Abstract
Background
Using a pilot system we have categorised this review as: Historical question ‐ no update intended. Please see "Published notes" section of the review for more details.
Since 2001, the World Health Organization has recommended that antimalarial drug combinations be used for uncomplicated falciparum malaria and that monotherapy should no longer be used. For the most up‐to‐date information on malaria combination treatment, please refer to Sinclair D, Zani B, Donegan S, Olliaro P, Garner P. Artemisinin‐based combination therapy for treating uncomplicated malaria. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD007483. DOI: 10.1002/14651858.CD007483.pub2.
Amodiaquine has been widely used to treat malaria. Fatal adverse reactions have been reported in adults taking it for prophylaxis. This has led some authorities to suggest it is withdrawn as a first line treatment for malaria.
Objectives
To compare amodiaquine with chloroquine or sulfadoxine‐pyrimethamine for treating uncomplicated Plasmodium falciparum malaria.
Search methods
We searched the Cochrane Infectious Diseases Group specialized trials register (February 2003), The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2003), MEDLINE (1966 to February 2003), EMBASE (1980 to December 2002), LILACS (February 2003). We contacted researchers in the field and pharmaceutical companies.
Selection criteria
Randomised and quasi‐randomised trials.
Data collection and analysis
Two reviewers independently extracted data and assessed trial quality.
Main results
56 studies included, mostly from Africa. Treatment allocation was adequately concealed in three trials, and unclear or inadequate in the remainder. Amodiaquine was more effective than chloroquine for parasite clearance (day 7, Peto odds ratio 4.42 (95% confidence interval 3.65 to 5.35); day 14, Peto odds ratio 6.44 (95% confidence interval (CI) 5.09 to 8.15). Comparisons with sulfadoxine/pyrimethamine were more mixed, with sulfadoxine/pyrimethamine more effective on day 28 (Peto odds ratio 0.41; 95% CI 0.28 to 0.61). No significant difference for adverse events was observed between amodiaquine and chloroquine and sulfadoxine/pyrimethamine. Reported adverse effects were minor or moderate. No life threatening events were detected.
Authors' conclusions
There is evidence to support the continued use of amodiaquine to treat uncomplicated malaria, although local drug resistance patterns need to be considered. Monitoring for adverse events should continue.
This review summarizes trials up to 2003. For the reasons in the 'What's new' section, this review will no longer be updated.
23 April 2019
No update planned
Intervention not in general use or been superseded
Since 2011, the WHO has recommended that monotherapy should not be used. For the most up‐to‐date information on malaria combination treatment, see: Sinclair 2009 https://doi.org/10.1002/14651858.CD007483.pub2
Plain language summary
Amodiaquine for treating malaria
Using a pilot system we have categorised this review as: Historical question ‐ no update intended. Please see "Published notes" section of the review for more details.
Since 2001, the World Health Organization has recommended that antimalarial drug combinations be used for uncomplicated falciparum malaria and that monotherapy should no longer be used.
Background
Amodiaquine (AQ) is a 4‐aminoquinoline, similar to chloroquine (CQ), that has been used widely to treat and prevent malaria. AQ is a cheap alternative to CQ, and is available in several countries, some with local production facilities. It is more palatable than CQ and therefore easier to administer to children. It has also been suggested that it may be a less toxic alternative to sulphadoxine‐pyrimethamine (SP) in people infected with HIV in Sub Saharan Africa (Coopman 1993). It is also used in combination with the antimalarial drugs artesunate and SP. These combinations are the subject of other Cochrane Reviews (IASG 2002; MacIntosh 2002).
Amodiaquine was first added to the World Health Organization (WHO) Essential Drugs List (EDL) in 1977. In 1979, the committee decided to delete it from the List due to its similarity with CQ. However, it was quickly reinstated in the same year (WHO 2002). In the mid 1980s, fatal adverse drug reactions were described in travellers using AQ for prophylaxis (Hatton 1986; Neftel 1986). As a result, the manufacturer (Parke‐Davis) modified the labelling and withdrew prophylaxis as an indication, while, in 1988, the WHO deleted it from the EDL and prevented its use in malaria control programmes (WHO 1990).
The WHO'srecommendations confused policy and practice. Several countries banned its use altogether, whilst others have continued to use the drug as first line treatment for uncomplicated malaria ‐ either giving it alone or in combination with other drugs. In the light of this, the 19th Expert Committee on Malaria, held in 1993, modified their statement to say that "amodiaquine could be used for treatment if the risk of infection outweighs the potential for ADRs [adverse drug reactions]", but still did not recommend AQ as first line treatment (WHO 1993).
This Cochrane Review, first published in 1996, compares the effectiveness of AQ, CQ and SP for treating uncomplicated falciparum malaria. The 1996 version concluded that AQ was a valuable drug and supported its continued use for the treatment of uncomplicated malaria with the proviso that, due to the partial cross‐resistance with CQ, research must continue into both its effectiveness and safety. These findings led the WHO to modify its recommendations and reinstate AQ as an option for treating falciparum malaria (WHO 1997).
Objectives
To compare amodiaquine with chloroquine and sulphadoxine‐pyrimethamine for treating uncomplicated malaria in adults and children.
Methods
Criteria for considering studies for this review
Types of studies
Randomized and quasi‐randomized controlled trials conducted during and after 1980.
The year restriction takes account of the changing patterns of resistance development to antimalarial drugs, which can affect the treatment outcome.
Types of participants
Individuals with uncomplicated falciparum malaria infection. Defined as either: (1) fever or a history of fever, accompanied by P. falciparum parasitaemia ("symptomatic") or; (2) P. falciparum parasitaemia detected through blood survey and no fever ("asymptomatic").
Types of interventions
Intervention
Amodiaquine (AQ).
Control
Chloroquine (CQ) or sulphadoxine‐pyrimethamine (SP).
Types of outcome measures
Primary
Parasitological conversion, defined as conversion from a positive blood smear at baseline to a negative smear for P. falciparum at day 7, 14, or 28.
Secondary
Time to sustained parasite clearance (restricted to days 0 through 7).
Adverse events
Adverse events that are: 1. Fatal, life threatening, or require hospitalization; 2. Result in the discontinuation of treatment.
Search methods for identification of studies
We attempted to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress).
We used the following search terms for all trial registers and databases: malaria; amod*.
We searched the Cochrane Infectious Diseases Group specialized trials register for relevant trials up to February 2003. Full details of the Cochrane Infectious Diseases Group methods and the journals hand searched are published in The Cochrane Library in the section on Collaborative Review Groups.
We searched the Cochrane Central Register of Controlled Trials, published in The Cochrane Library (Issue 1, 2003). This contains mainly reference information to randomized controlled trials and controlled clinical trials in health care.
We searched the following electronic databases using the topic search terms in combination with the search strategy developed by the Cochrane Collaboration and detailed in the Cochrane Reviewers' Handbook (Clarke 2003); MEDLINE (1966 to February 2003); EMBASE (1980 to December 2002); and LILACS (La Literatura Latinoamericana y del Caribe de Informacion en Ciencias de Salud) www.bireme.br; accessed February 2003.
We contacted organizations, individual researchers working in the field, and pharmaceutical companies for unpublished and ongoing trials.
We sought unpublished and raw data by extensive liaison with experienced researchers in the field, and by requests to the pharmaceutical companies manufacturing the product. In view of the large amount of unpublished studies known to exist on amodiaquine, we contacted key researchers known to the World Health Organization and set up meetings, during which we explained the objectives of the systematic review, sought and collected data, reviewed and discussed the results.
We also checked the reference lists of all trials identified by the above methods.
Data collection and analysis
Selection of studies
The main author scanned the results of the literature search for potentially relevant trials. We retrieved the full articles for all trials thought to be potentially relevant. Three people independently assessed the potentially relevant trials for inclusion in the review.
Data extraction and management
The data were extracted by two reviewers independently, using a data extraction form. Where there were disagreements, these were resolved by discussion. The data were entered into Review Manager 5 by the main reviewer, and checked by Ms Mussano for all editions of the review. We contacted the authors to obtain additional data, unpublished components of studies, and to clarify details of the methods used.
Assessment of risk of bias in included studies
We assessed the methodological quality of each included trial with respect to the generation of allocation sequence, allocation concealment, blinding, and loss to follow up.
Data synthesis
We analysed data using Review Manager 5.
Whenever possible, we contacted authors and asked them to help in the production of this review by reanalysing their data and/or to provide individual patient data to reanalyse the data using pre‐specified outcome measures. In cases where the authors provided crude data, we entered these into a statistical package for analysis.
