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Efficacy and tolerability of artesunate-amodiaquine (Camoquin plus®) versus artemether-lumefantrine (Coartem®) against uncomplicated Plasmodium falciparum malaria: Multisite trial in Senegal and Ivory Coast
Tropical Medicine & International Health
Abstract
To compare, in a phase IV trial, the efficacy and tolerability of artesunate-amodiaquine (Camoquin plus) dosed at 300 and 600 mg of amodiaquine per tablet to artemether-lumefantrine (Coartem) for the treatment of Plasmodium falciparum uncomplicated malaria in Ivory Coast and Senegal.
Multisite, randomised, open-labelled study in patients over the age of 7 years. The primary endpoint for efficacy was adequate clinical and parasitological response (ACPR) at day 28. The secondary endpoints were fever and parasite clearance and gametocyte carriage in each treatment group. Drug tolerability was assessed comparing adverse events and modification of biological parameters between D0 and D7. Data were analysed on an intention-to-treat and per protocol basis.
We included 322 patients; 316 patients completed the monitoring to D28 (155 in AS + AQ group and 161 in AL group). In ITT analysis, an ACPR corrected rate of 97.4% was observed in AS + AQ group versus 97% in AL group (P = 0.99). No parasite recrudescence was observed in AS + AQ arm. All patients in both groups had a fever and parasite clearance at D2. Gametocytes had disappeared by D14 in the AL group and by D21 in the AS + AQ group. No serious adverse events were observed. Minor adverse events were significantly more frequent in the AS + AQ arm. Biological parameters between D0 and D7 did not show any significant statistical variations except for anaemia.
This study demonstrates the efficacy and tolerability of AS + AQ for uncomplicated Plasmodium falciparum malaria treatment in African patients over the age of 7 years.
... In both drug arms, fever and parasite disappeared gradually by day 3. Rapid fever and parasite clearance rates have been reported before in Senegal/Ivory Coast [65,66], Cameroon [13], and Togo [67]. The presence of gametocytes at enrollment and during follow-up days was found to be higher in the AS-AQ group when compared to the AL group. ...
... The presence of gametocytes at enrollment and during follow-up days was found to be higher in the AS-AQ group when compared to the AL group. These observations are in harmony with those reported in Senegal/Ivory coast [65,66] and Togo [67]. A meta-analysis from individual patient data conducted by the Worldwide Antimalarial Resistance Network (WWARN) Gametocyte Study Group confirmed that AL is more effective than the AS-AQ fixed dose combination in preventing gametocyte carriage shortly after treatment [68]. ...
... It was also shown that AS-AQ and AL drugs had varying effects on alanine aminotransferase (ALAT) and creatinine (CREA) levels on day 0 and day 7. These results corroborate with those realized in Senegal and Ivory Coast [65]. These observations also confirm the findings of the study on the efficacy and safety of ACTs in Garoua and Mutengene, Cameroon reported by Nji and colleagues in 2015 [13]. ...
Background: Many studies have reported high efficacy and safety of artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) when administered under direct observation in Cameroon. There is paucity of data to support their continuous use in home-based treatment of uncomplicated Plasmodium falciparum malaria in Cam-eroon. Hence, this study aimed to assess the effectiveness and safety of AS-AQ versus AL for home-based treatment of uncomplicated P. falciparum malaria among children 6-120 months in Yaoundé, Cameroon. Methods: A two-arm, open-label, randomized, controlled trial comparing the equivalence of AS-AQ (experimental group) and AL (control group) was carried out from May 2019 to April 2020 at two secondary hospitals in Yaoundé. Participants were randomized to receive either AS-AQ or AL. After the first dose, antimalarial drugs were given at home, rather than under direct observation by a study staff. The conventional on-treatment and post-treatment laboratory and clinical evaluations were not done until day 3 of the full antimalarial treatment course. The evaluation of effectiveness was mainly based on per protocol polymerase chain reaction adjusted adequate clinical and parasito-logical response (PP PCR adjusted ACPR) on day 28 post-treatment. Safety was based on assessment of adverse events (AEs) and severe adverse events (SAEs) from day 1 to day 28.
... In both drug arms, fever and parasite disappeared gradually by day 3. Rapid fever and parasite clearance rates have been reported before in Senegal/Ivory Coast [65,66], Cameroon [13], and Togo [67]. The presence of gametocytes at enrollment and during follow-up days was found to be higher in the AS-AQ group when compared to the AL group. ...
... The presence of gametocytes at enrollment and during follow-up days was found to be higher in the AS-AQ group when compared to the AL group. These observations are in harmony with those reported in Senegal/Ivory coast [65,66] and Togo [67]. A meta-analysis from individual patient data conducted by the Worldwide Antimalarial Resistance Network (WWARN) Gametocyte Study Group confirmed that AL is more effective than the AS-AQ fixed dose combination in preventing gametocyte carriage shortly after treatment [68]. ...
... It was also shown that AS-AQ and AL drugs had varying effects on alanine aminotransferase (ALAT) and creatinine (CREA) levels on day 0 and day 7. These results corroborate with those realized in Senegal and Ivory Coast [65]. These observations also confirm the findings of the study on the efficacy and safety of ACTs in Garoua and Mutengene, Cameroon reported by Nji and colleagues in 2015 [13]. ...
Background
Many studies have reported high efficacy and safety of artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) when administered under direct observation in Cameroon. There is paucity of data to support their continuous use in home-based treatment of uncomplicated Plasmodium falciparum malaria in Cameroon. Hence, this study aimed to assess the effectiveness and safety of AS-AQ versus AL for home-based treatment of uncomplicated P. falciparum malaria among children 6–120 months in Yaoundé, Cameroon.
Methods
A two-arm, open-label, randomized, controlled trial comparing the equivalence of AS-AQ (experimental group) and AL (control group) was carried out from May 2019 to April 2020 at two secondary hospitals in Yaoundé. Participants were randomized to receive either AS-AQ or AL. After the first dose, antimalarial drugs were given at home, rather than under direct observation by a study staff. The conventional on-treatment and post-treatment laboratory and clinical evaluations were not done until day 3 of the full antimalarial treatment course. The evaluation of effectiveness was mainly based on per protocol polymerase chain reaction adjusted adequate clinical and parasitological response (PP PCR adjusted ACPR) on day 28 post-treatment. Safety was based on assessment of adverse events (AEs) and severe adverse events (SAEs) from day 1 to day 28.
Results
A total of 242 children were randomized to receive AS-AQ (n = 114) and AL (n = 128). The PP PCR adjusted day 28 cure rates were [AS-AQ = 96.9% (95% CI, 91.2–99.4) versus AL = 95.5% (95% CI, 89.9–98.5), P = 0.797]. Expected mild to moderate adverse events were reported in both arms [AS-AQ = 83 (84.7%) versus AL = 99 (86.1%), P = 0.774]. The most common adverse events included: transient changes of hematologic indices and fever.
Conclusions
This study demonstrated that AS-AQ and AL are effective and safe for home management of malaria in Yaoundé. The evidence from this study supports the parallel use of the two drugs in routine practice. However, the findings from this study do not describe the likely duration of antimalarial effectiveness in holoendemic areas where multiple courses of treatment might be required.
Trial registration: This study is a randomized controlled trial and it was retrospectively registered on 23/09/2020 at ClinicalTrials.gov with registration number NCT04565184.
... A fixed-dose combination of artesunate and amodiaquine (ASAQ Winthrop [ASAQ]), developed by a partnership between the Drugs for Neglected Diseases initiative (DNDi) and Sanofi, was prequalified by the WHO in 2008 and included in the List of Essential Medicines in 2011 [3][4][5]. Subsequent studies confirmed a high therapeutic efficacy (94%-98%) of ASAQ [3,[6][7][8][9][10][11][12], non-inferiority to AL [7,10,12] and comparable safety profiles when used for a single episode of uncomplicated malaria [3,[6][7][8][9][10][11][12]. In most endemic areas, recurrent malaria that requires repeated administration of ACT is inevitable, however the efficacy and particularly the safety of repeated use of ASAQ and other ACT remains to be established. ...
... A fixed-dose combination of artesunate and amodiaquine (ASAQ Winthrop [ASAQ]), developed by a partnership between the Drugs for Neglected Diseases initiative (DNDi) and Sanofi, was prequalified by the WHO in 2008 and included in the List of Essential Medicines in 2011 [3][4][5]. Subsequent studies confirmed a high therapeutic efficacy (94%-98%) of ASAQ [3,[6][7][8][9][10][11][12], non-inferiority to AL [7,10,12] and comparable safety profiles when used for a single episode of uncomplicated malaria [3,[6][7][8][9][10][11][12]. In most endemic areas, recurrent malaria that requires repeated administration of ACT is inevitable, however the efficacy and particularly the safety of repeated use of ASAQ and other ACT remains to be established. ...
... The PCR-corrected ACPR for ASAQ was 97.5% and was non-inferior to the rate for AL (97.0%). The PCR-corrected cure rates for ASAQ are comparable to findings reported previously in West and Central Africa (94% to 98%) [3,[6][7][8][9][10][11][12]. The study also showed that both ACT, cleared parasites within 3 days, Hb concentrations returned to normal within 14 days, and gametocytes were cleared within 21 days. ...
The safety and efficacy of the two most widely used fixed-dose artemisinin-based combination therapies (ACT), artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) are well established for single episodes of uncomplicated Plasmodium falciparum malaria, but the effects of repeated, long-term use are not well documented. We conducted a 2-year randomized, open-label, longitudinal, phase IV clinical trial comparing the efficacy and safety of fixed-dose ASAQ and AL for repeated treatment of uncomplicated malaria in children under 5 years at Nagongera Health Centre, Uganda. Participants were randomized to ASAQ or AL and all subsequent malaria episodes were treated with the same regimen. 413 children were enrolled and experienced a total of 6027 malaria episodes (mean 15; range, 1-26). For the first malaria episode, the PCR-corrected-cure rate for ASAQ (97.5%) was non-inferior to that for AL (97.0%; 95% CI [-0.028; 0.037]). PCR-corrected cure rates for subsequent malaria episodes that had over 100 cases (episodes 2-18), ranged from 88.1% to 98.9% per episode, with no clear difference between the treatment arms. Parasites were completely cleared by day 3 for all malaria episodes and gametocyte carriage was less than 1% by day 21. Fever clearance was faster in the ASAQ group for the first episode. Treatment compliance for subsequent episodes (only first dose administration observed) was close to 100%. Adverse events though common were similar between treatment arms and mostly related to the disease. Serious adverse events were uncommon, comparable between treatment arms and resolved spontaneously. Anemia and neutropenia occurred in <0.5% of cases per episode, abnormal liver function tests occurred in 0.3% to 1.4% of cases. Both regimens were safe and effective for repeated treatment of malaria.
Current Controlled Trials NCT00699920.
... The effects of AL on gametocyte carriage and malaria transmission to mosquitoes have also been compared with those of other ACT. Key findings are summarized in Table 3 [31,33,36,40,63,65,69,70] (and Additional file 4 [31,33,36,40,63,65,69,70]) and discussed below. For some ACT, the findings have to be interpreted with some caution since resistance to partner drugs (e g. ...
... The effects of AL on gametocyte carriage and malaria transmission to mosquitoes have also been compared with those of other ACT. Key findings are summarized in Table 3 [31,33,36,40,63,65,69,70] (and Additional file 4 [31,33,36,40,63,65,69,70]) and discussed below. For some ACT, the findings have to be interpreted with some caution since resistance to partner drugs (e g. ...
... In a randomized, open-label phase IV study, a reduction in gametocyte carriage was demonstrated in AL and AS + AQ treatment arms, although clearance was more rapid following AL than AS + AQ; gametocytes had disappeared by day 14 in the AL group and by day 21 in the AS + AQ group [36]. An earlier study of 298 children from the Republic of Congo reported a similar gametocyte carriage rate with AL, AS + AQ and AS + SP; an increase in gametocytes was observed during the first two days of treatment, but reduced during the four weeks of follow-up, from 8 to 1% in the AL group, from 23 to 3% in the AS + AQ group, and from 26 to 5% in the AS + SP group [63]. ...
While significant advances have been made in the prevention and treatment of malaria in recent years, these successes continue to fall short of the World Health Organization (WHO) goals for malaria control and elimination. For elimination strategies to be effective, limited disease transmission, achieved through rapid reduction in the infectious parasite reservoir and decreased gametocyte carriage, will be critical. Artemisinin-based combination therapy (ACT) forms the cornerstone of WHO-recommended treatment for uncomplicated Plasmodium falciparum malaria, and in combination with other effective interventions will undoubtedly play a vital role in elimination programmes. The gametocytocidal properties of artemisinins are a bonus attribute; there is epidemiological evidence of reductions in malaria incidence and transmission in African regions since the introduction of these agents. Many studies and analyses have specifically investigated the effects of the ACT, artemether-lumefantrine (AL) on gametocyte carriage. In this systematic review of 62 articles published between 1998 and January 2014, the effects of AL on gametocyte carriage and malaria transmission are compared with other artemisinin-based anti-malarials and non-ACT. The impact of AL treatment of asymptomatic carriers on population gametocyte carriage, and the potential future role of AL in malaria elimination initiatives are also considered. Despite the inherent difficulties in comparing data from a range of different studies that also utilized different diagnostic approaches to assess baseline gametocyte counts, the gametocytocidal effect of AL was proportionately consistent across the studies reviewed, suggesting that AL will continue to play a vital role in the treatment of malaria and contribute to clearing the path towards malaria elimination. However, the specific place of AL is the subject of much ongoing research and will undoubtedly be dependent on different demographic and geographical scenarios. Utilizing ACT, such as AL, within malaria elimination strategies is also associated with a number of other challenges, such as balancing potential increased use of ACT (e g, treatment of asymptomatic carriers and home-based treatment) with rational use and avoidance of drug resistance development.
