Choice of and Adherence to Prophylactic Antimalarials

Larry Goodyer BPharm, MPharm, PhD, Leanne Rice MSc Cstat, Alan Martin MSc
DOI: http://dx.doi.org/10.1111/j.1708-8305.2011.00534.x 245-249 First published online: 1 July 2011

Abstract

Background There were 1,370 cases of imported malaria and six fatalities in the UK in 2008, the majority of which were due to chloroquine‐resistant Plasmodium falciparum. Poor adherence to prescribed regimens is known to be an important factor in these cases.

Method An observational study utilizing questionnaires both pre‐ and post‐travel was conducted to assess the adherence behavior of UK travelers undertaking trips of less than 28 days duration, who were prescribed one of three antimalarials recommended to prevent P falciparum malaria (atovaquone plus proguanil, doxycycline, or mefloquine) in travel clinics in England and Scotland. The primary objectives of the study were to assess travelers' perceptions of, and self‐reported adherence to antimalarial medication. A secondary objective was to examine the reasons for the choice of antimalarial therapy from the perspective of prescriber and traveler.

Results For the primary end point of self‐reported adherence specified as the proportion of antimalarial tablets prescribed that were actually taken, statistically significantly higher adherence overall and post‐travel was seen with atovaquone plus proguanil compared with doxycycline. It was not possible to calculate the statistical significance of comparisons with mefloquine, but adherence to mefloquine appeared similar to or better than doxycycline and similar to atovaquone plus proguanil for categorical adherence. Effectiveness, side effects, previous experience of antimalarials, and dosing convenience were the main determinants of both travelers and practitioner's choice of antimalarial. The practitioner's recommendation was highly important for 63% of travelers.

Conclusion A shorter post‐travel regimen has a significant impact on adherence to antimalarial prophylaxis. A reassessment of the risk by travelers on returning home may be a major contributor to this poor adherence.

Between 1,300 and 2,000 cases of imported malaria (including between 6 and 16 fatalities) were reported in the UK each year for the period 1998 and 2008. The majority of cases (over 70%) were due to Plasmodium falciparum and contracted in areas where chloroquine‐resistant P falciparum (cr PF) is endemic. 1 This is despite the fact that most cases are preventable with the proper use of chemoprophylactic agents. The Advisory Committee on Malaria Prevention recommends three antimalarials, atovaquone plus proguanil (Malarone, GlaxoSmithKline)(At+Pro), doxycycline (eg Vibramycin, Pfizer) (Dxy) and mefloquine (Lariam, Roche)(Mfl) for the use in cr PF malarious zones, and all are considered equally effective if used correctly. 2 Unfortunately, many travelers fail to complete the full course of their medication. In 2005, 78% of reported cases of malaria, where prophylaxis history was known, had taken either no antimalarial medication or incorrect medication. 2 Factors that influence adherence are therefore an important consideration for healthcare professionals (HCPs) when prescribing antimalarials. It has recently been suggested that an observed difference of effectiveness of agents from retrospective observational data may be explained by adherence issues. 3

Choice of antimalarial may be an important factor. In studies, different rates of occurrence of side effects such as neuropsychiatric problems, Candida, photosensitivity, and gastrointestinal irritations have been observed for At+Pro, Dxy, and Mfl. 4–6 In addition, the three antimalarials are characterized by very different dosing regimens: At+Pro and Dxy are taken on a daily basis before, during, and after traveling, whereas Mfl is taken weekly; At+Pro and Dxy must be taken 1 to 2 days prior to travel, compared with at least 1 week (preferably 2–3 wk) for Mfl; and after return Dxy and Mfl must be taken for 4 weeks post‐travel, compared with 1 week for At+Pro. 7 These variations in side‐effect profile and dosing convenience may impact the adherence behavior of travelers taking these medications. Other factors such as travelers' beliefs about malaria and antimalarial medication and previous experience of taking antimalarials may also be important.

Data on the impact of travelers' beliefs or choice of antimalarial on adherence behavior are limited, especially in the UK, and no studies have compared At+Pro with Dxy. 5,8–10 There is, therefore, a need for further research to provide HCPs with the information they need if they are to promote adherence to antimalarial medication.

This observational study examines two areas related to antimalarial use: the adherence behavior of travelers from the UK to cr PF malarious zones, who were prescribed a recommended antimalarial (primary objective), and the factors influencing selection of the antimalarial from the perspective of the prescriber and traveler.

