Intervention Review

You have free access to this content

Artemisinin-based combination therapy for treating uncomplicated Plasmodium vivax malaria

  1. Nithya Gogtay1,
  2. Sridharan Kannan2,
  3. Urmila M Thatte2,
  4. Piero L Olliaro3,
  5. David Sinclair4,*

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 25 OCT 2013

Assessed as up-to-date: 28 MAR 2013

DOI: 10.1002/14651858.CD008492.pub3


How to Cite

Gogtay N, Kannan S, Thatte UM, Olliaro PL, Sinclair D. Artemisinin-based combination therapy for treating uncomplicated Plasmodium vivax malaria. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD008492. DOI: 10.1002/14651858.CD008492.pub3.

Author Information

  1. 1

    Seth GS Medical College and KEM Hospital, Mumbai, India

  2. 2

    Seth GS Medical College & KEM Hospital, Department of Clinical Pharmacology, Mumbai, Maharashtra, India

  3. 3

    World Health Organization, UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), Geneva, Switzerland

  4. 4

    Liverpool School of Tropical Medicine, Department of Clinical Sciences, Liverpool, UK

*David Sinclair, Department of Clinical Sciences, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK. sinclad@liverpool.ac.uk.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 25 OCT 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Ashley 2004 THA

MethodsTrial design: A 3-arm randomized controlled trial (RCT)

Follow-up: Temperature and blood smears daily until clearance of fever and parasites, then weekly attendance until day 63

Adverse event monitoring: Adverse events defined as signs or symptoms that occurred or became more severe after treatment started


ParticipantsNumber: 32 participants had P. vivax parasitaemia at baseline in treatment groups included in this review, all were co-infections with P. falciparum (530 randomized in total)

Inclusion criteria: Age 1 to 65 yrs, symptomatic P. falciparum parasitaemia, informed consent

Exclusion criteria: Pregnancy or lactation, signs or symptoms of severe malaria, > 4% of red blood cells parasitized, contraindication to mefloquine, treatment with mefloquine in the previous 60 days


Interventions1. Dihydroartemisinin-piperaquine, fixed-dose combination: 40 mg/320 mg (Artekin: Holleykin)

  • Total dose: 6.4 mg/kg DHA and 51.2 mg/kg P in 4 divided doses at 0, 8, 24, and 48 hours


2. Artesunate plus mefloquine, loose combination (Artesunate: Guilin, Mequin: Atlantic)

  • AS 4 mg/kg once daily for 3 days
  • MQ 8 mg/kg once daily for 3 days


All doses supervised

Primaquine was not given


Outcomes
  1. Recurrent P. vivax parasitaemia at 14, 28, 42 and 63 days


Not included in this review:

  1. Fever clearance time (not available for P. vivax patients only)
  2. Parasite clearance time (not available for P. vivax patients only)
  3. P. falciparum cure rate at day 63
  4. P. falciparum gametocyte development during follow-up
  5. Mean hematocrit at days 0 and 7 (not available for P. vivax patients only)
  6. Adverse events (not available for P. vivax patients only)


NotesCountry: Thailand

Setting: 4 rural clinics on the Thai-Myanmar border

Transmission: Low and unstable

Resistance: CQ resistance amongst P. vivax has not been widely reported in Thailand

Dates: Jul 2002 to Apr 2003

Funding: Wellcome Trust of Great Britain. DHA-P supplied by Holleykin Pharmaceutical.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk'The randomisation was computer generated (STATA; version 7; Statacorp)'. Randomized in blocks of 9.

Allocation concealment (selection bias)Low risk'The treatment allocation was concealed in sealed envelopes labelled with the study code'.

Blinding (performance bias and detection bias)
All outcomes
Low risk'Laboratory staff reading the blood smears had no knowledge of the treatment received'. No other blinding described.

Incomplete outcome data (attrition bias)
All outcomes
High riskThe included sample size was very low. Although attrition was low in absolute numbers they represent up to 50% of the P. vivax patients.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting.

Other biasHigh riskFor the purpose of this review we are including only a small subset of the original randomized patients. This sample may not therefore be truly randomized and the small sample size means that prognostic balance between groups is unlikely.

Ashley 2005 THA

MethodsTrial design: A 3-arm RCT

Follow-up: Temperature and blood smears daily until clearance of fever and parasites, then weekly attendance for examination, symptom enquiry, malaria smear and hematocrit until day 63

Adverse event monitoring: Adverse events defined as signs or symptoms that occurred or became more severe after treatment started. Symptoms were screened at each visit


ParticipantsNumber: 47 participants had P. vivax parasitaemia at baseline and are included in this review (499 randomized in total).

Inclusion criteria: Age 1 to 65 yrs, symptomatic P. falciparum infection (only mixed infections included in this review), informed consent

Exclusion criteria: Pregnancy or lactation, signs or symptoms of severe malaria, > 4% of red blood cells parasitized, treatment with mefloquine in the previous 60 days


Interventions1. Dihydroartemisinin-piperaquine, fixed-dose combination: 40 mg/320 mg (Artekin: Holleykin)

  • Total dose: 6.4 mg/kg DHA and 51.2 mg/kg P in 4 divided doses at 0, 8, 24, and 48 hours


2. Dihydroartemisinin-piperaquine, fixed-dose combination: 40 mg/320 mg (Artekin: Holleykin)

  • Total dose: 6.4 mg/kg DHA and 51.2 mg/kg P in 3 divided doses at 0, 24, and 48 hours


3. Artesunate plus mefloquine, loose combination (Artesunate: Guilin, Mequin: Atlantic)

  • AS 4 mg/kg once daily for 3 days
  • MQ 8 mg/kg once daily for 3 days


All doses supervised

Primaquine was not given


Outcomes
  1. Recurrence of P. vivax during follow-up at day 14, 28, 42, 63


Not included in this review:

  1. Fever clearance (not available for P. vivax patients only)
  2. Parasite clearance (not available for P. vivax patients only)
  3. P. falciparum cure rate at days 63, 42, and 28, PCR adjusted and unadjusted
  4. P. falciparum gametocyte development during follow-up
  5. Mean hematocrit during follow-up (not available for P. vivax patients only)
  6. Adverse events (not available for P. vivax patients only)


NotesCountry: Thailand

Setting: 4 clinics on the Thai-Myanmar border

Transmission: Low and unstable

Resistance: CQ resistance amongst P. vivax has not been widely reported in Thailand

Dates: Apr 2003 to Apr 2004

Funding: Medicines for Malaria Venture, Wellcome Trust of Great Britain


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk'The randomisation list was generated using STATA; version 7 (Stata)'. Randomized in blocks of 9.

Allocation concealment (selection bias)Low risk'The treatment allocation was concealed in sealed envelopes labelled with the study code'.

Blinding (performance bias and detection bias)
All outcomes
Low risk'Laboratory staff reading the blood smears had no knowledge of the treatment received'. No other blinding described.

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe included sample size is very low. Attrition is low in absolute numbers and unlikely to have introduced significant bias.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting.

Other biasHigh riskFor the purpose of this review we are including only a small subset of the original randomized patients. This sample may not therefore be truly randomized and the small sample size means that prognostic balance between groups is unlikely.

Awab 2010 AFG

MethodsTrial design: An open-label RCT

Follow-up: Clinical assessment, blood smears and haemoglobin on days 0 to 3 then weekly until day 56

Adverse event monitoring: Astandard symptom questionnaire at each visit


ParticipantsNumber: 536 randomized

Inclusion criteria: Febrile patients aged > 3 months, slide confirmed P. vivax mono-infection, a negative pregnancy test, informed consent

Exclusion criteria: Pregnancy or lactation, clinical or laboratory features of severe malaria, haemoglobin < 7 g/dL, concomitant disease that would mask treatment responses, known allergy to study drugs, antimalarial treatment in the past month, anticipated inability or unwillingness to complete the 56 day follow-up


Interventions1. Dihydroartemisinin-piperaquine, fixed-dose combination: 40 mg/320 mg (Artekin: Holleypharm)

  • Total dose: 6 mg/kg DHA and 48 mg/kg P in 3 divided doses over 3 days


2. Chloroquine (IDA)

  • Total dose:25 mg base/kg in divided doses over 3 days


All doses supervised

Primaquine was not given


Outcomes
  1. Recurrence of P. vivax during follow-up at day 14, 28, and 56
  2. Fever clearance day 0 to 3
  3. Parasite clearance day 0 to 3
  4. Adverse events


Not included in this review:

  1. Predictors of treatment failure
  2. Gametocytemia at time of relapse


NotesCountry: Afghanistan

Setting: 3 provincial malaria control centres, one in the east and two in the north

Transmission: Seasonal

Resistance: CQ resistance amongst P. vivax has not been widely reported in Afghanistan

Dates: Jul 2007 to Feb 2009

Funding: Mahidol-Oxford Research Unit, Thailand International Development and Cooperation Agnecy, UK MRC Clinical Science Fellowship, Wellcome Trust of Great Britain


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk'a pre-generated randomization list made in blocks of 20 that was produced and held independently of the field teams by a statistician'.

