Description of the condition

P vivax infection caused an estimated 7.5 million cases of malaria in 2018 (WHO 2019). The geographical distribution of P vivax malaria is more widespread than any of the other forms of human malaria, with around 35% of the world’s population thought to be at risk (Howes 2016). Co‐infection with P falciparum is also common in many regions (Kumar 2007; Mueller 2009). As malaria control accelerates, the P vivax proportion in co‐endemic areas tends to rise compared to that of P falciparum, which highlights the importance and challenge of this infection (John 2012).

P vivax is important because as many countries progress towards malaria elimination, the parasite becomes a roadblock to eradication (Cibulskis 2015; Bassat 2016). Despite a reported 45% reduction in P vivax malaria cases between 2010 and 2016 (WHO 2017), the parasite has several characteristics that enable it to evade control (Newby 2016). The early appearance of gametocytes in the blood, often prior to symptoms of malaria, increases the chance of onward transmission by mosquitoes (Mendis 2001). P vivax differs from P falciparum in that as well as having a blood‐stage infection, hypnozoites develop in the liver that can be dormant for weeks to months before developing into an infection (White 2011). What triggers these relapses is not well‐understood. There is difficulty in distinguishing between relapse (hypnozoite activation), recrudescence (subpar treatment of the initial blood‐stage infection), and re‐infection (new infection with P vivax) (Imwong 2007). A study in Papua New Guinea suggested that relapses cause four‐fifths of P vivax infections (Robinson 2015), reinforcing the importance of relapse in sustaining transmission (White 2011). Parasites show high genetic diversity, even in countries that are at malaria elimination stage (Koepfli 2015). P vivax is likely underestimated worldwide, as the dormant liver stage is not detected in routine surveys (Gething 2012). Submicroscopic infections and asymptomatic infection reservoirs may also lead to underdiagnosis or misdiagnosis. A systematic review showed that across all study sites, the polymerase chain reaction (PCR) prevalence of P vivax was significantly higher than that identified by light microscopy (Cheng 2015). The effect this may have on P vivax malaria studies is unclear.

There are different strains of P vivax according to geographical region/endemicity areas, with relapse patterns that vary by latency (time to first relapse), likelihood of relapse, and frequency of relapses, which further complicates the assessment of efficacy of drugs on relapses (Battle 2014; White 2016). Strains commonly found in Southeast Asia and Oceania (including the ‘Chesson’ strain isolated from an individual infected in Papua New Guinea) have the shortest latency time to relapse, starting as early as three weeks after first infection (if untreated with a hypnozoiticidal drug) (Ehrman 1945). These areas correspond to zones 10 and 12 in Battle 2014. Indian and Pakistan strains (zone 8) exhibit heterogeneity in relapse latency, incidence, and frequency, while South American strains (zone 3) have a pattern of short latency to first relapse and less frequent relapses than in zones 10 and 12 (Battle 2014). The temperate strains (which include those from Korea in zone 11) relapse much more slowly (John 2012; Battle 2014). Strains of the type in zones 10 and 12, referred to here as 'East Asia and Oceania', are recommended to receive higher doses of primaquine (the high‐standard course of 0.5 mg/kg/day rather than standard 0.25 mg/kg/day for 14 days) to prevent relapses (WHO 2015), apparently based on research done in the 1950s and 1960s (Coatney 1953; Jones 1953; Vivona 1961; Maffi 1971; Clyde 1977), although not all these studies were done with strains from the targeted geographic area.

