Atovaquone–Proguanil (Malarone): an Effective Treatment for Uncomplicated Plasmodium falciparum Malaria in Travelers from Denmark Sören Thybo, Ida Gjorup,Anita M. Ronn, Dan Meyrowitsch, and Ib C. Bygberg

Background: Previous experience with unacceptable adverse effects with mefloquine as treatment for uncomplicated Plasmodium falciparum malaria prompted an evaluation of the effectiveness and side effects of atovaquone–proguanil (Malarone) in a hospital setting. Methods: Atovaquone–proguanil was given as standard treatment (1,000/400 mg q.d. for 3 days) to 50 adults who had traveled in Africa and returned with uncomplicated Plasmodium falciparum malaria. Half of the treated patients were African and had lived outside Africa for varying periods of time; the other half were Danish-born persons without any previous immunity towards malaria. Results: All patients treated with Malarone were cured without complications. The mean fever clearance times differed among the groups and according to various degrees of prior exposure to malaria and ranged from 1.3 to 2.2 days. Adverse effects during treatment were mild, and were likely to be due to the malaria itself. Fourteen people who had acquired falciparum malaria in spite of taking proguanil–chloroquine prophylaxis were also cured uneventfully without recrudescence. Conclusions: Malarone appears to be an effective, safe and acceptable oral treatment for uncomplicated malaria.

At the Department of Infectious Diseases of Rigshospitalet—a 1,600-bed Danish University Hospital— for a number of years mefloquine has been the standard treatment for imported noncomplicated/nonsevere falciparum malaria with absence of cerebral symptoms and with parasitemia below 5%. Treatment was given in divided doses up to a total of 25 mg mefloquine/kg body

weight. However, even when given with a small meal, mefloquine often provoked vomiting, necessitating supplementary dosages, and a high proportion of patients (28%) in a previous study from this hospital had additional, unacceptable side effects also found in other studies.1,2 Malarone (the combination of atovaquone and proguanil) was registered for use against malaria in Denmark as early as 1999. Owing to its promising profile, we decided to test and to monitor the use of Malarone as standard treatment and its possible side effects. The combination of chloroquine and proguanil is still used frequently as prophylaxis against malaria among Danish travelers. Therefore, it was also the aim of the study specifically to find whether Malarone would be effective in the treatment of these patients who had proven breakthrough of malaria on this prophylaxis, containing—like Malarone— proguanil.

Sören Thybo, MD, MSc, and Anita M. Ronn, MD, PhD: Department of Infectious Diseases, Rigshospitalet, Copenhagen; Ida Gjorup, MD: Department of Medicine, Herlev Hospital, Herlev; Dan Meyrowitsch, MD, PhD: Institute of Public Health, University of Copenhagen; Gitte Kronborg, Dr Med: Department of Infectious Diseases, Hvidovre Hospital; Ib C. Bygberg, Dr Med: Institute of International Health, University of Copenhagen, Copenhagen, Denmark. The authors had no financial or other conflicts of interest to disclose.

Methods and Materials

Reprint requests: Dr Sören Thybo, Infectious and Tropical Diseases, Internal Medicine, Department of Infectious Diseases, M 5132, University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.

The study was approved by the the Scientific Ethical Committee of Copenhagen, and written informed consent was obtained from all individuals included in the study. Those with noncomplicated malaria were defined

J Travel Med 2004; 11:220–224.

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T h y b o e t a l . , A t o v a q u o n e – P r o g u a n i l ( M a l a r o n e ) Tr e a t m e n t f o r P. f a l c i p a r u m M a l a r i a