To minimize selection bias and the effect of participant attrition, we calculated the proportion of parasitological conversion from the total number of participants reportedly "evaluable" on day 7, 14, and 28. "Success" was a participant who was assessed and had a negative smear, while "failures" were participants who were either assessed and had a positive smear, or were lost to follow up. We calculated the Peto odds ratio and 95% confidence intervals (log odds, Peto) for individual studies and in meta‐analysis.
We calculated the time to sustained parasitological clearance, for individual studies and the pooled data, using the Kaplan‐Meier method. We created two pools of data, dependent on the time points available for analysis, for trials using chloroquine as the comparator drug.Pool A had 6 time points (days 0, 1, 2, 3, 5, and 7); and pool B had assessments only on days 0, 1, 2, and 7. For trials of comparisons of amodiaquine (AQ) and sulphadoxine‐pyrimethamine, we used 5 time points (day 0, 1, 2, 3, and 7). We used the log‐rank test to compare the results in the AQ and comparator arms. Parasite clearance times, reported in the individual papers, measure the time to clearance of only those participants who were eventually cured, and exclude people that are treatment failures. However, in the various analyses described above, we considered all participants with a baseline positive smear regardless of whether they achieved parasite clearance or not.
Results
Description of studies
[See Appendices]
Eligibility
Of the 101 studies identified, 56 met the inclusion criteria. Where articles or communications reported more than one study; each study has been individually referenced (Appendix 1).
Publication status and language
The eligible studies included both published (47) and unpublished (9) reports. We also analyzed the single patient data where this was made available by the trialists or Parke‐Davis (18 studies, published and unpublished). Single patient data accounted for approximately one fourth of total amodiaquine (AQ) participants in the studies compared with chloroquine (CQ) and approximately half of those comparing AQ with sulphadoxine‐pyrimethamine (SP).
The studies were written in English (34); French (20); Portuguese (1); and Spanish (1).
Study location
The majority of studies were conducted between 1983 and 2001 in the following Africa countries (Appendix 2): Burkina Faso (1); Cameroon (12); Congo (4); Equatorial Guinea (1); Gabon (2); Gambia (1); Ivory Coast (1); Kenya (17); Madagascar (2); Malawi (1); Mozambique (1); Nigeria (3); Senegal (3); Tanzania (2); and Uganda (1). Studies were also conducted in China (1); Brazil (1); Colombia (1); and the Philippines (1).
Participants
A total number of 2429 participants were followed up in the 56 studies (Appendix 3). Comparisons of AQ with CQ were made in 41 studies (34 involving symptomatic participants and 7 involving asymptomatic participants); and comparisons of AQ with SP were made in 19 studies (all with symptomatic malaria). Appendix 1 shows the studies included.
The number of patients followed up decreases with the length of follow up, which ranges from 7 to 28 days (Appendix 2). This is due to the combined effect of fewer studies following up participants for longer periods and increasing dropout rates. Some studies only reported results at the end of the follow‐up period, that is, with no results available at intermediate times. Appendix 5 summarises the evaluable patients.
Interventions
AQ was administered, at doses ranging from 15.6 to 35 mg/kg, over three days. It was compared to CQ administered at doses ranging from 25 to 35 mg/kg over three days and SP (fixed ratio sulfadoxine:pyrimethamine of 1:20) administered as standard single dose of 25 mg of sulfadoxine (Appendix 2).
Outcomes
All studies reported on the outcome of parasitological conversion (Appendix 4). Eighteen of these studies sought adverse outcomes, either clinical or laboratory.
As some studies conducted multiple comparisons and varied in their reporting of results at day 7, 14 and/or 28, the breakdown for individual comparisons do not add up to these totals. Considering all parasitological outcomes, 1538 and 1166 AQ symptomatic patients were reported for the comparisons with CQ and SP, respectively. In the comparator arms, 101 asymptomatic infections and 1538 uncomplicated malaria cases were treated with CQ, while 1158 cases were treated with SP (Appendix 4).
Risk of bias in included studies
Generation of allocation sequence
Six trials specified the method of generating the allocation sequence; 22 mentioned randomization but were not specific about the method used; and 28 used other methods that appeared to be unbiased.
Allocation concealment
Allocation was adequately concealed in three trials, and was either not clearly described or unconcealed in the remaining 53.
Blinding
With the exception of one trial in the Philippines and one in China, no study was blinded.
Loss to follow up
Nine studies used an intention‐to‐treat analysis with few losses to follow up. Eight trials reported exclusion levels of less than 10%, while in the remaining 23 trials, there was either no reporting of exclusions, or exclusions were greater than 10%.
Quality of number generation and analysis was better in the three trials with adequate concealment of allocation. There were 8 trials that scored low on all three quality parameters.
Diagnostic procedures varied between centres.In most, patients were admitted on the basis of thick and thin blood film results. No quality control of slide reading was mentioned in any of the studies. In Kenya, an observer checked 10% of slides without knowledge of the first reading.
Effects of interventions
Parasitological outcomes
1. Amodiaquine versus chloroquine
In 34 studies, a total of 1538 participants receiving amodiaquine (AQ) were compared with 1166 participants receiving chloroquine (CQ). These studies were conducted at 33 different sites, 30 of them in Africa (accounting for 96% of the AQ participants), predominantly Kenya and Cameroon.
a. Parasitological conversion
i. Symptomatic participants
Twenty seven studies reported parasitological conversion. On day 7, a total of 1230 participants received AQ while 1234 received CQ. The parasitological conversion success rate ranged from 33% to 100% for AQ and from 9 to 100% for CQ. The meta‐analysis shows that, on day 7, those receiving AQ had a statistically significantly higher level of parasitological conversion than those receiving CQ (Peto odds ratio (Peto OR) 4.42; 95% confidence interval (CI) 3.65 to 5.35). In this analysis, participants with a positive smear, or no data, on day 7 were deemed 'failures'.
One thousand six hundred and ten participants (802 receiving AQ; and 808 receiving CQ) were followed up to day 14 . The parasitological conversion success rate ranged from 15% to 100% for AQ and from 10 to 93% for CQ. Participants receiving AQ experienced statistically significantly higher levels of parasitological conversion (Peto OR 6.44; 95% CI 5.09 to 8.15).
Only three studies reported results on day 28.Two hundred and fifty four participants received AQ while 248 received CQ. The parasitological conversion success rate ranged from 25% to 95% for AQ and from 24% to 58% for CQ. As for day 7 and day 14, participants receiving AQ experienced statistically significantly higher levels of parasitological conversion than those receiving CQ (Peto OR 3.62; 95% CI 2.49 to 5.29).
There was significant heterogeneity in all comparisons, as may be anticipated with varying age groups and malaria endemicities.
The Peto ORs for days 7, 14, and 28 should not be compared directly for two reasons: (1) participants who were not available for follow up at day 14 were simply excluded in most cases and; (2) some studies reported results on only one of the three visits.
No variation was observed when the analysis was restricted to the African studies. The Peto OR was 4.94 (95% CI 4.06 to 6.02) at day 7; 6.86 (95% CI 5.38 to 8.75) at day 14; and 3.62 (95% CI 2.49 to 5.29) at day 28.
ii. Asymptomatic participants
An additional nine studies tested AQ against CQ in people who were asymptomatic but found to be parasitaemic at cross sectional blood survey. In these studies, 543 participants received AQ and were compared to 586 participants who received CQ. AQ recipients experienced statistically significantly higher levels of parasitological conversion at day 7 than CQ recipients (Peto OR 3.64; 95% CI 2.65 to 5.00).
b. Time to sustained parasite clearance
i. Symptomatic participants
Time to sustained parasite clearance (day 0 through 7) was calculated for participants with 6 data points (pool A: day 0, 1, 2, 3, 5, and 7) or 4 data points (pool B: day 0, 1, 2, and 7). Pool A comprised 3 studies with 108 AQand 109 CQrecipients, of whom 99 and 78, respectively, achieved a sustained parasitological conversion. Pool B (11 studies) included 519 AQand 509 CQrecipients, with 478 and 307 successes, respectively. The time to parasite clearance was significantly shorter for AQ in both analyses (log to rank p = 0.0025 and 0.0001, respectively).
ii. Asymptomatic participants
No data.
c. Adverse events
No difference in event rate was seen between the two groups (Peto OR 0.85, 95%CI 0.50 to 1.42).
2. Amodiaquine versus sulphadoxine‐pyrimethamine
Sulphadoxine‐pyrimethamine (SP) was used as comparator in 19 studies (16 from Africa), enrolling 1166 amodiaquine (AQ) and 1158 SP recipients ("evaluable patient population").
a. Parasitological conversion
i. Symptomatic participants
Parasitological outcome was reported by 14 studies on day 7 and 14; five of these studies only reported results for day 14. Seven studies reported results on day 28.
