Primaquina en esquemas de dosis alternativos para la prevención de la recurrencia en pacientes con paludismo por Plasmodium vivax
Referencias
Referencias de los estudios incluidos en esta revisión
Referencias de los estudios excluidos de esta revisión
Referencias de los estudios en curso
Referencias adicionales
Referencias de otras versiones publicadas de esta revisión
Characteristics of studies
Characteristics of included studies [ordered by study ID]
| Study characteristics | ||
| Methods | RCT July 1994 to June 1995 | |
| Participants | 120 participants enrolled. Inclusion criteria
Exclusion criteria
Diagnosis: microscopy. G6PD status not stated. No details CYP2D6 status. | |
| Interventions |
(Additional arm chloroquine 10 mg/kg + primaquine 0.5 mg/kg for 5 days not included as total dose (150 mg) less than standard treatment (210 mg)) Although different doses of chloroquine in the 2 arms, all participants had negative parasitaemia within 72 hours. Primaquine and chloroquine given concurrently. Supervised treatment. | |
| Outcomes |
Follow‐up 180 days | |
| Notes | Location: Belém, state of Pará, Brazil Setting: not stated Source of funding: not stated | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | No details supplied on randomization process. |
| Allocation concealment (selection bias) | Unclear risk | No details supplied on allocation. |
| Blinding of participants and personnel (performance bias) | High risk | Open‐label. |
| Blinding of outcome assessment (detection bias) | High risk | Open‐label. |
| Incomplete outcome data (attrition bias) | Low risk | One loss to follow‐up as moved out of area. |
| Selective reporting (reporting bias) | Low risk | Unable to find protocol but relapse and standard errors (SEs) reported as would be expected. |
| Other bias | Unclear risk | Funding not stated. |
| Study characteristics | ||
| Methods | RCT Dates not provided | |
| Participants | 167 participants enrolled. Inclusion criteria
Exclusion criteria
Diagnosis: microscopy. No details on pregnant/breastfeeding women. No details CYP2D6 status. | |
| Interventions |
Open randomization to chloroquine treatment – either 300 mg or 450 mg on day 1 of admission. Re‐allocated after recovery of acute symptoms (double‐blind RCT). Chloroquine course completed and parasitological clearance confirmed prior to randomization to primaquine group (exact time between treatment courses not specified). Supervised treatment in hospital. | |
| Outcomes |
Follow‐up 6 months | |
| Notes | Location: Thailand Setting: not stated Funding: not stated | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | 1st step chloroquine is open randomization, then PQ stage randomized. No details on randomization process. |
| Allocation concealment (selection bias) | Unclear risk | No details. |
| Blinding of participants and personnel (performance bias) | Low risk | Reported as double‐blind. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Reported as double‐blind but there were no details as to whether microscopy was blinded or whether there was double reading of smears. |
| Incomplete outcome data (attrition bias) | High risk | Unexplained high loss to follow‐up. |
| Selective reporting (reporting bias) | Unclear risk | No protocol. |
| Other bias | Unclear risk | Funding not disclosed. |
| Study characteristics | ||
| Methods | RCT September 2003 to September 2006 | |
| Participants | 133 patients enrolled across 2 arms (total 188 counting arms not included in review) Inclusion criteria
Exclusion criteria
Diagnosis: microscopy. No details CYP2D6 status or breastfeeding mothers. | |
| Interventions |
(Additional arms: 0.83 mg/kg day for 3 days (total dose 149.4 mg) and 0.58 mg/kg day for 3 days (total dose 104.4 mg) not included as total dose less than standard treatment) Primaquine given simultaneously with chloroquine. Supervised treatment. | |
| Outcomes |
Follow‐up 120 days | |
| Notes | Location: Colombia Setting: patients that attended the local health clinics in Turbo and El Bagre Funding: Colciencias (government agency), Dirección Seccional de Salud de Antioquia (DSSA), Universidad de Antioquia | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Details of randomization not given. |
| Allocation concealment (selection bias) | Unclear risk | No details supplied. |
| Blinding of participants and personnel (performance bias) | High risk | Not blinded. |
| Blinding of outcome assessment (detection bias) | High risk | Not blinded and no mention on blinding in blood smear assessment. |
| Incomplete outcome data (attrition bias) | Low risk | 2 lost per group, no explanations given, but less than 5% of total across groups. |
| Selective reporting (reporting bias) | Unclear risk | Protocol not found. No safety data were provided (which might have been expected to have been provided). |
| Other bias | Low risk | Government and academic funding. |
| Study characteristics | ||
| Methods | RCT February 2012 to July 2015 | |
| Participants | 680 participants enrolled. Inclusion criteria
Exclusion criteria
Diagnosis: microscopy No details CYP2D6 | |
| Interventions |
Supervised treatment. Not specified whether primaquine given concurrently with chloroquine/dihydroartemisinin‐piperaquine. | |
| Outcomes |
Follow‐up: 3 months, 4 months, 6 months, 8 months, 1 year | |
| Notes | Location: Thailand Setting: Clinics along the Thailand‐Myanmar border Source of funding: The Wellcome Trust Authors were contacted and provided 3‐month and 6‐month recurrence data for Analysis 4.3 and Analysis 4.4 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: “Randomization was computer generated in blocks of 20” |
| Allocation concealment (selection bias) | Unclear risk | Not reported |
| Blinding of participants and personnel (performance bias) | High risk | Quote: “open 2‐way randomized controlled trial” |
| Blinding of outcome assessment (detection bias) | High risk | Open‐label and no mention of blood smear blinding |
| Incomplete outcome data (attrition bias) | Unclear risk | Overall, 40% left the study before the end of 1‐year follow‐up. 4% of enrolled participants did not receive blood‐stage treatment and were not included in any analyses. A further 20% had left the study at 6 months and another 17% after 1 year. No imputations were used to account for participants that left the study early. However, dropouts were balanced between groups and reasons for leaving the study were provided. |
| Selective reporting (reporting bias) | Low risk | NCT record (NCT01640574) reports little information on outcomes, however all are reported in the study |
| Other bias | Low risk | We did not detect any other sources of bias. |
| Study characteristics | ||
| Methods | RCT March 2006 to August 2008 | |
| Participants | 360 participants Inclusion criteria
Exclusion criteria
Diagnosis: light microscopy. Parasite genotyping with PCR also performed ‐ 5 microsatellite loci used to determine whether homologous relapse. | |
| Interventions |
(Additional arm of chloroquine + primaquine 0.5 mg/kg/day for 5 days excluded as total dose 150 mg, which was less than standard treatment.) Supervised. Primaquine administered concurrently with chloroquine. | |
| Outcomes |
Follow‐up: 210 days | |
| Notes | Location: Peru Setting: Padre Cocha and the San Juan Health Centers and Santa Clara Health Center The periphery of the city of Iquitos, which is located on the river bank of the Amazon River and is the largest city in the Peruvian rainforest. Funding: the US Department of Defense Global Emerging Infections Surveillance and Response System (DoD‐GEIS), the National Institute of Health of Peru, and the Pan‐American Health Organization/US Agency for International Development (PAHO‐USAID) Americas Malaria Initiative/Amazonic Network of Antimalarial Drug Resistance, AMI/RAVREDA project. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated block randomization table. |
