scholarly journals How radical is radical cure? Site-specific biases in clinical trials underestimate the effect of radical cure on Plasmodium vivax hypnozoites

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
John H. Huber ◽  
Cristian Koepfli ◽  
Guido España ◽  
Narimane Nekkab ◽  
Michael T. White ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Vector Control ◽  
Plasmodium Vivax ◽  
Trial Data ◽  
Control Measures ◽  
Transmission Model ◽  
Radical Cure ◽  
Major Barrier ◽  
Site Specific ◽  
Treatment Regimens

Abstract Background Plasmodium vivax blood-stage relapses originating from re-activating hypnozoites are a major barrier for control and elimination of this disease. Radical cure is a form of therapy capable of addressing this problem. Recent clinical trials of radical cure have yielded efficacy estimates ranging from 65 to 94%, with substantial variation across trial sites. Methods An analysis of simulated trial data using a transmission model was performed to demonstrate that variation in efficacy estimates across trial sites can arise from differences in the conditions under which trials are conducted. Results The analysis revealed that differences in transmission intensity, heterogeneous exposure and relapse rate can yield efficacy estimates ranging as widely as 12–78%, despite simulating trial data under the uniform assumption that treatment had a 75% chance of clearing hypnozoites. A longer duration of prophylaxis leads to a greater measured efficacy, particularly at higher transmission intensities, making the comparison between the protection of different radical cure treatment regimens against relapse more challenging. Simulations show that vector control and parasite genotyping offer two potential means to yield more standardized efficacy estimates that better reflect prevention of relapse. Conclusions Site-specific biases are likely to contribute to variation in efficacy estimates both within and across clinical trials. Future clinical trials can reduce site-specific biases by conducting trials in low-transmission settings where re-infections from mosquito bite are less common, by preventing re-infections using vector control measures, or by identifying and excluding likely re-infections that occur during follow-up, by using parasite genotyping methods.

scholarly journals How radical is radical cure? Site-specific biases in phase-III clinical trials underestimate the effect of radical cure against Plasmodium vivax hypnozoites

2021 ◽  
Author(s):  
John H. Huber ◽  
Cristian Koepfli ◽  
Guido España ◽  
Narimane Nekkab ◽  
Michael T. White ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Vector Control ◽  
Plasmodium Vivax ◽  
Trial Data ◽  
Phase Iii ◽  
Transmission Model ◽  
Radical Cure ◽  
Major Barrier ◽  
Site Specific ◽  
Phase Iii Clinical Trials

ABSTRACTBackgroundPlasmodium vivax relapses caused by reactivating hypnozoites are a major barrier for elimination and control of this form of malaria. Radical cure is a form of therapy capable of addressing this problem. Recent clinical trials of radical cure have yielded efficacy estimates ranging from 65% to 94%, with substantial variation across trial sites. We performed an analysis of simulated trial data using a transmission model to demonstrate that variation in efficacy estimates across trial sites can arise from differences in the conditions under which trials are conducted.Methods and FindingsOur analysis revealed that differences in transmission intensity, heterogeneous exposure, and relapse rate can yield efficacy estimates ranging as wide as 11-82%, despite simulating trial data under the uniform assumption that treatment had a 75% chance of clearing hypnozoites. A longer duration of prophylaxis leads to a greater measured efficacy, particularly at higher transmission intensities, making the comparison of the protection of different radical cure treatment regimens against relapse more challenging. We show that vector control and parasite genotyping offer two potential means to yield more standardized efficacy estimates that better reflect protection against relapse.ConclusionsWe predict that site-specific biases are likely to contribute to variation in efficacy estimates both within and across phase-III clinical trials. Future clinical trials can reduce site-specific biases by conducting trials in low-transmission settings where reinfections from mosquito biting are less common, by preventing reinfections using vector control measures, or by identifying and excluding reinfections that occur during follow-up using parasite genotyping methods.

scholarly journals Increased Primaquine Total Dose in Patients with Multiple Plasmodium vivax Relapses Associated with Impaired CYP2D6 Activity: Report of Three Cases