On day seven, 824 participants received AQ while 818 received SP. The parasitological conversion success rate ranged from 42% to 100% for AQ and from 67% to 100% for SP. The graphical display shows no obvious trend, and meta‐analysis did not demonstrate a statistically significant difference between AQ and SP for parasitological conversion (Peto OR 0.73; 95% CI 0.53 to1.01).
On day 14, 786 participants received AQand 821 received SP. The parasitological conversion success rate ranged from 58% to 100% for AQ and from 65% to 100% for SP. As for day 7, the graphical display showed no trend and there was no statistically significant difference between AQ and SP for parasitological conversion (Peto OR 0.86; 95% CI 0.64 to 1.14).
By day 28, 667 participants remained in the analysis was (345 receiving AQ;and 322 receiving SP). The parasitological conversion success rate ranged from 48% to 92% for AQ and from 54% to 100% forCQ. SP recipients had a statistically significantly higher level of parasitological conversion than AQ recipients (Peto OR 0.41; 95% CI 0.28 to 0.61).
The Peto ORs remained almost unchanged when the analyses were restricted to studies conducted in Africa, or to Africa after 1990 (when the use of SP started, particularly in the East and the South of the continent). In this latter case, the Peto ORs on day 7, 14, and 28 were 0.81 (95% CI 0.57 to 1.15); 0.92 (95% CI 0.68 to 1.23); and 0.58 (95% CI 0.37 to 0.91), respectively.
ii. Asymptomatic participants
Two of the AQ versus CQ studies (above), on asymptomatic P.falciparum infected participants, also had an SP arm. They enrolled 143 participants to receive AQ and 122 to receive SP, with a success rate on day 7 of 93% and 99%, respectively.
b. Time to sustained parasite clearance
i. Symptomatic participants
The time to sustained parasitological clearance (days 0 to 7) was similar in the two groups. Participants had parasitological assessments on day 0, 1, 2, 3, and 7. Overall, 385 of the 424 participants receiving AQ, and 401 of the 451 participants receiving SP, reached the endpoint and remained negative until day 7 (log to rank p value = 0.27).
ii. Asymptomatic participants
No data available.
c. Adverse effects
Three studies reported on this, with no obvious difference between the two groups (Peto OR 1.68, 95%CI 0.84 to 3.38).
Results are summarised in Appendix 6.
Adverse events were reported for 52 AQ recipients (8.8%), 36 CQ recipients (8.8%), and 15 SP recipients (14.3%). The most commonly reported adverse events were gastrointestinal adverse events (nausea and vomiting) and pruritus. The adverse events were reportedly minor and moderate; no serious or life‐threatening adverse events were reported among AQ recipients.
No statistically significant difference was observed in the incidence of adverse events between AQ and CQ recipients (Peto OR 0.85; 95% CI 0.50 to 1.42) or AQ and SP recipients (Peto OR 1.68; 95% CI 0.84 to 3.38).
A complete biochemical and haematological evaluation was performed for the 62 AQ and 59 CQrecipients recruited to a study in Ivory Coast. No difference was observed between the two groups. Neutrophil counts on thick smear were available for 191 AQ, 22 CQ, and 116 SP recipients from Kenya. Paired observations of neutrophil counts on day 14 (compared to baseline values of Ivory Coast and Kenya patients) showed no significant change.
A systematic review of prospective observational and experimental studies of adverse events is currently under way (MacLehose H, Klaes D, Garner P. Amodiaquine: a systematic review of adverse events [2003] (unpublished document)). This review will include additional studies to those reported in this Cochrane Review. The results of this review are available on http://archives.who.int/eml/expcom/expcom13/Amodiaquine‐adv‐events.pdf. We will update the Cochrane Review with a summary derived from the systematic review of adverse events in subsequent issues of the Cochrane Library.
Discussion
Some of the methodological deficiencies of articles and trials have inevitably led to a bias in the analyses. Most articles report data only on the patients deemed "evaluable" as per the protocol, usually those who completed the scheduled study period (7, 14, or 28 days). As no details were given on the "eligible" patients, and those prematurely discontinued, withdrawn, or lost to follow to up, no true intent‐to‐treat analysis could be performed here. Obtaining raw data has partially rectified the problem, although a selection bias still remains in favour of sensitivity. In contrast, the criteria adopted in the analysis of efficacy (that is, missing data counted as failures) will introduce a bias toward resistance. In fact, non‐attendees were shown to do well in an ad‐hoc study in Kenya (C.Nevill, unpublished). The availability of data to reanalyze has led us to identify two populations, the "evaluable" patients, and those actually assessed at each target visit. The denominator did not vary substantially, though, and nor did the level of significance of the comparisons in the sets of patients.
The data are mainly from Africa (Eastern, Central, and Western countries) and ,although a wide range of malaria epidemiological patterns and levels of drug resistance are represented, care should be taken in transposing these results elsewhere. In this review, amodiaquine (AQ) was found to be significantly more effective than chloroquine (CQ) in clearing parasites. With respect to sulphadoxine‐pyrimethamine (SP), no difference in parasitological outcomes was observed within 7 days of study.However, SP showed superiority during longer‐term follow to up. This finding is not unexpected owing to the long half life of SP. Whether the difference observed is due to recrudescent parasites, or to re‐infections, cannot be verified. As reported previously, an improvement in symptomatic amelioration was apparent with AQ. This could be ascribed to the anti‐inflammatory/antipyretic effect of the aminoquinolines.
Based on the results of this review, AQ (when administered at a dose of up to 35 mg/kg, over 3 days) appears to be no more toxic than CQ or SP when used for treating adults and children with uncomplicated falciparum malaria. Under these conditions of use, and within the limitations of the sample size, no severe, life‐threatening or fatal adverse reaction occurred.
Location and year of study are potential confounders particularly for the comparison with SP. The efficacy of this drug is known to decline with use, due to the selection of parasites with increasing numbers of mutations in their genome associated with resistance.
After oral intake, AQ is rapidly and extensively metabolised to a pharmacologically active metabolite, desethylamodiaquine. Both AQ and desethylamodiaquine are chemically unstable in aqueous solutions, and undergo transformation yielding a protein‐arylating quinone imine (Maggs 1988). The mechanism of toxicity of AQ seems not to be related to direct toxicity of the parent compound or metabolites in bone marrow cell precursors (Winstanley 1990), but rather to the immunogenic properties of the quinone imine (Clarke 1990). It is still unclear why, while most people exposed would have antidrug antibody, only very few people suffer from organ specific toxicity.
So far, serious and life‐threatening adverse drug reactions have been described only during prophylaxis. Based on reported rates, the risk of serious adverse drug reactions associated with the prophylactic use of AQ can be estimated to be approximately 1:2,100 treatments for agranulocytosis; 1:15,500 for hepatotoxicity; and 1:30,000 for aplastic anaemia, with a total case fatality rate of 1:15,650 (Phillips‐Howard, personal communication). The risk of fatal adverse drug reactions to AQ is in the same order of magnitude to that to SP.
Thus, AQ treatment appears to be safer than AQ prophylaxis.
Authors' conclusions
Implications for practice.
This review has collected convincing evidence of amodiaquine (AQ) superiority over chloroquine (CQ), even in areas with considerable CQ resistance. Clearly, therefore, there is a role for AQ in areas with CQ resistance although the lifespan of that role may be curtailed by partial AQ cross resistance with CQ.
The comparison with sulphadoxine‐pyrimethamine (SP) is potentially more important in view of the value of low cost antimalarial drugs and the concerns around the lifespan of long half‐life sulfadrugs after introduction for wide use in sub‐Saharan Africa. While the faster symptomatic recovery with AQ would not necessitate concurrent antipyretics, the longer protection induced by SP may prove a hazard long‐term as it could encourage the selection of resistant parasites.
This review makes the most comprehensive attempt to date to identify all published and unpublished trials relevant to the inclusion criteria. Another review (A. Rietveld and P. Trigg, unpublished data), using a different methodology, also assessed the World Health Organisations (WHO) recommendation to no longer use AQ for treatment in malaria control programmes. This review was more prudent than practical, particularly in light of the limited availability of alternative affordable antimalarial drugs. When CQ, AQ, and SP are no longer effective, the next antimalarial drugs in line cost at least 7 to 60 times as much (A.Rietveld, personal communication). This places a full treatment course financially out of reach of many patients.
In terms of adverse events, this review of Randomised Controlled Trials (RCTs) has not identified a problem. It is apparent that serious and life threatening adverse drug reactions have been described only during prophylaxis in case reports.
Implications for research.
The review supports the continued use of AQ in the treatment of uncomplicated malaria, with the proviso that there is partial cross resistance between CQ and AQ, and that monitoring of effectiveness, as well as surveillance for evidence of toxicity, must continue.
