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Mefloquine for preventing malaria during travel to endemic areas

Abstract Background Mefloquine is one of four antimalarial agents commonly recommended for preventing malaria in travellers to malaria‐endemic areas. Despite its high efficacy, there is controversy about its psychological side effects. Objectives To summarize the efficacy and safety of mefloquine used as prophylaxis for malaria in travellers. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published on the Cochrane Library; MEDLINE; Embase (OVID); TOXLINE (https://toxnet.nlm.nih.gov/newtoxnet/toxline.htm); and LILACS. We also searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; http://www.who.int/ictrp/en/) and ClinicalTrials.gov (https://clinicaltrials.gov/ct2/home) for trials in progress, using 'mefloquine', 'Lariam', and 'malaria' as search terms. The search date was 22 June 2017. Selection criteria We included randomized controlled trials (for efficacy and safety) and non‐randomized cohort studies (for safety). We compared prophylactic mefloquine with placebo, no treatment, or an alternative recommended antimalarial agent. Our study populations included all adults and children, including pregnant women. Data collection and analysis Two review authors independently assessed the eligibility and risk of bias of trials, extracted and analysed data. We compared dichotomous outcomes using risk ratios (RR) with 95% confidence intervals (CI). Prespecified adverse outcomes are included in 'Summary of findings' tables, with the best available estimate of the absolute frequency of each outcome in short‐term international travellers. We assessed the certainty of the evidence using the GRADE approach. Main results We included 20 RCTs (11,470 participants); 35 cohort studies (198,493 participants); and four large retrospective analyses of health records (800,652 participants). Nine RCTs explicitly excluded participants with a psychiatric history, and 25 cohort studies stated that the choice of antimalarial agent was based on medical history and personal preference. Most RCTs and cohort studies collected data on self‐reported or clinician‐assessed symptoms, rather than formal medical diagnoses. Mefloquine efficacy Of 12 trials comparing mefloquine and placebo, none were performed in short‐term international travellers, and most populations had a degree of immunity to malaria. The percentage of people developing a malaria episode in the control arm varied from 1% to 82% (median 22%) and 0% to 13% in the mefloquine group (median 1%). In four RCTs that directly compared mefloquine, atovaquone‐proguanil and doxycycline in non‐immune, short‐term international travellers, only one clinical case of malaria occurred (4 trials, 1822 participants). Mefloquine safety versus atovaquone‐proguanil Participants receiving mefloquine were more likely to discontinue their medication due to adverse effects than atovaquone‐proguanil users (RR 2.86, 95% CI 1.53 to 5.31; 3 RCTs, 1438 participants; high‐certainty evidence). There were few serious adverse effects reported with mefloquine (15/2651 travellers) and none with atovaquone‐proguanil (940 travellers). One RCT and six cohort studies reported on our prespecified adverse effects. In the RCT with short‐term travellers, mefloquine users were more likely to report abnormal dreams (RR 2.04, 95% CI 1.37 to 3.04, moderate‐certainty evidence), insomnia (RR 4.42, 95% CI 2.56 to 7.64, moderate‐certainty evidence), anxiety (RR 6.12, 95% CI 1.82 to 20.66, moderate‐certainty evidence), and depressed mood during travel (RR 5.78, 95% CI 1.71 to 19.61, moderate‐certainty evidence). The cohort studies in longer‐term travellers were consistent with this finding but most had larger effect sizes. Mefloquine users were also more likely to report nausea (high‐certainty evidence) and dizziness (high‐certainty evidence). Based on the available evidence, our best estimates of absolute effect sizes for mefloquine versus atovaquone‐proguanil are 6% versus 2% for discontinuation of the drug, 13% versus 3% for insomnia, 14% versus 7% for abnormal dreams, 6% versus 1% for anxiety, and 6% versus 1% for depressed mood. Mefloquine safety versus doxycycline No difference was found in numbers of serious adverse effects with mefloquine and doxycycline (low‐certainty evidence) or numbers of discontinuations due to adverse effects (RR 1.08, 95% CI 0.41 to 2.87; 4 RCTs, 763 participants; low‐certainty evidence). Six cohort studies in longer‐term occupational travellers reported our prespecified adverse effects; one RCT in military personnel and one cohort study in short‐term travellers reported adverse events. Mefloquine users were more likely to report abnormal dreams (RR 10.49, 95% CI 3.79 to 29.10; 4 cohort studies, 2588 participants, very low‐certainty evidence), insomnia (RR 4.14, 95% CI 1.19 to 14.44; 4 cohort studies, 3212 participants, very low‐certainty evidence), anxiety (RR 18.04, 95% CI 9.32 to 34.93; 3 cohort studies, 2559 participants, very low‐certainty evidence), and depressed mood (RR 11.43, 95% CI 5.21 to 25.07; 2 cohort studies, 2445 participants, very low‐certainty evidence). The findings of the single cohort study reporting adverse events in short‐term international travellers were consistent with this finding but the single RCT in military personnel did not demonstrate a difference between groups in frequencies of abnormal dreams or insomnia. Mefloquine users were less likely to report dyspepsia (RR 0.26, 95% CI 0.09 to 0.74; 5 cohort studies, 5104 participants, low certainty‐evidence), photosensitivity (RR 0.08, 95% CI 0.05 to 0.11; 2 cohort studies, 1875 participants, very low‐certainty evidence), vomiting (RR 0.18, 95% CI 0.12 to 0.27; 4 cohort studies, 5071 participants, very low‐certainty evidence), and vaginal thrush (RR 0.10, 95% CI 0.06 to 0.16; 1 cohort study, 1761 participants, very low‐certainty evidence). Based on the available evidence, our best estimates of absolute effect for mefloquine versus doxycyline were: 2% versus 2% for discontinuation, 12% versus 3% for insomnia, 31% versus 3% for abnormal dreams, 18% versus 1% for anxiety, 11% versus 1% for depressed mood, 4% versus 14% for dyspepsia, 2% versus 19% for photosensitivity, 1% versus 5% for vomiting, and 2% versus 16% for vaginal thrush. Additional analyses, including comparisons of mefloquine with chloroquine, added no new information. Subgroup analysis by study design, duration of travel, and military versus non‐military participants, provided no conclusive findings. Authors' conclusions The absolute risk of malaria during short‐term travel appears low with all three established antimalarial agents (mefloquine, doxycycline, and atovaquone‐proguanil). The choice of antimalarial agent depends on how individual travellers assess the importance of specific adverse effects, pill burden, and cost. Some travellers will prefer mefloquine for its once‐weekly regimen, but this should be balanced against the increased frequency of abnormal dreams, anxiety, insomnia, and depressed mood. 12 April 2019 Up to date All studies incorporated from most recent search All eligible published studies found in the last search (22 Jun, 2017) were included


S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
M efloquine compared with atovaquone-proguanil for preventing malaria in travellers Population: non-im m une adults and children travelling to or living in m alaria-endem ic settings Intervention: m ef loquine 250 m g weekly Comparison: atovaquone-proguanil (250 m g atovaquone and 100 m g proguanil hydrochloride) daily Outcome data collection: physicians perf orm ed blinded assessm ent of whether reported sym ptom s could be related to the study drug

B A C K G R O U N D Description of the condition
Malaria is a parasitic protozoal infection which is usually transmitted through the bite of female Anopheles mosquitoes (Warrell 2002). It is most common in tropical and subtropical regions. Clinical disease is caused by infection of red blood cells by one of four Plasmodium species: P. falciparum, P. vivax,P. ovale, andP. malariae (WHO 2017). Humans can also become infected by forms of malaria that usually infect animals, such asP. knowlesi (WHO 2017). Clinical presentation is nonspecific and varied; symptoms include fever, chills, headache, diarrhoea, muscle cramps, and abdominal pain (WHO 2015). Severe disease is usually caused by infection with P. falciparum, but can also occur following infection with P. vivax and P. knowlesi. Host factors determining severity include genetics, host immune status, and age (WHO 2015).
The true global incidence and prevalence of malaria is difficult to determine; the highest disease burden occurs in sub-Saharan Africa where vital registration and disease notification systems are weak (Murray 2014). However, the latest World Health Organization (WHO) figures estimate 212 million new cases of malaria in 2015 leading to 429,000 deaths (WHO 2016). Around 125 million travellers visit malaria-endemic areas annually, and all need to take steps to prevent infection with malaria (Croft 2005). Each year there are between 10,000 and 30,000 known cases of malaria in returned travellers, but the real figure is likely to be higher due to under-reporting (WHO 2017). The individual risk of acquiring malaria is determined by the host immune status, the area travelled to, the duration of travel and season, and the use of prevention measures. Pregnant women, young children and non-immune travellers are particularly vulnerable to severe disease if they become infected (WHO 2015). In Europe, the incidence of malaria is higher in people who travel to their country of origin to visit friends and relatives than in tourists (Behrens 2015). However, mortality is higher in tourists (Behrens 2015).
The natural life cycle of malaria involves the consecutive infection of two hosts: female Anopheles mosquitoes and humans (CDC 2015a). The female mosquito acquires the disease when taking a blood meal from an infected human host. It will then become infectious over a period of 10 to 14 days depending on the region. Sporozoites are injected into the human host the next time the mosquito feeds. These travel via the blood stream to the liver and develop into schizonts which then rupture releasing merozoites. Merozoites invade erythrocytes and undergo asexual replication. Some of these develop through ring stage trophozoites into schizonts which rupture releasing further merozoites and thus perpetuate the infection. Others will develop into female and male gametocytes which are ingested by Anopheles mosquitoes during a blood meal leading to the spread of disease.

Description of the intervention
Mefloquine has been available for use in Europe since 1985 and the USA since 1990 (Schlagenhauf 1999). Alongside atovaquoneproguanil and doxycycline, it is considered standard chemoprophylaxis by many international health guidelines (CDC 2015b; PHAC 2014; PHE 2015; WHO 2017). Mefloquine belongs to the aryl amino acid group of antimalarial agents. Mefloquine has a long half life and is given as a weekly dose of 250 mg when used for prophylaxis in adults (Schlagenhauf 2010). Mefloquine is effective against all five strains of malaria known to affect humans. Although guidelines vary, many state that mefloquine should be taken for two to three weeks before travel and continued for four weeks following return (WHO 2017).
There are several situations in which mefloquine is potentially advantageous. All guidelines recommend that where avoidable pregnant women should not travel to areas where malaria is endemic (WHO 2017). However, where travel is essential, mefloquine is often the preferred option. Mefloquine is widely considered to be safe within the second and third trimesters of pregnancy and guidelines increasingly recommend its use in the first trimester (CDC 2015b; Schlagenhauf 2010). Mefloquine is suitable for both children who weigh more than 5 kg and breastfeeding mothers (Schlagenhauf 2010). Doxycycline has restrictions on its use during pregnancy due to effects on skeletal development found in animal studies. The use of atovaquone-proguanil is limited by a lack of evidence for safety (PHE 2015). Chloroquine-proguanil is considered safe for pregnant women, but its use is limited by widespread resistance (PHAC 2014).
The main side effects of mefloquine are gastrointestinal, neurological and psychological. Psychological side effects vary from those considered to be very common (including insomnia and abnormal dreaming) to those with unknown frequency (including psychosis and suicidal ideation) (eMC 2015a). Existing drug labels suggest that these side effects are both prodromal and dose related (eMC 2015a).

How the intervention might work
Malaria chemoprophylaxis is defined as the use of antimalarial medication to prevent the clinical symptoms of malaria (Schlagenhauf 2010). This is because no drugs are able to prevent the introduction of infection by destroying the sporozoites injected by the female Anopheles mosquito. Chemoprophylaxis is one of several tools used to prevent malaria; other recommended measures include sleeping under insecticide-treated bed nets, wearing insecticide-treated clothing, and applying chemical repellent sprays to the skin surface (WHO 2017). None of these methods provide complete protection and a combination of approaches is advised. Chemoprophylaxis works by blocking the development or repro-duction of the malaria parasite at various stages in its life cycle: • doxycycline and mefloquine are examples of suppressive prophylactics and act in the blood stream as the schizonts invade erythrocytes. Doxycycline therefore needs to be taken for at least one month after returning from endemic areas (Shanks 2005); • atovaquone-proguanil and primaquine have effects on the early liver stages of Plasmodium spp and prevent the progression to blood stage parasites which cause clinical illness. These agents therefore only need to be taken for one week after leaving the malaria-endemic area (Shanks 2005).
Currently, the baseline efficacy of doxycycline, atovaquoneproguanil and mefloquine when used as prophylaxis to prevent malaria is thought to be similar. Most guidelines therefore recommend selecting appropriate antimalarial prophylaxis based on individual choice, pre-existing conditions, side effect profile, and drug resistance patterns in the destination country (CDC 2015b; PHE 2015; WHO 2017). Drug resistance to all antimalarial agents is a growing concern, and mefloquine resistance has been reported in some areas of north-western Thailand (Treiber 2010; Treiber 2011). In addition, the efficacy of all forms of malaria prevention is impeded by adherence. Nearly all cases of fatal malaria in travellers occur due to non-adherence with prophylactic measures (Schlagenhauf 2010). However, this needs to be balanced against the tolerability and safety of chemoprophylaxis; the frequency of mild to moderate adverse drug reactions varies from 32% to 45% (Schlagenhauf 2003). Both policy makers and individual travellers need to balance carefully the risk benefit profile of contracting malaria against using chemoprophylaxis.

