Prof Richard Price
|Research Area:||Global Health|
|Scientific Themes:||Tropical Medicine & Global Health|
|Keywords:||malaria, epidemiology, drug resistance and clinical trials|
The main focus of our research programme is to rationalise the control of drug resistant Plasmodium vivax by improving strategies to optimise its surveillance and management. To achieve this we are: i) defining the burden of vivax malaria in South East Asia with particularly attention to areas where chloroquine resistance is emerging, ii) conducting clinical studies to optimise the prevention and treatment of vivax malaria iii) developing ex vivo tools to improve the surveillance and characterisation of drug resistance in P. vivax and iv) evaluating the impact and cost effectiveness of widespread deployment of artemisinin combination therapies on malaria related morbidity and mortality.
The programme is being conducted in collaboration with the Mahidol Oxford Research Unit (MORU) in Thailand and the Menzies School of Health Research (MSHR) in Darwin, with partners in the Indonesian Ministry of Health. Our field site in Papua currently employs 15 full time staff, with a research agenda that spans epidemiology, health economics, clinical trials, pathophysiology, immunology, in vitro studies and molecular biology.
- Epidemiology studies of chloroquine resistant P. vivax.
- Clinical trials of new treatments for drug resistant malaria.
- Molecular and in vitro studies to characterise drug resistance in P. falciparum and P. vivax.
- Impact and cost effectiveness studies of artemisinin combination therapy for drug resistant P. falciparum and P. vivax in Papua, Indonesia.
|Prof Nicholas Anstey||International Health Division, Menzies School of Health Research||Australia|
|David Fidock||Columbia University, NYC||United States|
|Tim ANDERSON||Southwest Foundation Texas||United States|
|Qin Cheng||Australian Malaria Institute, Brisbane||Australia|
|Julie Simpson||Melbourne University||Australia|
|Emiliana Tjitra||National Institue of Health Research and Development||Indonesia|
A case of fevers, sepsis and chest lesions on CT scan following burns to the feet in an Indigenous man in northern Australia is described. Sputum polymerase chain reaction testing revealed Mycobacterium leprae and and fine needle aspirate of the chest lesions demonstrated Cryptococcus co-infection. Hide abstract
Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001: were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine. Hide abstract
Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life-cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have activity in the prevention and treatment of blood stage infection in a mouse model of malaria. Consistent with the activity profile of this series the clinical candidate KAF156 shows blood schizonticidal activity with IC50 values of 6-17.4 nM against P. falciparum drug-sensitive and drug-resistant strains as well as potent therapeutic activity in a mouse models of malaria with ED50/90/99 values of 0.6/0.9/1.4 mg/kg respectively. When administered prophylactically in a sporozoite challenge mouse model KAF156 is completely protective as a single oral dose of 10 mg/kg. Finally, KAF156 displays potent Plasmodium transmission blocking activities both in vitro and in vivo. Collectively our data suggest that KAF156, currently under evaluation in clinical trials, has the potential to treat, prevent and block the transmission of malaria. Hide abstract
Endothelial nitric oxide (NO) bioavailability, microvascular function, and host oxygen consumption have not been assessed in pediatric malaria. We measured NO-dependent endothelial function by using peripheral artery tonometry to determine the reactive hyperemia index (RHI), and microvascular function and oxygen consumption (VO2) using near infrared resonance spectroscopy in 13 Indonesian children with severe falciparum malaria and 15 with moderately severe falciparum malaria. Compared with 19 controls, children with severe malaria and those with moderately severe malaria had lower RHIs (P = .03); 12% and 8% lower microvascular function, respectively (P = .03); and 29% and 25% higher VO2, respectively. RHIs correlated with microvascular function in all children with malaria (P < .001) and all with severe malaria (P < .001). Children with malaria have decreased endothelial and microvascular function and increased oxygen consumption, likely contributing to the pathogenesis of the disease. Hide abstract
Am J Trop Med Hyg, 91 (1), pp. 3-4. | Read more2014. Improving the Radical Cure of Plasmodium vivax Malaria.
Artemisinin combination therapy (ACT) is recommended for the treatment of multidrug resistant malaria in the second and third trimesters of pregnancy, but the experience with ACTs is limited. We review the exposure of pregnant women to the combination dihydroartemisinin-piperaquine over a 6 year period. Hide abstract
The Lancet, 383 (9922), pp. 1020-1021. | Read more2014. Single-dose radical cure of Plasmodium vivax: A step closer
Most adults dying from falciparum malaria will die within 48 hours of their hospitalisation. An essential component of early supportive care is the rapid identification of patients at greatest risk. In resource-poor settings, where most patients with falciparum malaria are managed, decisions regarding patient care must frequently be made using clinical evaluation alone. Hide abstract
Lancet, 383 (9922), pp. 1020-1021. | Read more2014. Single-dose radical cure of Plasmodium vivax: a step closer.
Background:Dihydroartemisinin-piperaquine (DP) is increasingly recommended for antimalarial treatment in many endemic countries; however, concerns have been raised over its potential under dosing in young children. We investigated the influence of different dosing schedules on DP's clinical efficacy.Methods and Findings:A systematic search of the literature was conducted to identify all studies published between 1960 and February 2013, in which patients were enrolled and treated with DP. Principal investigators were approached and invited to share individual patient data with the WorldWide Antimalarial Resistance Network (WWARN). Data were pooled using a standardised methodology. Univariable and multivariable risk factors for parasite recrudescence were identified using a Cox's regression model with shared frailty across the study sites. Twenty-four published and two unpublished studies (n = 7,072 patients) were included in the analysis. After correcting for reinfection by parasite genotyping, Kaplan-Meier survival estimates were 97.7% (95% CI 97.3%-98.1%) at day 42 and 97.2% (95% CI 96.7%-97.7%) at day 63. Overall 28.6% (979/3,429) of children aged 1 to 5 years received a total dose of piperaquine below 48 mg/kg (the lower limit recommended by WHO); this risk was 2.3-2.9-fold greater compared to that in the other age groups and was associated with reduced efficacy at day 63 (94.4% [95% CI 92.6%-96.2%], p<0.001). After adjusting for confounding factors, the mg/kg dose of piperaquine was found to be a significant predictor for recrudescence, the risk increasing by 13% (95% CI 5.0%-21%) for every 5 mg/kg decrease in dose; p = 0.002. In a multivariable model increasing the target minimum total dose of piperaquine in children aged 1 to 5 years old from 48 mg/kg to 59 mg/kg would halve the risk of treatment failure and cure at least 95% of patients; such an increment was not associated with gastrointestinal toxicity in the ten studies in which this could be assessed.Conclusions:DP demonstrates excellent efficacy in a wide range of transmission settings; however, treatment failure is associated with a lower dose of piperaquine, particularly in young children, suggesting potential for further dose optimisation.Please see later in the article for the Editors' Summary. © 2013 Price et al. Hide abstract
The burden of anemia attributable to non-falciparum malarias in regions with Plasmodium co-endemicity is poorly documented. We compared the hematological profile of patients with and without malaria in southern Papua, Indonesia. Hide abstract
Nitric oxide (NO), a key macrophage antimycobacterial mediator that ameliorates immunopathology, is measurable in exhaled breath in individuals with pulmonary tuberculosis. We investigated relationships between fractional exhale NO (FENO) and initial pulmonary tuberculosis severity, change during treatment, and relationship with conversion of sputum culture to negative at 2 months. Hide abstract
Vitamin D (vitD) and L-arginine have important antimycobacterial effects in humans. Adjunctive therapy with these agents has the potential to improve outcomes in active tuberculosis (TB). Hide abstract
Heme oxygenase 1 expression is increased in pediatric patients with malaria. The carboxyhemoglobin level (a measure of heme oxygenase 1 activity) has not been assessed in adult patients with malaria. Results of pulse co-oximetry revealed that the mean carboxyhemoglobin level was elevated in 29 Indonesian adults with severe falciparum malaria (10%; 95% confidence interval [CI], 8%-13%) and in 20 with severe sepsis (8%; 95% CI, 5%-12%), compared with the mean levels in 32 patients with moderately severe malaria (7%; 95% CI, 5%-8%) and 36 controls (3.6%; 95% CI, 3%-5%; P < .001). An increased carboxyhemoglobin level was associated with an increased odds of death among patients with severe malaria (odds ratio, 1.2 per percentage point increase; 95% CI, 1.02-1.5). While also associated with severity and fatality, methemoglobin was only modestly increased in patients with severe malaria. Increased carboxyhemoglobin levels during severe malaria and sepsis may exacerbate organ dysfunction by reducing oxygen carriage and cautions against the use of adjunctive CO therapy, which was proposed on the basis of mouse models. Hide abstract
Designing interventions that will reduce transmission of vivax malaria requires knowledge of Plasmodium vivax gametocyte dynamics. Hide abstract
Parasitaemia on Day 3 has been proposed as a useful alert of potential artemisinin resistance, however, the normal variation of parasite clearance observed in artemisinin-based combination therapy clinical trials is poorly documented. Hide abstract
The goal for developing new antimalarial drugs is to find a molecule that can target multiple stages of the parasite's life cycle, thus impacting prevention, treatment, and transmission of the disease. The 4(1H)-quinolone-3-diarylethers are selective potent inhibitors of the parasite's mitochondrial cytochrome bc1 complex. These compounds are highly active against the human malaria parasites Plasmodium falciparum and Plasmodium vivax. They target both the liver and blood stages of the parasite as well as the forms that are crucial for disease transmission, that is, the gametocytes, the zygote, the ookinete, and the oocyst. Selected as a preclinical candidate, ELQ-300 has good oral bioavailability at efficacious doses in mice, is metabolically stable, and is highly active in blocking transmission in rodent models of malaria. Given its predicted low dose in patients and its predicted long half-life, ELQ-300 has potential as a new drug for the treatment, prevention, and, ultimately, eradication of human malaria. Hide abstract
J Infect Dis, 207 (11), pp. 1627-1629. | Read more2013. Potential of artemisinin-based combination therapies to block malaria transmission.
Despite significant progress in the control of malaria in Malaysia, the complex transmission dynamics of P. vivax continue to challenge national efforts to achieve elimination. To assess the impact of ongoing interventions on P. vivax transmission dynamics in Sabah, we genotyped 9 short tandem repeat markers in a total of 97 isolates (8 recurrences) from across Sabah, with a focus on two districts, Kota Marudu (KM, n = 24) and Kota Kinabalu (KK, n = 21), over a 2 year period. STRUCTURE analysis on the Sabah-wide dataset demonstrated multiple sub-populations. Significant differentiation (F ST = 0.243) was observed between KM and KK, located just 130 Km apart. Consistent with low endemic transmission, infection complexity was modest in both KM (mean MOI = 1.38) and KK (mean MOI = 1.19). However, population diversity remained moderate (H E = 0.583 in KM and H E = 0.667 in KK). Temporal trends revealed clonal expansions reflecting epidemic transmission dynamics. The haplotypes of these isolates declined in frequency over time, but persisted at low frequency throughout the study duration. A diverse array of low frequency isolates were detected in both KM and KK, some likely reflecting remnants of previous expansions. In accordance with clonal expansions, high levels of Linkage Disequilibrium (I A (S) >0.5 [P<0.0001] in KK and KM) declined sharply when identical haplotypes were represented once (I A (S) = 0.07 [P = 0.0076] in KM, and I A (S) = -0.003 [P = 0.606] in KK). All 8 recurrences, likely to be relapses, were homologous to the prior infection. These recurrences may promote the persistence of parasite lineages, sustaining local diversity. In summary, Sabah's shrinking P. vivax population appears to have rendered this low endemic setting vulnerable to epidemic expansions. Migration may play an important role in the introduction of new parasite strains leading to epidemic expansions, with important implications for malaria elimination. Hide abstract
Anti-malarial efficacy needs to be monitored continually to ensure optimal dosing in the face of emerging anti-malarial drug resistance. The efficacy of artemisinin based combination therapies (ACT) is assessed by repeated measurements of parasite density in the blood of patients following treatment. Parasite density is measured from a capillary or venous blood sample, but this can be logistically and ethically challenging if multiple samples are required within a short time period. The aim of this work was to apply optimal design theory to derive clinically feasible blood sampling schedules from which parasite clearance could be defined using the Parasite Clearance Estimator (PCE), a recently developed tool to identify and quantify artemisinin resistance. Hide abstract
The analysis of in vitro anti-malarial drug susceptibility testing is vulnerable to the effects of different statistical approaches and selection biases. These confounding factors were assessed with respect to pfmdr1 gene mutation and amplification in 490 clinical isolates. Two statistical approaches for estimating the drug concentration associated with 50% effect (EC50 ) were compared: the commonly used standard two-stage (STS) method, and nonlinear mixed-effects modelling. The in vitro concentration-effect relationships for, chloroquine, mefloquine, lumefantrine and artesunate, were derived from clinical isolates obtained from patients on the western border of Thailand. All isolates were genotyped for polymorphisms in the pfmdr1 gene. The EC50 estimates were similar for the two statistical approaches but 15-28% of isolates in the STS method had a high coefficient of variation (>15%) for individual estimates of EC50 and these isolates had EC50 values that were 32 to 66% higher than isolates derived with more precision. In total 41% (202/490) of isolates had amplification of pfmdr1 and single nucleotide polymorphisms were found in 50 (10%). Pfmdr1 amplification was associated with an increase in EC50 for mefloquine (139% relative increase in EC50 for 2 copies, 188% for 3+ copies), lumefantrine (82% and 75% for 2 and 3+ copies respectively) and artesunate (63% and 127% for 2 and 3+ copies respectively). In contrast pfmdr1 mutation at codons 86 or 1042 were associated with an increase in chloroquine EC50 (44-48%). Sample size calculations showed that to demonstrate an EC50 shift of 50% or more with 80% power if the prevalence was 10% would require 430 isolates and 245 isolates if the prevalence was 20%. In conclusion, although nonlinear mixed-effects modelling did not demonstrate any major advantage for determining estimates of anti-malarial drug susceptibility, the method includes all isolates, thereby, potentially improving confirmation of candidate molecular markers of anti-malarial drug susceptibility. Hide abstract
Decreased nitric oxide (NO) and hypoargininemia are associated with severe falciparum malaria and may contribute to severe disease. Intravenous L-arginine increases endothelial NO in moderately-severe malaria (MSM) without adverse effects. The safety, efficacy and pharmacokinetics of L-arginine or other agents to improve NO bioavailability in severe malaria have not been assessed. Hide abstract
ADVANCES IN PARASITOLOGY, VOL 81: EPIDEMIOLOGY OF PLASMODIUM VIVAX: HISTORY, HIATUS AND HUBRIS, PT B, 81 pp. XI-XII.2013. ADVANCES IN PARASITOLOGY PREFACE
The diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency is a crucial aspect in the current phases of malaria control and elimination, which will require the wider use of 8-aminoquinolines for both reducing Plasmodium falciparum transmission and achieving the radical cure of Plasmodium vivax. 8-aminoquinolines, such as primaquine, can induce severe haemolysis in G6PD-deficient individuals, potentially creating significant morbidity and undermining confidence in 8-aminoquinoline prescription. On the other hand, erring on the side of safety and excluding large numbers of people with unconfirmed G6PD deficiency from treatment with 8-aminoquinolines will diminish the impact of these drugs. Estimating the remaining G6PD enzyme activity is the most direct, accessible, and reliable assessment of the phenotype and remains the gold standard for the diagnosis of patients who could be harmed by the administration of primaquine. Genotyping seems an unambiguous technique, but its use is limited by cost and the large range of recognized G6PD genotypes. A number of enzyme activity assays diagnose G6PD deficiency, but they require a cold chain, specialized equipment, and laboratory skills. These assays are impractical for care delivery where most patients with malaria live. Improvements to the diagnosis of G6PD deficiency are required for the broader and safer use of 8-aminoquinolines to kill hypnozoites, while lower doses of primaquine may be safely used to kill gametocytes without testing. The discussions and conclusions of a workshop conducted in Incheon, Korea in May 2012 to review key knowledge gaps in G6PD deficiency are reported here. Hide abstract
Adv Parasitol, 81 pp. xi-xii. | Read more2013. The epidemiology of Plasmodium vivax. Preface.
