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Article ; Online: Balancing Statistical Power and Risk in HIV Cure Clinical Trial Design.

Lau, Jillian S Y / Cromer, Deborah / Pinkevych, Mykola / Lewin, Sharon R / Rasmussen, Thomas A / McMahon, James H / Davenport, Miles P

The Journal of infectious diseases

2022 Volume 226, Issue 2, Page(s) 236–245

Abstract: Background: Analytical treatment interruptions (ATI) are pauses of antiretroviral therapy (ART) in the context of human immunodeficiency virus (HIV) cure trials. They are the gold standard in determining if interventions being tested can achieve ... ...

Abstract	Background: Analytical treatment interruptions (ATI) are pauses of antiretroviral therapy (ART) in the context of human immunodeficiency virus (HIV) cure trials. They are the gold standard in determining if interventions being tested can achieve sustained virological control in the absence of ART. However, withholding ART comes with risks and discomforts to trial participant. We used mathematical models to explore how ATI study design can be improved to maximize statistical power, while minimizing risks to participants. Methods: Using previously observed dynamics of time to viral rebound (TVR) post-ATI, we modelled estimates for optimal sample size, frequency, and ATI duration required to detect a significant difference in the TVR between control and intervention groups. Groups were compared using a log-rank test, and analytical and stochastic techniques. Results: In placebo-controlled TVR studies, 120 participants are required in each arm to detect 30% difference in frequency of viral reactivation at 80% power. There was little statistical advantage to measuring viral load more frequently than weekly, or interrupting ART beyond 5 weeks in a TVR study. Conclusions: Current TVR HIV cure studies are underpowered to detect statistically significant changes in frequency of viral reactivation. Alternate study designs can improve the statistical power of ATI trials.
MeSH term(s)	Anti-Retroviral Agents/therapeutic use ; Clinical Trials as Topic/methods ; HIV Infections/drug therapy ; Humans ; Research Design ; Risk Assessment ; Viral Load/statistics & numerical data ; Withholding Treatment
Chemical Substances	Anti-Retroviral Agents
Language	English
Publishing date	2022-02-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiac032
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Article ; Online: Timing of initiation of anti-retroviral therapy predicts post-treatment control of SIV replication.

Pinkevych, Mykola / Docken, Steffen S / Okoye, Afam A / Fennessey, Christine M / Del Prete, Gregory Q / Pino, Maria / Harper, Justin L / Betts, Michael R / Paiardini, Mirko / Keele, Brandon F / Davenport, Miles P

PLoS pathogens

2023 Volume 19, Issue 10, Page(s) e1011660

Abstract: One approach to 'functional cure' of HIV infection is to induce durable control of HIV replication after the interruption of antiretroviral therapy (ART). However, the major factors that determine the viral 'setpoint' level after treatment interruption ... ...

Abstract	One approach to 'functional cure' of HIV infection is to induce durable control of HIV replication after the interruption of antiretroviral therapy (ART). However, the major factors that determine the viral 'setpoint' level after treatment interruption are not well understood. Here we combine data on ART interruption following SIV infection for 124 total animals from 10 independent studies across 3 institutional cohorts to understand the dynamics and predictors of post-treatment viral control. We find that the timing of treatment initiation is an important determinant of both the peak and early setpoint viral levels after treatment interruption. During the first 3 weeks of infection, every day of delay in treatment initiation is associated with a 0.22 log10 copies/ml decrease in post-rebound peak and setpoint viral levels. However, delay in initiation of ART beyond 3 weeks of infection is associated with higher post-rebound setpoint viral levels. For animals treated beyond 3 weeks post-infection, viral load at ART initiation was the primary predictor of post-rebound setpoint viral levels. Potential alternative predictors of post-rebound setpoint viral loads including cell-associated DNA or RNA, time from treatment interruption to rebound, and pre-interruption CD8+ T cell responses were also examined in the studies where these data were available. This analysis suggests that optimal timing of treatment initiation may be an important determinant of post-treatment control of HIV.
MeSH term(s)	Animals ; HIV Infections/drug therapy ; CD8-Positive T-Lymphocytes ; RNA, Viral ; Viral Load ; Anti-Retroviral Agents/pharmacology ; Anti-Retroviral Agents/therapeutic use
Chemical Substances	RNA, Viral ; Anti-Retroviral Agents
Language	English
Publishing date	2023-10-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011660
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Article ; Online: Impact of fluctuation in frequency of human immunodeficiency virus/simian immunodeficiency virus reactivation during antiretroviral therapy interruption.