What's new
| Date | Event | Description |
|---|---|---|
| 10 August 2011 | Amended | Classification added; description included in "Published notes" section of review |
| 10 August 2011 | Review declared as stable | Since 2001, the WHO has recommended that monotherapy should not be used. For the most up‐to‐date information on malaria combination treatment, please see: Sinclair D, Zani B, Donegan S, Olliaro P, Garner P. Artemisinin‐based combination therapy for treating uncomplicated malaria. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD007483. DOI: 10.1002/14651858.CD007483.pub2. |
History
Protocol first published: Issue 1, 1995 Review first published: Issue 2, 1996
| Date | Event | Description |
|---|---|---|
| 5 August 2009 | Amended | Tables 1 to 6 for this review formerly available on the Infectious Diseases' web site ‐ http://cidg.cochrane.org/en/related_reviews.html have been added to the Appendix of the review as Appendices 1 to 6. |
| 12 February 2009 | Amended | Contact details updated |
| 23 September 2008 | Amended | Converted to new review format with minor editing. |
| 25 August 2005 | Amended | Since 2001 the World Health Organization has recommended that single‐agent treatment of uncomplicated falciparum malaria should be replaced with antimalarial drug combinations. This recommendation is supported by evidence generated by an individual patient data (IPD) meta‐analysis of randomized studies. As a consequence, amodiaquine should no longer be used alone. Whether amodiaquine is effective and the degree of parasite resistance, in a given setting, is important now only to predict whether a combination including amodiaquine should be tested in that location. |
| 27 August 2003 | Amended | EMBASE search date corrected. |
| 28 February 2003 | Amended | Title modified, and most review sections edited. |
| 4 February 2003 | New search has been performed | New studies found and included or excluded. |
| 3 September 1996 | Amended | Several review sections edited. |
Notes
2011, Issue 9: The Cochrane Infectious Diseases Group are piloting a system to indicate whether the question is currently relevant, and the status of the review with regards to being up to date.
For relevance, we classify reviews into:
historical question, where an intervention or policy has been superseded by new medical developments (such as a new drug),
current question, which are still relevant to current policy or practice.
For status, we have three categories, with an explanation after each: “up to date”; “update pending”; “no update intended”.
For this review, we have categorised the review as: Historical question ‐ no update intended.
For the most up‐to‐date information regarding malria treatments, please see: Sinclair D, Zani B, Donegan S, Olliaro P, Garner P. Artemisinin‐based combination therapy for treating uncomplicated malaria. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD007483. DOI: 10.1002/14651858.CD007483.pub2.)
February 2003: review updated and text amended; tables describing studies revised.
Acknowledgements
This review was made possible by researchers who kindly provided data and made comments, and include Dr B.Greenwood and Dr O.Müller (The Gambia); L.Salako (Nigeria); A.Shapira (World Health Organisation (WHO), Vietnam); B.Dubois (Parke‐Davis, France). Data on amodiaquine adverse events was kindly provided by M Petersson, WHO Collaborating Centre, Sweden. Other people who have helped with specialist advice include Dr A.Rietveld and Mrs V.Mattei (WHO, Switzerland); Mr J.Portal (Parke‐Davis, France); Dr P.Winstanley (UK); Dr A.Oxman (Denmark); Dr A.Herxheimer (UK). Elements of an unpublished WHO study by A.Rietveld and P.Trigg were also used. This review was conducted as an activity of the Cochrane Infectious Diseases Group, who are supported by a grant from the Department for International Development (UK), and of the United Nations Development Programme (UNDP)/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR). However, the data presented and the views expressed are the responsibility of the authors of this paper, and not the agencies employing them or providing them with funds.
Appendices
Appendix 1. References to studies conducted at several sites with different identifiers in the review
| Burkina‐Faso98 Cameroon98 Gabon‐Libreville98 Senegal‐Dakar 96‐98 Senegal‐Mlomp 96‐98 |
Brasseur, et al. Amodiaquine remains effective for treating uncomplicated malaria in West and Central Africa. Transactions of the Royal Society of Tropical Medicine and Hygiene 1999;93:645‐50. |
| CamerounBangangte92 Congo 92 CamerounYaounde92 CamerounKumba92 |
Brasseur P, et al. Interet de l'amodiaquine pour le traitement du paludisme a Plasmodium falciparum en Afrique de l'ouest et du centre [Interest of amodiaquine for the treatment of Plasmodium falciparum malaria in West and Central Africa] |
| Kenya‐Entosopia 91 Kenya‐Migori 1990 Kenya‐Ortum 1991 Kenya‐Turiani 1991 Kenya‐Turiani 1992 |
Nevill C, et al. Amodiaquine not sulphadoxine‐pyrimethamine should replace chloroquine for the primary treatment of non‐severe P. falciparum malaria in Kenya |
| Kenya‐Kibwezi97 Tanzania‐Kigoma97 |
Gorissen E, et al. In vivo efficacy study of amodiaquine and sulphadoxine‐pyrimethamine in Kibwezi, Kenya and Kigoma, Tanzania. Tropical Medicine and International Health 2000;5(6):459‐63 |
.
Appendix 2. Characteristics of included studies
| Study |
Country (location) |
Year |
AQ (mg/kg) |
CQ (mg/kg) |
SP (mg/kg) |
Other comparators (mg/kg) |
Follow up (days) |
| Brazil 1983‐84 | Brazil | 1983‐84 | 25 | 25 | 25 | 7 | |
| Burkina‐Faso98 | Burkina‐Faso | 1998 | 30 | 25 | 14 | ||
| Cameroon98 | Cameroon | 1998 | 30 | 25 | 14 | ||
| Cameroun‐Centre 94 | Cameroon (centre) | 1994 | 25 | 25 | 7 | ||
| Cameroun‐Est 1993 | Cameroon (east) | 1993 | 25 | 25 | 7 | ||
| Cameroun‐Hevecam2001 | Cameroon (Hevecam) |
2001 | 30 | single dose | AQ+SP | 28 | |
| Cameroun‐Hevecam88‐9 | Cameroon (Hevecam) |
1988‐9 | 25 (over 3 days) |
25 (over 3 days) |
inpatient (7 days) | 14 | |
| Cameroun‐Kumba 92 | Cameroon (Kumba) |
1992 | 35 | 25 | 7 | ||
| Cameroun‐South 88 | Cameroun (South) | 1988 | 35 | ?? | 7 | ||
| Cameroun‐South94a | Cameroon (South) |
1994 | 25 | 25 | 7 | ||
| Cameroun‐South94b | Cameroon (South) |
1994 | 25 | 25 | 7 | ||
| Cameroun‐Yaounde97‐9 | Cameroon (Yaounde) |
1997‐99 | 30 mg | single dose (over 3 days) | 14 (28) | ||
| Cameroun Bangangte92 |
Cameroon (Bangangte) |
1992 | 25 | 25 | 7 | ||
| CamerounYaounde 92 | Cameroon (Yaounde) | 1992 | 25 | 25 | 7 | ||
| China 1986 | China | 1986 | 1800 mg | 1500 | AQ+SP | 28 | |
| Colombia‐Antioquia98 | Colombia (Antioquia) |
1998 | 25 | 25 | single dose | 14 | |
| Congo 92 | Congo | 1992 | 25 | 25 | 7 | ||
