Primaquine for preventing relapse in people with Plasmodium vivax malaria treated with chloroquine
Abstract
Background
Plasmodium vivax infections are an important contributor to the malaria burden worldwide. The World Health Organization recommends a 14‐day course of primaquine (0.25 mg/kg/day, giving an adult dose of 15 mg/day) to eradicate the liver stage of the parasite and prevent relapse of the disease. Many people find a 14‐day primaquine regimen difficult to complete, and there is a potential risk of haemolytic anaemia in people with glucose‐6‐phosphate‐dehydrogenase enzyme (G6PD) deficiency. This review evaluates primaquine in P. vivax, particularly alternatives to the standard 14‐day course.
Objectives
To compare alternative primaquine regimens to the recommended 14‐day regimen for preventing relapses (radical cure) in people with P. vivax malaria treated for blood stage infection with chloroquine. We also summarize trials comparing primaquine to no primaquine that led to the recommendation for the 14‐day regimen.
Search methods
We searched the Cochrane Infectious Diseases Group's Specialized Register, CENTRAL (The Cochrane Library), MEDLINE, EMBASE and LILACS up to 8 October 2013. We checked conference proceedings, trial registries and reference lists and contacted researchers and pharmaceutical companies for eligible studies.
Selection criteria
Randomized controlled trials (RCTs) and quasi‐RCTs comparing various primaquine dosing regimens with the standard primaquine regimen (15 mg/day for 14 days), or with no primaquine, in people with vivax malaria treated for blood stage infection with chloroquine.
Data collection and analysis
We independently assessed trial eligibility, trial quality, and extracted data. We calculated risk ratios (RR) with 95% confidence intervals (CI) for dichotomous data, and used the random‐effects model in meta‐analyses if there was significant heterogeneity. We assessed the overall quality of the evidence using the GRADE approach.
Main results
We included 15 trials (two cluster‐RCTs) of 4377 adult and child participants. Most trials excluded people with G6PD deficiency. Trials compared various regimens of primaquine with the standard primaquine regimen, or with placebo or no treatment. All trials treated blood stage infection with chloroquine.
Alternative primaquine regimens compared to 14‐day primaquine
Relapse rates were higher over six months with the five‐day primaquine regimen than the standard 14‐day regimen (RR 10.05, 95% CI 2.82 to 35.86; two trials, 186 participants, moderate quality evidence). Similarly, relapse over six months was higher with three days of primaquine than the standard 14‐day regimen (RR 3.18, 95% CI 2.1 to 4.81; two trials, 262 participants, moderate quality evidence; six months follow‐up); and with primaquine for seven days followed up over two months, compared to 14‐day primaquine (RR 2.24, 95% CI 1.24 to 4.03; one trial, 126 participants, low quality evidence).
Relapse with once‐weekly supervised primaquine for eight weeks was little different over nine months follow‐up compared to 14‐day self‐administered primaquine in one small study (RR 2.97, 95% CI 0.34 to 25.87; one trial, 129 participants, very low quality evidence).
Primaquine regimens compared to no primaquine
The number of people that relapsed was similar between people given five days of primaquine or given placebo or no primaquine (four trials, 2213 participants, high quality evidence; follow‐up six to 15 months); but lower with 14 days of primaquine (RR 0.6; 95% CI 0.48 to 0.75; ten trials, 1740 participants, high quality evidence; follow‐up seven weeks to 15 months).
No serious adverse events were reported. Treatment‐limiting adverse events were rare and non‐serious adverse events were mild and transient. Trial authors reported that people tolerated the drugs.
We did not find trials comparing higher dose primaquine regimens (0.5 mg/kg/day or more) for five days or more with the 14‐day regimen.
Authors' conclusions
The analysis confirms the current World Health Organization recommendation for 14‐day primaquine (15 mg/day) to prevent relapse of vivax malaria. Shorter primaquine regimens at the same daily dose are associated with higher relapse rates. The comparative effects with weekly primaquine are promising, but require further trials to establish equivalence or non‐inferiority compared to the 14‐day regimen in high malaria transmission settings.
PICOs
Plain language summary
Primaquine for preventing relapses in people with Plasmodium vivax malaria
Malaria due to Plasmodium vivax parasites is widespread. The World Health Organization (WHO) recommends that people with P. vivax malaria are treated with chloroquine for three days to eliminate the parasites in the blood that cause the symptoms of malaria, followed by 15 mg/day of primaquine for 14 days to treat the liver stage of the infection to prevent the disease recurring. However, many people do not complete the primaquine treatment once they feel better after chloroquine treatment. In addition, primaquine can destroy red blood cells in people with a genetic enzyme deficiency (glucose‐6‐phosphate‐dehydrogenase enzyme (G6PD) deficiency), and clinicians avoid giving primaquine in areas where people commonly have this deficiency. Shorter courses of primaquine could potentially increase treatment completion and reduce adverse events.
The review authors included 15 trials of 4377 adults and children older than one year with vivax malaria. All were treated with chloroquine for the blood stage infection, and then randomized to the 14‐day primaquine course, or to shorter primaquine courses (three, five, or seven days); or to higher doses of primaquine given once a week for eight weeks; or to a placebo or no treatment. In twelve studies, treatments were supervised. The evidence is current to 8 October 2013.
Relapse over six months to one year is probably higher with shorter regimens when compared to the standard 14‐day primaquine regimen (moderate quality evidence). We do not know from the available evidence whether the number of relapses with weekly primaquine differs from 14 days of primaquine treatment based on one study of 126 people followed up for nine months (very low quality evidence). Better conducted studies on more people are needed to be sure that they are equally effective against relapse. Five days of primaquine was as ineffective against relapse as placebo or no treatment over six months to 15 months based on four studies (high quality evidence). The 14‐day primaquine course prevented many more people relapsing with vivax malaria over 12 months than placebo (high quality evidence). No serious adverse reactions to primaquine were reported.
This review update confirms that the 14‐day primaquine course recommended by the WHO is more effective against relapse of vivax malaria than treatment with shorter courses of primaquine.
Authors' conclusions
Summary of findings
| What are the effects of five days of primaquine compared to 14 days of primaquine for preventing relapses in people with P. vivax malaria treated for blood stage infections with chloroquine? | ||||||
| Patient or population: People with P. vivax malaria1 | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Primaquine 14 days | Primaquine 5 days | |||||
| P. vivax parasitaemia detected > 30 days after starting primaquine | 21 per 1000 | 183 more per 1000 | RR 10.05 | 186 | ⊕⊕⊕⊝ | |
| Serious adverse events | none reported | none reported | Not estimable | 186 | ||
| Other adverse events | none reported | none reported | Not estimable | 186 | ||
| *The basis for the assumed risk is the average of the risk in the control groups of the two studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Gogtay 1999 was done in Mumbai, India, and Villalobos 2000 was done in Porto Velho, Brazil; treatments were supervised in both and follow‐up was for three to six months. Kim 2012 was done in Kolkata, India; primaquine was not supervised; follow‐up was for 15 months. 2 Data from a third trial (Kim 2012) were not pooled due to substantial heterogeneity (I2 = 87%). This trial was at risk of selection and detection bias, and the trial authors reported that the lack of significant difference in recurrences over 15 months (27%, 16/59 with 5‐day primaquine; 38%, 16/42 with 14‐day primaquine) was likely due to non‐adherence to unsupervised primaquine. | ||||||
| What are the effects of primaquine (3 days) compared to primaquine (14 days) for preventing relapses in people with P. vivax malaria treated for blood‐stage infections with chloroquine? | ||||||
| Patient or population: People with P. vivax malaria1 | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Primaquine 14 days | Primaquine three days | |||||
| P. vivax parasitaemia detected > 30 days after starting primaquine | 167 per 1000 | 363 more per 1000 | RR 3.18 | 262 | ⊕⊕⊕⊝ | |
| Serious adverse events | None reported | None reported | Not estimable | 262 | ||
| Other adverse events | Not reported | Not reported | Not estimable | 262 | ||
| *The basis for the assumed risk is the average of the risk in the control group in the two trials. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Alvarez 2006 and Carmona‐Fonseca 2009 conducted the trials in the same semi‐rural areas of Columbia, South America. | ||||||
| What are the effects of primaquine (seven days) compared to primaquine (14 days) for preventing relapses in people with P. vivax malaria treated for blood stage infections with chloroquine? | ||||||
| Patient or population: People with P. vivax malaria1 | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| 14 days primaquine | 7 days primaquine | |||||
| P. vivax parasitaemia detected > 30 days after starting primaquine | 188 per 1000 | 233 more per 1000 | RR 2.24 | 126 | ⊕⊕⊝⊝ | |
| Severe adverse events | None reported | None reported | Not estimable | 126 | ||
| Other adverse events | Not reported | Not reported | Not estimable | 126 | ||
| *The basis for the assumed risk is the risk in the control group. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Alvarez 2006 was conducted in Columbia, South America. | ||||||
| What are the effects of supervised primaquine (weekly for 8 weeks) versus primaquine (daily for 14 days) for preventing relapses in people with P. vivax malaria treated for blood stage infections with chloroquine? | ||||||
| Patient or population: Children and adults with blood smear positive P. vivax malaria1 | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Primaquine for 14 days | Primaquine weekly for eight weeks | |||||
| P. vivax parasitaemia detected > 30 days after starting primaquine | 18 per 1000 | 36 more per 1000 | RR 2.97 | 129 | ⊝⊝⊝⊝ | |
| Serious adverse events | None reported | None reported | Not estimable | 129 | ||
| Adverse events | None reported | None reported | Not estimable | 129 | ||
| *The basis for the assumed risk is the risk in the control group. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Leslie 2008 was conducted in three Afghan refugee camps in North West Frontier Province in Pakistan during a period of low transmission. 6 Trial authors allocated insufficient numbers of people with G6PD deficiency (only one in the report) to the 8‐week arm to be sure that intermittent primaquine is a safer alternative than 14 days of primaquine; none given the 14‐day regimen had this deficiency. | ||||||
| What are the effects of primaquine (five days) compared to no intervention or placebo for preventing relapses in people with P. vivax malaria treated for blood stage infections with chloroquine? | ||||||
| Patient or population: People with P. vivax malaria1 Intervention: Chloroquine (25 mg/kg for three days) plus primaquine (0.25 mg/kg) for five days2 | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No primaquine | 5 days primaquine | |||||
| P. vivax parasitaemia detected > 30 days after starting primaquine | 193 per 10002 | 4 fewer per 1000 | RR 0.98 | 2213 | ⊕⊕⊕⊕ | |
| Serious adverse events | None reported | None reported | Not estimable | 2213 | ||
| Other adverse events | None reported | None reported | Not estimable | 2213 | ||
| *The basis for the assumed risk is the median control group risk across the four studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Trial authors performed trials in outpatients in Mumbai, India (Gogtay 1999; Rajgor 2003) and Kolkota, India (Kim 2012), and in the Adizai Afghan refugee camp in the North West Frontier Province of Pakistan (Rowland 1999b). | ||||||
| What are the effects of primaquine (14 days) compared to no intervention or placebo for preventing relapses in people with P. vivax malaria treated for blood stage infection with chloroquine? | ||||||
| Patient or population: People with P. vivax malaria1 | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No primaquine | Primaquine 14 days | |||||
| P. vivax parasitaemia detected > 30 days after starting primaquine | 84 per 1000 | 34 fewer per 1000 | RR 0.60 | 1740 | ⊕⊕⊕⊕ | |
| Serious adverse events | None reported | None reported | Not estimable | 1740 | ||
| Other adverse events | None reported | None reported | Not estimable | 1740 | ||
| *The basis for the assumed risk is the median risk in the control group. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Trial authors conducted the studies in Ethiopia (Yeshiwondim 2010), India (Gogtay 1999; Rajgor 2003; Kim 2012; Ganguly 2013), Pakistan (Rowland 1999a; Leslie 2004; Walsh 2004; Leslie 2008) and Thailand (Pukrittayakamee 1994). | ||||||
Background
Description of the condition
Malaria is usually caused by the parasites Plasmodium vivax and Plasmodium falciparum. In 2010, malaria episodes occurred in an estimated 149 million to 274 million people worldwide, approximately 81% of whom were living in Africa, and 13% in South‐East Asia (WHO 2011). In 2010, malaria killed between 537,000 to 907,000 people; and 86% of these deaths were children under five years of age (WHO 2011). P. vivax infects an estimated 130 million to 391 million people annually (Hay 2004; Price 2007). Around 40% of the world's population living in 95 countries in Central, South East, and South Asia; Africa; and South America are at risk of P. vivax infection. The geographical distribution of vivax malaria is more widespread than falciparum malaria (Guerra 2010). Co‐infection with P. falciparum is also common in many of these regions (Kumar 2007; Mueller 2009). Vivax infections during pregnancy increase neonatal, infant, and maternal morbidity and mortality (Poespoprodjo 2008; ter Kuile 2008; Poespoprodjo 2009; Price 2009). Case series studies of adults and children in endemic areas have documented severe disease in people with confirmedP. vivax mono‐infections, similar to that produced by P. falciparum (Anstey 2007; Barcus 2007; Beg 2008; Genton 2008; Tjitra 2008; Mueller 2009; Price 2009; Valecha 2009; Kochar 2010; Maguire 2010; Saravu 2011; Srivastava 2011; Singh 2011; Tanwar 2011). Also, less severe forms of vivax malaria can adversely affect personal well‐being, growth, and economic performance at the individual, family, community, and national level (Breman 2001; Mendis 2001).