Allocation concealment (selection bias)Low risk'The individual allocations were kept in sealed opaque envelopes and opened only after enrolment'.

Blinding (performance bias and detection bias)
All outcomes
Low risk'Patients and clinical field workers were not blinded to the treatment arm after allocation. Microscopists were blinded to treatment allocation at follow-up examinations'.

Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up were low: 25/268 (9.3%) DHA-P versus 13/268 (4.9%) CQ.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting.

Other biasLow riskNo other bias detected.

Hasugian 2007 IDN

MethodsTrial design: An open label RCT

Follow-up: Daily until fever and parasites cleared then weekly until day 42, for a physical examination, a symptom questionnaire and malaria film. Haemoglobin measured on days 0, 7, 28 and day of failure.

Adverse event monitoring: Assessed at each follow-up visit


ParticipantsNumber: 114 had P. vivax parasitaemia at baseline (340 randomized in total)

Inclusion criteria: Age > 1 yr, weight > 5 kg, slide confirmed malaria (P. falciparum, P. vivax or both), fever or history of fever in the preceding 48 hours

Exclusion criteria: Pregnancy or lactation, danger signs or signs of severe malaria, > 4% red blood cells parasitized, concomitant disease that required hospital admission


Interventions1. Dihydroartemisinin-piperaquine, fixed-dose combination:40 mg/320 mg (Artekin: Holley)

  • Total dose: 6.75 mg/kg DHA and 54 mg/kg PQP in 3 divided doses given once daily for 3 days


2. Artesunate plus amodiaquine, loose combination (Arsumax: Guilin, Flavoquine: Aventis)

  • AS 4 mg/kg once daily for 3 days
  • AQ 10 mg/kg once daily for 3 days


All doses supervised

Both groups were offered an unsupervised course of Primaquine 0.3mg base/kg for 14 days, on completion of the study regimen


Outcomes
  1. Parasitological failure with P. vivax on days 14, 28 and 42


Not included in the review:

  1. Fever clearance (not available for P. vivax patients only)
  2. Parasite clearance (not available for P. vivax patients only)
  3. Parasitological failure due to P. falciparum
  4. P. falciparum gametocyte carriage after treatment
  5. Anaemia at day 0, 7, 28 (not available for P. vivax patients only)
  6. Adverse events (not available for P. vivax patients only)


NotesCountry: Indonesia

Setting: Rural clinics

Transmission: High

Resistance: CQ resistance among P. vivax is high at this study site

Dates: Jul 2005 to Dec 2005

Funding: Wellcome Trust - National Health and Medical Research Council


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk'A randomisation list was generated in blocks of 20 by an independent statistician'.

Allocation concealment (selection bias)Low risk'Treatment allocation concealed in an opaque, sealed envelope that was opened once the patient had been enrolled'.

Blinding (performance bias and detection bias)
All outcomes
Low risk'All slides were read by a certified microscopist who was blinded to treatment allocation'. An open label trial.

Incomplete outcome data (attrition bias)
All outcomes
High riskThe primary outcome data are unpublished data including only participants with P. vivax mono-infection at baseline. Attrition although balanced between groups was > 15% at day 28 and > 20% at day 42.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting.

Other biasLow riskNo other bias detected.

Hutagalung 2005 THA

MethodsTrial design: An open-label RCT

Follow-up: Examination and malaria film daily until fever and parasites cleared then weekly to day 42 or any other day they became unwell

Adverse event monitoring: At each visit a questionnaire on adverse events was completed


ParticipantsNumber: 24 participants had P. vivax co-infections at baseline (490 randomized)

Inclusion criteria: Weight > 10 kg, slide confirmed P. falciparum +/- P. vivax, informed consent

Exclusion criteria: Pregnancy, clinical or laboratory signs of severe illness and/or severe and complicated malaria severe malaria, treatment with mefloquine in previous 63 days


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • < 15 kg 1 tablet twice daily for 3 days
  • 15 to 24 kg 2 tablets twice daily for 3 days
  • 25 to 34 kg 3 tablets twice daily for 3 days
  • > 35 kg 4 tablets twice daily for 3 days
  • Plus glass of chocolate milk with each dose


2. Artesunate plus mefloquine, loose combination (Artesunate: Guilan, Lariam: Hoffman-La Roche)

  • AS 4 mg/kg once daily for 3 days
  • MQ 15 mg/kg on day 1 and 10 mg/kg on day 2


All doses supervised

Primaquine not given


Outcomes
  1. P. vivax parasitaemia on days 0 to 3
  2. P. vivax recurrence at days 14 and 28


Not included in the review:

  1. Fever clearance (P. falciparum)
  2. Parasite clearance (P. falciparum)
  3. Gametocyte clearance (data only for P. falciparum)
  4. Failure due to P. falciparum
  5. Adverse events


NotesCountry: Thailand

Setting: Malaria clinics of the Shoklo Malaria Research Unit

Transmission: Low and unstable

Resistance: CQ resistance amongst P. vivax has not been widely reported in Thailand

Dates: July 2001 to June 2002

Funding: Wellcome Trust of Great Britain


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk'Computerized randomisation was in blocks of ten'.

Allocation concealment (selection bias)Unclear riskNone described.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskAn open label trial. No comment on blinding of laboratory staff.

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe included sample size is very low. Attrition was low in absolute numbers and unlikely to have significantly biased the result.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting.

Other biasHigh riskFor the purpose of this review we are including only a small subset of the original randomized patients. This sample may not therefore be truly randomized and the small sample size means that prognostic balance between groups is unlikely.

Karunajeewa 2008 PNG

MethodsTrial design: A 4-arm open label RCT

Follow-up: Standardized follow-up including temperature and malaria film on days 0, 1, 2, 3, 7, 14, 28, and 42. Drug levels assayed on day 7.

Adverse event monitoring: None described


ParticipantsNumber: 195 had P. vivax parasitaemia at baseline (372 randomized in total)

Inclusion criteria: Age 0.5 to 5 years, axillary temp > 37.5 ºC or history of fever in the preceding 24 hours, > 1000/µL asexual P. falciparum or > 250/µL asexual P. vivax, P. ovale or P. malariae, informed consent

Exclusion criteria: Features of severe malaria, evidence of another infection or coexisting condition including malnutrition, intake of study drug in previous 14 days


Interventions1. Artesunate plus sulphadoxine-pyrimethamine, loose combination (Sanofi-Aventis, Roche)

  • AS 4 mg/kg once daily for 3 days
  • SP 25/1.25 mg/kg once on the first day


2. Dihydroartemisinin-piperaquine, fixed dose combination: 40 mg/320 mg (Beijing Holley-Cotec)

  • DHA 2.5 mg/kg once daily for 3 days
  • P 20 mg/kg once daily for 3 days


3. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg (Novartis), given with milk

  • A 1.7 mg/kg twice daily for 3 days
  • L 10 mg/kg twice daily for 3 day


4. Chloroquine plus sulphadoxine-pyrimethamine, loose combination (Aspen Healthcare, Roche)

  • CQ 10 mg base/kg once daily for 3 days
  • SP 25/1.25 mg/kg once on the first day


All doses supervised except the evening dose of AL6

Primaquine was not given


Outcomes
  1. Recurrence of P. vivax at day 14, 28, and 42
  2. Fever clearance
  3. Parasite clearance


Not included in this review:

  1. Drug levels day 7
  2. ACPR (P. falciparum) at days 28 and 42, PCR adjusted and unadjusted
  3. P. falciparum gametocyte prevalence during follow-up
  4. Adverse events (not available for P. vivax patients only)


NotesCountry: Papua New Guinea

Setting: Health centres

Transmission: High

Resistance: CQ resistance among P. vivax rising since 1980s

Dates: Apr 2005 to Jul 2007

Funding: WHO Western Pacific Region, Rotary against Malaria in Papua New Guinea, National Health and Medical Research Council of Australia


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk'Computer-generated randomised assignment with blocks of 24 for each site'.