| Congo P‐Noire 86 | Congo (P‐Noire) |
1986 | 25 | 25 | 7 | ||
| CongoBrazzaville86 | Congo (Brazzaville) | 1986 | 25 | 25 | 7 | ||
| CongoBrazzaville90 | Congo (Brazzaville) | 1990 | 25, 30 | 25, 35 | ? | ||
| EquatorialGuinea91 | Equatorial Guinea | 1991 | 25 (over 3 days) |
25 (over 3 days) |
single dose | 14 | |
| Gabon‐Libreville98 | Gabon (Libreville) |
1998 | 30 | 25 | 14 | ||
| Gabon97‐98 | Gabon | 1997‐8 | 25 (over 3 days) |
25 (over 3 days) |
14 | ||
| Gambia 94 | Gambia | 1994 | 25 | 25 | single dose | 28 | |
| Ivory Coast 93 | Ivory Coast | 1993 | 30 (over 3 days) |
30 (over 3 days) | 7 | ||
| Kenya 1989 | Kenya | 1989 | 25 | 25 | 14 | ||
| Kenya‐Eldoret94 | Kenya (Eldoret) |
1994 | 27 (over 3 days) |
25 (over 3 days) |
single dose | Halofantrine: 24 mg/kg over 3 doses | 28 |
| Kenya‐Entosopia 91 | Kenya (Entosopia) |
1991 | 25 | 25 | 7 | ||
| Kenya‐Entosopia 94 | Kenya (Entosopia) |
1994 | 30 | single dose | 14 | ||
| Kenya‐Kibwezi97 | Kenya (Kibwezi) |
1997 | 30 (over 3 days) |
single dose | 14 | ||
| Kenya‐Kilifi 1993 | Kenya (Kilifi) |
1993 | 25 |
25 | 14 | ||
| Kenya‐Malindi 1984 | Kenya (Malindi) |
1984 | 25 | 25 | |||
| Kenya‐Malla 1994 | Kenya (Malla) |
1994 | 30 | single dose | 14 | ||
| Kenya‐Migori 1990 | Kenya (Migori) |
1990 | 25 | 25 | 7 | ||
| Kenya‐Mombasa 90 | Kenya (Mombasa) |
1990 | 25 | single dose | SL/P: | 24 | |
| Kenya‐Nangina 1993 | Kenya (Nangina) |
1993 | 30 | single dose | 7 | ||
| Kenya‐Ortum 1991 | Kenya (Ortum) |
1991 | 25 | 25 | 7 | ||
| Kenya‐Sololo 1993 | Kenya (Sololo) |
1993 | 30 | 7 | |||
| Kenya‐Taveta 1994 | Kenya (Taveta) |
1994 | 30 | single dose | 14 | ||
| Kenya‐Turiani 1991 | Kenya (Turiani) |
1991 | 25 | 25 | 7 | ||
| Kenya‐Turiani 1992 | Kenya (Turiani) |
1992 | 25 | 25 | 14 | ||
| Kenya‐West 1987 | Kenya (West) |
1987 | 25 | CQ: 25 im+po CQ: 25 + Fe |
SP + quinine: | 7 | |
| Madagascar 83/84 | Madagascar | 1983‐4 | 15.6 | 25 | 28 | ||
| Madagascar 85/86 | Madagascar | 1985‐6 | 15.6 | 25 | 28 | ||
| Malawi 1985 | Malawi | 1985 | 10 25 |
25 | single dose | 21 | |
| Mozambique 1986 | Mozambique | 1986 | 25‐30 |
25‐30 |
single dose | AQ +SP | 28/35 |
| Nigeria‐Ibadan 84 | Nigeria (Ibadan) |
1984 | 15 | 25 | 28 | ||
| Nigeria‐Ibadan 90 | Nigeria (Ibadan) |
1990 | 25 |
25 |
single dose | Quinine: Mefloquine: 15 Mefloquine: 25 |
28 |
| Nigeria‐Ibadan2000 | Nigeria (Ibadan) |
2000 | 30 (over 3 days) |
30 | 28 | ||
| Philippines 84/85 | Philippines | 1984‐5 | 25 | 25 | 14 | ||
| Senegal‐Dakar 96‐98 | Senegal (Dakar) |
1996‐8 | 30 | 25 | 14 | ||
| Senegal‐Mlomp 96‐98 | Senegal (Mlomp) |
1996‐8 | 30 | 25 | 14 | ||
| Senegal‐Diohine96 | Senegal (Diohine) |
1996 | 25 (over 3 days) |
25 | single dose | ||
| Tanzania‐Centre 88 | Tanzania (centre) |
1988 | 25 | 25 |
single dose | SL/P: | 7 |
| Tanzania‐Kigoma97 | Tanzania (Kigoma) |
1997 | 30 (over 3 days) | single dose | 14 | ||
| Uganda‐Kampala99 | Uganda (Kampala) |
1999 | 25 (over 3 days) | single dose | AQ+SP | 14 |
AQ, amodiaquine; CQ, chloroquine; SP, sulfadoxine‐pyrimethamine
Appendix 3. Participant characteristics
| Study | Number of participants | P. falciparum malaria | Inclusion criteria | Age range | Male | Female | |
| Mild symptomatic | Asymptomatic | ||||||
| Brazil 1983‐84 | Y | >1000 to 10,000 parasites/ul (thick smear) | All ages | Y | Y | ||
| Burkina‐Faso98 | Y | >1000 parasites/ul; >37.5 °C fever | All ages | Y | Y | ||
| Cameroon98 | Y | >1000 parasites/ul; >37.5 °C fever | All ages | Y | Y | ||
| Cameroun‐Centre 94 | 200 screened 115 eligible |
Y | school children; no other details available | 2 to 12 years | Y | Y | |
| Cameroun‐Est 1993 | 300 screened 156 eligible |
Y | school children; ; no other details available | 5 to 16 years | Y | Y | |
| Cameroun‐Hevecam2001 | 191 enrolled 185 evaluable (day 14) 177 evaluable (day 28) |
Y | >2000 parasites/ul; <38 °C fever; >15% Ht | >10 years | Y | Y | |
| Cameroun‐Hevecam88‐9 | 3082 screened 1783 “malaria” 170 eligible (reasons for exclusion reported) 166 evaluable (those who completed 14 days follow up, but inconsistent with data presented) |
Y | Inpatients >1000 parasites/ul (thick film); fresh (negative test for chloroquine) |
10 years | Y | Y | |
| Cameroun‐Kumba 92 | 25 eligible | Y | >1000 trophozoites/ul [thick film/500 white blood cells; 8000 white blood cells/ul]; fresh (no antimalarial drugs 14 days prior) | ? School children | Y | Y | |
| Cameroun‐South 88 | 3785 screened (1650 with suspected malaria) 505 P. falciparum positive 236 eligible 165 evaluable |
Y | >1000 parasites [thick film/2000 white blood cells; 8000 white blood cells/ul]; fresh (no history of prior treatment with “effective dose” of 4‐amodiaquine 38% of the participants included reported prior treatment) | 9 to 12 years | Y | Y | |
| Cameroun‐South94a | 409 screened | Y | school children; no other details available | 4 to 17 years | Y | Y | |
| Cameroun‐South94b | 970 screened | Y | school children; no other details available | 1 to 14 years | Y | Y | |
| Cameroun‐Yaounde97‐9 | 140 enrolled 117 evaluable (day 14) |
Y | Age >5 years; >5000 parasites/ul [thick smear]; >37.5 °C fever; negative urine test | >5 years | Y | Y | |
| Cameroun Bangangte92 |
148 eligible 123 evaluable |
Y | >1000 parasites/ul [thick film/500 white blood cells; 8000 white blood cells/ul]; fresh (no antimalarial drugs 14 days prior) | 1 to 55 years | Y | Y | |
| CamerounYaounde 92 | 148 eligible 123 evaluable |
Y | >1000 parasites/ul [thick film/500 white blood cells; 8000 white blood cells/ul]; fresh (no antimalarial drugs 14 days prior) | 1 to 55 years | Y | Y | |
| China 1986 | 169 eligible 162 evaluable |
Y | >500 parasites/ul; fresh (negative test for chloroquine, sulfadoxine‐pyrimethamine; no treatment with 28 days prior) | > 12 years | Y | Y | |
| Colombia‐Antioquia98 | Y | >900; <80,000 parasites/ul; fresh (negative test for chloroquine, sulfadoxine‐pyrimethamine) | > 1 year | Y | Y | ||
| Congo 92 | 148 eligible 123 evaluable |
Y | >1000 parasites/ul [thick film/500 white blood cells; 8000 white blood cells/ul]; fresh (no antimalarial drugs 14 days prior) | 1 to 55 years | Y | Y | |
| Congo P‐Noire 86 | 602 P. falciparum positive 44 eligible 24 evaluable |
Y | >1000 parasites/ul; fresh (no prior antimalarial drugs, negative urine test) | 6 months to 15 years | Y | Y | |
| CongoBrazzaville86 | 241 screened 150 P. falciparum positive 75 eligible 64 evaluable |
Y | school children >1000 parasites/ul [thick film/200 white blood cells, 6000 white blood cells) |
6 to 7 years | Y | Y | |
| CongoBrazzaville90 | Y | school children >1000 parasites/ul [thick film/1000 white blood cells, 6000 white blood cells] |
6 to 8 years | Y | Y | ||
| EquatorialGuinea91 | 3082 screened 1763 “malaria” 170 eligible (reason for exclusion reported) 166 evaluable (who completed 14 day follow up, but inconsistent with data presented) |
