Artesunate-amodiaquine Groups Research Articles

Evidence of artemisinin partial resistance in northwestern Tanzania: clinical and molecular markers of resistance

In 2021, nationwide malaria molecular surveillance revealed a high prevalence of a validated artemisinin resistance marker, the kelch13 (k13) Arg561His mutation, in the Kagera region of northwestern Tanzania. We aimed to investigate the efficacy of artemether-lumefantrine and artesunate-amodiaquine and to confirm the presence of artemisinin partial resistance (ART-R) in the Karagwe district of this region. This single-arm, therapeutic efficacy study was carried out at the Bukangara dispensary in the Karagwe district of the Kagera region in northwestern Tanzania. Eligible participants were aged between 6 months and 120 months, had confirmed Plasmodium falciparum asexual parasitaemia, and met other inclusion criteria according to WHO's standard protocol. Participants were enrolled, treated sequentially with either artemether-lumefantrine or artesunate-amodiaquine, and assessed clinically and parasitologically for 28 days as per WHO protocol. Parasitaemia was measured every 8 h until day 3, on day 7, and then during weekly follow-up visits until day 28. Mutations in the k13 gene and extended haplotypes with the mutations were analysed, and comparisons were made with previous samples collected in the same region of Kagera and in Rwanda and southeast Asia. The primary endpoint was PCR-corrected cure rate. Between April 29 and Sept 1, 2022, 343 patients were screened, of whom 176 were enrolled: 88 in each treatment group. The PCR-corrected cure rate was 98% (95% CI 91-100) in the artemether-lumefantrine group and 100% (96-100) in the artesunate-amodiaquine group. Persistent parasitaemia on day 3 occurred in 11 (13%) of 88 patients in the artemether-lumefantrine group and 17 (19%) of 88 patients in the artesunate-amodiaquine group. Arg561His mutations on day 0 and parasitaemia on day 3 were reported in eight (9%) of 87 patients in the artemether-lumefantrine group and ten (12%) of 86 patients in the artesunate-amodiaquine group. The median parasite clearance half-life in patients harbouring parasites with Arg561His mutation was 6·1 h in the artemether-lumefantrine group and 6·0 h in the artesunate-amodiaquine group. Parasites with the Arg561His mutation were not similar to those from southeast Asia and Rwanda but had similar haplotypes to parasites reported in the same Tanzanian region of Kagera in 2021. This study confirms the presence of ART-R in Tanzania, although artemether-lumefantrine and artesunate-amodiaquine showed high efficacy. A context-specific response strategy and vigilance to detect the reduced efficacy of current antimalarial treatments and ART-R in other parts of the country are urgently needed. The Bill & Melinda Gates Foundation and the US National Institutes of Health.

Effectiveness and safety of intermittent preventive treatment with dihydroartemisinin–piperaquine or artesunate–amodiaquine for reducing malaria and related morbidities in schoolchildren in Tanzania: a randomised controlled trial