In addition, people infected with P. vivax may have relapses of the disease. The infective stage of the parasite (sporozoites) is injected into a person's bloodstream through the bite of a female anopheline mosquito, enters the liver within minutes, invades liver cells, and develops into either of two stages. The asexual blood‐stage infection results in the clinical symptoms of vivax malaria; while a dormant liver‐stage infection (hypnozoite) that can be activated weeks to years after the initial infection, causes relapses of the blood‐stage infection, and increases the potential for transmission of the sexual gametocyte forms (Krotoski 1985; Baird 2009; Doolan 2009; Mueller 2009). Relapse occurrence varies depending on the genetic makeup of the sporozoites (Cogswell 1992; Craig 1996; Rowland 2001), the number of sporozoites inoculated, and climatic conditions that favour transmission (White 2011). In general, people infected with tropical strains from Asia have high relapse rates (80% to 100%), with relapses usually occurring within six months of treatment (Fonseka 1987; Looareesuwan 1997; Luxemburger 1999; Pukrittayakamee 2004; Krudsood 2008). Relapse rates with vivax strains from India are reportedly lower, but are highly variable (8% to 40%); and although the majority occur within the first six months (Gogtay 2000) relapses can also occur within a few weeks to a year or more, in different parts of the country (White 2011). People infected with tropical strains from New Guinea (the Chesson strain) relapse within or shortly after a month and relapses occur several times over a period of a year or more (Collins 1996; Baird 2009). Relapses usually occur much later with temperate strains, such as the North Korean strain (Collins 1996; White 2011).
Re‐infection is also a problem with vivax malaria. Apart from innate (or natural) immunity to malaria, a partial immunity (acquired immunity) that mitigates the clinical effects of malaria develops in individuals who live in areas where malaria is highly endemic (Doolan 2009). This clinical immunity is lost when individuals living in endemic areas move to non‐endemic areas (Maguire 2010). In highly endemic areas, the risk of severe P. vivax disease is highest among children less than two years of age, while uncomplicated P. vivax illness is less common in children over five years of age, though infections occur even in adolescents and adults (Michon 2007; Genton 2008; Lin 2010). However, in many parts of the world, relapses caused by the hypnozoite represent the dominant source of recurrences of parasitaemia compared to new infections (Maguire 2010; White 2011).
Description of the intervention
People with vivax malaria require effective treatment with a combination of chloroquine to treat the blood‐stage infection, and primaquine to treat hypnozoites and prevent relapses (radical cure). The recommended adult treatment with chloroquine is 25 mg/kg body weight administered daily over three days. Chloroquine is inexpensive and people usually tolerate it well. People frequently report itching from chloroquine but they do not usually discontinue treatment for this reason (Valecha 2006). The standard recommended dose of primaquine is 15 mg per day (0.25 mg/kg) for 14 days, delivering a total dose of 210 mg of primaquine. Primaquine may cause abdominal pain, nausea, and vomiting, but these adverse events are dose‐dependant and are minimized if people take the drug after meals (Parfitt 1999; Vale 2008; Baird 2009).
Glucose‐6‐phosphate dehydrogenase (G6PD) enzyme deficiency
Primaquine also causes the destruction of red blood cells (haemolysis) in people with a hereditary enzyme deficiency known as glucose‐6‐phosphate dehydrogenase (G6PD) enzyme deficiency, which occurs due to mutations in the G6PD gene (q28 locus on the X chromosome) (Beutler 2007; Cappellini 2008). Over 400 million people worldwide have this enzyme deficiency; and the enzyme deficiency variant and dose of primaquine determine the severity of haemolytic anaemia (Hill 2006; Beutler 2007). G6PD deficiency that is common in Africa, and the Mahidol variant seen in Thailand and Malaysia, result in mild and self‐limiting haemolysis that permits primaquine use even at high doses (Beutler 2007). In the Middle East and India, where over 60% of G6PD deficient individuals carry the Mediterranean variant, haemolysis due to primaquine can be severe and prolonged (Beutler 2007). Variations in the frequency and variants of G6PD enzyme deficiency occur within countries, and even within tribal communities in the same country (Bouma 1995; Tripathy 2007). This deficiency can be detected by various tests, but these may not always be affordable or feasible in many parts of the developing world.
Methaemoglobinaemia
Less commonly, primaquine treatment can result in methaemoglobinaemia. Methaemoglobin (MetHB) is a reduced form of haemoglobin that results from oxidative stress, which normally is kept under 1% within the red blood cells through normal enzymatic activity. When this level exceeds 2%, methaemoglobinaemia is diagnosed. Levels greater than 30% can lead to breathing difficulties, cardiovascular and neurological symptoms; and levels above 70% are invariably fatal. However, in usual practice this increase in methaemoglobin levels with primaquine is usually less than 20%, and symptoms are mild, self‐limited, and well‐tolerated in otherwise healthy people, even at higher than normal doses (Hill 2006; Carmona‐Fonseca 2009a).
Other drugs for radical cure of vivax malaria
Artemesinin‐based combination therapy (ACT) is at least as effective as chloroquine in treating the blood stage P. vivax infection, but current drugs that constitute ACT are not effective against the liver stage of P. vivax (Douglas 2010; Sinclair 2011). Primaquine is still the only commercially available drug for widespread use to achieve radical cure. Two longer‐acting synthetic analogues of primaquine undergoing evaluation and not yet available for widespread commercial use are tafenoquine (Walsh 2004; Kitchner 2007; Baird 2009) and bulaquine (also called elubaquine; CDRI 80/53) (Adak 2001; Krudsood 2006; Vale 2008).
How the intervention might work
Chloroquine acts on the blood stages of the parasite and also has schizonticidal activity (against the mature, infective stage of the malaria parasite). Chloroquine‐sensitive P. vivax are suppressed by whole‐blood concentrations of 70 to 90 ng/mL of chloroquine and its metabolite, mono‐desethyl‐chloroquine (WHO 2010b). Due to the persistence of therapeutic blood levels for 21 to 35 days, chloroquine also eliminates blood forms that emerge from hypnozoites within the first month (Baird 1997). Primaquine has some schizonticidal activity against the blood stages of vivax malaria, but is more effective against hypnozoites (liver stage) and gametocytes (only the mature sexual gametocytes) of P. vivax; it therefore has the potential to block the transmission of vivax malaria, if used with a drug active against blood forms of the parasite (Pukrittayakamee 2008; Baird 2009; Maguire 2010).
Differentiating recrudescence, relapse and re‐infection
Following treatment of the blood stage of malaria, P. vivax parasites may be found in peripheral blood smears because of recrudescence (due to blood stage parasites that were not eliminated from the original infection due to a failure of chloroquine); relapse (due to new parasites emerging from hypnozoites due to failure of primaquine); or a re‐infection due to new parasites from fresh mosquito bites (Baird 2009). The termrecurrence is used for parasitaemia of unknown origin (unclear if a recrudescence, relapse, or re‐infection) (Baird 2009). Recrudescence and relapse of vivax malaria may also be due to inadequate doses or drug levels of either drug, apart from drug resistance (Duarte 2001).
Primaquine treatment failure or relapse is 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). In endemic areas with a high risk of re‐infection, microscopy cannot reliably differentiate new infections with the same or different strains of P. vivax from relapses of the original infecting strain due to failure of primaquine. Attempts to differentiate a new infection (re‐infection) from a relapse of the initial infection using the polymerase chain reaction (PCR) technique, which compares parasite genotypes (gene types), were based on the assumption that parasites causing a relapse would be a sub‐set of the parasites that caused the primary infection. A true relapse was confirmed when the genotypes of parasites collected on the first day of the infection were similar to those that re‐appeared during the follow‐up period, and a new infection when the genotypes were different (Craig 1996; Looareesuwan 1997).
However, due to the considerable genetic diversity seen in vivax infections, relapses (particularly in adults) may originate from reactivation of either the same parasite clone found in the primary blood‐stage infection (homologous hypnozoites) or another genetically different clone (heterologous hypnozoites); or due to relapses from infections with multiple P. vivax strains (Chen 2007; Imwong 2007a; Karunaweera 2008; Orjuela‐Sanchez 2009; Imwong 2012). Thus, mismatched primary and secondary parasite populations may represent either a new infection or a relapse, and this genetic diversity makes current methods of genotyping of recurrent infections with PCR in differentiating relapse from re‐infections of limited utility in vivax malaria (Imwong 2007a). This is in contrast to the value of molecular techniques in falciparum malaria, where three‐loci genotyping has proved useful in detecting recrudescence (Baird 2009). Increasing the number of genetic markers also increases the possibility of detecting multiple clones in vivax recurrence; and micro‐satellite genotyping, using five to eight or more genetic loci, appears promising as a method to reliably differentiate relapses, recrudescence or re‐infection with P. vivax (Imwong 2007b; Havryliuk 2009; Gunawardena 2010; Van den Eede 2010a; Van den Eede 2011; Imwong 2012). However, these methods have yet to be validated for widespread use.
Therefore, the demonstration of clearance of parasite within the first month after treatment with chloroquine, and the timing of recurrences after primaquine are used to determine the efficacy of radical cure in vivax malaria (Baird 2003a; Baird 2009). Recurrence of parasitaemia in the three to six months after primaquine is likely to be a relapse (Alves 2002; Carmona‐Fonseca 2006). Differentiating a relapse from a re‐infection beyond six months is more difficult, as the chances of re‐infections (new primary infections) increases. This time frame may also differ in areas of high transmission, with the strain of parasite, due to seasonal variations, and due to unstable transmission patterns from year to year.
