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JAC Advance Access published online on September 10, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm337
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Systematic review

A systematic review and meta-analysis of the effectiveness and safety of atovaquone–proguanil (Malarone) for chemoprophylaxis against malaria

Halima Nakato, Roberto Vivancos and Paul R. Hunter*

School of Medicine, Health Policy and Practice, University of East Anglia, Norwich NR4 7TJ, UK

* Corresponding author. Tel: +44-1603-591004; Fax: +44-1603-593752; E-mail: Paul.Hunter{at}uea.ac.uk

Received 24 April 2007; returned 16 June 2007; revised 6 August 2007; accepted 9 August 2007


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Objectives: A systematic review and meta-analysis of the effectiveness of atovaquone–proguanil (Malarone) as a chemoprophylactic agent against malaria.

Methods: The data sources searched for this study included Cochrane systematic reviews (on infectious diseases), MEDLINE and EMBASE, Web of Knowledge and Annals of Tropical Medicine. All unconfounded randomized controlled trials assessing the chemoprophylaxis against malaria with atovaquone–proguanil were included in the review. Data on study design, study sample, inclusion and exclusion criteria, allocation, blinding, primary and secondary study end points were all extracted by one reviewer and independently rechecked by the second reviewer.

Results: In general, all 10 studies identified had excellent quality with total scores of ≥4 using the Jadad criteria. Ten controlled trials comprising 4539 participants were included for this review. A meta-analysis of six of the ten studies found chemoprophylaxis with atovaquone–proguanil, with a prophylaxis efficacy of 95.8% (95% CI = 91.5–97.9), to be superior to placebo. It was also considered safe and better tolerated with fewer treatment-related adverse events that could lead to premature discontinuation of prophylaxis than in controls. Comparison with alternative chemoprophylaxis also showed atovaquone–proguanil to be better tolerated with fewer treatment-related self-reported adverse events (RR = 0.8234; 95% CI = 0.673164–1.01) or severe adverse events (RR = 0.6140; 95% CI = 0.420055–0.8975). Atovaquone–proguanil is well tolerated with no difference in non-compliance with placebo (RR = 0.8804; 95% CI = 0.6964–1.113; I2 = 31.4%).

Conclusions: Evidence from this review shows that atovaquone–proguanil is highly efficacious as a prophylactic agent against malaria infection and is very well tolerated compared with other antimalarial agents.

Key Words: travel , tropical medicine , Plasmodium falciparum , randomized controlled trial


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Approximately 10 000 North Americans and Europeans acquire malaria each year while travelling abroad and there has been a noted increase in the reported cases in travellers over the years.1,2 Chemoprophylaxis is one of the most important measures, along with avoidance of mosquito bites, in reducing risk in travellers to malaria endemic areas.3 Reliance on chloroquine or mefloquine is no longer possible because of increased drug resistance and is also problematic because of reported neuropsychiatric adverse events.1 Atovaquone–proguanil (Malarone) is the most recent recommended regimen for prophylaxis in areas with chloroquine resistance, but so far there has been no systematic review of its efficacy or tolerability and safety.

As far as we know, this is the first systematic review of chemoprophylaxis with atovaquone–proguanil against malaria.


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The objective was to evaluate all existing data, using randomized trials, on the efficacy, safety and tolerance of atovaquone–proguanil as a chemoprophylaxis agent against malaria infection.

Search strategy and selection process

The search strategy used these sources to identify relevant data in the following electronic databases: Ovid MEDLINE and EMBASE (since 1950s), Cochrane Library on infectious disease (up to 2006), Reference articles cited in the Annals of Tropical Medicine and Web of Knowledge (up to 2006), cited articles from the retrieved reference lists and CDC and WHO web sites on the current recommended antimalarial prophylaxis (up to 2007).

The search terms were Atovaquone OR Malarone (Mesh heading or text) AND malaria, AND prophylaxis OR prevention. The initial search was done to the end of 2006, though repeated June 2007.

The search strategy did not exclude non-English language papers, though none was found that satisfied the inclusion criteria.

Data extraction: inclusion/exclusion criteria

Data were extracted by one reviewer and cross-checked by another. In case of any suggestion that the study could be relevant, it was retrieved for further assessment by both the reviewers. Criteria for inclusion were use of randomization, reporting on pre- and post-intervention patient information and either effectiveness or safety outcome measures.