... Asthenia is considered among common undesirable effects of ASAQ Winthrop (SmPC ASAQ Winthrop®), similar to what is noted for AL [3]. No differences in fatigue or asthenia between AS + AQ and AL arms were reported in four recent studies [11,24,30,31]. In the present trials, fatigue was among the symptoms prompted by the physicians during clinical examination, and some degree of over-reporting of more subjective symptoms such as fatigue cannot be fully excluded in an open-label trial. ...
... The incidence of early vomiting immediately after drug intake though was reassuringly low in both study arms. Recent trials conducted in Ghana, Senegal and Ivory Coast, respectively, also reported nausea and vomiting AEs at higher frequency in the AS + AQ arm when compared to AL [24,30]. No differences in gastro-intestinal AEs were reported in three other trials [11,24,31] . ...
... In the present studies, ASAQ was not administered with food, since a high fat meal may modify the bioavailability of AS and AQ [32]. Mild or moderate anemia AEs were also more frequent in the ASAQ arm, similar to one recent study [30]. Mean Hb values remained within the normal range in both treatment arms, indicating that a potential effect of the treatment(s) on haemoglobin value was overall very moderate. ...
Safety surveillance of widely used artemisinin-based combination therapy (ACT) is essential, but tolerability data in the over five years age group are largely anecdotal.
Two open-label, randomized trials were conducted in Nimba County, Liberia: i) the main tolerability trial with 1,000 Plasmodium falciparum malaria patients aged over five years (Study-T), and, ii) an efficacy trial with a secondary objective of collecting tolerability data among 300 children age six to 59 months (Study-E). In both studies patients were randomized to fixed-dose artesunate-amodiaquine (ASAQ Winthrop(R)) or artemether-lumefantrine (AL, Coartem(R)), respectively. Clinical- and laboratory-adverse events (AEs) were recorded until day 28.
Study-T: most patients experienced at least one AE. Severe AEs were few, primarily asymptomatic blood system disorders or increased liver enzyme values. No treatment or study discontinuation occurred. Mild or moderate fatigue (39.8% vs 16.3%, p & 0.001), vomiting (7.1% vs 1.6%, p & 0.001), nausea (3.2% vs 1.0%, p = 0.01), and anaemia (14.9% vs 9.8%, p = 0.01) were more frequently recorded in the ASAQ versus AL arm. Study-E: mild or moderate AEs were common, including anaemia, fatigue, vomiting or diarrhoea. The few severe events were asymptomatic blood system disorders and four clinical events (pneumonia, malaria, vomiting and stomatitis).
Both ASAQ and AL were well tolerated in patients of all age groups. No unexpected AEs occurred. Certain mild or moderate AEs were more frequent in the ASAQ arm. Standardised safety surveillance should continue for all forms of ACT.Trial registration: The protocols were registered with Current Controlled Trials, under the identifier numbers ISRCTN40020296, ISRCTN51688713 (http://www.controlled-trials.com).
... This observation may be explained by the longer terminal half-life of amodiaquine (approximately 10 days) over lumefantrine (approximately 4 days) resulting in a higher post-treatment prophylactic effect of AS-AQ [21,22]. This notwithstanding, PCR-corrected cure rates for AS-AQ and AL were comparable in the forest and savannah zones of Ghana (100 % for AS-AQ and 97.2-100 % for AL) as in other studies [5,[22][23][24][25][26]. ...
... These findings suggest that ACT treatment for uncomplicated malaria has a positive effect on post-treatment haemoglobin levels. Though some studies have not shown significantly improved post-treatment haemoglobin levels after ACT treatment [26,28,30], others have [5,27,31]. ...
Background: Case management based on prompt diagnosis and adequate treatment using artemisinin-based combination therapy (ACT) remains the main focus of malaria control in Ghana. As part of routine surveillance on the therapeutic efficacy of ACT in Ghana, the efficacy of amodiaquine-artesunate (AS-AQ) and artemether-lumefantrine (AL) were studied in six sentinel sites representing the forest and savannah zones of the country.
Methods: Three sites representing the two ecological zones studied AS-AQ whilst the other three sites studied AL. In each site, the study was a one-arm prospective evaluation of the clinical, parasitological, and haematological responses to directly observed therapy for uncomplicated malaria with either AS-AQ or AL among children aged 6 months and 9 years. The WHO 2009 protocol for monitoring anti-malarial drug efficacy was used for the study
between July 2013 and March 2014.
Results: Per-protocol analyses on day 28 showed an overall PCR-corrected cure rate of 100 % for AS-AQ and 97.6 % (95 % CI 93.1, 99.5) for AL: 97.2 % (95 % CI 92.0, 99.4) in the forest zone and 100 % in the savannah zone. Kaplan–Meier survival analysis showed similar outcomes. Prevalence of fever decreased by about 75 % after the first day of treatment
with each ACT in the two ecological zones. No child studied was parasitaemic on day 3, and gametocytaemia was generally maintained at low levels (<5 %). Post-treatment mean haemoglobin concentrations significantly increased in the two ecological zones.
Conclusions: Therapeutic efficacy of AS-AQ and AL remains over 90 % in the forest and savannah zones of Ghana. Additionally, post-treatment parasitaemia on day 3 is rare suggesting that artemisinin is still efficacious in Ghana.
... Consistent with this understanding, in trials in East Africa, AL consistently outperformed AS/AQ [10][11][12][13][14]. In other regions of Africa, AL and AS/AQ have generally shown equivalent efficacy [3,[15][16][17][18]. ...
... In all of these studies, risks of recrudescence following treatment were low. Most studies elsewhere in Africa showed similar performance for AL and AS/AQ [3,[15][16][17][18]34], although some in West Africa showed superiority of AS/AQ over AL [3,35]. These results are consistent with the longer half-life of amodiaquine as compared to lumefantrine and the lower levels of amodiaquine resistance in West Africa as compared to other regions. ...
Background:
In treating malaria in Uganda, artemether-lumefantrine (AL) has been associated with a lower risk of recurrent parasitemia compared to artesunate-amodiaquine (AS/AQ), but changing treatment practices may have altered parasite sensitivities.
Methods:
We enrolled 602 children aged 6-59 months with uncomplicated falciparum malaria from 3 health centers in 2013-14 and randomly assigned treatment with AS/AQ or AL. Primary outcomes were risks of recurrent parasitemia within 28 days, unadjusted or adjusted to distinguish recrudescence from new infection. Drug safety and tolerability and Plasmodium falciparum resistance-mediating polymorphisms were assessed.
Results:
Of enrolled patients, 594 (98.7%) completed the 28-day study. Risks of recurrent parasitemia were lower with AS/AQ at all three sites (overall 28.6% vs. 44.6%; p<0.001). Recrudescences were uncommon and all after AL (0% vs. 2.5%; p=0.006). Hemoglobin recovery was greater with AS/AQ (1.73 vs. 1.39 g/dl, p=0.04). Both regimens were well tolerated; serious adverse events were uncommon (1.7% AS/AQ; 1.0% AL). AS/AQ selected for mutant and AL for wild type pfcrt/pfmdr1 polymorphisms associated with altered drug sensitivity.
Conclusions:
AS/AQ was followed by fewer recurrences than AL, contrasting with older data. Each regimen selected for polymorphisms associated with decreased response. Research should consider multiple or rotating regimens to maintain treatment efficacies.
... In Côte d'Ivoire, AS-AQ and AL have been recommended respectively in first-and second-line treatment since 2005 following earlier studies [5][6][7]. Continued use of amodiaquine or artesunate monotherapies, persistence of substandard ACT in the private sector [8][9][10] and resistance to artesunate and/or amodiaquine may jeopardize the future use of AS-AQ and AL as an effective artemisinin-based combination therapy. Constant diligent surveillance with the aim of monitoring the susceptibility of malaria parasites to artemisinin, its derivatives, and partner drugs in endemic areas is, therefore essential. ...
... Asthenia is considered among common undesirable effects of AS-AQ [29]. No differences in fatigue or asthenia between AS-AQ and AL in some studies [5,25] were observed. AS-AQ presents the advantage of requiring one intake per day without fatty food while AL is twice per day with fatty food. ...
Emergence of artemisinin resistance has raised concerns that the most potent anti-malarial drug may be under threat. Artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) are, respectively, the first- and second-line treatments for uncomplicated falciparum malaria in Cote d'Ivoire. Constant monitoring by National Malaria Control Programme (NMCP) of drug efficacy is an important tool in establishing rational anti-malarial drug policies in Cote d'Ivoire.
In an open label, randomized controlled clinical trial, children and adults were randomized to receive AS-AQ or AL. Both drug regimens were given for three days, and follow-up was for 42 days. The primary endpoint was the 42-day cure rate and was defined as proportion of patients with PCR-corrected cure rate after 42 days of follow-up.
A total of 383 patients who were attending the Anonkoua-koute (Abidjan), Petit Paris (Korhogo) and Libreville (Man) hospitals and presenting with symptomatic acute uncomplicated falciparum malaria were randomized to receive AS-AQ (188) and AL (195). The intention-to-treat analysis showed effectiveness rates of 94.7% and 96.4% for AS-AQ and AL, respectively on day 42. After adjustment for PCR, these rates were 96.8% and 99%, respectively. At day 42, in per-protocol analysis, Adequate clinical and parasitological response (ACPR) PCR uncorrected was 97.8% and 97.4% for AS-AQ and AL, respectively. The PCR adjusted ACPR was 100% for each combination and both regimens were well tolerated.
This study has shown the high efficacy of AS-AQ in patients of all ages with acute uncomplicated falciparum malaria and AS-AQ was non-inferior to AL. Continuous efficacy monitoring is recommended.
... The fever and parasite clearance was obtained respectively at day 2 and day 3 after the initial dose. Similar results were obtained by Tine et al., Faye et al. in Senegal and Gbotosho et al. in Nigeria [13,14,28]. ...
... However abdominal pains were more frequent in patients treated with ASAQ, vomiting was more frequent in patients treated with DHAPQ and labial herpes was more frequent in AL group. Previous study demonstrated that these ACTs are well tolerated [13][14][15]. ...
Malaria remains a major public health problem in developing countries. Then in these countries prompt access to effective antimalarial treatment such as Artemisinin based-Combination Therapies (ACT) proves to be an essential tool for controlling the disease. In Senegal, since 2006 a nationwide scaling up program of ACT is being implemented. In this context it has become relevant to monitor ACT efficacy and provide recommendations for the Senegalese national malaria control program.
An open randomized trial was conducted during two malaria transmission seasons (2011 and 2012) to assess the efficacy and safety of three combinations: dihydro-artemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ). The primary end point of the study was represented by a PCR adjusted adequate clinical and parasitological response (ACPR) at day 28. Secondary end points included: (i) a ACPR at days 35 and 42, (ii) a parasite and fever clearance time, (iii) ACTs safety and tolerability. The 2003 WHO's protocol for antimalarial drug evaluation was used to assess each outcome.
Overall, 534 patients were randomized selected to receive, either ASAQ (n = 180), AL (n = 178) or DHAPQ (n = 176). The PCR adjusted ACPR at day 28 was 99.41% for the group ASAQ, while that was 100% in the AL and DHAPQ groups (p = 0.37). The therapeutic efficacy was evaluated at 99.37% in the ASAQ arm versus 100% in AL and DHAPQ arm at day 35 (p = 0.37). At day 42, the ACPR was 99.27% in the ASAQ group versus 100% for both AL and DHAPQ groups, (p = 0.36). No serious adverse event was noted during the study period. Also a similar safety profile was noted in the 3 study groups.
In the context of scaling up of ACTs in Senegal, ASAQ, AL and DHAPQ are highly effective and safe antimalarial drugs. However, it's remains important to continue to monitor their efficacy.Trial registration: PACTR 201305000552290.
... The combination has the advantage of once daily administration, thus increasing compliance. The results of this study are in line with the results obtained in Cameroon, Madagascar, Mali [13], Senegal [13,14], and Ivory Coast [14] and Myanmar [15]. A recent study carried out in Senegal has shown the utility of ASAQ in recurrent uncomplicated falciparum malaria [16] Currently, AS + SP has been recommended by the National Vector Borne Disease Control Programme in India. ...
... The combination has the advantage of once daily administration, thus increasing compliance. The results of this study are in line with the results obtained in Cameroon, Madagascar, Mali [13], Senegal [13,14], and Ivory Coast [14] and Myanmar [15]. A recent study carried out in Senegal has shown the utility of ASAQ in recurrent uncomplicated falciparum malaria [16] Currently, AS + SP has been recommended by the National Vector Borne Disease Control Programme in India. ...
Artemisinin-based combination therapy (ACT) has been recommended for the treatment of falciparum malaria by the World Health Organization. Though India has already switched to ACT for treating falciparum malaria, there is need to have multiple options of alternative forms of ACT. A randomized trial was conducted to assess the safety and efficacy of the fixed dose combination of artesunate-amodiaquine (ASAQ) and amodiaquine (AQ) for the treatment of uncomplicated falciparum malaria for the first time in India. The study sites are located in malaria-endemic, chloroquine-resistant areas.
This was an open label, randomized trial conducted at two sites in India from January 2007 to January 2008. Patients between six months and 60 years of age having Plasmodium falciparum mono-infection were randomly allocated to ASAQ and AQ arms. The primary endpoint was 28-day PCR-corrected parasitological cure rate.
