Treatment Of Vivax Malaria Research Articles

Real-life quantitative G6PD screening in Plasmodium vivax patients in the Brazilian Amazon: A cost-effectiveness analysis.

BackgroundAs quantitative glucose 6-phosphate dehydrogenase deficiency (G6PDd) screening tools are evaluated in operational studies, questions remain as to whether they are cost-effective. Here, a cost-effectiveness analysis (CEA) was performed to estimate the Incremental Cost-effectiveness Ratio (ICER) of the introduction of quantitative screening test to detect G6PDd among P. vivax carriers in two municipalities in the Brazilian Amazon.Methodology/Principal findingsThis cost-effectiveness analysis evaluated the use of the Standard G6PD quantitative screening test in vivax malaria treatment units in two municipalities of the Brazilian Amazon. Using the perspective of the Brazilian public health system, the analysis was performed for the outcome ‘PQ-associated hospitalization avoided’, based on a decision tree model. The results indicated that the G6PDd screening strategy compared with the routine strategy was highly cost-effective, with an ICER of US$495 per additional hospitalization avoided, which represented less than 8% of one Brazilian gross domestic product per capita (US$6,822). The uncertainties evaluated in the sensitivity analysis did not significantly affect the ICER identified in the base-case.Conclusions/SignificanceThis cost-effectiveness analysis showed the quantitative G6PD testing was effective in avoiding PQ-associated hospitalizations. The incorporation of G6PD screening is of paramount importance towards P. vivax malaria elimination in the Amazon to promote the safe use of primaquine and tafenoquine.

Efficacy and safety of dihydroartemisinin\u2013piperaquine for the treatment of uncomplicated Plasmodium falciparum and Plasmodium vivax malaria in Papua and Sumatra, Indonesia

BackgroundDihydroartemisinin–piperaquine (DHA–PPQ) has been adopted as first-line therapy for uncomplicated falciparum malaria in Indonesia since 2010. The efficacy of DHA–PPQ was evaluated in 2 sentinel sites in Keerom District, Papua and Merangin District, Jambi, Sumatra from April 2017 to April 2018.MethodsClinical and parasitological parameters were monitored over a 42-day period following the World Health Organization standard in vivo protocol and subjects meeting the inclusion criteria were treated with DHA–PPQ once daily for 3 days, administered orally.ResultsIn Papua, 6339 subjects were screened through active and passive cases detection. Of the 114 falciparum and 81 vivax cases enrolled, 102 falciparum and 80 vivax cases completed the 42 day follow up, and 12 falciparum and 1 vivax cases were either lost to follow up or withdrawn. Kaplan–Meier analysis of microscopy readings of 102 falciparum cases revealed 93.1% (95% CI 86.4–97.2) as Adequate Clinical and Parasitological Response (ACPR). No delay in parasite clearance nor severe adverse reaction was observed. Recurrent parasites of Plasmodium falciparum were detected in 7 cases and categorized as late treatment failures (LTF) at days 21, 35, and 42 and one of which was reinfected by Plasmodium vivax at day 42. Two cases were confirmed as recrudescent infection and 4 were re-infection. The PCR-corrected DHA–PPQ efficacy for P. falciparum was 97.9% (95% CI 92.7–99.7). Of the 80 cases of P. vivax that were followed up, 71 cases were completely cured and classified as ACPR (88.8%, 95% CI 79.7–94.7) and 9 cases showed recurrent infection at days 35 and 42, and classified as LTF. In Sumatra, of the 751 subjects screened, 35 vivax subjects enrolled, 34 completed the 42 day follow up. Thirty-three cases were completely cured and classified as ACPR (97.1%, 95% CI 84.7–99.9) and 1 recurrent infection was observed and classified as LTF. No delay in parasite clearance nor severe adverse reaction was observed. Analysis of the Pfk13 gene in P. falciparum cases from Papua revealed no mutations associated with artemisinin resistance in the 20 SNPs previously reported. Analysis of the Pfpm2 gene at day 0 and day of recurrence in recrudescent cases revealed the same single copy number, whereas 3 of the 4 re-infection cases carried 2–3 Pfpm2 gene copy numbers.ConclusionTreatment of falciparum and vivax malaria cases with DHA–PPQ showed a high efficacy and safety.