Quality assessment of the included studies

The same reviewers independently reviewed all trials included in the review. The quality of the methodology of each selected trial was rated using the Jadad 1996 criteria score 5/5 and the QUORUM statement checklist.4

Quantitative data analysis

All analyses were done using StatsDirect.5 For studies of prophylactic efficacy, the primary outcome was parasitaemia. For measures of safety, the principal outcome measure was reporting of any side effects. A fixed effect model was used to estimate pooled relative risks through meta-analysis if the I2 statistic was low.


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Initial searches identified 120 papers, of which 10 were included in further analyses after evaluation.6–15 All case reports, studies that were not randomized and those studies that looked at maintenance antimalarial treatments were excluded. These studies compared atovaquone–proguanil as a chemoprophylaxis agent with placebo or atovaquone–proguanil with another chemoprophylaxis agent. The final 10 reports for this review included data on 4539 participants. Table 1 summarizes the characteristics of these 10 studies.


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  		Table 1. Characteristics of the randomized controlled trials (RCTs) assessing the effectiveness of current antimalarial prophylaxis treatments

 
Type of participants

Demographic characteristics varied, for example, three studies involved paediatric subjects,6,8,14 whereas the remaining six studies involved adult participants.7,9–13 The average age for each paediatric subject was between 3 and 16 years and their weight between 10 and 50 kg. The average age of adult participants was between 18 and 65 years and a mean weight of ≥50 kg. The ratio between men and women was not clearly identified, however, it was noted that most studies included more men than women. Similarities included very rigorous inclusion and exclusion criteria: most studies excluded participants with co-morbidities such as HIV/AIDS, G6PD deficiency and underlying blood disorders. Also excluded were women who were pregnant or breast feeding, those not willing to avoid pregnancy for the whole period of the study, subjects with previous malaria before recruitment or subjects receiving other forms of antimalarial therapies at the time of the assessment and at any time during the study period. Six trials were conducted on non-immune subjects, either travellers or migrant population,6,7,9,10,12,15 whereas those remaining were in populations living in highly endemic areas.8,11,13,14

Type of interventions

Six studies compared atovaquone–proguanil with placebo, whereas the remaining studies compared it with an alternative type of antimalarial chemoprophylaxis. Only 5 out of the 10 studies had a pre-study radical treatment phase, to ensure that subjects who were randomized had identical outcomes.8,9,11,13,14

Type of outcomes

Parasitaemia was the primary outcome in all of the studies, except for one. This trial was concerned with comparing safety and tolerability of atovaquone–proguanil with three other antimalarials (mefloquine, doxycycline and chloroquine–proguanil).15 All trials reported adverse effects and tolerability.

Methodological quality

The studies differed in sample size, two studies had 1013 and 1083 subjects randomized, respectively.7,10 The remaining eight studies had varied sample sizes ranging between 180 and 320 subjects.6,8,9,11–15 Randomization was well described by all ten studies. Eight of the 10 studies used double-blind, placebo-controlled methods,6–14,15 and one study was an open-label study.5 Most of the studies described their measures to ensure that confounding factors were avoided, i.e. exclusion of subjects that were immune to malaria or those who were taking other antimalarial therapies. Assessment of data collection revealed that most studies reported adequate allocation concealment, i.e. tablets were identical in appearance and taste and neither staff nor subjects were aware of treatment allocation2–4 and double-blind data collection by the investigators.7–9 All ten trials carried out intention-to-treat analyses with varied losses to follow-up.

All studies complied with the appropriate ethical considerations by obtaining written consent from each adult subject (for children consent was obtained from their parents or legal representative) and ethical approval from the appropriate Ethics Committees.

Efficacy

Five studies included in this meta-analysis compared the efficacy of atovaquone–proguanil with placebo in preventing malaria (Figure 1).8,9,11–13 The pooled relative risk of malaria in the intervention arm was 0.0423 (95% CI = 0.021–0.0853; I2 = 0%). Therefore, the protective efficacy of atovaquone–proguanil was 95.8% (95% CI = 91.5–97.9).


Figure 1
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  		Figure 1. Effect of atovaquone–proguanil on parasitaemia versus control.

 
Three studies compared atovaquone–proguanil with alternative antimalarial prophylactic agents, two with chloroquine–proguanil6,7 and one with mefloquine.10 In only one of these three studies were any subjects diagnosed with malaria. In this one study, three subjects in the chloroquine–proguanil group developed Plasmodium falciparum malaria compared with none in the atovaquone–proguanil group.7 As only one study reported any malarial infections, no meta-analysis was done comparing the efficacy of atovaquone–proguanil with alternatives. However, the data from the two studies that compared atovaquone–proguanil with chloroquine–proguanil were combined. Although all three malaria cases were in the chloroquine–proguanil group, this was not statistically significant (P = 0.25; Fisher's exact test).