as P. falciparum parasite-positive individuals who, on admission to the hospital, presented parasitemia
5% and an absence of cerebral symptoms. The adult individuals were recruited consecutively for Malarone treatment if they fulfilled these criteria and were not pregnant. All patients were hospitalized and treated with a standard dose of 1000 mg atovaquone  400 mg proguanil (Malarone, GSK, Copenhagen, Denmark) once-daily with a meal for 3 days. Dosages of Malarone were reduced according to the recommendations of the producer for body weight below 40 kg. Blood slides were prepared daily to monitor parasitemia, and hematology, liver biochemistry and p-creatinine were measured daily during treatment. Temperature was monitored twice-daily. Parasite clearance time (PCT) was defined as the time between the start of antimalaria treatment and the disappearance of trophozoites of P falciparum from the blood. Fever clearance time (FCT) was defined as the time between the start of treatment and the first normal temperature reading in a patient who then subsequently remained without fever. The patients remained hospitalized until parasitemia was clearly decreasing or absent and they felt clinically improved. A subgroup of the first 28 of 50 patients to be included was interviewed specifically about side effects by the medical doctor attending them. Side effects were categorized by organ systems and qualified with respect to strength and severity by the patients during the daily interviews. Patients were encouraged to come back for control malaria slides on days 7 and 28 after the start of treatment. Results In total, 61 patients with P. falciparum malaria were identified during the period January 1999 to April 2000. Among these, 50 patients fulfilled the inclusion criteria. The characteristics of these patients are shown in Table 1. Among those not included, four cases had already started treatment elsewhere, seven patients were treated with quinine due to either concurrent pregnancy (two cases) or complicated malaria (three cases with parasitemia  5%, two cases with cerebral malaria). The 50 patients included represented three different groups: Danish tourists and travelers (48%) with no previous exposure to malaria (group 1); African people (46%) who had stayed abroad and away from areas with malaria for more than 1 year (group 2); and a small number of Africans (6%) who had been out of Africa for less than 1 year and thus probably had some preserved immunity towards falciparum malaria (group 3). Overall, 28 people (56%) had taken no prophylaxis during their travel, 14 (28%) had taken chloroquine and proguanil, and eight (16%) had taken other types of prophylaxis. However, only 16 of those taking prophylaxis

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had done so regularly, leaving more than two-thirds of the study population with little or no medical prevention. Sixty-six percent (66%) of the patients had contracted their malaria in West Africa, and 28% in East Africa. Eighty-two percent of the malaria patients had returned from areas of malaria exposure within the last 4 weeks prior to the start of their clinical malaria attack. On average, 3.7 days had elapsed between the start of symptoms and the time of diagnosis. Danish patients on average reported to hospital only slightly earlier (3.8 days) than immigrants who had resided in Denmark for more than 1 year (4.0 days). The reporting time was— on average—shortest for persons from endemic areas who had been in Denmark for less than 1 year (1.7 days). There was a minor and insignificant difference in delay from the start of symptoms to admission to hospital between those patients claiming to use choloquine–proguanil prophylaxis and those who had taken no medical prophylaxis (4.6 (SD  3.4) vs. 3.5 (SD  1.7) days. Nevertheless, 28% of all patients only reported for examination and diagnosis 5 days or longer after the start of symptoms (data not shown in the tables). For all three groups of patients, parasitemia was low; thus three-quarters had parasitemia of 1% or less at the time of diagnosis. FCT on average was between 1.3 days (patients from malaria-endemic areas, group 3) and 2.2 days (patients with no previous exposure to malaria, group 1). The longest mean FCT was observed in group 1 (2.2 days), followed by group 2 (1.9 days) and group 3 (1.3 days). Owing to the small sample size of group 3, statistical analysis was only performed for data obtained from groups 1 and 2. The FCTs did not differ significantly between groups 1 and 2 (t-test, p  .29). In groups 1 and 2, the mean PCTs were 4.1 and 4.4 days, respectively, and this difference was not significant (t-test, p  .053). All patients who complied with examination on day 7 (84%) had cleared their parasites. At day 28, all examined patients (14/28) still presented with negative blood smears. All patients completed their 3 days of treatment, and there was in no case a need for supplementary doses due to vomiting within 1 h after the oral administration of the drug. All patients were successfully cured. This was also true of the 14 people (28%) who had been taking proguanil and chloroquine prophylaxis. All side effects registered were qualified by the patients as being mild, and in no case did Malarone have to be discontinued due to adverse reactions. In the category of “neurologic side effects”, headache was especially common during the first 2 days of treatment, affecting roughly one-third of the subgroup of 28 patients interviewed specifically about side effects (Table 2). Few of these patients required painkillers, and then only for the first 2 days of treatment. A single patient also complained