Y | Inpatients >1000 parasites ul (thick film); fresh case (negative test for chloroquine) |
<10 years | Y | Y | |
| Gabon‐Libreville98 | Y | >1000 parasites/ul; >37.5C fever | All ages | Y | Y | ||
| Gabon97‐98 | 74 enrolled 48 evaluable day 7 22 evaluable day 14 |
Y | >1000 parasites/ul | 1 to 15 years | Y | Y | |
| Gambia 94 | 30 excluded | Y | >5000 parasites/ul; no prior treatment | 6 to 10 years | Y | Y | |
| Ivory Coast 93 | 295 screened 136 P. falciparum positive 121 eligible 100 evaluable |
Y | >1000 parasites/ul [thick smear]; fresh cases (no antimalarial drugs 5 days prior) | 1 to 15 years | Y | Y | |
| Kenya 1989 | 158 eligible 139 evaluable |
Y | [thick film/200 white blood cells]; fresh (negative test for chloroquine) | ||||
| Kenya‐Eldoret94 | Y | Entry parasitaemia and fever no specified Haemoglobin >5g/dl Inpatients for =/> 2 days |
Mean age 61.7 to 67.5 months | Y | Y | ||
| Kenya‐Entosopia 91 | Y | [thick film/200 white blood cells]; fresh (negative test for chloroquine) | |||||
| Kenya‐Entosopia 94 | Y | [thick film/200 white blood cells]; fresh (negative test for chloroquine) | |||||
| Kenya‐Kibwezi97 | 103 randomized 75 eligible 67 evaluable (75 participants presented for intention‐to‐treat) |
Y | >1000 to <250,000 parasites/ul; haemoglobin 4.9 g/dl | <10 years | Y | Y | |
| Kenya‐Kilifi 1993 | Y | [thick film/200 white blood cells]; fresh (negative test for chloroquine) | |||||
| Kenya‐Malindi 1984 | 423 screened 188 P. falciparum positive 139 evaluable |
Y | School children [thick film/300 white blood cells]; fresh (no treatment prior 14 days; negative test for chloroquine) |
6 to 17 years | Y | Y | |
| Kenya‐Malla 1994 | Y | [thick film/200 white blood cells]; fresh (negative test for chloroquine) | |||||
| Kenya‐Migori 1990 | Y | [thick film/200 white blood cells]; fresh (negative test for chloroquine) | |||||
| Kenya‐Mombasa 90 | 728 screened 76 eligible 73 evaluable |
Y | >10 parasites/300 white blood cells [thick smear = 200 trophozoites/ul?]; fresh (no antimalarial drug 2 months prior, negative urine test) | 7 to 16 years | Y | Y | |
| Kenya‐Nangina 1993 | Y | [thick film/200 white blood cells]; fresh (negative test for chloroquine) | |||||
| Kenya‐Ortum 1991 | Y | [thick film/200 white blood cells]; fresh (negative test for chloroquine) | |||||
| Kenya‐Sololo 1993 | Y | [thick film/200 white blood cells]; fresh (negative test for chloroquine) | |||||
| Kenya‐Taveta 1994 | Y | [thick film/200 white blood cells]; fresh (negative test for chloroquine) | |||||
| Kenya‐Turiani 1991 | Y | [thick film/200 white blood cells]; fresh (negative test for chloroquine) | |||||
| Kenya‐Turiani 1992 | Y | [thick film/200 white blood cells]; fresh (negative test for chloroquine) | |||||
| Kenya‐West 1987 | 142 eligible 98 evaluable |
Y | >500 to <100,000 trophozoits/ul [/300 white blood cells, adjusted to 6,000 white blood cells]; fresh (no antimalarial drugs during prior 2 weeks) [ELISA test for chloroquine done, but not reason for exclusion] | 6 months to 4 years | Y | Y | |
| Madagascar 83/84 | 1521 screened 134 eligible |
Y | >0.01% parasitaemia [thin smear,/10K red blood cells]; fresh (negative test for chloroquine) | 1 to 16 years | Y | Y | |
| Madagascar 85/86 | 2298 screened 782 P. falciparum positive 122 eligible 115 evaluable |
Y | >500 trophozoites/ul [thin smear,10K red blood cells]; fresh (negative test for chloroquine) | 1 to 34 years | Y | Y | |
| Malawi 1985 | Y | <2000 trophozoites/ul [thick smear/100 fields]; fresh (negative urine test for chloroquine) | < 5 years | Y | Y | ||
| Mozambique 1986 | 200 eligible 131 evaluable |
Y | School children >800 trophozoites/ul [/500 white blood cells]; fresh (no treatment during prior 2 weeks); microscopist blinded |
School children | Y | Y | |
| Nigeria‐Ibadan 84 | 87 eligible 44 evaluable |
Y | microscopically confirmed malaria (no detail provided) | 1 to 10 years | Y | Y | |
| Nigeria‐Ibadan 90 | 3203 screened 2009 P. falciparum positive 427 eligible325 evaluable |
Y | >3000 trophozoites/ul [thick smear/1000 white blood cells, 6000 white blood cells]; fresh (negative test for chloroquine, sulfadoxine‐pyrimethamine) | ||||
| Nigeria‐Ibadan2000 | 503 screened 276 P. falciparum positive 230 eligible/enrolled 228 evaluable |
Y | >2000 parasites/ul [thick film/500 white blood cells assume 6000/ul]; fresh (negative test for chloroquine, sulfadoxine‐pyrimethamine, or history of treatment) | < 10 years | Y | Y | |
| Philippines 84/85 | Y | >1000 trophozoites/ul; fresh (no treatment 3 weeks prior; negative urine test for chloroquine and sulfadoxine‐pyrimethamine) | |||||
| Senegal‐Dakar 96‐98 | Y | >1000 parasites/ul; >37.5 C fever | All ages | Y | Y | ||
| Senegal‐Mlomp 96‐98 | Y | >1000 parasites/ul; >37.5 C fever | All ages | Y | Y | ||
| Senegal‐Diohine96 | 319 enrolled 266 evaluable |
Y | <5000 parasites/ul; PCV <17% | 6 months to 16 years | Y | Y | |
| Tanzania‐Centre 88 | 3258 screened 1995 P. falciparum positive 560 eligible 401 evaluable |
Y | School children >400 trophozoites/ul [/? white blood cells]; fresh (negative urine chloroquine test) |
7 to 18 years | Y | Y | |
| Tanzania‐Kigoma97 | 171 randomized/eligible 134 evaluable (intention‐to‐treat presented for 171 participants) |
Y | >1000 to <250,000 parasites/ul; haemoglobin >4.9 g/dl | < 10 years | Y | Y | |
| Uganda‐Kampala99 | 1914 screened 668 randomized 445 enrolled 400 evaluable |
Y | age >6 years; >5 kg; >38C fever; PCV >17% | > 6 years | Y | Y | |
Appendix 4. Outcomes
| Study | Parasitological conversion (day) | Safety | Other | |
| Adverse events | Laboratory‐based outcomes | |||
| Brazil 1983‐84 | 7 | In vivo sensitivity: S/RI, RII, RIII. Parasite clearance time. |
||
| Burkina‐Faso98 | 1, 2, 3, 7, 14, (28) | Yes | Haematology Liver enzymes |
In vivo sensitivity at day 14, (28): S/RI, RII, RIII. ACR ETF LTF In vitro sensitivity. IC50 |
| Cameroon98 | 1, 2, 3, 7, 14, (28) | Yes | Haematology Liver enzymes |
Report d14, (28) In vivo sensitivity: S/RI, RII, RIII ACR ETF LTF In vitro sensitivity IC50 |
| Cameroun‐Centre 94 | 3, 7 | |||
| Cameroun‐Est 1993 | 3, 7 | |||
| Cameroun‐Hevecam2001 | 2, 3, 7, 14, 28 | Yes | Clinical outcome: day 2, 3, 7, 14, 28 % parasite negative ACR parasite negative/positive: day 14, 28 Parasite clearance time Fever clearance time Hb |
|
| Cameroun‐Hevecam88‐9 | 1 to 7, 14 | In vivo sensitivity: S, RI, RII, RIII Parasite clearance time |
||
| Cameroun‐Kumba 92 | 1 to 3, 5, 7 | Yes | ||
| Cameroun‐South 88 | 7 | Liver function tests | ||
| Cameroun‐South94a | 3, 7 | |||
| Cameroun‐South94b | 3, 7 | |||