Whole genome sequencing (WGS) of Plasmodium vivax is problematic due to the reliance on clinical isolates which are generally low in parasitaemia and sample volume. Furthermore, clinical isolates contain a significant contaminating background of host DNA which confounds efforts to map short read sequence of the target P. vivax DNA. Here, we discuss a methodology to significantly improve the success of P. vivax WGS on natural (non-adapted) patient isolates. Using 37 patient isolates from Indonesia, Thailand, and travellers, we assessed the application of CF11-based white blood cell filtration alone and in combination with short term ex vivo schizont maturation. Although CF11 filtration reduced human DNA contamination in 8 Indonesian isolates tested, additional short-term culture increased the P. vivax DNA yield from a median of 0.15 to 6.2 ng µl(-1) packed red blood cells (pRBCs) (p = 0.001) and reduced the human DNA percentage from a median of 33.9% to 6.22% (p = 0.008). Furthermore, post-CF11 and culture samples from Thailand gave a median P. vivax DNA yield of 2.34 ng µl(-1) pRBCs, and 2.65% human DNA. In 22 P. vivax patient isolates prepared with the 2-step method, we demonstrate high depth (median 654X coverage) and breadth (≥89%) of coverage on the Illumina GAII and HiSeq platforms. In contrast to the A+T-rich P. falciparum genome, negligible bias was observed in coverage depth between coding and non-coding regions of the P. vivax genome. This uniform coverage will greatly facilitate the detection of SNPs and copy number variants across the genome, enabling unbiased exploration of the natural diversity in P. vivax populations. Hide abstract
Organ dysfunction and tissue hypoxia in severe falciparum malaria result from an imbalance between oxygen delivery and demand. In severe malaria, microvascular obstruction from parasite sequestration decreases oxygen delivery. However, host microvascular function (defined as the capacity to increase oxygen delivery in response to ischemia) and oxygen consumption have not been assessed. Hide abstract
In this review we present recent developments in the analysis of Plasmodium vivax clinical trials and ex vivo drug-susceptibility assays, as well approaches currently being used to identify molecular markers of drug resistance. Clinical trials incorporating the measurement of in vivo drug concentrations and parasite clearance times are needed to detect early signs of resistance. Analysis of P. vivax growth dynamics ex vivo have defined the criteria for acceptable assay thresholds for drug susceptibility testing, and their subsequent interpretation. Genotyping and next-generation sequencing studies in P. vivax field isolates are set to transform our understanding of the molecular mechanisms of drug resistance. Hide abstract
Current understanding of the spatial epidemiology and geographical distribution of Plasmodium vivax is far less developed than that for P. falciparum, representing a barrier to rational strategies for control and elimination. Here we present the first systematic effort to map the global endemicity of this hitherto neglected parasite. Hide abstract
Primaquine has been the only widely available hypnozoitocidal anti-malarial drug for half a century. Despite this its clinical efficacy is poorly characterized resulting in a lack of consensus over the optimal regimen for the radical cure of Plasmodium vivax. Hide abstract
Effective use of anti-malarial drugs is key to reducing the transmission potential of Plasmodium vivax. In patients presenting with symptomatic disease, treatment with potent and relatively slowly eliminated blood schizontocidal regimens administered concurrently with a supervised course of 7 mg/kg primaquine over 7-14 days has potential to exert the greatest transmission-blocking benefit. Given the spread of chloroquine-resistant P. vivax strains, the artemisinin combination therapies dihydroartemisinin + piperaquine and artesunate + mefloquine are currently the most assured means of preventing P. vivax recrudescence. Preliminary evidence suggests that, like chloroquine, these combinations potentiate the hypnozoitocidal effect of primaquine, but further supportive evidence is required. In view of the high rate of P. vivax relapse following falciparum infections in co-endemic regions, there is a strong argument for broadening current radical cure policy to include the administration of hypnozoitocidal doses of primaquine to patients with Plasmodium falciparum malaria. The most important reservoir for P. vivax transmission is likely to be very low-density, asymptomatic infections, the majority of which will arise from liver-stage relapses. Therefore, judicious mass administration of hypnozoitocidal therapy will reduce transmission of P. vivax to a greater extent than strategies focused on treatment of symptomatic patients. An efficacious hypnozoitocidal agent with a short curative treatment course would be particularly useful in mass drug administration campaigns. Hide abstract
In this review we present recent developments in the analysis of Plasmodium vivax clinical trials and ex vivo drug-susceptibility assays, as well approaches currently being used to identify molecular markers of drug resistance. Clinical trials incorporating the measurement of in vivo drug concentrations and parasite clearance times are needed to detect early signs of resistance. Analysis of P. vivax growth dynamics ex vivo have defined the criteria for acceptable assay thresholds for drug susceptibility testing, and their subsequent interpretation. Genotyping and next-generation sequencing studies in P. vivax field isolates are set to transform our understanding of the molecular mechanisms of drug resistance. © 2012 Elsevier Ltd. Hide abstract
Plasmodium vivax threatens nearly half the world's population and is a significant impediment to achievement of the millennium development goals. It is an important, but incompletely understood, cause of anaemia. This review synthesizes current evidence on the epidemiology, pathogenesis, treatment and consequences of vivax-associated anaemia. Young children are at high risk of clinically significant and potentially severe vivax-associated anaemia, particularly in countries where transmission is intense and relapses are frequent. Despite reaching lower densities than Plasmodium falciparum, Plasmodium vivax causes similar absolute reduction in red blood cell mass because it results in proportionately greater removal of uninfected red blood cells. Severe vivax anaemia is associated with substantial indirect mortality and morbidity through impaired resilience to co-morbidities, obstetric complications and requirement for blood transfusion. Anaemia can be averted by early and effective anti-malarial treatment. Hide abstract
The emergence of highly chloroquine (CQ) resistant P. vivax in Southeast Asia has created an urgent need for an improved understanding of the mechanisms of drug resistance in these parasites, the development of robust tools for defining the spread of resistance, and the discovery of new antimalarial agents. The ex vivo Schizont Maturation Test (SMT), originally developed for the study of P. falciparum, has been modified for P. vivax. We retrospectively analysed the results from 760 parasite isolates assessed by the modified SMT to investigate the relationship between parasite growth dynamics and parasite susceptibility to antimalarial drugs. Previous observations of the stage-specific activity of CQ against P. vivax were confirmed, and shown to have profound consequences for interpretation of the assay. Using a nonlinear model we show increased duration of the assay and a higher proportion of ring stages in the initial blood sample were associated with decreased effective concentration (EC(50)) values of CQ, and identify a threshold where these associations no longer hold. Thus, starting composition of parasites in the SMT and duration of the assay can have a profound effect on the calculated EC(50) for CQ. Our findings indicate that EC(50) values from assays with a duration less than 34 hours do not truly reflect the sensitivity of the parasite to CQ, nor an assay where the proportion of ring stage parasites at the start of the assay does not exceed 66%. Application of this threshold modelling approach suggests that similar issues may occur for susceptibility testing of amodiaquine and mefloquine. The statistical methodology which has been developed also provides a novel means of detecting stage-specific drug activity for new antimalarials. Hide abstract
The declining efficacy of artemisinin derivatives against Plasmodium falciparum highlights the urgent need to identify alternative highly potent compounds for the treatment of malaria. In Papua Indonesia, where multidrug resistance has been documented against both P. falciparum and P. vivax malaria, comparative ex vivo antimalarial activity against Plasmodium isolates was assessed for the artemisinin derivatives artesunate (AS) and dihydroartemisinin (DHA), the synthetic peroxides OZ277 and OZ439, the semisynthetic 10-alkylaminoartemisinin derivatives artemisone and artemiside, and the conventional antimalarial drugs chloroquine (CQ), amodiaquine (AQ), and piperaquine (PIP). Ex vivo drug susceptibility was assessed in 46 field isolates (25 P. falciparum and 21 P. vivax). The novel endoperoxide compounds exhibited potent ex vivo activity against both species, but significant differences in intrinsic activity were observed. Compared to AS and its active metabolite DHA, all the novel compounds showed lower or equal 50% inhibitory concentrations (IC(50)s) in both species (median IC(50)s between 1.9 and 3.6 nM in P. falciparum and 0.7 and 4.6 nM in P. vivax). The antiplasmodial activity of novel endoperoxides showed different cross-susceptibility patterns in the two Plasmodium species: whereas their ex vivo activity correlated positively with CQ, PIP, AS, and DHA in P. falciparum, the same was not apparent in P. vivax. The current study demonstrates for the first time potent activity of novel endoperoxides against drug-resistant P. vivax. The high activity against drug-resistant strains of both Plasmodium species confirms these compounds to be promising candidates for future artemisinin-based combination therapy (ACT) regimens in regions of coendemicity. Hide abstract
Maternal mortality is high in developing countries, but there are few data in high-risk groups such as migrants and refugees in malaria-endemic areas. Trends in maternal mortality were followed over 25 years in antenatal clinics prospectively established in an area with low seasonal transmission on the north-western border of Thailand. Hide abstract
The need for robust surveillance of antimalarial drugs is more urgent than it has ever been. In the western region of Cambodia, artemisinin resistance has emerged in Plasmodium falciparum and threatens to undermine the efficacy of highly effective artemisinin combination therapies. Although some manfestations of artemisinin tolerance are unique to this class of drug, many of its properties mirror previous experience in understanding and tracking resistance to other antimalarials. In this review we outline the spectrum of approaches that were developed to understand the evolution and spread of antifolate resistance, highlighting the importance of integrating information from different methodologies towards a better understanding of the underlying biologic processes. We consider how to apply our experience in investigating and attempting to contain antifolate resistance to inform our prospective assessment of novel antimalarial resistance patterns and their subsequent spread. Hide abstract
Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD) model for predicting within-host parasite response was performed. Hide abstract
Infection by Plasmodium vivax poses unique challenges for diagnosis and treatment. Relatively low numbers of parasites in peripheral circulation may be difficult to confirm, and patients infected by dormant liver stages cannot be diagnosed before activation and the ensuing relapse. Radical cure thus requires therapy aimed at both the blood stages of the parasite (blood schizontocidal) and prevention of subsequent relapses (hypnozoitocidal). Chloroquine and primaquine have been the companion therapies of choice for the treatment of vivax malaria since the 1950s. Confirmed resistance to chloroquine occurs in much of the vivax endemic world and demands the investigation of alternative blood schizontocidal companions in radical cure. Such a shift in practice necessitates investigation of the safety and efficacy of primaquine when administered with those therapies, and the toxicity profile of such combination treatments, particularly in patients with glucose-6-phosphate dehydrogenase deficiency. These clinical studies are confounded by the frequency and timing of relapse among strains of P. vivax, and potentially by differing susceptibilities to primaquine. The inability to maintain this parasite in continuous in vitro culture greatly hinders new drug discovery. Development of safe and effective chemotherapies for vivax malaria for the coming decades requires overcoming these challenges. Hide abstract
