thus, recurrences, presumed to be relapses, occur earlier after artemether + lumefantrine than after dihydroartemisinin + piperaquine or artesunate + mefloquine because lumefantrine is eliminated more rapidly than either mefloquine or piperaquine. A similar temporal pattern of recurrence with each of the drugs is seen in the P. vivax infections that follow up to one third of acute falciparum malaria infections in South-East Asia.
In areas with chloroquine-resistant P. vivax
ACTs containing piperaquine, mefloquine or lumefantrine are the recommended treatment, although artesunate + amodiaquine may also be effective in some areas.
In the systematic review of ACTs for treating P. vivax malaria, dihydroartemisinin + piperaquine provided a longer prophylactic effect than ACTs with shorter half-lives (artemether + lumefantrine, artesunate + amodiaquine), with significantly fewer recurrent parasitaemias during 9 weeks of follow-up (RR, 0.57; 95% CI, 0.40–0.82, three trials, 1066 participants). The half-life of mefloquine is similar to that of piperaquine, but use of dihydroartemisinin + piperaquine in P. vivax mono-infections has not been compared directly in trials with use of artesunate + mefloquine.
In the first-trimester of pregnancy, quinine should be used in place of ACTs (section 5.1).
6.4.2. UNCOMPLICATED P. OVALE, P. MALARIAE OR P. KNOWLESI MALARIA
Resistance of P. ovale, P. malariae and P. knowlesi to antimalarial drugs is not well characterized, and infections caused by these three species are generally considered to be sensitive to chloroquine. In only one study, conducted in Indonesia, was resistance to chloroquine reported in P. malariae.
The blood stages of P. ovale, P. malariae and P. knowlesi should therefore be treated with the standard regimen of ACT or chloroquine, as for vivax malaria.
6.4.3. MIXED MALARIA INFECTIONS
Mixed malaria infections are common in endemic areas. For example, in Thailand, despite low levels of malaria transmission, 8% of patients with acute vivax malaria also have P. falciparum infections, and one third of acute P. falciparum infections are followed by a presumed relapse of vivax malaria (making vivax malaria the most common complication of falciparum malaria).
Mixed infections are best detected by nucleic acid-based amplification techniques, such as PCR; they may be underestimated with routine microscopy. Cryptic P. falciparum infections in vivax malaria can be revealed in approximately 75% of cases by RDTs based on the PfHRP2 antigen, but several RDTs cannot detect mixed infection or have low sensitivity for detecting cryptic vivax malaria. ACTs are effective against all malaria species and so are the treatment of choice for mixed infections.
6.5. TREATMENT OF THE LIVER STAGES (HYPNOZOITES) OF P. VIVAX AND P. OVALE
Preventing relapse in P. vivax or P. ovale malaria
To prevent relapse, treat P. vivax or P. ovale malaria in children and adults (except pregnant women, infants aged < 6 months, women breastfeeding infants < 6 months, women breastfeeding older infants unless they are known not to be G6PD deficient and people with G6PD deficiency) with a 14-day course of primaquine in all transmission settings.
Strong recommendation, high-quality evidence
In people with G6PD deficiency, consider preventing relapse by giving primaquine base at 0.75 mg base/kg bw once a week for 8 weeks, with close medical supervision for potential primaquine-induced adverse haematological effects.
Conditional recommendation, very low-quality evidence
In a systematic review of primaquine for radical cure of P. vivax malaria, 14 days of primaquine was compared with placebo or no treatment in 10 trials, and 14 days was compared with 7 days in one trial. The trials were conducted in Colombia, Ethiopia, India, Pakistan and Thailand between 1992 and 2006.
In comparison with placebo or no primaquine:
14 days of primaquine (0.25 mg/kg bw per day) reduced relapses during 15 months of follow-up by about 40% (RR, 0.60; 95% CI, 0.48–0.75, 10 trials, 1740 participants, high-quality evidence).