2021 ◽  
Author(s):  
Anielle da Pina-Costa ◽  
Ana Carolina Rios Silvino ◽  
Edwiges Motta dos Santos ◽  
Renata Pedro ◽  
Jose Moreira ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Active Metabolite ◽  
Radical Cure ◽  
Major Barrier ◽  
Cyp2d6 Activity ◽  
Factors Associated ◽  
Endemic Setting ◽  
Multiple Relapses ◽  
Activity Report ◽  
Travel Clinic

Abstract BackgroundThe relapsing nature of Plasmodium vivax infection is a major barrier to its control and elimination. Factors such as adequate dosing, adherence, drug quality, and pharmacogenetics can impact the effectiveness of radical cure of P. vivax and need to be properly evaluated. CYP2D6 pathway mediates the activation of primaquine (PQ) into an active metabolite(s) in hepatocytes, and impaired activity has been linked to higher risk of relapse. Cases presentationThree patients diagnosed with P. vivax malaria presented repeated relapses after being initially treated with chloroquine (25mg/kg) and primaquine (3.5mg/kg in 14 days) at a non-endemic travel clinic. Recurring episodes were subsequently treated with higher dose of primaquine (7mg/kg in 14 days), which prevented further relapses in two patients. However, one patient still presented 2 episodes after higher primaquine dose and was prescribed 300mg of chloroquine weekly to prevent further episodes. Impaired CYP2D6 function was observed in all of them. ConclusionLack of response to PQ was associated with impaired CYP2D6 activity in three patients presenting multiple relapses followed in a non-endemic setting. Higher PQ dosage was a safe and effectively prevented relapses in two patients and should be further investigated as an option in Latin America. It is important to investigate the factors associated with unsuccessful radical cure and alternative therapeutic options.

scholarly journals Increased primaquine total dose prevents Plasmodium vivax relapses in patients with impaired CYP2D6 activity: report of three cases

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Anielle de Pina-Costa ◽  
Ana Carolina Rios Silvino ◽  
Edwiges Motta dos Santos ◽  
Renata Saraiva Pedro ◽  
José Moreira ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Active Metabolite ◽  
Radical Cure ◽  
Major Barrier ◽  
Cyp2d6 Activity ◽  
Factors Associated ◽  
Endemic Setting ◽  
Multiple Relapses ◽  
Activity Report ◽  
Travel Clinic

Abstract Background The relapsing nature of Plasmodium vivax infection is a major barrier to its control and elimination. Factors such as adequate dosing, adherence, drug quality, and pharmacogenetics can impact the effectiveness of radical cure of P. vivax and need to be adequately evaluated. CYP2D6 pathway mediates the activation of primaquine (primaquine) into an active metabolite(s) in hepatocytes, and impaired activity has been linked to a higher risk of relapse. Cases presentation Three patients diagnosed with P. vivax malaria presented repeated relapses after being initially treated with chloroquine (25 mg/kg) and primaquine (3.5 mg/kg in 14 days) at a non-endemic travel clinic. Recurring episodes were subsequently treated with a higher dose of primaquine (7 mg/kg in 14 days), which prevented further relapses in two patients. However, one patient still presented two episodes after a higher primaquine dose and was prescribed 300 mg of chloroquine weekly to prevent further episodes. Impaired CYP2D6 function was observed in all of them. Conclusion Lack of response to primaquine was associated with impaired CYP2D6 activity in three patients presenting multiple relapses followed in a non-endemic setting. Higher primaquine dosage was safe and effectively prevented relapses in two patients and should be further investigated as an option in Latin America. It is crucial to investigate the factors associated with unsuccessful radical cures and alternative therapeutic options.

scholarly journals Modelling the contribution of the hypnozoite reservoir to Plasmodium vivax transmission

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Michael T White ◽  
Stephan Karl ◽  
Katherine E Battle ◽  
Simon I Hay ◽  
Ivo Mueller ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Plasmodium Vivax ◽  
Blood Stage ◽  
Transmission Model ◽  
Line Treatment ◽  
First Line ◽  
Liver Stage ◽  
Initial Infection ◽  
Treatment Regimens ◽  
First Line Treatment