Why it is important to do this review
Although policies regarding radical cure of vivax malaria in India and Sri Lanka changed from five day to 14‐day primaquine regimens (NIMR 2011) following the 2007 version of this review (Galappaththy 2007), five days of primaquine is still used in many parts of South Asia, South‐East Asia, and Latin America for radical cure of vivax malaria (Leslie 2010). The main problems with the standard 14‐day course of 15 mg/day of primaquine following chloroquine are:
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Poor adherence, since people become rapidly asymptomatic after treatment with chloroquine and are poorly motivated to complete primaquine treatment (Grietens 2010);
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The risk (perceived and real) of adverse events;
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The lack of availability of cheap, rapid and practical tests for G6PD deficiency; and
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Less than optimal prevention of relapses in spite of adherence to the regimen, due to primaquine resistance in some areas of the world.
Thus practitioners are still struggling to successfully implement the 14‐day regimen. The alternatives suggested to the five and 14‐day primaquine treatments include:
Using higher doses of primaquine (after chloroquine) for shorter periods to overcome problems with adherence: Case series studies have shown that higher doses of primaquine given over fewer days are highly effective, well‐tolerated, and equivalent to the standard 15 mg/day for 14 days regimen for radical cure in vivax malaria (Schmidt 1977; Baird 2003a; Krudsood 2008; Ebringer 2011). In order to overcome adherence problems, the national drug policy in Peru recommends a shortened regimen of seven days of primaquine at an increased daily dosage of 0.5 mg/kg/day combined with three days of chloroquine (Van den Eede 2010a).
Using higher doses of primaquine (after chloroquine) for 14 days or longer to overcome primaquine resistance: Primaquine resistance is particularly important in some countries in the Western Pacific, South‐East Asia, South America, and parts of Africa (Charoenlarp 1973; Hill 2006; Baird 2009). The Centres for Disease Control (CDC 2005; CDC 2011) recommends a dose of 30 mg of primaquine for 14 days as standard therapy for radical cure of vivax malaria. This higher dose is also recommended for travellers with vivax malaria acquired in SE Asia and Oceania (Lalloo 2007; WHO 2010a; CDC 2011). It is also used in Thailand as second‐line treatment (Looareesuwan 1997). In parts of Latin America, primaquine is given at 0.25 (15 mg/day) or 0.5 mg/kg (30 mg/day) for longer courses up to 28 days in people who relapse with the standard 14‐day course (Carmona‐Fonseca 2006). Resistance to chloroquine is less of a global problem (Naing 2010), except in Indonesia, the Solomon Islands, and Vanuatu, where ACTs are used due to extensive chloroquine resistance (WHO 2010b).
Ensuring an adequate total dose of primaquine: Alving 1960 attempted to reduce the incidence of haemolysis with primaquine treatment and demonstrated good efficacy against relapse with eight weekly doses of 45 mg (360 mg in total). Some guidelines recommend 30 mg/day (0.5 mg/kg) for 14 days, or even higher doses of 45 mg/day (0.75 mg/kg) due to concerns about relapses because of inadequate doses in heavier people (Duarte 2001; WHO 2010a). Goller 2007 demonstrated that the total dose of primaquine, as well as the dose per kilogram of body weight, affects relapse rates. The relapse risk decreased by 60% for a total adult dose of 75 mg (15 mg/day for five days); by 80% for a total primaquine regimen of 210 mg (15 mg/day for 14 days), and by 95% for regimens of 315 mg (22.5 mg/day for 14 days) and 420 mg (30 mg/day for 14 days), compared to no primaquine (Goller 2007).
Concurrent (instead of sequential) administration of chloroquine and primaquine : Since primaquine has some activity against the asexual blood stages, Alving 1955 suggested that the efficacy of primaquine in preventing relapses may be greater when chloroquine is co‐administered with primaquine, than if it is administered sequentially, as is current practice. Carmona‐Fonseca 2006 demonstrated the safety of giving the two drugs in combination, but more data are needed to clarify the effects of concurrent versus sequential administration of chloroquine and primaquine on recrudescence and relapse. On the other hand, others postulate that since the long half life of chloroquine suppresses early relapses of blood stage infections from activation of hypnozoites, the delayed administration of primaquine after chloroquine (administering primaquine towards the latter part of the 28 to 35 day period of chloroquine's schizonticidal activity) has a greater likelihood to effect radical cure than if used immediately after chloroquine (Baird 2009).
Chloroquine monotherapy: Some policy experts recommend the use of only chloroquine to treat blood‐stage infection, in areas of low transmission; and the use of primaquine for 14 days only in those who relapse (Kshirsagar 2006). Chloroquine monotherapy is also used in some parts of the world due to fears of haemolysis with primaquine in people with G6PD deficiency (Beutler 1994).
The burden of disease caused by P. vivax infection and the substantial amount of money governments have to spend to treat relapses makes effective treatment a priority. With several primaquine regimens currently in use, it is important to determine the comparative effects of the different regimens.
This is an update of a Cochrane Review first published in The Cochrane Library in Issue 1, 2007.
Objectives
To compare alternative primaquine regimens to the recommended 14‐day regimen for preventing relapses (radical cure) in people with P. vivax malaria treated for blood stage infection with chloroquine. We also summarize the evidence from trials comparing primaquine to no primaquine that led to the recommendation for the 14‐day regimen.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials (RCTs) and quasi‐RCTs.
Types of participants
Adults and children with microscopically confirmed asexual P. vivax malaria. We excluded trials that recruited people with co‐infection with P. vivax and P. falciparum (mixed infections).
Types of interventions
Efficacy of alternative regimens
Intervention: primaquine (any dose or duration other than used in control group) plus chloroquine*.
Control: primaquine (15 mg/day for 14 days) plus chloroquine*.
Efficacy of regimens compared to either placebo or no treatment
Intervention: primaquine (any dose or duration) plus chloroquine*.
Control: placebo or no intervention plus chloroquine*.
*same dose in each group
Types of outcome measures
Primary outcomes
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P. vivax parasitaemia detected more than 30 days after starting primaquine.
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Serious adverse events (fatal, life threatening, or requiring hospitalization).
Secondary outcomes
-
Adverse events that result in the discontinuation of treatment.
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Events known to occur with primaquine (cyanosis, leucopenia, methaemoglobinaemia, hypertension, cardiac arrhythmia, abdominal pain, nausea, vomiting, and haemolysis) or those due to a comparator drug used along with primaquine.
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Other adverse events.
Search methods for identification of studies
We attempted to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress).
Electronic searches
Databases
On 8 October 2013, Vittoria Lutje (VL), the Cochrane Infectious Diseases Review Group's Information Specialist, updated searches of the following databases: Cochrane Infectious Diseases Group Specialized Register (August 2006 to October 2013); Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (2013, Issue 10); MEDLINE (August 2006 to October 2013); EMBASE (August 2006 to October 2013); and LILACS (August 2006 to November 2010), using the search terms and strategies described in Table 1. PT also searched the South Asian Database of Controlled Clinical Trials (http://www.cochrane‐sadcct.org/) on 4 February 2013 using the search terms "primaquine" AND "vivax", to identify trials from journals that may not be indexed in these databases,.
| Search set | CIDG SRa | CENTRAL | MEDLINEb | EMBASEb | LILACSb |
| 1 | Plasmodium vivax | primaquine | primaquine | primaquine | |
| 2 | vivax malaria | PRIMAQUINE | PRIMAQUINE | PRIMAQUINE | malaria |
| 3 | primaquine | 1 or 2 | 1 or 2 | 1 or 2 | Plasmodium vivax |
| 4 | — | Plasmodium vivax | MALARIA, VIVAX | malaria vivax | — |
| 5 | — | vivax malaria | Plasmodium vivax | PLASMODIUM VIVAX | — |
| 6 | — | 4 or 5 | 4 or 5 | 4 or 5 | — |
| 7 | — | 3 and 6 | 3 and 6 | 3 and 6 | — |
aCochrane Infectious Diseases Group Specialized Register.
bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Higgins 2005); upper case: MeSH or EMTREE heading; lower case: free text term.
Conference proceedings
We have listed the details of the conference proceedings searched in Appendix 1.
Clinical Trials Registries
On 8 October 2013, VL searched the WHO International Clinical Trials Platform Search Portal (http://www.who.int/ictrp/search/en/ ) and the metaRegister of Controlled Trials (mRCT) (http://www.controlled‐trials.com/mrct/ ) for ongoing trials using the terms "primaquine" AND "vivax".
Searching other resources
Researchers, organizations and pharmaceutical companies
On 18 November 2011, we contacted individual researchers working in the field, the WHO, and the pharmaceutical companies GlaxoSmithKline and Novartis for unpublished data.
Reference lists
We checked the reference lists of all studies identified by the above methods.
Data collection and analysis
Selection of studies
We independently assessed the full reports of all potentially relevant studies for inclusion using an eligibility form based on the inclusion and exclusion criteria. We scrutinized trial reports for multiple publications from the same data set. We stated the reasons for excluding studies in the Characteristics of excluded studies table and we resolved any disagreements through discussion.
Data extraction and management
We independently extracted data using data extraction forms. We resolved any disagreements by referring to the trial report and through discussion. Where data were insufficient or missing, we contacted authors for additional information.
Where possible, we extracted data to allow an intention‐to‐treat analysis, in which all randomized participants should have been analyzed in the groups to which they were originally assigned. If we identified any discrepancies in the number randomized to and analyzed in each treatment group, we calculated the percentage loss to follow‐up in each group and reported this information.
For dichotomous outcomes from individually randomized trials, we recorded the number of participants experiencing the event and the number analyzed in each treatment group.
For cluster‐RCTs, we recorded the number of clusters in the trial, the average size of clusters and the unit of randomization (for example, household or institution), when trial authors provided this data. We also documented the statistical methods trial authors used to analyze the trial, along with details describing whether these methods adjusted for clustering or other covariates. When reported, we recorded estimates of the intra‐cluster correlation (ICC) coefficient for each outcome.
Assessment of risk of bias in included studies
We independently assessed the risk of bias in the included trials on six domains: sequence generation; allocation concealment; blinding; incomplete outcome data; selective outcome reporting; and other biases. For each of these components, we assigned a judgment regarding the risk of bias as either high, low or unclear based on guidance in Higgins 2011a. We attempted to contact the trial authors if details were missing in the publications or were unclear. We resolved disagreements through consensus. We recorded our judgements and justifications in risk of bias tables for each included study and generated a risk of bias summary graph and figure. We used these judgements while grading of the overall quality of evidence for outcomes in the summary of findings tables for each comparison.
Measures of treatment effect
We compared dichotomous outcomes using the risk ratio (RR) and presented all results with their 95% confidence intervals (CIs).
Unit of analysis issues
Pooling data from cluster randomized trials (such as randomization by family or household) without accounting for intra‐class correlation leads to 'unit of analysis' errors in the analysis of treatment effects, whereby P values are spuriously low and CIs are unduly narrow (Divine 1992). We extracted the adjusted point estimates and their 95% CIs from cluster randomised trials that had adjusted results for clustering. We attempted to account for clustering in trials where authors had not provided adjusted results using approximate methods described in the Cochrane Handbook, Chapter 16.3.4 and 16.3.5 (Higgins 2011b). When data were insufficient to ensure the accuracy of the assumptions used to derive the adjusted effect estimates, we extracted the data as for the individually randomized trials and compared the results in sensitivity analyses.
In order to avoid a unit of analysis error in interpreting cumulative episodes of relapses (count data) as relapse rates (Deeks 2011), we extracted data for relapse rates only (the first relapse per individual) and subgrouped them according to the duration of follow‐up (more or less than six months).
Dealing with missing data
We conducted an intention‐to‐treat analysis in trials with no loss to follow‐up and completed‐case analysis for trials with incomplete follow‐up. We attempted to obtain missing data from study authors. We made no assumptions about those lost to follow‐up but utilised this information in assessing each study for the risk of attrition bias due to incomplete outcome data reporting; and in assessing the overall quality of evidence for each outcome in the summary of findings tables for each comparison.