| Cameroun‐Yaounde97‐9 | 1 to 3, 7, 14 | Yes | ACR parasite positive/negative; day 14 (28) Fever clearance time Parasite clearance time Gametocyte carriage: day 3, 7, 14. |
|
| Cameroun Bangangte92 |
1 to 3, 5, 7 | Parasite clearance time Fever clearance time |
||
| CamerounYaounde 92 | 1 to 3, 5, 7, 14 | Parasite clearance time Fever clearance time |
||
| China 1986 | 28 | Yes | Parasite clearance time Fever clearance time In vivo sensitivity: S, RI, RII, RIII |
|
| Colombia‐Antioquia98 | 1 to 3, 5, 7, 14 | In vivo sensitivity: S, RI, RII, RIII ACR ETF LTF |
||
| Congo 92 | 1, 3, 5, 7 | Parasite clearance time Fever clearance time |
||
| Congo P‐Noire 86 | 7 | |||
| CongoBrazzaville86 | 7 | In vivo sensitivity: S, RI, RII, RIII Parasite clearance time |
||
| CongoBrazzaville90 | 7 | |||
| EquatorialGuinea91 | 0, 1 to 7, 10, 14 | Parasite present on d7, 14 In vivo sensitivity: S, RI, RII, RIII Parasite clearance time |
||
| Gabon‐Libreville98 | 1, 2, 3, 7, 14, (28) | Yes | Haematology Liver enzymes |
Report day 14, (28) In vivo sensitivity: S/RI, RII, RIII ACR ETF LTF In vitro sensitivity IC50 |
| Gabon97‐98 | 0 to 3, 7, 14 | Haematology (including diff. count) Biochemistry |
ACR ECF LCT In vivo sensitivity: S/RI, RII, RIII |
|
| Gambia 94 | 7, 28 | |||
| Ivory Coast 93 | 1, 2, 7 | Yes | Yes | Parasite clearance time |
| Kenya 1989 | 7, 14 | Yes | Yes | In vivo sensitivity: S, RI, RII, RIII Parasite clearance time Fever clearance time |
| Kenya‐Eldoret94 | 2, 3, 7, 14, 28 | In vivo sensitivity on days 7 and 28 on evaluable participants and intention‐to‐treat: S, RI, RII, RIII Haemoglobin |
||
| Kenya‐Entosopia 91 | 1 to 4, 7 | |||
| Kenya‐Entosopia 94 | 1 to 4, 7, 14 | Parasite clearance time Fever clearance time |
||
| Kenya‐Kibwezi97 | 1, 2, 7, 14 | In vivo sensitivity on day 14 on evaluable participants and intention‐to‐treat: S, RI, RII, RIII | ||
| Kenya‐Kilifi 1993 | 1 to 4, 7, 14 | |||
| Kenya‐Malindi 1984 | 7, 14 | In vivo sensitivity: S, RI, RII, RIII | ||
| Kenya‐Malla 1994 | 1 to 4, 7, 14 | Parasite clearance time Fever clearance time |
||
| Kenya‐Migori 1990 | 1 to 3, 7 | |||
| Kenya‐Mombasa 90 | 28 | Parasite clearance time | ||
| Kenya‐Nangina 1993 | 1 to 3, 7 | |||
| Kenya‐Ortum 1991 | 1 to 4, 7 | |||
| Kenya‐Sololo 1993 | 1 to 4, 7 | |||
| Kenya‐Taveta 1994 | 1 to 4, 7, 14 | Parasite clearance time Fever clearance time |
||
| Kenya‐Turiani 1991 | 1 to 4, 7 | |||
| Kenya‐Turiani 1992 | 1 to 4, 7, 14 | |||
| Kenya‐West 1987 | 7 | Reticulocytes Haemoglobin Red blood cells Ht monitored day 0 and day 7 |
In vivo sensitivity: S, RI+ II, RIII | |
| Madagascar 83/84 | 7, 14, 28 | |||
| Madagascar 85/86 | 7, 14, 28 | |||
| Malawi 1985 | 7, 14, 21 | |||
| Mozambique 1986 | 7, 14, 28 | In vivo sensitivity: S, RI, RII, RIII | ||
| Nigeria‐Ibadan 84 | 28 | Yes | In vivo sensitivity: RI Parasite clearance time Fever clearance time |
|
| Nigeria‐Ibadan 90 | 1 to 4, 7, 14 | Parasite clearance time Fever clearance time |
||
| Nigeria‐Ibadan2000 | 1 to 4, (7), 14, 28 | Yes | Haemoglobin White blood cells at days 0 and 7 |
In vivo sensitivity at days 14, 21, and 28: S/RI, RII, RIII |
| Philippines 84/85 | 7, 14 | Yes | In vivo sensitivity: S, RI, RII, RIII | |
| Senegal‐Dakar 96‐98 | 1, 2, 3, 7, 14, (28) | Yes | Haematology Liver enzymes |
In vivo sensitivity at days 14, (28): S/RI, RII, RIII ACR ETF LTF In vitro sensitivity IC50 Drug levels |
| Senegal‐Mlomp 96‐98 | 1, 2, 3, 7, 14, (28) | Yes | Haematology Liver enzymes |
In vivo sensitivity at days 14, (28): S/RI, RII, RIII ACR ETF LTF In vitro sensitivity IC50 Drug levels |
| Senegal‐Diohine96 | 4, 7, 14 | In vivo sensitivity: S/RI, RII, RIII Gametocytaemia |
||
| Tanzania‐Centre 88 | 7 | In vivo sensitivity: S, RI, RII, RIII Parasite clearance time |
||
| Tanzania‐Kigoma97 | 1, 2, 7, 14 | In vivo sensitivity at day 14 (evaluable participants and intention‐to‐treat): S, RI, RII, RIII | ||
| Uganda‐Kampala99 | 1 to 3, 7, 14 | Yes | Haematology Blood chemistry |
In vivo sensitivity: S, RI, RII, RIII ACR ETF LTF Parasite clearance time Fever clearance time Gametocytes |
Appendix 5. Evaluable participants for parasitological outcomes at day 7, 14, and 28
| Number of participants | Total AQ participants in comparison | ||||||||
| Asymptomatic | Symptomatic | ||||||||
| AQ | CQ | AQ | CQ | AQ | SP | CQ | add. SP | Total | |
| Day 7 | 108 | 101 | 1230 | 1234 | 824 | 818 | 1230 | 549 | 1779 |
| add. day 14 | 0 | 0 | 258 | 268 | 342 | 340 | 258 | 342 | 600 |
| add. day 28 | 0 | 0 | 50 | 42 | 0 | 0 | 50 | 0 | 50 |
| Total reported | 108 | 101 | 1538 | 1544 | 1166 | 1158 | 1538 | 891 | 2429 |
AQ, amodiaquine; CQ, chloroquine; SP, sulfadoxine‐pyrimethamine
Appendix 6. Summary of results
| Comparison | Day | Number of studies |
Non‐ African |
Africa |
Year 1991+ |
#AQ |
Succ AQ |
%Succ AQ |
# comp |
Succ Comp |
% Succ Comp |
Odds ratio (95% confidence interval) |
| Chloroquine | 7 | 27 | 2 | 25 | 15 | 1230 | 1043 | 85 | 1234 | 718 | 58 | 4.42 (3.65 to 5.35) |
| Chloroquine | 14 | 18 | 1 | 17 | 12 | 802 | 716 | 89 | 808 | 453 | 56 | 6.44 (5.09 to 8.15) |
| Chloroquine | 28 | 3 | 0 | 3 | 3 | 254 | 193 | 76 | 248 | 122 | 49 | 3.62 (2.49 to 5.29) |
| Chloroquine ‐asymptomatic | 7 | 9 | 0 | 9 | 4 | 543 | 493 | 91 | 586 | 422 | 72 | 3.64 (2.65 to 5.00) |
| Sulfadoxine‐pyrimethamine | 7 | 14 | 2 | 12 | 9 | 824 | 716 | 87 | 818 | 735 | 90 | 0.73 (0.53 to 1.01) |
| Sulfadoxine‐pyrimethamine | 14 | 14 | 0 | 14 | 11 | 786 | 661 | 84 | 821 | 705 | 86 | 0.86 (0.64 to 1.14) |
| Sulfadoxine‐pyrimethamine | 28 | 7 | 1 | 6 | 4 | 345 | 243 | 70 | 322 | 273 | 85 | 0.41 (0.28 to 0.61) |
Data and analyses
Comparison 1. Amodiaquine vs chloroquine in symptomatic participants.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Parasitological conversion | 35 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 1.1 Day 7 | 27 | 2464 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 4.42 [3.65, 5.35] |
| 1.2 Day 14 | 18 | 1610 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 6.44 [5.09, 8.15] |
| 1.3 Day 21 to 28 | 3 | 502 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 3.62 [2.49, 5.29] |
| 2 Adverse events | 8 | 824 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.85 [0.50, 1.42] |
1.1. Analysis.
Comparison 1 Amodiaquine vs chloroquine in symptomatic participants, Outcome 1 Parasitological conversion.
1.2. Analysis.
Comparison 1 Amodiaquine vs chloroquine in symptomatic participants, Outcome 2 Adverse events.
Comparison 2. Amodiaquine vs chloroquine in asymptomatic participants.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Parasitological conversion on day 7 | 9 | 1129 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 3.64 [2.65, 5.00] |
2.1. Analysis.
Comparison 2 Amodiaquine vs chloroquine in asymptomatic participants, Outcome 1 Parasitological conversion on day 7.
