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SUCCESSFUL TREATMENT OF PLASMODIUM FALCIPARUM MALARIA WITH A SIX-DOSE REGIMEN OF ARTEMETHER-LUMEFANTRINE VERSUS QUININE-DOXYCYCLINE IN THE WESTERN AMAZON REGION OF BRAZIL

ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
This randomized, open-label study compared a three-day, six-dose regimen of artemether-lumefantrine with a five-day, 19-dose regimen of quinine-doxycycline for the treatment of Plasmodium falciparum malaria in the western Amazon region of Brazil. All patients remained hospitalized during their treatment and the study assessments were scheduled daily from the start of treatment (day 0) through day 6. By day 3, the percentage of infected patients was 0% in the artemether-lumefantrine group and 48.8% in the quinine-doxycycline group. Median parasite clearance time was significantly shorter in the artemether-lumefantrine group (two days) compared with the quinine-doxycycline group (three days) (P < 0.0001). Two patients in the quinine-doxycycline group left the study early because of treatment ineffectiveness or adverse event. Adverse events were reported by 91.5% of the study participants, most of which were mild in severity and/or not considered related to study treatment. Artemether-lumefantrine was shown to be an efficacious, safe, and convenient treatment for P. falciparum malaria in a highly drug-resistant region of South America.

INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Malaria remains a persistent health risk in many parts of the world despite temporary, localized regions of control over the years. Inadequate control efforts and emerging drug- and insecticide-resistant strains of malaria parasites continue to foster disease resurgence. This phenomenon has clearly been observed in many South American countries over recent decades, attributable in large part to a decrease in household insecticide use and an increase in parasite resistance.¹

Overall, 21 countries in the Americas have evidence of active malaria transmission.² Although a less deadly form of malaria, Plasmodium vivax, causes most of South American cases, P. falciparum is present in almost every geographic region of the continent affected by malaria. Despite an apparent decrease in P. falciparum malaria within the Brazilian Amazon in recent years, the disease continues to pose a substantial health hazard within the Amazon Basin region.² The increasing threat area stems from a widening pattern of the resistance of this parasite to commonly used first-line malaria treatments such as chloroquine.³ The situation is exacerbated further by the ongoing migration of non-immune individuals into the rain forest areas of the Amazon in search of mining, logging, or farming jobs.^4,5 An increasing number of malaria cases have also been observed among Pacific coast South American countries including Peru, Ecuador, and Colombia, particularly after the El Niño weather patterns of 1997–1998.²

Antimalarial drug resistance was first documented in South America in 1960, and by the mid-1980s, chloroquine resistance was widespread in the Amazon.¹ It is currently estimated that in the Amazon Basin of Peru, more than half of the patients with uncomplicated P. falciparum malaria fail to respond to chloroquine or sulfadoxine-pyrimethamine.⁶ As a result, the use of these drugs has basically been discontinued in South American countries, creating an urgent need for new, effective treatment options.¹ Quinine plus doxycycline is currently being used in Brazil as the first-line treatment for P. falciparum malaria, but some studies had already shown cure rates of approximately 77% in the Brazilian Amazon.^7,8

Artemether-lumefantrine (Coartem^®/Riamet^®; Novartis Pharma AG, Basel, Switzerland) is a new, oral, fixed-dose combination of artemether, an artemisinin derivative, and lumefantrine (previously known as benflumetol). This combination provides a higher rate of antimalarial effectiveness than when the individual components are used as mono-therapy. Artemether, like other artemisinin derivatives, produces rapid schizontocidal effects, resulting in prompt fever reduction and parasite clearance.^9,10 Recrudescence rates are high unless treatment is continued for at least 5–7 days, which increases the likelihood of compliance problems. Lumefan-trine has a much longer half-life and does not produce a high cure rate until several days of therapy have been given. Clinical and parasitologic response is much slower when compared with artemether. Used together, the artemether-lumefantrine combination produces both rapid antimalarial efficacy and low recrudescence rates.¹¹