Assessment of heterogeneity
We assessed heterogeneity between the trials by examining the forest plot to check for overlapping CIs, using the Chi2 test for heterogeneity with a 10% level of significance to detect inconsistency in study results that were not due to random error (chance), and the I2 statistic to denote the percentage of inconsistency in results due to inter‐trial variability that exceeded chance. In general, we interpreted an I2 value of 50% or greater to denote significant heterogeneity (Higgins 2003). We acknowledged that this cut‐off is arbitrary. We therefore interpreted I2 values between 0% to 40% as possibly unimportant, 30% to 60% as possibly significant, 50% to 90% as possibly substantial, and 75% to 100% as possibly considerable; depending on whether the inconsistency in results were due to differences in the direction of effects estimates between trials, rather than due to differences in the magnitude of effect estimates favouring an intervention; as well as the strength of the evidence for heterogeneity from the P value for the Chi2 test for heterogeneity (Deeks 2011).
Assessment of reporting biases
We planned to use funnel plots to assess publication bias if we included 10 or more trials in a meta‐analysis.
Data synthesis
We analyzed data using Review Manager 5.2. When data from trials using similar comparisons were available, we synthesized data using the Mantel‐Haenszel method to derive pooled, weighted risk ratios in fixed‐effect meta‐analyses. We used the random‐effects model for data synthesis when we identified heterogeneity was significant (see Assessment of heterogeneity) and we could not be explain it by subgroup analyses (see Subgroup analysis and investigation of heterogeneity).
We stratified (subgrouped) the data by length of follow‐up: six months or less and greater than six months.
We combined the results of cluster‐RCTs that had been adjusted for clustering with that of individually RCTs using the generic inverse variance method (Deeks 2011).
Subgroup analysis and investigation of heterogeneity
We undertook two of the planned subgroup analyses to explore potential sources of heterogeneity, for the primary outcome of P. vivax parasitaemia detected after day 30: based on 1) the length of follow‐up: six months or less; and greater than six months, and 2) chloroquine and primaquine doses supervised versus unsupervised. We intended to explore potential sources of heterogeneity in four additional subgroup analyses (defined in Galappaththy 2007, and in the Differences between protocol and review section). We did not undertake them since heterogeneity, when noted, was explained by differences in the duration of follow‐up or supervision of treatment.
Sensitivity analysis
When there were sufficient data, we undertook sensitivity analyses to investigate the robustness of the estimates for the primary outcome to the exclusion of trials at high risk of bias. We also undertook sensitivity analyses in order to explore assumptions used in cluster RCTs.
Summarising and interpreting results
We used the GRADE approach to interpret findings (Schunemann 2008). We used GRADE Profiler software (GRADE 2004), and imported data from Review Manager 5.2 to create 'Summary of findings' tables for each comparison included in this review. These tables provide information concerning the overall quality of the evidence from the trials, the magnitude of effect of the interventions examined, and the sum of available data on the primary outcome and secondary outcomes rated as important or critically important to health decision‐making.
The outcomes we selected for inclusion in these tables were:
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P. vivax parasitaemia detected more after than 30 days after starting primaquine;
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Serious adverse events;
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Adverse events leading to treatment discontinuation.
We used these summary findings to guide our conclusions and recommendations.
Results
Description of studies
Results of the search
We included 15 trials described in 18 reports in quantitative synthesis (meta‐analysis) in this review. No trials currently await classification (Figure 1). We identified 64 reports, of which we screened 53 abstracts for eligibility after removing duplicates and irrelevant reports. We obtained and scrutinized 24 potentially relevant full text articles. We included 10 trials from 14 reports in this review update. When we added these to the nine trials (described in eight reports) from the 2007 review, we included a total of 19 trials from 22 reports in the qualitative synthesis of this review update. Of these trials, four were on‐going trials that are described in Characteristics of ongoing studies. Excluded studies are detailed in the Characteristics of excluded studies section.
Study flow diagram: 2013 review update
Included studies
We have described these 15 trials in more detail in the Characteristics of included studies table. Rowland 1999a and Rowland 1999b were described in the same publication.
This 2013 update has, in addition to the previous addition, six new trials, conducted between 1997 to 2012, adding 4377 adults and children (aged older than one year) from Africa (Ethiopia, one trial), Asia (India, five trials; Pakistan, four trials; Thailand, two trials), South America (Brazil, one trial; and Columbia, two trials). .
Design
Of the 15 trials, one was a cluster RCT(Leslie 2004) that randomized households, and another used mixed cluster and individual randomization (Leslie 2008). One of the other 13 trials that individually randomized was a quasi‐RCT (Yeshiwondim 2010). Seven trials had multiple treatment arms, ranging from three (Pukrittayakamee 1994; Gogtay 1999; Leslie 2004; Alvarez 2006; Kim 2012), and four (Carmona‐Fonseca 2009) to six (Walsh 2004) intervention arms. We did not include some of the trial arms in this review as they were not relevant.
Interventions
All the included trials treated the blood stage of the parasite with identical chloroquine courses in the treatment arms.
Primaquine (any dose or duration) versus the standard regimen of primaquine (15 mg/day for 14 days)
Six trials had treatment arms that compared different dosing schedules of primaquine versus the standard primaquine regimen:
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Two trials compared three days of primaquine to standard primaquine treatment (Alvarez 2006; Carmona‐Fonseca 2009);
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Three trials compared five days of primaquine to the standard primaquine regimen (Gogtay 1999; Villalobos 2000; Kim 2012);
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One trial compared seven days of primaquine to standard primaquine treatment (Alvarez 2006);
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One trial compared primaquine (45 mg) given weekly for eight weeks, to 14 days of primaquine given at a higher dose than is standard (22.5 mg) daily(Leslie 2008).
Primaquine (any dose or duration) compared to no primaquine
Fourteen trials compared participants receiving primaquine with placebo or no anti‐relapse treatment:
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Four trials examined primaquine given for five days (Gogtay 1999; Rowland 1999b; Yadav 2002; Kim 2012);
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Ten trials evaluated primaquine given for 14 days (Gogtay 1999; Pukrittayakamee 1994; Rowland 1999a; Rajgor 2003; Leslie 2004; Walsh 2004; Leslie 2008; Yeshiwondim 2010; Kim 2012; Ganguly 2013).
Dosing regimens and supervision
All trials used the standard primaquine 0.25 mg/kg (15 mg per day) dosing regimen, except Leslie 2008 that used a higher dose of 22.5 mg primaquine base (0.5 mg/kg) in the 14‐day primaquine arm and 45 mg/week (0.75 mg/kg) in the once‐weekly primaquine arm. The total dose of primaquine delivered in different arms of the trials ranged from 45 mg (Alvarez 2006; Carmona‐Fonseca 2009); 75 mg (Gogtay 1999; Rowland 1999b; Villalobos 2000; Yadav 2002; Kim 2012); 105 mg (Alvarez 2006); 210 mg (Pukrittayakamee 1994; Gogtay 1999; Rowland 1999a; Rowland 1999b; Villalobos 2000; Rajgor 2003; Leslie 2004; Walsh 2004; Carmona‐Fonseca 2009; Yeshiwondim 2010; Kim 2012; Ganguly 2013); to 315 mg in the 14‐day daily primaquine arm; and 360 mg in the eight‐week primaquine arm (Leslie 2008).
Two trials from the same region in Columbia initiated primaquine treatment concurrently with chloroquine (Alvarez 2006; Carmona‐Fonseca 2009). One trial from Brazil (Villalobos 2000) compared five days of primaquine given concurrently with chloroquine versus the standard sequential administration of three days of chloroquine followed by 14 days of primaquine. In Yeshiwondim 2010 (Ethiopia), trial authors aimed to compare 14 days of primaquine versus chloroquine alone in treating acute symptoms, but they gave primaquine treatment for 14 days from day 29 in the chloroquine‐only arm to prevent relapses. We thus directly studied (as suggested by Baird 2009), the effects of delayed sequential administration of primaquine following treatment of the blood‐stage infection with chloroquine, compared with the control arm which was given the standard sequential regimen 14 days of primaquine immediately after three days of chloroquine treatment.
Eleven trials ensured compliance by directly supervising treatment in both arms for all participants. Leslie 2004 directly compared the effects of unsupervised and supervised 14 days of primaquine treatments (although we only used data from the unsupervised arm in meta‐analysis) with a placebo arm. Ganguly 2013 supervised chloroquine and the first seven of the 14‐day primaquine regimen. Three studies only supervised the administration of chloroquine and not of primaquine (Yadav 2002; Yeshiwondim 2010; Kim 2012); trial authors did not describe any methods to ascertain adherence.
Follow‐up
Trials varied the duration of follow‐up and used 42 days (Ganguly 2013); two months (Pukrittayakamee 1994); three months (Villalobos 2000; Walsh 2004); four months (Yeshiwondim 2010); six months (Gogtay 1999; Rajgor 2003; Alvarez 2006); nine months (Leslie 2004; Leslie 2008); 12 months (Rowland 1999a; Rowland 1999b; Yadav 2002); and 15 months (Kim 2012) follow‐up. We could not ascertain from some of the trials with shorter follow‐up periods whether the duration of follow‐up was from initiation or end of treatment. We subgrouped the results according to duration of follow‐up of six months or less, and greater than six months; this enabled us to evaluate the extent that relapses and re‐infections contributed to vivax parasitaemia at follow‐up.
Cluster RCTs
Leslie 2004 used cluster randomization of families but presented results for randomized individuals adjusted for clustering and also reported the number of clusters in each arm. For this update, since we chose to express results using relative risks rather than odds ratios (as in Galappaththy 2007), we calculated and combined the log of the risk ratio (adjusted for clustering) with its standard error with log risk ratios and standard errors computed for the other individually randomized trials using the generic inverse variance method in Review Manager 5.2.
Leslie 2008 also used cluster randomization by household in two of the study sites (refugee camps at Baghicha and Khagan villages) and used individual randomization in a third site (Adizai) that was added subsequently after an unscheduled interim analysis due to low rates of enrolment downsized the sample size estimate. The number of participants they randomized to each arm of this three‐armed trial were unequal with the majority recruited from Adizai (50%); and with Adizai accounting for the most treatment failures. The trial authors presented odds ratios, adjusted for clustering, village, age and sex; and we could not obtain intra‐cluster coefficient coefficients from the report or the authors. We calculated the log of the risk ratio with its standard error for the primary outcome assessed beyond six months, adjusted for clustering using the approximate methods described in Higgins 2011b. We also calculated and combined similar measures from the other relevant trials in meta‐analysis using the generic inverse variance method. Leslie 2008 did not report the number of participants randomized in clusters (families), and the number of clusters lost to follow‐up. Unequal rates of completion in the arms with cluster randomization can introduce biases due to loss of clusters (households). We, therefore, used the unadjusted relapse rates presented in the trial report in sensitivity analyses (ignoring the cluster effect, since participants from Adizai that constituted the majority of trial participants were individually randomized) to compare the robustness of the results with data that were adjusted for clustering.
Funding
One trial was partly funded by a drug company (Walsh 2004). The remainder were funded by academic institutions, local governments, international aid agencies, charitable donors, or by the UN/WHO.
Excluded studies
We excluded 65 studies (67 reports), including those excluded from the previous version of this review, and we listed the reasons for exclusion in the Characteristics of excluded studies. Of these excluded trials, 26 were not RCTs. Of the 39 that were RCTs, four randomized healthy volunteers, and five randomized people with falciparum malaria or with mixed vivax and falciparum infections. The remainder had comparisons that did not fulfil the inclusion and exclusion criteria.
