Assessment of acceptability and ease of use of atovaquone/proguanil medication in subjects undergoing malaria prophylaxis Objective: International travelers from non-endemic areas are at high risk of contracting
malaria due to their lack of immunity. Prevention is therefore of outmost importance and is achieved through effective and safe chemoprophylaxis, which reduces the risk of fatal disease. Among the various antimalarial drugs available, the synergistic combination of atovaquone and proguanil (A/P) (Malarone®; Glaxo-SmithKline) has proven a valuable option in terms of effective protection against chloroquine and multi-drug resistant falciparum malaria, safety, tolerability, and ease of use, thus favoring compliance. The purpose of the present study was to assess acceptability and ease of use of A/P chemoprophylaxis in a population of employees of the oil industry bound to malarious areas. Particular attention was paid to Milanese, Italy; 2S.A.V.E. Studi Analisi Methods:
A survey was conducted on a sample of 700 employees on A/P chemoprophylaxis. Demographic data and specifi c information on A/P treatment were collected by means of a 16-item questionnaire administered immediately before departure. All questionnaires returned were then entered into a database and statistically analyzed.
Results: Both habitual and fi rst-time travelers showed good adherence to A/P chemoprophylactic
regimen. In general, only few adverse side-effects were reported, none of which were serious.
Travelers with previous experience of other antimalarials stated A/P prophylaxis had proven advantageous due to fewer adverse reactions, better condition of administration, and better sense of protection compared with other available treatments.
Keywords: atovaquone and proguanil, Malarone, malaria prophylaxis, prevention,
Not foduction
Each year an estimated 50 million travelers visit malaria endemic areas (Schlagenhauf et al 2003) and 10,000–30,000 of them fall ill with malaria after returning home (Lobel and Kozarsky 1997; WHO 2008). This imported malaria, which represents an important public health problem with a high mortality rate (Muentener et at 1999), can be easily treated if diagnosed promptly, and it follows a serious course in only about 12% of individuals (Croft 2000).
The risk of infection varies considerably, depending on the degree of endemicity, the duration of stay, individual behavior, and preventive measures taken (Simons et al 2005). Risk is especially high in tropical Africa, where 80%–95% of infections are caused by Plasmodium falciparum (Steffen et al 2003), the most serious form. Most cases of falciparum malaria occur because of poor adherence to or complete failure to use chemoprophylaxis, combined with failure to take adequate precautions against Therapeutics and Clinical Risk Management 2008:4(5) 1–6 2008 Dove Medical Press Limited. All rights reserved Malaria control must be an essential part of health participate in the study. Just before departure, all subjects care programs provided by companies operating abroad in underwent clinical examination and referred to the malarious areas. This is especially important considering Saipem medical department where they received pretravel that travelers from malaria-free regions going to endemic advice on appropriate measures of individual protection, areas are highly vulnerable as they have little or no immu- chemoprophylaxis, and treatment. In concomitance with nity, and are often exposed to delayed or wrong diagnosis the counseling, they were administered a paper question- when returning to their home country (WHO 2007).
naire by Saipem’s travel medicine specialist with the aim Many companies have in-house medical depart- of gathering data on the use, management, and effects of ments providing the necessary assistance. Italian-based Saipem, a subsidiary of the Eni Group, is a case in point. The questionnaire, which was provided with detailed In compliance with Italian law 626/94, the company has instructions to ensure accurate completion, consisted of implemented a specifi c program for the prevention and 16 questions to be entered after departure from the malarious control of malaria in the case of workers traveling to or area. The information requested regarded demographic data residing in high risk endemic areas. Besides receiving pre- (age, sex, education), information on personal knowledge travel educational materials and medical advice, Saipem’s of malaria prevention/chemoprophylaxis, and possible use personnel are offered chemoprophylactic treatment with of antimalarial drugs in the past. The second part included atovaquone and proguanil hydrochloride (Malarone®; questions on A/P chemoprophylaxis: ease of use, adher- Glaxo-SmithKline) as effective chemoprophylactic regi- ence to the prescribed regimen, and experience of adverse men appropriate for subjects bound to malaria-endemic destinations. The fi xed-dose combination of atovaquone All 700 questionnaires were entered into a database and and proguanil (A/P) has been reported to be highly effec- analyzed. Statistical analysis was performed using Student’s tive for prophylaxis of malaria caused by P. falciparum t-test to compare average data of quantitative variables (Shanks et al 1998; Boggild et al 2007) having an excel- between patients who had either already traveled or were lent safety profi le during both prophylaxis and treatment traveling for the fi rst time as Saipem’s employees to a malaria-endemic area. Statistical signifi cance of differences In the case of individuals undergoing malaria prophylaxis in distribution frequency was tested by chi-square test while on duty, it is important that the treatment chosen has (Pearson) and analysis of contingency tables. A p value no negative effects that may interfere with their performance of Ͻ0.05 was considered to be statistically signifi cant. With respect to this, the choice of A/P appears to be more Analysis was carried out using statistical package SPSS advantageous compared to other antimalarials such as mefl o- quine and chloroquine for which severe neuropsychiatric disturbances have been reported in approximately 1 in 10,000 All 700 travelers completed the questionnaires in all their The present study is a questionnaire-based survey that parts for a response rate of 100% and delivered them to was conducted on a sample of healthy travelers to remote Saipem’s medical department on their return. Of these, worksites in malarious areas. The aim was to obtain some 85% were returned in electronic form and the remainder insights into A/P compliance in the attempt to acquire real- (15%) on paper. Ninety percent of the respondents were world data on the acceptability and tolerability of A/P treat- habitual travelers, whereas 10% were on their fi rst visit ment from the traveler’s point of view.