Influence of CYP2D6, CYP3A4 and CYP2C19 Genotypes on Recurrence of Plasmodium vivax

BackgroundThe influence of the CYPs (cytochrome P-450) in the success of antimalarial therapy remains uncertain. In this study, the association of CYP2D6, CYP2C19 and CYP3A4 polymorphisms and predicted phenotypes with malaria recurrence was investigated.MethodsAfter diagnosis of vivax malaria, individuals treated at a reference center in Manaus were followed up for 180 days. Patients were separated into two groups: a recurrence group and a non-recurrence group. Genotyping of CYP2D6, CYP2C19 and CYP3A4 was performed using a TaqMan™ assay and real-time PCR.FindingsThe frequencies of decreased-function and normal-function alleles and phenotypes for all CYPs were similar between the groups, except for the CYP2D6*2xN allele (p=0.047) and the CYP2D6 gUM phenotype (p=0.057), which were more frequent in individuals without recurrence. Despite this, the CYP2D6, CYP2C19 and CYP3A4 genotypes had no association with an increased risk of recurrence. CYPs polymorphisms also had no influence in parasite clearance, neither in the time nor the number of recurrence episodes. MAINConclusionThis prospective cohort study demonstrated that CYP2D6, CYP2C19 and CYP3A4 polymorphisms have no influence on malaria recurrence. Nonetheless, our findings suggest that the CYP2D6 predicted ultrarapid phenotype was less susceptible to recurrence, and that patients with the CYP2D6 gUM phenotype are less susceptible to primaquine failure. Additional investigation of pharmacogenetics and pharmacokinetics are needed before implementing CYP analysis to better orientate individualized radical treatment of vivax malaria in reference centers that treat patients with multiple recurrences.

A simple quinoline salt derivative is active in vitro against Plasmodiumfalciparum asexual blood stages and inhibits the development of cerebral malaria in murine model

Chloroquine (CQ) was the most effective and widely used drug for the prophylaxis and treatment of severe and non-severe malaria. Although its prophylactic use has led to resistance to P. falciparum in all endemic countries, CQ still remains the drug of choice for the treatment of vivax malaria. Otherwise, the speed in which parasite resistance to available antimalarials rises and spreads in endemic regions points to the urgent need for the development of new antimalarials. Quinoline derivatives have been used as a tool in the search for new drugs and were investigated in the present study in an attempt to produce a HIT compound to avoid the cerebral malarial (CM). Seven compounds were synthesized, including three quinoline derivate salts. The cytotoxicity and antiplasmodial activity were assayed in vitro, highlighting compound 3 as a HIT, which also showed interaction with ferriprotoporphyrin IX similarly to CQ. Physicochemical and pharmacokinetic properties of absorption were found to be favorable when analyzed in silico. The in vivo assays, using the experimental cerebral malaria (ECM) model, showed important values of parasite growth inhibition on the 7th day-post infection (Q15 15 mg/kg: 76.9%, Q30 30 mg/kg: 90,1% and Q50 50 mg/kg: 92,9%). Compound 3 also showed significant protection against the development of CM, besides hepatic and renal parameters better than CQ. In conclusion, this quinoline derivative demonstrated promising activity for the treatment of malaria and was able to avoid the development of severe malaria in mice.

Pharmacokinetics of chloroquine and primaquine in healthy volunteers

BackgroundVivax malaria is a neglected disease. There is an irrefutable need for better treatments with higher acceptability and efficacy. The treatment efficacy is influenced by many factors, including bioavailability. Hence, a straightforward strategy to improve vivax malaria treatment efficacy is the deployment of good quality formulations of primaquine and chloroquine. As these treatments were developed more than 70 years ago, many of the available data on blood levels of both drugs are based on obsolete analytical methodologies or pharmaceutical formulations, which are not available anymore. Herein, the results of three bioequivalence studies are presented, providing individual pharmacokinetic data on chloroquine and primaquine of more than a hundred healthy volunteers and using up-to-date analytical methods.MethodsThree trials were designed as a single centre, randomized, single dose, open label, fasting, crossover bioequivalence studies comparing a new coated chloroquine tablet to the uncoated tablet, and 5 and 15 mg primaquine formulations to either an international reference product or the currently distributed tablets. Plasma concentrations of chloroquine and primaquine were measured using a validated HPLC–MS/MS method in accordance with current international regulatory requirements for bio-analytical methods.ResultsIn total, a hundred eleven healthy volunteers of both genders were included in the three studies (n = 32; 30 and 56 respectively). No serious adverse events occurred. Drugs levels were measured in 5,520 blood samples. The estimated ratio of the geometric means of Cmax, AUC0-t and AUC0-inf of test and reference drugs and their 90% CI for chloroquine 150 mg, primaquine 15 mg and primaquine 5 mg were: 95.33% (89.18; 101.90), 86. 85% (82.61; 91.31), and 84.45% (76.95; 92.67); 93.28% (81.76; 106.41), 94.52% (86.13; 103.73) and 93.93% (85.83; 102.79); 97.44% (90.60; 104.78), 93.70% (87.04; 100.87) and 91.36% (85.27; 97.89), respectively. As Cmax and AUC0-t 90% CI were within the acceptance interval of 80–125% in all cases, the formulations tested were bioequivalent.ConclusionsIn conclusion, the three studies provided detailed chloroquine and primaquine pharmacokinetic data in accordance with current regulatory standards. Together with other open data initiatives, this individual data may increase the accuracy of pharmacokinetic models guiding best dose, new combinations, regimens and formulations to optimize the current chloroquine and primaquine treatments for vivax malaria. The data presented here may support the deployment of high-quality drugs and evidence-based public health policies.

