Allele frequency of Hemoglobin S among patients with uncomplicated Plasmodium falciparum malaria in N'Djamena, Chad.

Supervised versus unsupervised intake of six-dose artemether-lumefantrine for treatment of acute, uncomplicated Plasmodium falciparum malaria in Mbarara, Uganda: a randomised trial

We recently reported the results of a controlled trial conducted between June 1996 and December 1998 comparing a 3-day quinine-clindamycin (QC) regimen (53 patients) with a 7-day Q regimen (55 patients) for treating uncomplicated Plasmodium falciparum malaria in returned travelers (1). There was no significant difference between these regimens with regard to the 28-day cure rate and parasite and fever clearance times. Furthermore, we noted a trend towards a better tolerance of the QC regimen (1). Between January 1999 and December 2001, a total of 123 more patients with uncomplicated falciparum malaria received the previously studied 3-day treatment with intravenous QC (with Q at 8 mg/kg of body weight every 8 h and C at 5 mg/kg every 8 h). Patients had returned from areas in sub-Saharan Africa where malaria is endemic. During the treatment, 12 (9.8%) patients presented with minor side effects, including transient hypoacusis (4%), nausea (3.2%), transient hypoglycemia (1%), anxiety (0.8%), diarrhea (0.8%), and transient rash (0.8%). The treatment was stopped for two patients on day 2 because one had severe diarrhea and the other had intense abdominal pain. In both of these cases, the C was stopped and the patients completed therapy with a 7-day Q regimen and remained well. Bacteriological analyses of the feces, including a test for Clostridium difficile, were negative. When discharged on day 4, all 121 patients who completed the 3-day treatment were afebrile, and thick blood smears were negative in all cases. Thereafter, follow-up included physical examination and analysis of thick blood smears prepared during visits in our outpatient department on days 7 (74.4% of patients returned), 14 (61.1% returned), and 28 (40.5% returned). One patient had positive thick blood smears (parasitemia, <0.1%) on day 14 without any fever. He did not receive any treatment. He remained afebrile, and a thick blood smear on day 28 was negative. A second patient presented on day 14 with a positive blood smear that had been prepared and analyzed in a private laboratory (parasitemia, <0.1%). Although he had no fever, he treated himself with oral mefloquine before coming to the visit. This patient was excluded from the analysis. He remained well. All other patients seen at the follow-up visits presented with no fever, and their thick blood smears were negative. Concerning the patients who did not complete the follow-up procedure, all except two were reached by phone. None had a febrile illness or had been hospitalized for malaria recrudescence in the 6 months following the QC treatment. In summary, out of the 123 patients who received the QC treatment, 122 were included in the analysis and 1 was excluded. In the per-protocol analysis, 120 of 122 patients (98.4%) were considered successfully treated with the 3-day QC regimen. In the intention-to-treat analysis, 118 of 122 (96.7%) were considered successfully treated. We report here the results for the largest series of returned travelers with uncomplicated falciparum malaria treated with a 3-day QC combination. The data were obtained through an open protocol. However, 98.4% of the patients could be evaluated after a 6-month period by clinical and parasitological follow-up or by phone. The present data extend the results from our previous randomized study and confirm that a 3-day intravenous QC regimen for treating imported uncomplicated P. falciparum malaria in returned travelers is well tolerated and can be proposed as a first-line treatment regimen for imported uncomplicated falciparum malaria. The benefit includes the reduction of the duration of the Q treatment and its side effects. In our unit, around 30% of patients with uncomplicated malaria present with vomiting. Thus, intravenous treatment is often required. Both Q and C may be given by this route, and the combination may be as effective in oral treatment (in the absence of vomiting). As it is preferable that therapy of uncomplicated malaria be oral, a pilot study comparing 3-day oral QC treatment to mefloquine treatment has just started in our unit.

BackgroundAntipyretic drugs are widely used in children with fever, though there is a controversy about the benefit of reducing fever in children with malaria. In order to assess the effect of ibuprofen on fever compared to placebo in children with uncomplicated Plasmodium falciparum malaria in Gabon, a randomized double blind placebo controlled trial, was designed.MethodsFifty children between two and seven years of age with uncomplicated malaria were included in the study. For the treatment of fever, all patients "received" mechanical treatment when the temperature rose above 37.5°C. In addition to the mechanical treatment, continuous fanning and cooling blanket, patients were assigned randomly to receive ibuprofen (7 mg/kg body weight, every eight hours) or placebo.ResultsThe fever clearance time using a fever threshold of 37.5°C was similar in children receiving ibuprofen compared to those receiving placebo. The difference was also not statistically significant using a fever threshold of 37.8°C or 38.0°C. However, the fever time and the area under the fever curve were significantly smaller in the ibuprofen group compared to the placebo group.ConclusionIbuprofen is effective in reducing the time with fever. The effect on fever clearance is less obvious and depends on definition of the fever threshold.Trial registrationThe trial registration number is: NCT00167713