Risk of bias in included studies
Most trials were at low risk of bias in many of the six domains we assessed (Figure 2). See Figure 3 for a summary of the judgements of the risk of bias for each domain in each of the included trials.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Leslie 2008 was at high risk of selection bias due to the mixed methods trial authors used to recruiting participants, with resultant imbalances in the proportions randomized to each site, and in baseline prognostic variables; as well as site‐specific higher relapse rates. Kim 2012 was at high risk of bias for allocation concealment as the unequal numbers in the two primaquine arms were not explained by the methods of random sequence generation and allocation supposedly used. This suggested that allocation according to the randomization sequence was compromised; and although the presented baseline variables did not reveal serious imbalances across treatment arms, we could not rule out the risk of bias due to residual confounding. Rowland 1999a; Rowland 1999b; Yadav 2002 were at unclear risk of selection bias since trial authors provided insufficient details in their trial reports. Although Yeshiwondim 2010 used quasi‐random methods to recruit participants, an extensive list of baseline demographic, clinical, parasitological, and biochemical parameters were well‐balanced between intervention arms, indicating a low risk of selection bias. Ganguly 2013 did not describe the methods used to ensure allocation concealment, but described balanced prognostic variables at baseline in the intervention arms.
Blinding
All but one of the included trials (many open‐label) were at low risk of performance and detection bias for objectively determined outcomes. Kim 2012 was at high risk of outcome detection bias for efficacy outcomes and for serious adverse events because the trial authors reported that those allotted unsupervised primaquine had probably not adhered to treatment. This raises the possibility of unreliable effect estimates, even if the outcomes were objective.
Incomplete outcome data
Twelve trials included between 90% and 100% of randomized participants in the final analyses. Pukrittayakamee 1994 included 71%, and Rajgor 2003 followed up 75% of participants. Gogtay 1999 reported results for 76% of randomized participants who completed six months follow‐up, from a trial that appears to have been terminated early. Walsh 2004 reported results for 22/25 participants (88%) in the two arms that we included in this review. None of the trials with less than 90% follow‐up had significantly different rates of trial completion in the intervention and control arms, and hence were at low risk of attrition bias.
Selective reporting
Although only Leslie 2008 and Ganguly 2013 were prospectively registered, and only Kim 2012 (that was retrospectively registered) and Leslie 2008 had available trial protocols, all trials reported all pre‐stated outcomes and we did not detect instances of selective reporting.
Other potential sources of bias
It was unclear whether the interim analysis and revised sample size estimates in Leslie 2008 introduced biases other than the high risk of selection bias. Unequal rates of completion in treatment arms of cluster randomized trials can introduce biases due to loss of clusters (households); we were unable to obtain the data needed to evaluate this from the report. Walsh 2004 was also unclear for other biases as it was partly industry‐funded. Trial authors did not clarify the role of the industry sponsor in the trial report. Ganguly 2013 had a follow‐up of only 42 days, and effectively 14 days where relapses that were not eliminated by chloroquine could be detected. This trial was biased and could not detect further early and late relapses after 42 days.
Effects of interventions
See: Summary of findings for the main comparison Primaquine five days compared to 14 days; Summary of findings 2 Primaquine three days compared to 14 days; Summary of findings 3 Primaquine seven days compared to 14 days; Summary of findings 4 Primaquine (weekly for eight weeks) compared to daily primaquine for 14 days; Summary of findings 5 Primaquine for five days; Summary of findings 6 Primaquine for 14 days
Alternative regimens versus 14 days primaquine
Shorter daily regimens (five trials)
We first evaluated the effects of the widely used five‐day primaquine regimen (75 mg total dose) compared with the standard regimen (15 mg/day for 14 days; 210 mg in total). Three trials (Gogtay 1999; Villalobos 2000; Kim 2012) included 287 adults and children (aged older than three years). Gogtay 1999 was conducted in a hospital in Mumbai, India, where malaria transmission was stable and low, treatments were supervised, and participants were followed up for six months. Kim 2012 included outpatients attending a specialist malaria treatment centre in Kolkota, India. Chloroquine was supervised, and only the first dose of primaquine was supervised; follow‐up was for fifteen months. Villalobos 2000 included outpatients in the Western Amazon region of Brazil, treatments were supervised, and participants were followed up for three months. The trials used standard dosing (0.25 mg/kg) for primaquine; but Villalobos 2000 used five days of chloroquine given concurrently with five days of primaquine, compared with the standard regimen of three days of chloroquine followed by 14 days of primaquine.
Relapse was common over the first six months with five days of supervised primaquine: 25% (16/62) in Gogtay 1999, and 27% (8/30) in Villalobos 2000, with no failures in Gogtay 1999 and two in Villalobos 2000 in the supervised 14‐day primaquine arm (RR 10.05, 95% CI 2.82 to 35.86, I2 = 53%; two trials, 186 participants; Figure 4; Analysis 1.1). In Kim 2012, 27% (16/59) of participants given five days of unsupervised primaquine and 38% (16/42) given 14 days of unsupervised primaquine experienced a recurrence over 15 months of follow‐up. This difference was not statistically significant (Figure 4; Analysis 1.1), and the trial authors surmised that the lack of benefit seen with 14‐day primaquine was most likely due to poor adherence to the unsupervised 14‐day primaquine regimen.
Forest plot of comparison: 1 Primaquine: 5 days versus 14 days, outcome: 1.1 P. vivax parasitaemia > 30 days after starting primaquine.
We also included trials that evaluated three day regimens (two trials) and seven day regimens (one trial), both showing higher numbers of relapses in the shorter courses. For the three day regimen, we included two trials conducted in the same unstable malaria transmission area in Colombia on adults and children. Trial authors administered chloroquine and primaquine concurrently in these trials in both intervention arms. One trial (Alvarez 2006) administered a total dose of 45 mg primaquine in the three‐day arm versus 210 mg in 14‐day primaquine arm; and Carmona‐Fonseca 2009 administered 210 mg of primaquine for three days at a dose of 3.5 mg/kg (or 1.17 mg/kg/day), compared to the 0.25 mg/kg/day used with the standard 14‐day regimen in both trials. Relapse rates were significantly lower with 14‐day primaquine in both trials (53% versus 17%) over 3 to 6 months of follow‐up (RR 3.18, 95% CI 2.1 to 4.81; two trials, 262 participants; Analysis 2.1).
For the seven day regimen, Alvarez 2006 examined seven days of primaquine (105 mg) given concurrently with chloroquine. Relapse rates were 42% with 7‐day primaquine versus 19% with 14‐day primaquine at two months follow‐up (RR 2.24, 95% CI 1.24 to 4.03; one trial, 126 participants; Analysis 3.1).
For adverse events, none of the included trials reported severe or treatment limiting adverse events; and none provided numerical data on non‐serious adverse events. Gogtay 1999 reported that nausea and skin rash were mild and infrequent; and Villalobos 2000 reported frequent, mild, transient headache, vertigo, abdominal pain, and nausea. The other trials reported that primaquine regimens were well‐tolerated.
Sensitivity analysis was not indicated, as three of the trials were at low risk of bias; and we explained the heterogeneity detected when the results of Kim 2012 (that was at high risk of bias) were pooled with the results of Gogtay 1999 and Villalobos 2000 by follow‐up duration and whether treatments were supervised or not.
Weekly primaquine (one trial)
Leslie 2008 compared weekly supervised primaquine (45 mg/week; 360 mg in total) for eight weeks with self‐administered primaquine (22.5 mg/kg) for 14 days (315 mg in total) among refugees in an area of unstable, seasonal, low malaria transmission near the Pakistan‐Afganistan border. Relapses were infrequent over 11 months follow‐up: 4/74 (5.4%) in the weekly regimen, and 1/55 (1.8%) in the self‐treated regime; Analysis 4.1).
Trial authors did not report any adverse effects, except one person with G6PD directly allocated to the 8‐week primaquine arm who experienced a transient and mild drop in hematocrit but otherwise tolerated treatment well.
Any primaquine regimens compared to no intervention or placebo
Five days primaquine (four trials)
Four trials compared 5‐day primaquine (75 mg primaquine) versus placebo and included 2213 adults and children. Relapse was more frequent with five days of primaquine compared to placebo over six months in one small trial conducted in a hospital in Mumbai (Gogtay 1999) with follow‐up for six months (25% versus 12%, 122 participants; Analysis 5.1), but this difference was not statistically significant. Relapse was little different in the two arms in three trials followed up over 12 to 15 months (18% versus 20%; 2091 participants; Analysis 5.1), one of which was conducted in a mostly urban population in Kolkata, India (Kim 2012), the other in a refugee camp in Afghanistan (Rowland 1999b), and the third in tribal villages in Orissa, India (Yadav 2002). The pooled results for relapse from the three trials did not significantly differ for 5‐day primaquine or no primaquine (18% versus 19%; I2 = 50%; 2213 participants; Figure 5, Analysis 5.1).
Primaquine (5 days) plus chloroquine versus chloroquine: P. vivax parasitaemia detected > 30 days after starting primaquine.
Fourteen days primaquine (ten trials)
Ten trials evaluated primaquine given for 14 days versus placebo and randomized 1740 adults and children. Four were conducted in India: two in the same hospital in Mumbai (Gogtay 1999; Rajgor 2003) with six months of follow‐up and the other two included outpatients from the same centre in Kolkota (Kim 2012; Ganguly 2013), and followed up participants for 42 days from treatment initiation (Ganguly 2013), to 15 months after primaquine (Kim 2012). Two trials were in refugee camps in Pakistan in an area with unstable malaria transmission, one (Leslie 2004) during a period of high transmission, and the other (Leslie 2008) when transmission was low; follow‐up was for nine months. Two trials were conducted in Bangkok, Thailand (Pukrittayakamee 1994; Walsh 2004), where there is no local transmission of malaria; follow‐up was for two months. One trial was in an area of seasonal, unstable malaria transmission in Ethiopia (Yeshiwondim 2010), with four months follow‐up. Eight trials used standard 15 mg/day primaquine dosing with a total dose of 210 mg, but in Leslie 2008, the total dose in adults was (22.5 mg/day) 315 mg in the 14‐day primaquine arm. In Yeshiwondim 2010, trial authors gave primaquine treatment for 14 days from day 29 in the chloroquine arm, compared to the standard sequential dosing in the chloroquine and primaquine arm. Kim 2012 was the only trial where trial authors did not supervise primaquine treatments and did not monitor adherence. Two trials (Gogtay 1999; Rajgor 2003) supervised the first seven days of primaquine treatment and checked adherence for the remaining seven days of primaquine. The remaining trials supervised the 14 days of primaquine treatment.
With 14‐day primaquine, fewer people relapsed than with placebo over six weeks to 15 months of follow‐up (9% versus 18%; RR 0.60; 95% CI 0.48 to 0.75; 10 trials, 1740 participants; Figure 6, Analysis 6.1). We consistently observed this benefit for 14‐day primaquine in the subgroup of trials of supervised primaquine with follow‐up from seven weeks to six months (six trials, 937 participants), and beyond six months to one year (three trials, 711 participants; Analysis 6.1). The one trial of unsupervised primaquine (Kim 2012) failed to show any benefit for 14‐day primaquine over placebo (92 participants; Analysis 6.1), which the trial authors presumed was due to non‐adherence to primaquine.
Forest plot of comparison: 6 Chloroquine plus primaquine (14 days) versus chloroquine, outcome: 6.1 P. vivax parasitaemia detected > 30 days after starting primaquine.
