Malaria remains an important cause of illness and death in many tropical countries. In 2011, 216 million cases of malaria were estimated to have occurred globally and in 2010 there were approximately 655,000 deaths due to malaria (WHO 2012). Global malaria eradication efforts have resulted in a decrease in mortality and morbidity, with global mortality from malaria falling by 25% since 2000 (WHO 2012). The majority of malaria cases are caused by the species Plasmodium falciparum and Plasmodium vivax. P. falciparum causes a more severe form of malaria which affects several body organs. High mortality rates are observed in people with severe infection and high parasitaemia. In addition, the parasite is resistant to many first-line antimalarial agents (including chloroquine and sulfadoxine-pyrimethamine) (Fernando 2011a). P. vivax is less virulent than P. falciparum and seldom causes death. However, it causes substantive illness in endemic areas. The incidence of P. vivax infection has become particularly important in countries aiming for malaria elimination. Currently, there are 32 of these malaria endemic countries engaged in malaria elimination efforts, of which 25 of these countries are mainly targeting elimination of P. vivax. Another 67 countries are working towards reducing and controlling the high burden of malaria mortality and morbidity (Feachem 2010; Fernando 2011a). P. vivax infection has been treated with chloroquine but resistance to this widely available drug has been reported on all continents in which malaria caused by P. vivax is endemic (Rieckmann 1989; WHO 2009). Furthermore, eradication of liver stages of the disease is necessary to avoid relapses. Due to these facts and the large number of infections reported, malaria caused by P. vivax is increasingly being identified as an important public health problem in endemic areas (WHO 2009).
Description of the condition
Malaria caused by P. vivax results in significant morbidity and loss of productivity in endemic areas. It accounts for significant school absenteeism and recurrent infections may have a role in causing cognitive impairment in children (Fernando 2010). Furthermore, it is a major issue in pregnancy as it is a prime cause of anaemia, premature and low birth weight deliveries in endemic areas (Villegas 2007). Notably, the life cycles of P. falciparum and P. vivax differ. P. vivax can have dormant forms in the hepatocytes, known as hypnozoites, which can remain dormant for weeks or even months. Thus, a single infection with P. vivax can be responsible for a relapse or series of relapses after an apparent cure. Therefore eradication of the hepatic stage forms of the parasite after P. vivax infection is necessary to prevent recurrences. Treatment of people infected with P. vivax with blood schizontocidal agents alone will not result in complete cure as these agents are not capable of clearing the hepatic form of the parasite.
Primaquine, an 8-aminoquinoline, was first licensed for use in the 1950s by the Food and Drug Administration (FDA), United States (Hill 2006), for treatment of malaria caused by P. vivax infection. Since then, it has held an unchallenged place in the cure and prophylaxis of vivax malaria as it is the only licensed drug capable of eliminating the hypnozoites of P. vivax. Without administration of primaquine in adequate doses, complete cure of patients with P. vivax infection is difficult, and patients often have relapses of clinical disease (Fernando 2011b).
Description of the intervention
Primaquine is used for three indications in vivax malaria, namely: a) for radical cure of patients with confirmed parasitaemia; b) as primary prophylaxis (to be taken regularly during the exposure period to prevent a new infection); or c) as terminal prophylaxis (to be taken at the end of the exposure period to clear any liver forms of parasites and to avert any relapses) (Hill 2006). Currently, primaquine is not used for primary prophylaxis as there are safer and better tolerated drugs for this indication (Hill 2006; Fernando 2011a).
Despite being an effective drug, use of primaquine has caused some concerns. Firstly, it carries the unwarranted side effect of precipitating haemolysis (which can be life-threatening) in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked recessive condition (Ramos 2010). For this reason, it is contraindicated for use in pregnancy as the G6PD status of the fetus cannot be determined. In addition, other side effects include precipitation of methaemoglobinaemia and gastrointestinal disturbances (Carmona-Fonseca 2009). Secondly, primaquine resistance has been reported as isolated cases from different area pockets (Hill 2006). Primaquine is always administered with a blood schizontocidal agent. Therefore resistance to primaquine is difficult to discern from resistance to the schizontocidal agent. However, there are case reports of treatment failure when primaquine was administered with an effective schizontocidal agent in adequate doses (Reddy 2006). One of the earliest cases of primaquine failure was reported in Southeast Asia during the time of World War II (Chesson strain of P. vivax) (Ehrman 1944). Since then, there have been few reports of primaquine resistance. There is still doubt as to whether these reported cases of resistance are due to true resistance or treatment failure due to inadequate dosing (Fernando 2011b). Most cases of reported treatment failure are with the dosing regimen of 15 mg/day. Studies have shown that at increased dosage relapse rates diminish (Baird 2004). Furthermore, adjustment of dose according to bodyweight also helps to reduce the incidence of relapses (Goller 2007). True resistance to primaquine is possible and this could potentially be a serious situation as it is the only drug available in its class to clear hypnozoites. The third concern with primaquine is that when it is given for radical cure or for terminal prophylaxis it has to be continued for 14 days, which often leads to poor compliance (Hill 2006).