Allocation concealment (selection bias)Low riskInformation from authors - allocation was concealed in sealed opaque envelopes.

Blinding (performance bias and detection bias)
All outcomes
Low risk'All blood smears were subsequently reexamined independently by two skilled microscopists who were unaware of the treatment assignments'. An open label trial.

Incomplete outcome data (attrition bias)
All outcomes
High riskAttrition was high (> 10%) in all groups and could have introduced bias into the result.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting.

Other biasLow riskNo other bias detected.

Kolaczinski 2007 AFG

MethodsTrial design: An open label RCT

Follow-up: Clinical symptoms, temperature and malaria film recorded on days 0, 1, 2, 3, 7, 14, 28, 42 and when ill. PCV recorded on Day 0, and day 28 or day of failure

Adverse event monitoring: None described


ParticipantsNumber: 190 randomized

Inclusion criteria: Age > 2 years, Weight > 5 kg, microscopically confirmed P. vivax mono-infection > 1 asexual parasite per 10 fields, informed consent

Exclusion criteria: Pregnancy, severe malaria, evidence of concomitant infection or serious disease, recent use of antimalarial drugs, known allergy to study drugs


Interventions1. Artesunate plus sulphadoxine-pyrimethamine, loose combination (Plasmotrim, Mepha: Fansidar, Roche)

  • AS 4 mg/kg once daily for 3 days
  • SP 25/1.25 mg/kg once on the first day


2. Chloroquine (Nivaquine; Beacon)

  • CQ 25 mg/kg given over 3 days


All doses supervised

Primaquine was not given


Outcomes
  1. Recurrence of P. vivax at day 14, 28, and 42
  2. PCV on day 0 and 28 or day of failure
  3. Fever clearance
  4. Parasite clearance
  5. Gametocytemia
  6. Adverse events


NotesCountry: Afghanistan - Jalalabad, Nangahar Province

Setting: Malaria reference centre

Transmission: Seasonal and unstable

Resistance: Substantial CQ resistance has not been reported from Afghanistan (Author communication)

Dates: Mar 2004 to Aug 2004

Funding: UNDP, World Bank, WHO Special Programme for Research on Tropical Disease


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk'A computer-generated randomisation list (generated using Microsoft Excel; Microsoft Corp., Redmond, WA, USA) was used to randomly assign vivax cases within gender and age groups to one of two treatment regimens'.

Allocation concealment (selection bias)High risk'After determining suitability for inclusion, the study clinician enrolled each patient and allocated them to the treatment arm next indicated in the randomisation list. The allocation sequence was not concealed from the study clinician'.

Blinding (performance bias and detection bias)
All outcomes
Low risk'The clinical assistants responsible for directly observed treatment and clinical assessment during follow-up were blind to the nature of the treatment arms but were aware of the arm code to which patients were allocated (e.g. ‘arm 1’, ‘arm 2’; differences in dosages and tablet appearance would not have allowed complete concealment). The microscopists and laboratory technicians were blind to treatment allocations'.

Incomplete outcome data (attrition bias)
All outcomes
Low risk10 participants were lost to follow-up with similar numbers in each group. This is unlikely to have a major effect on the result.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting.

Other biasLow riskNo other bias detected.

Krudsood 2007 THA

MethodsTrial design: An open label RCT

Follow-up: Admitted to hospital for 28 days. Temperature and malaria film recorded every 12 hours until parasite and fever clearance then on days 3, 7, 14, 21, and 28

Adverse event monitoring: None described


ParticipantsNumber: 98 randomized

Inclusion criteria: Age > 15 years, Weight > 40 kg, microscopically confirmed P. vivax mono-infection, informed consent

Exclusion criteria: Pregnancy or lactation, severe malaria, concomitant febrile illness, severe malnutrition, ingestion of antimalarial drugs in the past 14 days, known allergy or intolerance to study drugs


Interventions1. Artemether-lumefantrine, fixed-dose combination: 120/20 mg (Coartem, Novartis)

  • AL 4 tablets at 0, 8, 24, 32, 48, and 60 hours


2. Chloroquine (Government Pharmaceutical Organisation)

  • CQ 25mg/kg given over 3 days


All doses supervised

Both regimens received additional primaquine (Government Pharmaceutical Organization)

  • PQ 15 mg daily for 14 days


Outcomes
  1. Recurrence of P. vivax at day 14 and 28
  2. Fever clearance
  3. Parasite clearance
  4. Serious adverse events
  5. Other adverse events (text summary only)


NotesCountry: Thailand

Setting: Bangkok Hospital for Tropical Diseases

Transmission: Low endemicity

Resistance: CQ resistance amongst P. vivax has not been widely reported in Thailand

Dates: Jun 2004 to May 2005

Funding: WHO, Ministry of Health, Labor, and Welfare of Japan, and Mahidol University Research Grants.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk'The patients were randomly assigned', no further description.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot described.

Incomplete outcome data (attrition bias)
All outcomes
High riskParticipants lost to follow-up were high in both groups ≈ 18%.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting.

Other biasLow riskNo other bias detected.

Phyo 2011 THA

MethodsTrial design: Assessor blind RCT

Follow-up: daily until afebrile and aparasitaemic and then weekly until day 63. Temperature, malaria film, hematocrit, and chloroquine plasma concentration at every visit.

Adverse event monitoring: At each visit a symptom questionnaire was completed.


ParticipantsNumber: 500 randomized

Incusion criteria: Age > 1 yr; Body weight > 5 kg; Microscopically confirmed monoinfection of P. vivax parasitaemia (> 5/500 WBC); Febrile (axillary temperature, > 37.5 °C) or had history of fever

Exclusion criteria: Known hypersensitivity to the study drugs; intercurrent illness; pregnant, lactating; severely anaemic (hematocrit < 20%); received mefloquine in the past 60 days; received dihydroartemisinin piperaquine in the past 3 months


Interventions1. Dihydroartemisinin-piperaquine, fixed-dose combination: 40 mg/320 mg (Duocotexin: Holley)

  • Total target dose: DHA 7 mg/kg + P 55 mg/kg in 3 divided doses, given once daily for 3 days with milk.


2. Chloroquine (Government Pharmaceutical Organization, Thailand)

  • Target dose: 25 mg base/kg in three divided doses, given once daily for 3 days


All patients with normal G6PD were administered Primaquine at the target dose of 0.5 mg/kg/day for a period of 14 days at the end of the follow-up period


Outcomes1. Recurrence of P. vivax on day 28, 63

2. Fever clearance

3. Parasite clearance within 24, 48, 72, and 96 hours

4. Adverse events


NotesCountry: Thailand-Myanmar border

Setting: Malaria Research Unit Clinic

Transmission: low and seasonal

Resistance: Decreased susceptibility to CQ in some isolates.

Dates: Jan 2007 to Dec 2008

Funding: Holley Pharm; Wellcome Trust


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk'Pateints were allocated to the treatment arms on a pre generated randomization list in blocks of 20'.

Allocation concealment (selection bias)Low risk'The individual allocations were concealed in sealed envelopes and opened only after enrollment'.

Blinding (performance bias and detection bias)
All outcomes
Low risk'Patients and clinic workers were not blinded. Laboratory technicians were unaware of treatment allocation'.

Incomplete outcome data (attrition bias)
All outcomes
Low risk35 lost to follow-up or excluded from analysis in the DHA-P arm (14%) and 37(14.8%) lost to follow-up or excluded from the chloroquine arm.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting.

Other biasLow riskNo evidence of other bias.

Poravuth 2010 ASIA

MethodsTrial design: Double-blind RCT

Follow-up: All participants were hospitalized for 3 days then seen for follow-up at day 7, 14, 21, 28, 35, and 42.

