Artemisinin-naphthoquine combination (ARCO™) therapy for uncomplicated falciparum malaria in adults of Papua New Guinea: A preliminary report on safety and efficacy

<p>Abstract</p> <p>Background</p> <p>The use of anti-malarial drug combinations with artemisinin or with one of its derivatives is now widely recommended to overcome drug resistance in falciparum as well as vivax malaria. The fixed oral dose artemisinin-naphthoquine combination (ANQ, ARCO™) is a newer artemisinin-based combination (ACT) therapy undergoing clinical assessment. A study was undertaken to assess the safety, efficacy and tolerability of ANQ combination in areas of multi-drug resistance to generate preliminary baseline data in adult population of Papua New Guinea.</p> <p>Methods</p> <p>The clinical assessment was an open-labeled, two-arm, randomized study comparing ANQ combination as a single dose regimen and three days regimen (10 mg/kg/day) of chloroquine plus single dose sulphadoxine-pyrimethamine (CQ+SP) for the treatment of uncomplicated falciparum malaria with 28 days follow-up in an adult population. The primary outcome measures for efficacy were day 1, 2, 3 7, 14 and 28-day cure rates. Secondary outcomes included parasite clearance time, fever clearance time, and gametocyte carriage. The main outcome measures for safety were incidences of post-treatment clinical and laboratory adverse events.</p> <p>Results</p> <p>Between June 2005 and July 2006, 130 patients with confirmed uncomplicated <it>P. falciparum </it>were randomly assigned to receive ANQ and CQ+SP, only 100 patients (51 in ANQ group and 49 in CQ+SP group) were evaluated for clinical and parasitological outcomes. All the patients treated with ANQ and CQ+SP showed adequate clinical and parasitological response with 28 days follow-up. The cure rate for ANQ on day 1, 2, 3, 7, 14, and 28 was 47%, 86%, 92%, 94%, 94% and 94%, respectively. Recrudescence account for 6%; all were cleared on day 21. For CQ+SP treated group the cure rates were 24%, 67%, 82%, 82%, 84% and 88%, respectively. Recrudescence accounted for 10%; all were cleared on day 28 except for one patient. Both regimens were well tolerated with no serious adverse events. The proportion of gametocyte carriers was higher in CQ+SP treated group than ANQ treatment (41% versus 12%; p < 0.05).</p> <p>Conclusion</p> <p>While these data are not themselves sufficient, it strongly suggests that the ANQ combination as a single dose administration is safe and effective for the treatment of uncomplicated <it>P. falciparum </it>malaria in the adult population of Papua New Guinea and deserves further clinical evaluation.</p

Large-scale survey for novel genotypes of Plasmodium falciparum chloroquine-resistance gene pfcrt

Background. In Plasmodium falciparum, resistance to chloroquine (CQ) is conferred by a K to T mutation at amino acid position 76 (K76T) in the P. falciparum CQ transporter (PfCRT). To date, at least 15 pfcrt genotypes, which are represented by combinations of five amino acids at positions 72-76, have been described in field isolates from various endemic regions. To identify novel mutant pfcrt genotypes and to reveal the genetic relatedness of pfcrt genotypes, a large-scale survey over a wide geographic area was performed. Methods. Sequences for exon 2 in pfcrt, including known polymorphic sites at amino acid positions 72, 74, 75 and 76, were obtained from 256 P. falciparum isolates collected from eight endemic countries in Asia (Bangladesh, Cambodia, Lao P.D.R., the Philippines and Thailand), Melanesia (Papua New Guinea and Vanuatu) and Africa (Ghana). A haplotype network was constructed based on six microsatellite markers located -29 kb to 24 kb from pfcrt in order to examine the genetic relatedness among mutant pfcrt genotypes. Results. In addition to wild type (CVMNK at positions 72-76), four mutant pfcrt were identified; CVIET, CVIDT, SVMNT and CVMNT (mutated amino acids underlined). Haplotype network revealed that there were only three mutant pfcrt lineages, originating in Indochina, Philippines and Melanesia. Importantly, the Indochina lineage contained two mutant pfcrt genotypes, CVIET (n = 95) and CVIDT (n = 14), indicating that CVIDT shares a common origin with CVIET. Similarly, one major haplotype in the Melanesian lineage contained two pfcrt genotypes; SVMNT (n = 71) and CVMNT (n = 3). In Africa, all mutant pfcrt genotypes were the CVIET of the Indochina lineage, probably resulting from the intercontinental migration of CQ resistance from Southeast Asia. Conclusions. The number of CQ-mutant lineages observed in this study was identical to that found in previous studies. This supports the hypothesis that the emergence of novel CQ resistance is rare. However, in the mutant pfcrt genotypes, amino acid changes at positions 72, 74 and 75 appear to have recently been generated at least several times, producing distinct pfcrt mutant genotypes. The occurrence of new mutations flanking K76T may yield stronger resistance to CQ and/or a higher fitness than the original pfcrt mutant

Pf7: an open dataset of Plasmodium falciparum genome variation in 20,000 worldwide samples

