Novel Insights into Plasmodium vivax Therapeutic Failure: CYP2D6 Activity and Time of Exposure to Malaria Modulate the Risk of Recurrence

ABSTRACT Plasmodium vivax relapse is one of the major causes of sustained global malaria transmission. Primaquine (PQ) is the only commercial drug available to prevent relapses, and its efficacy is dependent on metabolic activation by cytochrome P450 2D6 (CYP2D6). Impaired CYP2D6 function, caused by allelic polymorphisms, leads to the therapeutic failure of PQ as a radical cure for P. vivax malaria. Here, we hypothesized that the host immune response to malaria parasites modulates susceptibility to P. vivax recurrences in association with CYP2D6 activity. We performed a 10-year retrospective study by genotyping CYP2D6 polymorphisms in 261 malaria-exposed individuals from the Brazilian Amazon. The immune responses against a panel of P. vivax blood-stage antigens were evaluated by serological assays. We confirmed our previous findings, which indicated an association between impaired CYP2D6 activity and a higher risk of multiple episodes of P. vivax recurrence (risk ratio, 1.75; 95% confidence interval [CI], 1.2 to 2.6; P = 0.0035). An important finding was a reduction of 3% in the risk of recurrence (risk ratio, 0.97; 95% CI, 0.96 to 0.98; P < 0.0001) per year of malaria exposure, which was observed for individuals with both reduced and normal CYP2D6 activity. Accordingly, subjects with long-term malaria exposure and persistent antibody responses to various antigens showed fewer episodes of malaria recurrence. Our findings have direct implications for malaria control, since it was shown that nonimmune individuals who do not respond adequately to treatment due to reduced CYP2D6 activity may present a significant challenge for sustainable progress toward P. vivax malaria elimination.

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Recurrence Risk Ratio

Encyclopedia of Behavioral Medicine ◽

10.1007/978-1-4419-1005-9_719 ◽

2013 ◽

pp. 1633-1633

Author(s):

Kristine M. Molina ◽

Heather Honoré Goltz ◽

Marc A. Kowalkouski ◽

Stacey L. Hart ◽

...

Keyword(s):

Risk Ratio ◽

Recurrence Risk ◽

Recurrence Risk Ratio

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The Relationship between the Sibling Recurrence-Risk Ratio and Genotype Relative Risk

The American Journal of Human Genetics ◽

10.1086/302778 ◽

2000 ◽

Vol 66 (2) ◽

pp. 593-604 ◽

Cited By ~ 40

Author(s):

Benjamin A. Rybicki ◽

Robert C. Elston

Keyword(s):

Relative Risk ◽

Risk Ratio ◽

Recurrence Risk ◽

Genotype Relative Risk ◽

Recurrence Risk Ratio ◽

Sibling Recurrence Risk ◽

The Relationship

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Comparison of circulating tumor cells (CTC) and disseminated tumor cells (DTC) in patients with colorectal carcinoma for a predictive marker for tumor recurrence.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e14548 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e14548-e14548

Author(s):

Hideyasu Sakihama ◽

Nozomi Kobayashi ◽

Nozomi Minagawa ◽

Tatsushi Shimokuni ◽

Shigenori Homma ◽

...

Keyword(s):