| Allocation concealment (selection bias) | Low risk | The treatment allocation for each participant was placed in a sealed envelope, kept in an orderly manner, and opened only at the time of enrolment of a new participant to prevent selection bias by study physicians. |
| Blinding of participants and personnel (performance bias) | High risk | Open‐label. |
| Blinding of outcome assessment (detection bias) | High risk | Open‐label – no mention of blood smear blinding. |
| Incomplete outcome data (attrition bias) | Low risk | 8% to 10% loss following randomization, but all accounted for. |
| Selective reporting (reporting bias) | Low risk | Study protocol registered. Unable to find outcomes in protocol, but expected outcomes were reported on. |
| Other bias | Low risk | We did not detect any other sources of bias. |
| Study characteristics | ||
| Methods | RCT September 2004 to July 2006 | |
| Participants | 129 Afghan refugees Inclusion criteria
Exclusion criteria
Diagnosis: microscopy | |
| Interventions |
(Additional arm chloroquine + weekly placebo not included). Supervised. Not specified whether primaquine given concurrently with chloroquine. | |
| Outcomes |
Follow‐up: 9 months (11 months participation: 8 weeks treatment + 9 months follow‐up) | |
| Notes | Location: Pakistan Setting: Adizai, Baghicha, and Khagan villages, close to Peshawar, Northwest Frontier Province, Pakistan where Afghan refugees have been resident for more than 20 years Funding: UNDP/World Bank/WHO Special Program for Research in Tropical Diseases; Gates Malaria Partnership) | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | Two randomization methods were used. In Baghicha and Khagan villages, participants were randomized by household, whereas in Adizai, randomization was at the individual level. Randomization lists for each village were generated using a random number list (MS Excel, Microsoft Corp, Seattle, USA) by staff not involved in patient recruitment. Participants were randomized on enrolment by study staff in the BHUs based on house number or sequential patient numbers, depending on the study site. |
| Allocation concealment (selection bias) | High risk | Participants were randomized on enrolment by study staff in the BHUs based on house number or sequential patient numbers, depending on the study site. |
| Blinding of participants and personnel (performance bias) | High risk | Open‐label. |
| Blinding of outcome assessment (detection bias) | Low risk | Blood slides were double‐read by 2 microscopists working independently, who were blinded to the other's result. |
| Incomplete outcome data (attrition bias) | High risk | Higher loss to follow‐up in intervention group (6% to 8% versus 1% to 1.8%). |
| Selective reporting (reporting bias) | Low risk | Trial protocol available, all planned outcomes reported on. |
| Other bias | Low risk | We did not detect any other sources of bias. |
| Study characteristics | ||
| Methods | RCT | |
| Participants | 358 participants Inclusion criteria
Exclusion criteria
Diagnosis: microscopy. | |
| Interventions |
(Additional arm of chloroquine + primaquine 15 mg sustained release for 14 days not included in review). Primaquine given following completion of chloroquine course. Not supervised. | |
| Outcomes |
PCR genotyping done to see if true relapse (no details on genotyping method). Follow‐up: 5 months (6 months participation) | |
| Notes | Location: India. Setting: multicentre, no details as to centres involved. Funding: funded by drug manufacturer Ipca Laboratories Ltd. Anil Pareek and Nitin Chandurkar are the employees of Ipca Laboratories Ltd who sponsored this trial. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomization codes were generated using computer‐generated block randomization method. |
| Allocation concealment (selection bias) | Low risk | Patient‐specific sealed boxes of medicine were provided to each study site. (Sequentially numbered, sealed, opaque envelopes (from protocol)). |
| Blinding of participants and personnel (performance bias) | Low risk | Double‐blind, double‐dummy. |
| Blinding of outcome assessment (detection bias) | Unclear risk | No details as to whether microscopy was blinded or whether there was double reading of smears. |
| Incomplete outcome data (attrition bias) | Low risk | Loss to follow‐up equal between groups. Relapses counted as discontinued patients, but numbers provided so can be assessed. |
| Selective reporting (reporting bias) | High risk | Compliance added as an outcome, but original outcomes also reported on. Not clear why they have concluded that compliance increased with SR, as participants had to take 3 sets of pills as did those who took dummy versions, so all participants took 3 sets of drugs. No measurement of levels of PQ (pharmacokinetics), although states that PQ SR should have therapeutic concentration over 24 hours as part of the concept. PCR results are not well‐detailed. |
| Other bias | Unclear risk | The study was sponsored by Ipca Laboratories Ltd, who manufactures the drugs, and the principal investigators are employees of the company. |
| Study characteristics | ||
| Methods | RCT August 2001 to February 2004 | |
| Participants | 1159 participants enrolled. Inclusion criteria
Exclusion criteria
Diagnosis: microscopy. | |
| Interventions |
(Additional no‐primaquine arm not included in analysis). Supervised treatment. Primquine treatment commenced after chloroquine treatment (day 4). | |
| Outcomes |
Follow‐up: 6 months The secondary outcome also included comparison of number of participants classified as relapse and re‐infection by the 3 methods to determine the concordance between the methods used and the genetic diversity observed based on PCR sequencing method. The cases of recurrence were classified as relapse or re‐infection based on the 3 methods, the month of recurrence, and the 2 genotyping methods: PCR‐RFLP and PCR sequencing. | |
| Notes | Location: Mumbai, India. Setting: inpatient assessment in Mumbai. Funding: Indian Council of Medical Research. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | A simple, computer‐generated randomization scheme was used for the randomization of participants into the 3 PQ regimen groups. |
| Allocation concealment (selection bias) | High risk | This was an open‐label study, and no concealment of treatment allocation was followed. |
| Blinding of participants and personnel (performance bias) | High risk | Open‐label. |
| Blinding of outcome assessment (detection bias) | Low risk | Although the study was not blinded in terms of treatment administration, the person seeing the slides and carrying out other outcome assessments was blinded to the treatment group by coding of the samples. |
| Incomplete outcome data (attrition bias) | High risk | High percentage of participants not completing 6 months' follow‐up across all groups. Minimal explanation for discontinuation of participants. |
| Selective reporting (reporting bias) | Unclear risk | No registered protocol found ‐ reported on expected outcomes of efficacy and adverse events. Trial carried out 2001 to 2004 but not published until 2014. |
| Other bias | Low risk | We did not detect any other sources of bias. |
| Study characteristics | ||
| Methods | RCT, open‐label, pilot study March 2017 to August 2017 | |
| Participants | 50 participants enrolled. Patients presenting to Kasturba Hospital, Manipal and Dr TMA Pai Hospital, Udupi, India Inclusion criteria
Exclusion criteria
Primaquine given after blood‐stage treatment. Diagnosis: microscopy, but PCR also performed to genotype recurrences. No details CYP2D6. | |
| Interventions | Blood‐stage treatment: either CQ or ACT (artesunate with doxycycline or artemether‐lumefantrine as per the treating clinician’s judgement of severity).