Adverse event monitoring: Monitored throughout the study, 12-lead ECGs at day 0 2, 7, 14, and 42 if clinically indicated, laboratory tests at day 0, 3, 7, 28, and 42 if clinically indicated


ParticipantsNumber: 456 randomized

Inclusion criteria: Age 3 to 60 years, weight 20 to 90 kg, uncomplicated P. vivax mono-infection with a parasite density > 250 mL, fever or documented history of fever in the previous 24 hours

Exclusion criteria: pregnancy or lactation, any other condition requiring hospitalisation; haemoglobin < 8 g/dL; hepatic or renal impairment; malnutrition; presence or history of clinically significant disorders; known hypersensitivity to study drugs; known active hepatitis A IgM, hepatitis B surface antigen, hepatitis C antibody or seropositive for HIV antibody; used an antimalarial within the previous two weeks; used an antibacterial with anti-malarial activity within the previous two weeks


Interventions1. Artesunate-pyronaridine, fixed-dose combination 60 mg/180 mg (Shin Poong)

  • 20 kg to 25 kg 1 tablet once daily for 3 days
  • 26 kg to 44 kg 2 tablets once daily for 3 days
  • 45 kg to 64 kg 3 tablets once daily for 3 days
  • 65 kg to 90 kg 4 tablets once daily for 3 days
  • Target dose


2. Chloroquine tablets 155 mg (Shin Poong)

  • Adult target dose 620 mg on Days 0 and 1 and 310 mg on Day 2.
  • Child target dose 10 mg/kg on Days 0 and 1 and 5 mg/kg onDay 2.


All doses supervised

Primaquine was given for 14 days starting on day 28


Outcomes
  1. Recurrence of P. vivax at day 14, 28, and 42
  2. Median time to parasite clearance/parasitaemia on days 1, 2, and 3.
  3. Median time to fever clearance/fever on days 1, 2, and 3.
  4. Adverse events


NotesCountry: 5 study sites in Cambodia, Thailand, India and Indonesia

Setting: Local hospitals

Transmission: Not stated

Resistance: Not stated

Dates: Mar 2007 to Mar 2008

Funding: Shin Poong Pharmaceutical Company, Seoul, Republic of Korea, and the Medicines for Malaria Venture, Geneva, Switzerland


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk'A computer-generated randomization scheme was provided by the sponsor'.

Allocation concealment (selection bias)Low risk'Randomization numbers were assigned in ascending order to each subject according to the order recruited. The subject was allocated an individually numbered treatment pack, which contained sufficient tablets for 3 days’ therapy plus an overage bottle containing tablets in case the subject vomited the first dose'.

Blinding (performance bias and detection bias)
All outcomes
Low risk'Study drugs were administered on a double-blind, double-dummy basis. The investigator calculated the appropriate dose and study drug was administered by a different member of staff, designated by the investigator. All study investigators, laboratory technicians and patients were blind to treatment assignment. Active drugs and placebos were packaged similarly'.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNumber of participants lost to follow-up was low and balanced between groups: 4% AS-Py versus 8% CQ.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting.

Other biasHigh risk'The study sponsors were responsible for data collection, statistical analysis and interpretation'.

Ratcliff 2007 IDN

MethodsTrial design: An open-label RCT

Follow-up: A symptom questionnaire, physical examination, malaria film and haemoglobin measurement daily until fever and parasites cleared then weekly to day 42

Adverse event monitoring: A symptom questionnaire at each visit


ParticipantsNumber: 175 had P. vivax parasitaemia at baseline (774 randomized in total)

Inclusion criteria: Weight >10 kg, fever or a history of fever in the preceding 48 hrs, slide confirmed malaria (P. falciparum, P. vivax or mixed infections)

Exclusion criteria: Pregnancy or lactation, danger signs or signs of severity, parasitaemia > 4%, concomitant disease requiring hospital admission


Interventions1. Dihydroartemisinin-piperaquine, fixed-dose combination: 40 mg/320 mg (Artekin: Holleykin)

  • Total dose: DHA 6.75 mg/kg + P 54 mg/kg in 3 divided doses, given once daily for 3 days


2. Artemether-lumefantrine, fixed-dose combination: 20 mg/120 mg (Coartem: Novartis)

  • 10 kg to 15 kg 1 tablet twice daily for 3 days
  • 15 kg to 25 kg 2 tablets twice daily for 3 days
  • 25 kg to 35 kg 3 tablets twice daily for 3 days
  • > 35 kg 4 tablets twice daily for 3 days


Only the first dose of each day was supervised. All participants advised to take each dose with a biscuit or milk.

All patients were also given primaquine

  • PQ 0·3 mg base/kg 14 days starting on day 28


Outcomes
  1. P. vivax recurrence at day 14, 28, and 42


Not included in the review:

  1. Fever clearance (not available for P. vivax patients only)
  2. Parasite clearance (not available for P. vivax patients only)
  3. P. falciparum at days 42 and 28, PCR adjusted and unadjusted
  4. P. falciparum gametocyte carriage after treatment
  5. Anaemia during follow-up (not available for P. vivax patients only)
  6. Adverse events (not available for P. vivax patients only)


NotesCountry: Indonesia

Setting: Rural outpatient clinics

Transmission: High

Resistance: CQ resistance is high at this study site

Dates: Jul 2004 to Jun 2005

Funding: Wellcome Trust UK and National Health and Medical Research Council Australia


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk'A randomisation list was generated in blocks of 20 patients by an independent statistician'.

Allocation concealment (selection bias)Low risk'Treatment allocation concealed in an opaque sealed envelope that was opened once the patient had been enrolled'.

Blinding (performance bias and detection bias)
All outcomes
Low risk'All slides were read by a certified microscopist with at least 10 years experience, who was blinded to treatment allocation'. No other blinding was conducted.

Incomplete outcome data (attrition bias)
All outcomes
High riskThe primary outcome data are unpublished data including only participants with P. vivax mono-infection at baseline. Attrition although balanced between groups was >10% at day 28 and >15% at day 42.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting.

Other biasLow riskNo other bias detected.

Smithuis 2006 MMR

MethodsTrial design: A 4-arm open-label RCT

Follow-up: A symptom questionnaire, malaria film, and gametocyte count on days 0, 1, 2, 3, 7, 14, 21, 28, 35, and 42. Haemoglobin was measured on days 0 and 28.

Adverse event monitoring: A symptom questionnaire at each visit


ParticipantsNumber: 87 patients had P. vivax parasitaemia at baseline (652 randomized in total)

Inclusion criteria: Age > 1 year, axillary temperature > 37.5 ºC or history of fever in the previous 48 hours, P. falciparum mono-infection 500 to 100,000 parasites/µL or co-infection with P. vivax, informed consent

Exclusion criteria: Pregnancy, signs of severe malaria, signs or symptoms of other diseases, history of taking mefloquine in the previous 2 months or any other antimalarial in the previous 48 hours, history of psychiatric disease


Interventions1. Dihydroartemisinin-piperaquine, fixed-dose combination: 40 mg/320 mg (Artekin: Holleykin)

  • Total dose: DHA 6.3 mg/kg + P 50.4 mg/kg in 3 divided doses, given once daily for 3 days
  • Supervised


2. Dihydroartemisinin-piperaquine, fixed-dose combination: 40 mg/320 mg (Artekin: Holleykin)

  • Total dose: DHA 6.3 mg/kg + P 50.4 mg/kg in 3 divided doses, given once daily for 3 days
  • Unsupervised


3. Artesunate plus mefloquine, loose combination (artesunate: Guilin, Lariam: Hoffman-La Roche)

  • AS 4 mg/kg once daily for 3 days
  • MQ 25 mg base/kg as a single dose on day 0
  • Supervised


4. Artesunate plus mefloquine, loose combination (artesunate: Guilin, Lariam: Hoffman-La Roche)

  • AS 4 mg/kg once daily for 3 days
  • MQ 25 mg base/kg as a single dose on day 0
  • Unsupervised


Primaquine was not given


Outcomes
  1. P. vivax recurrence at day 14, 28, and 42
  2. Fever clearance
  3. Parasite clearance
  4. Mean change in haemoglobin from day 0 to day 28


Not included in the review:

  1. P. falciparum at days 42 and 28, 42 PCR unadjusted and PCR adjusted
  2. P. falciparum gametocyte appearance at day 7 and day 14
  3. P. falciparum gametocyte carriage at days 0, 7, 14, 21, and 28
  4. Adverse events (not available for P. vivax patients only)


NotesCountry: Myanmar

Setting: Rural village tracts

Transmission: Low and seasonal

Resistance: CQ resistance amongst P. vivax has not been widely reported in Myanmar

Dates: Nov 2003 to Feb 2004

Funding: Médecins sans Frontières (Holland)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk'At both study locations three boxes were prepared, one for each of the three age groups, by an administrator who was otherwise not connected with the study. In each box, 40 unmarked and sealed opaque envelopes were deposited. Each envelope contained a card that described the treatment assignment, and each treatment allocation had an equal number of cards (ten). Each new patient (or his or her carer) was asked to take one of the envelopes from the box for their age group. Treatment was then dispensed in accordance with the treatment allocation in the envelope. Whenever a box became empty, another 40 envelopes were put in that box'.