Three hundred patients were enrolled at two participating centres, Ranchi, Jharkhand and Rourkela, Odisha. Two patients in AQ arm had early treatment failure while there was no early treatment failure in ASAQ arm. Late treatment failures were seen in 13 and 12 patients in ASAQ and AQ arms, respectively. The PCR-corrected cure rates in intent-to-treat population were 97.51% (94.6-99.1%) in ASAQ and 88.65% (81.3-93.9%) in AQ arms. In per-protocol population, they were 97.47% (94.2-99.2%) and 88.30% (80-94%) in ASAQ and AQ arms respectively. Seven serious adverse events (SAEs) were reported in five patients, of which two were reported as related to the treatment. All SAEs resolved without sequel.
The fixed dose combination of ASAQ was found to be efficacious and safe treatment for P. falciparum malaria. Amodiaquine also showed acceptable efficacy, making it a suitable partner of artesunate. The combination could prove to be a viable option in case India opts for fixed dose combination ACT. CLINICAL TRIAL REGISTRY: ISRCTN84408319.
... Studies were identified through a systematic review of the literature conducted in 2008 and contacting investigators who may be willing to contribute their data [12] . A few additional comparative trials for the treatment of acute falciparum malaria in Sub-Saharan Africa [11,22,23] could not be included. Ideally, a database to monitor safety should be established and constantly updated. ...
... Deviation of laboratory values from normality is graded according to widely accepted severity criteria [23] ; however , establishing causality (drug-event relationship) is often a challenge for physicians. The incidence of TEAEs was calculated in the subgroup of patients with values on both Day 0 and post-treatment follow-up through Day 28 (only Day 14 was available for platelets) and found no difference between treatments for neutropaenia , and thrombocytopaenic but a higher risk of TEAEs for anaemia with ACT than with non-artemisinin combinations. ...
Artesunate-amodiaquine (AS&AQ) is a widely used artemisinin combination therapy (ACT) for falciparum malaria. A comprehensive appreciation of its effects on haematology vs other anti-malarials is needed in view of potential safety liabilities.
Individual-patient data analysis conducted on a database from seven randomized controlled trials conducted in sub-Saharan African comparing AS&AQ to reference treatments in uncomplicated falciparum malaria patients of all ages. Haematologic values (white cells total and neutrophil counts, haemoglobin/haematocrit, platelets) were analysed as both continuous and categorical variables for their occurrence, (severity grade 1-4) and changes during follow-up. Risks and trends were calculated using multivariate logistic random effect models.
4,502 patients (72% < 5 years old), from 13 sites in nine countries with 28-day follow-up were treated with AS&AQ (45%) or a comparator (other forms of ACT accounted for 27%, other combination 12%, mono-therapies 16%). Pre-treatment leucopaenia (3%) and neutropaenia (6%) were infrequent; anaemia was common (39%). The treatment-emergent adverse events incidence (TEAE = condition not present or less severe pre-treatment) was 11% for neutropaenia, 6% for thrombocytopaenia with AS&AQ and not different from treatment groups; anaemia was higher with AS&AQ (20%) or other forms of ACT (22%) than in non-artemisinin groups (4%, p = 0.001). Multivariate analysis showed that the risk of anaemia, thrombocytopaenia, and leucopaenia decreased with follow-up time, while neutropaenia increased; the risk of anaemia and thrombocytopaenia increased with higher baseline parasitaemia and parasitological reappearance. White cells total count was not a good surrogate for neutropaenia. No systematic significant difference between treatments was detected. Older patients were at lower risks.
The effects of AS&AQ on haematologic parameters were not different from those of other anti-malarial treatments used in sub-Saharan Africa. This analysis provides the basis for a broader evaluation of haematology following anti-malarial treatment. Continuing monitoring of haematologic safety on larger databases is required.
... Our results are consistent with several studies showing good efficacy for ACTs against gametocytes. However in these studies a proportion of patients remained gametocyte-positive during 2 or 3 weeks after treatment (Alvarez et al., 2010;Bousema et al., 2010;Bukirwa and Critchley, 2006;Carmona-Fonseca et al., 2008;Chen et al., 1994;Faye et al., 2010;Osorio et al., 2007;Shekalaghe et al., 2007;Sinclair et al., 2009;Tangpukdee et al., 2008;Vasquez et al., 2009). The addition of a single dose of PQ to ACT results in better control of gametocytemia. ...
... The same criteria should be taken into account when evaluating the anti-gametocyte activity of any antimalarial, since transmission persists unless gametocyte control is achieved. For that reason, patients in this study were only followed until day 8 when the gametocytemia peak is expected, instead of the usual follow-up of 3 or 4 weeks (Alvarez et al., 2010;Arango et al., 2004;Bousema et al., 2010;Carmona-Fonseca et al., 2008;Faye et al., 2010;Mendez et al., 2002;Osorio et al., 2002Osorio et al., , 2007Shekalaghe et al., 2007;Sinclair et al., 2009;Tangpukdee et al., 2008;Vasquez et al., 2009). ...
This study compared the efficacy against Plasmodium falciparum gametocytes of four regimens: amodiaquine-sulfadoxine/pyrimethamine (AQ-SP) and mefloquine-artesunate (MQ-AS), with and without primaquine (PQ) administered with the second dose of the schizonticide (AQ-SP; AQ-SP-PQ; MQ-AS; MQ-AS-PQ). Efficacy was determined by thick smear on days 1, 4 and 8 after the beginning of treatment. A total of 82 patients (19-23/group) were recruited. After AQ-SP administration, gametocytemia steadily increased until day 8. With AQ-SP-PQ, a marked decline in gametocytemia was detected on days 4 and 8. MQ-AS treatment resulted in reduced gametocytemia on days 4 and 8, and with MQ-AS-PQ it was reduced even further. None of the treatments cleared gametocytemia by day 8. Currently, artemisinin-based combination therapies plus PQ are the recommended treatment option against falciparum malaria; however, further studies are required to optimize the use of PQ. Issues to be addressed include the optimal time of administration, treatment duration, optimal daily and total dose, and day of evaluation of the gametocytocidal effect. In falciparum malaria, the WHO recommends a maximum of 4days of treatment; consequently, an effective regimen must clear asexual parasites and symptoms within this time frame. The same criteria should be taken into account when evaluating the anti-gametocyte activity.
... For example, clinical trials have shown a lower risk of recurrent parasitemia after treatment with AL compared to ASAQ [26,30,31]. Similarly, most studies conducted elsewhere in Africa have shown similar results for AL and ASAQ [14,[32][33][34], although other studies conducted in West Africa have shown that ASAQ was more effective than AL [3]. ...
The combinations of artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) are used as first-line treatments for uncomplicated malaria in the Ivory Coast. Different studies document the efficacy of two artemisinin-based combination therapies (ACTs) (AL and ASAQ) in the Ivory Coast. However, there is no meta-analysis examining the data set of these studies. The purpose of this work was to determine the prevalence of malaria treatment failure cases in randomized control trials with two artemisinin-based combination therapies (AL versus ASAQ) in the Ivory Coast between 2009 to 2016. This study is a meta-analysis of data from the results of four previous multicenter, open-label, randomized clinical trial studies evaluating the clinical and parasitological efficacy of artemether-lumefantrine and artesunate-amodiaquine conducted between 2009 and 2016 following World Health Organization (WHO) protocol at sentinel sites in the Ivory Coast. These drug efficacy data collected between 2009 and 2016 were analyzed. During these studies, to distinguish between recrudescence and new infection, molecular genotyping of genes encoding merozoite surface protein 1 and 2 was carried out using nested polymerase chain reaction (PCR). A total of 1575 patients enrolled in the four studies, including 768 in the AL arm and 762 in the ASAQ arm, which were fully followed either for 28 days or 42 days according to WHO protocol. The adequate clinical and parasitological response (ACPR) was higher than 95% in the two groups (intention to treat (ITT): AL = 96.59% and ASAQ = 96.81; Per Protocol (PP): AL = 99.48% and ASAQ = 99.61%) after PCR correction at day 28. Aggregate data analysis (2009–2016) showed that at day 28, the proportions of patients with recurrent infection was higher in the AL group (ITT: 3.79%, PP: 3.9%) than in the ASAQ group (ITT: 2.17%, PP: 2.23%). After PCR correction, most treatment failures were classified as new infections (AL group (ITT: 0.13%, PP: 0.13%); ASAQ group (ITT: 0.39%, PP: 0.39%). The recrudescent infections rate was high, at 0.39% compared to 0.13% for ASAQ and AL, respectively, for both ITT and PP, no significant difference. However, the Kaplan–Meier curve of cumulative treatment success showed a significant difference between the two groups after PCR from 2012–2013 (p = 0.032). Overall, ASAQ and AL have been shown to be effective drugs for the treatment of uncomplicated P. falciparum malaria in the study areas, 14 years after deployment of these drugs.
... In 2006, Senegal introduced ACT (artemether-lumefantrine, AL, and artesunate-amodiaquine, ASAQ) as rst-line and dihydroartemisinin-piperaquine (DHA-PQ) as second-line in the treatment of uncomplicated P. falciparum malaria. To date, prompt management of the malaria cases using these antimalarial drugs have contributed signi cantly to a reduction in malaria-related morbidity and mortality 26 , con rming that AL, ASAQ and DHA-PQ remain effective and well tolerated in Senegal [27][28][29][30] . However, 1.2% of AL and 2.5% of DHA-PQ treatment failures have been reported in Senegal in 2020 31 . ...
Background
Over the last decades, Plasmodium falciparum – the main causative agent of malaria – has constantly developed resistance to antimalarial drugs such as chloroquine, sulfadoxine-pyrimethamine or artemisinin derivatives. Therefore, active surveillance in the ex vivo susceptibility to the antimalarial drugs used as partner drugs in artemisinin-based combination therapies (the current frontline antimalarial) such as amodiaquine, lumefantrine or piperaquine, is essential.
Methods
Here, we evaluated the ex vivo susceptibility, expressed with the ex vivo SYBR™ Green, to six antimalarial drugs (amodiaquine, chloroquine, lumefantrine, mefloquine, piperaquine and quinine) from 34 P. falciparum isolates collected in 2018 in Thiès (Senegal). Whole-genome sequencing (WGS) was used to search for mutations in P. falciparum genes known to be associated with drug resistance.
Results
P. falciparum isolates showed reduced ex vivo susceptibility only to chloroquine (16% of the isolates). Mutations in pfcrt K76T (21%) and pfmdr1 Y184F (53%) were the most prevalent. A significant correlation was observed between the mutants pfcrt 76T and pfmdr1 184F and IC50 values for chloroquine. A significant decrease in ex vivo susceptibility to chloroquine and quinine associated with the pfcrt R371I was also detected (P < 0.001).
Conclusion
Our results suggest that the ex vivo susceptibility of P. falciparum isolates to amodiaquine, lumefantrine, mefloquine, piperaquine and quinine remains high in Thiès. Directly measuring ex vivo parasite drug response and sequencing resistance mutations overtime are both useful tools for monitoring parasite drug response in field samples.
... It was noted for a considerable variation of prevalence rates of gametocyte carriages ranging from 3.5% to 77% in various reports as most were the analysis from post-treatment blood samples 30,[37][38][39] . With routine microscopy, the gametocyte-positive rate was lower than 50% of clinical [40][41][42][43][44][45][46] and asymptomatic 47-49 P. falciparum-infected cases. Low density, asymptomatic infections with Plasmodium spp. ...
Background&objectives: Changes in parasite biology, particularly the gametocytogenesis process, could be one of the important contributing factors for worldwide malaria resurgence. The present study investigated the prevalence rates of pretreatment gametocyte carriage and density in Plasmodium falciparum and P. vivax infections in the low malaria-endemic area on the Thai-Myanmar border.
Methods:
One hundred and twenty-six blood samples were collected from patients with signs and symptoms of malaria who attended malaria clinics. Malaria positive cases detected by microscopic examination were confirmed by species-specific nested-PCR in 97 (29 and 68 samples for P. falciparum and P. vivax, respectively).
Results:
The proportion of P. vivax and P. falciparum-infected samples was 70.1: 29.9%. The density in P. falciparum positive samples [median (95%CI): 10,340 (5280-19,200) μ/l] was significantly higher than P. vivax positive samples [4508 (3240-6120) μ/l]. Sixteen out of twenty-nine (55.2%) and 36 out of 68 (52.9%) P. falciparum- and P. vivax-infected samples, respectively, were gametocyte-positive. Gametocyte density in the P. falciparum-infected[124 (69-253) /μl] was significantly higher than that of the P. vivax-infected [54 (45-70)/μl] samples. A significant correlation between gametocyte density and pretreatment parasitemia was only detected in P. falciparum-infected, but not P. vivax-infected samples.
Interpretation & conclusion:
The observed high prevalence rates of pretreatment gametocyte carriage of both malaria species, which serves as a large malaria reservoir, particularly in P. falciparum infection, could have a significant impact on malaria control in the endemic populations.
... The first-line antimalarial drug should be changed if the proportion of total treatment failures after molecular correction is ≥ 10%, after monitoring (in vivo) for therapeutic efficacy [39]. A number of studies have evaluated the efficacy and safety of ACTs, particularly in sub-Saharan Africa, and report cure rates of more than 90% after molecular correction as recommended by WHO [99][100][101][102][103]. Other studies specific to Mali have shown that ASAQ, ASSP, ASMQ and AL are safe and efficacious, with corrected cure rates of more than 95% ...
