A Randomized Trial of Artesunate-Mefloquine versus Artemether-Lumefantrine forTreatment of Uncomplicated Plasmodium falciparum Malaria in MaliIssakaSagara,* AbdoulbakiDiallo, MamadyKone, ModiboCoulibaly, SoryIbrahimaDiawara, OusmaneGuindo, Hamma Maiga, Mohamed Balla Niambele, Mady Sissoko, Alassane Dicko, Abdoulaye Djimde, and Ogobara K. DoumboMalaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Medicine, Pharmacy andOdonto-Stomatology, University of Bamako, Bamako, MaliAmerican Journal Of Tropical Medicine & Hygeine. 79(5),2008,pp.655-661 Tanoy Bose Post Graduate Trainee Moderator: Dr.A.K.Pegu Assistant Professor Department of Medicine Assam Medical College Dibrugarh
INTODUCTION Around 2 million laboratory confirmed cases of malaria are reported in the country annually. Out of the total malaria cases, 40-50% is P.falciparum.† In a recent study from India, the Pfcrt K76T mutation has been shown to be rampant (96−100%) in blood samples collected from patients infected with P. falciparum, especially in the northern and northeastern parts of India‡ †MALARIA DRUG POLICY(2007) Directorate of National Vector Borne Disease Control Programme (Directorate General of Health Services) Ministry of Health and Family Welfare 22-Shamnath Marg, Delhi-110054. ‡Vinayak S, Biswas S, Dev V, Kumar A, Ansari MA, Sharma YD, 2003. Prevalence of K76T mutation in the Pfcrt gene of Plasmodium falciparum among chloroquine responders in India. ActaTrop 87: 287–293.
WHO/INDIA : WHO Regional Office for South-East Asia 2008: Last update 7.08.2008 STATUS OF MALARIA : ASSAM & INDIA
RATIONALE OF USING ACT COMBINATION Rx In 3-day ACT regimens, the artemisinin component is present in the body during only two asexual parasite life-cycles (each lasting 2 days, except for P. malariae infections). This exposure to 3 days of artemisinin treatment reduces the number of parasites in the body by a factor of approximately one hundred million (104 × 104 = 108). However, complete clearance of parasites is dependent on the partner medicine being effective and persisting at parasiticidal concentrations until all the infecting parasites have been killed. Thus the partner compounds need to be relatively slowly eliminated. As a result of this the artemisinin component is “protected” from resistance by the partner medicine provided it is efficacious and the partner medicine is partly protected by the artemisinin derivative. Courses of ACTs of 1–2 days are not recommended; they are less efficacious, and provide less protection of the slowly eliminated partner antimalarial. The artemisinin compounds are active against all four species of malaria parasites that infect humans and are generally well tolerated. The only significant adverse effect to emerge from extensive clinical trials has been rare (circa 1:3000) type 1 hypersensitivity reactions (manifested initially by urticaria). These drugs also have the advantage from a public health perspective of reducing gametocyte carriage and thus the transmissibility of malaria. This contributes to malaria control in areas of low endemicity.
Recommendation of Rx of uncomplicated Pf under Malaria Drug Policy 2007: NVBDCP:DGHS;MOHFW,22-Shamnath Marg; Delhi-110054 Microscopically Pf+: Chloro 25mg/k X 3d+ SD Prima 0.75mg/k on day 1 In Chloro Res ∆: Artesun 4mg/k X 3d + Sulfadox/Sulfalene 25mg/k + Pyrem 1.25mg/k on day 1 Mefloquine should only be given to Chloro/multi resistant uncomplicated Pf cases in standard doses only to be provided to patients against the prescription of RMP supported by lab report showing ASEXUAL stg of Pf & not Gametocyte alone or other species: Artesun 4mg/k X 3d + Meflo 25 mg/k ( 15mg day2 +10mg day3)
Because Mefloquine has not been used widely as an antimalarial drug in malaria-endemic areas of Africa, it is expected that the combination of this drug with Artesunate will result in a highly efficacious treatment for P. falciparum malaria.
Also, because of the long half-life of Mefloquine, we believed that combination drug could be a potential candidate for intermittent preventive treatments in children or pregnant women. AL was used as a comparator because WHO has listed this drug as an essential antimalarial drug.