Why it is important to do this review
Mefloquine has long been associated with neurological and psychological side effects which range from mild headaches and dizziness to reports of suicide and psychosis. The frequency and severity of these outcomes has been debated. In 2013 the USA Food and Drug Administration (FDA) released a safety communication regarding potential long-term and significant neurological and psychiatric side effects of mefloquine (FDA 2013). This included the addition of a boxed warning to the drug label, the most serious form of warning that can be issued. Similarly in Europe in 2014 the European Medicine Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) required a change to the summary of product characteristics noting that "...in a small number of patients it has been reported that neuropsychiatric reactions (for example, depression, dizziness or vertigo and loss of balance) may persist for months or longer, even after discontinuation of the drug" (EMA 2014). This has been incorporated into summaries of product characteristics throughout Europe. Most recently the UK Defence Committee has suggested mefloquine should only be used as a drug of last resort (UK Parliament 2016). Previous reviews on this topic have limited analyses to randomized controlled trials (RCTs) (Jacquerioz 2009; Jacquerioz 2015). However, RCTs are not always the optimal study design to determine the type, prevalence or nature of adverse events and adverse effects, and many set inclusion criteria which exclude groups of people who are likely to be affected (Loke 2007). In addition, adverse effects are often the primary outcome measure of non-randomized trials, meaning that researchers may attempt to capture and define adverse events in a more rigorous manner than when they are a tertiary measure (Loke 2011). This Cochrane Review update broadened study inclusion criteria to include non-randomized studies that provide useful information regarding the side effect profile of mefloquine. This review did not address: • the efficacy or safety of alternative forms of malaria chemoprophylaxis; • the use by pregnant women of mefloquine as intermittent presumptive treatment of malaria, or; • the use by travellers of emergency standby malaria treatment.
This new edition replaces the Cochrane Review on mefloquine for preventing malaria in non-immune adult travellers (Jacquerioz 2015). Malaria

O B J E C T I V E S
To summarize the efficacy and safety of mefloquine used as prophylaxis for malaria in travellers.

Types of studies
For efficacy we included randomized and quasi-randomized controlled trials, including cluster-randomized trials. For safety we also included non-randomized controlled trials/cohort studies. We included both prospective and retrospective cohort studies, but excluded studies where recruitment was linked to the occurrence of specific adverse events. A list of study design features for all included studies is included in Appendix 1.

Data extraction and management
Two review authors independently extracted data using a standardized and pre-piloted data collection form. When available we extracted data on: • details of study: start and end dates, setting (country of recruitment and country of malaria exposure), study design, method of participant recruitment and selection, number of participants enrolled, number of participants for whom data was available, mean duration of exposure to malaria, antimalarial resistance pattern of mefloquine and the comparator; • study participants: inclusion and exclusion criteria, age, gender, body mass index (BMI), pregnancy status, risk factors (for malaria and for adverse outcomes), immune or non-immune participants, military or non military; • details of the intervention: drug dose during prophylaxis, use of a loading dose, duration of drug therapy before and after travel, frequency of drug administration and use of any cointerventions; • outcomes measured and reported including definition, method of detection, timing in relation to treatment, duration and frequency of monitoring.
We resolved any disagreements through discussion, and where necessary we consulted a third review author. If clarification was necessary, we attempted to contact the trial authors for further information.
For dichotomous data, we recorded the number of participants experiencing the event and the number analysed in each group. For continuous outcome data, we extracted arithmetic means and standard deviations for each group together with the numbers analysed in each group. We also extract medians and ranges where provided. We extracted details of all serious adverse events and effects. For non-serious adverse events and effects we sought information on the following specific symptoms and groups of symptoms which are frequently associated with mefloquine, doxycycline or atovaquone-proguanil: • ear and labyrinth disorders: vertigo; • eye disorders: visual impairment; • gastrointestinal disorders: nausea, vomiting, abdominal pain, diarrhoea, dyspepsia; • nervous system disorders: dizziness and headaches; • psychiatric disorders: abnormal dreams, insomnia, anxiety, depression, psychosis; and • skin and subcutaneous tissue disorders: pruritis, photosensitivity, vaginal candida.
We also reported data on all other very common (> 1/10) and common (> 1/100 to < 1/10) adverse events and adverse effects, as defined by the electronic Medicines Compendium (eMC 2015b). Where possible we attempted to derive absolute estimates of adverse outcomes (events or effects). For all adverse outcomes, we included only the denominator trials that actively reported the presence or absence of each specific adverse event or effect. Most RCTs and cohort studies collected data on self-reported or clinician-assessed symptoms rather than formal medical diagnoses. Therefore, we reported outcomes as symptoms. For example, we reported on 'depressed mood' rather than 'depression'. When deciding which relative effect measure to present in 'Summary of findings' tables, we considered which meta-analysis most closely answered our PICO (population, intervention, comparator, outcome/s) question. We created a decision tree in advance to assess the directness of a group of studies in relation to: the population studied (short-term international travellers versus other populations), outcomes measured (adverse effects versus adverse events), and study design (RCTs versus cohort studies). The intervention and comparator were fixed in each drug-pair comparison. Other less direct meta-analyses were used in our appraisal of the certainty of the evidence. The decision tree used is provided in Appendix 3. Conventionally, 'Summary of findings' tables include up to seven outcomes. However, the key questions for clinical decision making relate to adverse effects, and therefore limiting the number of outcomes a priori was problematic, as we could not know in advance which adverse effects mefloquine would have. To constrain the number of outcomes in the 'Summary of findings' tables to seven would mean only reporting outcomes where effects were shown, which would lead to selective reporting. We included 'Summary of findings' tables for comparisons of mefloquine with doxycycline and atovaquone-proguanil. This decision was made because chloroquine is used less frequently than mefloquine, doxycyline and atovaquone-proguanil. As reported in Results, the adverse effect profile of mefloquine in comparison to chloroquine was consistent with comparisons with doxycycline and atovaquone-proguanil.

Assessment of risk of bias in included studies
Two review authors independently assessed the risk of bias of each included study. For randomized and quasi-randomized controlled trials we used Cochrane's 'Risk of bias' tool (Higgins 2011). We followed the guidance for making judgements on the risk of bias in five domains: sequence generation; allocation concealment; blinding (of participants, personnel and outcome assessors); incomplete outcome data; selective outcome reporting and other risk of bias. We categorized these judgements as low risk of bias, high risk of bias, or unclear risk of bias. For non-randomized (cohort) studies we assessed the risk of bias using the Cochrane Risk of Bias Assessment Tool for Non-Randomized Studies of Interventions (now referred to as ROBINS-I) (ACROBAT-NSRI tool). We followed the guidance for making judgements on the risk of bias in eight domains: confounding, selection of participants into the study, measurement of interventions, departures from intended interventions, missing data, selection of the reported result and other risk of bias. We categorized these judgements as low risk of bias, moderate risk of bias, serious risk of bias and critical risk of bias. Where no information was provided on a category, this was stated. The criteria we used to make specific judgements are provided in Table 1. For adverse events and adverse effects, we assessed the risk of bias in the conduct of the study by examining whether harms were predefined using standardized or precise definitions, ascertainment methods were adequately described, monitoring was active or passive and data collection was prospective or retrospective ( Table 2). For laboratory tests and other investigations we assessed whether the number and timing of the tests was adequate. We resolved any disagreement through discussion, and where necessary, we consulted a third review author.

Measures of treatment effect
We analysed data using Review Manager 5 (RevMan 5) (RevMan 2014) and combined dichotomous data using risk ratios (RR). For continuous data summarized by arithmetic means and standard deviations, we combined data using mean differences (MD). We present RRs and MD with 95% confidence intervals (CI) and report medians and ranges in tables for non-RCTs.

Unit of analysis issues
When trials included more than two comparison groups, we split the trial for analysis as individual pair-wise comparisons. If more than one comparison group was included in a meta-analysis, we ensured that participants were only counted once by dividing the cases and participants evenly between the comparisons. For clinical cases of malaria, we included participants as the unit of analysis, such that each participant was counted once in the intervention or placebo arm. Where study reporting was unclear regarding the unit of analysis (that is, total clinical cases of malaria rather than clinical cases in each participant) we noted this in footnotes and performed a sensitivity analysis excluding these results.

Dealing with missing data
If data from trial reports were insufficient, unclear, or missing, we attempted to contact the trial authors for additional information. Our primary analysis was a complete-case analysis which excluded all participants without treatment outcomes. No imputation measures for missing data were applied. Where studies had grouped symptoms together by body system when reporting safety outcomes, we contacted authors to obtain disaggregated data. We obtained two additional full data sets (Cunningham 2014; Korhonen 2007) and received further clarification from two study authors (Kato 2013;Sonmez 2005). The full details of subsequent analyses are provided in the characteristics of included studies tables.

Assessment of heterogeneity
We assessed heterogeneity among trials by inspecting forest plots for overlapping CIs, applying the Chi² test with a 10% level of statistical significance, and using the I² statistic with a value of 50% to denote moderate levels of heterogeneity.

Assessment of reporting biases
We were unable to assess publication bias using funnel plots because there were too few trials reporting the same outcomes.

Data synthesis
We carried out statistical analyses using RevMan 5 (RevMan 2014). We analysed randomized controlled trials (RCTs) and non-RCTs separately, and compared interventions as individual pairwise comparisons. In the absence of heterogeneity, we used a fixed-effect model. Where we identified moderate heterogeneity, and it was appropriate to combine data, we used the random-effects model. When it was not appropriate to combine data in a meta-analysis, we tabulated data and reported outcomes as a narrative. We report the term used for each adverse event in each trial. Where trials used different terminology for similar adverse events and adverse effects, we coded them using the preferred term based on Medical Dictionary for Regulatory Activities (MedDRA) terminology (for example, sleepiness, somnolence) and analysed these together (MedDRA 2016).

Subgroup analysis and investigation of heterogeneity
We explored possible sources of heterogeneity using subgroup analyses (study design, military versus non-military participants, short-versus long-duration of travel).

Sensitivity analysis
We conducted sensitivity analyses to evaluate the robustness of the results to the risk of bias components, by excluding studies at high or unclear risk of bias.
Of these, we excluded 1953 after assessing titles and abstracts. We retrieved 209 full text publications to assess for inclusion.

Included studies
We included 20 randomized controlled trials (RCTs) (11, All 20 included RCTs and 35 cohort studies reported safety outcomes. Nine RCTs explicitly excluded participants with a psychiatric history, and 25 cohort studies stated that the choice of antimalarial agent was based on medical history and personal preference. Most RCTs and cohort studies collected data on self-reported or clinician-assessed 'symptoms', rather than formal medical diagnoses. Consequently, when describing these data we used non-medical descriptions such as 'depressed mood' rather than 'depression', even where the trial authors described the symptom as depression. However, four retrospective cohort studies analysed healthcare records (Eick-Cost 2017; Meier 2004; Schneider 2013; Wells 2006) and looked for people with formal mental health diagnoses. Where outcomes were presented grouped by organ system, we approached study authors for additional data and received full data sets for two studies (Cunningham 2014; Korhonen 2007) and additional information from another two (Kato 2013; Sonmez 2005). Three RCTs (1827 participants) and 24 cohort studies (170,487 participants) included short-term international travellers. Five cohort studies included long-term occupational travellers (UK Foreign and Commonwealth Office Staff and Peace Corps volunteers) (13,211 participants); four RCTs (961 participants) and six cohort studies (6588 participants) included military personnel (including 1 study with a mixed military and civilian population). Thirteen RCTs included local residents who did not travel outside their home countries: Australia (Davis 1996) (Schlagenhauf 1997) and Thailand (Boudreau 1991, Bunnag 1992, Nosten 1994, Pearlman 1980. Seven RCTs and three cohort studies were sponsored by Roche (manufacturer of mefloquine), three RCTs and one cohort study were sponsored by GlaxoSmithKline (manufacturer of atovaquone-proguanil), one RCT was sponsored by Pfizer (manufacturer of doxycycline), and one by Mepha Ltd (manufacturer of a film-coated form of mefloquine). Only one RCT and one cohort study reported whether the study sponsor had any influence over collecting, analysis or interpretation of study results or the decision to publish.

Excluded studies
We excluded 141 studies after full-text screening ( Figure 1). We excluded 37 studies because they were not research studies; 29 studies reported no relevant outcomes; 23 studies were single arm cohort studies and did not meet our inclusion criteria; 17 studies compared mefloquine with a regime which is not routinely used; 11 studies were not a randomized or cohort study (for example, case report or case-control study); in seven studies mefloquine was not used at a prophylactic dose, for example, treatment dose; seven studies were multiple publications from the same data set as included studies; four cohort studies the population was identified on the basis of having experienced adverse effects and we excluded 6 studies for other reasons. We have provided full details in the 'Characteristics of excluded studies' tables.

Risk of bias in included studies
We performed 'Risk of bias' assessments for the included RCTs using the Cochrane 'Risk of bias' assessment tool. We assessed the risk of bias in the cohort studies using the ACROBAT-NSRI tool (now referred to as ROBINS-I). For a summary of the 'Risk of bias' assessments for RCTs see Figure 2.

Allocation
Three trials were at low risk of selection bias, with adequate descriptions of generation of the random sequence and allocation concealment (Davis 1996;Overbosch 2001;van Riemsdijk 2002). A further 16 trials were at unclear risk of selection bias due to providing insufficient information regarding their methodology. One trial described sequential allocation of unblinded participants (Steketee 1996).

Incomplete outcome data
Six trials had low and balanced losses to follow-up rates for efficacy outcomes (Hale 2003; Nosten 1994; Overbosch 2001; Salako 1992; Sossouhounto 1995; Weiss 1995). One trial was at high risk of bias because investigators did not follow up participants beyond the active phase of treatment for relapses (Santos 1993). Two studies did not make the method of detection of malaria, frequency or duration of follow up clear (Arthur 1990;Schlagenhauf 2003). Seven trials had low losses to follow-up rates for adverse outcomes (Arthur 1990;Davis 1996;Hale 2003;Pearlman 1980;Salako 1992;Sossouhounto 1995;Weiss 1995). We judged four of the trials to be at high risk of bias because investigators did not provide numbers of participants lost to follow up across groups (Nosten 1994; Steketee 1996); did not assess all participants who received the study drug in the final analysis (Ohrt 1997); and because the proportion of participants who did not complete the study due to adverse outcomes varied significantly between groups (van Riemsdijk 2002).

