THERAPEUTIC EFFICACY OF ARTEMETHER-LUMEFANTRINE FOR THE TREATMENT OF UNCOMPLICATED PLASMODIUM FALCIPARUM MALARIA IN BANGLADESH

Multidrug resistance of Plasmodium falciparum is spreading throughout Asia and is impeding efforts to control malaria. The World Health Organization (WHO) reports a worsening malaria situation in Bangladesh, particularly in the hilly and forested areas in the Hill Tract Districts with reported chloroquine and sulfadoxine-pyrimethamine resistance.¹ Resistance to chloroquine in the southeastern regions of Bangladesh has been known for a relatively long time, but until very recently chloroquine was still the first-line treatment for uncomplicated P. falciparum malaria.^2–4 Recently, the Bangladesh Ministry of Health and Family Welfare decided to introduce an artemether-lumefantrine combination for the treatment of uncomplicated P. falciparum malaria.

Combinations of chemotherapeutic agents are generally used to accelerate therapeutic response, improve cure rates, and protect the component drugs against resistance. Artemether-lumefantrine has been given priority as a first-line artemisinin-based combination therapy (ACT) recommended by the WHO for the treatment of uncomplicated P. falciparum malaria. However, financial constraints and shortcomings in production of adequate drug quantities limit the availability of ACT in extremely poor regions such as Bangladesh. Since data on the efficacy of ACT in Bangladesh is limited, we conducted a baseline study to determine the therapeutic efficacy of artemether-lumefantrine for treatment of uncomplicated P. falciparum malaria in the southeastern parts of the country.

The study was performed at the field site of the International Center for Diarrheal Disease Research, Bangladesh in Chakaria, Cox’s Bazar district and Lama, Bandarban district, in the Chittagong Hill Tracts, a malaria-endemic area in southeastern Bangladesh, between July and September 2005. The study was carried out by the International Center for Diarrheal Disease Research, Bangladesh in collaboration with the Medical University of Vienna, Austria, and the Armed Forces Research Institute of Medical Sciences in Bangkok, Thailand. Written informed consent was obtained from all study participants and the study protocols were reviewed and approved by the Ethical Review Committee of the International Center for Diarrheal Disease Research, Bangladesh and the Human Use Review Committee of the United States Army.

All patients ≥ 18 years of age with laboratory-confirmed monoinfections with P. falciparum were invited to participate in the study. Pregnant women and patients with prior anti-malarial treatment within the preceding eight weeks were excluded. All patients agreed to undergo a 42-day follow-up. A total of 83 subjects were screened and 67 (80.7%) were enrolled in the study. Twenty-two (32.8%) patients were men and 45 (67.2%) were women. No patient was lost to follow-up during the 42-day follow-up. The median age was 22 years (range = 18–50 years).

All patients received treatment with artemisinin-lumefantrine. Artemisinin-lumefantrine tablets (Coartem^®; Novartis, Basel, Switzerland), each containing 20 mg of artemether and 120 mg of lumefantrine as a coformulated combination, were administered in six consecutive doses: four tablets each at 0 hours and 8 hours on the first day, then twice a day on two consecutive days (total = 480 mg of artemether and 2,880 mg of lumefantrine).

The study design essentially followed the WHO guidelines for the assessment and monitoring of antimalarial drug efficacy with an extension of follow-up until day 42.⁵ Patients were asked to return to the study center on days 1, 2, 3, and 7 and then weekly until day 42. If the patients did not return for the scheduled visits or missed an appointment they were seen at their homes by the study staff. Blood smears were prepared and body temperature was recorded at each visit. In case of any symptoms consistent with malaria, patients were advised to return to the center immediately.

Absence of parasitemia until day 42 irrespective of axillary temperature was categorized as an adequate clinical and parasitologic response (ACPR). Patients who had parasitemia and an axillary temperature ≥ 37.5°C on any day from day 4 to day 42 were classified as late clinical treatment failures (LCFs), and parasitemia on any day from day 7 to day 42 and an axillary temperature < 37.5°C were classified as late parasitologic failures (LPF). Patients who were parasitemic on day 3 with an axillary temperature ≥ 37.5°C or ≥ 25% of the parasite count on day 0 were categorized as early treatment failures (ETF).⁵

Fever clearance time was defined as the time from drug administration until the body temperature decreased to < 37.5°C and remained so for 48 hours. Parasite clearance time (PCT) was defined as the time from drug administration until the first in a series of negative blood smears. To determine whether the genotype before and after reappearance of parasites in the peripheral blood was identical, indicating a recrudescence, gene loci of pre-treatment and post-treatment sample pairs were compared by a polymerase chain reaction (PCR).