Taste-masked quinine pamoate tablets for treatment of children with uncomplicated Plasmodium falciparum malaria

SummaryBackgroundTriple antimalarial combination therapies combine potent and rapidly cleared artemisinins or related synthetic ozonides, such as arterolane, with two, more slowly eliminated partner drugs to reduce the risk of resistance. We aimed to assess the safety, tolerability, and efficacy of arterolane–piperaquine–mefloquine versus arterolane–piperaquine and artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in Kenyan children.MethodsIn this single-centre, open-label, randomised, non-inferiority trial done in Kilifi County Hospital, Kilifi, coastal Kenya, children with uncomplicated Plasmodium falciparum malaria were recruited. Eligible patients were aged 2–12 years and had an asexual parasitaemia of 5000–250 000 parasites per μL. The exclusion criteria included the presence of an acute illness other than malaria, the inability to tolerate oral medications, treatment with an artemisinin derivative in the previous 7 days, a known hypersensitivity or contraindication to any of the study drugs, and a QT interval corrected for heart rate (QTc interval) longer than 450 ms. Patients were randomly assigned (1:1:1), by use of blocks of six, nine, and 12, and opaque, sealed, and sequentially numbered envelopes, to receive either arterolane–piperaquine, arterolane–piperaquine–mefloquine, or artemether–lumefantrine. Laboratory staff, but not the patients, the patients' parents or caregivers, clinical or medical officers, nurses, or trial statistician, were masked to the intervention groups. For 3 days, oral artemether–lumefantrine was administered twice daily (target dose 5–24 mg/kg of bodyweight of artemether and 29–144 mg/kg of bodyweight of lumefantrine), and oral arterolane–piperaquine (arterolane dose 4 mg/kg of bodyweight; piperaquine dose 20 mg/kg of bodyweight) and oral arterolane–piperaquine–mefloquine (mefloquine dose 8 mg/kg of bodyweight) were administered once daily. All patients received 0·25 mg/kg of bodyweight of oral primaquine at hour 24. All patients were admitted to Kilifi County Hospital for at least 3 consecutive days and followed up at day 7 and, thereafter, weekly for up to 42 days. The primary endpoint was 42-day PCR-corrected efficacy, defined as the absence of treatment failure in the first 42 days post-treatment, of arterolane–piperaquine–mefloquine versus artemether–lumefantrine, and, along with safety, was analysed in the intention-to-treat population, which comprised all patients who received at least one dose of a study drug. The 42-day PCR-corrected efficacy of arterolane–piperaquine–mefloquine versus arterolane–piperaquine was an important secondary endpoint and was also analysed in the intention-to-treat population. The non-inferiority margin for the risk difference between treatments was −7%. The study is registered in ClinicalTrials.gov, NCT03452475, and is completed.FindingsBetween March 7, 2018, and May 2, 2019, 533 children with P falciparum were screened, of whom 217 were randomly assigned to receive either arterolane–piperaquine (n=73), arterolane–piperaquine–mefloquine (n=72), or artemether–lumefantrine (n=72) and comprised the intention-to-treat population. The 42-day PCR-corrected efficacy after treatment with arterolane–piperaquine–mefloquine (100%, 95% CI 95–100; 72/72) was non-inferior to that after treatment with artemether–lumefantrine (96%, 95% CI 88–99; 69/72; risk difference 4%, 95% CI 0–9; p=0·25). The 42-day PCR-corrected efficacy of arterolane–piperaquine–mefloquine was non-inferior to that of arterolane–piperaquine (100%, 95% CI 95–100; 73/73; risk difference 0%). Vomiting rates in the first hour post-drug administration were significantly higher in patients treated with arterolane–piperaquine (5%, 95% CI 2–9; ten of 203 drug administrations; p=0·0013) or arterolane–piperaquine–mefloquine (5%, 3–9; 11 of 209 drug administrations; p=0·0006) than in patients treated with artemether–lumefantrine (1%, 0–2; three of 415 drug administrations). Upper respiratory tract complaints (n=26 for artemether–lumefantrine; n=19 for arterolane–piperaquine–mefloquine; n=23 for arterolane–piperaquine), headache (n=13; n=4; n=5), and abdominal pain (n=7; n=5; n=5) were the most frequently reported adverse events. There were no deaths.InterpretationThis study shows that arterolane–piperaquine–mefloquine is an efficacious and safe treatment for uncomplicated falciparum malaria in children and could potentially be used to prevent or delay the emergence of antimalarial resistance.FundingUK Department for International Development, The Wellcome Trust, The Bill & Melinda Gates Foundation, Sun Pharmaceutical Industries