Allocation concealment (selection bias)Low riskSee above.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskAn open label trial. No comment on blinding of laboratory staff.

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe included sample size is low. Attrition is low in absolute numbers and unlikely to have introduced significant bias.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting.

Other biasHigh riskFor the purpose of this review we are including only a small subset of the original randomized patients. This sample may not therefore be truly randomized and the small sample size means that prognostic balance between groups is unlikely.

Smithuis 2010 MMR

MethodsTrial design: A 10-arm RCT

Follow-up: Patients were asked to return weekly for 9 weeks for assessment and at any other time they were unwell. Haemoglobin was measured on days 0 and 63.

Adverse event monitoring: Not described


ParticipantsNumber: 66 participants had P. vivax co-infections at baseline and are included in this review. The participants who received the one-off dose of primaquine are excluded from this review.

Inclusion criteria: Age > 6 months, weight > 5 kg, P. falciparum mono-infection 500 to 200,000 parasites/µL or co-infection with P. vivax, informed consent

Exclusion criteria: Pregnancy, signs of severe malaria, severe malnutrition, history of hypersensitivity to any of the study drugs, severe malnutrition, concomitant febrile illness, history of psychiatric disorder, a full course of mefloquine in the previous 9 weeks or any other antimalarial in the previous 48 hours


InterventionsEach of the five study arms were also divided into two where one half also received a one-off dose of 0.75 mg/kg primaquine.

1. Dihydroartemisinin-piperaquine, fixed-dose combination: 40 mg/320 mg or 20 mg/160 mg tablets (Artekin: Holleykin)

  • DHA 2.5 mg/kg once daily for 3 days
  • P 20 mg/kg once daily for 3 days


2. Artesunate plus amodiaquine, fixed dose combination: 25 mg/67.5 mg or 50 mg/135 mg or 100 mg/270 mg tablets.

  • AS 4 mg/kg once daily for 3 days
  • AQ 10.8 mg base/kg once daily for 3 days


3. Artemether-lumefantrine, fixed dose combination: 20 mg/120 mg tablets.

  • A 3.3 mg/kg in two divided doses each day for 3 days
  • L 19.8 mg/kg in two divided doses each day for 3 days
  • Plus advised to consume fatty food or breast feed before each dose


4. Artesunate plus mefloquine, fixed dose combination: 25 mg/55 mg or 100 mg/220 mg tablets (artesunate: Guilin, Lariam: Hoffman-La Roche)

  • AS 4 mg/kg once daily for 3 days
  • MQ 8.8 mg/kg once daily for 3 days


5. Artesunate plus mefloquine, loose combination (artesunate: Guilin, Lariam: Hoffman-La Roche)

  • AS 4 mg/kg once daily for 3 days
  • MQ 25 mg base/kg as a single dose on day 0


First dose supervised, all others unsupervised.

Primaquine was not given


Outcomes
  1. Recurrent parasitaemia at day 14, 28, 42, and 63


Not included in the review:

  1. Failure due to P. falciparum
  2. Gametocytemia (not available for P. vivax patients only)
  3. Haemoglobin (not available forP. vivax patients only)
  4. Adverse events


NotesCountry: Myanmar

Setting: Clinics

Transmission: Not described

Resistance: CQ resistance amongst P. vivax has not been widely reported in Myanmar

Dates: Dec 2008 to March 2009

Funding: Médecins sans Frontières (Holland)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk'They were stratified prospectively into three age groups...patients were randomly assigned in equal numbers to receive one of the five different treatments'.

Allocation concealment (selection bias)Low risk'Treatment allocations were put in sealed envelopes in blocks of 50 for each age-group...patients drawing an envelope from a box after enrolment'.

Blinding (performance bias and detection bias)
All outcomes
Low riskAn open label trial. 'Microscopists examining blood films were unaware of treatment allocation'.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition is low in absolute numbers and unlikely to have introduced significant bias.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting.

Other biasHigh riskFor the purpose of this review we are including only a small subset of the original randomized patients. This sample may not therefore be truly randomized and the small sample size means that prognostic balance between groups is unlikely.

Sutanto 2013 IDN

MethodsTrial design: An open-label RCT

Follow-up: Routine blood films were taken on days 3, 7, 14, 21, 28, 35, 41, 56, 63, 70, 84, 126, 140, 180, and 365, plus other visits to the clinic with illness

Adverse event monitoring: Symptom questionnaire and hematology and biochemistry investigations (WBC, RBC, MCV, MCHC, LFT, RFT, gamma glutathione hydroxylase, pyruvic transaminase, creatine kinase, serum electrolytes, G6PD) were performed on days 3, 7, 14, 28, 41, and 84


ParticipantsNumber: 116 randomized (41, 39, and 36 in each of the three arms)

Inclusion criteria: Indonesian soldiers after a year of duty in malarious Papua, Indonesia diagnosed with P. Vivax malaria by microscopy

Exclusion criteria: Refusal to consent; any condition requiring hospitalization; G6PD deficiency; SGOT, SGPT > 2.5 times upper limit of normal; QTcF > 450ms; anaemia (haemoglobin < 8 g/dL); definite plans for absence from the site in 28 days


Interventions1. Quinine 200mg tablets (Quinine: Kimia Pharma)

  • 10 mg/kg three times daily for 7 days
  • Plus primaquine 30 mg daily for 14 days, starting from day 0 (45 mg if weight > 70 kg)


2. Dihydroartemisinin-piperaquine, fixed-dose combination: 40 mg/320 mg (Eurartemisim: Sigma Tau)

  • Three tablets once daily for three days
  • Plus primaquine 30 mg daily for 14 days, starting from day 28 (45 mg if weight > 70 kg)


The third study arm received artesunate alone and was excluded from this review


Outcomes1. Recurrence of P. vivax at day 28

2. Recurrence of P. vivax between days 29 to 163

3. Parasite clearance at 72 hours

4. Anaemia

5. Adverse events


NotesCountry: Indonesia

Setting: Army base

Transmission: Soldiers had returned from endemic Papua, Indomesia to East Java, Indonesia where there is no endemic P. vivax.

Resistance: CQ resistance amongst P. vivax is prevalent in Papua

Dates: Enrolment Nov 2010 to Apr 2011

Funding: Medicines for Malaria Venture, Wellcome Trust. Sigma Tau provided the DHA-P.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk'A randomized list of study numbers that were block allocated was generated by varying the blocking number at random'.

Allocation concealment (selection bias)Low risk'An envelope revealing the assigned therapy was opened after informed consent'.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskAn open label trial. No comment on blinding of laboratory staff.

Incomplete outcome data (attrition bias)
All outcomes
Low riskThree were lost to follow-up in the quinine + primaquine arm (8%) and none in the other two arms.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting.

Other biasLow riskNo evidence of any other bias.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Batty 1998No ACT given. A pharmacokinetic study of artesunate monotherapy.

Betuela 2012There was no arm that has received ACT.

Dao 2007Not randomized. A single arm study of artesunate plus primaquine.

Davis 2011This study is a cost-effectiveness study already published in NEJM in 2008. We included the data from this study in the previous review.

Douglas 2010A review article, not a RCT.

Hamedi 2004No ACT given. An RCT of artesunate plus primaquine versus chloroquine plus primaquine.

Hombhanje 2009Participants did not have uncomplicated P. vivax at baseline. An RCT of artesunate-naphthoquine versus chloroquine plus sulfadoxine-pyrimethamine in P. falciparum malaria.