Primaquine, an 8‐aminoquinoline, has until very recently been the only drug available on the market for treating the hypnozoite stage of infection (Ashley 2014). One of the main barriers in P vivax treatment is the reluctance to use primaquine due to it potentially causing haemolysis in patients with glucose‐6‐phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency is the most common enzyme deficiency worldwide and affects red blood cells by leading to their premature lysis (Nkhoma 2009). G6PD deficiency is common in countries where P vivax malaria is endemic, with an estimated population prevalence of 8% (Howes 2012). Within G6PD deficiency, there are differing phenotypes, meaning some people may be mildly sensitive to primaquine, while others may be very sensitive and experience life‐threatening haemolysis (Baird 2015a), which explains the varying responses to primaquine. In many areas where P vivax is predominant, testing for G6PD deficiency is not available locally (Baird 2015b). In 2018 the US Food and Drug Administration (FDA) approved a newer alternative, another 8‐aminoquinoline known as tafenoquine (MMV 2018), which has shown promise in reducing relapses, but there are increased safety concerns in patients with undiagnosed G6PD deficiency compared to primaquine, due to its longer half‐life (Rajapakse 2015).

Description of the intervention

People with P vivax malaria require treatment with an antimalarial drug to treat the blood‐stage infection, and a drug to treat the hypnozoite stage (radical cure). The WHO recommends treatment with either chloroquine or an artemisinin‐based combination therapy (ACT) for the blood‐stage infection, with 0.25 to 0.5 mg/kg/day primaquine for 14 days for the liver stages (WHO 2015). Artemisinin‐based combination therapies and chloroquine have been shown to be effective and comparable in treating the blood‐stage infection of P vivax malaria (Gogtay 2013).

A previous Cochrane Review showed that primaquine regimens of five days or fewer had similar recurrence rates to placebo or no primaquine. Of the comparisons included in the review, a regimen of 0.25 mg/kg/day (15 mg) a day of primaquine for 14 days had the lowest recurrence rates of P vivax infection (Galappaththy 2013). There were no trials at that time that compared higher doses of primaquine at 14 or 7 days.

Primaquine was first made available to North American soldiers in the 1950s (Baird 2004). Its mechanism and metabolism are not widely understood, but it has a broad spectrum of activity against the Plasmodium parasite. As well as preventing relapse of P vivax malaria by targeting the latent and developing hypnozoites in the liver, it is also used in malaria prophylaxis (Baird 2003) and is gametocytocidal (Graves 2018). It is absorbed from the gastrointestinal tract, has a half‐life of about four to nine hours, and crosses the placenta in pregnancy (Baird 2004). New advancements in studying P vivax in humanized mice may lead to a greater understanding of the mechanism of action of the drug (Mikolajczak 2015).

Adverse events observed with primaquine include production of methaemoglobin, an oxidated state of haemoglobin that cannot transport oxygen to tissues. Methaemoglobinaemia (an abnormal buildup of methaemoglobin) can result in cyanosis when levels exceed 10% of the usual haemoglobin level (Vale 2009). As described above, primaquine causes haemolysis in people with G6PD deficiency, which leads to anaemia (Ashley 2014). When taken on an empty stomach it can cause abdominal pain and gastrointestinal upset (Vale 2009). Safe use of primaquine during pregnancy has not been established. The radical cure with primaquine can be delayed until after pregnancy. With regard to breastfeeding patients, a recent study showed that the levels of primaquine in breast milk may not be sufficient to cause haemolysis even in a G6PD‐deficient baby (Gilder 2018), but it is not recommended at this time.

How the intervention might work

The WHO advises that 0.25 mg (standard) to 0.5 mg/kg/day (high standard) of primaquine for 14 days (total dose 210 mg or 420 mg) should be used for radical cure of P vivax malaria in patients over six months old, excluding people with G6PD deficiency and those who are pregnant or breastfeeding (WHO 2015). Citing the review previous Cochrane Review of this topic (Galappaththy 2013), the WHO notes that the standard regimen reduced relapses during 15 months of follow‐up by about 40% compared to placebo or no primaquine (high‐quality evidence), and reduced relapses during six months follow‐up by over 50% compared to seven days primaquine (low‐quality evidence) (WHO 2015). The increased dosing in the high standard 0.5 mg/kg/day regimen was previously recommended in East Asia and Oceania based on suggestion of failure of the standard regimen of 0.25 mg/kg/day for 14 days for strains of P vivax in these areas (including the Chesson strain). The guidelines note that "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)". Given that the 15 trials included in the WHO assessment excluded G6PD‐deficient persons (12 trials) or did not comment on their exclusion, WHO guidelines also stated "in the absence of evidence to recommend alternatives, the guidelines development group consider 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", but no trials of this regimen were included in the WHO guidance (WHO 2015).