Kaplan-Meier analysis was performed to calculate the proportion of aparasitemic patients for each point in time (later referred to as cure rates). Patients with reinfection diagnosed by PCR and patients who developed P. vivax parasitemia during the follow-up were censored.

From a total of 83 screened subjects, 67 were enrolled in the study. Fifty-nine subjects were evaluable for primary endpoint on day 42. Seven patients (10.4%, 95% confidence interval [CI] = 4.3–20.3%) were censored after being treated with chloroquine and primaquine for P. vivax parasitemia, which appeared in the course of the follow-up. One patient (1.5%, 95% CI = 0.0–8.0%) was censored after a reappearing P. falciparum parasitemia could not be confirmed by PCR.

The overall cure rate after PCR adjustment calculated by Kaplan-Meier analysis after 42 days was 94.3%. The cure rates for day 7, 14, 21, 28 and 35 were 100.0, 100.0, 100.0, 98.3, and 94.7%, respectively. Nine (15.2%, 95% CI = 7.2–27.0%) of the 59 enrolled patients showed reappearance of parasites. All showed relatively late reappearances of parasites within a median time of 34 days (range = 25–39 days). After PCR adjustment, six (10.2%, 95% CI = 3.8–20.8%) had acquired a novel infection, whereas three (5.1%, 95% CI = 1.1–14.1%) were classified as LTFs. Two (3.4%, 95% CI = 0.4–11.7%) of these patients were classified as LCFs, and one (1.7%, 95% CI = 0.0–1.1%) was classified as an LPF. None of the patients had an ETF. Geometric mean parasite densities were not significantly higher (P > 0.05) in patients who later showed reappearance of parasites (parasitemia = 0.28%) than in patients who were classified as ACPRs (parasitemia = 0.27%). All patients with a recurrent P. falciparum parasitemia were treated according to national guidelines. The mean ± SD time until fever clearance was 25.82 ± 12.14 hours. The mean ± SD PCT was 30.36 ± 19.43 hours and was not significantly longer in patients who had a reappearance of parasites (P > 0.05) or in patients who experienced treatment failure (P > 0.05) than in those classified as cured.

Treatment was directly observed by the study team and by village volunteers. The overall compliance was good, no patient was lost to follow-up, and no severe adverse events were observed.

Our data suggest that artemisinin-lumefantrine may be superior to previously tested drug combinations (i.e., quinine plus sulfdoxine-pyremethamine) regarding cure rate and parasite and fever clearance.⁶ We have previously reported PCR-adjusted cure rates with quinine plus sulfdoxine-pyremethamine in a 42-day follow-up of 87.3% in a comparable group of patients.⁷ Because of their short half-lives and to protect the efficacy of artemisinin derivatives, they must be combined with longer-acting antimalarial drugs. Lumefantrine is a highly lipophilic substance and the oral bioavailability varies considerably between individuals and increases greatly if the drug is administered after a meal rich in fat.⁸ This remains a limitation to the effective usage of the drug because uptake may be reduced in fasting patients.

The four-dose regimen of artemisinin-lumefantrine showed cure rates greater than 95% in a 28-day follow up in Chinese, African, and Indian patients with either known semi-immunity to malaria or non-drug resistant infections, but showed lower cure rates of 83.3% and 81% in Thailand.^9,10 Studies from Thailand clearly showed that a six-dose regimen is essential for areas with a high percentage of multidrug-resistant P. falciparum parasites to reach high levels of efficacy.^10,11 The cure rate of 94.3% in a six-dose regimen after a 42-day follow-up in our study is consistent with previous studies in Laos,¹² along the Thailand-Myanmar border,¹³ and in the Chittagong Hill Tracks,¹⁴ with showed cure rates of 93.6%, 98.8%, and 97%, respectively.

The PCT is known to be short in the course of a treatment with artemisinin derivates.¹⁵ We observed rapid parasite clearance as well as fever clearance, which is consistent with previously reported data. Most patients cleared fever (79.1%, 95% CI = 67.4–88.1%) and parasites (83.58%, 95% CI = 72.5–91.5%) within one day of drug administration, and the time to complete parasite clearance was not significantly longer in patients who developed recrudescence than in those classified as cured. This suggests little influence of parasite density on the cure rate.

In the artemisinin-lumefantrine drug combination, lumefantrine is the slower and longer acting partner with a comparatively longer half-life. Lumefantrine has rarely been used in Bangladesh and closely related drugs such as mefloquine were never used as part of the national treatment guidelines. Reduced bioavailability because of limited drug uptake and absorption may therefore have a stronger influence on the cure rate than reduced drug sensitivity.

In conclusion, our data suggest that artemisinin-lumefantrine is a highly efficacious combination with rapid fever and parasite clearance. However, its use in Bangladesh is still constrained by a relatively high cost and difficulties with supplies. Alternative treatments should therefore be explored.