The recommendation of artemisinin-based combination therapy (ACT) as a first line treatment of malaria continues to be based only on data obtained from single episode treatment rather than repetitive treatment. However, malaria episodes are frequent and there is thus a need to understand the long-term impact of repeated use of ACT to treat consecutive episodes of malaria over successive seasons. My study aimed to define the risk of parasite recurrence as a function of the pharmacokinetic and pharmacodynamic characteristics of ACT partner drugs in patients re-treated for multiple malaria episodes. Participants from Mali were randomized into three treatment arms: dihydroartemisinin-piperaquine (DHA-PPQ), pyronaridine-artesunate (PA), and first-line ACT (either artemether-lumefantrine [AL] or artesunate-amodiaquine [ASAQ]). Participants received the same ACT for each new episode of malaria for two years. Clinical and parasitological data were collected at each visit. Plasma samples were collected at day 7 of follow-up for quantification of drugs using high-performance liquid chromatography methods. In total, study participants experienced 5,260 episodes of malaria during the two-year follow-up period. Major findings were: i) accumulation of desethylamodiaquine (DEAQ), the main and active metabolite of amodiaquine (AQ), in the study population after early (between 25 to 45 days) retreatment with ASAQ; ii) no association of DEAQ concentration on day 7 with treatment outcome; iii) an association between day 7 lumefantrine concentrations and a reduced risk of re-infections within day 28 follow-up (hazard ratio, HR = 0.605, CI (0.50 – 0.74), p < 0.001). This protection of lumefantrine was concentration dependent; a concentration below a threshold of 380 ng/ml did not protect against subsequent re-infection by day 28. Importantly, the majority of the children under five years (84 out of 140; 60%) had lumefantrine day 7 concentrations (median (interquartile range): 305 ng/ml (207 – 490 ng/ml)) below this threshold. In conclusion, my results demonstrated an accumulation of DEAQ in the study population after early re-treatment with ASAQ, and suggest a need of lumefantrine dose optimisation in under five years age group. My analyses also showcase the value of re-treatment studies for improving treatment recommendations.
... This demonstrates that ACTs remains highly efficacious, more than ten years after their implementation, consistent with previous studies showing high cure rates and well tolerance of these drugs [17][18][19][20][21][22][23][24] . ...
In 2006, Senegal adopted artemisinin-based combination therapy (ACT) as first-line treatment in the management of uncomplicated malaria. This study aimed to update the status of antimalarial efficacy more than ten years after their first introduction. This was a randomized, three-arm, open-label study to evaluate the efficacy and safety of artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ) and dihydroartemisinin-piperaquine (DP) in Senegal. Malaria suspected patients were screened, enrolled, treated, and followed for 28 days for AL and ASAQ arms or 42 days for DP arm. Clinical and parasitological responses were assessed following antimalarial treatment. Genotyping (msp1, msp2 and 24 SNP-based barcode) were done to differentiate recrudescence from re-infection; in case of PCR-confirmed treatment failure, Pfk13 propeller and Pfcoronin genes were sequenced. Data was entered and analyzed using the WHO Excel-based application. A total of 496 patients were enrolled. In Diourbel, PCR non-corrected/corrected adequate clinical and parasitological responses (ACPR) was 100.0% in both the AL and ASAQ arms. In Kedougou, PCR corrected ACPR values were 98.8%, 100% and 97.6% in AL, ASAQ and DP arms respectively. No Pfk13 or Pfcoronin mutations associated with artemisinin resistance were found. This study showed that AL, ASAQ and DP remain efficacious and well-tolerated in the treatment of uncomplicated P. falciparum malaria in Senegal.
... Therefore, based on these data, the choice of the two artemisinin-based combinations as first-line treatment for uncomplicated P. falciparum malaria was appropriate in Burkina Faso. Efficacy of both treatment was evaluated in other sub-Saharan African countries and similar good efficacy were reported in west Africa [34][35][36][37][38], and in eastern Africa [11,39]. In the current study, both treatments were equally efficacious with however, most treatment failure observed in AL arm (8.9%). ...
Background:
Artemisinin-based combination therapy (ACT) is recommended to improve malaria treatment efficacy and limit drug-resistant parasites selection in malaria endemic areas. 5 years after they were adopted, the efficacy and safety of artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ), the first-line treatments for uncomplicated malaria were assessed in Burkina Faso.
Methods:
In total, 440 children with uncomplicated Plasmodium falciparum malaria were randomized to receive either AL or ASAQ for 3 days and were followed up weekly for 42 days. Blood samples were collected to investigate the ex vivo susceptibility of P. falciparum isolates to lumefantrine, dihydroartemisinin (the active metabolite of artemisinin derivatives) and monodesethylamodiaquine (the active metabolite of amodiaquine). The modified isotopic micro test technique was used to determine the 50% inhibitory concentration (IC50) values. Primary endpoints were the risks of treatment failure at days 42.
Results:
Out of the 440 patients enrolled, 420 (95.5%) completed the 42 days follow up. The results showed a significantly higher PCR unadjusted cure rate in ASAQ arm (71.0%) than that in the AL arm (49.8%) on day 42, and this trend was similar after correction by PCR, with ASAQ performing better (98.1%) than AL (91.1%). Overall adverse events incidence was low and not significantly different between the two treatment arms. Ex vivo results showed that 6.4% P. falciparum isolates were resistant to monodesthylamodiaquine. The coupled in vivo/ex vivo analysis showed increased IC50 values for lumefantrine and monodesethylamodiaquine at day of recurrent parasitaemia compared to baseline values while for artesunate, IC50 values remained stable at baseline and after treatment failure (p > 0.05).
Conclusion:
These findings provide substantial evidence that AL and ASAQ are highly efficacious for the treatment of uncomplicated malaria in children in Burkina Faso. However, the result of P. falciparum susceptibility to the partner drugs advocates the need to regularly replicate such surveillance studies. This would be particularly indicated when amodiaquine is associated in seasonal malaria chemoprophylaxis (SMC) mass drug administration in children under 5 years in Burkina Faso. Trial registration clinicaltrials, NCT00808951. Registered 05 December 2008,https://clinicaltrials.gov/ct2/show/NCT00808951?cond=NCT00808951&rank=1.
... Regarding biological aspects, mean haemoglobin concentration observed at day 28 post-treatment was increased in both groups but was statistically significantly higher in the AS-AQ group and not in the AL group. There are equivocal results from previous studies on the effect of ACT on post-treatment haemoglobin levels [30,[43][44][45]. ...
Background:
Malaria remains a major public health problem, affecting mainly low-and middle-income countries. The management of this parasitic disease is challenged by ever increasing drug resistance. This study, investigated the therapeutic efficacy, tolerability and safety of artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ), used as first-line drugs to treat uncomplicated malaria in Lambaréné, Gabon.
Methods:
A non-randomized clinical trial was conducted between October 2017 and March 2018 to assess safety, clinical and parasitological efficacy of fixed-doses of AL and AS-AQ administered to treat uncomplicated Plasmodium falciparum malaria in children aged from 6 months to 12 years. After 50 children were treated with AL, another 50 children received ASAQ. The 2009 World Health Organization protocol for monitoring of the efficacy of anti‑malarial drugs was followed. Molecular markers msp1 and msp2 were used to differentiate recrudescence and reinfection. For the investigation of artemisinin resistant markers, gene mutations in Pfk13 were screened.
Results:
Per-protocol analysis on day 28 showed a PCR corrected cure rate of 97% (95% CI 86-100) and 95% (95% CI 84-99) for AL and AS-AQ, respectively. The most frequent adverse event in both groups was asthenia. No mutations in the kelch-13 gene associated with artemisinin resistance were identified. All participants had completed microscopic parasite clearance by day 3 post-treatment.
Conclusion:
This study showed that AL and AS-AQ remain efficacious, well-tolerated, and are safe to treat uncomplicated malaria in children from Lambaréné. However, a regular monitoring of efficacy and a study of molecular markers of drug resistance to artemisinin in field isolates is essential. Trial registration ANZCTR, ACTRN12616001600437. Registered 18 November, http://www.anzctr.org.au/TrialSearch.aspx?searchTxt=ACTRN12616001600437p&isBasic=True.
... The reason for this difference is not clear, although increased plasma concentrations of the drugs might be achieved in children as a result of weight-based dosing; fixed doses are used in adults, including pregnant women, with little or no consideration for the pregnancy-induced changes in weight and plasma volume [18]. The present finding that adverse effects were more common with artesunate-amodiaquine than with artemether-lumefantrine is in line with previous studies [14,19,20]. However, weakness and pruritus were the only adverse effects encountered in the present study. ...
... Adverse events were reported in 15.4% of the participants with the most frequent being dizziness (12.5%) but didn't persist beyond day 14 of the follow-up. These events have also been reported in other studies [26,35,36]. ...
... This reveals that AL is highly effective in the treatment of uncomplicated P. falciparum malaria. Similar findings were reported by other studies conducted in different parts of the world [16,[53][54][55]. Studies conducted in East African countries also report a high efficacy of AL [56][57][58][59]. ...
Background:
As Ethiopia is one of the sub-Saharan countries with a great burden of malaria the effectiveness of first line anti-malarial drugs is the major concern. The aim of this study was to synthesize the available evidence on the efficacy of artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Ethiopia. This was done by performing a meta-analysis of recent studies conducted in the country on this topic.
Methods:
Studies published between January 2010 and January 2017 that reported on the efficacy of artemether-lumefantrine in the treatment of P. falciparum malaria in Ethiopian patients were searched for using the PubMed and Google Scholar databases. Ten prospective single-arm cohort studies that followed patients for 28-42 days were included in this analysis. All of the included studies were deemed to be of high quality.
Results:
Ten studies involving 1179 patients that were eligible for meta-analysis were identified. At recruitment, the average parasite count per patient was 1 2981/μl of blood. On the third day of treatment, 96.7% and 98.5% of the study subjects become fever-free and parasite-free, respectively. Based on the per protocol analysis, the cure rate after use of artemether-lumefantrine was 98.2% (polymerase chain reaction corrected) and 97.01% (polymerase chain reaction uncorrected) after 28 days of follow-up. The reinfection rate within 28 days was 1.1% and the recrudescence rate was 1.9%.
Conclusions:
This review found that the cure rate for uncomplicated P. falciparum malaria using artemether-lumefantrine in Ethiopia is still high enough to recommend the drug as a first-line agent. There should be careful periodic monitoring of the efficacy of this drug, as treatment failure may occur due to resistance, sub-therapeutic levels that may occur due to non-adherence, or inadequate absorption.
... However, other studies revealed no difference in fatigue between the AA and AL treatment groups. [34][35][36] In this study, most of the observed adverse effects were mild and well tolerated which is in keeping with other reports. According to Ndiaye et al, 37,38 dizziness and somnolence were the predominant neurological effects reported in the AA group which corroborates our findings. ...
A comparative clinical study was conducted to evaluate the safety and tolerability of two commonly used fixed dose artemisinin-based combinations for the treatment of uncomplicated Plasmodium falciparum malaria in the second and third trimester of pregnancy. To achieve this, a total of 155 participants were recruited for the study. Eighty of these were drawn from pregnant women who came for routine antenatal care while 40 nonpregnant participants were recruited from apparently healthy females in the community. Eighty pregnant participants with uncomplicated P. falciparum malaria were randomized into artesunate/amodiaquine (AA) and artemether/lumefantrine (AL) treatment arms while 40 nonpregnant and 35 nonmalarious pregnant women were used as control. The interventional groups received standard fixed dose combinations of AA (100/270 mg) daily or AL (20/120 mg) twice daily for 3 days. Blood samples were collected on day 4 and patients were followed-up closely to ascertain the safety of the drugs. The study showed a significant (p<0.0001) elevation of alkaline phosphatase in the AA and AL group compared to the nonpregnant control and a significant (p<0.05) elevation of alanine transaminase and aspartate transaminase level in the AL combination group when compared with the AA group. The elevated hepatic enzymes were within the normal range for pregnancy and were not clinically significant. Adverse event rate was higher in the AA group (n=28 [70%]) when compared to the AL group (n=4 [10%]) although the drugs were well-tolerated in both treatment arms. In conclusion, the use of these combinations is safe in the second and third trimester of pregnancy. However, we recommend active pharmacovigilance and spontaneous drug reporting of the agents in order to continuously monitor safety in the vastly heterogeneous population.
... Between 2004 and 2007, a fixed-dose, combined formulation containing artesunate (AS) and amodiaquine (AQ) in a single tablet, was developed by Sanofi in partnership with Drugs for Neglected Disease initiative (DNDi) (ASAQ Winthrop ® ) [3]. A large number of clinical trials [4] have shown that the ASAQ fixed-dose combination is effective in clearing Plasmodium falciparum parasites from infected individuals [5][6][7][8][9][10][11][12][13]. ...
Background
In many malaria-endemic, sub-Saharan African countries, existing pharmacovigilance systems are not sufficiently operational to document reliably the safety profile of anti-malarial drugs. This study describes the implantation of a community-based pharmacovigilance system in Côte d’Ivoire and its use to document the safety of ASAQ Winthrop® (artesunate–amodiaquine).