Safety of Weekly Primaquine in Glucose 6 Phosphatase Dehydrogenase (G6PD) Deficient Children

Aim: To assess the Safety of weekly Primaquine in Glucose 6 Phosphatase Dehydrogenase (G6PD) deficient children, for radical treatment of Plasmodium vivax malaria
 Study Design: cross sectional study
 Place and Duration: Pediatrics Out Patient Department, Liaquat University of Medical and Health Sciences Hyderabad from 11 January 2018 to 31st August 2019 (total 20 months’ duration)
 Methodology: A sample of 40 patients was studied during study period. Male children between 4 years to 12 years of age having confirmed vivax malaria were included in the study. If G6PD result showed decreased level of G6PD level then, they were enrolled for study. MP was checked by thick and thin slide method. 5 ml blood was taken in anticoagulant bottle for G6PD, liver function test, creatinine, complete blood count, and reticulocyte count tests. Haemoglobin < 7 g/dL, reticulocyte count > 4, SGPT > 80, G6PD Level < 60% of normal and creatinine > 1.2 was considered significant. Treatment was given with Artemether and Lumefantrine for 3 days while Primaquine, 0 .75 mg base/kg body weights once a week was given for 8 weeks. Patients were followed at OPD initially on 3rd day of therapy then every week for 8 weeks for any hemolysis. 
 Results: There was no hemolysis during the first week and 8 weeks after therapy. Most common side effect was abdominal pain 4 (10%). Mean hemoglobin was 11.8mg/dl. Plasmodium vivax was negative on 3rd day of therapy, it was also negative on 8 week of therapy. Reticulocyte count, Liver function test, creatinine were also normal on 8 weeks of therapy.
 Conclusion: Primaquine 0.75mg//kg/week for total eight weeks is highly effective for the radical cure of Plasmodium vivax in G6PD deficient children. There is no recurrence of Plasmodium vivax after 8 weeks of therapy. We found this regimen safe as there was no hemolysis demonstrated in children.

In vivo efficacy of anti-malarial drugs against clinical Plasmodium vivax malaria in Ethiopia: a systematic review and meta-analysis

BackgroundEthiopia is one of the few countries in Africa where Plasmodium vivax commonly co-exists with Plasmodium falciparum, and which accounts for ~ 40% of the total number of malaria infections in the country. Regardless of the growing evidence over many decades of decreasing sensitivity of this parasite to different anti-malarial drugs, there has been no comprehensive attempt made to systematically review and meta-analyse the efficacy of different anti-malarial drugs against P. vivax in the country. However, outlining the efficacy of available anti-malarial drugs against this parasite is essential to guide recommendations for the optimal therapeutic strategy to use in clinical practice. The aim of this study was to synthesize evidence on the efficacy of anti-malarial drugs against clinical P. vivax malaria in Ethiopia.MethodsAll potentially relevant, peer-reviewed articles accessible in PubMed, Scopus, Web of Science, and Clinical Trial.gov electronic databases were retrieved using a search strategy combining keywords and related database-specific subject terms. Randomized controlled trials (RCTs) and non-randomized trials aiming to investigate the efficacy of anti-malarial drugs against P. vivax were included in the review. Data were analysed using Review Manager Software. Cochrane Q (χ2) and the I2 tests were used to assess heterogeneity. The funnel plot and Egger’s test were used to examine risk of publication bias.ResultsOut of 1294 identified citations, 14 articles that presented data on 29 treatment options were included in the analysis. These studies enrolled 2144 clinical vivax malaria patients. The pooled estimate of in vivo efficacy of anti-malarial drugs against vivax malaria in Ethiopia was 97.91% (95% CI: 97.29–98.52%), with significant heterogeneity (I2 = 86%, p < 0.0001) and publication bias (Egger’s test = -12.86, p < 0.001). Different anti-malarial drugs showed varied efficacies against vivax malaria. The duration of follow-up significantly affected the calculated efficacy of any given anti-malarial drug, with longer duration of the follow-up (42 days) associated with significantly lower efficacy than efficacy reported on day 28. Also, pooled PCR-corrected efficacy and efficacy estimated from altitudinally lower transmission settings were significantly higher than PCR-uncorrected efficacy that estimated for moderate transmission settings, respectively.ConclusionThe overall efficacy of anti-malarial drugs evaluated for the treatment of vivax malaria in Ethiopia was generally high, although there was wide-ranging degree of efficacy, which was affected by the treatment options, duration of follow-up, transmission intensity, and the confirmation procedures for recurrent parasitaemia. Regardless of evidence of sporadic efficacy reduction reported in the country, chloroquine (CQ), the first-line regimen in Ethiopia, remained highly efficacious, supporting its continuous utilization for confirmed P. vivax mono-infections. The addition of primaquine (PQ) to CQ is recommended, as this is the only approved way to provide radical cure, and thus ensure sustained efficacy and longer protection against P. vivax. Continuous surveillance of the efficacy of anti-malarial drugs and clinical trials to allow robust conclusions remains necessary to proactively act against possible emergence and spread of drug-resistant P. vivax in Ethiopia.