Vivax malaria was historically described as 'benign tertian malaria' because individual clinical episodes were less likely to cause severe illness than Plasmodium falciparum. Despite this, Plasmodium vivax was, and remains, responsible for major morbidity and significant mortality in vivax-endemic areas. Single infections causing febrile illness in otherwise healthy individuals rarely progress to severe disease. Nevertheless, in the presence of co-morbidities, P. vivax can cause severe illness and fatal outcomes. Recurrent or chronic infections in endemic areas can cause severe anaemia and malnutrition, particularly in early childhood. Other severe manifestations include acute lung injury, acute kidney injury and uncommonly, coma. Multiorgan failure and shock are described but further studies are needed to investigate the role of bacterial and other co-infections in these syndromes. In pregnancy, P. vivax infection can cause maternal anaemia, miscarriage, low birth weight and congenital malaria. Compared to P. falciparum, P. vivax has a greater capacity to elicit an inflammatory response, resulting in a lower pyrogenic threshold. Conversely, cytoadherence of P. vivax to endothelial cells is less frequent and parasite sequestration is not thought to be a significant cause of severe illness in vivax malaria. With a predilection for young red cells, P. vivax does not result in the high parasite biomass associated with severe disease in P. falciparum, but a four to fivefold greater removal of uninfected red cells from the circulation relative to P. falciparum is associated with a similar risk of severe anaemia. Mechanisms underlying the pathogenesis of severe vivax syndromes remain incompletely understood. Hide abstract
Plasmodium vivax occurs globally and thrives in both temperate and tropical climates. Here, we review the evidence of the biological limits of its contemporary distribution and the global population at risk (PAR) of the disease within endemic countries. We also review the most recent evidence for the endemic level of transmission within its range and discuss the implications for burden of disease assessments. Finally, the evidence-base for defining the contemporary distribution and PAR of P. vivax are discussed alongside a description of the vectors of human malaria within the limits of risk. This information along with recent data documenting the severe morbid and fatal consequences of P. vivax infection indicates that the public health significance of P. vivax is likely to have been seriously underestimated. Hide abstract
The epidemiology of congenital malaria was investigated in a hospital-based malaria surveillance study in Papua, Indonesia. Hide abstract
Chloroquine (CQ) remains the treatment of choice for Plasmodium vivax malaria. Initially confined to parts of Indonesia and Papua, resistance of P. vivax to CQ seems to be spreading, and alternative treatments are required. Hide abstract
Nucleic acid amplification provides the most sensitive and accurate method to detect and identify pathogens. This is primarily useful for epidemiological investigations of malaria because the infections, often with two or more Plasmodium species present simultaneously, are frequently associated with microscopically sub-patent parasite levels and cryptic mixed infections. Numerous distinct equally adequate amplification-based protocols have been described, but it is unclear which to select for epidemiological surveys. Few comparative studies are available, and none that addresses the issue of inter-laboratory variability. Hide abstract
For over 50 years, the treatment of Plasmodium vivax has relied on a combination of chloroquine and primaquine, but this strategy is under threat. Chloroquine efficacy is now compromised across much of the vivax endemic world and there are significant operational difficulties in deploying primaquine. We review the recent advances in P. vivax chemotherapy that may influence the future management of this neglected pathogen. Hide abstract
Ferroquine (FQ; SSR97193), a ferrocene-containing 4-aminoquinoline derivate, has potent in vitro efficacy against chloroquine (CQ)-resistant Plasmodium falciparum and CQ-sensitive P. vivax. In the current study, ex vivo FQ activity was tested in multidrug-resistant P. falciparum and P. vivax field isolates using a schizont maturation assay. Although FQ showed excellent activity against CQ-sensitive and -resistant P. falciparum and P. vivax (median 50% inhibitory concentrations [IC(50)s], 9.6 nM and 18.8 nM, respectively), there was significant cross-susceptibility with the quinoline-based drugs chloroquine, amodiaquine, and piperaquine (for P. falciparum, r = 0.546 to 0.700, P < 0.001; for P. vivax, r = 0.677 to 0.821, P < 0.001). The observed ex vivo cross-susceptibility is likely to reflect similar mechanisms of drug uptake/efflux and modes of drug action of this drug class. However, the potent activity of FQ against resistant isolates of both P. falciparum and P. vivax highlights a promising role for FQ as a lead antimalarial against CQ-resistant Plasmodium and a useful partner drug for artemisinin-based combination therapy. Hide abstract
Coma complicates Plasmodium falciparum infection but is uncommonly associated with P. vivax. Most series of vivax coma have been retrospective and have not utilized molecular methods to exclude mixed infections with P. falciparum. Hide abstract
Quantitative data are lacking on published malaria research. The purpose of the study is to characterize trends in malaria-related literature from 1990 to 2009 in 11 Asian-Pacific countries that are committed to malaria elimination as a national goal. Hide abstract
INTERNAL MEDICINE JOURNAL, 41 pp. 13-13.2011. PROSPECTIVE STUDY OF MELIOIDOSIS AT ROYAL DARWIN HOSPITAL DURING THE 2009-2010 WET SEASON; COMPARISONS WITH THE PRECEDING 20 YEARS
Plasmodium falciparum and Plasmodium vivax are co-endemic in the Asia-Pacific region. Their capacity to induce and sustain diverse T-cell responses underpins protective immunity. We compared T-cell responses to the largely conserved merozoite surface protein-5 (PfMSP5) during acute and convalescent falciparum and vivax malaria. Hide abstract
Plasmodium vivax malaria commonly follows treatment of falciparum malaria in regions of co-endemicity. This is an important cause of preventable morbidity. Hide abstract
PLoS Medicine, 8 (1), pp. e1000402. Read abstract2011. A research agenda for malaria eradication: drugs
Antimalarial drugs will be essential tools at all stages of malaria elimination along the path towards eradication, including the early control or "attack" phase to drive down transmission and the later stages of maintaining interruption of transmission, preventing reintroduction of malaria, and eliminating the last residual foci of infection. Drugs will continue to be used to treat acute malaria illness and prevent complications in vulnerable groups, but better drugs are needed for elimination-specific indications such as mass treatment, curing asymptomatic infections, curing relapsing liver stages, and preventing transmission. The ideal malaria eradication drug is a coformulated drug combination suitable for mass administration that can be administered in a single encounter at infrequent intervals and that results in radical cure of all life cycle stages of all five malaria species infecting humans. Short of this optimal goal, highly desirable drugs might have limitations such as targeting only one or two parasite species, the priorities being Plasmodium falciparum and Plasmodium vivax. The malaria research agenda for eradication should include research aimed at developing such drugs and research to develop situation-specific strategies for using both current and future drugs to interrupt malaria transmission. Hide abstract
Histone acetylation plays an important role in regulating gene transcription and silencing in Plasmodium falciparum. Histone deacetylase (HDAC) inhibitors, particularly those of the hydroxamate class, have been shown to have potent in vitro activity against drug-resistant and -sensitive laboratory strains of P. falciparum, raising their potential as a new class of antimalarial compounds. In the current study, stage-specific ex vivo susceptibility profiles of representative hydroxamate-based HDAC inhibitors suberoylanilide hydroxamic acid (SAHA), 2-ASA-9, and 2-ASA-14 (2-ASA-9 and 2-ASA-14 are 2-aminosuberic acid-based HDAC inhibitors) were assessed in multidrug-resistant clinical isolates of P. falciparum (n = 24) and P. vivax (n = 25) from Papua, Indonesia, using a modified schizont maturation assay. Submicromolar concentrations of SAHA, 2-ASA-9, and 2-ASA-14 inhibited the growth of both P. falciparum (median 50% inhibitory concentrations [IC₅₀s] of 310, 533, and 266 nM) and P. vivax (median IC₅₀s of 170, 503, and 278 nM). Inverse correlation patterns between HDAC inhibitors and chloroquine for P. falciparum and mefloquine for P. vivax indicate species-specific susceptibility profiles for HDAC inhibitors. These HDAC inhibitors were also found to be potent ex vivo against P. vivax schizont maturation, comparable to that in P. falciparum, suggesting that HDAC inhibitors may be promising candidates for antimalarial therapy in geographical locations where both species are endemic. Further studies optimizing the selectivity and in vivo efficacy of HDAC inhibitors in Plasmodium spp. and defining drug interaction with common antimalarial compounds are warranted to investigate the role of HDAC inhibitors in antimalarial therapy. Hide abstract
Reports of potential drug-resistant strains of Plasmodium malariae in western Indonesia raise concerns that chloroquine resistance may be emerging in P. malariae and P. ovale. In order to assess this, in vivo and in vitro efficacy studies were conducted in patients with monoinfection in Papua, Indonesia. Consecutive patients with uncomplicated malaria due to P. ovale or P. malariae were enrolled in a prospective clinical trial, provided with supervised chloroquine treatment, and followed for 28 days. Blood from patients with P. malariae or P. ovale parasitemia greater than 1,000 per microliter underwent in vitro antimalarial drug susceptibility testing using a modified schizont maturation assay. Of the 57 evaluable patients in the clinical study (P. malariae, n = 46; P. ovale, n = 11), none had recurrence with the same species during follow-up. The mean parasite reduction ratio at 48 h was 86 (95% confidence interval [CI], 57 to 114) for P. malariae and 150 (95% CI, 54 to 245) for P. ovale (P = 0.18). One patient infected with P. malariae, with 93% of parasites at the trophozoite stage, was still parasitemic on day 4. In vitro drug susceptibility assays were carried out successfully for 40 isolates (34 infected with P. malariae and 6 with P. ovale). The P. malariae infections at trophozoite stages had significantly higher chloroquine 50% effective concentrations (EC(50)s) (median, 127.9 nM [range, 7.9 to 2,980]) than those initially exposed at the ring stage (median, 14.0 nM [range, 3.5 to 27.0]; P = 0.01). The EC(50) for chloroquine in P. ovale was also higher in an isolate initially at the trophozoite stage (23.2 nM) than in the three isolates predominantly at ring stage (7.8 nM). Chloroquine retains adequate efficacy against P. ovale and P. malariae, but its marked stage specificity of action may account for reports of delayed parasite clearance times. Hide abstract
Pyronaridine, a Mannich base antimalarial, has demonstrated high in vivo and in vitro efficacy against chloroquine-resistant Plasmodium falciparum. Although this drug has the potential to become a prominent artemisinin combination therapy, little is known about its efficacy against drug-resistant Plasmodium vivax. The in vitro antimalarial susceptibility of pyronaridine was assessed in multidrug-resistant P. vivax (n = 99) and P. falciparum (n = 90) isolates from Papua, Indonesia, using a schizont maturation assay. The median 50% inhibitory concentration (IC(50)) of pyronaridine was 1.92 nM (range, 0.24 to 13.8 nM) against P. falciparum and 2.58 nM (range, 0.13 to 43.6 nM) against P. vivax, with in vitro susceptibility correlating significantly with chloroquine, amodiaquine, and piperaquine (r(s) [Spearman's rank correlation coefficient] = 0.45 to 0.62; P < 0.001). P. falciparum parasites initially at trophozoite stage had higher IC(50)s of pyronaridine than those exposed at the ring stage (8.9 nM [range, 0.6 to 8.9 nM] versus 1.6 nM [range, 0.6 to 8.9 nM], respectively; P = 0.015), although this did not reach significance for P. vivax (4.7 nM [range, 1.4 to 18.7 nM] versus 2.5 nM [range, 1.4 to 15.6 nM], respectively; P = 0.085). The excellent in vitro efficacy of pyronaridine against both chloroquine-resistant P. vivax and P. falciparum highlights the suitability of the drug as a novel partner for artemisinin-based combination therapy in regions where the two species are coendemic. Hide abstract
Lancet Infect Dis, 10 (10), pp. 654-655. | Read more2010. Maximising the public health benefit of antimalarials.