In comparison with 7 days of primaquine:
14 days of primaquine (0.25 mg/kg bw per day) reduced relapses during 6 months of follow-up by over 50% (RR, 0.45; 95% CI, 0.25–0.81, one trial, 126 participants, low-quality evidence).
No direct comparison has been made of higher doses (0.5 mg/kg bw for 14 days) with the standard regimen (0.25 mg/kg bw for 14 days).
Twelve of the 15 trials included in the review explicitly excluded people with G6PD deficiency; the remaining three did not report on this aspect. No serious adverse events were reported.
Other considerations
In the absence of evidence to recommend alternatives, the guideline development group considers 0.75 mg/kg bw primaquine given once weekly for 8 weeks to be the safest regimen for people with mild-to-moderate G6PD deficiency.
Galappaththy GNL, Tharyan P, Kirubakaran R. Primaquine for preventing relapse in people with Plasmodium vivax malaria treated with chloroquine. Cochrane Database Systemat Rev. 2013;10 CD004389. [PMC free article: PMC6532739] [PubMed: 24163057] [CrossRef].
6.5.1. PRIMAQUINE FOR PREVENTING RELAPSE
To achieve radical cure (cure and prevention of relapse), relapses originating from liver hypnozoites must be prevented by giving primaquine. The frequency and pattern of relapses varies geographically, with relapse rates generally ranging from 8% to 80%. Temperate long-latency P. vivax strains are still prevalent in many areas. Recent evidence suggests that, in endemic areas where people are inoculated frequently with P. vivax, a significant proportion of the population harbours dormant but “activatable” hypnozoites. The exact mechanism of activation of dormant hypnozoites is unclear. There is evidence that systemic parasitic and bacterial infections, but not viral infections, can activate P. vivax hypnozoites, which explains why P. vivax commonly follows P. falciparum infections in endemic areas where both parasites are prevalent. Thus, the radical curative efficacy of primaquine must be set against the prevalent relapse frequency and the likely burden of “activatable” hypnozoites. Experimental studies on vivax malaria and the relapsing simian malaria P. cynomolgi suggest that the total dose of 8-aminoquinoline given is the main determinant of radical curative efficacy. In most therapeutic assessments, primaquine has been given for 14 days. Total doses of 3.5 mg base/kg bw (0.25 mg/kg bw per day) are required for temperate strains and 7 mg base/kg bw (0.5 mg/kg bw per day) is needed for the tropical, frequent-relapsing P. vivax prevalent in East Asia and Oceania. Primaquine causes dose-limiting abdominal discomfort when taken on an empty stomach; it should always be taken with food.
Primaquine formulation: If available, administer scored tablets containing 7.5 or 15 mg of primaquine. Smaller-dose tablets containing 2.5 and 5 mg base are available in some areas and facilitate accurate dosing in children. When scored tablets are not available, 5 mg tablets can be used.
Therapeutic dose: 0.25–0.5 mg/kg bw per day primaquine once a day for 14 days (see Annex 5, A5.11).