A search for a replacement drug for primaquine in its curative role has been ongoing for the last few decades. Several options have been explored, including tafenoquine, bulaquine, tinidazole and inidazolidinone. Bulaquine is the pro-drug of primaquine and is currently not licensed for sale outside India (Wells 2010). Of these drug options, tafenoquine has shown the greatest potential to replace primaquine in treatment regimens.
How the intervention might work
Tafenoquine is an 8-aminoquinoline (Wells 2010) and is a synthetic analogue of primaquine (Walsh 2004). The exact mechanism of action of tafenoquine is not yet known. Based on early studies, some specialists believe it is longer acting, safer, and more effective than primaquine (Walsh 2004). Preclinical studies showed better activity of tafenoquine compared to primaquine against both hepatic and erythrocytic forms of the parasite. Phase I and II trials have been conducted to evaluate its safety (Brueckner 1998a; Brueckner 1998b). As it has been more than a decade since tafenoquine use has been studied for treating vivax malaria.,
Why it is important to do this review
Primaquine is a unique drug in combating vivax malaria but has side effects which can sometimes be life-threatening especially in people with G6PD deficiency. In addition, the parasite may be developing resistance to the drug. Tafenoquine is a possible alternative that has shown promise in replacing primaquine. Therefore, it is important to compare the efficacy and safety of tafenoquine for radical cure, primary prophylaxis and terminal prophylaxis of vivax malaria from the available data of controlled clinical trials conducted to date.
- To assess effects of tafenoquine in relation to cure and prophylaxis of P. vivax malaria
- To compare the side effects and adverse events of tafenoquine versus placebo or other antimalarial drugs.
Criteria for considering studies for this review
Types of studies
We will include randomized controlled clinical trials (RCTs).
Types of participants
1. For trials evaluating radical cure, we will include patients that contracted malaria caused by P. vivax and were treated with either tafenoquine or other drugs.
2. Regarding trials assessing the efficacy of tafenoquine for primary prophylaxis, we will include healthy individuals exposed to the infection in endemic areas.
3. For trials assessing terminal prophylaxis, we will include individuals who were exposed to the infection in an endemic area and received malaria prophylaxis but later on moved to non-endemic areas.
Types of interventions
For radical cure, the use of tafenoquine to achieve clinical and parasitological cure in infected patients and prevention of further relapses from vivax malaria compared against placebo or other standard antimalarial therapy used for the same purpose.
For primary prophylaxis, comparison of tafenoquine in preventing malaria in healthy individuals during the period of exposure compared against placebo or other standard antimalarial therapy.
For terminal prophylaxis, the use of tafenoquine to clear the hepatic hypnozoites in participants who were to leave from an endemic area to a non-endemic area after a period of exposure compared against the use of primaquine for a similar population. During the period of exposure, primary prophylaxis would have been provided by use of a schizontocidal agent.
Types of outcome measures
1. For trials on radical cure: relapses of vivax malaria during the period of follow-up after being cured of the initial infection.
2. For trials on primary prophylaxis: new infections of vivax malaria that were confirmed clinically and parasitologically during the period of exposure.
3. For trials on terminal prophylaxis: new infections of vivax malaria that were confirmed clinically and parasitologically during the period of follow-up after leaving the endemic area.
Side effects and adverse events of tafenoquine versus other standard antimalarial treatments and placebo.
Search methods for identification of studies
We will attempt to identify all relevant trials regardless of language or publication status (published, unpublished, in press and in progress).
We will search the following databases using the search terms detailed in Appendix 1: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; CINAHL; SCOPUS; and LILACS. We will also search the World Health Organization (WHO) clinical trial registry platform and the metaRegister of Controlled Trials (mRCT) for ongoing trials using "tafenoquine" and "malaria" as search terms.
Searching other resources
We will search relevant proceedings of the Multilateral Initiative on Malaria (MIM) Pan-African Malaria Conference and the American Society of Tropical Medicine and Hygiene, Annual Meeting from1990 onwards for trial information.
We will contact researchers working in the field and the WHO for unpublished and ongoing trials.
We will check the reference lists of existing reviews and of all trials identified by the above methods.
Data collection and analysis
Selection of studies
In the initial stage of selection, we (SR, CR and SDF) will independently screen the abstracts of search results to identify studies that meet the inclusion criteria. Depending on the content, we will divide the articles into one of three categories, namely 'relevant', 'not relevant' or 'unclear'. We will then merge the results of individual authors. If we identify any discrepancies, we will resolve them through discussion and the consensus of all authors. We will conduct a search of the bibliographies of the articles in the 'relevant' and 'unclear' categories, as well as review articles on the topic, to identify any missed sources of data. If any potential articles for inclusion are identified, we will also screen and categorize the articles as described above. We will obtain the full text articles for articles that are in the 'relevant' and 'unclear' categories. After reading full text articles, we will re-categorize studies in the 'unclear' category as either 'relevant' or 'not relevant'. We will contact individual authors for further details regarding study methodology if we have any doubts outstanding regarding the classification of studies.