Age and host genetics are important determinants of malaria severity. Lymphotoxin-alpha (LTalpha) has been associated with the development of cerebral malaria (CM) and other severe malaria (SM) syndromes. Mutations in genes regulating LTalpha production contribute to other acute vascular diseases and may contribute to malaria pathogenesis. Hide abstract
Pathogenic mechanisms underlying vivax malaria are poorly understood, with few studies comparing endothelial and inflammatory responses with falciparum malaria. In adults with uncomplicated vivax or falciparum malaria, we compared plasma measurements of endothelial Weibel-Palade body release (angiopoietin-2) and activation (ICAM-1, E-selectin), as well as selected cytokines. Despite a lower median parasite count, angiopoietin-2 concentrations were higher in patients with vivax malaria, compared with falciparum malaria. Per peripheral parasite, median plasma angiopoietin-2, ICAM-1, E-selectin, interleukin-6, and interleukin-10 concentrations were higher in patients with malaria due to Plasmodium vivax. P. vivax induces greater endothelial Weibel-Palade body release and activation and greater host inflammatory responses, compared with Plasmodium falciparum. Hide abstract
Early parasitological diagnosis and treatment with artemisinin-based combination therapies (ACTs) are key components of worldwide malaria elimination programmes. In general, use of ACTs has been limited to patients with falciparum malaria whereas blood-stage infections with Plasmodium vivax are mostly still treated with chloroquine. We review the evidence for the relative benefits and disadvantages of the existing separate treatment approach versus a unified ACT-based strategy for treating Plasmodium falciparum and P vivax infections in regions where both species are endemic (co-endemic). The separate treatment scenario is justifiable if P vivax remains sensitive to chloroquine and diagnostic tests reliably distinguish P vivax from P falciparum. However, with the high number of misdiagnoses in routine practice and the rise and spread of chloroquine-resistant P vivax, there might be a compelling rationale for a unified ACT-based strategy for vivax and falciparum malaria in all co-endemic regions. Analyses of the cost-effectiveness of ACTs for both Plasmodium species are needed to assess the role of these drugs in the control and elimination of vivax malaria. Hide abstract
Malaria parasites vary in phenotypic traits of biomedical or biological interest such as growth rate, virulence, sex ratio and drug resistance, and there is considerable interest in identifying the genes that underlie this variation. An important first step is to determine trait heritability (H(2)). We evaluate two approaches to measuring H(2) in natural parasite populations using relatedness inferred from genetic marker data. We collected single-clone Plasmodium falciparum infections from 185 patients from the Thailand-Burma border, monitored parasite clearance following treatment with artemisinin combination therapy (ACT), measured resistance to six antimalarial drugs and genotyped parasites using 335 microsatellites. We found strong relatedness structure. There were 27 groups of two to eight clonally identical (CI) parasites, and 74 per cent of parasites showed significant relatedness to one or more other parasites. Initially, we used matrices of allele sharing and variance components (VC) methods to estimate H(2). Inhibitory concentrations (IC(50)) for six drugs showed significant H(2) (0.24 to 0.79, p = 0.06 to 2.85 x 10(-9)), demonstrating that this study design has adequate power. However, a phenotype of current interest--parasite clearance following ACT--showed no detectable heritability (H(2) = 0-0.09, ns) in this population. The existence of CI parasites allows the use of a simple ANOVA approach for quantifying H(2), analogous to that used in human twin studies. This gave similar results to the VC method and requires considerably less genotyping information. We conclude (i) that H(2) can be effectively measured in malaria parasite populations using minimal genotype data, allowing rational design of genome-wide association studies; and (ii) while drug response (IC(50)) shows significant H(2), parasite clearance following ACT was not heritable in the population studied. Hide abstract
Vertical transmission of Plasmodium falciparum is under-recognized and usually associated with asymptomatic low-level parasitemia at birth. We report symptomatic congenital malaria presenting as a neonatal sepsis syndrome. The presence at birth of a high asexual parasitemia, gametocytemia, and splenomegaly indicated in utero rather than intrapartum transmission. The neonate was successfully treated with intravenous artesunate followed by oral dihydroartemisinin-piperaquine, without apparent adverse effects. Hide abstract
Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is a predictor of mortality in critical illness. Severe malaria (SM) is associated with decreased NO bioavailability, but the contribution of ADMA to the pathogenesis of impaired NO bioavailability and adverse outcomes in malaria is unknown. In adults with and without falciparum malaria, we tested the hypotheses that plasma ADMA would be: 1) increased in proportion to disease severity, 2) associated with impaired vascular and pulmonary NO bioavailability and 3) independently associated with increased mortality. We assessed plasma dimethylarginines, exhaled NO concentrations and endothelial function in 49 patients with SM, 78 with moderately severe malaria (MSM) and 19 healthy controls (HC). Repeat ADMA and endothelial function measurements were performed in patients with SM. Multivariable regression was used to assess the effect of ADMA on mortality and NO bioavailability. Plasma ADMA was increased in SM patients (0.85 microM; 95% CI 0.74-0.96) compared to those with MSM (0.54 microM; 95%CI 0.5-0.56) and HCs (0.64 microM; 95%CI 0.58-0.70; p<0.001). ADMA was an independent predictor of mortality in SM patients with each micromolar elevation increasing the odds of death 18 fold (95% CI 2.0-181; p = 0.01). ADMA was independently associated with decreased exhaled NO (r(s) = -0.31) and endothelial function (r(s) = -0.32) in all malaria patients, and with reduced exhaled NO (r(s) = -0.72) in those with SM. ADMA is increased in SM and associated with decreased vascular and pulmonary NO bioavailability. Inhibition of NOS by ADMA may contribute to increased mortality in severe malaria. Hide abstract
Parasite clearance data from 18,699 patients with falciparum malaria treated with an artemisinin derivative in areas of low (n=14,539), moderate (n=2077), and high (n=2083) levels of malaria transmission across the world were analyzed to determine the factors that affect clearance rates and identify a simple in vivo screening measure for artemisinin resistance. The main factor affecting parasite clearance time was parasite density on admission. Clearance rates were faster in high-transmission settings and with more effective partner drugs in artemisinin-based combination treatments (ACTs). The result of the malaria blood smear on day 3 (72 h) was a good predictor of subsequent treatment failure and provides a simple screening measure for artemisinin resistance. Artemisinin resistance is highly unlikely if the proportion of patients with parasite densities of <100,000 parasites/microL given the currently recommended 3-day ACT who have a positive smear result on day 3 is <3%; that is, for n patients the observed number with a positive smear result on day 3 does not exceed (n + 60)/24. Hide abstract
World Health Organization treatment guidelines recommend that adults with severe malaria be admitted to an intensive care unit (ICU). However, ICU facilities are limited in the resource-poor settings where most malaria occurs. Identification of patients at greater risk of complications may facilitate their triage and resource allocation. Hide abstract
PLoS Pathogens, 6 (4), pp. 1-8. Read abstract2010. Increased asymmetric dimethylarginine in severe falciparum malaria: Association with impaired nitric oxide bioavailability and fatal outcome
Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is a predictor of mortality in critical illness. Severe malaria (SM) is associated with decreased NO bioavailability, but the contribution of ADMA to the pathogenesis of impaired NO bioavailability and adverse outcomes in malaria is unknown. In adults with and without falciparum malaria, we tested the hypotheses that plasma ADMA would be: 1) increased in proportion to disease severity, 2) associated with impaired vascular and pulmonary NO bioavailability and 3) independently associated with increased mortality. We assessed plasma dimethylarginines, exhaled NO concentrations and endothelial function in 49 patients with SM, 78 with moderately severe malaria (MSM) and 19 healthy controls (HC). Repeat ADMA and endothelial function measurements were performed in patients with SM. Multivariable regression was used to assess the effect of ADMA on mortality and NO bioavailability. Plasma ADMA was increased in SM patients (0.85 μM; 95% CI 0.74-0.96) compared to those with MSM (0.54 μM; 95%CI 0.5-0.56) and HCs (0.64 μM; 95%CI 0.58-0.70; p<0.001). ADMA was an independent predictor of mortality in SM patients with each micromolar elevation increasing the odds of death 18 fold (95% CI 2.0-181; p = 0.01). ADMA was independently associated with decreased exhaled NO (r =20.31) and endothelial function (r =20.32) in all malaria patients, and with reduced exhaled NO (r =-0.72) in those with SM. ADMA is increased in SM and associated with decreased vascular and pulmonary NO bioavailability. Inhibition of NOS by ADMA may contribute to increased mortality in severe malaria. Hide abstract
Severe malaria (SM) syndromes caused by Plasmodium falciparum infection result in major morbidity and mortality each year. However, only a fraction of P. falciparum infections develop into SM, implicating host genetic factors as important determinants of disease outcome. Previous studies indicate that tumour necrosis factor (TNF) and lymphotoxin alpha (LTα) may be important for the development of cerebral malaria (CM) and other SM syndromes. Hide abstract
New diagnoses of tuberculosis (TB) present important opportunities to detect and treat HIV. Rates of HIV and TB in Indonesia's easternmost Papua Province exceed national figures, but data on co-infection rates and outcomes are lacking. We aimed to measure TB-HIV co-infection rates, examine longitudinal trends, compare management with World Health Organisation (WHO) recommendations, and document progress and outcome. Hide abstract
Clin Infect Dis, 49 (11), pp. 1638-1640. | Read more2009. Artemisinin combination therapy for malaria: beyond good efficacy.
Hemolysis causes anemia in falciparum malaria, but its contribution to microvascular pathology in severe malaria (SM) is not well characterized. In other hemolytic diseases, release of cell-free hemoglobin causes nitric oxide (NO) quenching, endothelial activation, and vascular complications. We examined the relationship of plasma hemoglobin and myoglobin to endothelial dysfunction and disease severity in malaria. Hide abstract
Unlike Plasmodium falciparum, Plasmodium vivax rarely causes severe disease in healthy travellers or in temperate endemic regions and has been regarded as readily treatable with chloroquine. However, in tropical areas, recent reports have highlighted severe and fatal disease associated with P. vivax infection. We review the evidence for severe disease and the spread of drug-resistant P. vivax and speculate how these maybe related. Hide abstract
In areas where malaria is endemic, infants aged <3 months appear to be relatively protected from symptomatic and severe Plasmodium falciparum malaria, but less is known about the effect of Plasmodium vivax infection in this age group. Hide abstract
The Plasmodium purine salvage enzyme, hypoxanthine guanine xanthine phosphoribosyl transferase (HGXPRT) can protect mice against Plasmodium yoelii pRBC challenge in a T cell-dependent manner and has, therefore, been proposed as a novel vaccine candidate. It is not known whether natural exposure to Plasmodium falciparum stimulates HGXPRT T cell reactivity in humans. Hide abstract
An assessment of the correlation between anti-malarial treatment outcome and molecular markers would improve the early detection and monitoring of drug resistance by Plasmodium falciparum. The purpose of this systematic review was to determine the risk of treatment failure associated with specific polymorphisms in the parasite genome or gene copy number. Hide abstract
Long considered a benign infection, Plasmodium vivax is now recognized as a cause of severe and fatal malaria, despite its low parasite biomass, the increased deformability of vivax-infected red blood cells and an apparent paucity of parasite sequestration. Severe anemia is associated with recurrent bouts of hemolysis of predominantly uninfected erythrocytes with increased fragility, and lung injury is associated with inflammatory increases in alveolar-capillary membrane permeability. Although rare, vivax-associated coma challenges our understanding of pathobiology caused by Plasmodium spp. Host and parasite factors contribute to the risk of severe disease, and comorbidities might contribute to vivax mortality. In this review, we discuss potential mechanisms underlying the syndromes of uncomplicated and severe vivax malaria, identifying key areas for future research. Hide abstract
Severe Plasmodium falciparum malaria is a major cause of global mortality, yet the immunological factors underlying progression to severe disease remain unclear. CD4(+)CD25(+) regulatory T cells (Treg cells) are associated with impaired T cell control of Plasmodium spp infection. We investigated the relationship between Treg cells, parasite biomass, and P. falciparum malaria disease severity in adults living in a malaria-endemic region of Indonesia. CD4(+)CD25(+)Foxp3(+)CD127(lo) Treg cells were significantly elevated in patients with uncomplicated (UM; n = 17) and severe malaria (SM; n = 16) relative to exposed asymptomatic controls (AC; n = 10). In patients with SM, Treg cell frequency correlated positively with parasitemia (r = 0.79, p = 0.0003) and total parasite biomass (r = 0.87, p<0.001), both major determinants for the development of severe and fatal malaria, and Treg cells were significantly increased in hyperparasitemia. There was a further significant correlation between Treg cell frequency and plasma concentrations of soluble tumor necrosis factor receptor II (TNFRII) in SM. A subset of TNFRII(+) Treg cells with high expression of Foxp3 was increased in severe relative to uncomplicated malaria. In vitro, P. falciparum-infected red blood cells dose dependently induced TNFRII(+)Foxp3(hi) Treg cells in PBMC from malaria-unexposed donors which showed greater suppressive activity than TNFRII(-) Treg cells. The selective enrichment of the Treg cell compartment for a maximally suppressive TNFRII(+)Foxp3(hi) Treg subset in severe malaria provides a potential link between immune suppression, increased parasite biomass, and malaria disease severity. The findings caution against the induction of TNFRII(+)Foxp3(hi) Treg cells when developing effective malaria vaccines. Hide abstract
N Engl J Med, 360 (12), pp. 1254. | Read more2009. Antimalarial therapies in children from Papua New Guinea.