Primaquine and the power of adherence in radical cure

Primaquine has long held pride of place in malaria treatment as the only 8-aminoquinoline with the main indication of providing a radical cure—ie, destruction of the liver hypnozoites unique to Plasmodium vivax and Plasmodium ovale malaria. 1 Baird JK 8-Aminoquinoline therapy for latent malaria. Clin Microbiol Rev. 2019; 32: e00011-e00019 Crossref PubMed Scopus (32) Google Scholar Supervised versus unsupervised primaquine radical cure for the treatment of falciparum and vivax malaria in Papua, Indonesia: a cluster-randomised, controlled, open-label superiority trialIn this area of moderate malaria transmission, supervision of primaquine radical cure treatment reduced the risk of P vivax recurrence. This finding was apparent for patients presenting with either P falciparum or P vivax malaria. Further studies are warranted to investigate the safety and efficacy of radical cure for patients presenting with uncomplicated falciparum malaria in other co-endemic areas. Full-Text PDF Open Access

Supervised versus unsupervised primaquine radical cure for the treatment of falciparum and vivax malaria in Papua, Indonesia: a cluster-randomised, controlled, open-label superiority trial

SummaryBackgroundThere is a high risk of Plasmodium vivax recurrence in patients treated for Plasmodium falciparum malaria in co-endemic areas. Primaquine radical cure has the potential to reduce P vivax recurrences in patients presenting with P falciparum as well as P vivax malaria but is undermined by poor adherence to the currently recommended 14-day regimen. We aimed to assess the efficacy and safety of supervised versus unsupervised primaquine radical cure in patients presenting with uncomplicated malaria.MethodsWe did a cluster-randomised, controlled, open-label superiority trial in Papua, Indonesia. 21 clusters of village health posts, matched by annual parasite index, were randomly assigned (1:1) to treat patients (age >12 months and body weight >5 kg) presenting with confirmed uncomplicated P falciparum or P vivax malaria with oral dihydroartemisinin–piperaquine plus either a supervised or unsupervised 14-day course of oral primaquine (0·5 mg/kg per day). Patients in the supervised group were supervised taking their primaquine dose on alternate days. Patients were followed-up for 6 months and those who presented again with malaria were retreated with the same drug regimen. Masking was not possible due to the nature of the study. The primary outcome was the incidence risk of P vivax malaria over 6 months, assessed in the modified intention-to-treat population (all patients who were assigned to a treatment group, excluding patients who were lost to follow-up after their first visit). This trial is now complete, and is registered with ClinicalTrials.gov, NCT02787070.FindingsBetween Sept 14, 2016, and July 31, 2018, 436 patients were screened for eligibility and 419 were enrolled; 223 (53%) patients in 11 clusters were assigned to supervised primaquine treatment and 196 (47%) in ten clusters to unsupervised primaquine treatment. 161 (72%) of 223 patients in the supervised group and 151 (77%) of 196 in the unsupervised group completed 6 months of follow-up. At 6 months, the incidence risk of P vivax recurrence in the supervised group was 29·7% (95% CI 16·4–49·9) versus 55·8% (32·3–81·8) in the unsupervised group (hazard ratio 0·23 [95% CI 0·07–0·76]; p=0·016). The incidence rate for P vivax recurrence was 539 (95% CI 390–747) infections per 1000 person-years in the supervised group versus 859 (673–1096) in the unsupervised group (incidence rate ratio 0·63 [95% CI 0·42–0·94]; p=0·025). The corresponding rates in the 224 patients who presented with P falciparum malaria were 346 (95% CI 213–563) and 660 (446–977; incidence rate ratio 0·52 [95% CI 0·28–0·98]; p=0·043). Seven serious adverse events were reported (three in the supervised group, four in the unsupervised group), none of which were deemed treatment-related, and there were no deaths.InterpretationIn this area of moderate malaria transmission, supervision of primaquine radical cure treatment reduced the risk of P vivax recurrence. This finding was apparent for patients presenting with either P falciparum or P vivax malaria. Further studies are warranted to investigate the safety and efficacy of radical cure for patients presenting with uncomplicated falciparum malaria in other co-endemic areas.FundingThe Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Foreign Affairs and Trade of the Australian Government.TranslationFor the Indonesian translation of the abstract see Supplementary Materials section.