Data extraction and management
CR and SR will extract data from the selected studies and record outcomes independently. SDF will be consulted if there is a discrepancy in opinion. We will develop and use a data extraction and assessment form suited for the needs of this study according to the instructions provided by the Cochrane collaboration (Higgins 2011). We will use Review manager for data analysis and storage (RevMan 2011). In each of the selected studies, we will go through to identify key information including demographic characteristics of selected populations, G6PD status of the subjects, study design and measures to minimize bias, treatment offered in different trial arms with respect to dose and duration, duration of follow up, recorded adverse events and side effects, statistical analysis and reported outcomes. We will also note the limitations noted in each of the studies.Individual study authors will be contacted for missing information.The extracted data will be analysed to meet the objectives mentioned above.
Assessment of risk of bias in included studies
We (SR, CR and SDF) will independently assess the risk of bias for each study using a risk of bias assessment form. We will resolve any discrepancies between the results of the risk of bias analysis through discussion and consensus with individual authors. We will consult other experts if necessary. If data are unclear or not reported, we will write to the trial authors for clarification. Quality scores for individual studies will not be calculated as it is not perceived by some authors as an objective measure of risk of bias (Greenland 1994).
We will assess the risk of bias for individual studies using the Cochrane risk of bias tool. This covers six domains of bias: allocation (selection bias), blinding (performance bias and detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias) and other potential sources of bias. Furthermore, we will summarize the risk of bias for individual studies in a risk of bias table.
Measures of treatment effect
We will express the effect of treatment within trials as risk ratio (RR) for dichotomous outcomes (e.g. relapse of vivax malaria, new infections of vivax malaria). We will summarize continuous outcomes by using arithmetic means and standard deviations (eg duration for a relapse or a new infection). We will calculate the mean difference (MD) to compare continuous outcomes between treatment groups. We will define the level of significance of differences we observe according to the Chi
Unit of analysis issues
When individual trials have not reported specific outcomes in units of analysis, we will attempt to calculate or convert the results to the units used in this analysis. If data are incomplete, we will contact individual authors for missing details. If cluster randomized trials are included, we will make adjustments for clustering effect by a patient-level analysis. We will correct test statistics using the calculated design effect. Trials may use different doses of tafenoquine in multiple-treatment arms against a control. If there are trial arms between different trials that use comparable dosages of tafenoquine and a control, we will combine them for pair-wise comparison in a meta-analysis.
Dealing with missing data
For missing data, we will employ a per protocol analysis for dichotomous data and an available case analysis for continuous data. We will report the missing data in the final analysis and we will contact individual authors to validate whether the data are missing or whether they were available but not published.
Assessment of heterogeneity
We will assess heterogeneity using the I
Assessment of reporting biases
If there are a sufficient number of RCTs (approximately 10) for each primary objective, we will construct funnel plots to look for evidence of publication bias.
We will ana lyze data using Review Manager (RevMan 2011). The initial analysis will be performed by CR, with double checking and recalculations done by SR and SDF independently. For trials on prophylaxis (primary or terminal), we will compare incidence of new malarial infections between tafenoquine and other standard antimalarial drugs or placebo. For trials on radical cure, we will compare relapses following treatment between groups treated with tafenoquine-containing drug regimens and others (without tafenoquine). We will perform the data analyses independently for the three primary objectives. Also, we will collate the data on side effects and adverse events of tafenoquine and we will express these findings as percentage values. Assuming different baseline characteristics of populations in which trials had been carried out (exposure to infection, endemicity and prevalence of infection, prevalence of G6PD deficiency) can influence the effect sizes. Therefore, we will use a random-effects model.
Subgroup analysis and investigation of heterogeneity
If several trials are combined in a meta-analysis, we will conduct subgroup analyses and calculation of heterogeneity to express the treatment effect of tafenoquine versus standard antimalarial treatment or placebo, to elicit a dose-dependent effect of tafenoquine and effect of treatment based on characteristics of recipients such as G6PD status, age and sex. In a similar manner, we will compare the side effects and adverse events attributable to tafenoquine against that of primaquine in trials that have used it in the control arm. We will analyse this further according to the subgroups mentioned above.
If several controlled trials are combined in a meta-analysis, we will use sensitivity analyses to investigate the validity of the results. We will use these analyses to account for the variations attributable to missing data and method of analysis (either fixed-effect model or random-effects model).
We acknowledge Dr. Dulika Sumatipala for her assistance in preparing this protocol. The editorial base for the Cochrane Infectious Diseases Group is funded by UKaid from the UK Government for the benefit of developing countries.
Appendix 1. Detailed search strategies
Contributions of authors
CR, SR and SDF will independently undertake screening of all articles to identify relevant studies for inclusion in the review. CR, SR and SDF will then compare results of article screening and we will resolve any areas of disagreement through discussion. CR will perform the initial data synthesis and this will be independently verified by SR and SDF. CR will write the first draft of the manuscript in consultation with SR and SDF. We will all read the final draft of the review before submission for publication.
Declarations of interest
SR: none known
CR: none known
SDF: none known
Sources of support
- University of Colombo, Sri Lanka.For providing institutional access to databases
- NHS Lincolnshire Trust, UK.For providing access to databases