The results of this study should better equip HCPs to provide information and advice to travelers when prescribing antimalarials.

Methods

This study was a noninterventional, observational study conducted in travel clinics in England and Scotland between December 2004 and April 2006, to assess the adherence behavior of individuals prescribed a licensed antimalarial at a travel clinic for a trip to a cr PF malarious zone. Eleven clinics participated from London, Manchester, Glasgow, Cambridge, Bristol, and Edinburgh: six Medical Advisory Services for Travelers Abroad (MASTA) travel clinics, four Nomad travel clinics and the Royal Free Hospital travel clinic. The study was approved by Cambridge Local Research Ethics Committee and informed consent was obtained from all participants.

The investigators in this study were mostly nurse practitioners responsible for the selection and supply of antimalarials under a system of patient group directions (PGD). 11 All individuals having a naturally occurring consultation with a participating practitioner requesting antimalarial protection for travel to cr PF malarious zones were considered for participation in the study once a decision to prescribe an antimalarial had been made as per routine practice. Treatment choice was solely at the discretion of the traveler and practitioner. To be eligible, travelers had to be at least 18 years of age and to have been prescribed or supplied under PGD an antimalarial medication as a result of planned travel for a duration of 28 days or less. Travelers participating in other prospective clinical research or observational studies, pregnant travelers or travelers planning to get pregnant during the study were excluded.

Once enrolled and consented a baseline questionnaire was completed by the traveler and prescribing investigator. Both were asked to rate the importance (as “high,”“medium,”“low/not important,” or “don't know”) of each of a set of factors for their choice of antimalarial. A post‐travel questionnaire was sent to the participant to be self‐completed, approximately 1 week after they were due to complete their course of medication. If not returned within 2 weeks, the traveler was administered the questionnaire over the telephone. The post‐travel questionnaire included a self‐assessment of the amount of antimalarial medication actually taken. Travelers were asked to state the amount of antimalarial medication taken in two ways: the number of tablets taken pre‐, during, and post‐travel, and also on a categorical adherence scale where they were asked to indicate whether they took “all,”“most,”“about half,” or “very few” of the medication prescribed pre‐, during, post‐travel, and overall. Also included on the questionnaire was a single free‐text question asking travelers to describe any side effects of antimalarial medication.

Statistical Analysis

The primary end point was self‐reported adherence specified as the proportion of antimalarial tablets prescribed that were actually taken. Secondary end points were percentage of travelers reporting adverse events; reasons for travelers preferring a particular antimalarial medication; reasons for HCPs prescribing a particular antimalarial medication.

Although the original intention of the study was to compare all three antimalarial medications, it was not possible to recruit enough travelers into the Mfl group, so the statistical analysis was powered only for the comparison of At+Pro and Dxy. The sample size was determined to look for a difference of 10% in percentage adherence between At+Pro and Dxy. Using an SD of 18%, a 5% significance level and 80% power, 60 evaluable travelers in each group were required. This also took into account the asymptotic relative efficiency of the Wilcoxon–Mann–Whitney U‐test, which has been taken to be 86.4%. 12

Percentage adherence was compared between medications using the Wilcoxon rank sum test, with the 95% CI calculated using the Hodges–Lehmann approach. This was also the case for the self‐report categorical adherence scale. Good compliance was defined as having taken at least 80% of prescribed medication, analyzed from the number of tablets reported as taken by the traveler. As a further analysis, the odds of taking all or at least 80% of the post‐travel medication were calculated for the comparison between At+Pro and Dxy, along with the 95% CI. Results were determined as being statistically significant if the p‐value was <0.05.

It should be noted that an adherence percentage of >100% was possible when assessed as number of tablets reportedly taken. This occurred when travelers recorded that more doses of the antimalarial treatment had been taken than had been prescribed by the investigator. It was not possible to go back to the traveler to obtain the reasons for this.

Results

Of 252 travelers consented into the study, 251 completed the pre‐travel questionnaire (intention‐to‐treat). Of these, 185 completed the pre‐ and post‐travel questionnaires and these make up the total analyzed sample. No differences of note were seen between the characteristics of those who completed both questionnaires and those who only completed the pre‐travel questionnaire. The number of travelers taking each of the medications together with their age and sex are shown in Table 1. The distribution of males and females between the groups was similar, but there were statistically significant differences in mean age, with travelers in the Mfl and At+Pro groups tending to be older than in the Dxy group. The reasons for travel were identified as: business 28%, holiday 59%, visit friends/relatives 8%, and other 5%. The median time of travel was 14 days (inter‐quartile range: 9–20 d). Thirty‐six percent of the travelers had previously taken one or more of the antimalarials being studied.

