A systematic review of factors affecting adherence to malaria chemoprophylaxis amongst travellers from non-endemic countries

A search was performed using Ovid, in the MEDLINE, Embase, PsycINFO and Global Health databases. Databases were searched from inception. The search was initially conducted on 28th December 2015, updated on 28th January 2017 and further updated on 4th April 2019. The following search terms were used: (malaria) AND (adherence OR compliance OR uptake) AND (prophyl* OR prevention OR atovaquone OR proguanil OR malarone OR chloroquine OR doxycycline OR mefloquine OR lariam OR primaquine). The results of this search were then filtered to remove duplicates and non-English results. Any studies categorized on the databases as ‘non-human’ were also removed. Those publications that were left were assessed for their relevance against the inclusion criteria by first screening their titles and abstracts and then screening the full-texts of any that appeared potentially relevant.

Studies were included if they:

For every included paper, details were tabulated relating to citation, year of publication, the sample that was studied, sample size, study design, the adherence rate to chemoprophylaxis, predictors of actual or intended adherence, self-reported reasons for actual or intended adherence, and a quality assessment grade. Any other details felt to be of importance in understanding the study were also noted.

Where possible, adherence rates for each study were calculated as the percentage of all participants who took all their tablets as recommended. It was not always possible to calculate this, however. For example, the nearest data reported by Cunningham et al. [12] was the percentage of participants who took more than 95% of their tablets as recommended.

A methodological quality assessment was conducted based on a simplified version of the Delphi list [13]. Studies received one point for meeting each of the following criteria:

Studies scoring zero or one out of three were classified as ‘low’ quality. Those scoring two were classified as ‘medium’ quality. Studies scoring three were categorized as ‘high’ quality.

The search, data extraction, assessment of risk of bias and data synthesis was carried out by JA with advice from GJR and JW. An updated search, data extraction, assessment of risk of bias and data synthesis was carried out by SKB with advice from GJR. Any uncertainties were resolved through discussion.

Adherence rates varied widely, ranging from 0% for corporate workers placed in Ghana for over a year [27] to 89% for travellers from the USA [31].

Forgetting to take the medication was reported as a reason for non-adherence in four studies [15, 33, 37, 40, 42]. Several studies also reported concerns with side-effects: this included concerns about the safety of long-term use of anti-malarial medication [12, 21, 40], as well as experienced (both past and present) or anticipated side-effects [15, 21, 23, 26‐28, 31, 33, 37, 40, 42]. Other reasons included having too many pills to take [37]; not seeing any mosquitoes [28, 37, 42]; tiredness [37]; price [23, 37, 42]; lack of pills [37]; not thinking that prophylaxis was necessary [15, 21, 31]; being advised (for example, by a tour guide, locals or colleagues) that it was not necessary [15, 21, 27, 31, 42] and not liking to take medication [33, 37]. A higher perceived risk of catching malaria was associated with greater adherence and having a self-reported low perceived risk [27, 42] was associated with poor adherence. Thinking there was no malaria [23] was associated with poor adherence, as was: presumed immunity [23, 26, 33]; high standard of on-site medical care, for example, at a mine in Mali [26]; taking an active decision not to take medication [22, 23]; being unable to obtain the tablets [23, 42]; thinking it is easier to cure malaria than to take the tablets [23, 33]; having travelled for a short period and deciding to take the risk [23], losing the medication [42] and having travelled at short notice [15].

Eleven studies found that older participants were more likely to be adherent [12, 17, 18, 20, 21, 24, 30, 32, 38‐40]. Another study reported that those under 30 were less likely to be adherent than older people [22], but significance was not reported. In addition, one study showed that those aged under 5 were significantly less likely to take their tablets correctly [36]. However, Joshi et al. [33] found that age was not a predictor of adherence as did Farquharson et al. [25].

A participant’s country of residence was shown to influence adherence in three studies [18, 29, 41], though not in two studies [14, 42]. For example, Baggett et al. [29] showed that US citizens were significantly more likely to be adherent than non-US citizens; whilst Shady [41] found that those of Kuwaiti nationality are shown to have significantly better adherence when compared with non-Kuwaiti individuals.