Amodiaquine retains efficacy against infection by chloroquine-resistant Plasmodium falciparum; however, little information is available on its efficacy against infection by chloroquine-resistant Plasmodium vivax. Patients presenting to a rural clinic with a pure P. vivax infection that recurred after recent antimalarial treatment were retreated, this time with amodiaquine monotherapy, and the risk of further recurrence within 4 weeks was assessed. Of the 87 patients with pure P. vivax infection, 15 patients did not complete a full course of treatment, 4 of whom were intolerant to treatment. In the 72 patients completing treatment, 91% (63 of 69) had cleared their parasitemia within 48 h with no early treatment failure. Follow-up to day 28 or recurrent parasitemia was achieved for 56 patients (78%). The cumulative incidence of treatment failure by day 28 was 22.8% (95% confidence interval, 7.3 to 38%). The in vitro sensitivity profile was determined for a separate set of isolates from outpatients with pure P. vivax infection. The median 50% inhibitory concentration of amodiaquine was 11.3 nM (range, 0.37 to 95.8) and was correlated significantly with that of chloroquine (Spearman rank correlation coefficient, 0.602; P < 0.001). Although amodiaquine results in a rapid clinical response, the risk of recurrence by day 28 is unacceptably high, reducing its suitability as an alternative treatment of infection by chloroquine-resistant P. vivax in this region. Hide abstract
Maturation of Plasmodium falciparum decreases the deformability of infected red blood cells (RBCs), increasing their clearance as they attempt to pass through endothelial slits of the splenic sinus. Previous studies of Plasmodium vivax-infected RBCs led to opposite conclusions with respect to cellular deformability. To resolve this controversy, P. vivax-infected RBCs were passed through a 2-microm microfluidic channel. In contrast to P. falciparum-infected RBCs, mature P. vivax-infected RBCs readily became deformed through 2-microm constrictions. After this extreme deformation, 67% of P. vivax-infected RBCs recovered a normal appearance; however, 15% of uninfected RBCs were destroyed. Results suggest mechanisms for both avoidance of splenic clearance and anemia in vivax malaria. Hide abstract
New England Journal of Medicine, 360 (12), pp. 1254.2009. Antimalarial therapies in children from Papua New Guinea
Artemisinin combination treatments (ACT) are recommended as first line treatment for falciparum malaria throughout the malaria affected world. We reviewed the efficacy of a 3-day regimen of mefloquine and artesunate regimen (MAS(3)), over a 13 year period of continuous deployment as first-line treatment in camps for displaced persons and in clinics for migrant population along the Thai-Myanmar border. Hide abstract
Analytical approaches for the interpretation of anti-malarial clinical trials vary considerably. The aim of this study was to quantify the magnitude of the differences between efficacy estimates derived from these approaches and identify the factors underlying these differences. Hide abstract
Characterization of anti-malarial drug concentration profiles is necessary to optimize dosing, and thereby optimize cure rates and reduce both toxicity and the emergence of resistance. Population pharmacokinetic studies determine the drug concentration time profiles in the target patient populations, including children who have limited sampling options. Currently, population pharmacokinetic studies of anti-malarial drugs are designed based on logistical, financial and ethical constraints, and prior knowledge of the drug concentration time profile. Although these factors are important, the proposed design may be unable to determine the desired pharmacokinetic profile because there was no formal consideration of the complex statistical models used to analyse the drug concentration data. Hide abstract
The aim of this study was to identify and compare factors associated with Plasmodium falciparum gametocyte carriage in three regions of differing malaria endemicity. Hide abstract
Severe malaria is associated with decreased nitric oxide (NO) production and low plasma concentrations of L-arginine, the substrate for NO synthase. Supplementation with L-arginine has the potential to improve NO bioavailability and outcomes. We developed a pharmacokinetic model for L-arginine in moderately severe malaria to explore the concentration-time profile and identify important covariates. In doses of 3, 6, or 12 g,L-arginine was infused over 30 min to 30 adults with moderately severe malaria, and plasma concentrations were measured at 8 to 11 time points. Patients who had not received L-arginine were also assessed and included in the model. The data were analyzed using a population approach with NONMEM software. A two-compartment linear model with first-order elimination best described the data, with a clearance of 44 liters/h (coefficient of variation [CV] = 52%) and a volume of distribution of 24 liters (CV = 19%). The natural time course of L-arginine recovery was described empirically by a second-order polynomial with a time to half recovery of 26 h. The half-life of exogenous L-arginine was reduced in patients with malaria compared with that for healthy adults. Weight and ethnicity were significant covariates for clearance. MATLAB simulations of dosing schedules for use in future studies predicted that 12 g given over 6, 8, or 12 h will provide concentrations above the K(m) of endothelial cell CAT-1 transporters in 90%, 75%, and 60% of patients, respectively. Hide abstract
Multidrug-resistant strains of Plasmodium vivax are emerging in Southeast Asia. Hide abstract
Adherence of parasitized erythrocytes to activated endothelium causes microvascular obstruction, tissue ischemia, and clinical complications in severe malaria (SM); however, the mechanisms leading to endothelial activation remain unclear. The angiogenic factors, angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) are modulators of endothelial activation, with Ang-2 release from Weibel-Palade bodies (WPBs) being regulated by endothelial nitric oxide (NO). We explored the relationships between endothelial NO bioavailability, Ang-2, VEGF, tissue perfusion, and clinical outcomes in SM. We measured plasma Ang-2 and VEGF, together with biomarkers of severity from 146 adults with and without SM, in parallel with longitudinal measures of endothelial function by using reactive hyperemia peripheral arterial tonometry (a measure of endothelial NO bioavailability). Regression was used to relate concentrations of Ang-2/VEGF with malaria disease severity, biomarkers of perfusion, endothelial activation, and parasite biomass. The longitudinal relationship between Ang-2 and endothelial function was assessed by using a mixed-effects model. Ang-2 concentrations were elevated in SM and associated with increased venous lactate, plasma intercellular cell adhesion molecule-1 concentrations, parasite biomass, and mortality. In contrast, VEGF concentrations were inversely associated with these biomarkers. Ang-2 concentrations were significantly better predictors of death than venous lactate (P = 0.03). Recovery of endothelial function was associated with falling concentrations of Ang-2. Ang-2 release from endothelial cells with reduced NO bioavailability is likely to contribute to endothelial activation, sequestered parasite biomass, impaired perfusion, and poor outcome in severe falciparum malaria. Agents that improve endothelial NO, reduce WPB exocytosis, and/or antagonize Ang-2 may have therapeutic roles in SM. Hide abstract
Multidrug resistance has emerged to both Plasmodium vivax and Plasmodium falciparum and yet the comparative epidemiology of these infections is poorly defined. Hide abstract
The reported case-fatality rate associated with severe malaria varies widely. Whether age is an independent risk factor is uncertain. Hide abstract
Merozoite surface protein (MSP) 5 is a candidate antigen for a malaria vaccine. In cross-sectional and longitudinal studies, we measured MSP5 antibody responses in Papuans with acute Plasmodium falciparum malaria, Plasmodium vivax malaria, and mixed P. falciparum and P. vivax malaria and in those with past exposure. Hide abstract
Recent studies using laboratory clones have demonstrated that several antiretroviral protease inhibitors (PIs) inhibit the growth of Plasmodium falciparum at concentrations that may be of clinical significance, especially during human immunodeficiency virus type 1 (HIV-1) and malaria coinfection. Using clinical isolates, we now demonstrate the in vitro effectiveness of two HIV-1 aspartic PIs, saquinavir (SQV) and ritonavir (RTV), against P. vivax (n = 30) and P. falciparum (n = 20) from populations subjected to high levels of mefloquine and artesunate pressure on the Thailand-Myanmar border. The median 50% inhibitory concentration values of P. vivax to RTV and SQV were 2,233 nM (range, 732 to 7,738 nM) and 4,230 nM (range, 1,326 to 8,452 nM), respectively, both within the therapeutic concentration range commonly found for patients treated with these PIs. RTV was fourfold more effective at inhibiting P. vivax than it was at inhibiting P. falciparum, compared to a twofold difference in SQV sensitivity. An increased P. falciparum mdr1 copy number was present in 33% (3/9) of isolates and that of P. vivax mdr1 was present in 9% of isolates (2/22), but neither was associated with PI sensitivity. The inter-Plasmodium sp. variations in PI sensitivity indicate key differences between P. vivax and P. falciparum. PI-containing antiretroviral regimens may demonstrate prophylactic activity against both vivax and falciparum malaria in HIV-infected patients who reside in areas where multidrug-resistant P. vivax or P. falciparum is found. Hide abstract
L-arginine infusion improves endothelial function in malaria but its safety profile has not been described in detail. We assessed clinical symptoms, hemodynamic status and biochemical parameters before and after a single L-arginine infusion in adults with moderately severe malaria. Hide abstract
Multidrug-resistant Plasmodium vivax (Pv) is widespread in eastern Indonesia, and emerging elsewhere in Asia-Pacific and South America, but is generally regarded as a benign disease. The aim of the study was to review the spectrum of disease associated with malaria due to Pv and P. falciparum (Pf) in patients presenting to a hospital in Timika, southern Papua, Indonesia. Hide abstract
Plasmodium falciparum infection exerts a considerable burden on pregnant women, but less is known about the adverse consequences of Plasmodium vivax infection. Hide abstract
The blood concentration profiles of most antimalarial drugs vary considerably between patients. The interpretation of antimalarial drug trials evaluating efficacy and effectiveness would be improved considerably if the exposure of the infecting parasite population to the antimalarial drug treatment could be measured. Artemisinin combination treatments are now recommended as first-line drugs for the treatment of falciparum malaria. Measurement of the blood, serum or plasma concentration of the slowly eliminated partner antimalarial drug on day 7 of follow-up is simpler and might be a better determinant of therapeutic response than the area under the concentration-time curve. Measurement of the day-7 drug level should be considered as a routine part of antimalarial drug trials. Hide abstract
In Papua, Indonesia, the antimalarial susceptibility of Plasmodium vivax (n = 216) and P. falciparum (n = 277) was assessed using a modified schizont maturation assay for chloroquine, amodiaquine, artesunate, lumefantrine, mefloquine, and piperaquine. The most effective antimalarial against P. vivax and P. falciparum was artesunate, with geometric mean 50% inhibitory concentrations (IC50s) (95% confidence intervals [CI]) of 1.31 nM (1.07 to 1.59) and 0.64 nM (0.53 to 0.79), respectively. In contrast, the geometric mean chloroquine IC50 for P. vivax was 295 nM (227 to 384) compared to only 47.4 nM (42.2 to 53.3) for P. falciparum. Two factors were found to significantly influence the in vitro drug response of P. vivax: the initial stage of the parasite and the duration of the assay. Isolates of P. vivax initially at the trophozoite stage had significantly higher chloroquine IC50s (478 nM [95% CI, 316 to 722]) than those initially at the ring stage (84.7 nM [95% CI, 45.7 to 157]; P < 0.001). Synchronous isolates of P. vivax and P. falciparum which reached the target of 40% schizonts in the control wells within 30 h had significantly higher geometric mean chloroquine IC50s (435 nM [95% CI, 169 to 1,118] and 55.9 nM [95% CI, 48 to 64.9], respectively) than isolates that took more than 30 h (39.9 nM [14.6 to 110.4] and 36.9 nM [31.2 to 43.7]; P < 0.005). The results demonstrate the marked stage-specific activity of chloroquine with P. vivax and suggest that susceptibility to chloroquine may be associated with variable growth rates. These findings have important implications for the phenotypic and downstream genetic characterization of P. vivax. Hide abstract
Plasmodium vivax is a major cause of malaria and is still primarily treated with chloroquine. Chloroquine inhibits the polymerization of haem to inert haemozoin. Free haem monomers are thought to catalyze oxidative damage to the Plasmodium spp. trophozoite, the stage when haemoglobin catabolism is maximal. However preliminary in vitro observations on P. vivax clinical isolates suggest that only ring stages (early trophozoites) are sensitive to chloroquine. In this study, the stage specific action of chloroquine was investigated in synchronous cryopreserved isolates of P. vivax. Hide abstract
Malaria is a very important cause of anaemia in tropical countries. Anaemia is assessed either by measurement of the haematocrit or the haemoglobin concentration. For comparisons across studies, it is often necessary to derive one measure from the other. Hide abstract
Am J Trop Med Hyg, 77 (6 Suppl), pp. 79-87. Read abstract2007. Vivax malaria: neglected and not benign.
Plasmodium vivax threatens almost 40% of the world's population, resulting in 132-391 million clinical infections each year. Most of these cases originate from Southeast Asia and the Western Pacific, although a significant number also occurs in Africa and South America. Although often regarded as causing a benign and self-limiting infection, there is increasing evidence that the overall burden, economic impact, and severity of disease from P. vivax have been underestimated. Malaria control strategies have had limited success and are confounded by the lack of access to reliable diagnosis, emergence of multidrug resistant isolates, the parasite's ability to transmit early in the course of disease and relapse from dormant liver stages at varying time intervals after the initial infection. Progress in reducing the burden of disease will require improved access to reliable diagnosis and effective treatment of both blood-stage and latent parasites, and more detailed characterization of the epidemiology, morbidity, and economic impact of vivax malaria. Without these, vivax malaria will continue to be neglected by ministries of health, policy makers, researchers, and funding bodies. Hide abstract
AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 77 (6), pp. 79-87.2007. Vivax malaria: Neglected and not benign
Dihydroartemisinin-piperaquine (DHP) is an important new treatment for drug-resistant malaria, although pharmacokinetic studies on the combination are limited. In Papua, Indonesia, we assessed determinants of the therapeutic efficacy of DHP for uncomplicated malaria. Plasma piperaquine concentrations were measured on day 7 and day 28, and the cumulative risk of parasitological failure at day 42 was calculated using survival analysis. Of the 598 patients in the evaluable population 342 had infections with Plasmodium falciparum, 83 with Plasmodium vivax, and 173 with a mixture of both species. The unadjusted cumulative risks of recurrence were 7.0% (95% confidence interval [CI]: 4.6 to 9.4%) for P. falciparum and 8.9% (95% CI: 6.0 to 12%) for P. vivax. After correcting for reinfections the risk of recrudescence with P. falciparum was 1.1% (95% CI: 0.1 to 2.1%). The major determinant of parasitological failure was the plasma piperaquine concentration. A concentration below 30 ng/ml on day 7 was observed in 38% (21/56) of children less than 15 years old and 22% (31/140) of adults (P = 0.04), even though the overall dose (mg per kg of body weight) in children was 9% higher than that in adults (P < 0.001). Patients with piperaquine levels below 30 ng/ml were more likely to have a recurrence with P. falciparum (hazard ratio [HR] = 6.6 [95% CI: 1.9 to 23]; P = 0.003) or P. vivax (HR = 9.0 [95% CI: 2.3 to 35]; P = 0.001). The plasma concentration of piperaquine on day 7 was the major determinant of the therapeutic response to DHP. Lower plasma piperaquine concentrations and higher failure rates in children suggest that dose revision may be warranted in this age group. Hide abstract
Severe falciparum malaria (SM) is associated with tissue ischemia related to cytoadherence of parasitized erythrocytes to microvascular endothelium and reduced levels of NO and its precursor, l-arginine. Endothelial function has not been characterized in SM but can be improved by l-arginine in cardiovascular disease. In an observational study in Indonesia, we measured endothelial function using reactive hyperemia-peripheral arterial tonometry (RH-PAT) in 51 adults with SM, 48 patients with moderately severe falciparum malaria (MSM), and 48 controls. The mean RH-PAT index was lower in SM (1.41; 95% confidence interval [CI] = 1.33-1.47) than in MSM (1.82; 95% CI = 1.7-2.02) and controls (1.93; 95% CI = 1.8-2.06; P < 0.0001). Endothelial dysfunction was associated with elevated blood lactate and measures of hemolysis. Exhaled NO was also lower in SM relative to MSM and controls. In an ascending dose study of intravenous l-arginine in 30 more patients with MSM, l-arginine increased the RH-PAT index by 19% (95% CI = 6-34; P = 0.006) and exhaled NO by 55% (95% CI = 32-73; P < 0.0001) without important side effects. Hypoargininemia and hemolysis likely reduce NO bioavailability. Endothelial dysfunction in malaria is nearly universal in severe disease, is reversible with l-arginine, and likely contributes to its pathogenesis. Clinical trials in SM of adjunctive agents to improve endothelial NO bioavailability, including l-arginine, are warranted. Hide abstract
Accurate diagnosis of Plasmodium spp. is essential for the rational treatment of malaria. Despite its many disadvantages, microscopic examination of blood smears remains the current "gold standard" for malaria detection and speciation. PCR assays offer an alternative to microscopy which has been shown to have superior sensitivity and specificity. Unfortunately few comparative studies have been done on the various molecular based speciation methods. Hide abstract
The proliferation of antimalarial drug trials in the last ten years provides the opportunity to launch a concerted global surveillance effort to monitor antimalarial drug efficacy. The diversity of clinical study designs and analytical methods undermines the current ability to achieve this. The proposed World Antimalarial Resistance Network (WARN) aims to establish a comprehensive clinical database from which standardised estimates of antimalarial efficacy can be derived and monitored over time from diverse geographical and endemic regions. The emphasis of this initiative is on five key variables which define the therapeutic response. Ensuring that these data are collected at the individual patient level in a consistent format will facilitate better data management and analytical practices, and ensure that clinical data can be readily collated and made amenable for pooled analyses. Such an approach, if widely adopted will permit accurate and timely recognition of trends in drug efficacy. This will guide not only appropriate interventions to deal with established multidrug resistant strains of malaria, but also facilitate prompt action when new strains of drug resistant plasmodia first emerge. A comprehensive global database incorporating the key determinants of the clinical response with in vitro, molecular and pharmacokinetic parameters will bring together relevant data on host, drug and parasite factors that are fundamental contributors to treatment efficacy. This resource will help guide rational drug policies that optimize antimalarial drug use, in the hope that the emergence and spread of resistance to new drugs can be, if not prevented, at least delayed. Hide abstract
Am J Trop Med Hyg, 77 (3), pp. 447-450. Read abstract2007. Electrocardiographic safety evaluation of dihydroartemisinin piperaquine in the treatment of uncomplicated falciparum malaria.