Wu, Yuhuang / Pinkevych, Mykola / Xu, Zhuang / Keele, Brandon F / Davenport, Miles P / Cromer, Deborah

Proceedings. Biological sciences

2020 Volume 287, Issue 1933, Page(s) 20200354

Abstract: Antiretroviral therapy (ART) provides effective control of human immunodeficiency virus (HIV) replication and maintains viral loads of HIV at undetectable levels. Interruption of ART causes rapid recrudescence of HIV plasma viremia due to reactivation of ...

Abstract	Antiretroviral therapy (ART) provides effective control of human immunodeficiency virus (HIV) replication and maintains viral loads of HIV at undetectable levels. Interruption of ART causes rapid recrudescence of HIV plasma viremia due to reactivation of latently HIV-infected cells. Here, we characterize the timing of both the initial and subsequent successful viral reactivations following ART interruption in macaques infected with simian immunodeficiency virus (SIV). We compare these to previous results from HIV-infected patients. We find that on average the time until the first successful viral reactivation event is longer than the time between subsequent reactivations. Based on this result, we hypothesize that the reactivation frequency of both HIV and SIV may fluctuate over time, and that this may impact the treatment of HIV. We develop a stochastic model incorporating fluctuations in the frequency of viral reactivation following ART interruption that shows behaviours consistent with the observed data. Furthermore, we show that one of the impacts of a fluctuating reactivation frequency would be to significantly reduce the efficacy of 'anti-latency' interventions for HIV that aim to reduce the frequency of reactivation. It is therefore essential to consider the possibility of a fluctuating reactivation frequency when assessing the impact of such intervention strategies.
MeSH term(s)	Animals ; Anti-Retroviral Agents ; HIV ; HIV Infections ; Humans ; Simian Immunodeficiency Virus ; Viral Load ; Virus Replication
Chemical Substances	Anti-Retroviral Agents
Language	English
Publishing date	2020-08-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209242-6
ISSN	1471-2954 ; 0080-4649 ; 0962-8452 ; 0950-1193
ISSN (online)	1471-2954
ISSN	0080-4649 ; 0962-8452 ; 0950-1193
DOI	10.1098/rspb.2020.0354
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Article ; Online: Preferential selection of viral escape mutants by CD8+ T cell 'sieving' of SIV reactivation from latency.

Docken, Steffen S / McCormick, Kevin / Pampena, M Betina / Samer, Sadia / Lindemuth, Emily / Pinkevych, Mykola / Viox, Elise G / Wu, Yuhuang / Schlub, Timothy E / Cromer, Deborah / Keele, Brandon F / Paiardini, Mirko / Betts, Michael R / Bar, Katharine J / Davenport, Miles P

PLoS pathogens

2023 Volume 19, Issue 11, Page(s) e1011755

Abstract: HIV rapidly rebounds after interruption of antiretroviral therapy (ART). HIV-specific CD8+ T cells may act to prevent early events in viral reactivation. However, the presence of viral immune escape mutations may limit the effect of CD8+ T cells on viral ...