Drug therapy not supervised. | |
| Outcomes | 1. Recurrence. (2. Primaquine level in the blood at 7 days) Follow‐up 6 months | |
| Notes | Location: Udupi district of Karnataka State, India Setting: typical tropical climatic conditions. Malaria incidence throughout the year with peaks around June to July. Urban and rural settings in catchment area. Source of funding: seed Grant Award from Manipal McGill Center for Infectious Diseases | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Block randomization – 5 blocks of 10, randomization within each block done by a lottery method. |
| Allocation concealment (selection bias) | Unclear risk | No details. |
| Blinding of participants and personnel (performance bias) | High risk | Open‐label. |
| Blinding of outcome assessment (detection bias) | High risk | Open‐label. |
| Incomplete outcome data (attrition bias) | High risk | High percentage of loss to follow‐up by 6 months in both arms – results difficult to interpret. |
| Selective reporting (reporting bias) | Low risk | Outcomes reported as per protocol. |
| Other bias | Low risk | Supported by a seed Grant Award from Manipal McGill Center for Infectious Diseases, MAHE, Manipal. |
| Study characteristics | ||
| Methods | RCT October 1998 to January 1999 | |
| Participants | 60 participants enrolled. Inclusion criteria
Exclusion criteria
No details about inclusion/exclusion of G6PD‐deficient/pregnant/breastfeeding patients. Diagnosis: microscopy. | |
| Interventions |
Directly observed therapy. Primaquine given after chloroquine course. | |
| Outcomes |
Follow‐up: 60 days (total enrolment 60 days) | |
| Notes | Location: Peru. Setting: patients treated at San Martín de Pangoa Hospital, Junín Funding: US Naval Medical Research Institute Detachment. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | No details on randomization process. |
| Allocation concealment (selection bias) | Unclear risk | No details on allocation process. |
| Blinding of participants and personnel (performance bias) | High risk | Open‐label. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Samples double‐checked, but no details as to whether blinded. |
| Incomplete outcome data (attrition bias) | Low risk | Missing data accounted for, similar in each group. |
| Selective reporting (reporting bias) | Unclear risk | No details. |
| Other bias | Low risk | We did not detect any other sources of bias. |
| Study characteristics | ||
| Methods | RCT, multicentre July 2014 to November 2018 | |
| Participants | 2336 participants were randomised. Inclusion criteria
Exclusion criteria
Diagnosis: microscopy Patients with G6PD deficiency were excluded from the randomised trial, but were enrolled into a parallel observational group and treated with chloroquine or dihydroartemisinin‐piperaquine plus supervised primaquine (0.75 mg/kg) once a week for 8 weeks. No details CYP2D6 status. | |
| Interventions |
(Additional arm Standard blood schizonticidal therapy plus 14 days placebo was not included in the review; no primaquine was administered to participants in this arm). Supervised treatment. Primaquine and blood schizonticidal therapy given concurrently. Standard blood schizonticidal therapy was chloroquine in Ethiopia, Afghanistan, and Vietnam and dihydroartemisinin‐piperaquine in Indonesia, according to local guidelines | |
| Outcomes |
Follow‐up: 28 days, 42 days, 3 months, 6 months, 1 year. | |
| Notes | Location: Afghanistan (Jalalabad, Laghman), Ethiopia (Arba Minch, Metahara), Indonesia (Hanura, Tanjung Leidong), and Vietnam (Dak O & Bu Gia Map, Krong Pa). Setting: Two health‐care clinics in each country. Funding: UK Department for International Development, UK Medical Research Council, UK National Institute for Health Research, and the Wellcome Trust through the Joint Global Health Trials Scheme and the Bill & Melinda Gates Foundation. Authors were contacted and provided 3‐month and 6‐month recurrence data presented in Appendix 3b. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: “Randomisation was done using STATA version 14.1.(StataCorp, College Station, TX, USA), which generated blocks of 20 for each dosing band”. |
| Allocation concealment (selection bias) | Low risk | Quote: “The independent statistician who generated the randomisation list and selected code letters for primaquine or placebo was not otherwise involved in the conduct of the trial and did not visit any of the study sites. Identical primaquine and placebo tablets were produced by the same manufacturer” |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: “Participants and all of the local study team were masked to treatment assignments.” |
| Blinding of outcome assessment (detection bias) | Low risk | 98.6% accuracy in expert quality control of microscopy malaria films: Quote: "Microscopists were trained in study laboratory procedures on‐site and continuous quality control was implemented at all sites. Approximately 10% of slides, including all the slides from day 0, the day of recurrent parasitaemia, and the 6‐month follow‐up visits were assessed periodically over the course of the trial by expert malaria microscopists" Safety outcomes: Quote: “The Data and Safety Monitoring Board did a blinded safety review every 6 months” |
| Incomplete outcome data (attrition bias) | Unclear risk | Available case analysis, attrition after one year was 32% (297/935) in 7‐day primaquine group and 29% (270/937) in 14‐day primaquine group, reasons for leaving the study early were reported. |
| Selective reporting (reporting bias) | Low risk | Protocol and online trial registry were checked; all outcomes and sensitivity analyses were reported. |
| Other bias | Low risk | We did not detect any other sources of bias. |
Abbreviations: ACT: artemisinin‐based combination therapy; CQ: chloroquine; CYP2D6: cytochrome P450 2D6; G6PD: glucose‐6‐phosphate dehydrogenase; PCR: polymerase chain reaction; PCR‐RFLP: polymerase chain reaction‐restriction fragment length polymorphism; PQ: primaquine; RCT: randomized controlled trial; SE: standard error; SR: sustained release; WHO: World Health Organization.
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
| No PQ comparison group. | |
| Comparison regimens are of a lower total dose than the control (15 mg/day for 3 days or 7 days) – shown to be inferior in Galappaththy 2013. | |
| Low‐dose, shorter regimens of PQ. | |
| Only one treatment group received primaquine. | |
| Wrong outcomes: primary outcome of this analysis was the fractional haematocrit reduction up to day 14 after enrolment. | |
| No primaquine comparison arm. | |
| Not an RCT, observational single‐arm trial. | |
| Not an RCT. | |
| Not properly randomized (randomized according to whether the end of the notes code is odd or even), low‐dose comparison PQ group. | |
| Wrong comparator: same dose primaquine in all treatment arms (two tablets of 15 mg PQ for 7, 8 or 9 days, total dose between 3.0 and 4.2 mg/kg). | |
| Low‐dose 15 mg for shorter time period (5 days) – shown to be ineffective in Galappaththy 2013. | |
| Not an RCT – logistic regression using already‐published RCTs and observational studies (not primary trial). | |
| Wrong comparator: Artesunate and Sulphadoxine/pyrimethamine + concomitant versus delayed 14‐day primaquine. | |
| Wrong comparator: low‐dose for 5 days ‐ shown to be ineffective in Galappaththy 2013. | |
| Not an RCT. | |
| Artesunate only as blood‐stage treatment (does not meet inclusion criteria) and follow‐up only 28 days. | |
| Wrong comparator: concomitant versus delayed regimen (chloroquine with primaquine 0.5 mg/kg once a day, for seven days (total dose, 3.5mg/kg) versus chloroquine with primaquine introduced on day 28 | |
| No PQ comparison group: supervised versus unsupervised therapy. | |
| Duplicate of Leslie 2008 PAK; conference abstract title only for session at ASTMH 57th Annual Meeting. | |
| Not randomized, participants were sequentially allocated into either the directly observed therapy (DOT) group or the self‐administered therapy (SAT) group. No PQ comparison group, supervised versus non‐supervised therapy. | |
| Not an RCT. | |
| Not an RCT | |
| No PQ comparison group. | |
| No PQ comparison group. | |
| No blood‐stage antimalarial treatment used in primaquine comparison group according to inclusion criteria. | |
| Presumptive treatment of 45 mg PQ given to all participants before randomization. | |
| No PQ comparison group: supervised versus non‐supervised therapy. | |
| Wrong comparator: lower dose of PQ in comparison group (total dose 150 mg) ‐ shown to be ineffective in Galappaththy 2013. | |
| No primaquine comparison arm, ophthalmological outcomes. |
Abbreviations: PQ: primaquine; RCT: randomized controlled trial.