Socio-economic and education status also influenced adherence rates. Blue-collar workers were more likely to be non-adherent compared with white-collar workers [41]. Having an above secondary-level education improved adherence, whilst going to university was associated with poor adherence [41]. However, three studies [14, 21, 33] found no association between education level and adherence. Children from mono-parental families were more likely to exhibit poor adherence [36]. Cobelens et al. [21] and Farquharson et al. [25] found that gender did not significantly predict adherence; one study [22] reported that females were less likely to be adherent than males, though significance was not reported.

Length of stay was reported in numerous studies as influencing adherence, with longer stays associated with poorer adherence [6, 12, 18, 19, 24, 27, 38, 40]. Similarly, shorter travel was shown by most, though not all studies [28, 42], to be associated with better adherence [20, 37, 39]. Farquharson et al. [25] found that poor adherence (compared with partial adherence) was associated with going on a longer trip but also noted that full adherence (compared with partial adherence) was associated with going on a longer trip. Belderok et al. [35] noted that those spending 14 to 29 days in an endemic area were significantly more adherent compared with travellers spending less than 13 days, or more than 29 days, in endemic areas. Conversely, two studies [22, 24] found that poor adherence was associated with travelling for more than 3 weeks, though only one of these studies [24] reported the significance level. One study [43] found that duration of travel was not associated with the likelihood of carrying anti-malarial medication.

Previous travel was shown to be a predictor of poor adherence in four studies [19, 29, 31, 33], though one study found no association between previous travel experience and intention to take anti-malarial medication [43] and a further study [14] also found no significant difference in adherence based on previous travel. Having previously acquired malaria [38] was also shown to be associated with lower rates of adherence, though endemicity of country of birth was not [42].

Destination [20, 21, 28, 31, 35, 36, 41] significantly affected adherence. For example, Depetrillo et al. [31] showed that adherence was greater for those travelling to sub-Saharan Africa compared with central America; Ropers et al. [28] showed there was greater adherence in those travelling to Kenya compared with Senegal; and Shady [41], Belderok et al. [35] and Caillet-Gossot et al. [36] demonstrated that adherence was greatest amongst those travelling to African destinations than to Asia, the Indian Ocean or South America. Travel to urban areas [39] or areas of mass tourism [37] was also associated with better adherence rates that those travelling, for example, to rural areas. No effect was found for whether the destination was partially or entirely endemic [42].

The nature and purpose of travel also significantly affected adherence rates. Package tours [20] and those booked through agents [41] compared with more adventurous (e.g. backpacking [21, 39]) or independent [41] travel styles showed greater adherence rates.

Those travelling to visit friends and relatives, for non-tourism reasons, or those travelling for business, showed worse adherence in most [18, 24, 29, 33], but not all [44, 42] studies—travelling for family-related as opposed to business-related reasons was shown in one study [38] to be associated with greater adherence. Those travelling for a holiday [33] or leisure [41] showed greater adherence than those travelling for business.

Having a basic knowledge of malaria [33] or receiving training [6] was associated with better adherence rates, as was receiving pretravel advice [18, 28, 38]. Farquharson et al. [25] noted that poor adherence (compared to full adherence) was associated with greater amounts of health professional discussion in the medical consultation; they also noted that greater amounts of traveller information and questions were associated with both poor adherence (compared with partial adherence) as well as full adherence (compared with partial adherence). There were variations noted depending on the source of the information, however, with higher adherence rates being reported if information was delivered by a physician, compared with if it was not [34]. Those receiving information from one information source were also more likely to be adherent when compared with those using no information source [18]. Rolling et al. [43] found that travellers were more likely to be carrying anti-malarial medication if they had had a medical consultation prior to travelling, especially with a travel medicine specialist. Forgetting to take tablets, which was a self-reported reason for non-adherence, may also be related to capability [15, 33, 37, 40, 42].

Physical opportunity factors included losing medication or simply not having adequate chemoprophylaxis medication [21, 22]. Social opportunity factors included personal interactions with someone perceived to be knowledgeable about malaria or the side-effects of prophylaxis. Those who received advice from others to discontinue their prophylaxis were less likely to be adherent [15, 21, 27, 31]. Being unable to obtain tablets, which was previously explained as a self-reported reason for non-adherence [23, 42], is also related to opportunity.