A Profile of Glucose-6-Phosphate Dehydrogenase Variants and Deficiency of Multicultural Families in Korea.

Vivax malaria incidence in Korea is now decreased and showing a low plateau. Nowadays, vivax malaria in Korea is expected to be successfully eliminated with anti-malaria chemotherapy, primaquine, and vector control. The glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with potential hemolytic anemia after primaquine administration. This inborn disorder has a pivotal polymorphism with genetic variants and is the most prevalent X-chromosome-linked disorder. The prevalence of G6PD deficiency was previously reported negligible in Korea. As the population of multicultural families pertaining marriage immigrants and their adolescents increases, it is necessary to check G6PD deficiency for them prior to primaquine treatment for vivax malaria. The prevalence of G6PD variants and G6PD deficiency in multicultural families was performed in 7 counties and 2 cities of Jeollanam-do (Province), Gyeonggi-do, and Gangwon-do. A total of 733 blood samples of multicultural family participants were subjected to test the phenotypic and genetic G6PD deficiency status using G6PD enzyme activity quantitation kit and PCR-based G6PD genotyping kit. The G6PD phenotypic deficiency was observed in 7.8% of male adolescent participants and 3.2% of materfamilias population. Based on the PCR-based genotyping, we observed total 35 participants carrying the mutated alleles. It is proposed that primaquine prescription should seriously be considered prior to malaria treatment.

Reference and point-of-care testing for G6PD deficiency: Blood disorder interference, contrived specimens, and fingerstick equivalence and precision.

Certain clinical indications and treatments such as the use of rasburicase in cancer therapy and 8-aminoquinolines for Plasmodium vivax malaria treatment would benefit from a point-of-care test for glucose-6-phosphate dehydrogenase (G6PD) deficiency. Three studies were conducted to evaluate the performance of one such test: the STANDARD™ G6PD Test (SD BIOSENSOR, South Korea). First, biological interference on the test performance was evaluated in specimens with common blood disorders, including high white blood cell (WBC) counts. Second, the test precision on fingerstick specimens was evaluated against five individuals of each, deficient, intermediate, and normal G6PD activity status. Third, clinical performance of the test was evaluated at three point-of-care settings in the United States. The test performed equivalently to the reference assay in specimens with common blood disorders. High WBC count blood samples resulted in overestimation of G6PD activity in both the reference assay and the STANDARD G6PD Test. The STANDARD G6PD Test showed good precision on multiple fingerstick specimens from the same individual. The same G6PD threshold values (U/g Hb) were applied for a semiquantitative interpretation for fingerstick- and venous-derived results. The sensitivity/specificity values (95% confidence intervals) for the test for G6PD deficiency were 100 (92.3–100.0)/97 (95.2–98.2) and 100 (95.7–100.0)/97.4 (95.7–98.5) for venous and capillary specimens, respectively. The same values for females with intermediate (> 30% to ≤ 70%) G6PD activity were 94.1 (71.3–99.9)/88.2 (83.9–91.7) and 82.4 (56.6–96.2)/87.6(83.3–91.2) for venous and capillary specimens, respectively. The STANDARD G6PD Test enables point-of-care testing for G6PD deficiency.

The prevention and treatment of Plasmodium vivax malaria.

Cindy S Chu and co-authors review options for diagnosis, safe and radical cure, and relapse prevention of Plasmodium Vivax.

CYP2D6 Genetic Variation and Its Implication for Vivax Malaria Treatment in Madagascar.

Plasmodium vivax is one of the five human malaria parasite species, which has a wide geographical distribution and can cause severe disease and fatal outcomes. It has the ability to relapse from dormant liver stages (hypnozoites), weeks to months after clearance of the acute blood-stage infection. An 8-aminoquinoline drug primaquine (PQ) can clear the hypnozoites, and thus can be used as an anti-relapse therapeutic agent. Recently, a number of studies have found that its efficacy is compromised by polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene; decreased or absence of CYP2D6 activity contributes to PQ therapeutic failure. The present study sought to characterize CYP2D6 genetic variation in Madagascar, where populations originated from admixture between Asian and African populations, vivax malaria is endemic, and PQ can be deployed soon to achieve national malaria elimination. In a total of 211 samples collected from two health districts, CYP2D6 decreased function alleles CYP2D6*10, *17, *29, *36+*10, and *41 were observed at frequencies of 3.55–17.06%. In addition, nonfunctional alleles were observed, the most common of which were CYP2D6*4 (2.13%), *5 (1.66%), and the *4x2 gene duplication (1.42%). Given these frequencies, 34.6% of the individuals were predicted to be intermediate metabolizers (IM) with an enzyme activity score (AS) ≤ 1.0; both the IM phenotype and AS ≤ 1.0 have been found to be associated with PQ therapeutic failure. Furthermore, the allele and genotype frequency distributions add to the archaeological and genomic evidence of Malagasy populations constituting a unique, Asian-African admixed origin. The results from this exploratory study provide fresh insights about genomic characteristics that could affect the metabolism of PQ into its active state, and may enable optimization of PQ treatment across human genetic diversity, which is critical for achieving P. vivax elimination.