Selective reporting
Fourteen trials reported on efficacy outcomes, and twelve of these appropriately reported all outcomes. However, 21 trials reported on our safety outcomes and only nine of these appropriately reported on all pre-specified outcomes. Three of these trials only reported on statistically significant differences between groups (Boudreau 1993; Pearlman 1980; Schlagenhauf 1997), and another four did not report data from all time points (Bunnag 1992;Nosten 1994;Ohrt 1997;Overbosch 2001). Two trials reported aggregate data across multiple time points (Schlagenhauf 2003;Steketee 1996), one trial only reports symptoms which occurred in > 10% of participants in each study arm (Davis 1996). Vuurman 1996 only reported events which occurred more than once and Hale 2003 reports the total number of serious adverse events does not allocate them to a drug regimen.  Nine RCTs comparing prophylactic mefloquine with placebo reported efficacy (4032 participants, Table 3), and 13 reported safety outcomes (4293 participants, Table 4). The trials were conducted between 1977 and 2003, and none included participants travelling outside their home country. One trial conducted among soldiers in Indonesia described participants as non-immune (Ohrt 1997), but immunity is likely to be low in other trials from Asia (Bunnag 1992;Nosten 1994;Pearlman 1980). The participants in four trials from Africa were described as semi-immune (Hale 2003;Salako 1992;Sossouhounto 1995;Weiss 1995). Santos 1993 was conducted in an area of Brazil in which endemic transmission occurs.

Effects of interventions
Seven trials used mefloquine at a dose of 250 mg weekly (or equivalent doses for children), four at 250 mg weekly for the first four weeks and then 125 mg weekly for the remainder of the study, and one trial used mefloquine doses of 500 mg every four weeks and 250 mg every two weeks (Santos 1993). Pearlman 1980 used mefloquine doses of 180 mg weekly, 360 mg weekly and 360 mg fortnightly. Trial duration varied from 48 hours to 26 weeks. For safety, nine trials used interviews with study personnel to elicit adverse events (Bunnag 1992;Hale 2003;Nosten 1994;Ohrt 1997;Salako 1992;Santos 1993;Schlagenhauf 1997;Vuurman 1996;Weiss 1995). Of these, six trials questioned participants about symptoms at least weekly (Hale 2003; Nosten 1994; Ohrt 1997; Salako 1992; Vuurman 1996; Weiss 1995). Two trials used participant self-reported diaries to record any adverse events (Davis 1996, Potasman 2002. Pearlman 1980 used a weekly 'sick call' by study personnel and Sossouhounto 1995 provided 'access to the village health centre'. Only two trials used explicit definitions for adverse events and effects that allow for reproducible ascertainment (Davis 1996, Vuurman 1996. For safety outcomes, nine of the 13 trials adequately described how adverse events were ascertained. Eleven trials actively sought adverse events, and all 13 collected data prospectively ( Table 5). Eleven of thirteen which assessed safety outcomes trials did not adequately describe random sequence generation or allocation concealment, and eight did not adequately describe how outcome assessors and study personnel were blinded. We judged eight trials to be at high risk of selective outcome reporting with regard to safety outcomes. In two trials, this was because the overall number of adverse events in each study arm was reported, but not the type or severity (Bunnag 1992; Potasman 2002). Davis 1996 reported only adverse events that occurred in more than 10% of participants in both study arms; Vuurman 1996 reported only adverse events that occurred more than once; and Nosten 1994 only reported on adverse events in the second phase of the trial. Five trials were funded by Roche (manufacturer of mefloquine) (Bunnag 1992;Davis 1996;Santos 1993;Schlagenhauf 1997;Vuurman 1996) and one by GlaxoSmithKline (manufacturer of atovaquone-proguanil) (Hale 2003) and one by Mepha Ltd (manufacturer of a film-coated form of mefloquine) (Potasman 2002).

Cohort studies
Five cohort studies compared mefloquine users with participants who travelled but did not take antimalarial prophylaxis at all ( Hoebe 1997;Rietz 2002;van Riemsdijk 1997;Wells 2006). Four of these were conducted in travellers, and one in military personnel (Table 4). Two cohort studies included travellers who were prescribed an antimalarial agent but did not commence using (Hoebe 1997;  and two asked travellers about an extensive list of general complaints which could have occurred during their journey (Rietz 2002;van Riemsdijk 1997). Wells 2006 was a retrospective healthcare record analysis looking at hospitalizations in active-duty USA military personnel (397, 442 participants). Two cohort studies had non-response rates of over 20%. Wells 2006 was at serious risk for selection of participants and measurement of outcomes because start of follow up began after participants had finished taking mefloquine, authors used surrogate measures for mefloquine exposure and there was a possibility that some participants in the reference groups took mefloquine. Four cohort studies actively sought information from participants about adverse events and only one (van Riemsdijk 1997) obtained information prospectively (see Figure 3).
Mefloquine is highly efficacious in reducing clinical cases of malaria compared to placebo, although there were important differences among trials, particularly regarding the dose of mefloquine used, populations studied and the risk of malaria in the control group (Analysis 1.1). The risk of malaria was highest in the trial in military personnel travelling to Indonesia, described as "largely non-immune", where 53/65 (81%) of those in the placebo group had an episode of malaria compared to 0/67 (0%) with mefloquine (RR 0.01, 95% CI 0.00 to 0.16; Ohrt 1997, 126 participants). In the remaining trials the risk of malaria with placebo ranged from 1% to 59% (Bunnag 1992;Hale 2003;Nosten 1994;Pearlman 1980;Salako 1992;Santos 1993;Sossouhounto 1995;Weiss 1995). Although quantitative heterogeneity was high, the direction of the effect was consistent across all trials. We performed a series of subgroup analyses by dose and immune status of participants, but this did not explain the heterogeneity or provide a reliable point estimate of efficacy with subgroups. Five trials also reported the effect on parasitaemia (which was much more common than clinical malaria) (Hale 2003; Nosten 1994; Salako 1992; Sossouhounto 1995; Weiss 1995). Overall, mefloquine reduced numbers of participants who developed parasitaemia by around 80% (RR 0.18, 95% CI 0.06 to 0.55; 3 trials, 414 participants, Analysis 1.2), and substantially reduced the number of episodes of parasitaemia (RR 0.05, 95% CI 0.00 to 5.25; 2 trials, 510 participants, Analysis 1.2).

Serious adverse events or effects
Only three serious adverse events were reported from six RCTs, none of which were attributed to the drug regimen (1/592 mefloquine users versus 2/629 placebo; 6 trials; 1221 participants, Analysis 1.3). The serious event in the mefloquine user was the death of a pregnant woman who received mefloquine (septic shock after an emergency caesarean section for obstructed labour) (Nosten 1994). For serious pregnancy-related outcomes, Nosten 1994 reported four congenital malformations in the mefloquine group: limb dysplasia (1 case), ventricular septal defect (2 cases), amniotic bands (1 case) and one in the placebo group: anencephaly. All were considered unrelated to the drug regimen (Table 6). By comparison in cohort studies, seven serious adverse effects (all attributed by study authors to the drug regimen) were reported among 913 mefloquine users, compared to none in 254 travellers who did not use antimalarials (RR 3.08, 95% CI 0.39 to 24.11; 2 studies, 1167 participants; Analysis 1.3; Table 7). Five of these were psychological (depression) and two were neurological adverse effects (dizziness). Wells 2006 was a retrospective healthcare record analysis that reported adverse events. It compared numbers of hospitalizations in military personnel who had been prescribed mefloquine and were deployed to active duty in malarial areas, with those who had been deployed to non-malarial areas, and with military personnel with duty zip codes for Europe or Japan, who had not been deployed to active duty. Mefloquine users were less likely to be hospitalized (after deployment) with mood disorders (RR 0.38, 95% CI 0.17 to 0.86; 241,239 participants) or for any cause (RR 0.60, 95% CI 0.51 to 0.71; 241,239 participants) than military personnel who did not receive any antimalarial agents (but who were deployed to a war zone).

Discontinuations due to adverse effects
Within RCTs the number of people who discontinued the study drug due to adverse effects was low in both groups: 6/541 (1.1%) with mefloquine versus 4/583 (0.7%) with placebo (RR 1.64, 95% CI 0.55 to 4.88; 7 trials, 1124 participants, Analysis 1.4). No comparative data were available on this outcome from cohort studies because the comparison was with no treatment.

Prespecified adverse events or effects
None of the RCTs or cohort studies for this comparison reported on adverse effects (symptoms attributed by researchers or participants to the drug regimen). All comparisons were for adverse events (all symptoms that occurred while taking the study drug).

Gastrointestinal symptoms
Within RCTs, participants who received mefloquine were more likely to experience nausea than those who took placebo (RR 1.35, 95% CI 1.05 to 1.73; 2 trials, 244 participants, Analysis 1.5), but there was no difference between groups for vomiting, abdominal pain or diarrhoea (Analysis 1.6; Analysis 1.7; Analysis 1.8). The results from cohort studies were consistent with this finding, with more mefloquine users experiencing nausea (RR 1.85, 95% CI 1.42 to 2.43; 3 studies, 1901 participants, Analysis 1.5). One RCT in pregnant women (Nosten 1994) reported on both upper and lower abdominal pain. Inclusion of both groups of results in sensitivity analyses had no impact on the results.

Neurological symptoms
Mefloquine users in RCTs were no more likely that recipients who took placebo to experience headache (RR 0.84, 95% CI 0.71 to 0.99; 5 trials, 791 participants, Analysis 1.9) or dizziness (RR 1.03, 95% CI 0.90 to 1.17; 3 trials, 452 participants, Analysis 1.10). This is in contrast to cohort studies, in which participants who took mefloquine were significantly more likely to experience dizziness than participants who travelled but took no prophylaxis (RR 1.80, 95% CI 1.29 to 2.49; 3 studies, 1901 participants, Analysis 1.10).

Other symptoms
Mefloquine users in cohort studies were more likely to experience pruritis (RR 6.71, 95% CI 1.58 to 28.55; 1 cohort study, 197 participants, Analysis 1.16). However, this finding was not replicated in RCTs (RR 0.86, 95% CI 0.60 to 1.24; 3 RCTs, 609 participants, Analysis 1.16). There was no difference between groups for visual impairment and vertigo in either RCTs nor cohort studies (Analysis 1.17; Analysis 1.18). Other adverse events reported in more than 1% of study participants (in either study arm) in RCTs and cohort studies are presented in Analysis 1.19 and Analysis 1.20. Only respiratory tract infection reached statistical significance between groups; data were from a single trial with few events (RR 2.63, 95% CI 1.04 to 6.61; 1 trial, 140 participants). Studies reporting groups of symptoms or other outcomes which could be used as proxy markers of psychological or neurological adverse effects are reported in Appendix 4.

Adherence
In their RCT, Davis 1996 reported on any measure of adherence to the drug regimen assessed by pill count and direct questioning. Reported adherence was 100% in both arms.

Comparison 2: Mefloquine versus doxycycline
Description of studies

RCTs
Four RCTs, enrolling 1317 participants, reported on both efficacy and safety (Table 8). One was conducted in short-term travellers (Schlagenhauf 2003), two in military personnel (Arthur 1990;Ohrt 1997) and one in Kenyan children (Weiss 1995). The populations were described as non-immune (Arthur 1990;Schlagenhauf 2003), "largely" non-immune (Ohrt 1997) and semi-immune (Weiss 1995). Trial duration varied from four weeks to four months. The method for detecting malaria was unclear in two trials (Arthur 1990;Schlagenhauf 2003). Three studies conducted daily interviews with participants to monitor for adverse events (Arthur 1990; Ohrt 1997; Weiss 1995) and one used a participant self-reporting questionnaire (Schlagenhauf 2003). None of the RCTs adequately described allocation concealment. Blinding of participants was adequately described in all but Weiss 1995; two trials did not adequately describe how outcome assessors were blinded (Arthur 1990;Schlagenhauf 2003). We also considered Ohrt 1997 and Schlagenhauf 2003 to be at high risk of selective outcome reporting because they did not report all collected data: Ohrt 1997 completed an exit questionnaire within the last month of the study, but did not report all results; Schlagenhauf 2003 collected data at baseline, twice before travel and once on return, but only presented data for participants "who completed questionnaires at recruitment and at least one of the follow up periods". All four studies collected information on adverse events actively and prospectively (Table 9). Schlagenhauf 2003 was funded by GlaxoSmithKline (manufacturer of atovaquone-proguanil) and Roche (manufacturer of mefloquine) and Ohrt 1997 was funded by Roche and Pfizer (manufacturers of doxycycline) but specified that "neither of the pharmaceutical companies that provided support played any role in the gathering, analysing or interpreting the data".

Cohort studies
We included 20 cohort studies that assessed and reported safety outcomes, in a total of 435,209 participants. Of these, 10 were conducted in short-term travellers ( (Figure 4). We judged two to be at high risk of missing data; Goodyer 2011 included pre-and post-travel questionnaires, with an interim loss to follow-up rate of 27%, and Terrell 2015 excluded participants from the analysis if they reported an adverse effect but did not record its impact on their ability to work. None of these studies blinded participants or mentioned outcome assessors being blinded to intervention status. Seven studies collected data retrospectively, and eight collected information at an unclear or variable time point during treatment (Table 9). One study (Goodyer 2011) was funded by Glaxo-SmithKline (manufacturer of atovaquone-proguanil), one (Meier 2004) by Roche (manufacturer of mefloquine), and one (Philips 1996) by Roche and Pfizer (manufacturers of doxycycline) (see Figure 4).
Only seven episodes of malaria were reported while participants were receiving prophylaxis; similar numbers of participants were infected in both arms (4 episodes in 378 mefloquine users versus 3 episodes in 366 doxycycline users: RR 1.35, 95% CI 0.35 to 5.19; 4 trials, 744 participants, Analysis 2.1). Weiss 1995 reported on episodes of parasitaemia in the semi-immune population. There was no clear difference between groups (RR 1.47, 95% CI 0.68 to 3.14; 62 participants).