Abstract	HIV rapidly rebounds after interruption of antiretroviral therapy (ART). HIV-specific CD8+ T cells may act to prevent early events in viral reactivation. However, the presence of viral immune escape mutations may limit the effect of CD8+ T cells on viral rebound. Here, we studied the impact of CD8 immune pressure on post-treatment rebound of barcoded SIVmac293M in 14 Mamu-A01 positive rhesus macaques that initiated ART on day 14, and subsequently underwent two analytic treatment interruptions (ATIs). Rebound following the first ATI (seven months after ART initiation) was dominated by virus that retained the wild-type sequence at the Mamu-A01 restricted Tat-SL8 epitope. By the end of the two-month treatment interruption, the replicating virus was predominantly escaped at the Tat-SL8 epitope. Animals reinitiated ART for 3 months prior to a second treatment interruption. Time-to-rebound and viral reactivation rate were significantly slower during the second treatment interruption compared to the first. Tat-SL8 escape mutants dominated early rebound during the second treatment interruption, despite the dominance of wild-type virus in the proviral reservoir. Furthermore, the escape mutations detected early in the second treatment interruption were well predicted by those replicating at the end of the first, indicating that escape mutant virus in the second interruption originated from the latent reservoir as opposed to evolving de novo post rebound. SL8-specific CD8+ T cell levels in blood prior to the second interruption were marginally, but significantly, higher (median 0.73% vs 0.60%, p = 0.016). CD8+ T cell depletion approximately 95 days after the second treatment interruption led to the reappearance of wild-type virus. This work suggests that CD8+ T cells can actively suppress the rebound of wild-type virus, leading to the dominance of escape mutant virus after treatment interruption.
MeSH term(s)	Animals ; Simian Acquired Immunodeficiency Syndrome ; Simian Immunodeficiency Virus ; Macaca mulatta ; Virus Replication/physiology ; CD8-Positive T-Lymphocytes ; HIV Infections ; Epitopes ; Viral Load ; Anti-Retroviral Agents/therapeutic use ; Anti-Retroviral Agents/pharmacology
Chemical Substances	Epitopes ; Anti-Retroviral Agents
Language	English
Publishing date	2023-11-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011755
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Article ; Online: Predictors of SIV recrudescence following antiretroviral treatment interruption.

Pinkevych, Mykola / Fennessey, Christine M / Cromer, Deborah / Reid, Carolyn / Trubey, Charles M / Lifson, Jeffrey D / Keele, Brandon F / Davenport, Miles P

eLife

2019 Volume 8

Abstract: There is currently a need for proxy measures of the HIV rebound competent reservoir (RCR) that can predict viral rebound after combined antiretroviral treatment (cART) interruption. In this study, macaques infected with a barcoded SIVmac239 virus ... ...

Abstract	There is currently a need for proxy measures of the HIV rebound competent reservoir (RCR) that can predict viral rebound after combined antiretroviral treatment (cART) interruption. In this study, macaques infected with a barcoded SIVmac239 virus received cART beginning between 4- and 27 days post-infection, leading to the establishment of different levels of viral dissemination and persistence. Later treatment initiation led to higher SIV DNA levels maintained during treatment, which was significantly associated with an increased frequency of SIV reactivation and production of progeny capable of causing rebound viremia following treatment interruption. However, a 100-fold increase in SIV DNA in PBMCs was associated with only a 2-fold increase in the frequency of reactivation. These data suggest that the RCR can be established soon after infection, and that a large fraction of persistent viral DNA that accumulates after this time makes relatively little contribution to viral rebound.
MeSH term(s)	Animals ; Anti-Retroviral Agents/therapeutic use ; DNA, Viral/genetics ; DNA, Viral/metabolism ; Leukocytes, Mononuclear/pathology ; Leukocytes, Mononuclear/virology ; Macaca mulatta ; Male ; Prognosis ; Recurrence ; Simian Acquired Immunodeficiency Syndrome/drug therapy ; Simian Acquired Immunodeficiency Syndrome/virology ; Simian Immunodeficiency Virus/drug effects ; Simian Immunodeficiency Virus/genetics ; Simian Immunodeficiency Virus/growth & development ; Simian Immunodeficiency Virus/pathogenicity ; Time-to-Treatment/statistics & numerical data ; Treatment Outcome ; Viral Load ; Virus Activation ; Virus Replication
Chemical Substances	Anti-Retroviral Agents ; DNA, Viral
Language	English
Publishing date	2019-10-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.49022
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Article ; Online: Early antiretroviral therapy in SIV-infected rhesus macaques reveals a multiphasic, saturable dynamic accumulation of the rebound competent viral reservoir.