The artemether-lumefantrine combination is in a single-tablet dosage form, with each tablet containing 20 mg of artemether and 120 mg of lumefantrine. The product is usually given for only three days, a feature that may foster patient compliance with therapy.^11,12 More importantly, artemether and lumefantrine act synergistically in vitro against P. falciparum, which theoretically reduces the risk of resistance developing to either compound.¹³ The single-tablet formulation prevents patients from taking either drug component alone, further averting resistance problems. Neither clinical nor in vitro resistance to artemisinin compounds has yet been reported, despite widespread use in places such as China and Vietnam.^14,15

Clinical studies conducted in China, The Gambia, Tanzania, Thailand, and India have already proven artemether-lumefantrine to be highly effective against multidrug-resistant strains of malaria, and well tolerated in adults and children.^{9,12,13,16–19} The combination has never been studied in Brazil. The recommended dose regimen in areas of multidrug resistance for adults ( 12 years of age and 35 kg body weight) is six doses of four tablets per dose given twice a day over a three-day period.¹¹

The objective of this study was to compare the efficacy and safety of artemether-lumefantrine with that of quinine-doxycycline in the treatment of non-complicated P. falciparum malaria in the Western Amazon region. The same first-line quinine-doxycycline regimen recommended by the Brazilian National Antimalarials Policy was chosen as the comparator. It is currently the first-line regimen replacing chloroquine because of the high resistance to this drug in the study region.

MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
This was a randomized, open-label, comparative, parallel-group study carried out in Brazil at the Tropical Medicine Foundation of Amazonas in Manaus and the University of São Paulo Tropical Medicine Advanced Center in Santarém. The study was performed in accordance with the Declaration of Helsinki and Directive 91/507/EEC (rules governing medicinal products in the European community). Institutional Review Board approval was obtained and all subjects provided informed consent.

Study population. The study population included male and female patients 16 years of age with a diagnosis of P. falciparum malaria with a blood trophozoite count of 1,000–50,000/mm³. Patients were excluded for any of the following reasons: vomiting/diarrhea or inability to take food by mouth for any reason; clinical or laboratory indications of severe malaria; prior use of antimalarial medication to treat the current infection; concomitant use of antibiotics, antiarrhythmics, or cardiotonic drugs; presence of schizonts in peripheral blood. Pregnant and breast-feeding women were not allowed to participate.

Drug treatment. Patients were randomly assigned to receive treatment with one of the two study regimens in an open-label fashion. Randomization was performed by Novartis Drug Supply Management using a validated, automated system. Patients in the artemether-lumefantrine group were given tablets containing 20 mg of artemether and 120 mg of lumefantrine. Four tablets were taken for the first dose, followed by four tablets eight hours later. During the next two days, dosing continued at four tablets every 12 hours. Patients in the quinine-doxycycline group took 500 mg of quinine every eight hours for three days and 100 mg of doxycycline every 12 hours for 5 days. Both drugs were started on the same day, giving a total therapy duration of five days (Q3D5).