The 14‐day course of primaquine at any dose, as well as the eight‐week course, can lead to treatment adherence issues, as well as to safety concerns about haemolysis in places where G6PD testing is not available, meaning that shorter courses of primaquine are desirable. Failure to treat the hypnozoite stage of P vivax malaria leads to repeated relapses, morbidity, and persistent infection.

It has long been suggested that it may be the total dose of primaquine that is important in the treatment of the hypnozoite stage rather than the length of the course (Schmidt 1977). If a higher dose of primaquine could be administered safely over a shorter period of time, it may improve adherence rates, thus reducing relapse rates and morbidity and mortality resulting from P vivax infection. There are small trials from the 1970s that suggest that shorter, higher‐dose regimens were as efficacious as the 14‐day courses (Clyde 1977; Saint‐Yves 1977). At the time of the previous Cochrane Review (Galappaththy 2013), there were no recent large high‐quality trials that had investigated the use of the same total dose as the standard regimen (210 mg), or higher total doses, given over either shorter or longer periods. We planned to include any such trials in this Cochrane Review.

Why it is important to do this review

The use of primaquine for radical cure of P vivax malaria continues to pose a therapeutic dilemma for healthcare providers in areas without adequate screening for G6PD status. Clinicians must either choose to give primaquine and risk haemolysis if the patient is G6PD‐deficient, or withhold treatment and accept the complications of ongoing parasite infection and relapses. This is why when clinicians choose to treat with primaquine they prefer a lower dose over a more prolonged period, which then risks difficulties with adherence and thus reduced effectiveness.

We know from the previous Cochrane Review on primaquine with chloroquine for radical cure that the standard 14‐day regimen of 0.25 mg/kg/day (15 mg per day or 210 mg total dose) is better than shorter regimens of similar daily doses and placebo (Galappaththy 2013). In fact, the regimen of 0.25 mg/kg/day for five days of primaquine did not reduce recurrences compared to treating with chloroquine alone.

A major problem with the radical cure of P vivax is difficulty with the adherence to the 14‐day course of primaquine, which has led to many countries shortening the regimen. Peru was one such example, although a study revealed that patients often still discontinued the therapy after around three days, when they started to feel better (Grietens 2010). A study that compared directly observed therapy (DOT) for 14 days of primaquine versus non‐DOT primaquine found that the P vivax recurrence rate was significantly lower in the DOT group (Takeuchi 2010). These problems have led to a more urgent call for shorter treatment regimens. Various trials are investigating regimens that revise dosing and duration of treatment in order to improve adherence and reduce the potential for incomplete treatment and development of resistance. As mentioned previously, the significance of the total cumulative primaquine dose given, rather than the length of the course, is one avenue of investigation. In areas where G6PD screening is present, using higher dosing regimens over shorter time periods, if at least similarly efficacious, could improve adherence and reduce morbidity associated with P vivax parasitaemia.

World Health Organization guidelines suggest a higher dosing regimen of primaquine for the tropical, frequent‐relapsing strains of P vivax in East Asia and Oceania (WHO 2015), although the previous Cochrane Review, Galappaththy 2013, did not find any trials assessing this. Investigating the evidence base for this is therefore important. The 2015 WHO guidelines also suggest an alternate dosing regimen of weekly primaquine, which may be safer in patients with G6PD deficiency. As the previous Cochrane Review included data from only one trial assessing this, it is useful to investigate whether there is further evidence to substantiate this guidance.