Serious adverse events or effects
Only Ohrt 1997 described an adverse event as "serious" (acute hysteria) in a doxycycline user, but did not provide sufficient detail to meet our definition. No other serious adverse outcomes were described in RCTs including 348 mefloquine users and 334 doxycycline users (Analysis 2.2; Table 6). In comparison, three cohort studies reported a total of 29 serious adverse effects (attributed to the study drug by users): 19 in 2125 mefloquine users, and 10 in 1597 doxycycline users (RR 1.53, 95% CI 0.23 to 10.24; 3 cohort studies, 3722 participants; Analysis 2.2, Table 7). Serious adverse effects in mefloquine users were psychological (4 cases) or due to dizziness (3), heart palpitations (2), limb numbness (1), abdominal pain (1), visual disturbance (1), yeast infection (1), passing out (2), seizure (1) and three hospitalizations with "either gastrointestinal or neurologic symptoms". In contrast, serious adverse effects in doxycycline users were due to gastrointestinal disturbance (6), anaemia (1), photosensitivity (1), oesophagitis (1) and cough (1). In addition, a cohort study (Lobel 2001) reported on hospitalizations in users of mefloquine and doxycycline which were not necessarily attributed to the drug regimen (adverse events). There were eight hospitalizations in 3703 mefloquine users, and none in 69 doxycycline users, with no statistically significant difference between groups (RR 0.32, 95% CI 0.02 to 5.51; 3772 participants, Table 6).

Discontinuations due to adverse effects
There were no overall differences between groups in numbers of discontinuations due to adverse effects in the RCTs (

Prespecified adverse outcomes
Prespecified adverse effects (attributed to the study drug) were only reported by cohort studies conducted in long-term occupational travellers (3 studies) and military personnel (3 studies). These form our primary analysis (see Appendix 3 for decision tree). One RCT in military personnel (Ohrt 1997) and one cohort study in short-term international travellers (Philips 1996) reported on all symptoms experienced by participants while taking the study drug (adverse events). Two large retrospective analyses of health records in general practice (Meier 2004) and USA military personnel (Eick-Cost 2017) databases compared rates of incident neurological or psychological diagnoses in participants who had received a prescription for mefloquine or doxycycline (adverse events).

Gastrointestinal symptoms
Across the cohort studies reporting adverse effects, mefloquine users were less likely to report nausea (RR 0.37, 95% CI 0.30 to 0.45; 5 cohort studies, 2683 participants, Analysis 2.4), vomiting (RR 0.18, 95% CI 0.12 to 0.27; 4 cohort studies, 5071 participants, Analysis 2.5), abdominal pain (RR 0.30, 95% CI 0.09 to 1.07; 4 cohort studies, 2569 participants, Analysis 2.6) and diarrhoea (RR 0.28, 95% CI 0.11 to 0.73; 5 cohort studies, 5104 participants, Analysis 2.7). However, this finding was not consistent across study types. In the single RCT in military personnel that reported adverse events, no differences were demonstrated for nausea, vomiting, abdominal pain or diarrhoea. In the single cohort study in short-term international travellers reporting adverse events, mefloquine users were more likely to report nausea and diarrhoea; there was no difference between groups for abdominal pain (Analysis 2.4; Analysis 2.5; Analysis 2.6; Analysis 2.7). Dyspepsia was consistently more common in doxycycline users but there was substantial heterogeneity in the size of this effect (RR 0.26, 95% CI 0.09 to 0.74; 5 cohort studies, 5104 participants, I² statistic = 77%, Analysis 2.8)
In the RCT in military personnel (Ohrt 1997) and a cohort study in short-term international travellers (Philips 1996) both headache and dizziness were more common in mefloquine users. However, a large retrospective analysis of health records in military personnel (Eick-Cost 2017) found higher rates of dizziness in doxycycline users (Analysis 2.9; Analysis 2.10).

Psychological symptoms
In the cohort studies reporting adverse effects, mefloquine users were more likely to report abnormal dreams (RR 10 The findings of the single cohort study in short-term international travellers reporting adverse events (Philips 1996) were consistent with this. However in the single RCT (Ohrt 1997) and the large retrospective healthcare record analyses, there were either no differences between groups, or doxycycline users were more likely to experience psychological symptoms (Analysis 2.11; Analysis 2.12; Analysis 2.13; Analysis 2.14; Analysis 2.15).

Other prespecified symptoms
Pruritis was more common in doxycycline users in cohort studies reporting adverse effects (RR 0.52, 95% CI 0.30 to 0.91; 2 cohort studies, 1794 participants, Analysis 2.16), but more common with mefloquine in the single cohort in short-term travellers reporting adverse events (RR 2.69, 95% CI 0.93 to 7.78; 1 cohort study, 668 participants). In cohort studies reporting adverse effects, photosensitivity was more common in doxycycline users (

Other adverse events and effects
A range of other adverse effects were reported by the cohort studies. These included alopecia (hair loss), asthenia (physical weakness), balance disorder, decreased appetite, fatigue, hypoaesthesia (numbness), malaise, mouth ulcers, palpitations and tinnitus (Analysis 2.20). Mefloquine users were more likely to report alopecia ( Studies reporting groups of symptoms or other outcomes that could be used as proxy markers of psychological or neurological adverse effects are reported in Appendix 5.

Adherence
Arthur 1990, an RCT, performed serological assays to assess adherence. Arthur 1990 reported measurable serum drug levels at the end of the trial in 87% of 119 military personnel prescribed doxycycline and 92% of 134 who were prescribed mefloquine. However, medication was administered under the supervision of each participant's squad leader. Thirteen cohort studies compared the proportion of participants with 100% self-reported adherence and found higher rates of adherence during travel in mefloquine users (RR 1.15, 95% CI 1.12 to 1.18; 13 cohort studies, 15,583 participants, Analysis 2.23), but no differences between groups in the post-travel period (RR 1.08, 95% CI 0.95 to 1.22; 4 cohort studies, 840 participants, Analysis 2.23). Most (77%) mefloquine users described themselves as adherent during travel (range 24% to 100%), compared to 63% of doxycycline users (range 37% to 92%). In the post-travel period this dropped to 55% of mefloquine users (range 50% to 87%) and 51% of doxycycline users (range 27% to 75%). There was no difference in the results when the analysis was limited to shortterm international travellers (RR 1.11, 95% CI 1.06 to 1.17; 4 cohort studies; 8390 participants). . Seven studies collected adverse event data retrospectively and six collected these data at an unclear or variable time point during treatment (Table 11). One study (Goodyer 2011) was funded by GlaxoSmithKline (manufacturer of atovaquoneproguanil) and one (Schneider 2013) was funded by Roche (manufacturer of mefloquine) ( Figure 5).

Serious adverse events or effects
Overbosch 2001, an RCT, reported 10 serious adverse events in 483 participants who received mefloquine and four in 493 participants who received atovaquone-proguanil. None were considered attributable to the drug regimen (Table 6). Three cohort studies reported a total of 15 serious adverse effects (attributed by participants to the study drug) in 2651 mefloquine users (Table 7). There were no serious adverse effects reported in participants who received atovaquone-proguanil (940 users). The difference between groups was not statistically significant (RR 1.40, 95% CI 0.08 to 23.22; 3 cohort studies, 3591 participants, Analysis 3.2). The serious adverse effects in mefloquine users were: psychological (4 cases), dizziness (3), heart palpitations (2), limb numbness (1), abdominal pain (1), visual disturbance (1), yeast infection (1), and passing out (2).

Neurological symptoms
Mefloquine users were more likely to report headache although this did not reach standard levels of statistical significance in the RCT (RR 1.72, 95% CI 0.99 to 2.99; 976 participants). The effect was larger and consistent across the cohort studies (RR 3.42, 95% CI 1.71 to 6.82; 8 cohort studies, 4163 participants, I² statistic = 0%, Analysis 3.9). Similarly, dizziness was more common in mefloquine users in the RCT (RR 3.99, 95% CI 2.08 to 7.64) and consistently more common in the cohort studies (RR 3.83, 95% CI 2.23 to 6.58; 8 cohort studies, 3986 participants, Analysis 3.10). The same trend was seen in the retrospective healthcare record analyses, although the effect size was smaller (RR 1.23, 95% CI 1.04 to 1.46; 49,419 participants).

Psychological symptoms
In the RCT, mefloquine users were more likely than atovaquoneproguanil users to report abnormal dreams ( Analysis 3.14). In addition, 21 mefloquine users and no atovaquone-proguanil users reported abnormal thoughts or perceptions, but the difference between groups was not statistically significant (RR 1.50, 95% CI 0.30 to 7.42; 3 cohort studies, 2441 participants, Analysis 3.15). Consistent effects were seen in the retrospective healthcare record analysis (adverse events, Eick-Cost 2017) although the effect size was smaller.

Other adverse outcomes
Other adverse effects reported in more than 1% of study participants in cohort studies (in either study arm) included: allergic reaction, alopecia (hair loss), asthenia (weakness), balance disorder, cough, disturbance in attention, dyspepsia, fatigue, hypoaesthesia, loss of appetite, muscle pain, palpitation, photosensitization, pyrexia, rash, restlessness, slight illness, somnolence, tinnitus and circulatory disorders (Analysis 3.18). Mefloquine Analysis 3.20). However, analysis in the post-travel period found that mefloquine users were less likely to complete the regimen (RR 0.80, 95% CI 0.74 to 0.85; 966 participants); 93% of mefloquine users were adherent during travel, dropping to 70% in the post-travel period, compared to 95% and 88% for atovaquone-proguanil. Six cohort studies compared the proportion of participants with 100% self-reported adherence and found no difference during travel (RR 1.08, 95% CI 0.86 to 1.34; 6 cohort studies, 5577 participants, Analysis 3.21) or in the post-travel period (RR 0.89, 95% CI 0.64 to 1.23; 2 cohort studies, 422 participants, Analysis 3.21). In these studies, 60% of mefloquine users described themselves as adherent during travel, dropping to 51% in the posttravel period, compared to 53% and 62% respectively for people who took atovaquone-proguanil. Belderok 2013 categorized travellers as adherent if they took at least 75% of prescribed doses. Belderok 2013 reported higher rates of adherence in participants who took mefloquine both during and after travel. Meta-analysis of these results did not result in a significant difference (during travel: RR 1.04, 95% CI 0.77 to 1.40; 5 cohort studies, 2810 participants, post-travel: RR 1.07, 95% CI 0.72 to 1.59; 3 cohort studies, 941 participants).

Pregnancy outcomes
One cohort study included respondents who were pregnant (Cunningham 2014) but did not report which prophylaxis the women took or on any outcomes related to pregnancy.

RCTs
We included five RCTs comparing mefloquine with chloroquine that reported on efficacy and six on safety (Table 12). Trials were conducted in immune or semi-immune adult populations in the Ivory Coast (Sossouhounto 1995), Malawi (Steketee 1996), Nigeria (Salako 1992) Thailand (Boudreau 1991; Bunnag 1992) and the USA. (Boudreau 1993). The Malawi trial by Steketee 1996 was limited to pregnant women. None included non-immune travellers or children. All six trials used interview with study personnel to obtain information about adverse events. Boudreau 1993 excluded participants with a history of psychiatric or neurological problems. None of the trials adequately described random sequence generation or allocation concealment. Participants were adequately blinded in four trials (Boudreau 1993; Bunnag 1992; Salako 1992; Sossouhounto 1995), the trial in pregnant women did not blind participants or outcome assessors (Steketee 1996). We judged three of the trials to be at high risk of selective reporting of safety outcomes. Bunnag 1992 was funded by Roche (manufacturer of mefloquine). Five trials actively sought information on adverse events (Boudreau 1991; Boudreau 1993; Bunnag 1992; Salako 1992; Steketee 1996) and all collected information prospectively (Table 13).

Cohort studies
We included 15 cohort studies in this comparison; 12 included short-term travellers   (Steffen 1993, 145,003 participants), collected information from travellers flying back to Europe from Africa. The remaining three studies collected information through interviews with study personnel Hill 2000;Napoletano 2007) Eight of the cohort studies had non-response rates of over 20% ( Figure 6). We judged 14 cohort studies to be at low risk of missing data, the largest study ) was at moderate risk due to a 15% loss to follow-up between the first and second questionnaire in the second phase of the study. Steffen 1993 did not report on non-serious adverse effects from the first phase of the study (44,677 participants) and was funded by Roche (manufacturer of mefloquine  Figure 6).
Participants who took mefloquine were less likely to experience malaria than participants who took chloroquine (RR 0.38, 95% CI 0.28 to 0.52; 4 RCTs, 877 participants, Analysis 4.1). However, two RCTs were conducted in settings with known chloroquine resistance at the study sites, and the other two reported no episodes of malaria in either study arm. All RCTs included semi-immune populations, and were conducted over 20 years ago.

Serious adverse events or effects
Across four RCTs, two serious adverse events were reported in 529 mefloquine users and none in 471 chloroquine users; the difference between groups was not significant (RR 2.77, 95% CI 0.32 to 23.85; 5 RCTs, 1000 participants, Analysis 4.2, Table 6). Both events were psychiatric admissions due to depression and suicidal thoughts; both study participants had previous psychiatric histories. In one case, the participant's psychiatrist did not think the event was drug-related, and in the other "felt this individual's current depression was not drug related, unless it was aggravated by inability to sleep". Additionally, Steketee 1996 described one withdrawal due to a "neuropsychiatric side effect" (disorientation to time and place) but did not provide enough detail to meet our definition of serious adverse event or effect. Four cohort studies reported a total of 29 serious adverse effects (attributed by users to the study drug) in 56,674 mefloquine users, and 13 serious adverse effects in 22,583 chloroquine users. The difference between groups was not statistically significant (RR 1.14, 95% CI 0.62 to 2.07; 6 cohort studies; 79,257 participants; Analysis 4.2). Serious side effects in mefloquine users were psychological (11 cases), dizziness (5), seizures (3), heart palpitations (2), abdominal pain (1), blackout (2), visual disturbance (1), limb numbness (1), yeast infection (1), and two which were not described (Table 7). Those in chloroquine users were psychological (4 cases), seizures (3), abdominal pain (1) and visual disturbance (1).