Study assessments. All patients remained hospitalized during their treatment. Study assessments were scheduled daily from the start of treatment (day 0) through day 6, with the exception of day 5. At each assessment, patients were evaluated by means of a physical examination, medical history, thick blood smear for parasitemia, and a quantitative buffy coat (QBC) test. Thick blood smears were stained with Giemsa and the parasite density was calculated by counting the number of asexual parasites per 500 white blood cells, based on the white blood cell count of each patient. Essentially, the parasite density was used only as an inclusion criterion. For the QBC test, blood (55–65 µL) was collected into commercially supplied malaria detection tubes (Becton Dickinson, Inc., Franklin Lakes, NJ) following the manufacturer’s instructions; the tubes were centrifuged at 10,000 x g for five minutes and examined with a microscope (Nikon, Tokyo, Japan) fitted with a Paralens UV microscope adaptor (10x wide-field eyepieces and a 60x oil-immersion lens) (Becton Dickinson, Inc.) The QBC test was performed as a more sensitive test to detect minimal peripheral parasitemia and the results were given as positive or negative. Both blood smears and the QBC test were examined by two experienced microscopists. Laboratory tests were obtained at baseline and on day 6, and an electrocardiogram (ECG) was performed at baseline and on days 2 and 6. All study doses were administered under the supervision of hospital staff. Any unused medication was recorded at the end of the study. Patients’ temperatures were taken four times a day. The observation period was limited to six days (i.e., as long as the patients were confined to the hospital). Due to long travel distances, additional study visits were not possible. Primary efficacy parameters were parasite clearance time (PCT) (time from first dose until first total and continued disappearance of asexual parasite forms that remained at least for an additional 48 hours) and percentage of infected patients (ratio between the number of patients with detectable parasitemia in the thick blood smear or the QBC and total of patients per group x 100) in each study group.

Secondary parameters included resolution of fever and evidence of clinical improvement. Safety assessments consisted of the daily recording of all adverse events and the regular monitoring of vital signs, physical condition, and blood chemistries, as well as an ECG. The QT intervals were measured using lead V2 from the onset of the QRS complex to the end of the T wave, defined as return of the terminal limb to baseline. The QT interval corrected for heart rate (QTc) was calculated according to Bazett’s formula, i.e., QTc = QT/RR (the RR interval is defined as the time interval between the peaks of two consecutive R waves). A QTc value of 440 msec was considered the normal upper limit of QTc. Designated investigator staff entered the information required by the protocol onto the case report forms (CRFs). Data and text (e.g., comments) items from the CRFs were entered centrally into the study database by Novartis Data Management staff using single-data entry and checked manually against the CRF. The study was carried out from December 2000 to January 2002, and was professionally monitored by the Department of Clinical Research from Novartis Biosciences S.A.

Statistical methods. Continuous variables are reported as mean, standard deviation, and range. Results relating to discrete variables are presented using frequency distribution. Parasite clearance time was analyzed using survival analysis techniques. Proportions were compared using the Pearson chi-square test. Linear models were fitted, considering the repeated measurements along study visits, to compare continuous variables. The study was not powered to demonstrate therapeutic equivalence, but with the proposed number of patients it was expected that medically significant differences between the two treatment groups can be shown.

RESULTS

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A total of 59 patients were enrolled, 28 in the artemether-lumefantrine group and 31 in the quinine-doxycycline group. Demographic characteristics were similar between the two treatment groups, as shown in Table 1. Three patients did not complete the study. One patient in the artemether-lumefantrine group withdrew consent on day 3 because of personal problems, and two patients in the quinine-doxycycline group withdrew because of an adverse event (vomiting) and treatment ineffectiveness, respectively. Protocol deviations (exclusion criteria a posteriori) were noted in nine patients, as listed in Table 2. Separate data analyses were performed excluding these patients and are also presented.

View larger version (8K): [in this window] [in a new window]       FIGURE 1. Percentages of patients (pts) with detectable parasites in the artemether-lumefantrine (A/L) and quinine-doxycycline (Q/D) study groups on each day of the study (inclusive of patients with protocol deviations). The difference between groups was statistically significant (P < 0.0001).

View larger version (6K): [in this window] [in a new window]       FIGURE 2. Percentages of patients (pts) with positive quantitative buffy coat test results on each study day. A/L = artemether-lumefantrine; Q/D = quinine-doxycycline. Differences between groups were statistically significant on days 2 (P < 0.0001), 3 (P = 0.0024), and 4 (P < 0.0001).

Safety findings. At least one adverse event was reported by 54 of the 59 study participants (91.5%). The comparative frequency of reported adverse events was statistically similar between the artemether-lumefantrine group (89.2%) and the quinine-doxycycline group (93.6%) (P = 0.5572). In the artemether-lumefantrine group, 39 of 106 reported adverse events (37%) were considered related to drug administration. Of the 144 adverse events reported in the quinine-doxycycline group, 81 (56%) were considered related to treatment. One patient in the quinine-doxycycline group discontinued drug because of an adverse event on day 1 (vomiting).