Leang 2013Although the study reports outcome measures for different arms including one with ACT, there is no mention on whether the study is randomized.

Luxemburger 1996Not randomized. Trial authors gave all participants with P. vivax a single dose of mefloquine.

Naing 2010Review article.

Price 2007aUses data from Hasugian 2007 IDN and Ratcliff 2007 IDN. No new efficacy or safety data.

Pukrittayakamee 2000No ACT given. A RCT of eight different monotherapies.

Rueangweerayut 2012The participants of this study had only P. falciparum infection.

Senn 2013This study is on intermittent preventive treatment in infants (IPTi).

Thimasarn 1997Participants did not have uncomplicated P. vivax malaria. RCT of different treatment combinations for P. falciparum.

Tjitra 2002Not randomized. Two separate trials are reported: a quasi-RCT of chloroquine versus chloroquine plus sulfadoxine-pyrimethamine, followed by a single arm study of artesunate plus sulfadoxine-pyrimethamine.

Tjitra 2012Trial authors only gave the comparator artemisinin-napthoquine as a single dose ACT.

van Vugt 1998Artesunate plus mefloquine versus a four-dose course of artemther-lumefantrine. This regimen is no longer recommended as it was shown to be inferior to six doses for treating P. falciparum.

Yeshiwondim 2010No participants received ACT.

Yohannes 2011Quasi-RCT: alternate allocation.

Zwang 2009An individual patient data meta-analysis of six clinical trials including Ashley 2004 THA, Ashley 2005 THA, Janssens 2007a, Smithuis 2010 MMR and two other trials which did not include patients with P. vivax at baseline. No new efficacy data.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Janssens 2007

MethodsTrial design: Open label RCT

Follow-up: Monitored daily until fever and parasites cleared then weekly to day 63. Temperature, symptom questionnaire, malaria film, and hematocrit at each visit.

Adverse event monitoring: An adverse event defined as any new sign or symptom appearing after treatment started. At each visit a symptom questionnaire was completed.

ParticipantsNumber: It is unclear whether any participants had P. vivax infection at baseline (464 randomized in total)

Inclusion criteria: Age > 1 yr, axillary temp > 37.5 ºC or history of fever, signs and symptoms of uncomplicated malaria, P. falciparum mono or mixed infections, written informed consent

Exclusion criteria: Pregnancy or lactation, signs or symptoms of severe malaria, > 4% red blood cells parasitized, a history of convulsions or neuropsychiatric disorder, treatment with mefloquine in the past 60 days

Interventions1. Dihydroartemisinin-piperaquine, fixed-dose combination, 40 mg/320 mg tablets (Artekin: Holleykin)

  • Adult total dose: 6 mg/kg DHA and 48 mg/kg P in 4 divided doses, given at 0, 8, 24, and 48 hours
  • Children total dose: 6.4 mg/kg DHA + 51.2 mg/kg P in 4 divided doses, given at 0, 8, 24, 48 hours


2. Artesunate plus mefloquine, loose combination (Artesunate: Guilin, Mefloquine: Mepha)

  • Adults: 100 mg AS plus 500 mg MQ twice daily on day 0, then 200 mg AS once daily on day 1 and day 2
  • Children: AS 4 mg/kg once daily for 3 days plus 25 mg/kg MQ split into 2 doses on day 0


All doses supervised

Primaquine was not given

Outcomes
  1. P. vivax recurrence at day 14, 28, 42 and 63


Not included in the review:

  1. Fever clearance (not available for P. vivax patients only)
  2. Parasite clearance (not available for P. vivax patients only)
  3. P. falciparum at days 63, 42, and 28, PCR adjusted and unadjusted
  4. Mean hematocrit at day 0 and 63 (not available for P. vivax patients only)
  5. Adverse effects (not available for P. vivax patients only)

NotesCountry: Cambodia

Setting: Rural health centres and outreach malaria clinics

Transmission: Low and seasonal

Resistance: Not stated

Dates: Oct 2002 to March 2003

Funding: Médecins sans Frontières

Shin 2011

MethodsTrial design: Randomized, double-blind, double-dummy, comparative study

Inclusion criteria: Age between 3 and 60 years; body weight between 20 and 90 kg; acute uncomplicated P. vivax mono-infection confirmed with fever and positive microscopy of P. vivax with parasite density = 250/µL of blood and a rapid negative test for P. falciparum.

ParticipantsNumber: 30

InterventionsPyronaridine (180 mg) + artesunate (60 mg) once a day for 3 days

Chloroquine (155 mg) once a day for 3 days

Outcomes1. Cure rate at Day 14

2. Proportion of patients cured at day 28 and day 42

3. Parasite clearance time

4. Fever clearance time

5. Proportion of patients aparasitaemic on days 1, 2 and 3

6. Adverse events

NotesThis is a conference abstract and no details of either the study or the contact information of the authors are available

van Vugt 2002

MethodsTrial design: Open label RCT

Follow-up: Monitored daily until fever and parasites cleared then weekly to day 42. Clinical examination, symptom questionnaire, malaria film, and hematocrit at each visit.

Adverse event monitoring: At each visit a symptom questionnaire was completed.

ParticipantsNumber: It is unclear whether any participants had P. vivax infection at baseline (1596 were randomized in total)

Inclusion criteria: Weight >10 kg, slide confirmed acute P. falciparum malaria, written informed consent

Exclusion criteria: Pregnancy, not obtunded or vomiting, no other clinical or laboratory signs of severe illness, treatment with mefloquine in the past 63 days

Interventions1. Artesunate plus mefloquine, loose combination

  • AS 4mg/kg once daily for 3 days
  • MQ 15 mg/kg on day 1 and 10 mg/kg on day 2


2. Artesunate plus atavoquone-proguanil

  • AS 4 mg/kg once daily for 3 days
  • Atavoquine 15 mg/kg once daily for 3 days
  • Proguanil 8 mg/kg once daily for 3 days


3. Atavoquone-proguanil

  • Atavoquine 15 mg/kg once daily for 3 days
  • Proguanil 8 mg/kg once daily for 3 days


All doses supervised

Primaquine was not given

Outcomes
  1. P. vivax recurrence by day 42


Not included in the review:

  1. Parasite clearance
  2. P. falciparum at days 42, and 28, PCR adjusted and unadjusted
  3. Gametocyte carriage
  4. Adverse effects (not available for P. vivax patients only)

NotesCountry: Thailand

Setting: Malaria clinics of the Shoklo Malaria Research Unit

Transmission: Low transmission

Resistance: Not stated

Dates: July 1998 to July 2000

Funding: Atavoquine-proguanil was donated by Glaxo-SmithKline. The Wellcome Trust of Great Britain

 
Comparison 1. ACT versus Chloroquine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Parasite clearance4Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Remaining parasitaemic after 24 hours
41652Risk Ratio (M-H, Random, 95% CI)0.42 [0.36, 0.50]

    1.2 Remaining parasitaemic after 48 hours
41648Risk Ratio (M-H, Random, 95% CI)0.18 [0.05, 0.74]

    1.3 Remaining parasitaemic after 72 hours
41648Risk Ratio (M-H, Random, 95% CI)0.08 [0.01, 0.43]

 2 Fever clearance3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Remaining febrile after 24 hours
2990Risk Ratio (M-H, Random, 95% CI)0.55 [0.43, 0.70]

    2.2 Remaining febrile after 48 hours
31390Risk Ratio (M-H, Random, 95% CI)0.53 [0.31, 0.91]

    2.3 Remaining febrile after 72 hours
2985Risk Ratio (M-H, Random, 95% CI)0.60 [0.27, 1.36]

 3 Recurrence of parasitaemia5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 Before day 14
1427Risk Ratio (M-H, Random, 95% CI)2.88 [0.12, 70.22]

    3.2 Before day 28
51622Risk Ratio (M-H, Random, 95% CI)0.58 [0.18, 1.90]

    3.3 After day 28 (primaquine not given)
31066Risk Ratio (M-H, Random, 95% CI)0.57 [0.40, 0.82]

    3.4 After day 28 (primaquine given)
1376Risk Ratio (M-H, Random, 95% CI)0.27 [0.08, 0.94]

    3.5 During full follow-up period (42 or 56 days)
41460Risk Ratio (M-H, Random, 95% CI)0.59 [0.44, 0.78]

 4 Gametocytemia2Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    4.1 On Day 0
2Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.2 On Day 1
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.3 On Day 2
2Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.4 On Day 3
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Serious adverse events51775Risk Ratio (M-H, Random, 95% CI)1.0 [0.14, 7.04]