In this Cochrane Review, we have excluded comparisons between blood‐stage drug (chloroquine/ACT) with and without primaquine, as the rationale for primaquine use has been sufficiently demonstrated in a previous Cochrane Review (Galappaththy 2013). Similarly, we have not included comparisons between different blood‐stage drugs in which the same dose of primaquine was used; an update to an existing Cochrane Review, Gogtay 2013, is in progress and will address this. However, we planned to stratify our results according to partner drug, as there is increasing evidence that primaquine is metabolized via the cytochrome P450 2D6 (CYP2D6) pathway (Bennett 2013), and efficacy may thus be affected if the blood‐stage antimalarial drug is a CYP2D6 inhibitor (Baird 2018). This review excluded comparisons that do not use the standard (0.25 mg/kg/day) or high‐standard (0.5 mg/kg/day) regimens of 14 days of primaquine in the control groups. Also, it did not include comparisons of primaquine regimens of 0.25 mg/kg/day for less than 14 days, as Galappaththy 2013 has already assessed these shorter regimens at this dose.

There is currently a lack of consensus among studies as to what the minimum time frame for follow‐up of relapse in P vivax malaria should be. The WHO guidance on clinical trials in malaria sets out standard follow‐up for blood (or schizontal) stage infection as 28 days after treatment commencement, but has no clear definition on the follow‐up period for radical cure in primaquine studies. It states that "follow up varies from three months to a year in the literature, and should be adapted to regional parasite characteristics" (WHO 2009). In a recent review, John 2012 described relapse of the tropical frequently relapsing strain of P vivax as typically three weeks, but this varies according to blood‐stage treatment: "three weeks following quinine therapy" and "six to eight weeks following chloroquine" (White 2011). With exposure to primaquine ‐ even if radical cure is not achieved ‐ relapses may occur at longer intervals (Sutanto 2013). In the Cochrane Review (Galappaththy 2013), the follow‐up period started 30 days after completing primaquine treatment. Relapse is frequently defined as the presence of P vivax parasites more than 28 to 30 days after the full course of primaquine in people living in a non‐endemic area (Looareesuwan 1997). Due to the varying lengths of treatment and relapse time in P vivax malaria, 28 days from treatment completion may not allow true assessment of radical cure. It also makes assessment of the weekly primaquine regimen difficult, as the follow‐up time should start before the eight‐week treatment course has finished. In this Cochrane Review we planned to assess parasitaemia at three, six, and 12 months' follow‐up, in keeping with WHO guidance. We intended to describe the length of follow‐up across studies, and then group them into meaningful lengths of follow‐up, depending on the regimen.

Attention is needed to the problems of lack of completion of long treatment courses and potential insufficient dosing in some geographical areas, while maintaining daily doses within a safe range. We compare the efficacy and safety of alternative schedules to those currently recommended, or those with insufficient evidence in current recommendations. Specifically, we intended to answer the following questions by comparing alternative regimens with total adult dose of over 210 mg to the standard 14‐day regimen of primaquine (0.25 mg/kg/day,15 mg adult daily dose, total dose 210 mg), or the high‐standard 14‐day regimen (0.5 mg/kg/day,30 mg adult daily dose, total dose 420 mg).

• Is a shorter, higher daily dose regimen with same or higher total dose, given over seven days, as (or more) efficacious and safe as the standard or high standard regimens given over 14 days? (Comparisons 1 and 4)

• Is the high‐standard 14‐day regimen, with higher daily and total dose, as (or more) efficacious and safe as the standard 14‐day course, in all areas and/or where it was formerly recommended (East Asia and Oceania)? (Comparison 2)

• Is a weekly dosing regimen with higher daily dose given one day a week and with either higher or lower total dose, as (or more) efficacious and safe as the standard or high‐standard 14‐day regimens? (Comparison 3)