Adverse events and tolerability

There was no greater reporting of adverse effects in those taking atovaquone–proguanil compared with those taking placebo. Serious adverse events were rare. Only one adverse event related to atovaquone–proguanil was reported, and this was repeated vomiting requiring hospitalization.11 Three meta-analyses were done comparing tolerability compared with other antimalarial prophylactic agents; whether participants reported any adverse effects (Figure 2), severe adverse effects and for non-completion of the course. Patients on atovaquone–proguanil had fewer self-reported adverse effects (RR = 0.8234; 95% CI = 0.673164–1.01; I2 = 80.6%) and severe adverse effects (RR = 0.6140; 95% CI = 0.420055–0.8975; I2 = 0%) than those using other antimalarials, whereas neuropsychiatric adverse effects were similar (RR = 0.741928; 95% CI = 0.4787–1.1499; I2 = 86.7%). There was no significant difference in the proportion of study participants who completed their prescribed course (RR = 0.8804; 95% CI = 0.6964–1.113; I2 = 31.4%).


Figure 2
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  		Figure 2. Relative risk of self-reported adverse events of atovaquone–proguanil versus alternate antimalarial prophylaxis (Hogh and Camus = chloroquine–proguanil; Overbosch = mefloquine; Schlagenhauf = chloroquine–proguanil, mefloquine and doxycycline).

 

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The issue of prophylaxis efficacy has previously been reviewed.16,17 The six studies identified here comparing atovaquone–proguanil with placebo demonstrated a pooled protective efficacy and success rate of 95.5% (95% CI = 90.5–97.9). Also atovaquone–proguanil is very well tolerated with no more adverse effects being reported in people receiving the drug than in the placebo group. Assessment of safety revealed that atovaquone–proguanil was safe at the standard adult dose of 250 mg of atovaquone and 100 mg of proguanil hydrochloride.

The safe dose for children was dependent on the weight of the child using a standard dose of 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride, this review found no comparative studies for analysis.

One study assessing whether atovaquone–proguanil was safe at a higher dose found that there were no statistically significant differences in terms of adverse events between subjects taking the standard dose and a higher dose of 500 mg of atovaquone and 200 mg of proguanil hydrochloride.11 It should be noted that there were no significant differences between atovaquone–proguanil and placebo on the number of subjects discontinuing prophylaxis due to adverse events.

The two studies that compared atovaquone–proguanil with chloroquine–proguanil also found that atovaquone–proguanil was better tolerated, with fewer severe adverse events that could cause discontinuation of prophylaxis. For example, one study reported 10 subjects in the chloroquine–proguanil arm and only 1 subject in the atovaquone–proguanil group who had prematurely discontinued chemoprophylaxis due to adverse events.2 Two studies found a significantly greater number of gastrointestinal adverse events in the chloroquine–proguanil group than in the atovaquone–proguanil group.6,7 These findings are in accordance with the known side effects of chloroquine–proguanil.18–20

Although in the studies identified there were more male participants, there is no reason to believe that atovaquone–proguanil would be less effective in females. None of the studies included pregnant women, and as a result we have not been able to assess its safety as malaria chemoprophylaxis during pregnancy. None of the studies identified in this review assessed long-term use safety, although evidence from observational studies suggest that atovaquone–proguanil is well tolerated long-term.21,22

Although atovaquone–proguanil appears to be safe and well tolerated, the results of this meta-analysis are only based on a relatively small sample, compared with the number of people that could be prescribed antimalarial prophylaxis, and as a result, rarer adverse effects are difficult to ascertain. Two anecdotal case reports of more serious side effects have appeared in the literature, one of hepatitis and one of Stevens–Johnson syndrome.23,24 However, it is still not possible to be definitive about the incidence of rarer adverse effects, especially following long-term use. There is a continued need for post-marketing surveillance to determine these issues.