We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network.  It comprises over 20,000 samples from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented.  For the first time we include dried blood spot samples that were sequenced after selective whole genome amplification, necessitating new methods to genotype copy number variations.  We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show examples of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent.  We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS,S and R21 malaria vaccines.  Pf7 provides high-quality data on genotype calls for 6 million SNPs and short indels, analysis of large deletions that cause failure of rapid diagnostic tests, and systematic characterisation of six major drug resistance loci, all of which can be freely downloaded from the MalariaGEN website

Artemisinin-Naphthoquine Combination (ARCO®): An Overview of the Progress

With the rapidly spreading resistance of Plasmodium falciparum to available non-artemisinin antimalarial drugs, new and novel pharmaceuticals are needed. ARCO® is a new generation ACT, one of several artemisinin-based combinations developed in China to counter antimalarial drug resistance. ARCO® is a derivative of two independently developed antimalarials, artemisinin and naphthoquine phosphate, which were combined to form the artemisinin-naphthoquine combination. Both artemisinin and naphthoquine drugs have proven to be efficacious, safe and well tolerated as monotherapies. The artemisinin-naphthoquine combination offers a novel advantage over existing ACTs: it can be administered as a single oral dose (or a 1-day treatment). Several therapeutic studies conducted recently indicate that a single oral dose administration of artemisinin-naphthoquine combination is equally effective and safe as the 3-day treatment with artemether-lumefantrine combination and other existing ACTs. This would make ARCO® the next generation ACT for the treatment of uncomplicated falciparum malaria

Factors associated with children's health facility visits for primaquine treatment in rural Papua New Guinea

Abstract Background To control and eventually eliminate vivax malaria, radical treatment with primaquine (PQ) is essential after completion of blood-stage treatment. Although in many malaria-endemic countries, village health volunteers (VHVs) are engaged in diagnostic treatment of malaria in remote communities, they principally provide blood-stage treatment. In such a situation, access to PQ following blood-stage treatment can be a barrier to complete treatment. However, studies on access to PQ treatment have been scarce and limited in health facility-based settings. This study aimed to identify factors associated with access to PQ treatment in rural Papua New Guinea (PNG) from the community case management perspective. Methods A community-based, cross-sectional survey was conducted to collect sociodemographic information on children under 15 years of age, their households, and their caretakers in East Sepik Province, PNG. Data collection lasted from February to March, 2015. Information on the diagnoses of potential non-falciparum malaria and prescription of PQ in preceding year (January to December 2014) were obtained from child health-record books. Then, multilevel logistic regression model was used to determine the factors associated with formal health facility visits for PQ treatment among children with potential non-falciparum malaria. Results Of 420 episodes diagnosed as potential non-falciparum malaria, 46 (11%) were immediately given PQ. The rest were instructed to visit formal health facilities (HFs) for PQ, and the patients obtained PQ during the second visit to HFs was 44%. Consequently, the overall proportion of PQ prescription was 50%. Logistic regression analysis suggested that among the patients who were instructed to visit HFs for PQ treatment, the initial visit to VHV and higher transportation costs to HF were inversely associated with PQ prescription during the second visit to an HF. Conclusions Few children received PQ treatment during the second visit to HFs following diagnosis of potential non-falciparum malaria. These findings suggest a need to establish a policy to reduce structural and economic barriers and improve rural inhabitant access to PQ treatment

Comparison of Health Service Utilization for Febrile Children Before and After Introduction of Malaria Rapid Diagnostic Tests and Artemisinin-Based Combination Therapy in Rural Papua New Guinea

BackgroundIn Papua New Guinea (PNG), a malaria treatment policy using rapid diagnostic tests (RDTs) plus artemisinin-based combination therapy (ACT) was widely introduced to rural communities in 2012. The objectives of the study were to evaluate the effect of this RDT/ACT introduction to a rural PNG population on health service utilization and to compare factors associated with health service utilization before and after the RDT/ACT introduction.MethodsHousehold surveys with structured questionnaires were conducted before and after the introduction of RDT/ACT in a catchment area of a health center in East Sepik Province, PNG. We interviewed caregivers with children less than 15 years of age and collected data on fever episodes in the preceding 2 weeks. Using propensity score matching, febrile children before the introduction of RDT/ACT were matched to febrile children after the introduction. Then, the adjusted difference in the proportion of health service utilization [i.e., the average treatment effect (ATE) of the introduction of RDT/ACT on health service utilization] was estimated. We also employed a multilevel Poisson regression model to investigate factors influencing the use of health services.ResultsOf 4,690 children, 911 (19%) were reported to have a fever episode. The unadjusted proportion of health service utilization was 51.7 and 57.2% before and after the RDT/ACT introduction, respectively. After matching, no significant difference in the health service utilization was observed before and after the introduction of RDT/ACT (ATE: 0.063, 95% confidence interval −0.024 to 0.150). Multilevel regression analysis showed that the consistent factors associated with a higher utilization of health services were severe illness and being female.ConclusionThe utilization of health services was not significantly different before and after the introduction of RDT/ACT. Villagers may have neither sufficient informations on the new protocol nor high acceptance of RDT/ACT. The observed gender bias in health service utilization could be due to female caregivers’ preferences toward girls