Plasmodium vivax relapse infections occur following activation of latent liver-stages parasites (hypnozoites) causing new blood-stage infections weeks to months after the initial infection. We develop a within-host mathematical model of liver-stage hypnozoites, and validate it against data from tropical strains of P. vivax. The within-host model is embedded in a P. vivax transmission model to demonstrate the build-up of the hypnozoite reservoir following new infections and its depletion through hypnozoite activation and death. The hypnozoite reservoir is predicted to be over-dispersed with many individuals having few or no hypnozoites, and some having intensely infected livers. Individuals with more hypnozoites are predicted to experience more relapses and contribute more to onwards P. vivax transmission. Incorporating hypnozoite killing drugs such as primaquine into first-line treatment regimens is predicted to cause substantial reductions in P. vivax transmission as individuals with the most hypnozoites are more likely to relapse and be targeted for treatment.

scholarly journals First autochthonous malaria case due to Plasmodium vivax since eradication, Spain, October 2010

2010 ◽  
Vol 15 (41) ◽  
Author(s):  
P Santa-Olalla Peralta ◽  
M C Vazquez-Torres ◽  
E Latorre-Fandós ◽  
P Mairal-Claver ◽  
P Cortina-Solano ◽  
...  
Keyword(s):  
Vector Control ◽  
Plasmodium Vivax ◽  
Malaria Case ◽  
Control Measures ◽  
Vector Borne Diseases ◽  
Source Of Infection ◽  
Anopheles Atroparvus ◽  
North Eastern ◽  
Vector Borne ◽  
Autochthonous Transmission

In October 2010, one case of autochthonous malaria due to Plasmodium vivax was diagnosed in Spain. The case occurred in Aragon, north-eastern Spain, where the vector Anopheles atroparvus is present. Although the source of infection could not be identified, this event highlights that sporadic autochthonous transmission of vector-borne diseases in continental Europe is possible and calls for enhanced surveillance and vector control measures.

Clinical Trial Data Management Software: A Review of the Technical Features

2019 ◽  
Vol 14 (3) ◽  
pp. 160-172 ◽  
Author(s):  
Aynaz Nourani ◽  
Haleh Ayatollahi ◽  
Masoud Solaymani Dodaran
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Data Management ◽  
Clinical Data ◽  
Clinical Trial Data ◽  
Trial Data ◽  
Data Management System ◽  
Management Systems ◽  
Data Management Systems ◽  
Technical Features

Background:Data management is an important, complex and multidimensional process in clinical trials. The execution of this process is very difficult and expensive without the use of information technology. A clinical data management system is software that is vastly used for managing the data generated in clinical trials. The objective of this study was to review the technical features of clinical trial data management systems.Methods:Related articles were identified by searching databases, such as Web of Science, Scopus, Science Direct, ProQuest, Ovid and PubMed. All of the research papers related to clinical data management systems which were published between 2007 and 2017 (n=19) were included in the study.Results:Most of the clinical data management systems were web-based systems developed based on the needs of a specific clinical trial in the shortest possible time. The SQL Server and MySQL databases were used in the development of the systems. These systems did not fully support the process of clinical data management. In addition, most of the systems lacked flexibility and extensibility for system development.Conclusion:It seems that most of the systems used in the research centers were weak in terms of supporting the process of data management and managing clinical trial's workflow. Therefore, more attention should be paid to design a more complete, usable, and high quality data management system for clinical trials. More studies are suggested to identify the features of the successful systems used in clinical trials.

scholarly journals Widespread zoophagy and detection of Plasmodium spp. in Anopheles mosquitoes in southeastern Madagascar

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Micaela Finney ◽  
Benjamin A. McKenzie ◽  
Bernadette Rabaovola ◽  
Alice Sutcliffe ◽  
Ellen Dotson ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Vector Control ◽  
Plasmodium Vivax ◽  
Malaria Control ◽  
Feeding Behaviour ◽  
Enzyme Linked Immunosorbent Assay ◽  
Habitat Gradient ◽  
Blood Meals ◽  
Feeding Behaviours ◽  
Southeastern Madagascar