Dihydroartemisinin-piperaquine (DP) could become a leading fixed combination malaria treatment worldwide. Although there is accumulating evidence of efficacy and safety from clinical trials, data on cardiotoxicity are limited. In two randomized controlled trials in Thailand, 56 patients had ECGs performed before treatment, 4 hours after the first dose, and 4 hours after the last dose. The mean (95% CI) changes in QTc interval (Bazett's correction) were 2 (-6 to 9) ms and 14 (7 to 21) ms, respectively. These small changes on the third day of treatment are similar to those observed elsewhere in the convalescent phase following antimalarial treatment with drugs known to have no cardiac effects and are therefore likely to result from recovery from acute malaria and not the treatment given. At therapeutic doses, DP does not have clinically significant effects on the electrocardiogram. Hide abstract
JOURNAL OF INFECTIOUS DISEASES, 196 (4), pp. 647-648. | Read more2007. Tumor necrosis factor and increase in alveolar capillary barrier in malaria - Reply to Eisenhut
PLoS Med, 4 (8), pp. e267. | Read more2007. Improving case definitions for severe malaria.
Antimalarial drug resistance is now well established in both Plasmodium falciparum and Plasmodium vivax. In southern Papua, Indonesia, where both strains of plasmodia coexist, we have been conducting a series of studies to optimize treatment strategies. Hide abstract
To determine the level of antimalarial drug resistance in southern Papua, Indonesia, we assessed the therapeutic efficacy of chloroquine plus sulfadoxine-pyrimethamine (CQ+SP) for Plasmodium falciparum infections as well as CQ monotherapy for P. vivax infections. Patients with P. falciparum failing therapy were re-treated with unsupervised quinine+/-doxycycline therapy and those with P. vivax with either unsupervised quinine+/-doxycycline or amodiaquine. In total, 143 patients were enrolled in the study (103 treated with CQ+SP and 40 with CQ). Early treatment failures occurred in four patients (4%) with P. falciparum and six patients (15%) with P. vivax. The failure rate by Day 28 for P. vivax was 65% (95% CI 49-81). After PCR correction for re-infections, the Day 42 recrudescence rate for P. falciparum infections was 48% (95% CI 31-65). Re-treatment with unsupervised quinine+/-doxycycline resulted in further recurrence of malaria in 48% (95% CI 31-65) of P. falciparum infections and 70% (95% CI 37-100) of P. vivax infections. Eleven patients with recurrent P. vivax were re-treated with amodiaquine; there were no early or late treatment failures. In southern Papua, a high prevalence of drug resistance of P. falciparum and P. vivax exists both to first- and second-line therapies. Preliminary data indicate that amodiaquine retains superior efficacy compared with CQ for CQ-resistant P. vivax. Hide abstract
The burden of Plasmodium vivax infections has been underappreciated, especially in southeast Asia where chloroquine resistant strains have emerged. Our aim was to compare the safety and efficacy of dihydroartemisinin-piperaquine with that of artemether-lumefantrine in patients with uncomplicated malaria caused by multidrug-resistant P falciparum and P vivax. Hide abstract
The Journal of Infectious Diseases, 196 (4), pp. 647-648. | Read more2007. Reply to Eisenhut
Molecular markers for drug resistant malaria represent public health tools of great but mostly unrealized potential value. A key reason for the failure of molecular resistance markers to live up to their potential is that data on the their prevalence is scattered in disparate databases with no linkage to the clinical, in vitro and pharmacokinetic data that are needed to relate the genetic data to relevant phenotypes. The ongoing replacement of older monotherapies for malaria by new, more effective combination therapies presents an opportunity to create an open access database that brings together standardized data on molecular markers of drug resistant malaria from around the world. This paper presents a rationale for creating a global database of molecular markers for drug resistant malaria and for linking it to similar databases containing results from clinical trials of drug efficacy, in vitro studies of drug susceptibility, and pharmacokinetic studies of antimalarial drugs, in a World Antimalarial Resistance Network (WARN). This database will be a global resource, guiding the selection of first line drugs for treating uncomplicated malaria, for preventing malaria in travelers and for intermittent preventive treatment of malaria in pregnant women, infants and other vulnerable groups. Perhaps most important, a global database for molecular markers of drug resistant malaria will accelerate the identification and validation of markers for resistance to artemisinin-based combination therapies and, thereby, potentially prolong the useful therapeutic lives of these important new drugs. Hide abstract
Treatment failure of chloroquine for P. vivax infections has reached high levels in the eastern provinces of Indonesia, however, in vitro characterization of chloroquine resistance and its associated molecular profile have yet to be determined. Hide abstract
Increased pfmdr1 copy number is associated with reduced susceptibility to structurally unrelated antimalarial drugs. We assessed how administration of different antimalarial drugs altered pfmdr1 polymorphism in parasites from patients who experienced treatment failure. Hide abstract
AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 208-208.2006. Amodiaquine plus artesunate versus dihydroartemisinin-piperaquine for drug resistant P.falciparum and P.vivax in Papua, Indonesia
AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 286-286.2006. Impaired endothelial function in adults with severe falciparum malaria in Papua, Indonesia
AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 98-99.2006. L-arginine infusion increases no production and reverses endothelial dysfunction in adults with moderately severe falciparum malaria in Papua, Indonesia
AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 47-47.2006. Real-time bedside measurement of nitric oxide demonstrates impaired production in adults with severe malaria in papua, Indonesia
In vitro susceptibility tests provide information on the intrinsic response of Plasmodium vivax to antimalarials, free from confounding factors such as host immunity or relapse. This study examined the utility of radioisotope and PicoGreen assays as alternatives to the traditional microscopic examination for assessing response of P. vivax to antimalarial drugs. There was no significant difference in the mean chloroquine IC(50) of P. vivax (n=40) as determined by the microscopic (33.4 ng/ml), isotopic (33.6 ng/ml), and PicoGreen (39.1 ng/ml) assays, respectively (F=0.239, df=2, 51, and p=0.788). However measurement of IC(50)s by the microscopic method was slightly more successful in producing valid assays (57%), compared to the isotopic (32.5%) and PicoGreen (45.5%) methods. In a paired comparison of 20 fresh and cryopreserved isolates as examined by the microscopic method, there were no significant differences between the mean IC(50) responses (T=1.58, df=15, and p=0.34). Detailed methodologies for the short time culture of field and cryopreserved P. vivax are described. Although the microscopic in vitro assay provides a useful method for characterizing the drug susceptibility phenotype of P. vivax isolates, its utility is limited by a laborious methodology and need for highly skilled microscopists. Future efforts should focus on further development of high throughput assays such as the PicoGreen assay as described in this study. Hide abstract
Our study examined the relative contributions of host, pharmacokinetic, and parasitological factors in determining the therapeutic response to artemether-lumefantrine (AL). Hide abstract
Med J Aust, 184 (1), pp. 3-4.2006. Improving the availability of artesunate for treatment of severe malaria.
Addiction, 107 (10), pp. 1883. | Read more2012. Use of a 'microecologic technique' to study crime incidents around methadone maintenance treatment centers - a response: The journal publishes both invited and unsolicited letters.
Tropical Medicine and International Health, 11 (12), pp. 1898-1899.2006. In vivo sensitivity monitoring of mefloquine monotherapy and artesunate-mefloquine combinations for the treatment of uncomplicated falciparum malaria in Thailand in 2003
BMJ: British Medical Journal, 333 (7557), pp. 45.2006. We still need artesunate monotherapy
AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 73 (6), pp. 44-44.2005. Alternative treatment options for chloroquine resistant Plasmodium vivax in Papua, Indonesia
Lancet, 366 (9487), pp. 717-725. Read abstract2005. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial
BACKGROUND: In the treatment of severe malaria, intravenous artesunate is more rapidly acting than intravenous quinine in terms of parasite clearance, is safer, and is simpler to administer, but whether it can reduce mortality is uncertain. METHODS: We did an open-label randomised controlled trial in patients admitted to hospital with severe falciparum malaria in Bangladesh, India, Indonesia, and Myanmar. We assigned individuals intravenous artesunate 2.4 mg/kg bodyweight given as a bolus (n=730) at 0, 12, and 24 h, and then daily, or intravenous quinine (20 mg salt per kg loading dose infused over 4 h then 10 mg/kg infused over 2-8 h three times a day; n=731). Oral medication was substituted when possible to complete treatment. Our primary endpoint was death from severe malaria, and analysis was by intention to treat. FINDINGS: We assessed all patients randomised for the primary endpoint. Mortality in artesunate recipients was 15% (107 of 730) compared with 22% (164 of 731) in quinine recipients; an absolute reduction of 34.7% (95% CI 18.5-47.6%; p=0.0002). Treatment with artesunate was well tolerated, whereas quinine was associated with hypoglycaemia (relative risk 3.2, 1.3-7.8; p=0.009). INTERPRETATION: Artesunate should become the treatment of choice for severe falciparum malaria in adults. Hide abstract
In patients with severe malaria, acute respiratory distress syndrome usually develops after the start of drug treatment and is a major cause of death. Its pathogenesis is not well understood. Hide abstract
To determine the optimum duration of follow-up for the assessment of drug efficacy against Plasmodium falciparum malaria, 96 trial arms from randomized controlled trials (RCTs) with follow-up of 28 days or longer that were conducted between 1990 and 2003 were analyzed. These trials enrolled 13,772 patients, and participating patients comprised 23% of all patients enrolled in RCTs over the past 40 years; 61 (64%) trial arms were conducted in areas where the rate of malaria transmission was low, and 58 (50%) trial arms were supported by parasite genotyping to distinguish true recrudescences from reinfections. The median overall failure rate reported was 10% (range, 0 to 47%). The widely used day 14 assessment had a sensitivity of between 0 and 37% in identifying treatment failures and had no predictive value. Assessment at day 28 had a sensitivity of 66% overall (28 to 100% in individual trials) but could be used to predict the true failure rate if either parasite genotyping was performed (r(2) = 0.94) or if the entomological inoculation rate was known. In the assessment of drug efficacy against falciparum malaria, 28 days should be the minimum period of follow-up. Hide abstract
The borders of Thailand harbour the world's most multidrug resistant Plasmodium falciparum parasites. In 1984 mefloquine was introduced as treatment for uncomplicated falciparum malaria, but substantial resistance developed within 6 years. A combination of artesunate with mefloquine now cures more than 95% of acute infections. For both treatment regimens, the underlying mechanisms of resistance are not known. Hide abstract
Travellers to malaria-endemic destinations are at risk of significant disease and, sometimes, death. Current malaria protection strategies, including chemoprophylaxis, can never be completely effective. In some cases, protective measures are discontinued or misapplied while the risk of infection still exists. In others, suboptimal measures are used, or even no measures at all, because of poor information or inappropriate risk-benefit assessment. In very rare cases, inexplicable failure of prophylaxis occurs. If malaria is contracted whilst abroad the danger to the individual is often further compounded by a lack of high-quality medical facilities and an uncertain supply of effective drugs for treatment. The advent of newer, well tolerated, drugs for treating malaria provides an opportunity to review the role of standby emergency self-medication in travellers visiting or staying (for work or other reasons) in areas where there is a risk of contracting malaria. This article was prepared following a meeting convened in London on Africa Malaria Day in 2002, in which the current opinions of experts in travel medicine and specifically malaria were discussed. It reviews opinion on the current effectiveness and acceptance of prevention strategies, as well as the role of standby emergency medication for falciparum malaria. © 2004 Elsevier Ltd. All rights reserved. Hide abstract
Atovaquone/proguanil is a fixed-dose combination tablet of two antimalarial agents and is highly effective for the prevention of Plasmodium falciparum malaria. In combination with proguanil, the ability of atovaquone to inhibit parasitic mitochondrial electron transport is markedly enhanced. Both atovaquone and proguanil are active against hepatic (pre-erythrocytic) stages of P. falciparum, thereby providing causal prophylaxis and eliminating the need to continue post-travel treatment beyond 7 days. Both agents are also active against erythrocytic stages of P. falciparum, thereby providing suppressive prophylaxis. Atovaquone/proguanil is highly effective against drug-resistant strains of P. falciparum, and cross-resistance has not been observed between atovaquone and other antimalarial agents. In comparative, randomised clinical trials, there were no cases of P. falciparum malaria in nonimmune adults, adolescents and children (>/=11 kg) visiting malaria-endemic regions for </=28 days and receiving atovaquone/proguanil (250/100 mg in adults and dosage based on bodyweight in children <40 kg) once daily. The efficacy for the prevention of P. falciparum malaria was estimated at 100% for atovaquone/proguanil and for mefloquine, and 70% for chloroquine plus proguanil. In individuals (>/=11 kg) from endemic regions who may carry some immunity to malaria (semi-immune), the prophylactic efficacy rating for atovaquone/proguanil based on placebo-controlled trials was 95-100%. Atovaquone/proguanil is generally well tolerated by both adults and children. The most common treatment-related adverse events in placebo-controlled trials were headache and abdominal pain, which occurred at a rate similar to that observed with placebo. Atovaquone/proguanil therapy was associated with significantly fewer gastrointestinal adverse events than chloroquine plus proguanil, and significantly fewer neuropsychiatric adverse events than mefloquine in nonimmune individuals. Significantly fewer recipients of atovaquone/proguanil discontinued treatment because of adverse events than individuals receiving chloroquine plus proguanil or mefloquine (p < 0.05). Hide abstract
Communicable diseases intelligence, 27 (4), pp. 526-532. Read abstract2003. Prevention of opportunistic infections in immunosuppressed patients in the tropical top end of the Northern Territory
The population of the Top End of the Northern Territory has a high incidence of several infections of particular significance in the immunosuppressed. The following protocol for evaluation and treatment of patients prior to immunosuppression was developed in order to reduce the incidence of serious opportunistic infections. The infections discussed are Strongyloides stercoralis, tuberculosis, scabies, chronic hepatitis B, melioidosis and other bacterial infections. We recommend that all patients planned to receive more than 0.5 mg/kg/day of prednisolone for >14 days, or any more potent immunosuppressive drug, be evaluated and treated according to this protocol. Details of the rationale, evidence base, and proposed investigations and therapy for such patients are discussed. Hide abstract
Br J Clin Pharmacol, 53 (3), pp. 337-338. | Read more2002. The influence of body weight on the pharmacokinetics of mefloquine.