BackgroundArtemether/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.MethodsA 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.ResultsNinety 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.ConclusionThe once daily three-dose of artemether-lumefantrine suspension (Co-artesiane®) 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.Trial registrationClinicalTrials.gov NCT00529867

BackgroundMalaria is a complex disease, which varies in its epidemiology and clinical manifestation. Although artemether-lumefantrine has been used as first-line drug for uncomplicated Plasmodium falciparum malaria in Bahir Dar district since 2004, its efficacy has not yet been assessed. The main objective of this study was to quantify the proportion of patients with uncomplicated falciparum malaria who were prescribed artemether-lumefantrine and who failed treatment after a 28-day follow-up.MethodsThe research team attempted to conduct an observational cohort study on the assessment of therapeutic efficacy and safety of artemether-lumefantrine in falciparum malaria patients aged over five years in Bahir Dar district from March to July 2012.ResultsAmong 130 participants in the study, 60 % were males with 1:5 male to female ratio. The mean of asexual parasitaemia load was 8675 parasites/μL and 96.1 % participants were free from parasitaemia at day 3. At the end of the study, 98.5 % of participants showed adequate clinical and parasitological response of the drug. In the study, only 1.5 % of participants were shown late parasitological failure between seventh and 14th day follow-up and 1.3 % of participants were free from anaemia at the end of follow-up.ConclusionAccording to the research findings, artemether-lumefantrine fulfilled the inclusion criteria of WHO as first-line drug and continues to be the drug of choice for the treatment of uncomplicated falciparum malaria. Outputs from this study should be supported through advanced molecular techniques and blood concentration and pharmaco-vigilance of the drug.

Background Artemisinin-based Combination Therapies (ACTs) are widely used in the treatment of uncomplicated malaria. Plasmodium falciparum infection is often accompanied by disturbances of hematological and biochemical parameters. The objective of this study was to evaluate the changes in biochemical and hematological parameters during uncomplicated malaria in patients treated with ACTs. Methods Data from patient with uncomplicated Plasmodium falciparum malaria were pooled from different open-randomized trial evaluating the efficacy of Artesunate-Mefloquine (ASMQ), Artesunate-Amodiaquine (ASAQ), Artemether-Lumefantrine (AL), and Dihydro-artemisinin-Piperaquine (DHAPQ) combinations. Biochemical (transaminases, creatinine, and bilirubin) and hematological (hemoglobin and platelet levels) parameters were performed at baseline (D0) and at day 7 after treatment (D7). Data were analyzed as both continuous and categorical variables with 95% confidence interval. Risks and trends were calculated using multivariate logistic random effect models. Results A total of 720 patients with completed biological data were included in the analysis (320 in the AL arm, 160 in the ASMQ arm, 120 in the DHAPQ arm, and 88 in the ASAQ arm). The mean age of the patients was 9.43 ± 9.1 years. Male subjects represented 58.47% (sex ratio was 1.4 for males). The mean hemoglobin level at inclusion (D0) was 9.79 g/dl and anemia (Hb < 11 g/dl) was 71.43% (aOR = 1.16 [0.68 − 1.98]p = 0.57). At D7, hemoglobin level was 9.63 g/dl and anemia was significantly more frequent (78.29% [p = 0.002]). The mean platelet count at day 0 was 154075.5 platelets/mm3 of blood and 339328.7 platelets/mm3 at day 7. Thrombocytopenia was about 53.61% and was associated with malaria (aOR = 3.4 [2.18 − 5.3]p < 10−3). 19.58% of patients had abnormal ALT and 40.28% had abnormal AST at D0. 27.22% of patients had normal bilirubin at D0. Renal function was normal in all patients in the study. Normalization of transaminases was noted between D0 and D7. The percentage of subjects with normal bilirubin increased between D0 and D7. Renal function did not vary significantly between D0 and D7. Conclusion Results from this analysis showed that subjects with high parasitaemia had a greater risk of anemia and thrombocytopenia. Artemisinin combinations were well-tolerated as no major biological disturbances were noted. The effects of ACTs on hematologic and biochemical parameters were not different.