Keele, Brandon F / Okoye, Afam A / Fennessey, Christine M / Varco-Merth, Benjamin / Immonen, Taina T / Kose, Emek / Conchas, Andrew / Pinkevych, Mykola / Lipkey, Leslie / Newman, Laura / Macairan, Agatha / Bosche, Marjorie / Bosche, William J / Berkemeier, Brian / Fast, Randy / Hull, Mike / Oswald, Kelli / Shoemaker, Rebecca / Silipino, Lorna /

Gorelick, Robert J / Duell, Derick / Marenco, Alejandra / Brantley, William / Smedley, Jeremy / Axthelm, Michael / Davenport, Miles P / Lifson, Jeffrey D / Picker, Louis J

PLoS pathogens

2024 Volume 20, Issue 4, Page(s) e1012135

Abstract: The rebound competent viral reservoir (RCVR)-virus that persists during antiretroviral treatment (ART) and can reignite systemic infection when treatment is stopped-is the primary barrier to eradicating HIV. We used time to initiation of ART during ... ...

Abstract	The rebound competent viral reservoir (RCVR)-virus that persists during antiretroviral treatment (ART) and can reignite systemic infection when treatment is stopped-is the primary barrier to eradicating HIV. We used time to initiation of ART during primary infection of rhesus macaques (RMs) after intravenous challenge with barcoded SIVmac239 as a means to elucidate the dynamics of RCVR establishment in groups of RMs by creating a multi-log range of pre-ART viral loads and then assessed viral time-to-rebound and reactivation rates resulting from the discontinuation of ART after one year. RMs started on ART on days 3, 4, 5, 6, 7, 9 or 12 post-infection showed a nearly 10-fold difference in pre-ART viral measurements for successive ART-initiation timepoints. Only 1 of 8 RMs initiating ART on days 3 and 4 rebounded after ART interruption despite measurable pre-ART plasma viremia. Rebounding plasma from the 1 rebounding RM contained only a single barcode lineage detected at day 50 post-ART. All RMs starting ART on days 5 and 6 rebounded between 14- and 50-days post-ART with 1-2 rebounding variants each. RMs starting ART on days 7, 9, and 12 had similar time-to-measurable plasma rebound kinetics despite multiple log differences in pre-ART plasma viral load (pVL), with all RMs rebounding between 7- and 16-days post-ART with 3-28 rebounding lineages. Calculated reactivation rates per pre-ART pVL were highest for RMs starting ART on days 5, 6, and 7 after which the rate of accumulation of the RCVR markedly decreased for RMs treated on days 9 and 12, consistent with multiphasic establishment and near saturation of the RCVR within 2 weeks post infection. Taken together, these data highlight the heterogeneity of the RCVR between RMs, the stochastic establishment of the very early RCVR, and the saturability of the RCVR prior to peak viral infection.
MeSH term(s)	Animals ; Simian Acquired Immunodeficiency Syndrome/drug therapy ; Simian Immunodeficiency Virus/physiology ; Macaca mulatta ; Virus Replication ; Anti-Retroviral Agents/therapeutic use ; Anti-Retroviral Agents/pharmacology ; HIV Infections/drug therapy ; Viral Load
Chemical Substances	Anti-Retroviral Agents
Language	English
Publishing date	2024-04-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1012135
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Article ; Online: Modelling of anti-latency treatment in HIV; What is the optimal duration of anti-retroviral-free HIV remission?

Cromer, Deborah / Pinkevych, Mykola / Rasmussen, Thomas A / Lewin, Sharon R / Kent, Stephen J / Davenport, Miles P

Journal of virology

2017

Abstract: A number of treatment strategies are currently being developed to promote anti-retroviral free HIV cure or remission. While complete elimination of the HIV reservoir would prevent recurrence of infection, it is not clear how different remission lengths ... ...