Am J Trop Med Hyg, 65 (5), pp. 614-622. Read abstract2001. Factors contributing to anemia after uncomplicated falciparum malaria.
The factors contributing to anemia in falciparum malaria were characterized in 4,007 prospectively studied patients on the western border of Thailand. Of these, 727 patients (18%) presented with anemia (haematocrit < 30%), and 1% (55 of 5,253) required blood transfusion. The following were found to be independent risk factors for anemia at admission: age < 5 years, a palpable spleen, a palpable liver, recrudescent infections, being female, a prolonged history of illness (> 2 days) before admission, and pure Plasmodium falciparum infections rather than mixed P. falciparum and Plasmodium vivax infections. The mean maximum fractional fall in hematocrit after antimalarial treatment was 14.1% of the baseline value (95% confidence interval [CI], 13.6-14.6). This reduction was significantly greater in young children (aged < 5 years) and in patients with a prolonged illness, high parasitemia, or delayed parasite clearance. Loss of parasitized erythrocytes accounted for < 10% of overall red blood cell loss. Hematological recovery was usually complete within 6 weeks, but it was slower in patients who were anemic at admission (adjusted hazards ratio [AHR], 1.9, 95% CI, 1.5-2.3), and those whose infections recrudesced (AHR, 1.2, 95% CI, 1.01-1.5). Half the patients with treatment failure were anemic at 6 weeks compared with 19% of successfully treated patients (relative risk, 2.8, 95% CI, 2.0-3.8). Patients coinfected with P. vivax (16% of the total) were 1.8 (95% CI, 1.2-2.6) times less likely to become anemic and recovered 1.3 (95% CI, 1.0-1.5) times faster than those with P. falciparum only. Anemia is related to drug resistance and treatment failure in uncomplicated malaria. Children aged < 5 years of age were more likely than older children or adults to become anemic. Coinfection with P. vivax attenuates the anemia of falciparum malaria, presumably by modifying the severity of the infection. Hide abstract
The rising prevalence of multidrug resistant falciparum malaria is occurring at an alarming rate and has serious implications for the health of many of the world's poorest countries. The dangers of not changing treatment practices immediately are huge and irreversible, threatening to both exacerbate the scale and scope of the malaria pandemic, and deprive policymakers of future options against the disease. If a health care disaster is to be avoided then massive and long term funding is urgently required. Funds need to be applied in a cohesive manner, accountable to funding bodies and tailored to the specifics of each endemic region. The key elements of such an approach should be improving early diagnosis and treatment of infection and the deployment of combination regimens containing an artemisinin derivative. These short term measures will need to be accompanied by a longer term strategy to encourage antimalarial drug research and development. Hide abstract
Southeast Asian Journal of Tropical Medicine and Public Health, 32 (SUPPL. 1), pp. 1-3.2001. The use of antimalarial drug combinations containing an artemisinin derivative for the treatment of falciparum malaria
Antimalarial resistance develops and spreads when spontaneously occurring mutant malaria parasites are selected by concentrations of antimalarial drug which are sufficient to eradicate the more sensitive parasites but not those with the resistance mutation(s). Mefloquine, a slowly eliminated quinoline-methanol compound, is the most widely used drug for the treatment of multidrug-resistant falciparum malaria. It has been used at doses ranging between 15 and 25 mg of base/kg of body weight. Resistance to mefloquine has developed rapidly on the borders of Thailand, where the drug has been deployed since 1984. Mathematical modeling with population pharmacokinetic and in vivo and in vitro pharmacodynamic data from this region confirms that, early in the evolution of resistance, conventional assessments of the therapeutic response </=28 days after treatment underestimate considerably the level of resistance. Longer follow-up is required. The model indicates that initial deployment of a lower (15-mg/kg) dose of mefloquine provides a greater opportunity for the selection of resistant mutants and would be expected to lead more rapidly to resistance than de novo use of the higher (25-mg/kg) dose. Hide abstract
Following a marked decline in the efficacy in vivo of mefloquine between 1990 and 1994, a combination of artesunate (4 mg/kg/d for 3 d) and mefloquine (25 mg/kg) has been used as first line treatment of uncomplicated falciparum malaria in camps for displaced persons located along the north-western border of Thailand. Antimalarial drug susceptibility of fresh isolates of Plasmodium falciparum from this population was evaluated using a radioisotope microdilution assay between 1995 and 1999. In total, 268 isolates were collected, of which 189 were from primary infections and 79 from recrudescent infections. The geometric mean 50% inhibitory concentration (IC50) values from primary infections were: dihydroartemisinin 1.2 ng/mL, artesunate 1.6 ng/mL, artemether 4.8 ng/mL, atovaquone 0.4 ng/mL, lumefantrine 32 ng/mL, chloroquine 149 ng/mL, quinine 354 ng/mL, mefloquine 27 ng/mL and halofantrine 4.1 ng/mL. A significant positive correlation was found between the susceptibility in vitro to artesunate and quinine (r = 0.43, P < 0.001), mefloquine (r = 0.46, P < 0.001), and halofantrine (r = 0.51, P < 0.001). These levels of resistance in vitro are among the highest reported and confirm continuing high level multidrug resistance in this area. Despite intensive use of the combination between 1995 and 1999 there has been a significant improvement in mefloquine sensitivity (P < 0.001) and artesunate sensitivity (P < 0.001). This supports observations in vivo that the combination of artesunate and mefloquine has reversed the previous decline in mefloquine sensitivity. Hide abstract
Artemisinin and its derivatives, artesunate and artemether, represent a new class of antimicrobial drug with potent activity against Plasmodium falciparum. Although they show excellent efficacy in both severe and uncomplicated malaria, dosage regimens still need to be optimised and pharmacokinetic profiles defined. In the treatment of uncomplicated malaria, the artemisinin drugs should be used in combination with a long acting antimalarial to protect both drugs against the emergence of resistance. In the treatment of severe malaria, parenteral artemether is at least as effective as quinine and is simpler to use. The use of rectal preparations of artesunate and artemisinin at the rural health level will facilitate early initiation of the treatment of falciparum malaria and this may reduce the proportion of patients progressing to severe disease. All of the artemisinin drugs have comparable efficacy; the choice of derivative should be based upon availability, cost and quality of the preparation. Artemisinin, artesunate and artemether are well-tolerated in both adults and children, with no evidence to date of serious clinical toxicity. Hide abstract
Worsening drug resistance in Plasmodium falciparum malaria is a major threat to health in tropical countries. We did a prospective study of malaria incidence and treatment in an area of highly multidrug-resistant P. falciparum malaria. Hide abstract
Am J Trop Med Hyg, 62 (1), pp. 65-69. Read abstract2000. A case-control auditory evaluation of patients treated with artemisinin derivatives for multidrug-resistant Plasmodium falciparum malaria.
The artemisinin derivatives are now used widely in areas with multidrug-resistant Plasmodium falciparum malaria such as Southeast Asia, but concerns remain over their potential for neurotoxicity. Mice, rats, dogs, and monkeys treated with high doses of intramuscular artemether or arteether develop an unusual pattern of focal damage to brain stem nuclei (particularly those involved in auditory processing). To investigate whether a similar toxic effect occurs in patients treated with these compounds, clinical neurologic evaluation, audiometry and early latency auditory evoked responses were measured in a single-blind comparison of 79 patients who had been treated with > or =2 courses of oral artemether or artesunate within the previous 3 years, and 79 age- and sex-matched controls living in a malaria-endemic area on the northwestern border of Thailand. There were no consistent differences in any of these test results between the cases and controls. This study failed to detect any evidence of significant neurotoxicity in patients treated previously with oral artemether or artesunate for acute malaria. Hide abstract
Antimicrob Agents Chemother, 43 (12), pp. 2943-2949. Read abstract1999. The pfmdr1 gene is associated with a multidrug-resistant phenotype in Plasmodium falciparum from the western border of Thailand.
On the western border of Thailand, Plasmodium falciparum has become resistant to almost all antimalarial agents. The molecular basis of resistance in these parasite populations has not been well characterized. This study assessed genetic polymorphisms in the pfmdr1 gene in 54 parasites collected from the western border of Thailand to determine the relationship of pfmdr1 copy number and codon mutations with parasite sensitivities to mefloquine, chloroquine, halofantrine, quinine, and artesunate assessed in vitro. A point mutation at codon 86 (resulting in a change of Asn to Tyr) was associated with a significantly lower 50% inhibitory concentration (IC(50)) of mefloquine (median, 9 ng/ml versus 52.4 ng/ml; P = 0.003). Overall 35% of the isolates (19 of 54) had an increase in pfmdr1 copy number, and all 19 carried the wild-type allele at codon 86. Increased pfmdr1 copy number was associated with higher IC(50)s of mefloquine (P = 0.04) and artesunate (P = 0.005), independent of polymorphism at codon 86. The relationship between pfmdr1 and resistance to structurally distinct antimalarial agents confirms the presence of a true multidrug-resistant phenotype. Hide abstract
Genetic characterization of Plasmodium falciparum infections in north-western Thailand, a region of low transmission intensity (1 infection/person each year), has found a comparable number of parasite genotypes per infected person to regions with hyperendemic malaria. Clone multiplicity and parasite diversity were found to be homogeneous across 129 infected individuals comprising a range of age-groups (1.32 parasite genotypes; n = 98), patients (aged 2-16 years) with recrudescent infections (1.54; n = 13), and pregnant women (1.61; n = 18). Individuals belonging to groups with a high risk of infection, as deduced by clinical epidemiology, did not harbour a higher number of clones per infection, nor greater parasite diversity than low-risk groups. In fact, multiple genotype infections were as common in low-risk groups, suggesting that there is frequent transmission of polyclonal infections from a single inoculum, rather than superinfection. Such a polyclonal transmission system would enable generation of extensive parasite diversity by recombination, despite the low level of transmission. However, co-infection with P. vivax was associated with fewer P. falciparum genotypes per infection. Hide abstract
To construct a population pharmacokinetic model for mefloquine in the treatment of falciparum malaria. Hide abstract
Am J Trop Med Hyg, 60 (6), pp. 1019-1023. Read abstract1999. Risk factors for gametocyte carriage in uncomplicated falciparum malaria.
The factors affecting the development of patent Plasmodium falciparum gametocytemia were assessed in 5,682 patients entered prospectively into a series of antimalarial drug trials conducted in an area of low and seasonal transmission on the western border of Thailand. Of the 4,565 patients with admission thick smear assessments, 110 (2.4%) had gametocytemia. During the follow-up period 170 (3%) of all patients developed patent gametocytemia, which in 89% had developed by day 14 following treatment. In a multiple logistic regression model five factors were found to be independent risk factors at presentation for the development or persistence of gametocytemia during follow up; patent gametocytemia on admission (adjusted odds ratio [AOR] = 7.8, 95% confidence interval [CI] = 3.7-16, P < 0.001), anemia (hematocrit <30%) (AOR = 3.9, 95% CI = 2.3-6.5, P < 0.001), no coincident P. vivax malaria (AOR = 3.5, 95% CI = 1.04-11.5, P < 0.04), presentation with a recrudescent infection (AOR = 2.3, 95% CI = 1.3-4.1, P < 0.004), and a history of illness longer than two days (AOR = 3.3, 95% CI = 1.7-6.6, P < 0.001). Patients whose infections responded slowly to treatment or recrudesced subsequently were also more likely to carry gametocytes than those who responded rapidly or were cured (relative risks = 1.9, 95% CI = 1.3-2.7 and 2.8, 95% CI = 2.0-4.0, respectively; P < 0.001). These data provide further evidence of important epidemiologic interactions between P. falciparum and P. vivax, and drug resistance and transmission potential. Hide abstract
Am J Trop Med Hyg, 60 (4), pp. 547-555. Read abstract1999. Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives.
In prospective studies of acute uncomplicated, multidrug-resistant falciparum malaria on the western border of Thailand, the oral artemisinin derivatives were used alone in the treatment of 836 patients (artesunate 630, artemether 206), were combined with mefloquine (15-25 mg base/kg) in 2,826 patients, and mefloquine alone was used in 1,303 patients. The combined regimens of mefloquine plus an artemisinin derivative were associated with more side effects than those with an artemisinin derivative alone; acute nausea (31% versus 16%), vomiting (24% versus 11%), anorexia (51% versus 34%), and dizziness (47% versus 15%) (P < 0.001). Oral artesunate and artemether alone were very well tolerated. There was no difference in the incidence of possible adverse effects between the two drugs, and no evidence that either derivative caused allergic reactions, neurologic or psychiatric reactions, or cardiovascular or dermatologic toxicity. Blackwater fever occurred in three patients treated with mefloquine plus artesunate regimens. Oral artesunate and artemether are safe and well tolerated antimalarial drugs. Hide abstract
Antimicrob Agents Chemother, 43 (2), pp. 341-346. Read abstract1999. Pharmacokinetics of mefloquine combined with artesunate in children with acute falciparum malaria.