 
Comparison 2. ACT versus Chloroquine plus Sulfadoxine-pyrimethamine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Parasite clearance1Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Remaining parasitaemic after 24 hours
1195Risk Ratio (M-H, Random, 95% CI)0.22 [0.15, 0.34]

    1.2 Remaining parasitaemic after 48 hours
1195Risk Ratio (M-H, Random, 95% CI)0.09 [0.03, 0.27]

    1.3 Remaining parasitaemic after 72 hours
1195Risk Ratio (M-H, Random, 95% CI)0.17 [0.03, 0.81]

 2 Fever clearance1Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Remaining febrile after 24 hours
1195Risk Ratio (M-H, Random, 95% CI)1.05 [0.75, 1.48]

    2.2 Remaining febrile after 48 hours
1195Risk Ratio (M-H, Random, 95% CI)0.62 [0.31, 1.23]

    2.3 Remaining febrile after 72 hours
1195Risk Ratio (M-H, Random, 95% CI)0.77 [0.29, 2.02]

 3 Recurrence of parasitaemia1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    3.1 Before day 14
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.2 Before day 28
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.3 After day 28
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.4 During full follow-up period (42 days)
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 4 Serious adverse events1209Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 3. ACT versus Quinine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Parasite clearance172Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.19, 21.09]

    1.1 Remaining parasitaemia after 72 hours
172Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.19, 21.09]

 2 Recurrence of parasitaemia1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    2.1 Before day 14
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.2 Before day 28
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.3 After day 28
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.4 During full follow-up period (42 days)
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 
Comparison 4. ACT versus ACT

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Remaining parasitemic after 24 hours5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 DHA-P versus AS+MQ
3120Risk Ratio (M-H, Random, 95% CI)1.18 [0.28, 4.92]

    1.2 DHA-P versus AL6
183Risk Ratio (M-H, Random, 95% CI)0.78 [0.31, 1.94]

    1.3 AS+MQ versus AL6
124Risk Ratio (M-H, Random, 95% CI)1.02 [0.60, 1.72]

    1.4 DHA-P versus AS+SP
195Risk Ratio (M-H, Random, 95% CI)1.35 [0.49, 3.72]

 2 Remaining parasitemic after 48 hours5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 DHA-P versus AS+MQ
3120Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.2 DHA-P versus AL6
183Risk Ratio (M-H, Random, 95% CI)0.44 [0.04, 4.70]

    2.3 AS+MQ versus AL6
124Risk Ratio (M-H, Random, 95% CI)5.13 [0.29, 89.57]

    2.4 DHA-P versus AS+SP
195Risk Ratio (M-H, Random, 95% CI)3.47 [0.14, 83.00]

 3 Remaining febrile after 24 hours1Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 DHA-P versus AL6
183Risk Ratio (M-H, Random, 95% CI)1.39 [0.83, 2.33]

    3.2 DHA-P versus AS+SP
195Risk Ratio (M-H, Random, 95% CI)0.94 [0.64, 1.40]

 4 Remaining febrile after 48 hours1Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 DHA-P versus AL6
183Risk Ratio (M-H, Random, 95% CI)0.63 [0.22, 1.83]

    4.2 DHA-P versus AS+SP
195Risk Ratio (M-H, Random, 95% CI)1.45 [0.41, 5.06]

 5 Recurrent parasitaemia before day 288Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 DHA-P versus AS+MQ
4186Risk Ratio (M-H, Random, 95% CI)0.17 [0.02, 1.45]

    5.2 DHA-P versus AL6
3237Risk Ratio (M-H, Random, 95% CI)0.15 [0.04, 0.58]

    5.3 DHA-P versus AS+AQ
2108Risk Ratio (M-H, Random, 95% CI)0.04 [0.00, 0.73]

    5.4 DHA-P versus AS+SP
177Risk Ratio (M-H, Random, 95% CI)0.32 [0.15, 0.72]

    5.5 AS+MQ versus AL6
256Risk Ratio (M-H, Random, 95% CI)0.06 [0.01, 0.40]

    5.6 AS+MQ versus AS+AQ
134Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    5.7 AL6 versus AS+AQ
128Risk Ratio (M-H, Random, 95% CI)16.06 [1.03, 249.60]

    5.8 AL6 versus AS+SP
172Risk Ratio (M-H, Random, 95% CI)1.06 [0.67, 1.68]

 6 Recurrent parasitaemia after day 288Risk Ratio (M-H, Random, 95% CI)Subtotals only

    6.1 DHA-P versus AS+MQ
4169Risk Ratio (M-H, Random, 95% CI)0.80 [0.58, 1.09]

    6.2 DHA-P versus AL6
3168Risk Ratio (M-H, Random, 95% CI)0.40 [0.11, 1.38]

    6.3 DHA-P versus AS+AQ
295Risk Ratio (M-H, Random, 95% CI)0.54 [0.12, 2.40]

    6.4 DHA-P versus AS+SP
150Risk Ratio (M-H, Random, 95% CI)0.44 [0.14, 1.38]

    6.5 AS+MQ versus AL6
245Risk Ratio (M-H, Random, 95% CI)0.92 [0.61, 1.37]

    6.6 AS+MQ versus AS+AQ
136Risk Ratio (M-H, Random, 95% CI)1.06 [0.72, 1.55]

    6.7 AL6 versus AS+AQ
118Risk Ratio (M-H, Random, 95% CI)1.11 [0.68, 1.80]

    6.8 AL6 versus AS+SP
138Risk Ratio (M-H, Random, 95% CI)0.73 [0.29, 1.84]

 7 Recurrent parasitaemia during full follow-up period (0 to 42 or 63 days)8Risk Ratio (M-H, Random, 95% CI)Subtotals only

    7.1 DHA-P versus AS+MQ
4186Risk Ratio (M-H, Random, 95% CI)0.17 [0.02, 1.45]

    7.2 DHA-P versus AL6
3237Risk Ratio (M-H, Random, 95% CI)0.15 [0.04, 0.58]

    7.3 DHA-P versus AS+AQ
2108Risk Ratio (M-H, Random, 95% CI)0.04 [0.00, 0.73]

    7.4 DHA-P versus AS+SP
177Risk Ratio (M-H, Random, 95% CI)0.32 [0.15, 0.72]

    7.5 AS+MQ versus AL6
256Risk Ratio (M-H, Random, 95% CI)0.06 [0.01, 0.40]

    7.6 AS+MQ versus AS+AQ
134Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    7.7 AL6 versus AS+AQ
128Risk Ratio (M-H, Random, 95% CI)16.06 [1.03, 249.60]

    7.8 AL6 versus AS+SP
172Risk Ratio (M-H, Random, 95% CI)1.06 [0.67, 1.68]

 
Comparison 5. DHA-P versus alternative ACTs

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Recurrent parasitaemia - settings described as low transmission4Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Before day 28
4239Risk Ratio (M-H, Random, 95% CI)0.12 [0.02, 0.63]

    1.2 After day 28 - without primaquine
4187Risk Ratio (M-H, Random, 95% CI)0.80 [0.59, 1.09]

    1.3 During full follow-up period (42 to 63 days) - without primaquine
4201Risk Ratio (M-H, Random, 95% CI)0.76 [0.56, 1.02]

 2 Recurrent parasitaemia - settings described as high transmission3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Before day 28
3334Risk Ratio (M-H, Random, 95% CI)0.20 [0.08, 0.49]

    2.2 After day 28 - with primaquine
2179Risk Ratio (M-H, Random, 95% CI)0.21 [0.10, 0.46]

    2.3 After day 28 - without primaquine
166Risk Ratio (M-H, Random, 95% CI)0.40 [0.14, 1.10]

    2.4 During full follow-up period (42 days) - with primaquine
2210Risk Ratio (M-H, Random, 95% CI)0.16 [0.08, 0.32]

    2.5 During full follow-up period (42 days) - without primaquine
1108Risk Ratio (M-H, Random, 95% CI)0.42 [0.24, 0.72]

 
Summary of findings for the main comparison. Summary of findings: ACT versus CQ

Artemisinin-based combination therapy compared with chloroquine for uncomplicated P. vivax malaria