OBJECTIVES The primary objective was to test the hypothesis that AS + MEF is as efficacious as AL in treatment for uncomplicated P. falciparum malaria. The secondary objectives were to assess and compare the following outcomes in the two treatment arms Parasite and fever clearances Reinfection rate Gametocyte carriage rate Anemia correction rate Clinical and biologic adverse events.
A peri-urban village of Kati located 25 km from Bamako with a population of approximately 1,500.
Hyper-endemic and transmission is highly seasonal.
Plasmodium falciparum is the predominant infecting
species, accounting for more than 95% of malaria cases. Study period : August 2004 through January 2005
INCLUSION CRITERIA EXCLUSION CRITERIA Weight ≥ 10 kg Age≥ 1 yr A P. falciparum parasite density between 2,000 and 200,000/L An axillary temperature ≥ 37.5°C A resident of the study site Could take oral medication. Symptoms or signs of severe malaria Had a serious underlying disease Had an allergy to one or more study drugs Had used any component of the study drugs within 28 days of enrollment Were pregnant (detected either clinically or with a urine βHCG test).
METHODOLOGY Enrolled patients were randomly assigned to receive either AS + MEF or AL. Although this was an open, randomized, clinical trial, thick blood smear slide readers were kept blinded to the treatment arm until the end of the study; this was conducted to minimize assessment bias because malaria parasite count was the key outcome used to define treatment failure. AL was packaged in fixed-dose combination tablets, each containing 20 mg of artemether and 120 mg of lumefantrine. They were administered according to body: one dose was administered at enrollment, one dose 8 hours later, and then two doses on the second day after initiation of treatment. The AS + MEF treatment was supplied as two separate tablets in a single blister pack: a tablet of mefloquine and a tablet of artesunate. One dose was administered daily for three days. Dosage was determined by weight,
METHODOLOGY Study participants were examined in the study clinic 1, 2, 3, 7, 14, 21, and 28 days. A finger skin puncture was used to obtain blood for a thick blood smear and a filter paper dot (for future parasite DNA extraction) at each follow-up visit (except on day 1 when blood was used only for a filter paper dot). Giemsa-stained thick blood smears were read by experienced microscopists who were blinded to treatment allocation. Parasite densities were calculated by counting the number of asexual P. falciparum parasites until 300 leukocytes were observed and then converting that to parasites per microliter of blood, assuming an average leukocyte count of 7,500/L. A CBC + serum (ALT) and serum creatinine assessments were performed among the first enrolled on approximately 20% of the total participants at baseline and 14 days after initiation of treatment. Tests were also performed if clinically indicated or if a significant abnormality was detected on day 14. In addition, hemoglobin levels were measured at baseline, on day 14, and on day 28. For participants with recurrent parasitemia after day 7, paired polymerase chain reaction (PCR) blots (from day 0 and the day of parasitemia recurrence) were analyzed for parasite merozoite surface proteins (MSP-1 and MSP-2) and microsatellite CA1 to distinguish between reinfection and recrudescence.