In high transmission settings, most school-aged children harbour malaria parasites without showing symptoms, often leading to anaemia and possibly impaired psychomotor and cognitive abilities. We aimed to assess the effectiveness and safety of intermittent preventive treatment for malaria in school-aged children (IPTsc) living in highly endemic areas. We did an open-label randomised controlled trial in seven primary schools in northeastern Tanzania. Schoolchildren aged 5-15 years were individually randomly assigned (1:1:1) to receive dihydroartemisinin-piperaquine, artesunate-amodiaquine, or standard of care (control) using a balanced block design. Drugs were administered by schoolteachers, with supervision from study nurses, at months 0 (baseline), 4, and 8, and were given in line with manufacturer's recommendations with dose based on the child's bodyweight. The primary endpoints were change from baseline in mean haemoglobin concentration at months 12 and 20, and clinical incidence of malaria and prevalence of parasitaemia at months 12 and 20 in the intervention groups versus the control group. The outcome data were collected through longitudinal surveys conducted every 4 months. Data were analysed on the basis of intention to treat (including all randomised participants) and per protocol (comprising children who completed the full 3-day regimen of all three IPTsc treatment rounds as assigned). This study is registered with ClinicalTrials.gov (NCT03640403). Of the 1797 children scheduled for clinical screening, 1566 were enrolled and randomly allocated (526 to receive dihydroartemisinin-piperaquine, 527 to receive artesunate-amodiaquine, and 513 to receive standard of care). Due to COVID-19-related school closures, only two schools were visited at month 12 (135 children in the dihydroartemisinin-piperaquine group, 131 in the artesunate-amodiaquine group, and 118 in the control group). At month 12, compared with the control group, the change from baseline in mean haemoglobin concentration was increased by 0·5 g/dL (95% CI 0·2 to 0·8; p<0·0001) in the dihydroartemisinin-piperaquine group and 0·5 g/dL (0·2 to 0·7; p=0·0020) in the artesunate-amodiaquine group in the intention-to-treat analysis (with similar findings in the per protocol analysis). In the same period, in the intention-to-treat analysis, the prevalence of malaria parasitaemia increased from 28·5% (138 of 485 participants) to 33·6% (39 of 116) in the control group, but decreased from 28·0% (139 of 497) to 12·0% (15 of 125) in the dihydroartemisinin-piperaquine group (-21·6 percentage points [95% CI -31·9 to -11·3], p=0·0001 vs control at month 12) and from 24·7% (124 of 502) to 16·0% (20 of 125) in the artesunate-amodiaquine group (-17·6 percentage points [-28·4 to -6·9], p=0·0015). The decrease for artesunate-amodiaquine was larger in the per protocol analysis (-25·3 percentage points [-36·3 to -14·2], p<0·0001). The protective effect of IPTsc against malaria parasitaemia was 64% (95% CI 39 to 79; p<0·0001) for dihydroartemisinin-piperaquine and 52% (23 to 70; p=0·0015) for artesunate-amodiaquine in the intention-to-treat analysis, and was slightly higher on per protocol analysis. The protective effect against clinical malaria at month 12 was 20% (95% CI 9 to 29; p=0·0002) for dihydroartemisinin-piperaquine and 19% (8 to 28; p=0·0004) for artesunate-amodiaquine. No significant differences in any primary outcomes between the intervention and control groups were noted at month 20. Dihydroartemisinin-piperaquine and artesunate-amodiaquine were associated with a small number of mild adverse events, and there were no treatment-related serious adverse events or deaths. IPTsc with dihydroartemisinin-piperaquine or artesunate-amodiaquine is a safe and effective approach to reducing malaria parasitaemia, clinical malaria, and related morbidities, and is feasible to implement through programmes delivered by schoolteachers. Flemish Interuniversity Council (VLIRUOS), EU EDCTP2 programme (MaReCa project), and Global Minds 2019. For the Swahili translation of the abstract see Supplementary Materials section.

A High efficacy of Artemether–Lumefantrine and Artesunate-Amodiaquine for the treatment of uncomplicated falciparum malaria in Massokory, Mondo and Dourbali provinces (Chad).

Artemether-Lumefantrine (AL) and Artesunate-Amodiaquine (ASAQ) are recommended for the treatment of uncomplicated malaria in Chad. The objective of this study was to evaluate the High efficacy of Artemether–Lumefantrine and Artesunate-Amodiaquine for the treatment of uncomplicated falciparum malaria in Massokory, Mondo and Dourbali provinces (Chad).The study was&nbsp; carried out in 2019, 1113 patients children &nbsp;aged from 6 to 60 months were randomly assigned treatment with Artemether-Lumefantrine and Artesunate-Amodiaquine and followed up for 28 days. Primary endpoint was the treatment efficacy over 28 days. The early treatment failure was (0.13%) in AL group and (0.17%) in ASAQ group. No early clinical failure was found. Adequate clinical and parasitological responses were significantly higher in Artesunate-Amodiaquine group (ASAQ) (99.82% versus (99.10%) in Artemether-Lumefantrine (AL) group, p = 0.0009). All treatments had a similar and good tolerability profile that confirm the high efficacy of the first- and the newly recommended alternative ACT for treatments for uncomplicated falciparum malaria in Chad. The high parasite density clearance suggests absence of suspected artemisinin resistance, defined as delayed parasite clearance &nbsp

Clinical Efficacy of Artemether-Lumefantrine Artesunate-Amodiaquine of Children from Three Chadian Provinces with Acute of Uncomplicated &amp;lt;i&amp;gt;Falciparum malariae&amp;lt;/i&amp;gt; from 6 Months to 5 Years