Characteristics of ongoing studies [ordered by study ID]
| Study name | Evaluation of safety and efficacy of two primaquine dosing regimens for the radical treatment of Plasmodium vivax malaria in Vanuatu and Solomon Islands |
| Methods | RCT, open‐label |
| Participants | Children and adults aged 12 months to 60 years. Solomon Islands and Vanuatu. Inclusion criteria
Exclusion criteria
|
| Interventions | 1. Primaquine dose of 0.5 mg/kg/day for 14 consecutive days and standard age‐based dosage 3‐day course of artemether‐lumefantrine 2. Primaquine dose of 0.25 mg/kg for 14 consecutive days and standard age‐based dosage 3‐day course of artemether‐lumefantrine (3. Participants will receive a standard 3‐day treatment course of artemether‐lumefantrine at the standard age‐based dosage, but will not receive primaquine until the time of confirmed recurrent parasitaemia or completion of 3 months follow‐up) |
| Outcomes |
|
| Starting date | May 2013 |
| Contact information | Dr Ivo Mueller; [email protected] |
| Notes | Estimated completion date May 2015. Contacted for results ‐ no response. Protocol available at clinicaltrials.gov/ct2/show/NCT01837992 |
Abbreviations: G6PD: glucose‐6‐phosphate dehydrogenase; Hb: haemoglobin; PCR: polymerase chain reaction; RCT: randomized controlled trial; RDT: rapid diagnostic test; WHO: World Health Organization.
Data and analyses
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Recurrence by 6 to 7 months' follow‐up Show forest plot | 4 | 1211 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.66, 1.39] |
| Analysis 1.1  Comparison 1: 0.5 mg/kg/day 7 days versus standard 0.25 mg/kg/day 14 days, Outcome 1: Recurrence by 6 to 7 months' follow‐up | ||||
| 1.2 Recurrence by 6 to 7 months' follow‐up (PCR‐adjusted) Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 1.2  Comparison 1: 0.5 mg/kg/day 7 days versus standard 0.25 mg/kg/day 14 days, Outcome 2: Recurrence by 6 to 7 months' follow‐up (PCR‐adjusted) | ||||
| 1.3 Recurrence by 6 to 7 months subgrouped by geographical region Show forest plot | 4 | 1211 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.66, 1.39] |
| Analysis 1.3  Comparison 1: 0.5 mg/kg/day 7 days versus standard 0.25 mg/kg/day 14 days, Outcome 3: Recurrence by 6 to 7 months subgrouped by geographical region | ||||
| 1.3.1 South America | 2 | 397 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.70 [0.39, 1.26] |
| 1.3.2 Asia | 2 | 814 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.19 [0.73, 1.94] |
| 1.4 Recurrence by 6 to 7 months subgrouped by directly observed therapy (DOT) versus non‐DOT Show forest plot | 4 | 1211 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.66, 1.39] |
| Analysis 1.4  Comparison 1: 0.5 mg/kg/day 7 days versus standard 0.25 mg/kg/day 14 days, Outcome 4: Recurrence by 6 to 7 months subgrouped by directly observed therapy (DOT) versus non‐DOT | ||||
| 1.4.1 DOT | 3 | 1017 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.67, 1.43] |
| 1.4.2 Non‐DOT | 1 | 194 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.48 [0.04, 5.20] |
| 1.5 Serious adverse events Show forest plot | 5 | 1427 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| Analysis 1.5  Comparison 1: 0.5 mg/kg/day 7 days versus standard 0.25 mg/kg/day 14 days, Outcome 5: Serious adverse events | ||||
| 1.6 Adverse events that result in discontinuation of treatment Show forest plot | 5 | 1427 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.15, 7.38] |
| Analysis 1.6  Comparison 1: 0.5 mg/kg/day 7 days versus standard 0.25 mg/kg/day 14 days, Outcome 6: Adverse events that result in discontinuation of treatment | ||||
| 1.7 Adverse events during chloroquine administration Show forest plot | 1 | 779 | Risk Ratio (M‐H, Fixed, 95% CI) | 9.40 [0.51, 174.01] |
| Analysis 1.7  Comparison 1: 0.5 mg/kg/day 7 days versus standard 0.25 mg/kg/day 14 days, Outcome 7: Adverse events during chloroquine administration | ||||
| 1.8 Adverse effects during primaquine administration Show forest plot | 2 | 1019 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.64 [0.75, 3.57] |
| Analysis 1.8  Comparison 1: 0.5 mg/kg/day 7 days versus standard 0.25 mg/kg/day 14 days, Outcome 8: Adverse effects during primaquine administration | ||||
| 1.9 Other adverse events Show forest plot | 2 | 135 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.56 [0.23, 1.36] |
| Analysis 1.9  Comparison 1: 0.5 mg/kg/day 7 days versus standard 0.25 mg/kg/day 14 days, Outcome 9: Other adverse events | ||||
| 1.10 Anaemia or change in haemoglobin status Show forest plot | 1 | 240 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.00 [0.12, 72.91] |
| Analysis 1.10  Comparison 1: 0.5 mg/kg/day 7 days versus standard 0.25 mg/kg/day 14 days, Outcome 10: Anaemia or change in haemoglobin status | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Recurrence by 6 months' follow‐up Show forest plot | 2 | 677 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.49, 1.43] |
| Analysis 2.1  Comparison 2: High‐standard 0.5 mg/kg/day 14 days versus standard 0.25 mg/kg/day 14 days, Outcome 1: Recurrence by 6 months' follow‐up | ||||
| 2.1.1 6 months (chloroquine blood‐stage treatment) | 1 | 639 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.47, 1.43] |
| 2.1.2 6 months (chloroquine or ACT blood‐stage treatment) | 1 | 38 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.11 [0.17, 7.09] |
| 2.2 Recurrence by 6 months' follow‐up (PCR‐adjusted) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 2.2  Comparison 2: High‐standard 0.5 mg/kg/day 14 days versus standard 0.25 mg/kg/day 14 days, Outcome 2: Recurrence by 6 months' follow‐up (PCR‐adjusted) | ||||
| 2.3 Serious adverse events Show forest plot | 1 | 778 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| Analysis 2.3  Comparison 2: High‐standard 0.5 mg/kg/day 14 days versus standard 0.25 mg/kg/day 14 days, Outcome 3: Serious adverse events | ||||
| 2.4 Adverse events that result in discontinuation of treatment Show forest plot | 1 | 778 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.19 [0.90, 19.60] |
| Analysis 2.4  Comparison 2: High‐standard 0.5 mg/kg/day 14 days versus standard 0.25 mg/kg/day 14 days, Outcome 4: Adverse events that result in discontinuation of treatment | ||||
| 2.5 Other adverse events Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Analysis 2.5  Comparison 2: High‐standard 0.5 mg/kg/day 14 days versus standard 0.25 mg/kg/day 14 days, Outcome 5: Other adverse events | ||||
| 2.5.1 AEs during chloroquine treatment | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.5.2 AEs during primaquine treatment | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Recurrence Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 3.1  Comparison 3: 0.75 mg/kg/week 8 weeks versus high‐standard 0.5 mg/kg/day 14 days, Outcome 1: Recurrence | ||||
| 3.1.1 5 months | 1 | 129 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.23 [0.28, 99.15] |
| 3.1.2 8 months | 1 | 126 | Risk Ratio (M‐H, Fixed, 95% CI) | 7.00 [0.38, 127.32] |