Use of primaquine to prevent relapse in high-transmission settings was not recommended previously, as the risk for new infections was considered to outweigh any benefits of preventing relapse. This may have been based on underestimates of the morbidity and mortality associated with multiple relapses, particularly in young children. Given the benefits of preventing relapse and in the light of changing epidemiology worldwide and more aggressive targets for malaria control and elimination, the group now recommends that primaquine be used in all settings
6.5.2. PRIMAQUINE AND GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY
Any person (male or female) with red cell G6PD activity < 30% of the normal mean has G6PD deficiency and will experience haemolysis after primaquine. Heterozygote females with higher mean red cell activities may still show substantial haemolysis. G6PD deficiency is an inherited sex-linked genetic disorder, which is associated with some protection against P. falciparum and P. vivax malaria but increased susceptibility to oxidant haemolysis. The prevalence of G6PD deficiency varies, but in tropical areas it is typically 3–35%; high frequencies are found only in areas where malaria is or has been endemic. There are many (> 180) different G6PD deficiency genetic variants; nearly all of which make the red cells susceptible to oxidant haemolysis, but the severity of haemolysis may vary. Primaquine generates reactive intermediate metabolites that are oxidant and cause variable haemolysis in G6PD-deficient individuals. It also causes methemoglobinaemia. The severity of haemolytic anaemia depends on the dose of primaquine and on the variant of the G6PD enzyme. Fortunately, primaquine is eliminated rapidly so haemolysis is self-limiting once the drug is stopped. In the absence of exposure to primaquine or another oxidant agent, G6PD deficiency rarely causes clinical manifestationsso, many patients are unaware of their G6PD status. Screening for G6PD deficiency is not widely available outside hospitals, but rapid screening tests that can be used at points of care have recently become commercially available.
In patients known to be G6PD deficient, primaquine may be considered at a dose of 0.75 mg base/kg bw once a week for 8 weeks. The decision to give or withhold primaquine should depend on the possibility of giving the treatment under close medical supervision, with ready access to health facilities with blood transfusion services.
Some heterozygote females who test as normal or not deficient in qualitative G6PD screening tests have intermediate G6PD activity and can still haemolyse substantially. Intermediate deficiency (30–80% of normal) and normal enzyme activity (> 80% of normal) can be differentiated only with a quantitative test. In the absence of quantitative testing, all females should be considered as potentially having intermediate G6PD activity and given the 14-day regimen of primaquine, with counselling on how to recognize symptoms and signs of haemolytic anaemia. They should be advised to stop primaquine and be told where to seek care should these signs develop.
If G6PD testing is not available, a decision to prescribe or withhold primaquine should be based on the balance of the probability and benefits of preventing relapse against the risks of primaquine-induced haemolytic anaemia. This depends on the population prevalence of G6PD deficiency, the severity of the prevalent genotypes and on the capacity of health services to identify and manage primaquine-induced haemolytic reactions.
6.5.3. PREVENTION OF RELAPSE IN PREGNANT OR LACTATING WOMEN AND INFANTS
Preventing relapse in pregnant or lactating women
In women who are pregnant or breastfeeding, consider weekly chemoprophylaxis with chloroquine until delivery and breastfeeding are completed, then, on the basis of G6PD status, treat with primaquine to prevent future relapse.
Conditional recommendation, moderate-quality evidence
In a systematic review of malaria chemoprophylaxis in pregnant women, chloroquine prophylaxis against P. vivax during pregnancy was directly evaluated in one trial conducted in Thailand in 2001. In comparison with no chemoprophylaxis:
Chloroquine prophylaxis substantially reduced recurrent P. vivax malaria (RR, 0.02; 95% CI, 0.00–0.26, one trial, 951 participants, moderate-quality evidence).
Radeva-Petrova D, ter Kuile FO, Sinclair D, Kayentao K, Garner P. Drugs for preventing malaria in pregnant women in endemic areas: any drug regimen versus placebo/no treatment. Cochrane Database Systemat Rev. 2014;10 CD000169. [PMC free article: PMC4498495] [PubMed: 25300703] [CrossRef].
Primaquine is contraindicated in pregnant women and in lactating women (unless the infant is known not to be G6PD deficient).
As an alternative, chloroquine prophylaxis could be given to suppress relapses after acute vivax malaria during pregnancy. Once the infant has been delivered and the mother has completed breastfeeding, primaquine could then be given to achieve radical cure.
Few data are available on the safety of primaquine in infancy, and in the past primaquine was not recommended for infants. There is, however, no specific reason why primaquine should not be given to children aged 6 months to 1 year (provided they do not have G6PD deficiency), as this age group may suffer multiple relapses from vivax malaria. The guideline development group therefore recommended lowering the age restriction to 6 months.