Abstract	A number of treatment strategies are currently being developed to promote anti-retroviral free HIV cure or remission. While complete elimination of the HIV reservoir would prevent recurrence of infection, it is not clear how different remission lengths would affect viral rebound and transmission. In this work we use a stochastic model to show that a treatment that achieves a one-year average time to viral remission will still lead to nearly a quarter of subjects experiencing viral rebound within the first three months. Given quarterly viral testing intervals, this leads to an expected 39 (95%UI 22-69) heterosexual transmissions and up to 262 (95%UI 107-534) homosexual transmissions per 1,000 treated subjects over a 10-year period. Thus, a balance between high initial treatment levels, risk of recrudescence, and risk of transmission should be considered when assessing the 'useful' or optimal length of anti-retroviral-free HIV remission to be targeted. We also investigate the trade-off between increasing the average duration of remission, versus the risk of treatment failure (viral recrudescence) and the need for re-treatment. To minimise drug exposure, we find that the optimal target of anti-latency interventions is a 1700-fold reduction in the size of the reservoir, which would lead to an average time to recrudescence of 30 years. Interestingly, this is a significantly lower level of reduction than that required for complete elimination of the viral reservoir. Additionally we show that when shorter periods are targeted, there is a real probability of viral transmission occurring in between testing for viral rebound.
Language	English
Publishing date	2017-10-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01395-17
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Article ; Online: Estimating Initial Viral Levels during Simian Immunodeficiency Virus/Human Immunodeficiency Virus Reactivation from Latency.

Pinkevych, Mykola / Fennessey, Christine M / Cromer, Deborah / Tolstrup, Martin / Søgaard, Ole S / Rasmussen, Thomas A / Keele, Brandon F / Davenport, Miles P

Journal of virology

2018 Volume 92, Issue 2

Abstract: Human immunodeficiency virus (HIV) viremia rebounds rapidly after treatment interruption, and a variety of strategies are being explored to reduce or control viral reactivation posttreatment. This viral rebound arises from reactivation of individual ... ...

Abstract	Human immunodeficiency virus (HIV) viremia rebounds rapidly after treatment interruption, and a variety of strategies are being explored to reduce or control viral reactivation posttreatment. This viral rebound arises from reactivation of individual latently infected cells, which spread during ongoing rounds of productive infection. The level of virus produced by the initial individual reactivating cells is not known, although it may have major implications for the ability of different immune interventions to control viral rebound. Here we use data from both HIV and simian immunodeficiency virus (SIV) treatment interruption studies to estimate the initial viral load postinterruption and thereby the initial individual reactivation event. Using a barcoded virus (SIVmac239M) to track reactivation from individual latent cells, we use the observed viral growth rates and frequency of reactivation to model the dynamics of reactivation to estimate that a single reactivated latent cell can produce an average viral load equivalent to ∼0.1 to 0.5 viral RNA (vRNA) copies/ml. Modeling of treatment interruption in HIV suggests an initial viral load equivalent of ∼0.6 to 1 vRNA copies/ml. These low viral loads immediately following latent cell reactivation provide a window of opportunity for viral control by host immunity, before further replication allows viral spread. This work shows the initial levels of viral production that must be controlled in order to successfully suppress HIV reactivation following treatment interruption.
MeSH term(s)	Algorithms ; Animals ; Antiretroviral Therapy, Highly Active ; HIV/physiology ; HIV Infections/drug therapy ; HIV Infections/virology ; Humans ; Models, Biological ; Simian Acquired Immunodeficiency Syndrome/virology ; Simian Immunodeficiency Virus/physiology ; Time Factors ; Viral Load ; Virus Activation ; Virus Latency
Language	English
Publishing date	2018--15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01667-17
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Article ; Online: Time-to-infection by Plasmodium falciparum is largely determined by random factors.

Pinkevych, Mykola / Chelimo, Kiprotich / Vulule, John / Kazura, James W / Moormann, Ann M / Davenport, Miles P

BMC medicine

2015 Volume 13, Page(s) 19

Abstract: Background: The identification of protective immune responses to P. falciparum infection is an important goal for the development of a vaccine for malaria. This requires the identification of susceptible and resistant individuals, so that their immune ... ...