Methods
This prospective, longitudinal, descriptive, non-comparative, non-interventional study on the use of artesunate–amodiaquine in real-life conditions of use was conducted in seven Community Health Centres of the Agboville district in Côte d’Ivoire. Twenty trained Health Centre employees and 70 trained community health workers were involved in data collection in the field. All patients with suspected uncomplicated falciparum malaria, seeking treatment at one of the participating Health Centres, and treated with artesunate–amodiaquine could be enrolled. Two visits were planned, one for inclusion at the Health Centre and a second at home, performed by a community health worker 3–10 days after the inclusion visit. Administration of artesunate–amodiaquine was unsupervised. Adverse events (AEs) were documented at the home visit or during any unexpected visit to the Health Centre or to the hospital and coded and adjudicated by a local pharmacovigilance committee. Symptoms suggestive of hepatic failure, severe neutropaenia, extrapyramidal disorders and retinopathy were considered a priori as AEs of special interest.
Results
Some 15,228 malaria episodes in 12,198 patients were evaluated; 2545 AEs were documented during 1978 malaria episodes (13.0%). The most frequently observed events were asthenia (682 cases), vomiting (482 cases) and somnolence (174 cases). Most reported AEs were of mild or moderate intensity and resolved without corrective treatment. One-hundred and five (105) AEs reported during 100 episodes (0.7%) were considered as serious. Three serious cases of transient extrapyramidal disorders, identified as AEs of special interest were reported in three patients.
Conclusion
The fixed dose artesunate–amodiaquine combination ASAQ Winthrop® for the unsupervised treatment of uncomplicated falciparum malaria under real-life conditions of care in Côte d’Ivoire is well tolerated. The study emphasizes the interest of involving properly trained community health workers to collect pharmacovigilance data in the field in order to document rare AEs.
Electronic supplementary material
The online version of this article (doi:10.1186/s12936-016-1655-1) contains supplementary material, which is available to authorized users.
... ACT treatment failure of 0.9 % for AL was observed between 2004 and 2014 and it was 0.25 % for ASAQ treatment [2]. Previous studies showed that AL, DHAPQ and ASAQ are highly effective for the treatment of uncomplicated P. falciparum malaria in Senegal [31,32]. In Thiès (2012-2013) three recrudescent samples were observed and these did not reveal mutation in the K13 propeller region (Dieye et al. pers. ...
Background The use of artemisinin as a monotherapy resulted in the emergence of artemisinin resistance in 2005 in Southeast Asia. Monitoring of artemisinin combination therapy (ACT) is critical in order to detect and prevent the spread of resistance in endemic areas. Ex vivo studies and genotyping of molecular markers of resistance can be used as part of this routine monitoring strategy. One gene that has been associated in some ACT partner drug resistance is the Plasmodium falciparum multidrug resistance protein 1 (pfmdr1) gene. The purpose of this study was to assess the drug susceptibility of P. falciparum populations from Thiès, Senegal by ex vivo assay and typing molecular markers of resistance to drug components of ACT currently used for treatment. Methods The ex vivo susceptibility of 170 P. falciparum isolates to chloroquine, amodiaquine, lumefantrine, artesunate, and artemether was determined using the DAPI ex vivo assay. The high resolution melting technique was used to genotype the pfmdr1 gene at codons 86, 184 and 1246. ResultsA significant decrease in IC50 values was observed between 2012 and 2013: from 13.84 to 6.484 for amodiaquine, 173.4 to 113.2 for lumefantrine, and 39.72 to 18.29 for chloroquine, respectively. Increase of the wild haplotype NYD and the decrease of the mutant haplotype NFD (79 and 62.26 %) was also observed. A correlation was observed between the wild type allele Y184 in pfmdr1 and higher IC50 for all drugs, except amodiaquine. Conclusion
This study has shown an increase in sensitivity over the span of two transmission seasons, marked by an increase in the WT alleles at pfmdr1. Continuous the monitoring of the ACT used for treatment of uncomplicated malaria will be helpful.
... For example, studies from East African nations, where resistance to amodiaquine is common, suggest the superiority of AL (Table 3). On the other hand, reports from some West African nations (where amodiaquine resistance is low) indicated that ASAQ is noninferior to AL (Happi et al., 2006;Ndiaye et al., 2009;Faye et al., 2010). Such variation in response to a particular ACT has been reported even from the same country . ...
Malaria remains a disease of public health concern, which is associated with high mortality and morbidity, particularly in sub-Saharan Africa. This picture is mainly due to low effectiveness of antimalarials at the community level, a scenario caused by different factors related to the availability, quality, and efficacy of antimalarials as well as the degree of the patients' and providers' adherence to evidence-based recommendations about malaria treatment. This review presents an overview of the problem of low community effectiveness of antimalarials in sub-Saharan Africa, with a focus on the various causes as well as potential strategies to combat the problem.
... Moreover, a decrease in sensitivity of P. falciparum to AQ and SP in the country led to adoption of ACTs as the first line treatment for uncomplicated P. falciparum by the Ministry of Public Health since 2004 [28], with Artesunate-amodiaquine (AS/AQ) and artemether-lumefantrine (AL) currently recommended [29]. Although there have been previous reports on the efficacies of the AS/AQ combination and treatment failures in the center and northern regions of the country [28,30,31], studies in the southwestern region have been limited. There is therefore a need for routine monitoring of the efficacy of these antimalarials to identify and contain the spread of P. falciparum-resistant strains in regions where the disease is endemic. ...
Background:
The development and spread of antimalarial drug resistant parasites contributes to the global impact of the disease. In vivo efficacy assessments of treatments for Plasmodium falciparum malaria are essential for ensuring effective case management. Artemisinin-based combinations have been adopted as the first-line treatment for uncomplicated P. falciparum malaria in Cameroon since 2004.
Methods:
A total of 177 children aged six-months to 10 years with uncomplicated mono-infected falciparum malaria were randomized (1:1) to receive artesunate/sulphadoxine-pyrimethamine (AS/SP) or artesunate/amodiaquine (AS/AQ) pediatric tablets and followed up for 28 days according to the standard World Health Organization in vivo drug efficacy monitoring protocol. The primary and secondary endpoints were PCR uncorrected and corrected cure rates, as measured by adequate clinical and parasitological response (ACPR) on day 28.
Results:
The PCR corrected cure rate was high, overall (88.1%, 95% CI 83.1-93.1), 85.9% (95% CI 78.2-93.6), and 90.2% (95% CI 83.8-96.6) for AS/SP and AS/AQ, respectively. Twenty-one treatment failures were observed during follow-up, constituting one (4.6%), 14 (8.2%), and six (3.5%) early treatment failure (ETF), late clinical failure (LCF), and late parasitological failure (LPF), respectively. The drugs were well tolerated with no serious adverse events.
Conclusions:
Both AS/SP and AS/AQ are highly effective and well-tolerated treatments for uncomplicated P. falciparum malaria around the slope of Mount Cameroon.
... The reason for this difference is not clear, although increased plasma concentrations of the drugs might be achieved in children as a result of weight-based dosing; fixed doses are used in adults, including pregnant women, with little or no consideration for the pregnancy-induced changes in weight and plasma volume [18]. The present finding that adverse effects were more common with artesunate-amodiaquine than with artemether-lumefantrine is in line with previous studies [14,19,20]. However, weakness and pruritus were the only adverse effects encountered in the present study. ...
To compare the artesunate-amodiaquine and artemether-lumefantrine combinations in the treatment of acute uncomplicated falciparum malaria during pregnancy.
Between January and July, 2013, a double-blind randomized trial was undertaken of symptomatic pregnant women (second/third trimester) with malaria parasitemia who attended a center in Ile-Ife, Nigeria. Participants were assigned to receive artesunate-amodiaquine or artemether-lumefantrine (twice daily on days 1-3) according to a computer-generated randomization sequence. Participants and investigators were masked to group allocation. Clinical evaluations and malaria parasite counts were performed at baseline and on days 2, 3, 7, and 28. Mean interval to symptomatic relief, day-3 parasite clearance, day-28 cure rate, and adverse effects were assessed.
Of 75 women assigned to each group, 65 in the artesunate-amodiaquine group and 71 in the artemether-lumefantrine group completed the study. No significant differences between the artesunate-amodiaquine and artemether-lumefantrine groups were recorded for mean interval to symptomatic relief (2.2±1.0days vs 2.0±0.8days; P=0.090), day-3 parasite clearance (58/65 [89.2%] vs 66/71 [93.0%]; P=0.444), and day-28 cure rate (64/65 [98.5%] vs 67/71 [94.4%]; P=0.138). Adverse effects (body weakness and pruritus) were more common among women assigned to artesunate-amodiaquine (30/75 [40.0%]) than among those assigned to artemether-lumefantrine (2/75 [2.7%]; P<0.001).
Efficacies of the regimens are similar among pregnant women. However, adverse effects are more common with artesunate-amodiaquine. Pan-African Clinical Trial Registry: PACTR201310000484185.
Copyright © 2015. Published by Elsevier Ireland Ltd.
... Admittedly, the few studies that reported safety profile in the present review (e.g., only one study reported safety data on AS + AQ while the rest reported AL safety) would not enable a firm comparison of safety of different anti-malarials. However, other studies in Africa have shown that certain mild or moderate adverse events, such as vomiting and anaemia, were more frequent in patients treated with AS + AQ than those treated with AL [70,71]. This review has shown that respiratory infection, including cough, was the most frequent adverse event in children treated with AL. ...
Prompt diagnosis and effective treatment are considered the cornerstones of malaria control and artemisinin-based combination therapy (ACT) is currently the main anti-malarial drugs used for case management. After deployment of ACT due to widespread parasite resistance to the cheap and widely used anti-malarial drugs, chloroquine and sulphadoxine/pyrimethamine, the World Health Organization recommends regular surveillance to monitor the efficacy of the new drugs. The present paper assessed the implementation of anti-malarial efficacy testing for monitoring the therapeutic efficacy of ACT for treatment of uncomplicated malaria in Tanzania before and after policy changes in 2006.
A literature search was performed for published clinical trials conducted in Tanzania from 2001 to 2014. It focused on studies which assessed at least one form of ACT for treatment of uncomplicated falciparum malaria in children less than 10 years and reported efficacy and safety of the tested anti-malarials. References were imported into the Endnote library and duplicates removed. An electronic matrix was developed in Microsoft Excel followed by full text review with predetermined criteria. Studies were independently assessed and information related to ACT efficacy and safety extracted.
Nine papers were selected from 125 papers screened. The efficacy of both artemether-lumefantrine (AL) and artesunate-amodiaquine (AS + AQ) against uncomplicated P. falciparum infections in Tanzania was high with PCR-corrected cure rates on day 28 of 91-100% and 88-93.8%, respectively. The highest day-3 parasite positivity rate was 1.4%. Adverse events ranged from mild to serious but were not directly attributed to the drugs.
ACT is efficacious and safe for treatment of uncomplicated malaria in Tanzania. However, few trials were conducted in Tanzania before and after policy changes in 2006 and thus more surveillance should be urgently undertaken to detect future changes in parasite sensitivity to ACT.
... 44 The significantly lower prevalence of anemia post-treatment compared with pretreatment, and the similar anemia recovery times in both artesunate-amodiaquine-and artemetherlumefantrine-treated children suggest that both regimens are equivalent in their effects on malaria-associated anemia in children. However, in other studies, anemia has been shown to be more frequent and the average rate of hemoglobin 7 days after treatment began, lower in patients treated with artesunate-amodiaquine compared with those treated with artemether-lumefantrine. 46 Additionally, Zwang and others 47 have shown that the proportion of patients recovering from anemia 28 days after treatment began was significantly lower in patients treated with artesunate-amodiaquine compared with amodiaquine alone. The reasons for the significantly increased anemia recovery time in patients with parasitemia in excess of 50,000/μL of blood compared with those with parasitemia 50,000/μL of blood who were treated with artesunate-amodiaquine are not immediately apparent in this cohort of children. ...
The efficacy of 3-day regimens of artemether-lumefantrine and artesunate-amodiaquine were evaluated in 747 children < 5 years of age with uncomplicated malaria from six geographical areas of Nigeria. Fever clearance was significantly faster (P = 0.006) and the proportion of children with parasitemia 1 day after treatment began was significantly lower (P = 0.016) in artesunate-amodiaquine-compared with artemether-lumefantrine-treated children. Parasite clearance times were similar with both treatments. Overall efficacy was 96.3% (95% confidence interval [CI] 94.5-97.6%), and was similar for both regimens. Polymerase chain reaction-corrected parasitologic cure rates on Day 28 were 96.9% (95% CI 93.9-98.2%) and 98.3% (95% CI 96.1-99.3%) for artemether-lumefantrine and artesunate-amodiaquine, respectively. Gametocyte carriage post treatment was significantly lower than pretreatment (P < 0.0001). In anemic children, mean time to recovery from anemia was 10 days (95% CI 9.04-10.9) and was similar for both regimens. Both treatments were well tolerated and are safe and efficacious treatments of uncomplicated falciparum malaria in young Nigerian children.
... Safety concerns associated with the use of AA is the possible reason for this, in addition to availability of a wide range of other ACT. AA has been associated with varying degrees of sideeffects, which have limited its use, especially in adult patients [21][22][23]. The preference for AL may reflect expectation of efficacy and/or safety in the study environment. ...
Background
Malaria treatment policy recommends regular monitoring of drug utilization to generate information for ensuring effective use of anti-malarial drugs in Nigeria. This information is currently limited in the retail sector which constitutes a major source of malaria treatment in Nigeria, but are characterized by significant inappropriate use of drugs. This study analyzed the use pattern of anti-malarial drugs in medicine outlets to assess the current state of compliance to policy on the use of artemisinin-based combination therapy (ACT).
Methods
A prospective cross-sectional survey of randomly selected medicine outlets in Enugu urban, southeast Nigeria, was conducted between May and August 2013, to determine the types, range, prices, and use pattern of anti-malarial drugs dispensed from pharmacies and patent medicine vendors (PMVs). Data were collected and analyzed for anti-malarial drugs dispensed for self-medication to patients, treatment by retail outlets and prescription from hospitals.