When compared with mefloquine, atovaquone–proguanil was again better tolerated and had fewer severe adverse events reported. Although we have not found a significant difference in the reporting of neuropsychiatric adverse effects when compared with alternate therapies or with mefloquine alone, those that were reported tended to be less severe. Furthermore, fewer subjects discontinued the study drug prematurely in the atovaquone–proguanil group (64; 13.0%) compared with the mefloquine group (76; 15.7%), though this was not statistically significant (P = 0.236).10 However, given that there were no cases of malaria diagnosed in either study arm, it is not possible to comment on the protective efficacy between the two groups.

Overall all the 10 studies in this review were well designed and showed excellent quality by scoring more than four points on the Jadad criteria.

There were concerns about compliance with prophylaxis therapy among travellers to endemic areas. The lack of compliance with prescribed prophylaxis has been reported to be associated with the development of some cases of malaria.3,25 Although none of the studies in this review reported development of malaria due to poor compliance, this is an important issue that needs to be addressed by physicians prescribing chemoprophylaxis therapies.

However, there are some concerns (although not voiced in this review) about the cost implications of newer combination therapies like atovaquone–proguanil. Advocates of atovaquone–proguanil argue that the standard regimen is cost-effective because travellers take it for a shorter duration for prophylaxis and it is better tolerated with fewer adverse events compared with other chemoprophylaxis agents. In addition, atovaquone–proguanil is effective against liver stages of the parasite cycle, shortening the time medication needs to be taken as it does not need to continue post-travel.

All the 10 studies in this review excluded patients with co-morbidities e.g. HIV and AIDS; it would be interesting to assess the efficacy of atovaquone–proguanil in these groups of patients as they are highly vulnerable to malarial infections and may benefit from the protection that atovaquone–proguanil could provide.

One may argue that the use of atovaquone–proguanil in short-term travellers to endemic areas is justifiable but its use in long-term travellers and among residents in malaria endemic areas warrants assessment of its cost-effectiveness. Atovaquone–proguanil is an expensive agent and many individuals in endemic areas may not be able to afford it and so will keep taking less-effective but cheaper therapies.26 Addressing this issue needs the involvement of not only drug companies and researchers but the involvement of governments of those countries with high endemicity.

In conclusion, it can be stated that atovaquone–proguanil has demonstrated very good efficacy, safety and tolerability and is a good choice for travellers to endemic areas. It will find particular value in travellers to areas where there is resistance to other antimalarials. It is also a very good alternative for people for whom mefloquine is contraindicated due to concerns about the potential for neuropsychiatric side effects.


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This systematic review and meta-analysis were conducted as part of a medical student's selected study. No funding was required.


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None to declare.


   References
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1 . Legros F. Risk factors for imported fatal Plasmodium falciparum malaria, France, 1996–2003. Emerg Infect Dis (2007) 13:883–8.[Web of Science][Medline]

2 . Spinazzola F, Nicastri E, Vlassi C, et al. Imported malaria at Italy's National Institute for Infectious Diseases Lazzaro Spallanzani, 1984–2003. Eur J Clin Microbiol Infect Dis (2007) 26:175–9.[CrossRef][Web of Science][Medline]

3 . Centre for Disease Control and Prevention. Traveller's Health: Information for Health Care Providers: Prescription Drugs for Malaria—Determine your Patient's risk. (2006) National Centre for Infectious Diseases, Division of Global Migration and Quarantine, Department of Health and Human Services. 1–9.

4 . Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials (1996) 17:1–12.[CrossRef][Web of Science][Medline]

5 . StatsDirect Ltd, 2007. 4 April 2007, date last accessed. http://www.statsdirect.com/.

6 . Camus D, Djossou F, Schilthuis HJ, et al. Atovaquone-proguanil versus chloroquine-proguanil for malaria prophylaxis in nonimmune pediatric travelers: results of an international, randomized, open-label study. Clin Infect Dis (2004) 38:1716–23.[CrossRef][Web of Science][Medline]

7 . Hogh B, Clarke PD, Camus D, et al. Atovaquone-proguanil versus chloroquine-proguanil for malaria prophylaxis in non-immune travellers: a randomised, double-blind study. Malarone International Study Team. Lancet (2000) 356:1888–94.[CrossRef][Web of Science][Medline]

8 . Lell B, Luckner D, Ndjave M, et al. Randomised placebo-controlled study of atovaquone plus proguanil for malaria prophylaxis in children. Lancet (1998) 351:709–13.[CrossRef][Web of Science][Medline]

9 . Ling J, Baird JK, Fryauff DJ, et al. Randomized, placebo-controlled trial of atovaquone/proguanil for the prevention of Plasmodium falciparum or Plasmodium vivax malaria among migrants to Papua, Indonesia. Clin Infect Dis (2002) 35:825–33.[CrossRef][Web of Science][Medline]