| 3.1.3 11 months | 1 | 122 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.18 [0.37, 27.60] |
| 3.2 Serious adverse events Show forest plot | 1 | 129 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| Analysis 3.2  Comparison 3: 0.75 mg/kg/week 8 weeks versus high‐standard 0.5 mg/kg/day 14 days, Outcome 2: Serious adverse events | ||||
| 3.3 Anaemia (haemoglobin < 7 g/dL) Show forest plot | 1 | 129 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| Analysis 3.3  Comparison 3: 0.75 mg/kg/week 8 weeks versus high‐standard 0.5 mg/kg/day 14 days, Outcome 3: Anaemia (haemoglobin < 7 g/dL) | ||||
| 3.4 Other adverse events Show forest plot | 1 | 129 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| Analysis 3.4  Comparison 3: 0.75 mg/kg/week 8 weeks versus high‐standard 0.5 mg/kg/day 14 days, Outcome 4: Other adverse events | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | ||||||||||||||||||||||||
| 4.1 Recurrence by 12 months' follow‐up Show forest plot | 2 | 2526 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.82, 1.30] | ||||||||||||||||||||||||
| Analysis 4.1  Comparison 4: 1.0 mg/kg/day primaquine 7 days versus high‐standard 0.5 mg/kg/day 14 days, Outcome 1: Recurrence by 12 months' follow‐up | ||||||||||||||||||||||||||||
| 4.1.1 Chloroquine blood‐stage treatment | 2 | 1404 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.67, 1.22] | ||||||||||||||||||||||||
| 4.1.2 DHA‐PPQ blood‐stage treatment | 2 | 1122 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.24 [0.87, 1.77] | ||||||||||||||||||||||||
| 4.2 Recurrence by 12 months' follow‐up subgrouped by geographical region Show forest plot | 2 | 2526 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.82, 1.29] | ||||||||||||||||||||||||
| Analysis 4.2  Comparison 4: 1.0 mg/kg/day primaquine 7 days versus high‐standard 0.5 mg/kg/day 14 days, Outcome 2: Recurrence by 12 months' follow‐up subgrouped by geographical region | ||||||||||||||||||||||||||||
| 4.2.1 Afghanistan | 1 | 348 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.44, 1.28] | ||||||||||||||||||||||||
| 4.2.2 Ethiopia | 1 | 466 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.30 [0.74, 2.30] | ||||||||||||||||||||||||
| 4.2.3 Indonesia | 1 | 797 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.32 [0.86, 2.03] | ||||||||||||||||||||||||
| 4.2.4 Thailand | 1 | 654 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.57, 1.30] | ||||||||||||||||||||||||
| 4.2.5 Vietnam | 1 | 261 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.43, 2.53] | ||||||||||||||||||||||||
| 4.3 Recurrence by 6 months' follow‐up Show forest plot | 1 | 474 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.61, 1.97] | ||||||||||||||||||||||||
| Analysis 4.3  Comparison 4: 1.0 mg/kg/day primaquine 7 days versus high‐standard 0.5 mg/kg/day 14 days, Outcome 3: Recurrence by 6 months' follow‐up | ||||||||||||||||||||||||||||
| 4.3.1 Chloroquine blood‐stage treatment | 1 | 256 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.42, 1.86] | ||||||||||||||||||||||||
| 4.3.2 DHA‐PPQ blood‐stage treatment | 1 | 218 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.55 [0.60, 4.05] | ||||||||||||||||||||||||
| 4.4 Recurrence by 3 months' follow‐up Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |||||||||||||||||||||||||
| Analysis 4.4  Comparison 4: 1.0 mg/kg/day primaquine 7 days versus high‐standard 0.5 mg/kg/day 14 days, Outcome 4: Recurrence by 3 months' follow‐up | ||||||||||||||||||||||||||||
| 4.4.1 Chloroquine blood‐stage treatment | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |||||||||||||||||||||||||
| 4.4.2 DHA‐PPQ blood‐stage treatment | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |||||||||||||||||||||||||
| 4.5 P vivax parasitaemia Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |||||||||||||||||||||||||
| Analysis 4.5  Comparison 4: 1.0 mg/kg/day primaquine 7 days versus high‐standard 0.5 mg/kg/day 14 days, Outcome 5: P vivax parasitaemia | ||||||||||||||||||||||||||||
| 4.5.1 Day 28 | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |||||||||||||||||||||||||
| 4.5.2 Day 42 | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |||||||||||||||||||||||||
| 4.6 Serious adverse events Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||
| Analysis 4.6  Comparison 4: 1.0 mg/kg/day primaquine 7 days versus high‐standard 0.5 mg/kg/day 14 days, Outcome 6: Serious adverse events | ||||||||||||||||||||||||||||
| 4.6.1 Up to 42 days follow‐up | 1 | 1872 | Risk Ratio (M‐H, Fixed, 95% CI) | 12.03 [1.57, 92.30] | ||||||||||||||||||||||||
| 4.6.2 Up to 1 year follow‐up | 1 | 1872 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.61 [1.35, 9.68] | ||||||||||||||||||||||||
| 4.7 Adverse events that resulted in discontinuation of treatment Show forest plot | 2 | 2526 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.50 [0.49, 12.87] | ||||||||||||||||||||||||
| Analysis 4.7  Comparison 4: 1.0 mg/kg/day primaquine 7 days versus high‐standard 0.5 mg/kg/day 14 days, Outcome 7: Adverse events that resulted in discontinuation of treatment | ||||||||||||||||||||||||||||
| 4.8 Other adverse events Show forest plot | 2 | Other data | No numeric data | |||||||||||||||||||||||||
| Analysis 4.8
Comparison 4: 1.0 mg/kg/day primaquine 7 days versus high‐standard 0.5 mg/kg/day 14 days, Outcome 8: Other adverse events | ||||||||||||||||||||||||||||
| 4.8.1 Up to day 14 | 1 | Other data | No numeric data | |||||||||||||||||||||||||
| 4.8.2 Chloroquine group, up to day 42 | 1 | Other data | No numeric data | |||||||||||||||||||||||||
| 4.8.3 DHA‐PPQ group, up to day 42 | 1 | Other data | No numeric data | |||||||||||||||||||||||||
| 4.9 Anaemia Show forest plot | 2 | 2440 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.62, 1.41] | ||||||||||||||||||||||||
| Analysis 4.9  Comparison 4: 1.0 mg/kg/day primaquine 7 days versus high‐standard 0.5 mg/kg/day 14 days, Outcome 9: Anaemia | ||||||||||||||||||||||||||||
| 4.9.1 Up to 3 days | 1 | 1786 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.38, 2.66] | ||||||||||||||||||||||||
| 4.9.2 Up to 42 days follow‐up | 1 | 654 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.58, 1.44] | ||||||||||||||||||||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 5.1 Recurrence by 6 months' follow‐up Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 5.1  Comparison 5: 0.375 mg/kg/day primaquine for 14 days versus standard 14‐day regimen, Outcome 1: Recurrence by 6 months' follow‐up | ||||
| 5.1.1 6 months' follow‐up | 1 | 73 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.17 [0.01, 3.34] |
| 5.1.2 12 months' follow‐up | 1 | 49 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 5.1.3 18 months' follow‐up | 1 | 38 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 6.1 Recurrence by 4 months' follow‐up Show forest plot | 1 | 129 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.88 [2.11, 7.11] |
| Analysis 6.1  Comparison 6: 1.17 mg/kg/day primaquine for 3 days versus standard 14‐day regimen, Outcome 1: Recurrence by 4 months' follow‐up | ||||
Study flow diagram.