Colorectal Carcinoma ◽

Tumor Cells ◽

Risk Ratio ◽

Tumor Recurrence ◽

Significant Risk ◽

Predictive Marker ◽

Recurrence Risk ◽

Postoperative Recurrence ◽

Recurrence Rates ◽

Recurrence Risk Ratio

e14548 Background: Although the presence of CTC or DTC is proposed as a pridictive or a prognostic marker in the management of colorectal carcinoma patients, it is still well unknown what is different of both types of cells. The aim of this study is to compare CTC and DTC as a predictive marker for tumor recurrence by magnetic activated cell sorting system. Methods: Peripheral blood (PB) samples (n=139) and bone marrow (BM) samples (n=41) were preoperatively collected from colorectal carcinoma patients between February 2009 and March 2012. PB samples were obtainable from all patients who provided their BM samples (n=41). Enrichment of CTC was performed by direct immunomagnetic labeling of EpCAM + cells in PB. Enrichment of DTC was done by negative selection of CD45+cells. Subsequently, double immunofluorescences staining for cytokeratin and CD45 was performed to detect CTC or DTC. PB samples from 20 healthy volunteers and BM samples from 3 patients with benign disease were used as controls. Median follow-up time is 28.5 months (range 10-44). Written informed consent was obtained from all enrolled patients. Results: Preoperative positive rates of CTC and DTC were 20.9% (29/139) and 29.3% (12/41), respectively. No CTC or DTC was found in the control groups. In DTC+patients, only 4 patients were positive for CTC (33.3%), whereas 31% of DTC- patients had CTC. We found 13 patients who experienced postoperative recurrence among 139 patients, 7 patients of whom were CTC positive (53.8%). There is a significant higher incidence of recurrence in CTC+patients (risk ratio=4.4, p<0.01). As for DTC, we found 5 patients with recurrence in 41 patients, 4 patients of whom were DTC positive (80%). DTC+ patients have a significant risk of recurrence (risk ratio=9.7, p=0.01). The relationship of CTC / DTC status and the recurrence rates is as follows: 50 % in CTC+/DTC+ patients (2/4); 11.1% in CTC+/DTC- patients (1/9); 25% in CTC-/DTC+ patients (2/8); 0% in CTC-/DTC-patients (0/20). Conclusions: DTC status is more predictive for postoperative recurrence than CTC status. The combination of CTC and DTC analysis might predict recurrence risk more accurately than either of the two analyses.

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Familial Intracranial Aneurysms: Recurrence Risk and Accidental Aggregation Study

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s031716710003300x ◽

1997 ◽

Vol 24 (04) ◽

pp. 326-331 ◽

Cited By ~ 5

Author(s):

Jean Mathieu ◽

Gilles Hébert ◽

Louis Pérusse ◽

Claude Prévost ◽

Léo Cantin ◽

...

Keyword(s):

Risk Ratio ◽

Genetic Predisposition ◽

Intracranial Aneurysms ◽

Familial Aggregation ◽

Recurrence Risk ◽

Population Based ◽

Degree Relative ◽

Ruptured Intracranial Aneurysm ◽

Recurrence Risk Ratio ◽

Risk Of Disease

ABSTRACT:Background:The Saguenay-Lac-Saint-Jean (SLSJ) region is a geographically isolated area (population 285,955) located in the Northeastern part of the Province of Quebec, Canada. Using a population-based register, the genealogical reconstruction of 502 individuals with ruptured intracranial aneurysm (RIA) showed a familial aggregation (the presence of aneurysm in two or more first- to third-degree relatives) for 144 (28.7%) of them; this proportion is much higher than reported elsewhere.Objective:In order to assess the genetic predisposition to RIA in the SLSJ population, the objective of the present study is to compare familial and non-familial cases and to provide an estimate of the recurrence risk ratio for siblings.Results:The age at the time of rupture, the number of intracranial aneurysms for each patient and the location of RIAs were not statistically different in the familial versus the non-familial group. Of the 3449 siblings, 20 (0.58%) had suffered a RIA. The recurrence risk ratio calculated for siblings (defined as the risk of disease among siblings divided by the estimated population prevalence) is 1.6 (CI 95% 1.0 - 2.4). In other respects, we observed very large kinships in the SLSJ population, with an average number of siblings of 7.2 (SD ± 3.4), ranging from 0 to 17 individuals. With such large families and on the basis of chance alone, we expected 31.3% of the patients to have at least one first- to third-degree relative with RIA.Conclusion:These data show that siblings of patients with RIA in the SLSJ population have a greater risk of RIA than the general population. Nevertheless, the largest part of the familial occurrence observed in the SLSJ region can be explained by accidental aggregation, due to large kinships. We propose that, in this population, an underlying genetic predisposition must be suspected only when three or more cases of RIA are identified among first- to third-degree relatives.