Sensitivity analysis using data unadjusted for clustering in Leslie 2008, since the majority of participants were individually randomized, did not alter these estimates (RR 0.53, 0.42, 0.67). Three trials at risk of bias (Leslie 2008; Kim 2012; Ganguly 2013) contributed 15.5% weight to the pooled effect estimates, and their removal from further sensitivity analysis also did not alter the results appreciably (RR 0.53, 95% CI 0.42 to 0.68; seven trials, 1318 participants).
For adverse effects, no serious adverse events were reported in any of the trials. Only one trial withdrew one person because of adverse events (Yeshiwondim 2010) but did not provide any details. Two trials (Walsh 2004; Ganguly 2013) reported headache, nausea, vomiting, abdominal pain, diarrhoea, and itching in both treatment arms which were mild and transient. Walsh 2004 measured methaemoglobin levels, and rises were mild and also transient. The few patients in Rowland 1999a and Leslie 2008 with G6PD deficiency reportedly tolerated the 14 days of primaquine treatment well.
Discussion
Summary of main results
Efficacy
In evaluating alternative regimens of primaquine for people with vivax malaria treated with chloroquine: 14 days of primaquine (0.25 mg/kg/day; 210 mg total dose) is probably more effective than shorter primaquine‐containing regimens (total dose 45 mg to 105 mg) (summary of findings Table for the main comparison; summary of findings Table 2; summary of findings Table 3)
Weekly primaquine for eight supervised doses (45 mg; 360 mg in total) and 14 days of primaquine (22.5 mg/kg; 315 mg in total) were effective in reducing relapse but the weekly regimen needs further evaluation to show it is at least as good as 14‐day primaquine (summary of findings Table 4).
In trials of people with vivax malaria treated with chloroquine, and randomized to primaquine or placebo or no primaquine, five days of primaquine (0.25 mg/kg/day; 75 mg total dose) was associated with high relapse rates similar to relapse rates in those not given primaquine (summary of findings Table 5). Relapse rates were lower in people given 14 days of primaquine (0.25 mg/kg/day; 210 mg in total) compared to those given no primaquine (summary of findings Table 6).
Safety
Most trials excluded people with G6PD deficiency and none of the primaquine dosing regimens (45 mg to 325 mg over three to 14 days and 360 mg given weekly over eight weeks) in the 15 included trials that treated 4377 adults and children were reported to cause serious or treatment limiting adverse events. The few people with G6PD deficiency included in some of the trials, and exposed to primaquine, did not experience serious or non‐serious adverse events. Other adverse events were reportedly mild and transient. Elevated methaemoglobin levels, where measured, were not associated with symptoms of methaemoglobinaemia.
Overall completeness and applicability of evidence
Completeness
We identified six additional trials including one (Alvarez 2006) published before the updated 2007 review, but after the date of our last search in August 2006. None of the included trials compared higher doses of primaquine (0.5 mg/kg or 30 mg/day; 0.75 mg/kg or 45 mg per day) given for seven or 14 days; or the standard 0.25 mg/kg (15 mg/day) dose of primaquine given for periods longer than 14 days; with the standard 14‐day primaquine dosing regimen. None of the included trials reported infection with temperate strains of P. vivax.
The review did not specifically address the issues of treating mixed vivax and falciparum infections; preventing transmissibility of vivax infections to mosquitoes by the gametocidal activity of interventions, or directly evaluating the safety of different primaquine regimens in people with and without G6PD deficiency. We did not find any trials comparing alternative primaquine dosing regimens in people from regions with widespread resistance to the standard 0.25 mg per kg body weight of primaquine, and where other regimens are standard practice.
Applicability
The trials in this review included children and adults with confirmed vivax mono‐infections and evaluated a variety of primaquine dosing schedules that provide data to inform policy and practice. Most trials excluded people with G6PD deficiency.
Intermittent primaquine treatment requires further evaluation
Intermittent dosing of primaquine at higher doses given at weekly intervals for eight weeks, after three days of chloroquine treatment, may be an effective alternative to the standard 14‐day primaquine regimen in reducing relapses, but this needs evaluation in additional trials, powered to demonstrate equivalence or non‐inferiority, compared to the standard 14‐day primaquine regimen. Intermittent dosing is postulated to be safer in people with G6PD deficiency, but this also needs further evaluation in larger numbers of people with this deficiency.
The total dose of primaquine is important
The observations of Alving 1960 and Goller 2007 (see: Why it is important to do this review), and more recent observational data (John 2012) that total doses of primaquine of 210 mg or more result in greater reductions in relapse than with lower total doses of primaquine, were also evident in the randomized comparisons in this review. Significantly lower relapse occurred with primaquine doses of 210 mg or more, compared to primaquine given at lower doses. We presented relapse in the treatment arms of the trials in this review, grouped by the total dose and duration of primaquine, in Table 2. The comparisons of relapse are confounded by variable rates of vivax transmission between trials; but on average relapse was less common in the treatment arms where primaquine was given at a total dose of 210 mg or more, compared to the treatment arms where the total dose of primaquine was lower.
| Total dose of primaquine in intervention arms | Study | Duration of primaquine treatment | Relapse (%) | Mean relapse rate (95% CI); Median relapse rate |
| No primaquine | Nil | 4/30 (13) | 22% (19% to 26%); 12% | |
| 7/60 (12) | ||||
| 49/100 (49) | ||||
| 129/250 (5) | ||||
| 62/723 (9) | ||||
| 13/142 (9) | ||||
| 88/212 (42) | ||||
| 8/10 (80) | ||||
| 2/71 (3) | ||||
| 9/128 (7) | ||||
| 1/100 (1) | ||||
| 5/50 (15) | ||||
| 45 mg | 3 days | 32/65 (49) | 49% (38% to 61%) | |
| 75 mg* | 5 days | 16/62 (26) | 28% (27% to 30%); 27% | |
| 128/250 (51) | ||||
| 8/30 (27) | ||||
| 49/759 (7) | ||||
| 105 mg | 7 days | 26/62 (42) | 42% (31% to 54%) | |
| 210 mg* | 3 days | 37/65 (57) | 57% (45% to 68%) | |
| 14 days | 2/25 (8) | 12% (11% to 13%); 8% | ||
| 0/63 (0) | ||||
| 32/100 (32) | ||||
| 2/31 (7) | ||||
| 6/131 (5) | ||||
| 27/173 (16) | ||||
| 3/12 (25) | ||||
| 12/64 (19) | ||||
| 10/68 (15) | ||||
| 4/132 (3) | ||||
| 1/103 (1) | ||||
| 315 mg | 14 days | 0/55 (0) | 0% | |
| 360 mg | Weekly over 8 weeks | 3/74 (4) | 4% (1% to 11%) |
* We did not show data for 5 days primaquine (75 mg) and 14 days primaquine (210 mg) from Kim 2012 due to high risk of selection and detection bias. Also, the trial authors expressed doubts regarding patient adherence to primaquine in this unsupervised trial, raising concerns about the reliability of relapse estimates with primaquine.
The duration over which the total dose of primaquine was delivered also appeared to influence relapse (Table 2). Carmona‐Fonseca 2009 directly compared the efficacy of the same total dose of primaquine in people randomized to shorter versus longer courses of treatment. Relapse was higher in those randomized to 210 mg of primaquine administered over three days, compared to those randomized to 210 mg of primaquine over 14 days (57% versus 14%, RR 3.9, 95% CI 2.1 to 7.1; one trial, 133 participants). Trial authors administered primaquine and chloroquine concurrently in the shorter three‐day treatment arm and sequentially in the longer treatment arm of this trial (see next section below).
Concurrent versus sequential administration of chloroquine and primaquine
Primaquine usually follows on from chloroquine treatment. As discussed in the background section "Why it is important to do this review", in some parts of the world (primarily in Latin America), primaquine is co‐administered with chloroquine rather than sequentially after chloroquine. This is based on the premise that primaquine has some activity against the asexual blood stages, and the efficacy of primaquine in preventing relapses may be greater with the concurrent, rather than sequential, administration of chloroquine and primaquine.
Three trials in this review used concurrent chloroquine and primaquine in one or all their intervention arms. Villalobos 2000 (Brazil) directly compared the concurrent administration of chloroquine and primaquine, with each given for five days, versus the standard sequential administration of chloroquine for three days followed by primaquine for 14 days. Relapse was less frequent in the arm given sequential treatment of chloroquine and primaquine (3% versus 26%), but this result was confounded by the lower total dose of primaquine in the shorter concurrent treatment arm (105 mg) compared to the 210 total dose of primaquine in the longer sequential treatment arm.
Two trials conducted in Columbia (Alvarez 2006; Carmona‐Fonseca 2009) used concurrent chloroquine and primaquine in all intervention arms. However Alvarez 2006 used different total doses of primaquine in the three arms (210 mg, 105 mg, and 45 mg), again preventing unconfounded inferences of the efficacy of concurrent administration of the two drugs. As discussed previously, Carmona‐Fonseca 2009 compared a total dose of 210 mg of primaquine co‐administered with chloroquine over three days versus primaquine 210 mg co‐administered with chloroquine for the first three days, and continued until day 14. Relapse was significantly less frequent with 210 mg of primaquine given for 14 days, providing limited direct evidence to suggest that the co‐administration of primaquine with chloroquine may be less important than an adequate total dose of primaquine, given for a longer period after chloroquine, to eliminate emerging hypnozoites.
Another suggestion discussed in the background section to improve the efficacy of primaquine in preventing relapses is to delay the sequential administration of primaquine towards the latter part of the 28 to 35 day period of chloroquine's schizonticidal activity in order to increase the likelihood of radical cure, than if used immediately after chloroquine (Baird 2009). In Yeshiwondim 2010 (Ethiopia), relapse was more common in the treatment arm that delayed the sequential administration of 14‐day primaquine (210 mg total dose) after chloroquine to commence at day 28, than in the comparator arm, where 14‐day primaquine (210 mg total dose) was given sequentially but immediately after chloroquine (7% versus 3%). However, this difference was not statistically significant, possibly because this trial was primarily powered to demonstrate the efficacy of chloroquine against blood stage infections, and not the relative benefits of the delayed versus standard sequential administration of chloroquine and primaquine.
This review found evidence only to support the standard sequential administration of chloroquine followed by primaquine given for at least 14 days at a total dose of 210 mg or more of primaquine, or weekly treatment delivering 360 mg of primaquine.
Differentiating relapses from re‐infections may not be critical for reducing transmission of vivax malaria
It is not possible to reliably differentiate vivax relapses from re‐infections in endemic areas with currently available molecular techniques, and though newer techniques show promise, they are not available for routine use. However, the data in this review show that the 14‐day and weekly primaquine regimens are effective in the first six months of follow‐up in people living in endemic areas, as well as in trials with follow‐up at nine months to one year. Since hypnozoites form the major source of recurrent malaria episodes in many parts of the world where vivax malaria is a burden, widespread use of 14 days of primaquine has the potential to effectively reduce the hypnozoite pool and reduce transmission, and the burden of vivax malaria; provided concerns about poor compliance and safety in people with G6PD deficiency can be addressed.
Ensuring adherence to 14‐day primaquine regimens is important
Assessing adherence to primaquine was not a primary objective of this review, but is an important issue to consider if governments and national programmes are to continue to endorse, or be encouraged to switch to, the 14‐day regimen. All trials, apart from Kim 2012, Yadav 2002 and Yeshiwondim 2010, provided supervised primaquine, and the efficacy of 14 days of primaquine was seemingly not influenced in Yadav 2002, and Yeshiwondim 2010 by the provision of supervision. The authors of Kim 2012 believe that people given 14‐day primaquine were likely to have not been adherent, although they did not report the methods to monitor adherence, the proportions non‐adherent, or the extent of non‐adherence. Only Leslie 2004 formally evaluated the effects of supervised treatments, where in two of the three arms, 346 participants given chloroquine plus 14‐days of primaquine were randomized equally to supervised therapy or unsupervised therapy. Efficacy did not significantly differ between supervised and non‐supervised primaquine arms.