‘Risk of bias' summary: review authors' judgements about each ‘Risk of bias' item for each included study.
Comparison 1: 0.5 mg/kg/day 7 days versus standard 0.25 mg/kg/day 14 days, Outcome 1: Recurrence by 6 to 7 months' follow‐up
Comparison 1: 0.5 mg/kg/day 7 days versus standard 0.25 mg/kg/day 14 days, Outcome 2: Recurrence by 6 to 7 months' follow‐up (PCR‐adjusted)
Comparison 1: 0.5 mg/kg/day 7 days versus standard 0.25 mg/kg/day 14 days, Outcome 3: Recurrence by 6 to 7 months subgrouped by geographical region
Comparison 1: 0.5 mg/kg/day 7 days versus standard 0.25 mg/kg/day 14 days, Outcome 4: Recurrence by 6 to 7 months subgrouped by directly observed therapy (DOT) versus non‐DOT
Comparison 1: 0.5 mg/kg/day 7 days versus standard 0.25 mg/kg/day 14 days, Outcome 5: Serious adverse events
Comparison 1: 0.5 mg/kg/day 7 days versus standard 0.25 mg/kg/day 14 days, Outcome 6: Adverse events that result in discontinuation of treatment
Comparison 1: 0.5 mg/kg/day 7 days versus standard 0.25 mg/kg/day 14 days, Outcome 7: Adverse events during chloroquine administration
Comparison 1: 0.5 mg/kg/day 7 days versus standard 0.25 mg/kg/day 14 days, Outcome 8: Adverse effects during primaquine administration
Comparison 1: 0.5 mg/kg/day 7 days versus standard 0.25 mg/kg/day 14 days, Outcome 9: Other adverse events
Comparison 1: 0.5 mg/kg/day 7 days versus standard 0.25 mg/kg/day 14 days, Outcome 10: Anaemia or change in haemoglobin status
Comparison 2: High‐standard 0.5 mg/kg/day 14 days versus standard 0.25 mg/kg/day 14 days, Outcome 1: Recurrence by 6 months' follow‐up
Comparison 2: High‐standard 0.5 mg/kg/day 14 days versus standard 0.25 mg/kg/day 14 days, Outcome 2: Recurrence by 6 months' follow‐up (PCR‐adjusted)
Comparison 2: High‐standard 0.5 mg/kg/day 14 days versus standard 0.25 mg/kg/day 14 days, Outcome 3: Serious adverse events
Comparison 2: High‐standard 0.5 mg/kg/day 14 days versus standard 0.25 mg/kg/day 14 days, Outcome 4: Adverse events that result in discontinuation of treatment
Comparison 2: High‐standard 0.5 mg/kg/day 14 days versus standard 0.25 mg/kg/day 14 days, Outcome 5: Other adverse events
Comparison 3: 0.75 mg/kg/week 8 weeks versus high‐standard 0.5 mg/kg/day 14 days, Outcome 1: Recurrence
Comparison 3: 0.75 mg/kg/week 8 weeks versus high‐standard 0.5 mg/kg/day 14 days, Outcome 2: Serious adverse events
Comparison 3: 0.75 mg/kg/week 8 weeks versus high‐standard 0.5 mg/kg/day 14 days, Outcome 3: Anaemia (haemoglobin < 7 g/dL)
Comparison 3: 0.75 mg/kg/week 8 weeks versus high‐standard 0.5 mg/kg/day 14 days, Outcome 4: Other adverse events
Comparison 4: 1.0 mg/kg/day primaquine 7 days versus high‐standard 0.5 mg/kg/day 14 days, Outcome 1: Recurrence by 12 months' follow‐up
Comparison 4: 1.0 mg/kg/day primaquine 7 days versus high‐standard 0.5 mg/kg/day 14 days, Outcome 2: Recurrence by 12 months' follow‐up subgrouped by geographical region
Comparison 4: 1.0 mg/kg/day primaquine 7 days versus high‐standard 0.5 mg/kg/day 14 days, Outcome 3: Recurrence by 6 months' follow‐up
Comparison 4: 1.0 mg/kg/day primaquine 7 days versus high‐standard 0.5 mg/kg/day 14 days, Outcome 4: Recurrence by 3 months' follow‐up
Comparison 4: 1.0 mg/kg/day primaquine 7 days versus high‐standard 0.5 mg/kg/day 14 days, Outcome 5: P vivax parasitaemia
Comparison 4: 1.0 mg/kg/day primaquine 7 days versus high‐standard 0.5 mg/kg/day 14 days, Outcome 6: Serious adverse events
Comparison 4: 1.0 mg/kg/day primaquine 7 days versus high‐standard 0.5 mg/kg/day 14 days, Outcome 7: Adverse events that resulted in discontinuation of treatment
| Other adverse events | ||
| Study | 1.0 mg/kg/day for 7 days | High‐standard 0.5 mg/kg/day for 14 days |
|---|---|---|
| Up to day 14 | ||
| Taylor 2019 MULTI | 1819 events in 935 participants | 1732 events in 937 participants |
| Chloroquine group, up to day 42 | ||
| Chu 2019 THA | 97 events in 165 participants | 91 events in 164 participants |
| DHA‐PPQ group, up to day 42 | ||
| Chu 2019 THA | 72 events in 162 participants | 82 events in 163 participants |
Comparison 4: 1.0 mg/kg/day primaquine 7 days versus high‐standard 0.5 mg/kg/day 14 days, Outcome 8: Other adverse events
Comparison 4: 1.0 mg/kg/day primaquine 7 days versus high‐standard 0.5 mg/kg/day 14 days, Outcome 9: Anaemia
Comparison 5: 0.375 mg/kg/day primaquine for 14 days versus standard 14‐day regimen, Outcome 1: Recurrence by 6 months' follow‐up
Comparison 6: 1.17 mg/kg/day primaquine for 3 days versus standard 14‐day regimen, Outcome 1: Recurrence by 4 months' follow‐up
| 0.5 mg/kg primaquine/day for 7 days versus standard 0.25 mg/kg/day for 14 days for radical cure of P vivax malaria | ||||||
| Patient or population: adults and children with confirmed clinical and parasitological P vivax malaria | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with standard 14‐day course primaquine | Risk with 0.5mg/kg/day primaquine for 7 days | |||||
| Recurrence of P vivax parasitaemia | 84 per 1000 | 81 per 1000 | RR 0.96 | 1211 | ⊕⊕⊝⊝ due to risk of bias and imprecision | There may be little or no difference between 0.5 mg/kg/day primaquine for 7 days and the standard 14‐day course. |
| Serious adverse events | Not estimable (0 events in 723 participants) | Not estimable (0 events in 704 participants) | Not estimable | 1427 | — | No events reported. |
| Adverse events that result in the discontinuation of treatment | 3 per 1000 | 3 per 1000 | RR 1.04 | 1427 (5 RCTs) | ⊕⊝⊝⊝ due to risk of bias and serious imprecision | We do not know if there is any difference in adverse events that result in treatment discontinuation between 0.5 mg/kg/day primaquine for 7 days and the standard 14‐day course. |
| Anaemia or change in haemoglobin status | Not estimable (0 events in 120 participants) | Not estimable (1 event in 120 participants) | RR 3.0 (0.12 to 72.91) | 240 | ⊕⊝⊝⊝ due to risk of bias, indirectness, and serious imprecision | We do not know if the occurrence of anaemia differs between the 2 treatment regimens. |
| *The risk in the intervention group (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). Abbreviations: CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded once for risk of bias: Rajgor 2014 IND, which contributed the most weight to the meta‐analysis, was at high risk of selection bias due to no allocation concealment and high risk of attrition bias. Although Pareek 2015 IND was at risk of selection bias as well as other bias for being funded and carried out by drug company, it only contributed a small amount of weight to the meta‐analysis. | ||||||
| High standard 0.5 mg/kg primaquine /day for 14 days versus standard 0.25 mg/kg/day for 14 days for radical cure of P vivax malaria | ||||||
| Patient or population: adults and children with confirmed clinical and parasitological P vivax malaria | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with standard 14‐day course primaquine | Risk with high‐standard 14‐day course primaquine | |||||
| Recurrence of P vivax parasitaemia | 82 per 1000 | 69 per 1000 | RR 0.84 | 677 | ⊕⊕⊝⊝ due to risk of bias and imprecision | There may be little or no difference in P vivax recurrences between high‐standard or standard 14‐day courses of primaquine given with chloroquine or an ACT. |