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Table 1 Characteristics of Malaria Patients and Treatment Results

Origin Number of patients Age (years) (CI 95%) Sex (male/female) Parasitemia  1% but
5%  1% Fever clearance time (days) (CI 95%) Parasite clearance time (days) (CI 95%) Completed malarone treatment Need for supplementary malaria treatment Negative malaria slide, day 7 Negative malaria slide, day 28 Prophylaxis with chloroquine and proguanil

Denmark (Group 1)

Africa Residing for 1 Year or More in Denmark (Group 2)

Africa Residing for Less than 1 Year in Denmark (Group 3)

24 34.1 (26.4; 41.8) 14 : 10

23 31.1 (26.4; 35.8) 18 : 5

3 22.7 (13.2; 32.2) 3:0

7 (29.2%) 17 (70.8%) 2.2 (1.7; 2.7) 4.1 (3.6; 4.7) 100% None 20/20 13/13 12/24

6 (26.1%) 17 (73.9%) 1.9 (1.6; 2.3) 4.4 (3.9; 4.8) 100% None 20/20 13/13 2/23

0 (0%) 3 (100%) 1.3 (0.7; 1.9) 3.3 (1.6; 5.1) 100% None 2/2 2/2 0/3

of dizziness, but only on day 1. Concerning “psychiatric” adverse reactions, only two people (7%) reported mild phenomena. One person complained on the first day of treatment of “mild sadness” which disappeared on the next day. The other patient reported “vivid dreams with some hallucinations” but only on the first day of treatment when he still had high fever. In the same subgroup of 28 patients, 21 (75%) had marked thrombocytopenia before and under treatment, which normalized after treatment. Five patients before treatment, and seven patients under treatment, had very moderately increased liver enzymes, which normalized in all but four cases immediately after treatment. None of the patients had raised p-creatinine before, under or after treatment with Malarone (data not shown). Discussion In many Western countries, the treatment options for uncomplicated P. falciparum malaria are limited. Oral artemisinin preparations are probably among the most effective and safe drugs administered either alone or in combination with other antimalaria drugs for this type of malaria.1,3–5 However, these drugs are not registered or available for prescription in many countries in the West. Widespread resistance towards sulfadoxin and pyrimethamine in many areas of tropical Africa has rendered the use of Fansidar for falciparum malaria unreliable.6 The same is true of proguanil, and this might entail potential problems for treatment combinations containing this drug.7 Mefloquine has thus long been the most frequently used treatment option in Denmark. In our hospital, a prospective study of mefloquine given as standard treatment demonstrated a high occurrence (28%) of one or

more neuropsychiatric side effects.2 Hence there was a great need for a standard treatment that is both effective and without unacceptable adverse reactions. The combination of atovaquone and proguanil (Malarone) has been reported to have these qualities by a number of studies in countries with prevalent malaria.8–10 The present study demonstrates that Malarone is an effective and useful alternative in the therapy of noncomplicated falciparum malaria for travelers. All patients were cured with a standard oral 3-day regimen. We found no difference in PCT between persons with no prior exposure to malaria and the other half of the study population, who originated from Africa. However, the PCT in this study for both African and Danish travelers was longer than has been reported in other studies.5,9,10 No significant difference was demonstrated in FCT between the malaria patients originating from Denmark and those coming from Africa with presumed prior exposure to malaria. However, there seems to be a tendency for more rapid recovery from fever among people from Africa. For the latter group, the FCT found in this study is not different from data reported in other studies with Malarone or combination of mefloquine and artemisinine.5,9,10 For the group of Danish travelers, the FCT was slightly longer. Not all patients had day 7 and day 28 malaria control slides done. However, we saw no clinical recrudescent cases among the study population in our service, which has a centralized function with respect to the treatment of malaria and tropical medicine. None of the patients appeared in the Danish national patient register as admitted to other Danish hospitals with a diagnosis of malaria within the next 3 months. No case of death due to malaria was reported in Denmark for 1 year following the present study. We

T h y b o e t a l . , A t o v a q u o n e – P r o g u a n i l ( M a l a r o n e ) Tr e a t m e n t f o r P. f a l c i p a r u m M a l a r i a