Introduction: Artemisinin-based combination therapies are the first-line antimalarial drugs used to treat uncomplicated Plasmodium falciparum malaria in many endemic countries worldwide. In Chad, since the adoption of artemisinin-based combination therapy (ACTs) in its first-line treatment policy for uncomplicated malaria in 2005, Artemether-Lumefantrine and Artesunate-Amodiaquine have been used in many hospitals and health centers. The main objective of this study was to provide the baseline data of Artemether-Lumefantrine and Artesunate-Amodiaquine efficacy in three regions where many people suffered from malaria disease. Material and Methods: The baseline efficacy of two combination therapies was evaluated between January and April 2020 in Mosoro, Mondou and Dourbali Provinces in Chad. A two-arm single cohort study was conducted to assess the clinical efficacy of artesunate-amodiaquine and artemether-lumefantrine for the treatment of 1113 children aged from 6 to 59 months with uncomplicated Falciparum malariae diagnosed by thick blood smear examination, using the World Health Organization validated protocol. Results: On day 3, all patients in both groups had cleared parasitemia, after treatment, the patients presented a higher hemoglobin level in both groups artemether-lumefantrine (10.97 ± 1.39) and artesunate-amodiaquine (11.87 ± 1.81), respectively. On day 28, all patients had adequate clinical and parasitological responses with 99.82% of artesunate-amodiaquine and 99.10% of artemether-lumefantrine. Overall, both drugs were well tolerated at the clinical and biological level, no late parasitological failures have been recorded in artemether-lumefantrine and artesunate-amodiaquine groups, also both forms of Artemisinin-based combination therapy were still effective and safe in the treatment of uncomplicated P. falciparum malaria in Chad.

Hemoglobin change following first line treatment of uncomplicated falciparum malaria with artemether-lumefantrine and artesunate-amodiaquine in Burkina Faso

INTRODUCTION: Anemia is one of the common complications of malaria infection in endemic countries of sub-Saharan Africa. We investigated the hemoglobin change following first line therapies for uncomplicated malaria in Burkina Faso. METHODS: participants over 6 months old who consented to participate in opened randomized clinical trial were given either artemether-lumefantrine or artesunate-amodiaquine for three days and hemoglobin was measured and assessed on day 0, 7 and 28 (or last day) on venous blood. RESULTS: overall, 138 participants were enrolled in artemether-lumefantrine and 143 in artesunate-amodiaquine groups. The proportion of anemic participants increased in either group in the period day 0-7(52.99% versus 73.5% in artemether-lumefantrine and 51.18% versus 75.81% in artesunate-amodiaquine group) and decrease afterward between day 0 and day 28 (52.99% versus 35.65% in artemether-lumefantrine and 51.18% versus 37.6% in artesunate-amodiaquine group) and between day 7 and day 28(73.5% versus 35.65% in artemether-lumefantrine and 75.81% versus 37.6 % in artesunate-amodiaquine group). According to clinical outcome, 32.2% and 39.47% of cured participants in artmether-lumefantrine and artesunate-amodiaquine groups respectively remained anemic. CONCLUSION: despite successful treatment of uncomplicated malaria with artemether-lumefantrine and artesunate-amodiaquine, the first seven days following the onset of the treatment remained a period of risk for the patients; furthermore, this study confirmed that anemia goes beyond malaria. Integrated approaches are warranted for its control.

Investigating the Comparative Effects of Six Artemisinin-based Combination Therapies on Plasmodium-induced Hepatorenal Toxicity.