Abstract Background Malaria is a top cause of mortality on the island nation of Madagascar, where many rural communities rely on subsistence agriculture and livestock production. Understanding feeding behaviours of Anopheles in this landscape is crucial for optimizing malaria control and prevention strategies. Previous studies in southeastern Madagascar have shown that Anopheles mosquitoes are more frequently captured within 50 m of livestock. However, it remains unknown whether these mosquitoes preferentially feed on livestock. Here, mosquito blood meal sources and Plasmodium sporozoite rates were determined to evaluate patterns of feeding behaviour in Anopheles spp. and malaria transmission in southeastern Madagascar. Methods Across a habitat gradient in southeastern Madagascar 7762 female Anopheles spp. mosquitoes were collected. Of the captured mosquitoes, 492 were visibly blood fed and morphologically identifiable, and a direct enzyme-linked immunosorbent assay (ELISA) was used to test for swine, cattle, chicken, human, and dog blood among these specimens. Host species identification was confirmed for multiple blood meals using PCR along with Sanger sequencing. Additionally, 1,607 Anopheles spp. were screened for the presence of Plasmodium falciparum, P. vivax-210, and P. vivax 247 circumsporozoites (cs) by ELISA. Results Cattle and swine accounted, respectively, for 51% and 41% of all blood meals, with the remaining 8% split between domesticated animals and humans. Of the 1,607 Anopheles spp. screened for Plasmodium falciparum, Plasmodium vivax 210, and Plasmodium vivax 247 cs-protein, 45 tested positive, the most prevalent being P. vivax 247, followed by P. vivax 210 and P. falciparum. Both variants of P. vivax were observed in secondary vectors, including Anopheles squamosus/cydippis, Anopheles coustani, and unknown Anopheles spp. Furthermore, evidence of coinfection of P. falciparum and P. vivax 210 in Anopheles gambiae sensu lato (s.l.) was found. Conclusions Here, feeding behaviour of Anopheles spp. mosquitoes in southeastern Madagascar was evaluated, in a livestock rich landscape. These findings suggest largely zoophagic feeding behaviors of Anopheles spp., including An. gambiae s.l. and presence of both P. vivax and P. falciparum sporozoites in Anopheles spp. A discordance between P. vivax reports in mosquitoes and humans exists, suggesting high prevalence of P. vivax circulating in vectors in the ecosystem despite low reports of clinical vivax malaria in humans in Madagascar. Vector surveillance of P. vivax may be relevant to malaria control and elimination efforts in Madagascar. At present, the high proportion of livestock blood meals in Madagascar may play a role in buffering (zooprophylaxis) or amplifying (zoopotentiation) the impacts of malaria. With malaria vector control efforts focused on indoor feeding behaviours, complementary approaches, such as endectocide-aided vector control in livestock may be an effective strategy for malaria reduction in Madagascar.

scholarly journals High COVID-19 transmission potential associated with re-opening universities can be mitigated with layered interventions

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ellen Brooks-Pollock ◽  
Hannah Christensen ◽  
Adam Trickey ◽  
Gibran Hemani ◽  
Emily Nixon ◽  
...  
Keyword(s):  
Prediction Interval ◽  
Mitigation Strategies ◽  
Control Measures ◽  
Transmission Model ◽  
Model Parameters ◽  
Infection Rates ◽  
First Year Students ◽  
Transmission Potential ◽  
Plausible Model ◽  
Effective Option

AbstractControlling COVID-19 transmission in universities poses challenges due to the complex social networks and potential for asymptomatic spread. We developed a stochastic transmission model based on realistic mixing patterns and evaluated alternative mitigation strategies. We predict, for plausible model parameters, that if asymptomatic cases are half as infectious as symptomatic cases, then 15% (98% Prediction Interval: 6–35%) of students could be infected during the first term without additional control measures. First year students are the main drivers of transmission with the highest infection rates, largely due to communal residences. In isolation, reducing face-to-face teaching is the most effective intervention considered, however layering multiple interventions could reduce infection rates by 75%. Fortnightly or more frequent mass testing is required to impact transmission and was not the most effective option considered. Our findings suggest that additional outbreak control measures should be considered for university settings.

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