Although poor adherence with primaquine is reported as a major cause of relapse (Baird 2004; Hill 2006), recommending 14 days of primaquine should not be dismissed on grounds of adherence alone. Equally important are concerns expressed by some malaria experts that shorter courses of ineffective regimens could accelerate the selection of primaquine‐resistant strains (Collins 1996; Price 2011). Leslie 2004 demonstrated that, at least in the context of an RCT, simple measures such as health education messages were sufficient to improve adherence. If these measures were routinely employed in malaria control programmes, the effective life of this unique anti‐malarial drug could be prolonged. Ensuring adherence for 14‐day primaquine may not be as difficult as with long‐term interventions, since improving short‐term adherence is relatively successful with a variety of simple interventions (Haynes 2008). The evidence specific to improving adherence in malaria, such as unit‐dose packaging supported by educational interventions, though promising in general (Qingjun 1998), requires further evaluation (Orton 2005).
In contrast to the conclusions of Leslie 2004, two trials done along the Thai‐Myanmar border demonstrated superior efficacy with the 14‐day primaquine regimen following chloroquine in people randomized to receive primaquine by directly observed treatment (DOT) versus self‐administered treatment (Takeuchi 2010; Manneeboonyang 2011). Leslie 2004 conducted the trial in the relatively structured confines of a refugee camp where geographical mobility is likely to have been less than in the Thai‐Myanmar trials, and where health services were provided by a single agency. These conditions differ from the usual situations where vivax malaria is treated.
Primaquine and G6PD deficiency
Most of the trials had G6PD deficiency as a criterion for exclusion, so it is not surprising that treatment limiting adverse events were uncommon in the 1209 people given the 14‐day regimen. Leslie 2008 included people with G6PD deficiency in a safety arm given eight weekly doses of 45 mg primaquine base, but reported that only one person with the deficiency was in this safety arm. This trial was conducted in an area of Pakistan where primaquine was not used routinely due to fears of haemolysis given the estimated 15% to 17% prevalence of G6PD deficiency (Beutler 1994). The data from Leslie 2008 suggest that these fears are based on overestimates of the prevalence and the relevance of G6PD deficiency to relapse prevention with primaquine. Observational data suggest that haemolytic anaemia due to G6PD deficiency following exposure to primaquine among people infected with P. vivax might be lower than previously assumed; leading to inferences that G6PD deficiency (at least certain types) may confer protection against P. vivax infection, and may thus be less common among P. vivax‐infected patients than among the general population (Louicharoen 2009; Leslie 2010). These observations of the protection against P. vivax infection conferred by G6PD deficiency need replication in other settings, particularly where the Mediterranean variant is common and haemolysis due to primaquine can be severe and prolonged.
G6PD deficiency can be detected with either a quantitative determination of the enzyme level or a qualitative screening test; the latter is less expensive and is sufficient to identify individuals with a G6PD deficiency in most instances (Beutler 1994). However, many low‐income countries have limited facilities to detect this condition before administering primaquine. While eight weekly doses of primaquine may be safe in this population, data from the one person in the trial with this deficiency do not provide sufficient assurance to advocate the wider use of this regimen in people with this deficiency, without carefully monitoring their safety.
Primaquine in vulnerable populations
The trials in this review excluded very young children (younger than one year), pregnant and nursing mothers, people with severe malnutrition, and severe anaemia; and this review does not provide evidence of the safety of the 14‐day or the 8‐weekly dose primaquine regimens in these vulnerable populations.The data from Leslie 2004 and Leslie 2008, done during periods of high and low seasonal transmission respectively, indicate that very young children living in areas of high transmission are likely to have higher recurrence rates than older children and adults. The trial participants had lived in refugee camps for several years and hence differences in acquired immunity and re‐infections probably explain the age‐related recurrence rates, rather than differential efficacy of anti‐relapse regimens. Hence, the pooled effect estimates for the 14‐day and 8‐week primaquine regimens in Leslie 2008, particularly in very young children, may differ when applied elsewhere according to local transmission intensities and population migration patterns.
Quality of the evidence
We assessed the overall quality of the evidence using the GRADE approach (Schunemann 2008).
Alternative primaquine dosing regimens compared to the standard 14‐day primaquine regimen (blood stage infections treated with chloroquine)
The overall quality of evidence for relapse over six months of follow‐up with shorter courses of primaquine versus 14‐day primaquine was of "moderate quality" for the commonly used 5‐day primaquine regimen (summary of findings Table for the main comparison). This indicates that it is possible that further trials with follow‐up beyond six months, and in settings with different transmission intensities, may alter these estimates. However, considering the magnitude of the estimates favouring 14 days of primaquine, it is unlikely that these will be altered significantly in favour of a 5‐day primaquine regimen, unless primaquine doses higher than 0.25 mg/kg/day are used. The overall quality of the evidence of efficacy of the shorter 3‐day primaquine regimen was also "moderate quality" (summary of findings Table 2). Further research is likely to change these estimates; but unless higher doses given for five days or seven days are first shown effective, compared to 14‐day primaquine, research evaluating 3‐day regimens appear unwarranted. Data from the one trial evaluating the effects of seven days of primaquine were of "low quality" (summary of findings Table 3). It seems likely that the efficacy estimates will be significantly altered by further research, especially if higher primaquine doses (0.5 mg/kg or 0.75 mg/kg per day) are used.
Weekly primaquine versus 14‐day primaquine (blood stage infections treated with chloroquine)
The "very low quality" evidence from a single multicentre, multicountry trial of weekly primaquine means that we do not know if eight weekly doses of primaquine is as effective, or even non‐inferior to 14 days of primaquine in preventing recurrences over 11 months after an episode of vivax malaria (summary of findings Table 4). This uncertainty stems from very serious study limitations, serious indirectness, and very serious imprecision in the effect estimates of this trial.
Primaquine regimens versus no treatment or placebo (blood stage infections treated with chloroquine)
Primaquine (five days)
We graded the pooled effect estimates for relapse prevention with 5‐day primaquine versus placebo as "high quality" (summary of findings Table 5). Three of the four trials were free of the risk of bias, all four were consistent in their estimates in showing no significant difference, and were done in the usual situations and populations where vivax malaria is a burden. In spite of imprecision in the effect estimates, the trials had sufficient power (422 events in 2212 participants) to detect appreciable differences, had there been any. Additionally, the high estimated recurrence rates with five days of primaquine (mean 28%; 95% CI 27% to 30%) and with chloroquine alone (mean 22%; 95% CI 19% to 26%) in the treatment arms of the trials (Table 2) provide sufficient evidence to refute any suggestions of its efficacy as an anti‐relapse treatment for people with vivax malaria.
Primaquine (14 days)
We assessed the pooled effect estimates for relapse prevention with chloroquine plus primaquine (14 days) versus placebo as "high quality" for follow‐up periods ranging from one month to a year after interventions (summary of findings Table 6). Further research to compare 14 days of treatment versus no anti‐relapse treatment is unlikely to change this estimate, unless complemented by the use of multi‐locus molecular genetic tests that have been pre‐validated for the region, in order to correct for re‐infections, in people whose adherence to treatments are supervised, and followed up for at least one year. The corrected estimates could differentiate between true relapses and re‐infections (both early and late), but it is uncertain if this would significantly alter the estimates of the relative efficacy of the 14‐day primaquine regimen. Considering the magnitude of benefit favouring 14‐day primaquine, whatever contributions early and late new‐infections may add to this estimate, appreciable clinical benefits are likely to accrue for people with vivax malaria with 14 days of primaquine.
Potential biases in the review process
We stated that included trials should have used the same dose of chloroquine in all intervention arms, but in the 2007 version of this review we included Villalobos 2000 that used five days of chloroquine in one arm and three days in the other. We chose to retain this trial among the included trials because the trial ensured parasitic clearance in both arms by day 28 and they evaluated the anti‐relapse potential of primaquine. We also reviewed all other excluded trials to ensure that none were excluded on the basis of different doses of chloroquine used in the interventions.
We identified and included Yeshiwondim 2010 in this update, which gave primaquine, not immediately following chloroquine as is usually done, but after day 28 for 14 days in one intervention arm. We also included two trials where trial authors gave primaquine and chloroquine concurrently (Alvarez 2006; Carmona‐Fonseca 2009). We chose these departures from our approach in the 2007 review in order to address issues highlighted in the Why it is important to do this review section regarding the relative merits of concurrent and delayed sequential administration. We also ensured that none of the trials that we had previously excluded were due to concurrent administration of the two interventions or because of delayed sequential administration.
We also included the sole trial that used intermittent primaquine dosing compared to the 14‐day primaquine arm that used a dose was higher (22.5 mg/day) than the standard 15 mg/day dose recommended by the WHO. However, the WHO recommend 30 mg/day and even 45 mg/day for daily dosing (WHO 2010a).
Agreements and disagreements with other studies or reviews
The updated WHO malaria treatment guidelines (WHO 2010a) recommend the standard oral regimen of chloroquine (25 mg base/kg body weight) given over three days plus primaquine at either a low dose (0.25 mg base/kg body weight per day) for 14 days; or high dose (0.5 to 0.75 mg base/kg body weight per day) for 14 days, as effective and safe for the radical cure of chloroquine‐sensitive vivax malaria in patients with no G6PD deficiency. This review update provides direct and indirect evidence to support the efficacy and safety of 14 days of primaquine in reducing relapses due to vivax malaria. Only one of the included trials (Leslie 2008) used 0.5 to 0.75 mg base/kg body weight in the daily and intermittent dosing regimens; hence the recommendation for a higher daily dose requires further evaluation in head‐to‐head comparisons and in areas where there is a reported reduced efficacy of standard primaquine doses.
The strong recommendation of WHO 2010a endorsing 14 days of primaquine over five days of primaquine graded the overall evidence as "low quality" for the PCR‐uncorrected efficacy estimates from the two contributory trials directly comparing the two regimens, and as "very low quality" for the PCR‐corrected estimates from one of them. We did not include PCR‐corrected estimates as an outcome in this review update due to the unavailability for routine use of validated methods of molecular differentiation of relapses from re‐infections. Our judgements differ from the quality assessments for PCR‐uncorrected estimates of the WHO recommendation. We graded the overall quality for the PCR‐uncorrected efficacy estimates as of "moderate quality". Additional unpublished information from the first author of one of the trials (Gogtay 1999) permitted a more accurate estimation of the risk of bias in this study,
WHO 2010a also recommended a primaquine regimen of 0.75 mg base/kg body weight once per week for eight weeks as anti‐relapse therapy for P. vivax and P. ovale malaria in patients with mild G6PD deficiency, based on data from Leslie 2008. However they did not report the quality of the evidence supporting this recommendation. Our assessments of the same data suggest the WHO 2010a recommendation is based on "very low quality evidence".
Study flow diagram: 2013 review update
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Forest plot of comparison: 1 Primaquine: 5 days versus 14 days, outcome: 1.1 P. vivax parasitaemia > 30 days after starting primaquine.
Primaquine (5 days) plus chloroquine versus chloroquine: P. vivax parasitaemia detected > 30 days after starting primaquine.
Forest plot of comparison: 6 Chloroquine plus primaquine (14 days) versus chloroquine, outcome: 6.1 P. vivax parasitaemia detected > 30 days after starting primaquine.