Table 4 shows a complete list of the frequency of reported adverse events. The most commonly reported events in the artemether-lumefantrine group were headache (48.0%), upper abdominal pain (24.0%), asthenia (24.0%), dizziness (24.0%), and insomnia (24.0%). Frequently reported events in the quinine-doxycycline group included upper abdominal pain (41.4%), nausea (34.5%), headache (27.6%), asthenia (27.6%), and vomiting (27.6%). There were no serious adverse events reported during the study.

DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Resistance to conventional drugs is one of the biggest threats to the containment of malaria in many parts of the world. The Western Amazon is one region in particular with a high level of resistance to a number of antimalarial agents. This open-label study demonstrated artemether-lumefantrine therapy to be superior to quinine-doxycycline for the treatment of uncomplicated P. falciparum malaria in the Western Amazon. Despite the known drawbacks of an open-label trial design, it is doubtful that the results were biased significantly because the efficacy parameters were based almost exclusively upon objective measurements.

All patients treated with artemether-lumefantrine were cleared of their parasitemia within only three days of starting drug therapy. In contrast, only 50% of patients taking quinine-doxycycline were parasite free within three days, and a 0% parasitemia result was not achieved until day 6 in this group. The percentage of patients with positive QBC test results also decreased much more dramatically in the artemether-lumefantrine group. These results are consistent with the rapid and efficacious antimalarial activity associated with artemisinin derivatives. Previously reported studies conducted in China, The Gambia, Tanzania, Thailand, and India have shown artemether-lumefantrine to be highly effective against multidrug-resistant strains of malaria and well tolerated.^9,12,16–19 However, the regimen requires twice a day dosing, but a fixed combination of two antimalarial drugs has significant advantages over the free combination of such drugs, facilitating compliance, and preventing the patients from taking either drug alone. Furthermore, both effects help to inhibit the development of drug-resistant Plasmodia strains.

Both treatment regimens in this study were well tolerated. Although most subjects reported at least one adverse event, the vast majority of events were mild in severity. Furthermore, a large proportion of the reported events were consistent with symptoms of malaria such as headache, dizziness, asthenia, and gastrointestinal symptoms. Only one patient withdrew from the study because of an adverse event and he was taking quinine-doxycycline. A previously published analysis of 15 clinical trials with artemether-lumefantrine suggested that common events such as headache, dizziness, abdominal pain, anorexia, nausea, vomiting, diarrhea, pruritus, and rash may be related to drug treatment.¹⁹ Other complaints such as fatigue/asthenia, sleep disorders, arthralgia/myalgia, palpitation, and cough are events that commonly overlap with the symptoms of malaria. The investigators admitted that there is an intrinsic difficulty of determining the cause and effect of many events reported during antimalarial therapy.¹⁹

It is recognized that many commonly used antimalarial agents have tolerability problems, including some potentially serious cardiac side effects. In particular, quinine, quinidine, and halofantrine have been shown to prolong the QTc interval at therapeutic doses.^17,20 Studies to date have not found any evidence of cardiotoxicity with the use of artemether alone or in combination with lumefantrine.¹⁷ In a randomized, double-blind, crossover ECG study comparing the cardiac effects of artemether-lumefantrine and halofantrine, all 13 subjects demonstrated an increase in QTc interval after single oral doses of halofantrine (500 mg), but no effect on the QTc interval was observed after administration of 80 mg of artemether and 480 mg of lumefantrine.¹¹ Artemether-lumefantrine also produced no observable effects on the QTc interval when given in combination with mefloquine.²¹ One patient in our study had a prolonged QTc interval only on the second day of artemether-lumefantrine administration. An additional patient in the same treatment group had a prolonged QTc at baseline, but not at subsequent evaluations, while taking artemether-lumefantrine.