Results
A total of 1,321 anti-malarial drugs prescriptions were analyzed. ACT accounted for 72.7%, while monotherapy was 27.3%. Affordable Medicines Facility-malaria (AMFm) drugs contributed 33.9% (326/961) of ACT. Artemether-lumefantrine (AL), 668 (50.6%) was the most used anti-malarial drug, followed by monotherapy sulphadoxine-pyrimethamine (SP), 248 (18.8%). Median cost of ACT at $2.91 ($0.65-7.42) per dose, is about three times the median cost of monotherapy, $0.97 ($0.19-13.55). Total cost of medication (including co-medications) with ACT averaged $3.64 (95% CI; $3.53-3.75) per prescription, about twice the mean cost of treatment with monotherapy, $1.83 (95% CI; $1.57-2.1). Highest proportion 46.5% (614), of the anti-malarial drugs was dispensed to patients for self-treatment. Treatment by retail outlets accounted for 35.8% while 17.7% of the drugs were dispensed from hospital prescriptions. Self-medication, 82%, accounted for the highest source of monotherapy and a majority of prescriptions, 85.6%, was adults.
Conclusion
Findings suggest vastly improved use of ACT in the retail sector after eight years of policy change, with significant contributions from AMFm drugs. However the use of monotherapy, particularly through self-medication remains significant with increasing risk of undermining treatment policy, suggesting additional measures to directly target consumers and providers in the sector for improved use of anti-malarial drugs in Nigeria.
... Overall, the study showed a high efficacy of the two forms of ACTs in Nigerian children; the PCR-adjusted cure rate on day 28 was 100% in both treatment groups. These results are in agreement with earlier studies in Nigeria that have shown both combinations to be safe and well tolerated [7,8,17] and are also consistent with the high cure rates that have been reported for ACT in other malaria-endemic areas of Africa [18][19][20]. Artemisinin and related endo-peroxide antimalarials act rapidly by clearing P. falciparum in the blood, thereby providing prompt therapy for severe infections [21]. Moreover, artemisinins are also active against parasites resistant to two major classes of antimalarials, quinolines and antifolates, thereby making them the most potent and effective antimalarials presently used [22]. ...
The development and spread of Plasmodium falciparum resistance to most commonly used antimalarials remain a major challenge in the control of malaria. Constant monitoring of drug efficacy is an important tool in establishing rational antimalarial drug policies.
A randomized comparative study was conducted at the Wesley Guild Hospital, Ilesa, Nigeria between February 2010 and September 2011 comparing the efficacy and safety of artemether-lumefantrine (Coartem) and fixed dose of artesunate plus amodiaquine (Larimal) in the treatment of uncomplicated P. falciparum malaria in children betweem 6 and 144 months of age. P. falciparum malaria parasitemia was assessed by microscopy and rapid diagnostic test. Drugs were administered according to age for three days under supervision. The primary efficacy endpoint was a day 28 PCR-corrected parasitological cure.
A total of 182 patients were enrolled in the two treatment groups, Coartem (n = 101) and Larimal (n = 81), and tested after 28 days. In the intention-to-treat population, Coartem (n = 101) and Larimal (n = 81) had a PCR-corrected cure rate of 98% and 100% respectively, while in the per-protocol population, Coartem (n = 89) and Larimal (n = 71) both had a PCR-corrected cure rate of 100% at day 28. Although parasite and fever clearance time was faster in the Larimal group, no significant difference was observed between the two drugs. No serious adverse effects were reported.
Five years after being introduced in Nigeria, both Coartem and Larimal have been shown to be safe and highly effective in the treatment of uncomplicated P. falciparum malaria in children.
... Notably however, anecdotal reports suggested that the prescription of AS + AQ loose dose provided the opportunity to disregard the amodiaquine compound, referring to patients' and providers' concern on tolerability related to prescriptions of higher dose amodiaquine monotherapy in the past [21]. The present findings were also in line with efficacy results recently reported for ASAQ FDC and AL in Western-, Centraland Southern African regions or India6789222324 . A recent study also demonstrated good effectiveness of both ASAQ FDC and AL among children ≤ 5 years following unobserved treatment in Benin [25]. ...
Prospective efficacy monitoring of anti-malarial treatments is imperative for timely detection of resistance development. The in vivo efficacy of artesunate-amodiaquine (ASAQ) fixed-dose combination (FDC) was compared to that of artemether-lumefantrine (AL) among children aged six to 59 months in Nimba County, Liberia, where Plasmodium falciparum malaria is endemic and efficacy data are scarce.
An open-label, randomized controlled non-inferiority trial compared the genotyping adjusted day 42 cure rates of ASAQ FDC (ASAQ Winthrop(R)) to AL (Coartem(R)) in 300 children aged six to 59 months with uncomplicated falciparum malaria. Inclusion was between December 2008 and May 2009. Randomization (1:1) was to a three-day observed oral regimen (ASAQ: once a day; AL: twice a day, given with fatty food). Day 7 desethylamodiaquine and lumefantrine blood-concentrations were also measured.
The day 42 genotyping-adjusted cure rate estimates were 97.3% [95%CI: 91.6-99.1] for ASAQ and 94.2% [88.1-97.2] for AL (Kaplan-Meier (KM) survival estimates). The difference in day 42 cure rates was -3.1% [upper limit 95%CI: 1.2%]. These results were confirmed by observed proportion of patients cured at day 42 on the per-protocol population. Parasite clearance was 100% (ASAQ) and 99.3% (AL) on day 3. The probability to remain free of re-infection was 0.55 (95%CI 0.46-0.63) (ASAQ) and 0.66 (0.57-0.73) (AL) (p = 0.017).
Both ASAQ and AL were highly efficacious and ASAQ was non-inferior to AL. The proportion of patients with re-infection was high in both arms in this highly endemic setting. In 2010, ASAQ FDC was adopted as the first-line national treatment in Liberia. Continuous efficacy monitoring is recommended.Trial registration: The protocols were registered with Current Controlled Trials, under the identifier numbers ISRCTN51688713, ISRCTN40020296 (http://www.controlled-trials.com).
... There is significant interest in understanding the impact of different malaria control interventions, including treatment with artemisininbased combination therapies (ACTs) and chemoprevention regimens, on the development of gametocytes and their potential impact on malaria transmission. 1 ACTs have been shown to be highly efficacious against asexual parasites, [2][3][4][5][6] and several have been shown to be moderately effective against the gametocyte stage of infection and reduce transmission to mosquitoes. [7][8][9][10] However, data comparing the effect of two leading ACTs in Africa-artemether-lumefantrine (AL) and dihyroartemesinin-piperaquine (DP)-on gametocytes have been mixed. ...
Artemisinin-based combination therapies (ACTs) and trimethoprim-sulfamethoxazole (TS) prophylaxis are important tools for malaria control, but there are concerns about their effect on gametocytes, the stage of the parasite responsible for transmission. We conducted a longitudinal clinical trial in a cohort of HIV-infected and uninfected children living in an area of high malaria transmission intensity in Uganda. Study participants were randomized to artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) for all treatments of uncomplicated malaria (N = 4,380) as well as TS prophylaxis for different durations. The risks of gametocytemia detected by microscopy in the 28 days after antimalarial therapy were compared using multivariate analyses. The risk of gametocyte detection was significantly higher in patients treated with DP compared with AL (adjusted relative risk = 1.85, P < 0.001) and among children prescribed TS prophylaxis (adjusted relative risk = 1.76, P < 0.001). The risk of gametocytemia and its potential for increasing transmission should be considered when evaluating different ACTs and TS prophylaxis for malaria control.
... In 1996, 6% of isolates from Dielmo were resistant in vitro to lumefantrine [69]. In recent years, the efficacy of artemether-lumefantrine in several trials in Senegal has ranged from 96 to 100%707172. The prevalences of the Pfmdr1 mutations 86Y and 184F were 16.6% and 67.6%, respectively. ...
As a result of the widespread resistance to chloroquine and sulphadoxine-pyrimethamine, artemisinin-based combination therapy (ACT) (including artemether-lumefantrine and artesunate-amodiaquine) has been recommended as a first-line anti-malarial regimen in Senegal since 2006. Intermittent preventive treatments with anti-malarial drugs based on sulphadoxine-pyrimethamine are also given to children or pregnant women once per month during the transmission season. Since 2006, there have been very few reports on the susceptibility of Plasmodium falciparum to anti-malarial drugs. To estimate the prevalence of resistance to several anti-malarial drugs since the introduction of the widespread use of ACT, the presence of molecular markers associated with resistance to chloroquine and sulphadoxine-pyrimethamine was assessed in local isolates at the military hospital of Dakar.
The prevalence of genetic polymorphisms in genes associated with anti-malarial drug resistance, i.e., Pfcrt, Pfdhfr, Pfdhps and Pfmdr1, and the copy number of Pfmdr1 were evaluated for a panel of 174 isolates collected from patients recruited at the military hospital of Dakar from 14 October 2009 to 19 January 2010.
The Pfcrt 76T mutation was identified in 37.2% of the samples. The Pfmdr1 86Y and 184F mutations were found in 16.6% and 67.6% of the tested samples, respectively. Twenty-eight of the 29 isolates with the 86Y mutation were also mutated at codon 184. Only one isolate (0.6%) had two copies of Pfmdr1. The Pfdhfr 108N/T, 51I and 59R mutations were identified in 82.4%, 83.5% and 74.1% of the samples, respectively. The double mutant (108N and 51I) was detected in 83.5% of the isolates, and the triple mutant (108N, 51I and 59R) was detected in 75.3%. The Pfdhps 437G, 436F/A and 613S mutations were found in 40.2%, 35.1% and 1.8% of the samples, respectively. There was no double mutant (437G and 540E) or no quintuple mutant (Pfdhfr 108N, 51I and 59R and Pfdhps 437G and 540E). The prevalence of the quadruple mutant (Pfdhfr 108N, 51I and 59R and Pfdhps 437G) was 36.5%.
Since 2004, the prevalence of chloroquine resistance had decreased. The prevalence of isolates with high-level pyrimethamine resistance is 83.5%. The prevalence of isolates resistant to sulphadoxine is 40.2%. However, no quintuple mutant (Pfdhfr 108N, 51I and 59R and Pfdhps 437G and 540E), which is associated with a high level of sulphadoxine-pyrimethamine resistance, has been identified to date. The resistance to amodiaquine remains moderate.
Background
Plasmodium falciparum malaria is associated with anaemia-related morbidity, attributable to host, parasite and drug factors. We quantified the haematological response following treatment of uncomplicated P. falciparum malaria to identify the factors associated with malarial anaemia.
Methods
Individual patient data from eligible antimalarial efficacy studies of uncomplicated P. falciparum malaria, available through the WorldWide Antimalarial Resistance Network data repository prior to August 2015, were pooled using standardised methodology. The haematological response over time was quantified using a multivariable linear mixed effects model with nonlinear terms for time, and the model was then used to estimate the mean haemoglobin at day of nadir and day 7. Multivariable logistic regression quantified risk factors for moderately severe anaemia (haemoglobin < 7 g/dL) at day 0, day 3 and day 7 as well as a fractional fall ≥ 25% at day 3 and day 7.
Results
A total of 70,226 patients, recruited into 200 studies between 1991 and 2013, were included in the analysis: 50,859 (72.4%) enrolled in Africa, 18,451 (26.3%) in Asia and 916 (1.3%) in South America. The median haemoglobin concentration at presentation was 9.9 g/dL (range 5.0–19.7 g/dL) in Africa, 11.6 g/dL (range 5.0–20.0 g/dL) in Asia and 12.3 g/dL (range 6.9–17.9 g/dL) in South America. Moderately severe anaemia (Hb < 7g/dl) was present in 8.4% (4284/50,859) of patients from Africa, 3.3% (606/18,451) from Asia and 0.1% (1/916) from South America. The nadir haemoglobin occurred on day 2 post treatment with a mean fall from baseline of 0.57 g/dL in Africa and 1.13 g/dL in Asia. Independent risk factors for moderately severe anaemia on day 7, in both Africa and Asia, included moderately severe anaemia at baseline (adjusted odds ratio (AOR) = 16.10 and AOR = 23.00, respectively), young age (age < 1 compared to ≥ 12 years AOR = 12.81 and AOR = 6.79, respectively), high parasitaemia (AOR = 1.78 and AOR = 1.58, respectively) and delayed parasite clearance (AOR = 2.44 and AOR = 2.59, respectively). In Asia, patients treated with an artemisinin-based regimen were at significantly greater risk of moderately severe anaemia on day 7 compared to those treated with a non-artemisinin-based regimen (AOR = 2.06 [95%CI 1.39–3.05], p < 0.001).
Conclusions
In patients with uncomplicated P. falciparum malaria, the nadir haemoglobin occurs 2 days after starting treatment. Although artemisinin-based treatments increase the rate of parasite clearance, in Asia they are associated with a greater risk of anaemia during recovery.
Rationale
High mass and high spatial resolution MALDI imaging mass spectrometry (IMS) opens new possibilities for the detailed study of the hepatic metabolism of drugs. The spatial and temporal distribution of drug metabolites within liver lobules, anatomical subunits of the liver, may aid in the understanding of the formation of reactive metabolites that bind to liver proteins and cause drug‐induced liver injury.