Efficacy Study of Chloroquine to Plasmodium vivax Malaria in Darimu and Bure Districts, Southwest Ethiopia.

BackgroundChloroquine (CQ) is the first line treatment for vivax malaria in Ethiopia. However, the therapeutic efficacy of the drug is now declining. Several reports from different areas of the country showed CQ-vivax treatment failure increasing. This study therefore aimed to provide additional data on the therapeutic efficacy of CQ against Plasmodium vivax malaria from two districts of Southwestern Ethiopia.MethodsAn observational prospective study among P. vivax malaria infected individuals was conducted in two districts of Southwest Ethiopia for a period of 28 follow-up days. Study participants were treated with 25 mg/kg of standard CQ for 3 consecutive days according to the procedure. Microscopic blood film examinations and other clinical assessments were measured within the follow-up period on a weekly basis.ResultsA total of 115 patients were enrolled in the study. Sixty-five were from Darimu and 50 were from Bure districts. The majority (67%) of study participants were male and 86.1% (99/115) were below 35 years old. The study revealed that CQ treatment was able to clear vivax malaria parasites and febrile within a week. During the follow-up study period, recurrence of vivax parasitemia was not recorded. However, there was a marked heterogeneity with respect to fever clearance time, parasitemia load, and carriage of parasite gametocyte within 72 hours of post-treatment between the two study areas.ConclusionThe present study revealed that CQ has good clinical and parasitological response to vivax malaria in the study areas. Thus, it can be continued as the first line P. vivax malaria treatment. However, further monitoring and evaluation of the drug should be considered.

Towards one standard treatment for uncomplicated Plasmodium falciparum and Plasmodium vivax malaria: Perspectives from and for the Peruvian Amazon

Malaria continues to wreak havoc in the Peruvian Amazon. Lengthy research efforts have brought important lessons on its particular epidemiology: the heterogeneous levels of transmission, the large reservoir of both asymptomatic and submicroscopic infections, the co-transmission of Plasmodium vivax and Plasmodium falciparum in the same areas, and the limitations of current diagnostics. Based on these features, the national elimination program could greatly benefit from simplified standard treatment, with the use of artemisinin-based combination therapy and even shorter schemes of primaquine maintaing the total dosing. It is acknowledged that there is some uncertainty regarding the true prevalence of glucose-6-phosphate dehydrogenase deficiency (G6PD) and genetic polymorphisms related to cytochrome P-450 isozyme 2D6 functioning. Once we have a better understanding, tafenoquine, whether or not in combination with a rapid G6PD enzyme test, may become a future pathway to eliminate the otherwise hidden reservoir of the P. vivax hypnozoite through one standard Plasmodium treatment.

Clinical characteristics of 66 imported malaria cases in Xixi Hospital of Hangzhou