to a malarious region as employees of Saipem. Most were male (92%) in both groups. Mean age was 38.3 years in Participants and methods
the group of habitual travelers and 30.7 in those traveling A total of 700 Saipem’s healthy employees (643 males for the fi rst time. Most had a high educational background: and 57 females) traveling to malaria-endemic areas tertiary school (22%) or first degree or post-degree (Nigeria, Congo, Angola) in the period from January 2007 specialization (77%). Compliance was extremely high as to November 2007 were eligible for inclusion in the study. 99.6% of subjects adhered to the A/P chemoprophylactic Duration of trip was 7 days on average.
regimen, which required 1 adult tablet (atovaquone 250 mg + Subjects were consecutively enrolled from a larger proguanil hydrochloride 100 mg) daily beginning 1–2 days group of Saipem’s employees who voluntarily agreed to before exposure, throughout exposure, and continuing 7 days Therapeutics and Clinical Risk Management 2008:4(5) after departure from the malaria-endemic area (CDC 2007). Only 3 individuals were not compliant, and the reason for failing to adhere was explained as low perception of malaria Of the habitual travelers, most (88.5%) had used chemoprophylaxis with A/P on previous occasions (mean number of times 2.4) and for only 72 of them (11.5%) this was the fi rst time they had experienced A/P prophylaxis. Nearly all habitual travelers (96.5%) had taken other anti- malarials on past occasions, namely mefl oquine (67.7%), proguanil (12.6%), chloroquine (12.5%), and doxycy- cline (7.3%). Among fi rst-time travelers only mefl oquine (n = 30; 100%) was indicated as medication previously used When asked about the reason for choosing A/P as anti- malarial chemoprophylaxis, 44% of the habitual travelers and 59% of fi rst-time travelers responded that they were following medical advice. For an equal proportion in both groups (23%) the reason was because they were aware of the regimen benefi ts. Twenty-two percent of the habitual travelers compared with about 10% in the other group admitted having chosen A/P for the fewer adverse side- effects. Better sense of protection against the disease was First-time tra
the answer chosen by 10 % of habitual travelers against 8% of fi rst-time travelers (Figures 1 and 2).
When asked to highlight possible differences with other antimalarial drugs, the group of habitual travelers gener- ally declared having experienced much fewer (85.2%) or rather fewer (14.8%) adverse side-effects. Condition of administration was generally well accepted, being very easy (5.5%) and rather easy (94.5%) to manage. In terms of sense of protection against the disease, most had felt rather (77.2%) and much (22.8%) more protected if compared Habitual tra
with previous other prophylactic treatments (Table 3). The most common adverse reaction was abdominal pain in both habitual travelers (n = 61) and fi rst-time travelers (n = 24), followed by few cases of headache and nausea. No serious adverse reactions were reported (Table 4).