View this table:
Table 1

Age and sex of travelers in each group

At+ProDxyMflAll travelers
Age: mean (SD) [n]
‐ pre‐questionnaire completers37.6 (11.2) [114]33.8 (10.7) [100]43.3 (14.5) [35]36.9 (11.9) [249]
‐ pre‐ + post‐questionnaire completers38.5 (11.1) [84]34.6 (11.7) [70]44.2 (14.3) [30]38.0 (12.3) [184]
Sex: Female n (%) : Male n (%)
‐ pre‐questionnaire completers46 (40%) : 68 (60%)46 (46%) : 54 (54%)16 (46%) : 19 (54%)108 (43%) : 141 (57%)
‐ pre‐ + post‐ questionnaire completers38 (45%) : 46 (55%)34 (49%) : 36 (51%)14 (47%) : 16 (53%)86 (47%) : 98 (53%)

Adherence analyzed as the number of tablets reported as taken (as a percentage of prescribed), both overall, which includes pre‐, during, and post‐travel, (primary end point) and for each period separately are shown in Table 2. Statistically significant differences (at the 5% level) in median percentage adherence were seen between the At+Pro and Dxy groups for overall and post‐travel adherence, with travelers taking At+Pro having higher levels of adherence. Median percentage adherence in the Mfl group was numerically lower than for either At+Pro or Dxy overall, pre‐, and during travel, and numerically lower than for At+Pro post‐travel.

View this table:
Table 2

Median percentage adherence—pre‐ and post‐questionnaire completers

At+Pro (n = 84)Doxycyline (n = 70)At+Pro versus Dxy p‐valueMefloquine (n = 31)
Overall (ie pre, during and post)100%84% p = 0.00478%
median (IQR)(87%–103%)(55%–100%)(57%–100%)
Pre‐travel median (IQR)100%100% p = 0.38100%
(100%–200%)(100%–200%)(100%–200%)
During‐travel median (IQR)100%100% p = 0.70100%
(100%–100%)(100%–100%)(75%–100%)
Post‐travel median (IQR)100%75% p = 0.01475%
(71%–100%)(25%–100%)(38%–100%)

Adherence analyzed as the proportion of travelers, who reported taking all their medication from the categorical adherence scale, is shown in Table 3. A higher percentage of travelers in the At+Pro group compared with the Dxy group stated that they took all their medication overall, during, and post‐travel, with statistical significance for overall and post‐travel. Categorical adherence in the Mfl group was numerically similar or better than for At+Pro at all stages of travel.

View this table:
Table 3

Proportion of travelers reporting taking all medication (categorical adherence scale)—pre‐ and post‐travel questionnaire completers

At+Pro (n = 84)Dxy (n = 70)At+Pro versus Dxy p‐valueMfl (n = 31)
Overall
All56 (70%)29 (44%) p = 0.00121 (72%)
Most/about half/very few24 (30%)37 (56%)8 (28%)
Missing442
Pre‐travel
All59 (72%)47 (72%) p = 0.9623 (85%)
Most/about half/very few23 (28%)18 (28%)4 (15%)
Missing254
During travel
All57 (70%)39 (58%) p = 0.06724 (89%)
Most/about half/very few24 (30%)28 (42%)3 (11%)
Missing334
Post‐travel
All46 (57%)19 (29%) p = 0.00415 (56%)
Most/about half/very few35 (43%)47 (71%)12 (44%)
Missing344

Calculating odds ratios, travelers taking At+Pro were 2.59 times more likely to take all post‐travel medication compared with Dxy (95% CI 1.27–5.26, p = 0.008) and 2.6 times more likely to take ≥80% of post‐travel medication (95% CI 1.29–5.25, p = 0.007). Characteristics such as age or sex did not appear to influence whether travelers reported taking at least 80% or less than 80% of prescribed medication.

Factors considered highly important for their choice of antimalarial by travelers completing the pre‐travel questionnaire and investigators are shown in Figure 1. Effectiveness and side effects were considered highly important by more than 60% of both travelers and investigators, and previous experience of antimalarials and dosing convenience by more than 40%. The practitioner's recommendation was highly important for 63% of travelers.