Discontinuations of the study drug due to adverse effects
There was no differences between groups in the number of discontinuations due to adverse effects in the RCTs (

Prespecified adverse effects
The RCTs only reported adverse events (all symptoms without assessing whether they might be related to the study drug). Our primary analysis was therefore taken from the six cohort studies reporting adverse effects.

Gastrointestinal symptoms
There were no consistent differences between groups for nausea ( Overall, mefloquine users were less likely to report diarrhoea but this finding was from a single cohort study with over 90% of the weight in the meta-analysis (RR 0.84, 95% CI 0.74 to 0.95; 5 cohort studies, 5577 participants; Analysis 4.7). No difference was seen in the RCTs (Analysis 4.7).

Neurological symptoms
In the cohort studies, there was no substantial difference between groups in the proportion of participants reporting headache (RR 0.84, 95% CI 0.53 to 1.34; 6 cohort studies, 56,998 participants, Analysis 4.8), but mefloquine users reported more dizziness (RR 1.51, 95% CI 1.34 to 1.70; 5 cohort studies, 56,710 participants; Analysis 4.9). The RCTs reporting adverse events did not demonstrate a difference between groups (Analysis 4.8; Analysis 4.9).

Prespecified adverse symptoms restricted to cohort studies in short-term travellers
Analysis 4.18 presents the pre-specified adverse symptoms restricted to the cohort studies in short-term travellers.

Pregnancy-related outcomes
One quasi-randomized trial (Steketee 1996) was conducted in pregnant Malawian women and reported no difference between mefloquine and chloroquine for spontaneous abortions (RR 0.80, 95% CI 0.36 to 1.79; 2334 participants), still births (RR 1.01, 95% CI 0.67 to 1.52; 2334 participants) or congenital malformations (0 events in either study arm, 2334 participants, Analysis 4.21). Steketee 1996 sequentially allocated participants to each drug regimen, and did not blind participants or study personnel.

Adherence
Three cohort studies in short-term travellers (Hill 2000; Laver 2001; Rietz 2002) compared the proportion of participants with 100% self-reported adherence and found no difference overall (RR 1.00, 95% CI 0.90 to 1.13; 3 cohort studies, 852 participants, Analysis 4.22). Among participants in these studies, 84% of mefloquine users described themselves as adherent during travel (range 71% to 88%) compared to 82% of chloroquine users (range 82% to 85%). In the two studies in longer-term occupational travellers, self-reported adherence was higher in mefloquine users (RR 2.02, 95% CI 1.80 to 2.26; 2 cohort studies, 5777 participants). One study (Stoney 2016) measured adherence in the post-travel period and found no difference (RR 1.00, 95% CI 0.54 to 1.87; 46 participants, Analysis 4.22). However, rates of completion were low in both groups (56% in mefloquine users and 54% in chloroquine users).

Subgroup analyses
Given the similarity in adverse effect profiles for mefloquine compared to the two main alternatives (doxycycline and atovaquoneproguanil), we combined findings from the two comparisons and performed a series of subgroup analyses to explore the effects of study design, duration of travel, and military versus non-military participants.

Study design
Only one RCT performed a blinded assessment of whether there was a reasonable possibility that any reported symptoms could be related to the study drug (Overbosch 2001). We compared this with participants self-reporting of adverse effects in cohort studies. The findings were largely consistent across study designs with mefloquine users experiencing higher rates of headache (Analysis 5.4), dizziness (Analysis 5.5), abnormal dreams (Analysis 5.6), insomnia (Analysis 5.7), anxiety (Analysis 5.8) and depressed mood (Analysis 5.9). Although the relative risk of psychiatric side effects was consistently slightly higher in cohort studies, in only one case was the test for subgroup differences statistically significant (abnormal dreams: RCT: RR 2.04, 95% CI 1.37 to 3.04; 976 participants, cohort studies: RR 7.30, 95% CI 2.51 to 21.18; 7 cohort studies, 4543 participants, test for subgroup differences P = 0.03).

Duration of travel
The relative risk of all psychological adverse effects was higher with longer-term travel than in short-term travel; insomnia (short-term RR 3.09 versus longer-term RR 8.67), anxiety (short-term RR 3.26 versus longer-term RR 18.05), depressed mood (short-term RR 2.52 versus longer-term RR 12.59) and abnormal thoughts and perceptions (short-term RR 1.29 versus longer-term RR 7.78) (Table 14). However, in only one case was the test for subgroup differences statistically significant (P range 0.02 to 0.40). This same effect was not observed with gastrointestinal symptoms (nausea, abdominal pain, diarrhoea) or neurological symptoms (headache, dizziness).

Military versus non-military participants
There were no significant differences in the relative risk of adverse effects between military and non-military participants (Table 15). Very few cohort studies in military personnel reported on our prespecified symptoms. In one of these in which military personnel who took mefloquine for 6 months or longer (Andersson 2008), the rates of psychological side effects were significantly higher than in short-term travellers, but not significantly different from other trials in longer-term travellers.

Study design
Across cohort studies, self-reported complete adherence was slightly higher in participants who took mefloquine than in users of other antimalarial agents (RR 1.16, 95% CI 1.03 to 1.30; 11 cohort studies, 12131 participants, Analysis 5.13). However, there was no difference in self-reported completion of the treatment after return (RR 1.04, 95% CI 0.92 to 1.17; 4 cohort studies, 1221 participants, Analysis 5.14).

Duration of travel
Self-reported complete adherence was slightly higher in short-term travellers who took mefloquine than users of other antimalarial agents (RR 1.10, 95% CI 1.03 to 1.18; 7 cohort studies, 7241 participants). However, the same effect was not seen in longerterm travellers (RR 1.20, 95% CI 0.88 to 1.62; 4 cohort studies, 4890 participants, test for subgroup differences P = 0.61, Table  14). There was no overall difference in rates of completing the treatment regimen after return in short-term travellers who took mefloquine than in those who received other antimalarial agents (RR 1.04, 95% CI 0.92 to 1.17; 4 cohort studies, 1221 participants). No studies in longer-term travellers monitored adherence after return.

Military versus non-military participants
There were no differences in self-reported complete adherence when comparing military versus non-military participants, either during travel or after return (Table 15).

A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]
M efloquine compared with doxycycline for preventing malaria in travellers Population: Non-im m une adults and children travelling to m alaria-endem ic settings Intervention: M ef loquine 250 m g weekly Comparison: Doxycycline 100 m g daily Outcome data collection: Self -reported sym ptom s experienced whilst taking prophylaxis (adverse events)

Outcomes
Anticipated * The assumed risk is the m edian control group risk across cohort studies unless stated in f ootnotes. The corresponding risk (and its 95% conf idence interval) is based on the assum ed risk in the com parison group and the relative effect of the intervention (and its 95% CI). Where the control group risk was 0, we used a value of 0.5 to calculate the corresponding risk in the intervention group. Where no RCTs including short-term travellers reported on our prespecif ied adverse outcom es, we included inf orm ation f rom cohort studies as our prim ary analysis 'Sum m ary of f indings' tables are usually lim ited to seven outcom es. For adverse ef f ects this problem atic, as there are m any, and to include som e and not others risks selective reporting. We have theref ore included all prespecif ied outcom es in the table GRADE Working Group grades of evidence High certainty: f urther research is very unlikely to change our conf idence in the estim ate of ef f ect. M oderate certainty: f urther research is likely to have an im portant im pact on our conf idence in the estim ate of ef f ect and m ay change the estim ate.
Low certainty: f urther research is very likely to have an im portant im pact on our conf idence in the estim ate of ef f ect and is likely to change the estim ate. Very low certainty: we are very uncertain about the estim ate.
1 No serious risk of bias: none of the RCTs adequately described m ethods of random sequence generation or allocation concealm ent, However, given that so f ew events occurred in these trials, it is unlikely to have introduced bias. 2 No serious inconsistency: the direction of the ef f ect is consistent across study designs, or there in consistency in the f inding of no ef f ect. 3 No serious indirectness: the prim ary analysis included studies in short-term international travellers, longer-term occupational travellers, and m ilitary personnel. 4 Downgraded by two levels f or im precision: only seven episodes of clinical m alaria occurred in the f our trials, and consequently, the analysis was substantially underpowered to exclude im portant dif f erences. 5 For serious adverse outcom es we expressed the control group risk as the overall risk in the control group. 6 No serious risk of bias: all cohort studies had m ethodological problem s which could introduce conf ounding or bias. However, as the GRADE approach autom atically downgrades certainty by two levels f or non-random ized studies, we did not downgrade f urther. 7 Downgraded by one level f or serious im precision: the 95% conf idence interval includes both clinically im portant ef f ects and no ef f ect. 8 Downgrade by one level f or serious inconsistency: although there was no substantial dif f erence between drugs in the cohort studies, the proportion of discontinuations was higher with both drugs: 14% f or m ef loquine and 9% f or doxycycline. 9 Downgraded by one level f or indirectness: the prim ary analysis included only cohort studies in longer-term occupation travellers (USA Peace Corps volunteers) and m ilitary personnel. Adverse ef f ects in shorter-term international travellers m ay be lower. 10 No serious im precision: the ef f ect was statistically signif icant and the overall data (RCTs and cohort studies) were adequately powered to detect this ef f ect. 11 Downgraded by one level f or serious inconsistency: there was heterogeneity between trials in the direction of ef f ect.

Mefloquine efficacy
We included 12 randomized controlled trials (RCTs) that compared mefloquine with placebo; none were performed in shortterm international travellers, and most populations had a degree of immunity to malaria. The percentage of people developing a malaria episode in the control arm varied from 1% to 82% (median 22%) and in the mefloquine group 0% to 13% (median 1%). In four other RCTs that directly compared mefloquine, atovaquone-proguanil and doxycycline in non-immune, short-term international travellers, only one clinical case of malaria occurred (low certainty evidence).

Mefloquine safety versus currently used alternatives
Serious adverse effects have been reported for mefloquine and doxycyline, but not for atovaquone-proguanil. Serious adverse effects are uncommon, and on statistical testing, no difference was detected between mefloquine and atovaquone-proguanil (low-certainty evidence), or between mefloquine and doxycycline (very lowcertainty evidence). Participants who received mefloquine were more likely to discontinue their medication due to adverse effects than participants who received atovaquone-proguanil (high-certainty evidence), but there was no difference in comparisons with doxycycline (low-certainty evidence). We included one RCT and six cohort studies that reported our prespecified adverse effects that compared mefloquine and atovaquone-proguanil. In the RCT in short-term travellers, mefloquine users were more likely to report abnormal dreams (moderatecertainty evidence), insomnia (moderate-certainty evidence), anxiety (moderate-certainty evidence), and depressed mood during travel (moderate-certainty evidence). The cohort studies in longer-term travellers were consistent with these findings but most had larger effect sizes. Mefloquine users were also more likely to report nausea (high-certainty evidence) and dizziness (high-certainty evidence). We included six cohort studies in longer-term occupational travellers that compared mefloquine with doxycycline which reported our prespecified adverse effects. We also included one RCT in military personnel and one cohort in short-term travellers that reported adverse events. Mefloquine users were more likely to report abnormal dreams (very low-certainty evidence), insomnia (very low-certainty evidence), anxiety (very low-certainty evidence) and depressed mood (very low-certainty evidence). The findings of the single cohort study reporting adverse events in short-term international travellers were consistent with these findings but the single RCT in military personnel did not demonstrate a difference between groups in the frequency of abnormal dreams or insomnia.
Doxycycline users were more likely to report dyspepsia (very lowcertainty evidence), photosensitivity (very low-certainty evidence), vomiting (very low-certainty evidence) and vaginal thrush (very lowcertainty evidence). Comparisons with chloroquine showed a broadly consistent pattern with these results.