Comparison 1 Primaquine: 5 days versus 14 days, Outcome 1 P. vivax parasitaemia > 30 days after starting primaquine.
Comparison 2 Primaquine: 3 days versus 14 days, Outcome 1 P. vivax parasitaemia > 30 days after starting primaquine.
Comparison 3 Primaquine: 7 days versus 14 days, Outcome 1 P. vivax parasitaemia > 30 days after starting primaquine.
Comparison 4 Primaquine: weekly for 8 weeks versus daily for 14 days, Outcome 1 P. vivax parasitaemia > 30 days after starting primaquine.
Comparison 5 Primaquine 5 days versus no primaquine, Outcome 1 P. vivax parasitaemia > 30 days after starting primaquine.
Comparison 6 Primaquine 14 days versus no primaquine, Outcome 1 P. vivax parasitaemia detected > 30 days after starting primaquine.
| What are the effects of five days of primaquine compared to 14 days of primaquine for preventing relapses in people with P. vivax malaria treated for blood stage infections with chloroquine? | ||||||
| Patient or population: People with P. vivax malaria1 | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Primaquine 14 days | Primaquine 5 days | |||||
| P. vivax parasitaemia detected > 30 days after starting primaquine | 21 per 1000 | 183 more per 1000 | RR 10.05 | 186 | ⊕⊕⊕⊝ | |
| Serious adverse events | none reported | none reported | Not estimable | 186 | ||
| Other adverse events | none reported | none reported | Not estimable | 186 | ||
| *The basis for the assumed risk is the average of the risk in the control groups of the two studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Gogtay 1999 was done in Mumbai, India, and Villalobos 2000 was done in Porto Velho, Brazil; treatments were supervised in both and follow‐up was for three to six months. Kim 2012 was done in Kolkata, India; primaquine was not supervised; follow‐up was for 15 months. 2 Data from a third trial (Kim 2012) were not pooled due to substantial heterogeneity (I2 = 87%). This trial was at risk of selection and detection bias, and the trial authors reported that the lack of significant difference in recurrences over 15 months (27%, 16/59 with 5‐day primaquine; 38%, 16/42 with 14‐day primaquine) was likely due to non‐adherence to unsupervised primaquine. | ||||||
| What are the effects of primaquine (3 days) compared to primaquine (14 days) for preventing relapses in people with P. vivax malaria treated for blood‐stage infections with chloroquine? | ||||||
| Patient or population: People with P. vivax malaria1 | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Primaquine 14 days | Primaquine three days | |||||
| P. vivax parasitaemia detected > 30 days after starting primaquine | 167 per 1000 | 363 more per 1000 | RR 3.18 | 262 | ⊕⊕⊕⊝ | |
| Serious adverse events | None reported | None reported | Not estimable | 262 | ||
| Other adverse events | Not reported | Not reported | Not estimable | 262 | ||
| *The basis for the assumed risk is the average of the risk in the control group in the two trials. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Alvarez 2006 and Carmona‐Fonseca 2009 conducted the trials in the same semi‐rural areas of Columbia, South America. | ||||||
| What are the effects of primaquine (seven days) compared to primaquine (14 days) for preventing relapses in people with P. vivax malaria treated for blood stage infections with chloroquine? | ||||||
| Patient or population: People with P. vivax malaria1 | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| 14 days primaquine | 7 days primaquine | |||||
| P. vivax parasitaemia detected > 30 days after starting primaquine | 188 per 1000 | 233 more per 1000 | RR 2.24 | 126 | ⊕⊕⊝⊝ | |
| Severe adverse events | None reported | None reported | Not estimable | 126 | ||
| Other adverse events | Not reported | Not reported | Not estimable | 126 | ||
| *The basis for the assumed risk is the risk in the control group. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Alvarez 2006 was conducted in Columbia, South America. | ||||||
| What are the effects of supervised primaquine (weekly for 8 weeks) versus primaquine (daily for 14 days) for preventing relapses in people with P. vivax malaria treated for blood stage infections with chloroquine? | ||||||
| Patient or population: Children and adults with blood smear positive P. vivax malaria1 | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Primaquine for 14 days | Primaquine weekly for eight weeks | |||||
| P. vivax parasitaemia detected > 30 days after starting primaquine | 18 per 1000 | 36 more per 1000 | RR 2.97 | 129 | ⊝⊝⊝⊝ | |
| Serious adverse events | None reported | None reported | Not estimable | 129 | ||
| Adverse events | None reported | None reported | Not estimable | 129 | ||
| *The basis for the assumed risk is the risk in the control group. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Leslie 2008 was conducted in three Afghan refugee camps in North West Frontier Province in Pakistan during a period of low transmission. 6 Trial authors allocated insufficient numbers of people with G6PD deficiency (only one in the report) to the 8‐week arm to be sure that intermittent primaquine is a safer alternative than 14 days of primaquine; none given the 14‐day regimen had this deficiency. | ||||||
| What are the effects of primaquine (five days) compared to no intervention or placebo for preventing relapses in people with P. vivax malaria treated for blood stage infections with chloroquine? | ||||||
| Patient or population: People with P. vivax malaria1 Intervention: Chloroquine (25 mg/kg for three days) plus primaquine (0.25 mg/kg) for five days2 | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No primaquine | 5 days primaquine | |||||
| P. vivax parasitaemia detected > 30 days after starting primaquine | 193 per 10002 | 4 fewer per 1000 | RR 0.98 | 2213 | ⊕⊕⊕⊕ | |
| Serious adverse events | None reported | None reported | Not estimable | 2213 | ||
| Other adverse events | None reported | None reported | Not estimable | 2213 | ||
| *The basis for the assumed risk is the median control group risk across the four studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Trial authors performed trials in outpatients in Mumbai, India (Gogtay 1999; Rajgor 2003) and Kolkota, India (Kim 2012), and in the Adizai Afghan refugee camp in the North West Frontier Province of Pakistan (Rowland 1999b). | ||||||
| What are the effects of primaquine (14 days) compared to no intervention or placebo for preventing relapses in people with P. vivax malaria treated for blood stage infection with chloroquine? | ||||||
| Patient or population: People with P. vivax malaria1 | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No primaquine | Primaquine 14 days | |||||
| P. vivax parasitaemia detected > 30 days after starting primaquine | 84 per 1000 | 34 fewer per 1000 | RR 0.60 | 1740 | ⊕⊕⊕⊕ | |
| Serious adverse events | None reported | None reported | Not estimable | 1740 | ||
| Other adverse events | None reported | None reported | Not estimable | 1740 | ||
| *The basis for the assumed risk is the median risk in the control group. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Trial authors conducted the studies in Ethiopia (Yeshiwondim 2010), India (Gogtay 1999; Rajgor 2003; Kim 2012; Ganguly 2013), Pakistan (Rowland 1999a; Leslie 2004; Walsh 2004; Leslie 2008) and Thailand (Pukrittayakamee 1994). | ||||||
| Search set | CIDG SRa | CENTRAL | MEDLINEb | EMBASEb | LILACSb |
| 1 | Plasmodium vivax | primaquine | primaquine | primaquine | |
| 2 | vivax malaria | PRIMAQUINE | PRIMAQUINE | PRIMAQUINE | malaria |
| 3 | primaquine | 1 or 2 | 1 or 2 | 1 or 2 | Plasmodium vivax |
| 4 | — | Plasmodium vivax | MALARIA, VIVAX | malaria vivax | — |
| 5 | — | vivax malaria | Plasmodium vivax | PLASMODIUM VIVAX | — |
| 6 | — | 4 or 5 | 4 or 5 | 4 or 5 | — |
| 7 | — | 3 and 6 | 3 and 6 | 3 and 6 | — |
| aCochrane Infectious Diseases Group Specialized Register. | |||||
| Total dose of primaquine in intervention arms | Study | Duration of primaquine treatment | Relapse (%) | Mean relapse rate (95% CI); Median relapse rate |
| No primaquine | Nil | 4/30 (13) | 22% (19% to 26%); 12% | |
| 7/60 (12) | ||||
| 49/100 (49) | ||||
| 129/250 (5) | ||||
| 62/723 (9) | ||||
| 13/142 (9) | ||||
| 88/212 (42) | ||||
| 8/10 (80) | ||||
| 2/71 (3) | ||||
| 9/128 (7) | ||||
| 1/100 (1) | ||||
| 5/50 (15) | ||||
| 45 mg | 3 days | 32/65 (49) | 49% (38% to 61%) | |
| 75 mg* | 5 days | 16/62 (26) | 28% (27% to 30%); 27% | |
| 128/250 (51) | ||||
| 8/30 (27) | ||||
| 49/759 (7) | ||||
| 105 mg | 7 days | 26/62 (42) | 42% (31% to 54%) | |
| 210 mg* | 3 days | 37/65 (57) | 57% (45% to 68%) | |
| 14 days | 2/25 (8) | 12% (11% to 13%); 8% | ||
| 0/63 (0) | ||||
| 32/100 (32) | ||||
| 2/31 (7) | ||||
| 6/131 (5) | ||||
| 27/173 (16) | ||||
| 3/12 (25) | ||||
| 12/64 (19) | ||||
| 10/68 (15) | ||||
| 4/132 (3) | ||||
| 1/103 (1) | ||||
| 315 mg | 14 days | 0/55 (0) | 0% | |
| 360 mg | Weekly over 8 weeks | 3/74 (4) | 4% (1% to 11%) | |
| * We did not show data for 5 days primaquine (75 mg) and 14 days primaquine (210 mg) from Kim 2012 due to high risk of selection and detection bias. Also, the trial authors expressed doubts regarding patient adherence to primaquine in this unsupervised trial, raising concerns about the reliability of relapse estimates with primaquine. | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 P. vivax parasitaemia > 30 days after starting primaquine Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Follow‐up ≤ 6 months (supervised treatment) | 2 | 186 | Risk Ratio (M‐H, Fixed, 95% CI) | 10.05 [2.82, 35.86] |
| 1.2 Follow‐up > 6 months (unsupervised treatment) | 1 | 101 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.71 [0.40, 1.26] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 P. vivax parasitaemia > 30 days after starting primaquine Show forest plot | 2 | 262 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.18 [2.10, 4.81] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 P. vivax parasitaemia > 30 days after starting primaquine Show forest plot | 1 | 126 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.24 [1.24, 4.03] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 P. vivax parasitaemia > 30 days after starting primaquine Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 At 6 months | 1 | 129 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.23 [0.28, 99.15] |
| 1.2 At 11 months | 1 | 129 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.97 [0.34, 25.87] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 P. vivax parasitaemia > 30 days after starting primaquine Show forest plot | 4 | 2213 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.73, 1.30] |
| 1.1 Follow‐up ≤ 6 months | 1 | 122 | Risk Ratio (M‐H, Random, 95% CI) | 2.21 [0.98, 4.99] |
| 1.2 Follow‐up > 6 months | 3 | 2091 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.81, 1.09] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 P. vivax parasitaemia detected > 30 days after starting primaquine Show forest plot | 10 | 1740 | Risk Ratio (Fixed, 95% CI) | 0.60 [0.48, 0.75] |
| 1.1 Follow‐up ≤ 6 months (supervised treatment) | 6 | 937 | Risk Ratio (Fixed, 95% CI) | 0.40 [0.23, 0.68] |
| 1.2 Follow‐up > 6 months (supervised treatment) | 3 | 711 | Risk Ratio (Fixed, 95% CI) | 0.57 [0.44, 0.74] |
| 1.3 Follow‐up > 6 months (unsupervised treatment) | 1 | 92 | Risk Ratio (Fixed, 95% CI) | 1.27 [0.72, 2.25] |