Patient or population: Adults and children with uncomplicated P. vivax malaria

Settings: Endemic areas where chloroquine is still an effective treatment for the first 28 days

Intervention: Artemisinin-based combination therapy

Comparison: Chloroquine

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)

Assumed riskCorresponding risk

ChloroquineACT

Remaining parasitaemic at 24 hours52 per 10022 per 100
(19 to 26)
RR 0.42
(0.36 to 0.50)
1652
(4 studies1)
high2,3,4,5

Remaining febrile after 24 hours29 per 10016 per 100
(12 to 20)
RR 0.55
(0.43 to 0.7)
990
(2 studies6)
moderate2,4,5,7

Effective treatment of the blood stage parasite

As assessed by: Recurrent parasitaemia before day 28
3 per 1002 per 100
(1 to 6)
RR 0.58
(0.18 to 1.90)
1622
(5 studies8)
high2,3,4,9

Post-treatment prophylaxis

As assessed by: Recurrent parasitaemia between day 28 and day 42/56/63
With primaquineRR 0.27
(0.08 to 0.94)
376

(1 study10)
low11,12

6 per 1002 per 100
(0 to 6)

Without primaquineRR 0.57
(0.40 to 0.82)
1066
(3 studies13)
moderate3,5,14

40 per 10023 per 100
(16 to 33)

Serious adverse events0 per 1000 per 100
(0 to 2)
RR 1
(0.14 to 7.04)
1775
(5 studies8)
high2,3,4,9

*The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. 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).

CI: Confidence interval; RR: Risk ratio; ACT: artemisinin-based combination therapy.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Awab 2010 AFG (Afghanistan), Kolaczinski 2007 AFG (Afghanistan), Poravuth 2010 ASIA (multi-site), and Phyo 2011 THA (Thailand).
2 No serious study limitations: Awab 2010 AFG , Poravuth 2010 ASIA and Phyo 2011 THA adequately concealed allocation, Kolaczinski 2007 AFG did not, and Krudsood 2007 THA did not adequately describe allocation concealment.
3 No serious inconsistency: The findings of all the trials are consistent.
4 No serious indirectness: The findings of these three studies can reasonably be applied to other settings with similar transmission and resistance patterns.
5 No serious imprecision: The finding is of a clinically and statistically significant benefit with ACTs.
6 Awab 2010 AFG (Afghanistan) and Poravuth 2010 ASIA (multi-site).
7 Downgraded by 1 for serious inconsistency: The two additional trials (Kolaczinski 2007 AFG; Krudsood 2007 THA) report that fever clearance was not significantly different between the groups.
8 Awab 2010 AFG (Afghanistan), Kolaczinski 2007 AFG (Afghanistan), Krudsood 2007 THA (Thailand), Poravuth 2010 ASIA (multi-site), and Phyo 2011 THA (Thailand).
9 No serious imprecision: The finding is of no clinically important difference between ACTs and CQ. Although the 95% CI around the relative effect is very wide, recurrent parasitaemia before day 28 and serious adverse events were very rare and consequently the 95% CI around the absolute effect is very narrow.
10 Poravuth 2010 ASIA.
11 Downgraded by 1 for serious indirectness: Poravuth 2010 ASIA delayed primaquine until day 28 and so the course will not have completed until day 42 the last day of the trial. The effect seen may not be present if primaquine is given in the usual way (on completion of 3 days of ACT). The period of follow-up is also not long enough to fully assess this effect, the inevitable relapse may simply be delayed, rather than a reduction in clinical episodes.
12 Downgraded by 1 for serious imprecision: Although statistically significant the 95% CI is wide and includes the possibility of no appreciable benefit.
13 Awab 2010 AFG continued until day 56, Kolaczinski 2007 AFG to day 42 and Phyo 2011 THA to day 63 (Primaquine was administered to the participants after day 63).
14 Downgraded by 1 for serious indirectness: Both studies are from Afghanistan Awab 2010 AFG and Kolaczinski 2007 AFG where primaquine is not recommended due to a high prevalence of G6PD. The period of follow-up is also not long enough to fully assess this effect, the inevitable relapse may simply be delayed, rather than a reduction in clinical episodes.
 
Summary of findings 2. Summary of findings: DHA-P versus alternative ACTs in high transmission settings with known CQ resistance

Dihydroartemisinin-piperaquine compared with alternative artemisinin-based combination treatments for uncomplicated P. vivax malaria

Patient or population: Adults and children with uncomplicated P. vivax malaria

Settings: Settings with high transmission of P. vivax (chloroquine resistance is also reported as high)

Intervention: Dihydroartemisinin-piperaquine

Comparison: Alternative ACTs

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)

Assumed riskCorresponding risk

Alternative ACTDHA-P

Effective treatment of the blood stage parasite

As assessed by: Recurrent parasitaemia before day 28
35 per 1007 per 100
(3 to 17)
RR 0.20
(0.08 to 0.49)
334
(3 studies1,2)
moderate3,4,5,6

Post-treatment prophylaxis

As assessed by: Recurrent parasitaemia between day 28 and 42
With primaquineRR 0.21
(0.1 to 0.46)
179
(2 studies2)
low6,7,8,9

34 per 1007 per 100
(3 to 16)

Without primaquineRR 0.40
(0.14 to 1.10)
66
(1 study1)
very low10,11,12

33 per 10013 per 100
(5 to 37)

*The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. 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).

CI: Confidence interval; RR: Risk ratio; DHA-P: dihydroartemisinin-piperaquine; ACT: Artemisinin-based combination therapy.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Karunajeewa 2008 PNG (Papua New Guinea).
2 Hasugian 2007 IDN and Ratcliff 2007 IDN (Indonesia).
3 No serious risk of bias: Allocation was adequately concealed in these studies to be considered at low risk of bias.
4 Downgraded by 1 for serious inconsistency: There was some clinical heterogeneity between trials. DHA-P did not perform as well in Papua New Guinea as it has elsewhere, however it was still superior to AL6 and AS+SP.
5 No serious indirectness: Studies include adults and children and were conducted in areas where transmission is high and chloroquine resistance is well documented.
6 No serious imprecision: Both limits of the 95% CI suggest an appreciable clinical benefit with DHA-P.
7 Downgraded by 1 for serious risk of bias: Losses to follow-up were high (> 20% at this time-point).
8 No serious inconsistency: Statistical heterogeneity was low.
9 Downgraded by 1 for serious indirectness: Ratcliff 2007 IDN delayed the administration of Primaquine until day 28 and so the course will not have been completed until the last day of the trial. Hasugian 2007 IDN offered unsupervised primaquine to all participants on completion of their ACT, this reflects normal practice but it is not clear how many participants completed their course. The period of follow-up is also not long enough to fully assess this effect, the inevitable relapse may simply be delayed, rather than a reduction in clinical episodes.
10 Downgraded by 1 for serious risk of bias: Losses to follow-up were high (>20% at this time-point).
11 Downgraded by 1 for serious indirectness: Only one study has assessed this outcome. Recurrent parasitaemia was higher with all three ACTs than seen elsewhere. This trial is therefore not easily extrapolated to other sites.
12 Downgraded by 1 for serious imprecision: The 95% CI of the effect estimate is wide and includes an important clinical benefit and no difference between the treatments.
 
Table 1. Detailed search strategy

Search set Search terms used for all databases1

1vivax

2Arte*

3Dihydroarte*

42 or 3

51 and 4

6(search terms for RCTs)

75 and 6

8Limit 7  to Human

 1 Cochrane Infectious Disease Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; and LILACS.
 
Table 2. Median parasite clearance times

Study IDComparisonMedian parasite clearance time (range)P value

ACTCQ

Krudsood 2007 THAAL6 versus CQ41.6 hrs55.8 hrs< 0.01

Poravuth 2010 ASIAAS-Py versus CQ23.0 hrs (7.0 to 55.9)32.0 hrs (7.5 to 63.9)< 0.0001

 
Table 3. Fever clearance times

Study IDComparisonMedian fever clearance time (range)P value

ACTCQ

Krudsood 2007 THAAL6 versus CQ21.8 hrs25.3 hrs0.12

Poravuth 2010 ASIAAS-Py versus CQ15.9 hrs23.8 hrs0.0017