Combining artemisinin or a derivative with mefloquine increases cure rates in falciparum malaria patients, reduces transmission, and may slow the development of resistance. The combination of artesunate, given for 3 days, and mefloquine is now the treatment of choice for uncomplicated multidrug-resistant falciparum malaria acquired on the western or eastern borders of Thailand. To optimize mefloquine administration in this combination, a prospective study of mefloquine pharmacokinetics was conducted with 120 children (4 to 15 years old) with acute uncomplicated falciparum malaria, who were divided into four age- and sex-matched groups. The patients all received artesunate (4 mg/kg of body weight/day orally for 3 days and mefloquine as either (i) a single dose (25 mg/kg) on day 2 with food, (ii) a split dose (15 mg/kg on day 2 and 10 mg/kg on day 3) with food, (iii) a single dose (25 mg/kg) on day 0 without food, or (iv) a single dose (25 mg/kg) on day 2 without food. Delaying administration of mefloquine until day 2 was associated with a mean (95% confidence interval) increase in estimated oral bioavailability of 72% (36 to 109%). On day 2 coadministration with food did not increase mefloquine absorption significantly, and there were no significant differences between patients receiving split- and single-dose administration. In combination with artesunate, mefloquine administration should be delayed until the second or third day after presentation. Hide abstract
Am J Trop Med Hyg, 59 (6), pp. 883-888. Read abstract1998. Artesunate versus artemether for the treatment of recrudescent multidrug-resistant falciparum malaria.
The therapeutic efficacy and toxicity of artesunate (2mg/kg/day for five days, then 1 mg/kg/day for two days: total=12 mg/kg) was compared with that of artemether (4 mg/kg followed by 2 mg/kg/day for two days, then 1 mg/kg/day for four days: total=12 mg/kg) for the treatment of recrudescent multidrug-resistant falciparum malaria in an open randomized trial in 443 patients living on the western border of Thailand. Parasite and fever clearance times were similar in both groups; within 48 hr 94% (95% confidence interval [CI]=91-96%]) of the treated patients were aparasitemic and 93% (95% CI=89-96%) were afebrile. Symptom resolution and resolution of hepatomegaly were slightly slower in the artesunate group; adjusted hazards ratio=1.5 (95% CI=1-2.0, P < 0.01) and 2.2 (95% CI=1.4-8, P=0.04), respectively. There was no significant difference in times to resolution or development of anemia or splenomegaly between treatment groups. By day 28, 3% (95% CI=0.3-5%) of the patients treated with artesunate and 6% of those treated with artemether (95% CI = 2-9%) had recurrent infections (P=0.3). Both regimens were very well tolerated, with no significant adverse effects attributable to either derivative. Overall, these data suggest that the two oral artemisinin derivatives are safe, highly effective, and result in equivalent therapeutic responses in the treatment of drug-resistant falciparum malaria. Hide abstract
Trans R Soc Trop Med Hyg, 92 (5), pp. 562-563. | Read more1998. Early vomiting of mefloquine in children with malaria is not modified by the timing of antipyretic treatment.
Oral artesunate is the most effective treatment for uncomplicated hyperparasitaemia in falciparum malaria. To assess the contribution of mefloquine to therapeutic efficacy in an area endemic for mefloquine-resistant Plasmodium falciparum, an open randomized comparison of a 5 d course of oral artesunate (total dose 12 mg/kg) with and without a single dose of mefloquine (25 base mg/kg) was conducted in 100 adults and children with uncomplicated hyperparasitaemia (> 4% parasitized red blood cells). Both regimens were well tolerated and gave equally rapid clinical responses (84% of patients were aparasitaemic and 96% were afebrile within 48 h), but the recrudescence rate assessed at day 42 was 6% in those receiving artesunate with mefloquine compared to 36% in those receiving artesunate alone (adjusted hazard ratio 7, 95% confidence interval [95% CI] 2-32; P < 0.01). In addition, the efficacy of a 7 d course of artesunate, with and without the addition of mefloquine, was monitored in 178 patients who were not part of the randomized comparison. The failure rate was again lower in those receiving artesunate and mefloquine--7% (95% CI 2-13) compared with 26% (95% CI 8-44) in patients treated with artesunate alone. An oral regimen of 5 d or more of artesunate, together with mefloquine (25 mg/kg) given on day 2, is an effective treatment for uncomplicated hyperparasitaemic falciparum malaria in this area of high level multidrug resistance. Hide abstract
Am J Trop Med Hyg, 58 (2), pp. 195-203. Read abstract1998. Transmission intensity and Plasmodium falciparum diversity on the northwestern border of Thailand.
Genetic analysis of the number of Plasmodium falciparum genotypes per infected person in regions of holoendemic and hyperendemic malaria suggest that in areas of lower transmission intensity, significantly fewer parasite genotypes per infected person should be found. A predominance of single clone infections in the human population could generate the controversial clonal population structure proposed for P. falciparum by Tibayrenc and others. Characterization of P. falciparum from individuals on the Thai-Burmese border, an area of hypoendemic transmission, revealed a higher number of genotypes per infected person than that predicted. Possible reasons for this observation are discussed, with particular attention paid to human migration and multidrug resistance. Hide abstract
American Journal of Tropical Medicine and Hygiene, 59 (4), pp. 503.1998. Prolongation of the QTc interval in African children treated for falciparum malaria
On the western border of Thailand, in an area endemic for multi-drug resistant Plasmodium falciparum malaria, therapeutic responses were assessed in 1967 patients with uncomplicated falciparum malaria treated with 3 d of artesunate (total dose 12 mg/kg) plus mefloquine (total dose 25 mg/kg). The regimen was well tolerated and resulted in a rapid clinical response; within 48 h, 96% of patients were aparasitaemic and 94% were afebrile. After correcting for reinfections, the cure rate by day 42 was 89% (95% confidence interval [95% CI] 87-91%). Three independent factors were found to predict recrudescence: age < 14 years (adjusted hazards ratio [AHR] = 1.6, 95% CI 1.1-2.3), initial parasitaemia greater than > 40,000/microL (AHR = 1.6, 95%, CI 1.2-2.2), and pure P. falciparum infections (AHR = 1.8, 95% CI 1.3-2.7). These 3 factors combined accounted for 62% of all treatment failures. Patients who received mefloquine on admission with a high admission parasitaemia (> 40,000/microL) had a three-fold (95% CI 1.3-7) risk of subsequent recrudescence compared with those who received their mefloquine on the second or third day (P = 0.01). There has been no decline in the efficacy of the 3 d artesunate plus mefloquine regimen since it was introduced in 1992. This regimen is safe, well tolerated, and highly effective in the treatment of multi-drug resistant falciparum malaria. Hide abstract
The pfmdr1 gene encodes a Plasmodium falciparum homologue of the human P-glycoprotein expressed on the surface of the parasite food vacuole. Variation in copy number and specific codon mutations of pfmdr1 have been implicated in the development of parasite resistance to antimalarial drugs. We describe here the technique of Tandem-Competitive Polymerase Chain Reaction (TC-PCR), which allows accurate measurement of pfmdr1 copy number in parasite DNA obtained directly from small quantities (100 μl) of red blood cells. We reliably quantified pfmdr1 in previously well characterised strains of Plasmodium falciparum with differing pfmdr1 gene copy numbers using starting amounts of between 3000 and 40000 gene copies. We then used TC-PCR to determine pfmdr1 gene copy number in field specimens of venous blood taken from 10 patients with malaria contracted along the Thai-Burmese border. In this region of high grade parasite resistance to mefloquine greater than 70% of samples had a copy number greater than 1 of pfmdr1 determined with a repeatability coefficient of 0.58. Hide abstract
Background. Previous efficacy trials of SPf66 malaria vaccine have produced conflicting results in different populations. We report a randomised double-blind trial of the SPf66 vaccine conducted in Karen children aged 2-15 living in a malarious region of northwestern Thailand. Recombinant hepatitis B vaccine was used as a comparator. Methods. The study had a power of 90% to detect an efficacy of 30%, defined as a reduction in the incidence of first cases of symptomatic falciparum malaria after three doses of vaccine. 1221 children received three immunisations and were eligible for the primary efficacy analysis. Intense active and passive case detection continued over 15 months of follow-up. Findings. The SPf66 vaccine was well tolerated, although 26 children had mild or moderately severe local or systemic allergic reactions, compared with none in the comparator group. The vaccine was immunogenic; after three doses, 73% of recipients had seroconverted. There were no deaths due to malaria during the study. During the 15-month period of evaluation there were 379 first cases of symptomatic falciparum malaria (195 in the SPf66 recipients, 184 in the comparator group); an SPf66 efficacy of -9% (95% CI -33 to 14, p = 0.41). No significant differences between the two study groups in parasite density or any other measure of malaria-related morbidity were detected. Interpretation. These findings are consistent with a recent study showing lack of efficacy of SPf66 among Gambian infants and differ from earlier positive reports from South America and evidence of borderline efficacy from Tanzania. We conclude that SPf66 does not protect against clinical falciparum malaria and that further efficacy trials are not warranted. Hide abstract
On the western border of Thailand the efficacy of mefloquine in the treatment of falciparum malaria has declined while gametocyte carriage rates have increased, which suggests increased transmissibility of these resistant infections. We compared the following antimalarial drugs in relation to subsequent Plasmodium falciparum gametocyte carriage: mefloquine, halofantrine, quinine, and the artemisinin derivatives. Hide abstract
To compare the therapeutic efficacy of oral artesunate and artemether in combination with mefloquine for the treatment of multidrug resistant malaria, a trial was conducted in 540 adults and children on the Thai-Myanmar border. Three regimens were compared: artesunate (4 mg/kg/d for 3 d), artemether (4 mg/kg/d for 3 d), both in combination with mefloquine (25 mg/kg), and a single dose of mefloquine (25 mg/kg). The artesunate and artemether regimens gave very similar clinical and parasitological responses, and were both very well tolerated. There was no significant adverse effect attributable to the artemisinin derivatives. Fever and parasite clearance times with mefloquine alone were significantly longer (P < 0.001). After adjusting for reinfections the failure rates were 13.9% for the artesunate combination, 12.3% for the artemether combination and 49.2% for mefloquine alone (P < 0.0001; relative risk 3.8 [95% confidence interval 2.6-5.4]). Mefloquine should no longer be used alone for the treatment of multidrug resistant falciparum malaria in this area. Three-day combination regimens with artesunate or artemether are well tolerated and more effective. Hide abstract
Bull World Health Organ, 73 (5), pp. 631-642. Read abstract1995. Mefloquine treatment of acute falciparum malaria: a prospective study of non-serious adverse effects in 3673 patients.
Between 1990 and 1994, a series of prospective studies were conducted to optimize the treatment of multidrug-resistant falciparum malaria on the borders of Thailand. The tolerance of various treatment regimens containing either mefloquine 15 mg/kg (M15) or 25 mg/kg (M25) was evaluated in 3673 patients aged between 6 months and 88 years. Early vomiting (within 1 hour) is an important determinant of treatment outcome in these areas, despite re-administration of the dose. Overall, 7 % of the patients vomited within an hour. Significant risk factors were age < or = 6 years (relative risk (RR), 3.9) or > or 50 years (RR, 2.7), the higher mefloquine dose (M25) (RRm 2.7), vomiting < 24 hours before enrolment (RR, 2.5), axillary temperature > 38.0 degrees C (RR, 1.6), and parasitaemia > 10,000/microliter (RR, 1.3). In children < or = 2 years, 30% vomited with M25, and 13% did not tolerate a repeat dose. Vomiting was reduced 40% by splitting the higher dose (RR, 0.6; 95% CI, 0.4-0.8), and 50% by giving mefloquine on the second day in combination with artesunate (RR, 0.5; CI, 0.3-0.9). Anorexia, nausea, vomiting, dizziness, and sleeping disorders were 1.1-1.4 times more frequent with M25 than M15 in the three days following treatment, but were similar in the single or split-dose M25 groups, despite twofold higher mefloquine concentrations obtained with the latter. There was no evidence that diarrhoea, headache, and abdominal pain were associated with mefloquine use. High-dose mefloquine is well tolerated but should be given as a split dose. Hide abstract
Drug Safety, 12 (4), pp. 264-273. Read abstract1995. New antimalarials. A risk-benefit analysis
Although more than 40% of the world's population live in malaria endemic areas, there are only 6 available antimalarial drugs for the treatment of Plasmodium falciparum infections. Three of these have been developed in the last 20 years and are discussed in this review. Mefloquine is relatively well tolerated and has the advantage of a single day regimen. It has ideal properties for prophylactic use. However, although rare, serious adverse reactions do occur and the drug cannot be used in severe malaria. Resistance has already emerged in some parts of the world. Halofantrine is also well tolerated and has a rapid antimalarial activity. It is more expensive than other antimalarials and the existence of cross-resistance links its usefulness to the demise of mefloquine. The discovery of a potentially lethal cardiotoxicity associated with halofantrine casts a further shadow over its use. The artemisinin derivatives represent an exciting breakthrough in the treatment of malaria. They are cheap and have a very rapid action. They seem remarkably free from toxic adverse effects, although the neurotoxicity seen in animal studies with the liposoluble derivatives gives rise for concern. However, the lack of pharmacokinetic and toxicity data as yet preclude their approval by Western drug regulation authorities. All antimalarials are threatened by the emergence of parasite resistance. Combination therapy using mefloquine and an artemisinin derivative may provide a way in which resistance can be combated. Hide abstract
Indonesian Medical Journal, 15 pp. 221-258.Efficacy of existing antimalarial drugs for uncomplicated malaria in Timika, Papua, Indonesia
Experimental Parasitology, 114 pp. 34-39.Plasmodium vivax: Isotopic, PicoGreen, and microscopic assays for measuring chloroquine sensitivity in fresh and cryopreserved isolates
Annals of Tropical Paediatrics, 16 (4), pp. 281-286.Mefloquine in infants and young children