Background:Too many artemisinin-based combination therapies (ACTs) are available, thus creating a dilemma on the most preferred for the treatment of malaria.Aim:We compared the effect of six ACTs in mitigating Plasmodium-induced hepatorenal toxicity in experimental malaria.Materials and Methods:Forty adult male Swiss mice allotted into eight groups: Group 1 (normal control [NC] uninfected and untreated), Group 2 (parasitized nontreated – [PNT]), and Groups 3–8 received Plasmodium berghei inoculum. After 72 h, the initial parasitemia was established. Groups 3–8 were administered oral therapeutic doses of artesunate-amodiaquine (AA), artesunate-mefloquine (AM), artesunate-sulfadoxine-pyrimethamine (ASP), artemisinin-piperaquine (AP), dihydroartemisinin-piperaquine (DP), and artemether-lumefantrine (AL) per kg bodyweight, respectively, as standard regimen, and final parasitemia determined. Animals were euthanized via chloroform inhalation and blood collected for hepatorenal analysis. Liver and kidney were dissected out for histology.Results:Parasitemia was significantly (P < 0.05) decreased in tests compared to PNT, except in ASP group. Liver enzymes were significantly (P < 0.05) increased in PNT compared to tests and NC. Hyperplastic cells and portal tract inflammation were prominent in ASP group, but mild to moderate in other treated groups. Urea-creatinine were significantly (P < 0.05) increased in PNT compared to treated groups. The Na+ and Cl− were significantly (P < 0.05) reduced in PNT, with significantly (P < 0.05) increased K+ compared to NC and treated groups. Glomerulonephritis and glomerulus splitting was observed in PNT, while moderate distortions were observed in treated groups. The AA and AM groups had good kidney histoarchitecture.Conclusion:Parasitemia decreased in all the treatment groups except in PNT and ASP groups which had severe hepatorenal distortions. Hepatorenal histoarchitecture were mildly distorted in the AA, AM and AL-administered groups with lower hepatorenal indices comparable to NC. The least elevated liver enzymes were in AA and AM. In decreasing order ASP > DP > AL > AP > AM > AA.

Comparative analysis of the safety and tolerability of fixed-dose artesunate/amodiaquine versus artemether/lumefantrine combinations for uncomplicated falciparum malaria in pregnancy: a randomized open label study.

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.

Effect of Artesunate–Amodiaquine on Mortality Related to Ebola Virus Disease

BackgroundMalaria treatment is recommended for patients with suspected Ebola virus disease (EVD) in West Africa, whether systematically or based on confirmed malaria diagnosis. At the Ebola treatment center in Foya, Lofa County, Liberia, the supply of artemether–lumefantrine, a first-line antimalarial combination drug, ran out for a 12-day period in August 2014. During this time, patients received the combination drug artesunate–amodiaquine; amodiaquine is a compound with anti–Ebola virus activity in vitro. No other obvious change in the care of patients occurred during this period.MethodsWe fit unadjusted and adjusted regression models to standardized patient-level data to estimate the risk ratio for death among patients with confirmed EVD who were prescribed artesunate–amodiaquine (artesunate–amodiaquine group), as compared with those who were prescribed artemether–lumefantrine (artemether–lumefantrine group) and those who were not prescribed any antimalarial drug (no-antimalarial group).ResultsBetween June 5 and October 24, 2014, a total of 382 patients with confirmed EVD were admitted to the Ebola treatment center in Foya. At admission, 194 patients were prescribed artemether–lumefantrine and 71 were prescribed artesunate–amodiaquine. The characteristics of the patients in the artesunate–amodiaquine group were similar to those in the artemether–lumefantrine group and those in the no-antimalarial group. A total of 125 of the 194 patients in the artemether–lumefantrine group (64.4%) died, as compared with 36 of the 71 patients in the artesunate–amodiaquine group (50.7%). In adjusted analyses, the artesunate–amodiaquine group had a 31% lower risk of death than the artemether–lumefantrine group (risk ratio, 0.69; 95% confidence interval, 0.54 to 0.89), with a stronger effect observed among patients without malaria.ConclusionsPatients who were prescribed artesunate–amodiaquine had a lower risk of death from EVD than did patients who were prescribed artemether–lumefantrine. However, our analyses cannot exclude the possibility that artemether–lumefantrine is associated with an increased risk of death or that the use of artesunate–amodiaquine was associated with unmeasured patient characteristics that directly altered the risk of death.