Overall completeness and applicability of evidence
Mefloquine has been licensed for prevention of malaria in travellers since the late 1980s, and as such, it is perhaps surprising how few well-conducted RCTs were available. However, because we were mainly interested in the adverse effect profiles of different antimalarial agents, cohort studies (of which there are many) are probably the most appropriate study design despite their inherent limitations. Most RCTs excluded people with a previous history of mental health problems, precluding an analysis of whether psychological side effects are more common in this group. Conversely, many of the cohort studies explicitly stated that the choice of antimalarial agent was influenced by both past medical history and personal preference. While this undoubtedly introduces some confounding between study groups, we consider this confounding to be appropriate and directly applicable to clinical practice. Similarly, we would normally be cautious about interpreting unblinded self-reported assessments of adverse effects and causality. In this scenario, self-reported adverse effects provide useful and relevant information for travellers, who would also be unblinded. It should be noted that the reported adverse effects are largely self-reported psychiatric symptoms and not formal psychiatric diagnoses. Given the heterogeneity in trial design, mefloquine doses used, and the study population, we were unable to derive a reliable estimate for mefloquine efficacy. However, the evidence suggests that mefloquine is likely to be highly effective in reducing clinical episodes of malaria. Comparative trials found no difference in efficacy between mefloquine and atovaquone-proguanil or doxycycline for preventing clinical malaria, but the number of malaria episodes was very low, and consequently, much larger trials would be needed to exclude clinically important differences. As a consequence, knowledge about antimalarial resistance patterns in the country of travel seems an appropriate approach to decision making rather than further RCTs. The choice between antimalarial agents will therefore depend on how individual travellers rate the relative importance of specific adverse effects, pill burden and cost. Prophylactic mefloquine is widely acknowledged to cause abnormal dreams and psychological adverse effects and we found consistent evidence for these effects across comparisons with atovaquone-proguanil, doxycycline and chloroquine (the most commonly used alternatives). Doxycycline does not have the same risk of psychological adverse effects, but is associated with increased risk of photosensitivity, dyspepsia, and vaginal thrush, which some travellers will undoubtedly consider important. In line with this, participants who received mefloquine were more likely to discontinue treatment due to adverse effects than participants who received atovaquone-proguanil, but there was no difference in comparisons with doxycycline. We found estimating the risk of serious psychological adverse effects from the studies was not straightforward. Study authors used the term 'serious' loosely, and often did not provide us with the detail required to determine whether these events met standardized definitions. Furthermore, the estimates of the absolute risk in both mefloquine and comparator arm varied considerably between trials, which may be related to data collection methods and the cut-offs used rather than true differences among populations. Overall, we did not identify large differences in the risk of serious adverse effects among antimalarial agents; but what we did find was that the nature of these serious adverse effects corresponded with the known side effect profile of each drug. The findings of our related systematic review which analysed deaths and parasuicides associated with mefloquine prophylaxis, and included case reports, had findings consistent with this (Tickell-Painter 2017). This systematic review reports that there were no suicides we could reliably attribute to mefloquine prophylaxis, and one para-suicide with a possible causal association. In the analysed reports, we identified two deaths with a probable association that appeared to be idiosyncratic drug reactions; the remaining eight deaths we categorised as "unlikely" to be related to mefloquine, or "unclassifiable". We believe it is important that the large retrospective healthcare record analyses did not demonstrate a clear quantitative association between mefloquine use and formal mental health disorders. This may reflect the inadequacy of the study methods to detect this outcome, but may also reflect the transient nature of the mood disturbance, with resolution once mefloquine is discontinued. We were unable to comment on the severity or duration of the reported adverse effects based on the available data. The data on mefloquine at a prophylactic dose during pregnancy were limited (2 RCTs; no comparative cohort studies). Both RCTs included semi-immune populations who did not travel. Mefloquine has an advantage as the only malaria prophylaxis with a once weekly regimen. Many have cited this as a mechanism to improve adherence, which is notoriously low in all users of antimalarial prophylaxis. However, the evidence base for this assertion is weak, with almost all data originating from cohort studies which reported a variety of measures of self-reported complete adherence. We were unable to perform some prespecified subgroup analyses including children versus adults, female versus male travellers and pregnant versus non-pregnant women. This meant we were unable to test whether women were more likely to experience adverse effects from mefloquine use (which has been widely reported in the literature). We appreciate that the distinction between adverse events (all events regardless of relationship to the study drug) and adverse effects (events attributed by study authors or participants to the study drug) can seem arbitrary and cause confusion. However, we consulted extensively with methodologists who advised that both outcomes are useful to decision makers, and there is no overall gold standard. For example, reporting only the adverse effects (for example, hospitalizations, psychiatric side effects) thought to be attributed to the drug regimen can introduce selective bias by the study authors. For controversial or pharmaceutical companyfunded studies this can distort the outcomes. By comparing all events across both groups any difference in the relative risk can be compared without the potential for selective bias. However, this does have its own limitations, such as if the two groups were not comparable at baseline or if the sample size is not big enough to exclude differences due to chance. We therefore chose to include both options (events and effects) to give readers and decision makers the complete picture.

Quality of the evidence
In the 'Summary of findings' tables we present what we consider to be the best estimate of effect for each outcome, within each comparison. Where possible we chose the estimate from RCTs reporting adverse effects, but where this was not available we used estimates from cohort studies. However, when making judgements about the certainty of evidence we considered all the evidence available, as well as the consistency of the effect across different population groups and study designs. For the comparison of mefloquine with atovaquone-proguanil, the best estimates of effect came from a single, well-conducted RCT in short-term travellers, recording participant-reported adverse effects. The findings of this study were supported by seven cohort studies in long-term occupational travellers and military personnel. We considered the evidence of increased risk of abnormal dreams and insomnia to be high certainty because the effects were consistent across all population groups. However, we downgraded the effect estimate on anxiety and depressed mood for inconsistency to moderate certainty because there was substantial variation in the effect size across populations, with much larger effects in long-term travellers and military personnel. For the comparison of mefloquine with doxycycline, the only available RCT was very small, and reported adverse events rather than adverse effects. Consequently, we considered the effect estimates from cohort studies to be more reliable. Evidence from cohort studies was automatically downgraded to low based on the inherent bias in the study design. We further downgraded almost all estimates of effect for indirectness, because most data were from long-term travellers and military personnel, and may therefore over estimate the effect in short-term travel. The evidence is therefore considered to be very low-certainty with little confidence in the size of the effect. It is important to note however, that the pattern of adverse effects with mefloquine in these cohort studies is entirely consistent with the pattern seen in comparisons of mefloquine with atovaquone-proguanil and chloroquine.

Potential biases in the review process
During the course of this review we made changes to the protocol. Two changes were made to shorten the overall length of the review: • we excluded comparisons of mefloquine with primaquine and tafenoquine because these are planned for assessment in another Cochrane Review (Rodrigo 2016); • we excluded single-arm cohort studies because there were sufficient data from comparative studies to reach reasonable conclusions. These studies have been analysed for the very rare outcomes of death or attempted suicide in another systematic review (Tickell-Painter 2017).
We do not think these decisions biased the review.

Agreements and disagreements with other studies or reviews
Several recently published reviews regarding the safety of mefloquine have been narrative, and included little or no description of methods applied and a lack of clearly defined and prespecified outcomes ( Schlagenhauf 2010 highlighted several areas in which mefloquine prophylaxis may be considered advantageous (during pregnancy and while breastfeeding, in long-term travellers, travellers who are visiting friends and relatives and families with small children). The main disagreement with our review was in regard to safety in longterm travellers, in whom the review authors refer to mefloquine as "a good option if well tolerated". This is based on a narrative analysis of a single cohort study which compared mefloquine users with users of chloroquine-proguanil, which was not included in this review (Lobel 1993). Our review added data from several additional studies evaluating longer-term use (Andersson 2008; Cunningham 2014; Korhonen 2007; Landman 2015), and we found some observational evidence that risk of adverse effects was higher than with short-term travel. Our findings are broadly consistent with the previous version of this Cochrane Review, which was withdrawn (Jacquerioz 2015). Jacquerioz 2015 found higher rates of neuropsychiatric adverse events in mefloquine users compared with users of both atovaquone-proguanil and doxycycline. We expanded on this finding by providing estimated risks for specific neurological and psychiatric symptoms, and by including additional data from cohort studies. Jacquerioz 2015 included a brief analysis of case reports of deaths associated with mefloquine in the Discussion. We excluded this analysis from this update, but this aspect has been addressed in a separate review of single-arm cohort studies and case reports (Tickell-Painter 2017). Two recent reviews included evaluations of mefloquine efficacy and safety during pregnancy. González 2014 concluded there were no indications that mefloquine use during pregnancy carries an increased risk for the foetus. González 2014 included additional studies to those we included in this Cochrane Review, including mefloquine when used at treatment dose, or as intermittent presumptive treatment in pregnancy. Muanda 2015 also included mefloquine when used as intermittent presumptive treatment in pregnancy. Muanda 2015 reported findings from two trials in which the number of adverse events (Briand 2009), and number of serious adverse events (González 2014a) was higher in participants who received mefloquine as intermittent presumptive treatment in pregnancy than in those who received sulphadoxinepyrimethamine.

Implications for practice
The absolute risk of malaria during short-term travel appears to be very low with all three established antimalarial agents (mefloquine, doxycycline and atovaquone-proguanil).
The choice of antimalarial agent will therefore depend on how individual travellers rate the relative importance of specific adverse effects, pill burden and cost. Some will prefer mefloquine for its once-weekly regimen, but this should be balanced against the increased frequency of abnormal dreams, anxiety, insomnia, and depressed mood during travel.

Implications for research
Given the low absolute risk of malaria in travellers, very large trials would be necessary to exclude clinically important differences among antimalarial agents. As a consequence, knowledge about antimalarial resistance patterns in the country of travel seems an appropriate approach to decision making rather than further RCTs.
Although a large number of RCTs evaluating mefloquine prophylaxis have been performed, very few could be included in our analyses. Many RCTs chose to report proxy measures of psychiatric outcomes, such as Profile of Mood States questionnaires and Environmental Symptoms Questionnaires, which are difficult for clinicians and participants to interpret. Furthermore, many studies grouped symptoms together when reporting outcomes. 'Neuropsychiatric' or 'neuropsychologic' were commonly used terms, although the symptoms included varied from headaches to psychosis, making them of limited value in clinical decision making.
Even though we found moderate-and high-certainty evidence that mefloquine use is associated with a range of psychological adverse effects, further RCTs could increase confidence in the size of the effect. The relative risk of psychological side effects was higher with long-term use of mefloquine, although this finding was only statistically significant in one comparison. An alternative explanation is the possibility of an interaction between mefloquine and level of psychological stress given the occupation of participants surveyed (Foreign and Commonwealth Office workers, Peace Corps volunteers and military personnel). Further research should examine these potential interactions.
Furthermore, well-designed trials could test hypotheses regarding male versus female users, whether mefloquine users with a previous history of mental health problems are more likely to experience psychological adverse effects, and the severity or duration of the reported adverse effects.

A C K N O W L E D G E M E N T S
Dr Maya Tickell-Painter, Dr Rachel Saunders, and Dr David Sinclair received support from the by the Effective Health Care Research Consortium. The Consortium and the editorial base of the Cochrane Infectious Diseases Group are funded by UK aid from the UK Government for the benefit of developing countries (Grant: 5242). The funding body had no role in study design, data collection and analysis, or preparation of the manuscript. The views expressed in this review do not necessarily reflect UK government policy.

Albright 2002
Methods Design: retrospective cohort study. Study dates: November 1997 to January 2000 Malaria transmission pattern and local antimalarial drug resistance: various destinations, not specified Adverse event monitoring: one off telephone interview with parents whose children had previously been prescribed antimalarial prophylaxis week before travel and continuing throughout the period of deployment* Co-interventions: Both groups given doxycycline 100mg daily for suppression of P falciparum and primaquine 45 mg weekly for elimination of liver hypnozoites for 6 weeks on return to the USA *matched placebo for each treatment arm

Outcomes
Included in the review: week of the study, on days two and three, a single mefloquine tablet or placebo was administered. Both drugs and placebos had an extremely bitter taste... identical placebo tablets" Blinding of outcome assessment (detection bias) All outcomes Unclear

Davis 1996 (Continued)
Blinding of participants and personnel (performance bias) Adverse effects/events Low risk "Tablets were prepared in individually numbered but otherwise unlabelled containers... identical placebo tablets…" Blinding of outcome assessment (detection bias) All outcomes Unclear risk "Allocation of active or placebo formulation was by a random number code generated by independent Freemantle hospital staff who kept the code strictly confidential" Comment: not mentioned whether outcomes assessors were blinded

. Selection of participants into the study: low
Start of intervention and start of follow-up coincided for most participants. Retrospective medical records were used, therefore there were no non-responders 3. Measurement of interventions: moderate Information regarding drug prescriptions were obtained from a medical database, without any verification that users took the prescription

Departures from intended interventions: serious
Discontinuations and switches between prophylactic regimes were not recorded in the database 5. Missing data: low All records in the research database were included in the analysis 6. Measurement of outcomes: moderate Participants and outcome assessors (physicians) were not blinded. However, information was collected anonymously and on aggregate. Participants were unaware of their participation at the time of seeking healthcare 7. Selection of the reported results: low Outcome data were reported for all outcomes prespecified for analysis 8. Other: no information No information was available regarding the study sponsor. Funding sources: "The study was commissioned and paid for by GlaxoSmithKline"

Bias Authors' judgement Support for judgement
Other bias Unclear risk 1. Confounding: moderate "There were statistically significant differences in mean age" Several other confounders were not reported across groups

Selection of participants into the study: moderate
No information is provided regarding people who did not wish to participate

Measurement of interventions: low
The antimalarial prescription was provided by a travel clinic which also performed the study

Departures from intended interventions: moderate
No information was captured regarding switches between interventions of interest

Missing data: serious
185/252 participants completed the pre-and post-travel questionnaire. Interim loss to follow up 27% 6. Measurement of outcomes: serious Comment: the outcome measure was subjective; participants and personnel were not blinded 7. Selection of the reported results: moderate The number of reported side effects was reported, but not the types or severity 8. Other: serious Funded by GlaxoSmithKline; the role of the study sponsor was not made clear

Methods
Design: RCT Study dates: not mentioned Malaria transmission pattern and local antimalarial drug resistance: "the 20-week cumulative incidence of reinfection by P. falciparum to be nearly 100%". No mention of local drug resistance patterns Adverse event monitoring: "...during the prophylaxis and follow-up phases, health workers visited the subjects 3 times weekly. Subjects with physical complaints were examined by a study physician the next day or on an emergent basis, as needed. Hematologic analysis was done on days 4 and 10 after starting the loading dose phase and during weeks 4, 8, 12, and 15. Biochemical analysis was done during weeks 4, 8, 12, and 15" Participants Number enrolled: 530 enrolled and completed radical cure regimen. 509 participants took at least 1 dose of the weekly study drug or placebo and comprised the full intentionto-treat data set Inclusion criteria: "Inclusion criteria included the following: age of 18-60 years (men) or 50-60 years (women); lack of significant systemic illness as determined by history, physical examination, and clinical laboratory test results (including negative results of a urine pregnancy test for women); and absence of seizures or other neuropsychiatric illness (past or present)" Exclusion criteria: "The high rate of pregnancy and breast-feeding in women aged 18-49 years precluded their enrollment.

Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk "The randomization code was generated in blocks of 11 numbers" Comment: not mentioned how randomization code was produced Allocation concealment (selection bias) Unclear risk "Code numbers were assigned according to the chronological order of appearance of the subjects at screening. Study drugs were prepackaged and prelabeled with a unique study number according to the randomization code" Comment: no mention of opaque sealed envelopes Blinding of participants and personnel (performance bias) Adverse effects/events Unclear risk "A 'double-dummy' design allowed double-blind administration of tafenoquine and mefloquine active drugs and their corresponding placebos" "A placebo (tafenoquine placebo, Glaxo-Smith-Kline; mefloquine placebo, Hoffmann-La Roche) served as the negative comparator" Comment: does not report that the tablets were identical Blinding of outcome assessment (detection bias) All outcomes Unclear risk "All slides positive for the presence of malaria causing parasites, and an equal number of randomly selected slides with negative results were reevaluated by a second (blinded) microscopist." Comment: no other mention of outcome assessors being blinded and does not report that the researchers were blinded Incomplete outcome data (attrition bias); efficacy Low risk "Data analysis for efficacy used 2 data sets: the 'full, intent-to-treat' data set (n=509), comprising all subjects who took at least 1 dose of the weekly study drug or placebo, and the 'per-protocol' data set (n=428), comprising those subjects who strictly fulfilled the protocol criteria" Incomplete outcome data (attrition bias); safety Low risk Comment: The safety and tolerability analyses included data for all participants who received at least 1 dose of the study drug or placebo (N = 513) Selective reporting (reporting bias); efficacy Low risk Comment: total number of participants with positive blood smear result at any time during prophylaxis was reported. Clinical cases of malaria were reported Selective reporting (reporting bias); safety High risk "There were 9 serious adverse events in the study... No serious adverse events were considered by study physicians to be related to the study drug, and no deaths occurred" Comment: Data for serious adverse events were not attributed to the drug regimen.
No information was provided on how causality was assessed Other bias High risk Acknowledgement of "Philip Pickford and Rachel Moate (GlaxoSmithKline), for statistical and editorial advisement"

Hill 2000
Methods Design: retrospective cohort study Study dates: June 1989 to May 1991 Malaria transmission pattern and local antimalarial drug resistance: various, not specified Adverse event monitoring: patient self-reported questionnaire. "Any reported illness was followed up by telephone interview about the nature of the illness, during which time more complete information was obtained using standardized questions"

Bias Authors' judgement Support for judgement
Other bias Unclear risk 1. Confounding: moderate Age, sex, destination and duration of travel were measured but not reported across groups 2. Selection of participants into the study: moderate Non-response rate was not reported.

Measurement of interventions: low
The antimalarial prescription was provided by a travel clinic which also performed the study

Departures from intended interventions: moderate
Information was provided on discontinuations, but no information was captured on switches between interventions 5. Missing data: low Information on adverse effects was available for all participants who ever filled the prescription for the study drug (571/612, 93%) 6. Measurement of outcomes: serious Comment: the outcome measure was subjective; partici-

Hill 2000 (Continued)
pants and personnel were not blinded 7. Selection of the reported results: moderate It is unclear which questions were included in the questionnaire. Information was provided on aggregate 8. Other: no information No information provided on study sponsor

Hoebe 1997
Methods Design: retrospective cohort study Study dates: January to June 1995 Malaria transmission pattern and local antimalarial drug resistance: various, not specified Adverse event monitoring: one-off telephone interview between 4 and 20 weeks post-travell Participants Number enrolled: 454 eligible travellers, 300 successfully contacted and agreed to participate Inclusion criteria: subjects who visited the travel vaccination service of the regional public health institute in Maastricht if they had returned from their journey to tropical countries between 4 and 20 weeks previously. The group of nonusers was formed by people who travelled either to tropical countries without malaria risk or to cities in malarious areas, and by travellers who were prescribed an antimalarial drug but did not commence use The study authors provided us with access to the disaggregated study data for the specific symptoms mentioned above. The questionnaire in the paper allowed participants to describe side effects from the antimalarial they were currently taking, and any regimen they had previously used. For non-serious side effects, in line with the original paper, we only included side effects for the subject's original regimen. Where subjects had previously taken more than one regimen, we only include side effects for whichever regimen to which the participant attributed the greater number of side effects; this affected 70/2701 participants. This analysis resulted in a decrease in the effect size for side effects attributed to mefloquine. For serious side effects (hospitalizations) and discontinuations we included all participants entries for all regimens. In addition, our denominator differed from the original paper because we did not exclude participants who had been in post for fewer than six months

Bias Authors' judgement Support for judgement
Other bias Unclear risk 1. Confounding: moderate "The questionnaire did not collect demographic information because of privacy concerns" Comment: destination has been reported, but not by type of antimalarial chemoprophylaxis. Duration was set by the study design 2. Selection of participants into the study: serious "A total of 2701 surveys were received yielding a response rate of 43%"

Measurement of interventions: moderate
Participants were asked to self-report which prophylaxis they were currently taking and had previously taken

Departures from intended interventions: moderate
Switches between interventions of interest were reported. Approximately 1/3 of study participants had switched prophylactic regimens

Missing data: low
We were able to include all participants in the study analysis because we had access to the original data set 6. Measurement of outcomes: serious "If respondents identified any adverse event, the survey instructed them to self-report which drug they believed caused the adverse event" Comment: the outcome measure was subjective; participants and personnel were not blinded 7. Selection of the reported results: low We were able to include all results in the analysis because we had access to the original data set 8.

Bias Authors' judgement Support for judgement
Other bias Unclear risk 1. Confounding: moderate Sex (P < 0.008), education (P < 0.022), previous episodes of malaria (P < 0.001) and access to pre-travel advice (P < 0.001) were all significantly associated with reduced compliance at the significance value set by the study. None of these factors were adjusted for in the analysis 2. Selection of participants into the study: moderate "The nonresponse rate was about 10% (n = 65), with the main reason being the short transit time"

Measurement of interventions: low
Participants were asked to self-report which prophylactic regimen they were taking while they were still taking it

Departures from intended interventions: moderate
No information was provided regarding switches between prophylactic regimens 5. Missing data: low Adherence information was not available for 4/595 participants 6. Measurement of outcomes: serious The outcome measure was based on participant self-reporting; participants and personnel were not blinded 7. Selection of the reported results: moderate There was insufficient information provided to know what questions were asked regarding adherence 8. Other: low "The authors had no financial or other conflicts of interest to disclose"

Measurement of interventions: low
Participants were asked to provide information regarding their prophylactic regimen during their flight home, while they should have still been using it

Departures from intended interventions: moderate
No information was available regarding switches between alternative prophylactic regimens 5. Missing data: low 4934/4982 (99%) participants included in adverse event reporting 6. Measurement of outcomes: serious Comment: the outcome measure was subjective; participants and personnel were not blinded 7. Selection of the reported results: moderate There was insufficient information provided regarding the questions included in the questionnaire. Symptoms were grouped together to report outcomes 8. Other: low "The authors had no financial or other conflicts of interest to disclose"

Missing data: low
Two people (6%) were lost to follow-up in respect to data on efficacy. No participants were lost to follow-up when monitoring adherence 6. Measurement of outcomes: serious Adherence was monitored by the medical officer on the trip, and reporting may have been influenced by social desirability bias 7. Selection of the reported results: low All prespecified outcomes have been reported 8. Other: low Government funding

Meier 2004
Methods Design: retrospective cohort study Study dates: 1 January 1990 and 31 December 1999 Malaria transmission pattern and local antimalarial drug resistance: various, not specified Adverse event monitoring: incident cases of depression, psychoses and panic attacks severe enough to require hospitalisation, referral to a specialist or specific pharmacological treatment within the UK general practice research database Participants Number enrolled: 35,370 Inclusion criteria: "men and women aged 17-79 years who received between one and four prescriptions for mefloquine, proguanil and/or chloroquine, or subjects who received one prescription only for doxycycline... we included only those subjects who medical record contained a code indicating that the person received the drug for malaria prophylaxis within 1 week of the prescription date e.g. 'travel advice' or 'prophylactic drug use"' Exclusion criteria: "participants who received the study drugs on a longer-term basis...subjects had to be enrolled in the database for at least 12 months before the date of the first prescription for a study drug and had to have had some recorded activity (diagnoses or drug prescriptions) after the prescription(s) for an antimalarial drug.

Ohrt 1997 (Continued)
Blinding of participants and personnel (performance bias) Adverse effects/events Low risk "Drugs were packaged into weekly zipperlock plastic bags: each bag contained a mefloquine or mefloquine placebo tablet and a blister pack of seven doxycycline or doxycycline placebo capsules (doubledummy technique)" The placebo medication had an "identical appearance" Blinding of outcome assessment (detection bias) All outcomes Low risk "The randomisation code was stored in individual envelopes in a locked box at the study site. All investigators and study personnel did not have access to or know the randomisation code throughout the study" Incomplete outcome data (attrition bias); efficacy Unclear risk "Sixteen of the 204 participants did not complete the study" Comment: It was unclear whether the duration of follow up included the post-prophylaxis period to monitor for relapses Incomplete outcome data (attrition bias); safety High risk Exit questionnaire: "Only data from persons who were still receiving the study drug at the time of the questionnaire were included" Comment: numbers not reported Selective reporting (reporting bias); efficacy Low risk "The primary end point for efficacy was the first occurrence of malaria, as documented by a positive malaria smear" Comment: all cases of malaria were reported.
Selective reporting (reporting bias); safety High risk Comment: Not all data were reported from the exit questionnaire; the study reports ". ..the only statistically significant finding". Data on adverse symptoms were not reported for the placebo group Other bias Low risk "Neither of the pharmaceutical companies that provided support played any role in the gathering, analysing or interpreting the data"

Notes
Funding source: GlaxoSmithKline "Subjects were enrolled in study MAL30010"-Enrollment criteria and study conduct were described in a separate publication (Høgh 2000) which refers to a different study population (atovaquone-proguanil versus chloroquine-proguanil)

Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk "A computer-generated code was used to randomly assign a treatment number" ( Høgh 2000) Allocation concealment (selection bias) Low risk "Treatment codes were provided to investigators in opaque sealed envelopes, to be opened only if knowledge of study drug assignment was required for management of a medical emergency" (Høgh 2000) Blinding of participants and personnel (performance bias) Adverse effects/events Low risk "For each active drug, capsules or filmcoated tablets were identical in appearance to the matching placebo" Blinding of outcome assessment (detection bias) All outcomes Low risk "All subjects and study personnel remained blinded to treatment assignment with 5 exceptions. Two subjects in the atovaquoneproguanil group and 3 in the mefloquine group lost their study drug during their return trip from a malaria-endemic area, and the investigator broke the blind to enable completion of postexposure prophylaxis with active drug" Incomplete outcome data (attrition bias); efficacy

Pearlman 1980 (Continued)
Selective reporting (reporting bias); efficacy Low risk " Table 2 shows the number of subjects in each group who completed the study, the number infected with P. falciparum, and the number of episodes of asexual parasitemia" Selective reporting (reporting bias); safety High risk "There was no clinical evidence of drug toxicity in the 990 study participants" Comment: it was unclear whether all events that occurred during the 6 month trial period were included

. Measurement of interventions: serious
Participants were asked to self-report which prophylaxis they took after return. The time after return was not specified

Departures from intended interventions: no information
There was insufficient information provided to determine whether the questionnaire contained information regarding discontinuations or switches 5.

Measurement of interventions: low
The prescription was provided by a travel clinic which also performed the study

Departures from intended interventions: moderate
Discontinuations were reported, but not across groups. Switches were not recorded 5. Missing data: low All participants who completed both questionnaires were included in the analysis 6. Measurement of outcomes: moderate The outcome measure was subjective; participants and personnel were not blinded. Participants were asked to report all symptoms, and which they felt were due to prophylaxis 7. Selection of the reported results: moderate Symptoms were grouped to report outcomes 8. Other: low Source of funding not mentioned. "competing interests: none declared"

Salako 1992
Methods Design: RCT Study dates: July 1987 to June 1988 Malaria transmission pattern and local antimalarial drug resistance: "holoendemic for malaria... at the time of the trial, chloroquine resistance was not a problem" Adverse event monitoring: "study participants were seen weekly up to week 28". Interview with study personnel for events such as "fever, chills, malaise, nausea and vomiting, rashes and other symptoms and signs that could be regarded as adverse events"

Selection of participants into the study: low
Response rate 2351/2601 surveys (90%)

Measurement of interventions: moderate
Participants were asked to self-report which prophylaxis was used on return to the USA. It is unclear if participants were still receiving the intervention at this time 4. Departures from intended interventions: serious "There were 520 respondents (25.2%) reporting more than one medication used to prevent malaria over the course of the deployment" 5. Missing data: low Analysis included 1898/2011 (94.4%) respondents for doxycycline, 564/596 (94.6%) respondents for mefloquine 6. Measurement of outcomes: serious Comment: the outcome measure was subjective; participants and personnel were not blinded. Different criteria were used to assess adverse effects related to mefloquine and doxycycline 7. Selection of the reported results: serious There was insufficient information provided regarding the questionnaire to determine whether all included outcomes were reported. Data for doxycycline were provided by severity gradings but not for mefloquine

Other: no information
No information is provided regarding the study sponsor

Schlagenhauf 1997
Methods Design: cross-over RCT Study dates: 1993 to 1994 Malaria transmission pattern and local antimalarial drug resistance: not applicable Adverse event monitoring: "Throughout dosing, the participants were monitored and questioned regarding their general well-being. The participants were seen 1) prior to taking any medication, 2) at the end of the first week (during which the loading dose was administered, 3) one week before testing, and 4) on the testing day itself when they were asked to report any changes from normal and questioned with regard to any symptoms experienced while taking the drug" Participants Number enrolled: 23 Inclusion criteria: "conducted with trainee pilots attending the Swiss Civil Aviation School during the classroom phases of their study" Exclusion criteria: "history of a seizure disorder; psychosis or severe depression; known allergy or sensitivity to mefloquine or related compounds; concurrent use of cardioactive medication; compromised renal or hepatic function; pregnancy or the intention to become pregnant within three months of mefloquine use; use of mefloquine in the preceding two months, and use of hypnotics or tranquillizers during the two weeks prior to testing and alcohol within 12 hr of testing"

Schlagenhauf 2003 (Continued)
Incomplete outcome data (attrition bias); safety Unclear risk "Adverse events were analysed in 623 participants who completed questionnaires at recruitment and at least one of the follow up periods" "Data was collected during recruitment and at follow up 13-11 days before departure, 6-4 days before departure and 7-14 days after departure" Comment: it was unclear how many participants provided data at each time point Selective reporting (reporting bias); efficacy Low risk "No cases of malaria were reported for any study arm" Selective reporting (reporting bias); safety High risk "Adverse events were analysed in 623 participants who completed questionnaires at recruitment and at least one of the follow up periods" "Data was collected during recruitment and at follow up 13-11 days before departure, 6-4 days before departure and 7-14 days after departure" Comment: Data were presented on aggregate across multiple time points

Measurement of interventions: moderate
"We only included subjects who used anti-malarial drugs for malaria prophylaxis. We identified prescriptions for which the GP recorded -within a week of the anti-malarial drug prescription -specific codes indicating that the person received the prescription for malaria prophylaxis, such as 'travel advice' or "prophylactic drug use"

. Departures from intended interventions: low
Two discontinuations (158 participants) were reported 5. Missing data: serious "In addition, we directly contacted all travelers for complete follow-up and assessment of compliance. Fifty travelers taking primaquine completed a questionnaire regarding side effects" It was unclear how information on discontinuations and side effects were obtained for participants who did not take primaquine" 6. Measurement of outcomes: serious Comment: the outcome measure was subjective; participants and personnel were not blinded 7. Selection of the reported results: serious "In addition, we directly contacted all travelers for complete follow-up and assessment of compliance. Fifty travelers taking primaquine completed a questionnaire regarding side effects" It was unclear how information on discontinuations and side effects was obtained for participants who did not take primaquine  All participants completed questionnaires.