Methods
Frozen livers obtained from rats dosed orally with amodiaquine (100 mg/kg) were sectioned at 10 μm and coated with a MALDI matrix. The liver sections were then analyzed using a Fourier transform ion cyclotron resonance mass spectrometer. Images corresponding to amodiaquine and its metabolites were obtained at a spatial resolution of 25 μm.
Results
Molecular images of amodiaquine within liver lobules have higher intensities nearer the portal triad and lower intensities near the central vein.
Conclusions
This study demonstrates that MALDI imaging MS can be used to investigate the metabolism of drugs within liver lobules. The results are consistent with existing knowledge of amodiaquine metabolism and reactive metabolite formation.
Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria. Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites. Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites. There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.
The development of artemisinin resistance in the Greater Mekong Subregion poses a significant threat to malaria elimination. Artemisinin-based combination therapies including artemether-lumefantrine (AL) are recommended by WHO as first-line treatment for uncomplicated Plasmodium falciparum malaria. This article provides a comprehensive review of the existing and latest data as a basis for interpretation of observed variability in parasite sensitivity to AL over the last 5 years. Clinical efficacy and preclinical data from a range of endemic countries are summarized, including potential molecular markers of resistance. Overall, AL remains effective in the treatment of uncomplicated P. falciparum malaria in most regions. Establishing validated molecular markers for resistance and strict efficacy monitoring will reinforce timely updates of treatment policies.
Background:
Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination
therapies (ACTs) to t
reat uncomplicated
Plasmodium falciparum
malaria in Africa. We investigated the impact of
different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria.
Methods:
Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance
Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression
model with shared frailty across study sites.
Results:
Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%)
treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with
anon-fixeddosecombinationwithanAQtargetdos
e of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a
non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%)
with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median
dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated
with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25
(median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg
[IQR: 27-39.0]. After adjusting for rei
nfections, the corrected antimalarial efficacy on day 28 after treatment
was similar for co-blistered NFDC (97.9% [95% confiden
ce interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI:
97.6%-98.5%];
P
= 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30
(95.0% [95% CI: 94.1%-95.9%]) (
P
< 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and
region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted
hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12],
P
< 0.001) compared to FDC, and treatment with loose NFDC-30 was
associated with a higher risk of recrudescence at only three sites.
Conclusions:
There was substantial variation in the total dose of amodiaquine administered in different AS-AQ
combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial
treatment efficacy than the loose individual tablets in all age categories.
Background:
Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria.
Methods:
Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites.
Results:
Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites.
Conclusions:
There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.
4-(tert-Butyl)-2-((tert-butylamino)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-phenol (JPC-2997) is a new aminomethylphenol compound that is highly
active in vitro against the chloroquine-sensitive D6, the chloroquine-resistant W2, and the multidrug-resistant TM90-C2B Plasmodium falciparum lines, with 50% inhibitory concentrations (IC50s) ranging from 7 nM to 34 nM. JPC-2997 is >2,500 times less cytotoxic (IC50s > 35 μM) to human (HepG2 and HEK293) and rodent (BHK) cell lines than the D6 parasite line. In comparison to the chemically
related WR-194,965, a drug that had advanced to clinical studies, JPC-2997 was 2-fold more active in vitro against P. falciparum lines and 3-fold less cytotoxic. The compound possesses potent in vivo suppression activity against Plasmodium berghei, with a 50% effective dose (ED50) of 0.5 mg/kg of body weight/day following oral dosing in the Peters 4-day test. The radical curative dose of JPC-2997 was
remarkably low, at a total dose of 24 mg/kg, using the modified Thompson test. JPC-2997 was effective in curing three Aotus monkeys infected with a chloroquine- and pyrimethamine-resistant strain of Plasmodium vivax at a dose of 20 mg/kg daily for 3 days. At the doses administered, JPC-2997 appeared to be well tolerated in mice and monkeys.
Preliminary studies of JPC-2997 in mice show linear pharmacokinetics over the range 2.5 to 40 mg/kg, a low clearance of 0.22
liters/h/kg, a volume of distribution of 15.6 liters/kg, and an elimination half-life of 49.8 h. The high in vivo potency data and lengthy elimination half-life of JPC-2997 suggest that it is worthy of further preclinical assessment as
a partner drug.
Background: Artemisinin-based combination therapies (ACTs) are the mainstay for the management of uncomplicated
malaria cases. However, up-to-date data able to assist sub-Saharan African countries formulating appropriate antimalarial
drug policies are scarce.
Methods and Findings: Between 9 July 2007 and 19 June 2009, a randomized, non-inferiority (10% difference threshold in
efficacy at day 28) clinical trial was carried out at 12 sites in seven sub-Saharan African countries. Each site compared three
of four ACTs, namely amodiaquine-artesunate (ASAQ), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine
(AL), or chlorproguanil-dapsone-artesunate (CD+A). Overall, 4,116 children 6–59 mo old with uncomplicated Plasmodium
falciparum malaria were treated (1,226 with AL, 1,002 with ASAQ, 413 with CD+A, and 1,475 with DHAPQ), actively followed
up until day 28, and then passively followed up for the next 6 mo. At day 28, for the PCR-adjusted efficacy, non-inferiority
was established for three pair-wise comparisons: DHAPQ (97.3%) versus AL (95.5%) (odds ratio [OR]: 0.59, 95% CI: 0.37–0.94);
DHAPQ (97.6%) versus ASAQ (96.8%) (OR: 0.74, 95% CI: 0.41–1.34), and ASAQ (97.1%) versus AL (94.4%) (OR: 0.50, 95% CI:
0.28–0.92). For the PCR-unadjusted efficacy, AL was significantly less efficacious than DHAPQ (72.7% versus 89.5%) (OR: 0.27,
95% CI: 0.21–0.34) and ASAQ (66.2% versus 80.4%) (OR: 0.40, 95% CI: 0.30–0.53), while DHAPQ (92.2%) had higher efficacy
than ASAQ (80.8%) but non-inferiority could not be excluded (OR: 0.35, 95% CI: 0.26–0.48). CD+A was significantly less
efficacious than the other three treatments. Day 63 results were similar to those observed at day 28.
Conclusions: This large head-to-head comparison of most currently available ACTs in sub-Saharan Africa showed that AL,
ASAQ, and DHAPQ had excellent efficacy, up to day 63 post-treatment. The risk of recurrent infections was significantly
lower for DHAPQ, followed by ASAQ and then AL, supporting the recent recommendation of considering DHAPQ as a valid
option for the treatment of uncomplicated P. falciparum malaria.
Trial Registration: ClinicalTrials.gov NCT00393679; Pan African Clinical Trials Registry PACTR2009010000911750
The adoption of artemisinin-based combination therapy, together with other malaria control strategies, has played a significant role in reducing the burden of malaria in many endemic countries. The artemisinin-based combination therapy artemether-lumefantrine (AL; Coartem(®), Novartis Pharma AG, Basel, Switzerland) has demonstrated consistently high efficacy and safety for over a decade. Currently deployed as a first- or second-line treatment in most sub-Saharan African countries, its extensive use is endorsed by a lack of reported parasite resistance in Africa to date. With a focus on patient needs, AL offers a tailored formulation for infants and children, and packaging solutions to promote adherence. Working towards malaria elimination, innovative strategies using AL, such as treatment of asymptomatic carriers, will be of interest. AL has the potential to continue playing an important role in saving lives.
To review the pharmacology, pharmacokinetics, safety, and efficacy of artemether-lumefantrine for the treatment of Plasmodium falciparum malaria.
English-language articles indexed in PubMed (1947-November 2011) were identified, using the search terms artemether-lumefantrine, artemether-lumefantrine AND malaria, Coartem, and Coartem AND malaria.
Available English-language articles were reviewed. In addition, the malaria treatment regimens recommended by region as provided by the World Health Organization and the treatment guidelines from the Centers for Disease Control and Prevention were reviewed.
Artemether-lumefantrine is an artemisinin-derived combination antimalarial approved by the Food and Drug Administration in 2009 for the treatment of P. falciparum malaria. The dual mechanisms of action of artemether-lumefantrine provide rapid and sustained parasite clearance. In the reviewed studies, the polymerase chain reaction (PCR)-corrected 28-day cure rates of artemether-lumefantrine were noninferior to the most common comparators, including chloroquine, dapsone, and other artemisinin derivatives (86-100% vs 51-100%, respectively). PCR-corrected day-42 cure rates were 92-99.3% for artemether-lumefantrine versus 62-100% for the comparator groups. The major adverse effects (gastrointestinal and central nervous system) were mild to moderate in severity and did not require a change in therapy. Although adherence to artemether-lumefantrine has been described as a potential problem due to the complicated dosing schedule, studies have described clinical cure rates similar to those of other antimalarials.
Artemether-lumefantrine is a safe and effective treatment for children and adults with P. falciparum malaria.
Artesunate (AS) plus amodiaquine (AQ) is one artemisinin-based combination (ACT) recommended by the WHO for treating Plasmodium falciparum malaria. Fixed-dose AS/AQ is new, but its safety and efficacy are hitherto untested.
A randomized, open-label trial was conducted comparing the efficacy (non-inferiority design) and safety of fixed (F) dose AS (25 mg)/AQ (67.5 mg) to loose (L) AS (50 mg) + AQ (153 mg) in 750, P. falciparum-infected children from Burkina Faso aged 6 months to 5 years. Dosing was by age. Primary efficacy endpoint was Day (D) 28, PCR-corrected, parasitological cure rate. Recipients of rescue treatment were counted as failures and new infections as cured. Documented, common toxicity criteria (CTC) graded adverse events (AEs) defined safety.
Recruited and evaluable children numbered 750 (375/arm) and 682 (90.9%), respectively. There were 8 (AS/AQ) and 6 (AS+AQ) early treatment failures and one D7 failure (AS+AQ). Sixteen (AS/AQ) and 12 (AS+AQ) patients had recurrent parasitaemia (PCR new infections 10 and 6, respectively). Fourteen patients per arm required rescue treatment for vomiting/spitting out study drugs. Efficacy rates were 92.1% in both arms: AS/AQ = 315/342 (95% CI: 88.7-94.7) vs. AS+AQ = 313/340 (95% CI: 88.6-94.7). Non-inferiority was demonstrated at two-sided alpha = 0.05: Delta (AS+AQ - AS/AQ) = 0.0% (95% CI: -4.1% to 4.0%). D28, Kaplan Meier PCR-corrected cure rates (all randomized children) were similar: 93.7% (AS/AQ) vs. 93.2% (AS+AQ) Delta = -0.5 (95% CI -4.2 to 3.0%). By D2, both arms had rapid parasite (F & L, 97.8% aparasitaemic) and fever (97.2% [F], 96.0% [L] afebrile) clearances.Both treatments were well tolerated. Drug-induced vomiting numbered 8/375 (2.1%) and 6/375 (1.6%) in the fixed and loose arms, respectively (p = 0.59). One patient developed asymptomatic, CTC grade 4 hepatitis (AST 1052, ALT 936). Technical difficulties precluded the assessment and risk of neutropaenia for all patients.
Fixed dose AS/AQ was efficacious and well tolerated. These data support the use of this new fixed dose combination for treating P. falciparum malaria with continued safety monitoring.
Current Controlled Trials ISRCTN07576538.
Artemether/lumefantrine (AL) has been adopted as the treatment of choice for uncomplicated malaria in Kenya and other countries in the region. Six-dose artemether/lumefantrine tablets are highly effective and safe for the treatment of infants and children weighing between five and 25 kg with uncomplicated Plasmodium falciparum malaria. However, oral paediatric formulations are urgently needed, as the tablets are difficult to administer to young children, who cannot swallow whole tablets or tolerate the bitter taste of the crushed tablets.
A randomized, controlled, open-label trial was conducted comparing day 28 PCR corrected cure-rates in 245 children aged 6-59 months, treated over three days with either six-dose of artemether/lumefantrine tablets (Coartem) or three-dose of artemether/lumefantrine suspension (Co-artesiane) for uncomplicated falciparum malaria in western Kenya. The children were followed-up with clinical, parasitological and haematological evaluations over 28 days.
Ninety three percent (124/133) and 90% (121/134) children in the AL tablets and AL suspension arms respectively completed followed up. A per protocol analysis revealed a PCR-corrected parasitological cure rate of 96.0% at Day 28 in the AL tablets group and 93.4% in the AL suspension group, p = 0.40. Both drugs effectively cleared gametocytes and were well tolerated, with no difference in the overall incidence of adverse events.
The once daily three-dose of artemether-lumefantrine suspension (Co-artesiane(R)) was not superior to six-dose artemether-lumefantrine tablets (Coartem) for the treatment of uncomplicated malaria in children below five years of age in western Kenya.
Numerous trials have demonstrated high efficacy and safety of artemisinin-based combination therapy (ACT) under supervised treatment. In contrast, effectiveness studies comparing different types of ACT applied unsupervised are scarce. The aim of this study was to compare effectiveness, tolerability and acceptance of artesunate plus amodiaquine (ASAQ) against that of artemether-lumefantrine (AL) in Ghanaian children with uncomplicated Plasmodium falciparum malaria.
A randomized open-label trial was conducted at two district hospitals in the Ashanti region, Ghana, an area of intense malaria transmission. A total of 246 children under five years of age were randomly assigned to either ASAQ (Arsucam) or AL (Coartem). Study participants received their first weight-adjusted dose under supervision. After the parent/guardian was advised of times and mode of administration the respective three-day treatment course was completed unobserved at home. Follow-up visits were performed on days 3, 7, 14 and 28 to evaluate clinical and parasitological outcomes, adverse events, and haematological recovery. Length polymorphisms of variable regions of msp1 and msp2 were determined to differentiate recrudescences from reinfections. Acceptance levels of both treatment regimens were assessed by means of standardized interviews.