RESULTS No early Rx failures 14day ACPR similar 28day corrected ACPR similar 28day reinfection rate sign. ↓in AS+MEF Day 1 fev.clearance @ ↑ in AS+MEF ↓Gametocyte carriage @ similar Anemia correction @ similar Adv ev: similar ex. vomitting & total no of S/s ↑ in AS+MEF
RESULTS Participants with fever during first three days
RESULTS Participants with asexual P.falciparumparasitemia during first 3 days
RESULTS Participants with gametocytes @ baseline & follow-up
SUMMARY OF THE RESULTS AS +MEF & AL are equally efficacious inachieving 14 or 28 day cure rate adequate parasitological and clinical response Rapid parasite clearance ( No parasite carriers found in day 3 of both the arms) Decrease in gametocyte carriage rate Lowering prevalence of anemia by day 28 AS +MEF was superior to AL in Lower incidence of reinfection rate at 28 days ( 15.4% vs. 29.9% ; P< 0.001) Lower incidence of late clinical failure Higher incidence of day 1 fever clearance rate (95.7% vs. 85.9% ; P=0.001) Except for VOMITTING & Total Number of S/S , the proportion of reporting any S/S within first week after Rx was statistically similar between the arms (P>0.05)
DISCUSSION OF THE STUDY Both treatments are highly efficacious in treating uncomplicated P. falciparum malaria The high cure rates we found for AS + MEF were expected because of the high efficacy of artesunate, non-documented resistance of P. falciparum to mefloquine in Mali, as in most west African countries in general, and potentially because of the rare use of mefloquine as an antimalarial drug The advantage of a prolonged period of protection against new P. falciparum infections (longer half-life of mefloquine of approximately three 3 weeks) has been weighed against the suspected increase in the risk for the selection of drug-resistant isolates in areas of high malaria transmission More recently, however, the benefit of reduced rates of reinfection and relapse caused by long-acting antimalarial drugs has been emphasized (Van Vught M and others, unpublished data). The debate on this risk/benefit analysis is still ongoing and needs
DISCUSSION OF THE STUDY Differences in elimination half-life may explain the advantage of mefloquine over AL (3–6 days) in preventing reinfection. Both treatments were similar regarding the secondary endpoints of parasite clearance rate, fever clearance rate (except for day 1 when the fever clearance was greater in the AS + MEF arm), gametocytes carriage rate, and clinical (except for vomiting and total adverse events, which were more prevalent in AS + MEF arm) and laboratory adverse events. The easy (once a day) administration of AS + MEF compared with the twice a day administration of AL may be an important advantage for AS + MEF use with regard to patient compliance
DISCUSSION OF THE STUDY AS + MEF showed an additional benefit of preventing new infections (reinfection). This benefit maybe caused by mefloquine because of its long half-life compared with lumefantrine. Therefore, AS + MEF or mefloquine alone maybe a potential candidate for intermittent preventive treatment in infants, intermittent preventive treatment in children, or intermittent preventive treatment in pregnancy (IPTp) in Africa because sulfadoxine-pyrimetamine is showing an increased failure rate in many areas of Africa. Data are supportive for IPTp with sulfadoxine-pyrimetamine because the resistance rate is less than 40%
RELATED STUDIES AN OPEN RANDOMIZED CLINICAL TRIAL OF ARTEKIN® VS ARTESUNATE-MEFLOQUINE IN THE TREATMENT OF ACUTE UNCOMPLICATED FALCIPARUM MALARIA SOUTHEAST ASIAN J TROP MED PUBLIC HEALTHVol 36 No. 5 September 2005 A study comparing a standard treatment for acute uncomplicated falciparum malaria (artesunate 4 mg/kg/day together with mefloquine 8 mg/kg/day oral route once a day for 3 days) and a combination of dihydroartemisinin 40 mg and piperaquine 320 mg in the form of Artekin® given once a day for 3 days to determine safety, efficacy, and tolerability. CONCLUSION: There were no significant differences in fever clearance time or parasite clearance time between both groups. The 28- day cure rates were high, at 100% and 99%, in groups A and B, respectively. We conclude that Artekin® was as effective and well-tolerated as artesunate-mefloquine, and can be used alternatively as the current treatment for multidrug-resistant P. falciparum malaria
RELATED STUDIES A randomized trial of artemether-lumefantrine versus mefloquine-artesunate for the treatment of uncomplicated multi-drug resistant Plasmodium falciparum on the western border of Thailand. Malar J. 2005 Sep 22;4:46. Hutagalung R, Paiphun L, Ashley EA, McGready R, Brockman A, Thwai KL, Singhasivanon P, Jelinek T, White NJ, Nosten FH. The trial was an open-label, two-arm, randomized study comparing artemether-lumefantrine and mefloquine-artesunate for the treatment of uncomplicated falciparum malaria with 42 days of follow up. In both groups, the PCR adjusted cure rates by day 42 were high: 98.8% (95% CI 96.4, 99.6%) for artemether-lumefantrine and 96.3% (95% CI 93.1, 98.0%) for artesunate-mefloquine. Both regimens were very well tolerated with no serious adverse events observed attributable to either combination. CONCLUSION: Overall, this study confirms that these two artemisinin-based combinations remain highly effective and result in equivalent therapeutic responses in the treatment of highly drug-resistant falciparum malaria.