Abstract	Background: The identification of protective immune responses to P. falciparum infection is an important goal for the development of a vaccine for malaria. This requires the identification of susceptible and resistant individuals, so that their immune responses may be studied. Time-to-infection studies are one method for identifying putative susceptible individuals (infected early) versus resistant individuals (infected late). However, the timing of infection is dependent on random factors, such as whether the subject was bitten by an infected mosquito, as well as individual factors, such as their level of immunity. It is important to understand how much of the observed variation in infection is simply due to chance. Methods: We analyse previously published data from a treatment-time-to-infection study of 201 individuals aged 0.5 to 78 years living in Western Kenya. We use a mathematical modelling approach to investigate the role of immunity versus random factors in determining time-to-infection in this cohort. We extend this analysis using a modelling approach to understand what factors might increase or decrease the utility of these studies for identifying susceptible and resistant individuals. Results: We find that, under most circumstances, the observed distribution of time-to-infection is consistent with this simply being a random process. We find that age, method for detection of infection (PCR versus microscopy), and underlying force of infection are all factors in determining whether time-to-infection is a useful correlate of immunity. Conclusions: Many epidemiological studies of P. falciparum infection assume that the observed variation in infection outcomes, such as time-to-infection or presence or absence of infection, is determined by host resistance or susceptibility. However, under most circumstances, this distribution appears largely due to the random timing of infection, particularly in children. More direct measurements, such as parasite growth rate, may be more useful than time-to-infection in segregating patients based on their level of immunity.
MeSH term(s)	Adolescent ; Age Factors ; Aged ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Kenya ; Malaria, Falciparum/diagnosis ; Malaria, Falciparum/immunology ; Male ; Microscopy ; Middle Aged ; Models, Biological ; Plasmodium falciparum/genetics ; Plasmodium falciparum/isolation & purification ; Polymerase Chain Reaction ; Time Factors ; Young Adult
Language	English
Publishing date	2015-01-30
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1741-7015
ISSN (online)	1741-7015
DOI	10.1186/s12916-014-0252-9
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Article ; Online: Understanding the relationship between Plasmodium falciparum growth rate and multiplicity of infection.

Pinkevych, Mykola / Petravic, Janka / Bereczky, Sandor / Rooth, Ingegerd / Färnert, Anna / Davenport, Miles P

The Journal of infectious diseases

2015 Volume 211, Issue 7, Page(s) 1121–1127

Abstract: Natural infections with Plasmodium falciparum are often composed of multiple concurrent genetically distinct parasite clones. Such multiclonal infections are more common in areas of high transmission, and the frequency of multiclonal infection also ... ...

Abstract	Natural infections with Plasmodium falciparum are often composed of multiple concurrent genetically distinct parasite clones. Such multiclonal infections are more common in areas of high transmission, and the frequency of multiclonal infection also varies with age. A number of studies have suggested that multiclonal infection predicts the risk of subsequent clinical malaria. The multiplicity of infection is determined by the rate of new infections, the number of clones inoculated at each mosquito bite, and the duration of infections. Here, we used a mathematical modeling approach to understand how variation in the growth rate of blood-stage parasites affects the observed multiplicity of infection (MOI), as well as the relationship between the MOI and the risk of subsequent malaria. We then analyzed data from a study of multiclonal infection and malaria in an malaria-endemic area in Tanzania and show that the proportion of multiclonal infections varies with age and that the observed relationship between multiclonal infection and subsequent clinical events can be explained by a reduction in blood-stage parasite growth with age in this population.
MeSH term(s)	Adolescent ; Age Factors ; Antigens, Protozoan/genetics ; Child ; Child, Preschool ; Cohort Studies ; Coinfection ; Cross-Sectional Studies ; Genotype ; Humans ; Malaria, Falciparum/epidemiology ; Malaria, Falciparum/mortality ; Malaria, Falciparum/parasitology ; Male ; Models, Theoretical ; Parasitemia ; Plasmodium falciparum/genetics ; Plasmodium falciparum/growth & development ; Plasmodium falciparum/pathogenicity ; Poisson Distribution ; Protozoan Proteins/genetics ; Risk ; Survival Analysis ; Tanzania/epidemiology
Chemical Substances	Antigens, Protozoan ; Protozoan Proteins ; merozoite surface protein 2, Plasmodium
Language	English
Publishing date	2015-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiu561
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