Comparison 3. Amodiaquine vs sulphadoxine‐pyrimethamine in symptomatic participants.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Parasitological conversion | 19 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 1.1 day 7 | 14 | 1642 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.73 [0.53, 1.01] |
| 1.2 day 14 | 14 | 1607 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.86 [0.64, 1.14] |
| 1.3 day 21‐28 | 7 | 667 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.41 [0.28, 0.61] |
| 2 Adverse events | 3 | 232 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.68 [0.84, 3.38] |
3.1. Analysis.
Comparison 3 Amodiaquine vs sulphadoxine‐pyrimethamine in symptomatic participants, Outcome 1 Parasitological conversion.
3.2. Analysis.
Comparison 3 Amodiaquine vs sulphadoxine‐pyrimethamine in symptomatic participants, Outcome 2 Adverse events.
Comparison 4. AQ VS. CQ in symptomatic participants: Africa (sensitivity analysis).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Parasitological conversion | 32 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 1.1 day 7 | 25 | 2371 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 4.94 [4.06, 6.02] |
| 1.2 day 14 | 16 | 1539 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 6.86 [5.38, 8.75] |
| 1.3 day 21‐28 | 3 | 502 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 3.62 [2.49, 5.29] |
4.1. Analysis.
Comparison 4 AQ VS. CQ in symptomatic participants: Africa (sensitivity analysis), Outcome 1 Parasitological conversion.
Comparison 5. AQ vs SP in symptomatic participants: Africa (sensitivity analysis).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Parasitological conversion | 16 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 1.1 day 7 | 12 | 1505 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.80 [0.57, 1.13] |
| 1.2 day 14 | 13 | 1576 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.84 [0.63, 1.12] |
| 1.3 day 21‐28 | 6 | 596 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.44 [0.29, 0.66] |
5.1. Analysis.
Comparison 5 AQ vs SP in symptomatic participants: Africa (sensitivity analysis), Outcome 1 Parasitological conversion.
Comparison 6. AQ vs SP in symptomatic participants: Africa after 1990 (sensitivity analysis).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Parasitological conversion | 13 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 1.1 day 7 | 8 | 1189 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.81 [0.57, 1.15] |
| 1.2 day 14 | 10 | 1344 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.92 [0.68, 1.23] |
| 1.3 day 21‐28 | 4 | 475 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.58 [0.37, 0.91] |
6.1. Analysis.
Comparison 6 AQ vs SP in symptomatic participants: Africa after 1990 (sensitivity analysis), Outcome 1 Parasitological conversion.
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Brazil 1983‐84.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | ||
Burkina Faso 1998.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Cameroon 1998.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Cameroon‐Bangangte92.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Cameroon‐Centre 1994.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Cameroon‐East 1993.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Cameroon‐Hevécam88‐9.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Cameroon‐Hévécam2001.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Cameroon‐Kumba1992.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Cameroon‐South 1988.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Cameroon‐South 1994a.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Cameroon‐South 1994b.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Cameroon‐Yaounde 92.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Cameroon‐Yaounde97‐9.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
China 1986.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Colombia‐Antioquia98.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Congo 1992.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Congo‐Brazzaville 86.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Congo‐Brazzaville90.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Congo‐P Noire 1986.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Cote d'Ivoire 1993.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Equatorial Guinea 91.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Gabon 1997‐8.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Gabon‐Libreville 98.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Gambia 1994.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Kenya 1989.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Kenya‐Eldoret 1994.
| Methods | see Appendices | |
| Participants | _ | |
| Interventions | _ | |
| Outcomes | _ | |
| Notes | _ | |
Kenya‐Entosopia 91.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Kenya‐Entosopia 94.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Kenya‐Kibwezi 1997.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Kenya‐Kilifi 1993.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Kenya‐Malindi 1984.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Kenya‐Malla 1994.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Kenya‐Migori 1990.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Kenya‐Mombasa 90.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Kenya‐Nangina 1993.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Kenya‐Ortum 1991.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Kenya‐Sololo 1993.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Kenya‐Taveta 1994.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Kenya‐Turiani 1991.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Kenya‐Turiani 1992.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Kenya‐West 1987.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Madagascar 1983‐4.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Madagascar 1985‐6.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Malawi 1985.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Mozambique 1986.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Nigeria‐Ibadan 1984.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Nigeria‐Ibadan 1990.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Nigeria‐Ibadan 2000.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Philippines 1984‐5.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Senegal‐Dakar 1996‐8.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Senegal‐Mlomp 1996‐8.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Sénégal‐Diohine 1996.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Tanzania‐Centre 1988.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Tanzania‐Kigoma 1997.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Uganda‐Kampala 1999.
| Methods | see Appendices | |
| Participants | — | |
| Interventions | — | |
| Outcomes | — | |
| Notes | — | |
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Africa 1999 | — |
| AfricaMadagascar83‐6 | Does not meet inclusion criteria. |
| Benin‐Cotonou 1989 | Does not meet inclusion criteria. |
| Cameroon 1987‐90 | — |
| Cameroon 1990a | Does not meet inclusion criteria. |
| Cameroon 1990b | — |
| Cameroon 1993‐4 | Does not meet inclusion criteria. |
| Cameroon 1996 | — |
| Cameroon 1999 | — |
| Cameroon 2000 | — |
| Cameroon‐Bafoussam00 | — |
| Cameroon‐Edea 1987 | Does not meet inclusion criteria. |
| Cameroon‐Eséka 1999 | — |
| Cameroon‐Mengang1999 | — |
| Cameroon‐Nlongkak 99 | — |
| Cameroon‐S Est 1993 | Does not meet inclusion criteria. |
| Cameroon‐S West 1989 | Does not meet inclusion criteria. |
| Cameroon‐South 1993 | Does not meet inclusion criteria. |
| Cameroon‐Urban 1990 | — |
| Cameroon‐Yaounde 96 | — |
| Cameroon‐Yaounde1988 | Does not meet inclusion criteria. |
| Cameroon‐Yaounde87‐8 | — |
| Congo 1985‐9 | — |
| Congo 1986‐90 | — |
| Cote d'Ivoire 1990 | Does nor meet inclusion criteria. |
| Cote d'Ivoire 1995 | — |
| Gabon 1995 | — |
| India 1952 | — |
| India 1989‐90 | Does not meet inclusion criteria. |
| India 1989‐92 | — |
| Kenya 1993 | — |
| Kenya 1998 | — |
| Liberia 2000‐01 | — |
| Madagascar 1983a | Does not meet inclusion criteria. |
| Madagascar 1983b | — |
| Madagascar 1983c | — |
| Pakistan 1997 | — |
| PapuaNewGuinea 1989 | Does not meet inclusion criteria. |
| PapuaNewGuinea 1991 | Does not meet inclusion criteria. |
| RCA 1984‐6 | Does not meet inclusion criteria. |
| Rwanda 1986 | Does not meet inclusion criteria. |
| Sénégal 1997 | — |
| Tanzania 1988 | Does not meet inclusion criteria. |
| Uganda 1988 | — |
| Uganda‐Kampala 94‐7 | — |
| Zanzibar 1989 | Does not meet inclusion criteria. |
Contributions of authors
Piero Olliaro extracted the data in the first and second edition of the review; the second person extracting data independently was Ms Mussano and Philippe Brasseur (1st edition), and Pierre Ringwald (2nd edition). Dr Olliaro entered the data and this was checked by Ms Mussano.
Sources of support
Internal sources
UNDP/World Bank/WHO Tropical Diseases Programme, World Health Organization, Switzerland.
Liverpool School of Tropical Medicine, UK.
External sources
Department for International Development, UK.
Declarations of interest
We certify that we have no affiliations with or involvement in any organization or entity with a direct financial interest in the subject matter of the review (eg, employment, consultancy, stock ownership, honoraria, expert testimony).
Unchanged
References
References to studies included in this review
Brazil 1983‐84 {published data only}
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Cameroon‐Centre 1994 {published data only}
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Cameroon‐Kumba1992 {unpublished data only}
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Cameroon‐South 1988 {published data only}
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Cameroon‐Yaounde97‐9 {published data only}
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Congo‐Brazzaville 86 {published data only}
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Gabon 1997‐8 {published data only}
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Gabon‐Libreville 98 {published data only}
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Gambia 1994 {published data only}
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Kenya 1989 {published data only}
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Kenya‐Entosopia 94 {unpublished data only}
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Kenya‐Kibwezi 1997 {published data only}
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Kenya‐Mombasa 90 {published data only}
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Kenya‐Ortum 1991 {unpublished data only}
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Kenya‐Sololo 1993 {unpublished data only}
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Kenya‐Taveta 1994 {unpublished data only}
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Kenya‐Turiani 1991 {unpublished data only}
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Kenya‐Turiani 1992 {unpublished data only}
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Kenya‐West 1987 {published data only}
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Cameroon‐S Est 1993 {unpublished data only}
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Cameroon‐Yaounde87‐8 {published data only}
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