10 . Overbosch D, Schilthuis H, Bienzle U, et al. Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: results from a randomized, double-blind study. Clin Infect Dis (2001) 33:1015–21.[CrossRef][Web of Science][Medline]

11 . Shanks GD, Gordon DM, Klotz FW, et al. Efficacy and safety of atovaquone/proguanil as suppressive prophylaxis for Plasmodium falciparum malaria. Clin Infect Dis (1998) 27:494–9.[Web of Science][Medline]

12 . Soto J, Toledo J, Luzz M, et al. Randomized, double-blind, placebo-controlled study of Malarone for malaria prophylaxis in non-immune Colombian soldiers. Am J Trop Med Hyg (2006) 75:430–3.[Abstract/Free Full Text]

13 . Sukwa TY, Mulenga M, Chisdaka N, et al. A randomized, double-blind, placebo-controlled field trial to determine the efficacy and safety of Malarone (atovaquone/proguanil) for the prophylaxis of malaria in Zambia. Am J Trop Med Hyg (1999) 60:521–5.[Abstract]

14 . Faucher JF, Binder R, Missinou MA, et al. Efficacy of atovaquone/proguanil for malaria prophylaxis in children and its effect on the immunogenicity of live oral typhoid and cholera vaccines. Clin Infect Dis (2002) 35:1147–54.[CrossRef][Web of Science][Medline]

15 . Schlagenhauf P, Tschopp A, Johnson R, et al. Tolerability of malaria chemoprophylaxis in non-immune travellers to sub-Saharan Africa: multicentre, randomised, double blind, four arm study. BMJ (2003) 327:1078.[Abstract/Free Full Text]

16 . Boggild AK, Parise ME, Lewis LS, et al. Atovaquone-proguanil: report from the CDC expert meeting on malaria chemoprophylaxis (II). Am J Trop Med Hyg (2007) 76:208–23.[Abstract/Free Full Text]

17 . Patel SN, Kain KC. Atovaquone/proguanil for the prophylaxis and treatment of malaria. Expert Rev Anti Infect Ther (2005) 3:849–61.[CrossRef][Medline]

18 . Barrett PJ, Emmins PD, Clarke PD, et al. Comparison of adverse events associated with use of mefloquine and combination of chloroquine and proguanil as antimalarial prophylaxis: postal and telephone survey of travellers. BMJ (1996) 313:525–8.[Abstract/Free Full Text]

19 . Carme B, Peguet C, Nevez G. Compliance with and tolerance of mefloquine and chloroquine + proguanil malaria chemoprophylaxis in French short-term travellers to sub-Saharan Africa. Trop Med Int Health (1997) 2:953–6.[Web of Science][Medline]

20 . Durrheim DN, Gammon S, Waner S, et al. Antimalarial prophylaxis–use and adverse events in visitors to the Kruger National Park. S Afr Med J (1999) 89:170–5.[Web of Science][Medline]

21 . Overbosch D. Post-marketing surveillance: adverse events during long-term use of atovaquone/proguanil for travelers to malaria-endemic countries. J Travel Med (2003) 10(Suppl 1):S16–20. discussion S21–13.[Web of Science][Medline]

22 . Petersen E. The safety of atovaquone/proguanil in long-term malaria prophylaxis of nonimmune adults. J Travel Med (2003) 10(Suppl 1):S13–5. discussion S21.[Web of Science][Medline]

23 . Emberger M, Lechner AM, Zelger B. Stevens-Johnson syndrome associated with Malarone antimalarial prophylaxis. Clin Infect Dis (2003) 37:e5–7.[CrossRef][Web of Science][Medline]

24 . Grieshaber M, Lammli J, Marcus L. Acute hepatitis and atovaquone/proguanil. J Travel Med (2005) 12:289–90.[Web of Science][Medline]

25 . Lobel HO, Bernard KW, Williams SL, et al. Effectiveness and tolerance of long-term malaria prophylaxis with mefloquine. Need for a better dosing regimen. JAMA (1991) 265:361–4.[Abstract/Free Full Text]

26 . Bryan JP. Cost considerations of malaria chemoprophylaxis including use of primaquine for primary or terminal chemoprophylaxis. Am J Trop Med Hyg (2006) 75:416–20.[Abstract/Free Full Text]


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