The safety of artemether-lumefantrine in patients with acute, uncomplicated Plasmodium falciparum malaria was investigated prospectively using the auditory brainstem response (ABR) and pure-tone thresholds. Secondary outcomes included polymerase chain reaction-corrected cure rates. Patients were randomly assigned in a 3:1:1 ratio to either artemether-lumefantrine (N = 159), atovaquone-proguanil (N = 53), or artesunate-mefloquine (N = 53). The null hypothesis (primary outcome), claiming that the percentage of patients with a baseline to Day-7 ABR Wave III latency increase of > 0.30 msec is ≥ 15% after administration of artemether-lumefantrine, was rejected; 2.6% of patients (95% confidence interval: 0.7-6.6) exceeded 0.30 msec, i.e., significantly below 15% (P < 0.0001). A model-based analysis found no apparent relationship between drug exposure and ABR change. In all three groups, average improvements (2-4 dB) in pure-tone thresholds were observed, and polymerase chain reaction-corrected cure rates were > 95% to Day 42. The results support the continued safe and efficacious use of artemether-lumefantrine in uncomplicated falciparum malaria.

Artemisinin-based combination therapies (ACTs) are currently used as the first-line therapy for uncomplicated Plasmodium falciparum malaria. However, the recent emergence and/or spread of artemisinin resistance in parts of Greater Mekong Subregion (GMS) of southeast Asia requires close monitoring of the therapeutic efficacy of ACTs. This study was conducted from March 2012 to December 2013 in four clinics and seven villages along the China-Myanmar border. A total of 109 patients with uncomplicated falciparum malaria were treated with dihydroartemisinin-piperaquine (DP) and followed up on days 1, 2, 3, 7, 14, 21, 28, and 42 after treatment. A total of 71 patients (22 children and 49 adults) completed the 42-day follow-up. DP remained highly efficacious for treatment of uncomplicated falciparum malaria with an overall 42-day cure rate of 100%. The day 3 parasite-positive rate was 7.04% (5/71). Within 14 days of treatment, a total of 13 (18.31%) patients had detectable gametocytes and a large proportion of these were persistent from the first three days of treatment. The presence of gametocytes in patients through 14 days after DP treatment suggests that the incorporation of a single dose of primaquine for clearing gametocytemia should be considered for blocking parasite transmission.

Conclusions: These differences in the exposure to artesunate, dihydroartemisinin and mefloquine are unlikely to be of clinical relevance based on in vitro and clinical data. However, the results of this study do emphasise the importance of evaluating the bioavailability and bioequivalence of new formulations, particularly in specific patient groups.

BackgroundIn 2005, the Democratic Republic of Congo (DRC) adopted artesunate and amodiaquine (ASAQ) as first-line anti-malarial treatment. In order to compare the efficacy of the fixed-dose formulation ASAQ versus artemether-lumefantrine (AL), a randomized, non-inferiority open-label trial was conducted in Katanga.MethodsChildren aged six and 59 months with uncomplicated Plasmodium falciparum malaria were enrolled and randomly allocated into one of the two regimens. The risk of recurrent parasitaemia by day 42, both unadjusted and adjusted by PCR genotyping to distinguish recrudescence from new infection, was analysed.ResultsBetween April 2008 and March 2009, 301 children were included: 156 with ASAQ and 145 with AL. No early treatment failures were reported. Among the 256 patients followed-up at day 42, 32 patients developed late clinical or parasitological failure (9.9% (13/131) in the ASAQ group and 15.2% (19/125) in the AL group). After PCR correction, cure rates were 98.3% (95%CI, 94.1-99.8) in the ASAQ group and 99.1% (95%CI, 94.9-99.9) in the AL group (difference −0.7%, one sided 95% CI −3.1). Kaplan-Meier PCR-adjusted cure rates were similar. Both treatment regimens were generally well tolerated.ConclusionBoth ASAQ and AL are highly effective and currently adequate as the first-line treatment of uncomplicated falciparum malaria in this area of Katanga, DRC. However, in a very large country, such as DRC, and because of possible emergence of resistance from other endemic regions, surveillance of efficacy of artemisinin-based combination treatments, including other evaluations of the resistance of ASAQ, need to be done in other provinces.Trial registrationThe protocol was registered with the clinicaltrials.gov, open clinical trial registry under the identifier number NCT01567423.