Adequate clinical and parasitological responses after AL and ASAQ treatment were similar (88.3% and 91.7%, respectively). Interestingly, more late clinical failures until day 28 occurred in AL-treated children than in those who received ASAQ (17.5% and 7.3%, respectively; Hazard Ratio 2.41, 95% CI 1.00-5.79, p < 0.05).Haematological recovery and drug tolerability were not found to be significantly different in both study arms. The acceptance of treatment with ASAQ was higher than that with AL (rank-scores 10.6 and 10.3, respectively; p < 0.05).
Unobserved AL and ASAQ treatment showed high adequate clinical and parasitological responses, though AL was inferior in preventing late clinical failures.
The therapeutic efficacy of artesunate plus amodiaquine and artemether/lumefantrine were assessed in an area of Nigeria with high levels of Plasmodium falciparum resistance to chloroquine and sulphadoxine-pyrimethamine.
Children aged 6 to 59 months with uncomplicated P. falciparum infection and parasite density 1,000 to 200,000 parasites/microL enrolled following informed consent by parents.
Eligible children were randomly assigned to receive either a 3-day course of artesunate (4 mg/kg) plus amodiaquine (10 mg/kg) or 6-dose course of artemether/lumefantrine (20/120 mg tablets) over three days. Patients were followed up with clinical and laboratory assessments until day 14 using standard WHO in-vivo antimalarial drug test protocol.
A total 119 eligible children were enrolled but 111 completed the study. Adequate clinical and parasitological response (ACPR) was 47 (87.0%) and 47 (82.5%) for artemether-lumefantrine (AL) and artesunate+amodiaquine (AAMQ) respectively (OR 0.7, 95% confidence interval 0.22 to 2.22). Early treatment failure (ETF) occurred in one participant (1.8%) treated with AAQ but in none of those with AL. Two (3.7%) patients in the AL group and none in the AAQ group had late clinical failure. Late parasitological failure was observed in 9 (15.8) and 5 (9.3%) of patients treated with AAQ and AL respectively. None of participants had a serious adverse event.
Artemether-lumenfantrine and artesunate plus amodiaquine have high and comparable cure rates and tolerability among under-five children in Calabar, Nigeria.
Artesunate-amodiaquine combination for the treatment of childhood malaria is one of the artemisinin combination therapies (ACTs) recommended by National authorities in many African countries today. Effectiveness data on this combination in young children is scarce.
The effectiveness of three daily doses of artesunate plus amodiaquine combination given unsupervised (n = 32), compared with the efficacy when given under full supervision (n = 29) to children with falciparum malaria were assessed in an unrandomized study.
61 patients analysed revealed a PCR-corrected day-28 cure rate of 86 % (25 of 29 patients; CI 69-95 %) in the supervised group and 63 % (20 of 32 patients; CI 45-77 %) in the unsupervised group. The difference in outcome between both groups was statistically significant (p = 0.04). No severe adverse events were reported.
The effectiveness of this short course regimen in young children with falciparum malaria could be augmented by increased adherence and improved formulation.
In view of the high level of chloroquine resistance in many countries, WHO has recommended the use of combination therapy with artemisinin derivatives in the treatment of uncomplicated malaria due to Plasmodium falciparum. Four antimalarial drug combinations, artesunate plus amodiaquine (Arsucam), artesunate plus mefloquine (Artequin), artemether plus lumefantrine (Coartem; four doses and six doses), and amodiaquine plus sulphadoxine-pyrimethamine, were studied in five health districts in Senegal.
This is a descriptive, analytical, open, randomized study to evaluate the efficacy and tolerability of these four antimalarial combinations in the treatment of uncomplicated falciparum malaria using the 2002 WHO protocol.
All drug combinations demonstrated good efficacy. On day 28, all combinations resulted in an excellent clinical and parasitological response rate of 100% after correction for PCR results, except for the four-dose artemether-lumefantrine regimen (96.4%). Follow-up of approximately 10% of each treatment group on day 42 demonstrated an efficacy of 100%.The combinations were well tolerated clinically and biologically. No unexpected side-effect was observed and all side-effects disappeared at the end of treatment. No serious side-effect requiring premature termination of treatment was observed.
The four combinations are effective and well-tolerated.
There are no data on the long term use of an artemisinin combination treatment in moderate or high transmission areas of Africa.
Artesunate plus amodiaquine (AS+AQ) was used to treat slide-proven Plasmodium falciparum-infected patients of all ages in the Oussouye district, Casamance, Senegal, over a period of six years (2000 to 2005). Efficacy, by Kaplan Meier survival analysis (n = 966), and safety (adverse event rates, n = 752) were determined over 28 days. A weight-based dosing regimen was used for the loose tablets during 2000-2003 (n = 731) and a commercially available co-blister was used during 2004-2005 (n = 235). Annual crude (non PCR corrected) rates remained stable over the study period [range 88.5-96.7%; overall 94.6 (95% CI 92.9-95.9)]. Nine co-blister treated patients (0.9%) withdrew because of drug-related adverse events; seven had gastrointestinal complaints of whom two were hospitalized for vomiting. By Day 28, the mean total bilirubin (n = 72), AST (n = 94) and ALT (n = 95) values decreased. Three patients had Day 28 AST/ALT values > 40 < 200 IU/L. Changes in white cell counts were unremarkable (n = 87).
AS+AQ in combination was highly efficacious and well-tolerated in this area and justifies the decision to use it as first line treatment. Long-term monitoring of safety and efficacy should continue.
Artesunate plus amodiaquine is a coblistered ACT, given as a single daily intake. It has been suggested that, in view of the number of tablets to be taken (particularly in adults), it may be possible to improve compliance by allowing patients to divide the daily dose. The objectives of this randomized, comparative, open-label, multicentre study, conducted in Senegal and in Cameroon in 2005, was to demonstrate the non-inferiority and to compare the safety of artesunate plus amodiaquine, as a single daily intake versus two daily intakes.
A three-day treatment period and 14-day follow-up period was performed in any subject weighting more than 10 kg, presenting with a malaria paroxysm confirmed by parasitaemia ≥ 1,000/μl, after informed consent. Patients were randomly allocated into one of the two regimens, with dosage according to bodyweight range. All products were administered by an authorized person, blinded to both the investigating physician and the biologist. The primary endpoint was an adequate response to treatment on D14 (WHO definition). The two-sided 90% confidence interval of the difference was calculated on intent to treat (ITT) population; the acceptance limit for non-inferiority was 3%. The safety was evaluated by incidence of adverse events.
Three-hundred and sixteen patients were included in the study. The two patient groups were strictly comparable on D0. The adequate responses to treatment were similar for the two treatment regimens on D14, PCR-corrected (99,4% in the one-daily intake group versus 99,3% in the comparative group). The statistical analyses demonstrated the non-inferiority of administering artesunate/amodiaquine as two intakes. The drug was well tolerated. The main adverse events were gastrointestinal disorders (2.5%) and pruritus (2.5%); safety profiles were similar in the two groups.
This pilot study confirms the efficacy and good tolerability of artesunate plus amodiaquine, administrated either in one or in two daily intakes.
In order to improve the monitoring of the antimalarial drug resistance in Madagascar, a new national network based on eight sentinel sites was set up. In 2006/2007, a multi-site randomized clinical trial was designed to assess the therapeutic efficacy of chloroquine (CQ), sulphadoxine-pyrimethamine (SP), amodiaquine (AQ) and artesunate plus amodiaquine combination (ASAQ), the antimalarial therapies recommended by the National Malaria Control Programme (NMCP).
Children between six months and 15 years of age, with uncomplicated falciparum malaria, were enrolled. Primary endpoints were the day-14 and day-28 risks of parasitological failure, either unadjusted or adjusted by genotyping. Risks of clinical and parasitological treatment failure after adjustment by genotyping were estimated using Kaplan-Meier survival analysis. Secondary outcomes included fever clearance, parasite clearance, change in haemoglobin levels between Day 0 and the last day of follow-up, and the incidence of adverse events.
A total of 1,347 of 1,434 patients (93.9%) completed treatment and follow-up to day 28. All treatment regimens, except for the chloroquine (CQ) treatment group, resulted in clinical cure rates above 97.6% by day-14 and 96.7% by day-28 (adjusted by genotyping). Parasite and fever clearance was more rapid with artesunate plus amodiaquine, but the extent of haematological recovery on day-28 did not differ significantly between the four groups. No severe side-effects were observed during the follow-up period.
These findings (i) constitute an up-dated baseline data on the efficacy of antimalarial drugs recommended by the NMCP, (ii) show that antimalarial drug resistance remains low in Madagascar, except for CQ, compared to the bordering countries in the Indian Ocean region such as the Comoros Archipelago and (iii) support the current policy of ASAQ as the first-line treatment in uncomplicated falciparum malaria.
Artesunate-amodiaquine (AS+AQ) and artemether-lumefantrine (AM-L) are efficacious artemisinin combination therapy (ACT) regimens that have been widely adopted in sub-Saharan Africa. However, there is little information on the efficacy of these regimens on subsequent episodes beyond 28 days, or on the safety of repeated treatments.
Children aged six months to 14 years with uncomplicated malaria were randomly assigned to treatment with AS+AQ (n = 116), or AM-L (n = 111). Recruited subjects were followed-up, initially for 28 days, and then monthly for up to one year. All subsequent attacks of uncomplicated malaria after 28 days were treated with the same regimen as at randomization. Investigations aimed at determining efficacy and side effects were conducted.
Adequate clinical and parasitological response in subjects with evaluable end-points were, 97.1% (100/103) and 98.2% (107/109) on day 14, and 94.2% (97/103) and 95.3% (102/107) on day 28 in the AM-L and AS+AQ groups, respectively. Similar results were obtained after PCR correction. The incidence of malaria attacks in the year following recruitment was similar between the two treatment groups (p = 0.93). There was a high incidence of potentially AQ-resistant parasites in the study area. The incidence of adverse events, such as pruritus, fatigue and neutropaenia were similar in the two treatment groups. No patient showed signs of hearing impairment, and no abnormal neurological signs were observed during one year of follow-up. Other adverse events were mild in intensity and overlapped with known malaria symptomatology. No adverse event exacerbation was observed in any of the subjects who received multiple treatment courses with these ACT regimens during one year follow-up.
AS+AQ and AM-L were efficacious for treatment of children with uncomplicated malaria in Ghana and drug-related adverse events were rare in treated subjects during one year of follow-up. The high prevalence of potentially AQ resistant parasites raises questions about the utility of AQ as a partner drug for ACT in Ghana. The efficacy of AS+AQ in Ghana requires, therefore, continuous monitoring and evaluation.
NCT 00406146 http://www.clinicaltrials.gov.
Faced with the problem of resistance to chloroquine and sulfadoxine-pyrimethamine, the Ministry of Public Health of Burundi decided to study the efficacy of two artemisinin-based combinations, the fixed combination of artemether-lumefantrine and the combination of amodiaquine + artesunate. The efficacy of these combinations for the treatment of uncomplicated falciparum malaria was studied in two sites representative of the country, in Kigobe neighbourhood of Bujumbura, the capital city, and in Buhiga, a rural area. The study followed the standardized WHO protocol from October 2001 to November 2002. A total of 295 children under 5 years were included; 153 children were treated with artesunate and amodiaquine (77 at Buhiga and 76 at Kigobe), and 142 children with the combination of artemether-lumefantrine (64 at Buhiga and 78 at Kigobe). Among the 295 children, 290 were followed up to 14 days. In the group of 149 children treated with artesunate and amodiaquine, 142 (95.3%, 95% CI: 91.9-98.7%) presented with adequate clinical and parasitological response, five (3.3%) with late parasitological failure, one (0.7%) with late clinical failure and one (0.7%) with early treatment failure. Among the 141 children treated with artemether-lumefantrine, 140 (99.3%, 95% CI: 97.9-100%) presented with adequate clinical and parasitological response and one (0.7%) with late parasitological failure at Buhiga. Side-effects were comparable in both groups except for the vomiting. Vomiting was more frequent in the artesunate + amodiaquine on D1 and D2. Both treatments decreased the gametocyte carriage but without getting full clearance in all the patients. During a consensus workshop, the Ministry of Public Health agreed on the combination of artesunate and amodiaquine as the first line drug for the treatment of uncomplicated falciparum malaria in Burundi including epidemic outbreak.
To test the hypothesis that artesunate plus amodiaquine (ASAQ) is as effective as artemether-lumefantrine (AL) in the treatment of acute uncomplicated malaria in Nigerian children.
In an open label, randomized controlled clinical trial, children aged 6 months to 10 years were randomized to receive artesunate (4 mg/kg daily) plus amodiaquine (10 mg/kg daily) or AL (5-14 kg, one tablet; 15-24 kg, two tablets and 25-34 kg, three tablets twice daily). Both drug regimens were given for 3 days and follow-up was for 28 days.
A total of 132 children (66 in each group) were randomized to receive either ASAQ or AL. Day 28 cure rates in the per protocol (PP) population were 93% for ASAQ and 95% for AL (OR = 0.71, 95% CI = 0.12-3.99, rho = 0.66). Using Kaplan-Meier product-limit estimates of failure, the median survival time for ASAQ was 21 days and for AL 28 days (P = 0.294). PCR corrected day 28 cure rate for PP populations were 98.4% for ASAQ and 100% for AL. Both drugs were well-tolerated.
ASAQ is as effective as AL and both combinations were efficacious and safe.
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