Objective To analyze the clinical data and drug treatment of malaria patients Xixi Hospital of Hangzhou, February 2014 – December 2019, and we provide reference data for early clinical diagnosis, assessment of severity and treatment, and promote rational clinical medication. Methods A total of 66 malaria patients admitted to hospital from February 2014 to December 2019 were collected to distinguish mild and severe cases. The laboratory test results and drug use of the two groups were compared, and the indicators of the two groups were analyzed by multi-factor binary Logistic Stepwise regression analysis. Results In the treatment of 17 patients with severe falciparum malaria, 10 patients artesunate injection and subsequent dihydroartemisinin-piperaquine tablets were used to consolidate the treatment, and the treatment effect was good. Among 34 patients with mild falciparum malaria, 28 patients were treated with dihydroartemisinin-piperaquine tablets alone, with sensitive effect and high cure rate. For 8 cases of vivax malaria and 4 cases of ovale malaria, 6 patients were treated with chloroquine phosphate plus primaquine phosphate 8-day regimen, and 6 patients were treated with artemisinin-based drugs, and the treatment effect was good. There was statistically significant difference in age, cure time, white blood cells (WBC), red blood cells, hemoglobin, platelets, aspartate transaminase, total bilirubin, C-reactive protein and procalcitonin (PCT) between mild group and severe group ( P <0.05). Multi-factor binary Logistic Stepwise regression analysis showed that the related factors influencing the severity of malaria included age, WBC and PCT. Conclusion Artemisinin-based injections combined with ACTs (Combinatorial therapy) are more effective in treating severe and malignant diseases. Artemisinin alone is effective in the treatment of vivax malaria and ovale malaria in the absence of preferred drugs. There are many factors, such as age, cure time, white blood cells, red blood cells, hemoglobin, platelets, aspartate transaminase, total bilirubin, C-reactive protein and procalcitonin, influencing the severity of malaria, among which age, leukocyte and procalcitonin are of great significance for the prediction and evaluation of malaria severity. 摘要:目的 分析杭州市西溪医院2014年2 月一2019年 12月收治的疟疾患者临床资料及药物治疗情况,为临床早 期诊断、评估轻重以及治疗提供参考数据,促进临床合理用药。 方法 收集2014年 2 月一2019年12月收治人院的66 例疟疾患者资料,分为轻症组和重症组,对两组患者的实验室检测指标结果、药物使用情况进行比较,并采用多因素二 元 Logistic 对两组患者的指标作逐步回归分析。 结果 17 例重症恶性疟患者治疗中, 10 例患者尽早、足量、足疗程使用 青蒿琥酯针及后续双氢青蒿素哌喹片巩固治疗,效果良好。 34 例轻症恶性疟疾患者, 28 例单独使用双氢青蒿素哌喹 片,效果敏感,治愈率高。 8 例间日疟和 4 例卵形疟, 6 例患者使用磷酸氯喹加磷酸伯氨喹八日方案, 6 例患者选用青蒿 素类药物,效果均良好。经Pearson单因素分析,轻症组与重症组在年龄、治愈时间、白细胞、红细胞、血红蛋白、血小板、谷草转氨酶、总胆红素、C-反应蛋白及降钙素原间差异具有统计学意义( P <0.05);经多元 Logistic 回归分析,影响疟疾轻 重症分型的相关因素包括:年龄、白细胞计数、降钙素原。 结论 青蒿素类注射液治疗后联用青蒿素类复方(ACTs)能 更有效治疗重症恶性疟疾。在缺乏首选药物的情况下单用青蒿素类药物治疗间日疟、卵形疟效果良好。影响疟疾发 病后重症化的因素有年龄、治愈时间、白细胞、红细胞、血红蛋白、血小板、谷草转氨酶、总胆红素、C-反应蛋白及降钙素 原,其中年龄、白细胞及降钙素原对疟疾严重程度的预测评估意义重大。

Study of Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency and Genotype Polymorphism of G6PD B and G6PD (A+/A-) in Patients Treated for Plasmodium vivax Malaria in a Tertiary Care Hospital in North East India.

IntroductionGlucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency is the most common enzymopathy in humans, and its distribution has been historically described to be closely associated with that of malaria. North East India provides optimal conditions for transmission of malaria and bears a considerable burden of Plasmodium vivax (P. vivax) malaria. Primaquine, a mainstay in the treatment of vivax malaria, may trigger episodes of acute hemolysis in patients with G6PD deficiency. The present study sought to delineate the frequency and genotypes of G6PD deficiency among patients suffering from vivax malaria infections. MethodsBlood specimens from 80 individuals diagnosed with vivax malaria underwent enzyme assay for G6PD deficiency. Samples with deficient phenotype underwent isolation of DNA using a genomic DNA isolation kit (Qiagen India Pvt. Ltd., New Delhi, India). The genomic DNA underwent amplification, serial denaturation, annealing, extension, final extension followed by digestion with restriction endonucleases Nla III and Fok I. The digested products were subjected to horizontal agarose electrophoresis for the separation of digested fragments. Samples without nucleotide 376 adenine→guanine (A→G) mutation were classified as G6PD B. Those with the mutation were further classified into G6PD A(+) and G6PD A(-) based on the presence of Nla III site.ResultsTwenty-seven out of 80 individuals (33.75%) with P. vivax malaria were found to have G6PD deficiency, of which a majority (n=24) had G6PD B genotype. Three individuals had Asparagine→Aspartic Acid mutation at position 376 (A→G), of which G6PD A(+) and G6PD A(-) were present in two and one cases, respectively.ConclusionG6PD deficiency was noted in about a third of patients with vivax malaria. Since primaquine therapy is contraindicated in this group of patients, there is a rationale for looking into screening patients with vivax malaria from the region prior to primaquine therapy. Further large scale studies may substantiate this and help in better genotypic and geographic characterization of G6PD deficiency in the region.

The risk of adverse clinical outcomes following treatment of Plasmodium vivax malaria with and without primaquine in Papua, Indonesia.