Although not assessed in the present study, artemisinin derivatives such as artemether have the additional benefit of preventing gametocyte development, a feature that can reduce the transmissibility of P. falciparum malaria. This phenomenon has been observed in Southeast Asia.²² A study conducted on the western border of Thailand between 1990 and 1995 found a significantly higher gametocyte carriage rate after mefloquine therapy compared with artemisinin derivative therapy (person gametocyte week rates = 34.1 versus 3.9 per 1,000 person-weeks, respectively; P < 0.0001). The routine administration of artemisinin-based antimalarial therapy at the study center reportedly reduced the subsequent incidence of P. falciparum malaria by 47%.²³ In a comparative study with mefloquine, artemether-lumefantrine demonstrated a significantly shorter gametocyte clearance time (152 hours versus 331 hours; P < 0.001).²⁴ In light of such findings, the use of artemisinin-based regimens could have a substantial impact on limiting the spread of P. falciparum malaria because without gametocytes in the blood of patients, mosquitoes cannot become infected following a blood meal.

With regard to simplicity of drug administration and patient convenience, artemether-lumefantrine has a clear advantage compared with quinine-doxycycline. In this study, artemether-lumefantrine therapy required taking a single product twice a day for three days, for a total of six doses. The quinine-doxycycline regimen necessitated taking one medication on an every 8-hour schedule for the first 3 days of treatment, while at the same time taking a different medication on an every 12-hour schedule for 5 days. Patients using the latter combination required a total of 19 medication doses at various intervals. Drug accountability was monitored carefully during this study, resulting in good patient compliance in the controlled hospital setting of the study. However, compliance is a concern when drug regimens are prescribed to the general public outside the clinical investigation setting.

Artemether-lumefantrine offers one of the most convenient antimalarial regimens currently available, and its ease of use would be expected to maximize real-world treatment results. The results of this study confirm that artemether-lumefantrine is a safe and efficacious treatment for P. falciparum malaria.

Received June 24, 2004. Accepted for publication May 19, 2005.

Acknowledgments: We thank all patients for their willingness to participate in the study.

Financial support: This study was supported by Novartis.

Disclosure: The research published in the report was sponsored by Novartis. This statement is made in the interest of full disclosure and not because the authors consider this to be a conflict of interest.

^* Address correspondence to Marcus V. Lacerda, Laboratory of Malaria, Tropical Medicine Foundation of Amazonas, Av. Pedro Teixeira, 25, Manaus, Amazonas, Brazil. 69.040-000, E-mail: marcuslacerda{at}uol.com.br

Authors’ addresses: Maria G. Alecrim, Marcus V. Lacerda, Maria P. Mourão, and Wilson D. Alecrim, Centro Universitário Nilton Lins, UNICENTER, Sala 315, Av. Professor Nilton Lins, 3259, Parque das Laranjeiras/Flores, Manaus, Amazonas, Brazil, 69.058-040, E-mails: malecrim{at}niltonlins.br, marcuslacerda{at}uol.com.br, mpmourao{at}uol.com.br, and walecrim{at}uol.com.br. Alexandre Padilha, Bernardo S. Cardoso, and Marcos Boulos, University of São Paulo Tropical Medicine Advanced Center, Santarém, Pará, Brazil, E-mail: mboulos{at}usp.br.

Reprint requests: Marcus V. Lacerda, Laboratory of Malaria, Tropical Medicine Foundation of Amazonas, Av. Pedro Teixeira, 25, Manaus, Amazonas, Brazil, 69.040-000, E-mail: marcuslacerda{at}uol.com.br.

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				M. d. G. C. Alecrim, M. V. G. de Lacerda, M. P. G. Mourao, W. D. Alecrim, A. Padilha, B. Cardoso, and M. Boulos Letter to the editor. Am J Trop Med Hyg, August 1, 2006; 75(2): 187 - 187. [Full Text] [PDF]

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