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Table 2 Most Frequent Side Effects During Ongoing Malarone Treatment Side Effects Severe side effects Mild side effects Headache Psychiatrica Vomiting Dizziness Nausea

Day 1 of Treatment

Day 2 of Treatment

0/28

0/28

8 (29%) 2 (7%) 5 (18%) 4 (14%) 10 (36%)

10 (36%) 1 (4%) 2 (7%) 4 (14%) 4 (14%)

Day 3 of Treatment 0/28 6 (21%) 0 2 (7%) 3 (11%) 5 (18%)

a

Any signs of depression, hallucination, psychosis or sleep disorder.

therefore find it likely that all our patients were actually cured. During the 3 days of medication, the majority of patients showed no adverse effects from the treatment. Those who presented with one or more adverse effects had only mild symptoms. Headache is a well-known adverse reaction after treatment with Malarone but is also—together with vomiting and dizziness—a typical malaria disease symptom. Mefloquine (Lariam) malaria prophylaxis has become very unpopular with travelers in many places over the last 10 years, due to much public attention being given to its neuropsychiatric side effects. Also, in Denmark many travelers refuse to use mefloquine. Unfortunately, Malarone is only registered in Denmark for prophylaxis for shorter periods of time (for 1 month), due to the lack of knowledge concerning the possible long-term side effects of Malarone. This means that the combination of proguanil and chloroquine is still extensively prescribed to travelers for malaria prophylaxis, although the efficacy of this combination as prevention for malaria is not well documented. With growing and widespread resistance to both chloroquine and proguanil, the number of cases with “breakthrough” malaria in spite of this prophylaxis can be expected to increase. Normally, it is not advisable to use a drug for the cure of malaria when it has already proven unsuccessful as prevention. Atovaquone alone is not very effective in curing malaria and preventing recrudescence.11 Hence, Malarone treatment for falciparum malaria with proven resistance against proguanil might result in “monotherapy” with atovaquone and thus be ineffective. The development of resistance to proguanil in infections with P. falciparum is mediated by mutations in the genome that make the enzyme dihydrofolate reductase less susceptible to the effect of cycloguanil, which is the main metabolite of proguanil.7 The effectiveness of Malarone is probably due to a synergistic effect of atovaquone and proguanil itself,12 and thus its mechanism of action is not dependent on the mentioned mutations. In this context, it is interesting that the present study does not indicate any problem in curing the 14 patients

who acquired malaria in spite of having taken chloroquine and proguanil prophylaxis. Twelve of these 14 people (86%) claimed to have taken this prophylaxis regularly. Malarone therefore seems to be a good candidate for the treatment of nonsevere and uncomplicated falciparum malaria even when chloroquine has been used in combination with proguanil for prophylaxis. Since 1999, Malarone has been registered in an increasing number of countries, and it is now used extensively also for prophylaxis. The producer (GSK) has even offered a public–private partnership program for donation of the drug for treatment in Uganda and Kenya.13 Widespread use will necessarily entail resistance. The long half-life of atovaquone and the resulting “tail” of suboptimal concentrations in blood after treatment when proguanil has been excreted could increase the risk of growing Malarone resistance.14 The first treatment failure and in vitro demonstration of new mutations providing resistance against Malarone have already been reported,15 and genetic mutation markers in resistant P. falciparum are being explored.16 However, so far, Malarone seems to be a very safe and effective drug for uncomplicated falciparum malaria and may even be of use as a “standby selftreatment” for travelers and expatriates with poor access to appropriate medical care. However, it should be stressed that it should not be used for breakthrough disease after Malarone prophylaxis.

Conclusions Malarone for the treatment of uncomplicated P. falciparum malaria appears to be very effective, has FCTs and PCTs comparable to those quoted for other commonly used antimalaria drugs, and presents few and only mild side effects. In this study, there were no treatment failures with Malarone, and this was true also of the group of patients who had acquired malaria in spite of proguanil– chloroquine prophylaxis. Malarone appears to be a useful drug for the treatment of malaria and may even be used for “standby treatment” for those travelers who have not taken Malarone for prophylaxis.

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