Several studies assessed factors relating to motivation. Perhaps the most commonly identified factor was the presence of, or concerns about, side-effects of chemoprophylaxis [18, 19, 24, 32] or concerns about long-term adverse effects of taking the medication [40].

Other motivation related factors included the perceived risk of catching malaria [28, 40], the perceived severity of malaria [33, 34], perceived benefits of prophylaxis [14], perceptions and attitudes towards prophylaxis risks and whether the necessity of taking prophylaxis outweighed these risks (notably the safety and side-effects of any medication taken); or wrongly believing [38] that curing malaria would be easier that taking the prophylaxis. Other incorrect beliefs included perceived immunity ([33]—associated with worse adherence) and false belief in being vaccinated ([38]—associated with better adherence), as well as believing that anti-malarial medications are useless [32]. More automatic motivational factors included habitual behaviours such as previous adherence with prophylaxis recommendations and emotional fear of prophylaxis and side-effects. Farquharson et al. [25] found no significant difference in adherence based on previous experience of anti-malarial medication [14].

Low perceived risk, which was often a self-reported reason for non-adherence—as opposed to greater perceived risk, which was related to greater adherence—is also a motivation-related risk factor [23, 26, 27, 33, 42].

Several other predictors were identified pertaining to the medication itself. Weekly medication [19] was shown to be more likely to be taken correctly than daily [24] prophylaxis, though not in all studies [42]. Mefloquine showed better adherence rates as opposed to doxycycline or atovaquone–proguanil [40] and better adherence rates compared with atovaquone–proguanil or proguanil [35]. Lobel et al. [24] found that proguanil was associated with poorer adherence. Concurrent use of DEET [35] was also shown to be associated with better adherence.

Two studies [15, 17] commented that the majority of poor adherence was due to premature cessation of prophylaxis, when the participants returned home to their non-endemic country.

The quality of this systematic review was limited by the methods of the studies reviewed. In this regard, it is notable that only eight included studies were rated as being high quality. Many of the studies used different methods to assess adherence, and factors influencing adherence, amongst a wide range of participants. The definitions of adherence and the length of recommended treatment also differ greatly from study to study, meaning that a participant defined as adherent in one study might not have been in another. For example, Cunningham et al. [12] defined adherence as taking more than 95% of prescribed tablets, whereas Belderok et al. [35] reported those who took all their prescribed tablets; Rolling et al. [43] explored intention to adhere to anti-malarial medication simply by asking travellers at an airport if they were carrying tablets. The reliance of many studies on self-reported measures of adherence was also notable. Self-report has limitations as a method, reflecting participant recall and social desirability as well as genuine adherence. Future studies should explore alternative ways of measuring adherence.

The eight high-quality studies tended to have larger participant samples (ranging from 1001 to 42,202). It is perhaps an issue that many studies in this area use small sample sizes and there is a lack of large-scale randomized controlled trials. Those who reported overall adherence rates of the whole sample reported fairly similar prevalence rates (42.4–61.7%). Four of the eight high-quality studies examined pre-travel knowledge/advice as a determinant of adherence, and all found it a significant predictor, while three explored reason for travel and found that non-tourism reasons for travelling were associated with lower adherence.

Positively, the findings of this review seem to broadly correspond with a previous review, published in the form of a poster presentation and letter [14, 47]. However, there are some limitations to the review process. Due to pragmatic considerations, this review was limited to papers published in English. Papers in other languages, or which appeared only in the grey literature, may exist which would have added to the conclusions. Similarly, because the initial search itself was carried out by one individual, human error in the compilation of the literature database cannot be discounted. This may have resulted in some studies being erroneously excluded. Because studies with significant findings are more likely to be published and are usually easier to locate and identify, it is possible that some of the apparent predictors of adherence that were identified may be less robust than it currently appears. It should also be noted that conclusions are inevitably constrained by what currently exists in the literature and there may be scope for other, more imaginative interventions to promote adherence. It is also possible that there are different reasons for non-adherence in different populations and that reviews not focusing solely on travellers from non-endemic countries may uncover other factors associated with non-adherence.