Past studies, recently reviewed by Boggild et al (2007) have proved A/T effi cacy and optimum safety profi le, considering also its advantage over other antimalarial drugs in terms of efficacy against multidrug-resistant Our aim, however, was to assess the impact of A/P chemoprophylaxis in actual conditions of usage with particular attention to ease of use, individual capacity to Therapeutics and Clinical Risk Management 2008:4(5) Table 2 [caption to be supplied]
Habitual traveler
First-time traveler
you use A/P in the past?Did you use other Abbreviation: A/P, atovaquone/proguanil combination.
comply with the regimen prescribed, and experience of chemoprophylactic regimens is in fact frequently secondary adverse reactions. Of note, the survey was carried out on to drug side effects. Furthermore, in a study by McKeage a considerably large sample (n = 700), if compared with and Scott (2003) fewer recipients of A/P discontinued treat- available studies, whose samples do not usually exceed ment because of adverse events than individuals receiving chloroquine plus proguanil or mefl oquine. Most importantly, Our fi ndings are in line with other published data for safety no A/P-related neuropsychiatric disturbances were reported. and tolerability (Shanks et al 1998; Schlagenhauf et al 2003; These fi ndings refl ect those of previous studies demostrating Simons et al 2005), in that A/P prophylaxis was well tolerated, a lower frequency of neuropsychiatric adverse events with A/P with only mild to moderate adverse side-effects – namely, those compared with mefl oquine (Overbosch et al 2001). Considering reported by the manufacturer – and no serious adverse reactions. that approximately 1 in 10,000 travelers receiving mefl oquine We may speculate that the lack of important adverse reactions or chloroquine prophylaxis experience severe neuropsychiatric may have favored better adherence to the regimen prescribed as disturbances (WHO 2008), our results suggest that A/P may shown by the high proportion of travelers who reported regular be considered a valuable therapeutic option especially when chemoprophylaxis. As noted in a number of studies including treatment concerns subjects on duty where physical and mental the paper by Franco-Paredes et al (2006), non-adherence to fi tness is a prerequisite for their safety (Simons et al 2005).
Habitual traveler
First-time traveler
Figure 1 [caption to be supplied].
Figure 2 [caption to be supplied].
Therapeutics and Clinical Risk Management 2008:4(5) Compared with other available antimalarial drugs, prophylaxis with A/P appears to have appreciable advan- tages in terms of administration schedule and duration of recommended treatment. This aspect may also have favored the good level of adherence recorded. In fact, A/P prophylaxis can be started only 1–2 days before exposure and, above all, since the drug has casual prophylactic activity against the hepatic stages of P. falciparum (Shapiro et al 1999), it can be discontinued 7 days after departing a malarious region (Shanks et al 1999), com- pared with 4 weeks with other antimalarials. This more convenient dosage regimen, particularly in the post-travel period, should not be undervalued, considering that good chemoprophylaxis does reduce the risk of fatal disease (WHO 2008) especially in non-immune or semi-immune subjects when they return to their home country and that adherence rates for 4 weeks post exposure are generally Though it is noteworthy that the survey was conducted on a large sample, it is necessary to point out some limitations that suggest cautious interpretation of the fi ndings First-time tra
Treatment adherence was found to be very high (99%), which was probably the result of an overestimation because of the method employed. Questionnaire assess- ment, though widely used, has in fact some limitations because returning travelers tend to forget precise date and time of drug intake and over-report the correct regimen in an effort to please the investigator or to hide one’s failure As for the side effects reported, it must be noted that monitoring was focused more on acute events, since Habitual tra
questionnaires were delivered on return from the endemic area. As a consequence, under-reporting is likely to have occurred, especially on adverse reactions that emerged after some period of time. Moreover, it was not possible to assess possible interactions with other drugs as no specifi c medical data were collected from the sample. A further limitation is that our study lacks a control group using a different chemoprophylaxis and that most subjects included Nonetheless, data gathered from such a large number of subjects may be helpful in providing new insights into the real acceptability of A/P chemoprophylaxis. In the future it would be worth investigating further its good tolerability profi le and more convenient dosage regimen in well-designed eviation:
studies to prove their value in promoting better adherence Therapeutics and Clinical Risk Management 2008:4(5) Table 4 [caption to be supplied]
Habitual traveler
First-time traveler
Muentener P, Schlagenhauf P, Steffen R. 1999. Imported malaria (1985–1995): trends and perspectives. Bull WHO, 77:560–6.
No sources of funding were used to assist in the preparation Overbosch D, Schilthuis H, Bienzle U, et al. 2001. Atovaquone-proguanil of this review. The authors have no confl icts of interest that versus mefl oquine for malaria prophylaxis in nonimmune travelers: results from a randomized, double-blind study. CID, 33:1015–21.
are directly relevant to the content of this review.
Radloff PD, Philipps J, Nkeyi M, et al. 1996. Atovaquone and proguanil for References
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