In normal subjects, elevation of plasma free fatty acid (FFA) levels stimulates gluconeogenesis (GNG) and inhibits glycogenolysis (GLY). In adults with uncomplicated Plasmodium falciparum malaria, GNG is increased and GLY decreased. To test the hypothesis that FFAs are regulators of GNG and GLY in uncomplicated falciparum malaria, we investigated the effect of inhibition of lipolysis by acipimox in 12 patients with uncomplicated falciparum malaria. Six of them were given acipimox, and six served as controls. Also as controls, six matched healthy subjects were studied on two occasions with and without acipimox. After 16 h of fasting, glucose production and GNG were significantly higher in the malaria patients compared with the healthy controls (P = 0.003 and < 0.0001, respectively), whereas GLY was significantly lower (P < 0.001), together with elevated plasma concentrations of cortisol and glucagon. During the study, glucose production in patients declined over time (P < 0.0001), without a statistically significant difference between the acipimox-treated and untreated patients. In controls, however, with acipimox the decline was less outspoken compared with nontreated controls (P = 0.005). GNG was unchanged over time in patients as well as in healthy controls, and no influence of acipimox was found. In patients, GLY declined over time (P < 0.001), without a difference between acipimox-treated and untreated patients. In contrast, in controls treated with acipimox, no change over time was found, which was statistically different from the decline in untreated controls (P = 0.002). In conclusion, in falciparum malaria, FFAs are not involved in regulation of glucose production, nor of GNG or GLY.

In an unmatched case-control study of 63 non-immune European patients with uncomplicated (n = 52) and complicated (n = 11) falciparum malaria, serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), heart-type fatty acid-binding protein (H-FABP), myoglobin, troponin T and creatin kinase-muscle brain were compared. Elevated levels of NT-proBNP and H-FABP indicated myocardial impairment in complicated but not in uncomplicated falciparum malaria. The clinical impact of these findings remains to be evaluated. The pathophysiology of cardiac impairment in complicated falciparum malaria warrants further investigation.

BackgroundThe anti-malarial drug, amodiaquine, a commonly used, long-acting partner drug in artemisinin-based combination therapy, is metabolized to active desethyl-amodiaquine (DEAQ) by cytochrome P450 2C8 (CYP2C8). The CYP2C8 gene carries several polymorphisms including the more frequent minor alleles, CYP2C8*2 and CYP2C8*3. These minor alleles have been associated with decreased enzymatic activity, slowing the amodiaquine biotransformation towards DEAQ. This study aimed to assess the influence of these CYP2C8 polymorphisms on the efficacy and tolerability of artesunate–amodiaquine (AS–AQ) treatment for uncomplicated Plasmodium falciparum malaria in Zanzibar.MethodsDried blood spots on filter paper were collected from 618 children enrolled in two randomized clinical trials comparing AS–AQ and artemether-lumefantrine in 2002–2005 in Zanzibar. Study participant were under five years of age with uncomplicated falciparum malaria. Human CYP2C8*2 and CYP2C8*3 genotype frequencies were determined by PCR-restriction fragment length polymorphism. Statistical associations between CYP2C8*2 and/or CYP2C8*3 allele carriers and treatment outcome or occurrence of adverse events were assessed by Fisher’s exact test.ResultsThe allele frequencies of CYP2C8*2 and CYP2C8*3 were 17.5 % (95 % CI 15.4–19.7) and 2.7 % (95 % CI 1.8–3.7), respectively. There was no significant difference in the proportion of subjects carrying either CYP2C8*2 or CYP2C8*3 alleles amongst those with re-infections (44.1 %; 95 % CI 33.8–54.8) or those with recrudescent infections (48.3 %; 95 % CI 29.4–67.5), compared to those with an adequate clinical and parasitological response (36.7 %; 95 % CI 30.0-43.9) (P = 0.25 and P = 0.31, respectively). However, patients carrying either CYP2C8*2 or CYP2C8*3 alleles were significantly associated with an increased occurrence of non-serious adverse events, when compared with CYP2C8 *1/*1 wild type homozygotes (44.9 %; 95 % CI 36.1–54.0 vs. 28.1 %; 95 % CI 21.9–35.0, respectively; P = 0.003).ConclusionsCYP2C8 genotypes did not influence treatment efficacy directly, but the tolerability to AS–AQ may be reduced in subjects carrying the CYP2C8*2 and CYP2C8*3 alleles. The importance of this non-negligible association with regard to amodiaquine-based malaria chemotherapy warrants further investigation.