Figure 1

Factors considered highly important for choosing/prescribing antimalarial medication (n = 185).

Overall, fewer travelers in the At+Pro group (17%—14/84) compared to the Dxy group (34%—24/70) reported side effects. The majority of travelers in the Mfl group (55%—17/31) reported side effects. The most frequent side effects were gastrointestinal irritation, which occurred with all three antimalarials and neuropsychiatric events relating to changes in mood and behavior—nearly all of which occurred in the Mfl group. Photosensitivity was also reported in 13% of the Dxy group.

Discussion

The primary aim of this study was to assess traveler's perceptions of, and self‐reported adherence to, antimalarial medication in those traveling to cr PF zones from the UK. It is recognized that self‐reported adherence level are often higher than adherence measured by objective methods, as has been clearly demonstrated in a study examining mefloquine chemoprophylaxis. 13 Although the data concerning the mefloquine group has been included, the failure to achieve sufficient recruitment into this arm is perhaps a reflection of the lack of popularity of this agent in the UK and that only shorter term travelers were included.

A clear finding was that travelers prescribed At+Pro were more adherent to their medication than those prescribed Dxy. The situation with Mfl was less clear, partly due to the lack of statistical power, and partly due to the difference in results for median percentage and categorical measures of adherence. The latter was probably due to the once‐weekly regime for Mfl which would mean that misreporting of tablet numbers would have a proportionately greater impact on results. The results suggest that overall adherence to Mfl was either similar to or better than Dxy and similar to At+Pro for categorical adherence, but further research would be needed to establish this.

Self‐reported adherence was high both pre‐ and during the period of travel and the main period for reported non‐adherence appears to be in the post‐travel period. Absolute compliance with no missed doses was reported by 70%, compared to a recent study, 14 where 89% of participants claimed complete adherence. The study did not compare adherence to any other antimalarial and was assessed by telephone interview. That self‐reported adherence might be higher than actual adherence, has been shown in other studies. 15 An investigation into prophylaxis to Mfl 13 has also indicated that much of the poor adherence can be attributed to the post‐travel period. The results from the present study showed that travelers on At+Pro were more than twice as likely to report taking all or at least 80% of their post‐travel medication than travelers on Dxy. The most likely reason for this is the shorter post‐travel dosing period for At+Pro, 1 week compared with four weeks for Dxy. Travelers perception of risk may decline post‐travel, leading them not to complete longer post‐travel medication regimens. Amongst military personal an association has been found between contracting malaria 16 and failure to complete post‐travel courses, and in a survey of backpackers 30% were found to have stopped medication prematurely. 17

Travelers and prescribers agreed that effectiveness concerns about side effects, previous experience, and convenience of doses were the most important reasons for the choice of antimalarial. HCPs are recommended to take these factors into consideration when discussing appropriate malaria chemoprophylaxis with travelers to improve overall adherence. Travelers chose their antimalarial chemoprophylaxis as part of their usual consultations, and this study was not designed to look at any particular interventions to influence choice or to identify why a particular antimalarial was chosen. A study of 1,073 Swiss travelers demonstrated the value of detailed written information on informing choice and that adverse effect profiles, previous use, and cost were the most important factors. 18

There did not seem to be any characteristic of the traveler, such as length of travel and reason for traveling, determining choice of antimalarial other than those receiving Dxy tended to be younger. This may be related to the cost, where younger backpackers may self‐select for the somewhat cheaper Dxy regimens. These observation are only related to the decisions made by those traveling <28 days and may differ for those traveling longer term.

Conclusion

This study supports the assumption that the 1 week antimalaria post‐exposure course using At+Pro could be preferable to a 4‐week course with Dxy to encourage adherence to the prescribed regimen. Further work is required to identify the variety of factors that determine adherence to antimalarials.

Acknowledgments

We would like to acknowledge Professor Robert Horne for his help and advice on this project. We would also like to thank the study staff at MASTA, NOMAD travel clinics, and the Royal Free Hospital. The study was commissioned and paid for by GlaxoSmithKline.

Declaration of Interests

L. R. and A. M. are employees of GlaxoSmithKline. L L G. is the Superintendent Pharmacist and the Director of Nomad Travelstore Ltd.

References

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