The widespread use of primaquine (PQ) radical cure for P. vivax, is constrained by concerns over its safety. We used routinely collected patient data to compare the overall morbidity and mortality in patients treated with and without PQ without prior testing of Glucose-6-Phosphate-Dehydrogenase (G6PD) deficiency in Papua, Indonesia, where there is a low prevalence of G6PD deficiency. Records were collated from patients older than 1 year, with P. vivax infection, who were treated with an artemisinin combination therapy (ACT). The risks of re-presentation, hospitalization, major fall in haemoglobin and death within 30 days were quantified and compared between patients treated with and without PQ using a Cox regression model. In total 26,216 patients with P. vivax malaria presented to the hospital with malaria during the study period. Overall 27.56% (95% Confidence Interval (95%CI): 26.96–28.16) of 21,344 patients treated with PQ re-presented with any illness within 30 days and 1.69% (1.51–1.88) required admission to hospital. The corresponding risks were higher in the 4,872 patients not treated with PQ; Adjusted Hazard Ratio (AHR) = 0.84 (0.79–0.91; p<0.001) and 0.54 (0.41–0.70; p<0.001) respectively. By day 30, 14.15% (12.45–16.05) of patients who had received PQ had a fall in haemoglobin (Hb) below 7g/dl compared to 20.43% (16.67–24.89) of patients treated without PQ; AHR = 0.66 (0.45–0.97; p = 0.033). A total of 75 (0.3%) patients died within 30 days of treatment with a mortality risk of 0.27% (0.21–0.35) in patients treated with PQ, compared to 0.38% (0.24–0.60) without PQ; AHR = 0.79 (0.43–1.45; p = 0.448). In Papua, Indonesia routine administration of PQ radical cure without prior G6PD testing, was associated with lower risk of all cause hospitalization and other serious adverse clinical outcomes. In areas where G6PD testing is not available or cannot be delivered reliably, the risks of drug induced haemolysis should be balanced against the potential benefits of reducing recurrent P. vivax malaria and its associated morbidity and mortality.

Impact of Plasmodium vivax malaria and antimalarial treatment on cytochrome P450 activity in Brazilian patients.

To investigate the impact of Plasmodium vivax malaria and chloroquine-primaquine chemotherapy on CYP2D6 and CYP2C19 activity in patients from the Brazilian Amazon. Adult patients (n = 30) were given subtherapeutic doses of CYP2D6 and CYP2C19 phenotypic probes metoprolol (10 mg) and omeprazole (2 mg) in three different stages of vivax malaria illness: acute disease (study phase 1), post chemotherapy (phase 2) and convalescence (stage 3). Plasma concentrations of probes and CYP-hydroxylated metabolites (α-OH metoprolol and 5-OH omeprazole) were measured using LC/MS/MS. Two pharmacokinetic metrics were used to estimate CYP activity: (a) ratio of plasma concentrations of probe/metabolite at 240 minutes after administration of the probes and (b) ratio of areas under the time-concentration curves for probe/metabolite (AUC0-12h ). For statistical analysis, the pharmacokinetic metrics were normalized to the respective values in phase 3. Taqman assays were used for CYP2D6 and CYP2C19 genotyping. Cytokines levels were measured using cytometric bead array. Both pharmacokinetic metrics for metoprolol and omeprazole, and plasma concentrations of cytokines IL-6, IL-8 and IL-10 varied significantly across the three study phases (ANOVA P < 0.0001). Post hoc tests showed greater metoprolol:α-OH metoprolol ratios in phases 1 and 2 compared to phase 3, larger omeprazole:5-OH omeprazole ratios in phase 1 than in phases 2 and 3, and higher circulating IL-6, IL-8 and IL-10 in phase 1 than in phases 2 and 3. P. vivax malaria and treatment altered CYP2D6 and CYP2C19 metabolic phenotypes. CYP2C19 inhibition is attributed to a higher level of circulating proinflammatory cytokines, while suppression of CYP2D6 is ascribed mainly to chloroquine exposure.

Doses of primaquine administered to children with Plasmodium vivax according to an age-based dose regimen

ABSTRACT Primaquine is still the first-line drug to eliminate hypnozoites of Plasmodium vivax. The therapeutic efficacy is related to the total dose administered. In several endemic areas, the drug is administered for children in an age-based regimen, which can lead to inadequate exposure, increasing the rates of recurrence of the infection. The present study aims to describe the mg/kg total dose of primaquine administered to children for treatment for vivax malaria when an age-based regimen is used and to measure the plasma concentrations of primaquine and carboxyprimaquine. A total of 85 children were included in the study. The total dose of primaquine administered based on mg/kg had a median value of 3.22 mg/kg. The percentage of patients with a total dose below the required dose of 3.5 mg/kg was 55.75%. The median primaquine maximum concentration was 94 ng/ml. For carboxy-primaquine, the median maximum concentration was 375 ng/ml. The results suggest that age-based dosing regimens likely lead to substantial under-dosing of primaquine, which is evident in the youngest children and is reflected in decreased levels of primaquine and carboxy-primaquine in plasma samples 13.