Measurement of interventions: low
Type of prophylaxis used was set by the job of the included participants 4. Departures from intended interventions: low "Two non-aviators were dropped from the study because of receiving the wrong prescription" 5. Missing data: low "Two non-aviators were dropped from the study because of receiving the wrong prescription" Information was provided for the remaining 43 participants.

Measurement of outcomes: serious
Comment: the outcome measure was subjective; participants and personnel were not blinded 7. Selection of the reported results: moderate "...the questionnaire included questions about compliance, side effects attributed to chemoprophylaxis, and any illness after return" No information was provided regarding illness after return.

Other: no information
No information is provided regarding the study sponsor ..six students did not remember which prophylaxis had been prescribed" Students were asked to self-report which prophylaxis they took an average of 235 days after completing their trip 4. Departures from intended interventions: moderate "Eight students who used mefloquine (20%) stopped the drug prematurely as did ten students on atovaquoneproguanil (16%) and the student on doxycycline. Only two of these students switched to another prophylaxis" 5. Missing data: low "none of the questionnaires was incomplete" All participants were included in the analysis 6. Measurement of outcomes: serious The outcome measure was subjective; participants and personnel were not blinded 7. Selection of the reported results: moderate Insufficient information was provided on how data on adverse effects were sought 8. Other: low "There was no dedicated funding for this project"  The comparisons of the number of side effects of both regimes" the number of side effects for specific symptoms e.g. nausea was equivalent to the number of soldiers reporting that side effect. In addition, the authors were able to clarify a discrepancy in the original text: the paper states "27 mefloquine takers (41.2%) reported 43 side effects at the 2nd week of prophylaxis". The total number of mefloquine participants was 228; 41.2% equates to 94 participants. The authors confirmed that the correct figure was 27 mefloquine users (11%)

Steketee 1996 (Continued)
Random sequence generation (selection bias) High risk "Systematic assignment of regimens was done based on the clinic and day of enrol-ment… All women making their first antenatal clinic on a given day were assigned to the same regimen; the following day, enrolled women were assigned to the following regimen" Allocation concealment (selection bias) High risk "Systematic assignment of regimens was done based on the clinic and day of enrol-ment… All women making their first antenatal clinic on a given day were assigned to the same regimen; the following day, enrolled women were assigned to the following regimen" Blinding of participants and personnel (performance bias) Adverse effects/events excluded from the analysis" "For the purposes of malaria prevention and infant outcome we analysed the group of women… only if they were enrolled in the study for six or more weeks and had received the appropriate amount of medication during their participation" "A total of 1,790 women delivered in study health facilities had received proper dosing on their antimalarial regimen, and had their peripheral blood examined" Comment: women who had reported fever during pregnancy, and during the 2 weeks prior to delivery was reported, but not reported across antimalarial drug regimens Selective reporting (reporting bias); safety High risk "All other complaints e.g. weakness, heart palpitations accounted for less than 15% of reported symptoms" Comment: Data were collected weekly but only reported after the first and the fourth dose

Measurement of interventions: serious
Participants were asked to self-report which chemoprophylaxis they had taken at least 2 years after they had finished the course 4. Departures from intended interventions: serious Limited information was provided regarding switches between interventions. Participants were asked to self-report this information at least 2 years after finishing treatment 5. Missing data: low Information on adherence was reported for all participants who answered this question (5026 respondents/ 5055 who reported taking malaria prophylaxis) 6. Measurement of outcomes: serious Comment: the outcome measure was subjective; participants and personnel were not blinded 7. Selection of the reported results: moderate There was insufficient information provided to be sure that all outcomes included in the questionnaire were reported 8. Other: low "This research did not receive any specific grant from funding agencies in the public, commercial, or not-forprofit sectors"

Methods
Design: cross-sectional cohort study Study dates: 2012 and 2013 Malaria transmission pattern and local antimalarial drug resistance: "...high risk of malaria (mainly P. falciparum) in Kenya, although the risk is assessed as very low in Nairobi and in the highlands above 2,500 m... widespread resistance to chloroquine" Adverse event monitoring: "...questionnaire-based, two-arm cohort study" Funding sources: "The research was not sponsored by any external body" After we submitted the review for peer referee, the author sent us a spreadsheet containing numbers of events relating to a variety of symptoms after the review had been submitted for publication. These data are not included in the review and will require some clarification over how they were collected to allow us to assess risk of bias. This additional information will be considered in future updates

Bias Authors' judgement Support for judgement
Other bias Unclear risk 1. Confounding: moderate "Although not formally recorded, each unit can be assumed to be composed of similar populations in terms of number, age, gender, occupation, and general health" 2. Selection of participants into the study: serious "Completion rates were consistently poor throughout the study period with only 150 to 250 questionnaires returned per tranche of around 1,000 troops"

Measurement of interventions: low
Participants were asked to self-report which medication they were on while still taking the medication" 4. Departures from intended interventions: moderate "...
[participants] were invited to complete the questionnaire for whichever drug they took for the longer period" 5. Missing data: moderate "2,032 completed questionnaires available for analysis of which 10.8% (220) failed to indicate which drug they were taking" 6. Measurement of outcomes: serious The outcome measure was subjective; participants and personnel were not blinded 7. Selection of the reported results: serious "In both arms, some participants indicated that they had experienced an adverse effect but did not report how it had impacted upon their ability to work. They were excluded from the final analysis" Mefloquine: 71 participants, doxycycline: 67 participants 8. Other: low "The research was not sponsored by any external body" independently performed in a sample of patients from one center that participated in the MAL30010 multicenter clinical trial'-Enrollment criteria and study conduct were described in a separate publication (Høgh 2000) which refers to a different study population (atovaquone-proguanil versus chloroquine-proguanil) 'This study was planned and performed independently from the trial by other researchers and without knowledge of its results.' 'Subjects were separately recruited and asked for consent during the initial screening visit of the trial.'

Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk "A computer-generated code was used to randomly assign a treatment number to the three bottles of study drug for every individual. At all sites consecutively enrolled individuals who satisfied all entry criteria received the next treatment number" (Høgh 2000) Allocation concealment (selection bias) Low risk "Treatment codes were provided to investigators in opaque sealed envelopes, to be opened only if knowledge of study drug assignment was required for management of a medical emergency" (Høgh 2000)

van Riemsdijk 2002 (Continued)
Blinding of participants and personnel (performance bias) Adverse effects/events Unclear risk "To mask differences between the dosing regimes, placebo tablets were used... All placebo treatment regimens were identical to the aforementioned scheme for the active ingredient of mefloquine and atovaquone plus chloroguanide" Comment: did not mention whether the placebo and intervention tablets were identical in appearance Blinding of outcome assessment (detection bias) All outcomes Low risk "The assessments were made by researchers who were unaware of the treatment allocation" Incomplete outcome data (attrition bias); efficacy

Unclear risk N/A
Incomplete outcome data (attrition bias); safety High risk "We enrolled a total of 140 subjects in the cohort, 119 of whom completed the follow up" Comment: Those who did not complete follow up were not included in the subsequent statistical analysis. The proportion of participants who did not complete the study due to adverse outcomes varied significantly between groups (67% mefloquine and 33% atovaquone plus chloroguanide) Selective reporting (reporting bias); efficacy Unclear risk N/A Selective reporting (reporting bias); safety Low risk "Data were collected on concurrent medications, as well as subject's use of coffee, alcohol and illicit drugs" "stratification for sex and adjustment for potential confounders such as smoking and the use of coffee and tea did not affect the result" Comment: these data were not presented

Random sequence generation (selection bias)
Unclear risk "The study followed a randomised, 2-arm, double-blind, parallel group design" Comment: method of sequence generation not described Allocation concealment (selection bias) Unclear risk "The study followed a randomised, 2-arm, double-blind, parallel group design" Comment: method of allocation concealment not described

Measurement of interventions: low
Travellers were asked to self-report which prophylactic regimen they were taking while still using the drug

Departures from intended interventions: moderate
No discontinuations or switches were reported. This information was not included in the questionnaire 5. Missing data: low Outcome data were available for 973/978 mefloquine recipients and 80/80 doxycycline recipients 6. Measurement of outcomes: serious Comment: the outcome measure was subjective; participants and personnel were not blinded 7. Selection of the reported results: moderate Insufficient information provided on how data on adverse effects were obtained to determine whether all outcomes were reported 8. Other: no information No information was provided regarding the study sponsor.

Methods
Design: RCT Study dates: April to July 1993 Malaria transmission pattern and local antimalarial drug resistance: "Incidence of new cases of falciparum malaria during the rainy seasons has been measured at 90% in adults. P. falciparum accounts for > 95% of all malaria in Saradidi" Adverse event monitoring: "Each subject was visited daily at home by an assigned field worker, who asked about symptoms of malaria or drug side effects, obtained malaria smears, or administered drug doses if the subject was not at school" There was a possiblity that some participants in the second deployed reference group took mefloquine 4. Departures from intended interventions: moderate "Both reference groups were restricted to individuals who had no evidence of having received a prescription for mefloquine or chloroquine or a doxycycline prescription for more than 14 tablets" 5. Missing data: moderate "Individuals who could not be followed a minimum of 2 months were excluded from the study" Comment: number of participants in this group not reported 6. Measurement of outcomes: low The outcome measure (hospitalizations) was objective 7. Selection of the reported results: low All prespecified outcomes were reported 8. Other: low Government funding Test for overall effect: Z = 2.12 (P = 0.034)

Comparison 1. Mefloquine versus placebo/non users
Test for subgroup differences: Chi 2 = 0.00, df = 1 (P = 0.99), I 2 =0.0%     We assessed whether selection into the study was unrelated to intervention or unrelated to outcome, and whether start of intervention and start of follow up coincided for most subjects. Non-responder bias at the point of selection was considered here for cohort studies. We used the following cut offs for non-response rate: low risk < 10%, moderate risk 10% to 20%, serious risk > 20%

Measurement of interventions Low risk Moderate risk Serious risk Critical risk No information
We used the following criteria: Low risk: the prescription was provided by a travel clinic which also performed the study, and discontinuations were recorded and reported, or all participants were issued with their medication e.g. soldiers or participants were asked to self-report which medication they took whilst they were taking it Moderate risk: the prescription was provided by a travel clinic which also performed the study but no information regarding switches and discontinuations was We reported the study sponsor. We classified the analysis of studies sponsored by pharmaceutical companies as independent of the sponsor when it was clearly stated that the sponsor had no input to the trial analysis

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
In the protocol we planned to use a modified version of the ACROBAT-NRSI tool (now referred to as ROBINS-I) (ACROBAT-NSRI tool). In the full review we used the original version.
In the protocol we stated that we would include "clinical cases of malaria, diagnosed by PCR or microscopy". In the full review we included trials in which the methods of detection for malaria were unclear, or different (one RCT which tested for antibodies to a circumsporozoite protein four weeks after travel). This change occurred due to difficulties in establishing diagnoses of malaria in shortterm travellers. No cases of malaria occurred in any study arm in any of these additionally included studies.
In the full review we did not include comparisons with regimens that are currently not routinely used or single-arm cohort studies. These are planned to be analysed in separate systematic reviews (Rodrigo 2016; Tickell-Painter 2017).

Differences between 2015 review and this review update
We amended the review title from 'Drugs for preventing malaria in travellers' to 'Mefloquine for preventing malaria during travel to endemic areas. We rewrote the protocol. Criteria for included studies, methods, and outcomes were revised. The was externally peer refereed by two editors.
The scope of the review changed to cover only efficacy and safety of mefloquine. The search was updated. The types of studies were changed to include non-RCTs/cohort studies for analysis of safety. The control arm was changed to include placebo or no intervention, as well as the commonly used alternatives of atovaquone-proguanil, doxycycline, and chloroquine. Types of participants were changed to include all adults and children, including pregnant women (now includes immune and partially-immune participants). We altered the inclusion of adverse outcomes; we included measures of adherence to the drug regime and adverse pregnancy outcomes. We modified the 'Risk of bias' assessment to include methods of assessment for non-randomized trials and risk of bias in conduct and reporting of adverse events and adverse effects. We did not include any analysis of deaths, suicides, or parasuicides attributable to mefloquine prophylaxis; these are addressed in a separate review (Tickell-Painter 2017). The author team changed from Jacquerioz FA and Croft AM to Tickell-Painter M, Mayaan N, Saunders R, Pace C, and Sinclair D.