| Serious adverse events | Not estimable (0 events in 398 participants) | Not estimable (0 events in 380 participants) | Not estimable | 778 | — | No events reported. |
| Adverse events that result in the discontinuation of treatment | 5 per 1000 | 21 per 1000 | RR 4.19 | 778 | ⊕⊝⊝⊝ due to indirectness, risk of bias, and imprecision | We do not know if there is any difference in adverse events resulting in treatment discontinuation between high‐standard or standard 14‐day courses of primaquine. |
| *The risk in the intervention group (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). Abbreviations: ACT: artemisinin‐based combination therapy; CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded once for risk of bias: one study was open‐label with no allocation concealment (risk of selection bias) and risk of attrition bias due to high percentage not completing six months' follow‐up with minimal explanation; the other study had no blinding and a high rate of loss to follow‐up. | ||||||
| 0.75 mg/kg primaquine /week for 8 weeks versus high‐standard 0.5 mg/kg/day for 14 days for radical cure of P vivax malaria | ||||||
| Patient or population: adults and children with confirmed clinical and parasitological P vivax malaria | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with high‐standard 14‐day course primaquine | Risk with once‐weekly 0.75 mg/kg primaquine for 8 weeks | |||||
| Recurrence of P vivax malaria | 19 per 1000 | 59 per 1000 | RR 3.18 | 122 | ⊕⊝⊝⊝ due to risk of bias and serious imprecision | We do not know if weekly primaquine reduces the risk of malaria recurrences when compared to the high‐standard 14‐day course. |
| Serious adverse events | Not estimable (0 events in 55 participants) | Not estimable (0 events in 74 participants) | Not estimable | 129 | — | No events reported. |
| Anaemia (haemoglobin < 7 g/dL) | Not estimable (0 events in 55 participants) | Not estimable (0 events in 74 participants) | Not estimable | 129 | — | No events reported. |
| *The risk in the intervention group (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). Abbreviations: CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded once for risk of bias: Leslie 2008 PAK was at high risk of bias for randomization process, allocation concealment, and incomplete outcome data. | ||||||
| 1.0 mg/kg primaquine /day for 7 days versus high‐standard 0.5 mg/kg/day for 14 days for radical cure of P vivax malaria | ||||||
| Patient or population: adults and children with confirmed clinical and parasitological P vivax malaria Settings: Afghanistan, Ethiopia, Indonesia, Thailand, and Vietnam Intervention: 1.0 mg/kg/day primaquine for 7 days (adult dose 60 mg/day; total dose 420mg) Comparison: high‐standard 14‐day course primaquine (0.5 mg/kg/day, adult dose 30 mg/day; total dose 420mg) | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of Participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with high‐standard 14‐day course primaquine | Risk with 1.0 mg/kg/day primaquine for 7 days | |||||
| Recurrence of P vivax parasitaemia | 104 per 1000 | 107 per 1000 | RR 1.03 (0.82 to 1.30) | 2526 (2 RCTs) | ⊕⊕⊕⊝a due to risk of bias | There is probably little or no difference between 1.0 mg/kg/day primaquine for 7 days and the high‐standard 0.5 mg/kg/day for 14 days course |
| Serious adverse events Follow‐up: up to 42 days | 1 per 1000 | 13 per 1000 (2 to 99) | RR 12.03 (1.57 to 92.30) | 1872 (1 RCT) | ⊕⊕⊝⊝b,c LOW due to indirectness and imprecision | There may be a moderate to large increase in serious adverse events in the 1.0 mg/kg/day primaquine for 7 days compared with the high‐standard 0.5 mg/kg/day Chu 2019 THA provides overall narrative results only, see Effects of interventions text. |
| Adverse events the resulted in discontinuation of treatment | 2 per 1000 | 4 per 1000 | RR 2.50 (0.49 to 12.87) | 2526 (2 RCTs) | ⊕⊝⊝⊝a,b,d due to risk of bias, indirectness and serious imprecision | We do not know if there is any difference in adverse events resulting in treatment discontinuation between 1.0 mg/kg/day primaquine for 7 days and the high‐standard 0.5 mg/kg/day for 14 days course. |
| Anaemia Follow‐up: between 3 and 42 days follow‐up | 35 per 1000 | 33 per 1000 (22 to 50) | RR 0.93 (0.62 to 1.41) | 2440 | ⊕⊝⊝⊝a,b,e due to risk of bias, indirectness and imprecision | We do not know if there is any difference in anaemia between 1.0 mg/kg/day primaquine for 7 days and the high‐standard 0.5 mg/kg/day for 14 days course. |
| *The risk in the intervention group (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 | ||||||
| aDowngraded once for risk of bias: Chu 2019 THA was an open‐label trial with high risk of performance and detection bias; although drop‐outs were balanced between groups the proportion of drop‐outs after one year was high in both trials (30‐40%). | ||||||
| Objective | Intervention | Control |
|---|---|---|
| Are higher doses (0.5 mg/kg/day or 30 mg/day primaquine for 14 days) more effective in all areas, or only in areas where they are standard treatment (East Asia and Oceania)? | Blood‐stage antimalarial drug with primaquine 0.5 mg/kg/day (adult dose 30 mg) for 14 days (total dose 420 mg). Both intervention and control groups must have received the same treatment for the blood‐borne stage of infection, that is, either CQ or ACT. | Blood‐stage antimalarial drug with standard 14‐day course primaquine (0.25 mg/kg/day, adult dose 15 mg, total dose 210 mg). Both intervention and control groups must have received the same treatment for the blood‐borne stage of infection, that is, either CQ or ACT. |
| Are shorter, higher‐dose regimens of primaquine over 7 days as effective as treatment over 14 days (is the total dose rather than the length of treatment the important factor)? | Blood‐stage antimalarial drug with primaquine 0.5 mg/kg/day (adult dose 30 mg) for 7 days (total dose 210 mg) or 1 mg/kg/day (adult dose 60 mg) for 7 days (total dose 420 mg). Both intervention and control groups must have received the same treatment for the blood‐borne stage of infection, that is, either CQ or ACT. | Blood‐stage antimalarial drug with standard 14‐day course primaquine (0.25 mg/kg/day, adult dose 15 mg, total dose 210 mg) or high‐standard 14‐day course primaquine (0.5 mg/kg/day, adult dose 30 mg, total dose 420 mg). Both intervention and control groups must have received the same treatment for the blood‐borne stage of infection, that is, either CQ or ACT. |
| Are weekly dosing regimens (0.75 mg/kg/week or 45 mg/week for 8 weeks) as effective? | Blood‐stage antimalarial drug with primaquine 0.75/kg (45 mg) per week for 8 weeks (total dose 360 mg) | Blood‐stage antimalarial drug with standard 14‐day course primaquine (0.25 mg/kg/day, adult dose 15 mg, total dose 210 mg) or high‐standard 14‐day course primaquine (0.5 mg/kg/day, adult dose 30 mg, total dose 420 mg). Both intervention and control groups must have received the same treatment for the blood‐borne stage of infection, that is, either CQ or ACT. |