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Sustained attention deficits in nonpsychotic relatives of schizophrenic patients: a recurrence risk ratio analysis

Biological Psychiatry ◽

10.1016/j.biopsych.2004.01.010 ◽

2004 ◽

Vol 55 (10) ◽

pp. 995-1000 ◽

Cited By ~ 40

Author(s):

Wei J Chen ◽

Chin-Hao Chang ◽

Shi K Liu ◽

Tzung J Hwang ◽

Hai-Gwo Hwu, collaborators from the

Keyword(s):

Risk Ratio ◽

Sustained Attention ◽

Recurrence Risk ◽

Attention Deficits ◽

Ratio Analysis ◽

Recurrence Risk Ratio ◽

Schizophrenic Patients

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Recurrence of spondylarthropathy among first-degree relatives of patients: a systematic cross-sectional study

Annals of the Rheumatic Diseases ◽

10.1136/ard.2008.089599 ◽

2008 ◽

Vol 68 (4) ◽

pp. 502-507 ◽

Cited By ~ 22

Author(s):

E Dernis ◽

R Said-Nahal ◽

M-A D’Agostino ◽

P Aegerter ◽

M Dougados ◽

...

Keyword(s):

Risk Ratio ◽

Human Leukocyte ◽

Recurrence Risk ◽

Cross Sectional Study ◽

Linkage Study ◽

Hla B27 ◽

Cross Sectional ◽

First Degree Relatives ◽

Genetic Components ◽

Recurrence Risk Ratio

Objective:To examine the recurrence of manifestations belonging to the spectrum of spondylarthropathy (SpA) in first-degree relatives of patients with SpA, and to estimate the recurrence risk ratio.Methods:Parents and siblings of consecutive SpA probands have been thoroughly investigated, including clinical data collection, pelvic x ray and human leukocyte antigen (HLA)-B27 status determination. The diagnosis of SpA was made according to European Spondylarthropathy Study Group and/or the Amor criteria. The recurrence risk ratio λ1, which gives an estimate of the weight of genetic factors, was calculated as the ratio of the recurrence risk of SpA in first-degree relatives compared with the population prevalence of SpA. The λnon-HLA was obtained by similar calculations restricted to HLA-B27+ individuals.Results:Most manifestations of SpA were more frequent among the 157 HLA-B27+ relatives of 83 probands than among their 111 HLA-B27- relatives. A diagnosis of SpA was made in 50 relatives of 31 (37%) probands. Recurrence was very similar between parents and siblings, without gender difference, resulting in overall recurrence risk of 12% in first-degree relatives and of 22.7% in HLA-B27+ relatives. The λ1 value was 40 and the λnon-HLA value was 6.5, very close to the λHLA value of 6.25 estimated from linkage study in SpA.Conclusions:A similar recurrence risk of SpA was observed between parents and siblings, consistent with a model of inheritance with no dominance variance and without sex influence. The weight of the non-HLA genetic component was equivalent to that estimated for the HLA locus, and fitted a model of multiplicative interaction between HLA and non-HLA genetic components.

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Hashimoto's thyroiditis: relative recurrence risk ratio and implications for screening of first-degree relatives

Clinical Endocrinology ◽

10.1111/cen.13323 ◽

2017 ◽

Vol 87 (2) ◽

pp. 201-206 ◽

Cited By ~ 3

Author(s):

Nikita Bothra ◽

Nalini Shah ◽

Manjunath Goroshi ◽

Swati Jadhav ◽

Sheetal Padalkar ◽

...

Keyword(s):

Risk Ratio ◽

Hashimoto’S Thyroiditis ◽

Recurrence Risk ◽

Hashimoto's Thyroiditis ◽

First Degree Relatives ◽

Recurrence Risk Ratio

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Estimating the relative recurrence risk ratio using a global cross-ratio model

Genetic Epidemiology ◽

10.1002/gepi.10270 ◽

2003 ◽

Vol 25 (4) ◽

pp. 293-302 ◽

Cited By ~ 5

Author(s):

Chris Wallace ◽

David Clayton

Keyword(s):

Risk Ratio ◽

Recurrence Risk ◽

Cross Ratio ◽

Ratio Model ◽

Recurrence Risk Ratio

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

10.21203/rs.3.rs-232561/v1 ◽

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.

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