Safety of Artemisinin-Based Combination Therapies in Nigeria: A Cohort Event Monitoring Study

A pilot programme of Cohort Event Monitoring (CEM) was conducted across the six geopolitical zones of Nigeria on patients treated for uncomplicated malaria with artemisinin-based combination therapy (ACT). The emergence and spread of malaria parasites resistant to commonly available antimalarial drugs necessitated a shift in policy for malaria treatment by the Federal Government from the use of chloroquine and sulphadoxine-pyrimethamine (SP) as first-line treatments to ACTs. Initial reports following deployment of ACTs in clinical settings raised safety concerns regarding their use. Although artemisinin and its derivatives are generally thought to be safe, there are currently few or no data on their safety among populations in Nigeria. The main objectives of the CEM programme were to proactively determine the adverse event (AE) profile of artesunate/amodiaquine (AA) and artemether/lumefantrine (AL) in real-life settings and to find out the factors predisposing to AEs. The CEM study was observational, longitudinal, prospective, and inceptional. Patients were observed in real-life situations. It was conducted in six public health facilities in Nigeria on patients with a clinical diagnosis of uncomplicated malaria treated with ACTs. Patients were prescribed one of the ACTs on an alternate basis as they enrolled into the programme. Follow-up reviews were undertaken on days 3 and 7 following commencement of ACT treatment. At follow-up, patients were evaluated for any clinical event that they might have experienced following the use of the ACTs. We report the result of this initial pilot in which 3,010 patients treated for uncomplicated malaria with AA or AL were enrolled. The seven most common AEs seen were general body weakness 25.0/36.6% (AL/AA); dizziness 11.9/17.2% (AL/AA); vomiting 8.0/10.2% (AL/AA); abdominal pain 8.5/7.2% (AL/AA); insomnia 6.3/5.9% (AL/AA); body pains 3.4/5.2 (AL/AA) %; anorexia 8.5/4.6% (AL/AA). Most adverse events occurred from day 1 and peaked by day 2 and 3 of medication with the mean duration of events being 3 days. By the end of the follow-up visit on day 7, the AEs had resolved in the majority of patients. Adverse events were more common in the AA group than AL revealing a better safety profile for AL (p < 0.001). Both ACTs demonstrated good ability to resolve the clinical symptoms of uncomplicated malaria. In conclusion, this pilot CEM programme suggests that adverse events with ACTs were common. However, serious life-threatening events were not common. It appears that ACTs have a tolerable safety profile among Nigerians.

Oral Amodiaquine, Artesunate and Artesunate Amodiaquine Combination Affects Open Field Behaviors and Spatial Memory in Healthy Swiss Mice

Effects of amodiaquine, artesunate and artesunate amodiaquine combination on open field novelty-induced behaviors and spatial memory in healthy mice were studied. Forty mice were used in the open field and fifty each in the radial arm maze and Y maze; mice were assigned into four or five groups of ten each, Group A served as control (distilled water), Groups B, C and D received artesunate (4 mg/kg), amodiaquine (10 mg/kg) and artesunate-amodiaquine combination (4 mg/kg and10 mg/kg) respectively, while Group E animals (for the cognition tests) were given scopolamine (2 mg/kg). Drugs and vehicle were administered orally for three days. Results were analysed by one way analysis of variance followed by a posthoc test. Results showed that artesunate and amodiaquine either in combination or administered singly caused a significant increase in open field novelty-induced horizontal locomotion and rearing. Grooming in the open field showed increments in the artesunate alone and artesunate amodiaquine groups while significant reductions in spatial memory were also seen in the cognition models used.

HIGH EFFICACY OF TWO ARTEMISININ-BASED COMBINATIONS (ARTESUNATE + AMODIAQUINE AND ARTEMETHER + LUMEFANTRINE) IN CAALA, CENTRAL ANGOLA

In April 2004, 137 children 6-59 months of age with uncomplicated Plasmodium falciparum (Pf) malaria (Caala, Central Angola) were randomized to receive either artemether-lumefantrine (Coartem) or artesunate + amodiaquine (ASAQ). After 28 days of follow-up, there were 2/61 (3.2%) recurrent parasitemias in the Coartem group and 4/64 (6.2%) in the ASAQ group (P = 0.72), all classified as re-infections after PCR genotyping (cure rate = 100% [95%CI: 94-100] in both groups). Only one patient (ASAQ group) had gametocytes on day 28 versus five (Coartem) and three (ASAQ) at baseline. Compared with baseline, anemia was significantly improved after 28 days of follow-up in both groups (Coartem: from 54.1% to 13.4%; ASAQ: from 53.1% to 15.9%). Our findings are in favor of a high efficacy of both combinations in Caala. Now that Coartem has been chosen as the new first-line anti-malarial, the challenge is to insure that this drug is available and adequately used.