| Abbreviations: ACT = artemisinin‐based combination therapy; CQ = chloroquine. | ||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Recurrence by 6 to 7 months' follow‐up Show forest plot | 4 | 1211 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.66, 1.39] |
| 1.2 Recurrence by 6 to 7 months' follow‐up (PCR‐adjusted) Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.3 Recurrence by 6 to 7 months subgrouped by geographical region Show forest plot | 4 | 1211 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.66, 1.39] |
| 1.3.1 South America | 2 | 397 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.70 [0.39, 1.26] |
| 1.3.2 Asia | 2 | 814 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.19 [0.73, 1.94] |
| 1.4 Recurrence by 6 to 7 months subgrouped by directly observed therapy (DOT) versus non‐DOT Show forest plot | 4 | 1211 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.66, 1.39] |
| 1.4.1 DOT | 3 | 1017 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.67, 1.43] |
| 1.4.2 Non‐DOT | 1 | 194 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.48 [0.04, 5.20] |
| 1.5 Serious adverse events Show forest plot | 5 | 1427 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 1.6 Adverse events that result in discontinuation of treatment Show forest plot | 5 | 1427 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.15, 7.38] |
| 1.7 Adverse events during chloroquine administration Show forest plot | 1 | 779 | Risk Ratio (M‐H, Fixed, 95% CI) | 9.40 [0.51, 174.01] |
| 1.8 Adverse effects during primaquine administration Show forest plot | 2 | 1019 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.64 [0.75, 3.57] |
| 1.9 Other adverse events Show forest plot | 2 | 135 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.56 [0.23, 1.36] |
| 1.10 Anaemia or change in haemoglobin status Show forest plot | 1 | 240 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.00 [0.12, 72.91] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Recurrence by 6 months' follow‐up Show forest plot | 2 | 677 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.49, 1.43] |
| 2.1.1 6 months (chloroquine blood‐stage treatment) | 1 | 639 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.47, 1.43] |
| 2.1.2 6 months (chloroquine or ACT blood‐stage treatment) | 1 | 38 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.11 [0.17, 7.09] |
| 2.2 Recurrence by 6 months' follow‐up (PCR‐adjusted) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.3 Serious adverse events Show forest plot | 1 | 778 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 2.4 Adverse events that result in discontinuation of treatment Show forest plot | 1 | 778 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.19 [0.90, 19.60] |
| 2.5 Other adverse events Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.5.1 AEs during chloroquine treatment | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.5.2 AEs during primaquine treatment | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Recurrence Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1.1 5 months | 1 | 129 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.23 [0.28, 99.15] |
| 3.1.2 8 months | 1 | 126 | Risk Ratio (M‐H, Fixed, 95% CI) | 7.00 [0.38, 127.32] |
| 3.1.3 11 months | 1 | 122 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.18 [0.37, 27.60] |
| 3.2 Serious adverse events Show forest plot | 1 | 129 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 3.3 Anaemia (haemoglobin < 7 g/dL) Show forest plot | 1 | 129 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 3.4 Other adverse events Show forest plot | 1 | 129 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 Recurrence by 12 months' follow‐up Show forest plot | 2 | 2526 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.82, 1.30] |
| 4.1.1 Chloroquine blood‐stage treatment | 2 | 1404 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.67, 1.22] |
| 4.1.2 DHA‐PPQ blood‐stage treatment | 2 | 1122 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.24 [0.87, 1.77] |
| 4.2 Recurrence by 12 months' follow‐up subgrouped by geographical region Show forest plot | 2 | 2526 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.82, 1.29] |
| 4.2.1 Afghanistan | 1 | 348 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.44, 1.28] |
| 4.2.2 Ethiopia | 1 | 466 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.30 [0.74, 2.30] |
| 4.2.3 Indonesia | 1 | 797 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.32 [0.86, 2.03] |
| 4.2.4 Thailand | 1 | 654 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.57, 1.30] |
| 4.2.5 Vietnam | 1 | 261 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.43, 2.53] |
| 4.3 Recurrence by 6 months' follow‐up Show forest plot | 1 | 474 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.61, 1.97] |
| 4.3.1 Chloroquine blood‐stage treatment | 1 | 256 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.42, 1.86] |
| 4.3.2 DHA‐PPQ blood‐stage treatment | 1 | 218 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.55 [0.60, 4.05] |
| 4.4 Recurrence by 3 months' follow‐up Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 4.4.1 Chloroquine blood‐stage treatment | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 4.4.2 DHA‐PPQ blood‐stage treatment | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 4.5 P vivax parasitaemia Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 4.5.1 Day 28 | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 4.5.2 Day 42 | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 4.6 Serious adverse events Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.6.1 Up to 42 days follow‐up | 1 | 1872 | Risk Ratio (M‐H, Fixed, 95% CI) | 12.03 [1.57, 92.30] |
| 4.6.2 Up to 1 year follow‐up | 1 | 1872 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.61 [1.35, 9.68] |
| 4.7 Adverse events that resulted in discontinuation of treatment Show forest plot | 2 | 2526 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.50 [0.49, 12.87] |
| 4.8 Other adverse events Show forest plot | 2 | Other data | No numeric data | |
| 4.8.1 Up to day 14 | 1 | Other data | No numeric data | |
| 4.8.2 Chloroquine group, up to day 42 | 1 | Other data | No numeric data | |
| 4.8.3 DHA‐PPQ group, up to day 42 | 1 | Other data | No numeric data | |
| 4.9 Anaemia Show forest plot | 2 | 2440 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.62, 1.41] |
| 4.9.1 Up to 3 days | 1 | 1786 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.38, 2.66] |
| 4.9.2 Up to 42 days follow‐up | 1 | 654 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.58, 1.44] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 5.1 Recurrence by 6 months' follow‐up Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.1.1 6 months' follow‐up | 1 | 73 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.17 [0.01, 3.34] |
| 5.1.2 12 months' follow‐up | 1 | 49 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 5.1.3 18 months' follow‐up | 1 | 38 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 6.1 Recurrence by 4 months' follow‐up Show forest plot | 1 | 129 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.88 [2.11, 7.11] |
