HIV resistance testing in the USA – a model for the application of pharmacogenomics in the clinical setting

Blum, Ronald; Wylie, Neil; England, Tom; French, Cynthia L.

doi:10.1517/14622416.6.2.169

Cited by 9 publications

(5 citation statements)

References 43 publications

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“…It has been suggested that HIV viral genotyping, which is part of routine patient management in the USA, can serve as a paradigm for introduction of pharmacogenomics into patient care [1]. The important difference, however, is that viral genotyping predicts drug resistance very accurately, in addition to helping to trace the transmission of specific viral strains through susceptible communities.…”

Section: Clinical Importance Of Individual Pharmacogenomics Studiesmentioning

confidence: 99%

Translating Pharmacogenomics Discoveries into Clinical Practice: The Role of Curated Databases

Nadkarni

Wiepert

2005

Pharmacogenomics

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Pharmacogenomics-related genotype information is growing at a supra-linear rate, and phenotyperelated information, as determined by computer simulations, in vitro experiments and clinical studies, is also growing. Even when phenotypic information is confirmed via clinical research, numerous barriers exist in translating these discoveries into clinical practice. We consider two of them here: the uncertainty regarding the practical relevance of research observations, and translation of significant research findings into clinical practice and research through electronic information access. This form of access is critical because even leading clinical pharmacologists cannot fully retain mentally today's large volume of drug-related information. Clinical Importance of Individual Pharmacogenomics StudiesIt has been suggested that HIV viral genotyping, which is part of routine patient management in the USA, can serve as a paradigm for introduction of pharmacogenomics into patient care [1]. The important difference, however, is that viral genotyping predicts drug resistance very accurately, in addition to helping to trace the transmission of specific viral strains through susceptible communities. By contrast, detection of most human polymorphic gene variants (which, by definition, are reasonably common in individual populations) is often of less clear consequence: their effects are typically much less dramatic than those of the rare variants, such as atypical butyrylcholinesterase, which spurred classical pharmacogenetics Even for well-characterized polymorphisms that are widely accepted to be clinically important, the variation in phenotypic end-points such as metabolic ratios (MRs) of non-metabolized to metabolized drug is considerable. For example, in a study of 200 Iranian subjects phenotyped for CYP2D6 polymorphisms with dextromethorphan, a 520-fold inter-individual MR variation was observed across all subjects, with variation for poor metabolizers itself being 19.5-fold [2]. Even when genotype and phenotype correlate with high statistical significance, clinical importance is harder to assess. Thus, in a recent study of warfarin kinetics [3], multiple regression analysis of warfarin maintenance dose as a function of CYP2C9 genotype, age, lean body weight and concomitant treatment with warfarin yielded a statistically significant R 2 (coefficient of determination) of 0.37. This number, however, implies that 63% of the experimental variance is unaccounted for.Consequently, there are differences between the viewpoints of those generating the results and those who are expected to act on them. Despite recommendations that CYP2D6 genotyping "should be performed routinely because genotyping costs offset medical costs" [4], a recent Australasian survey of 629 individuals/centers [5] found that only one center was routinely

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Section: Clinical Importance Of Individual Pharmacogenomics Studiesmentioning

confidence: 99%

Translating Pharmacogenomics Discoveries into Clinical Practice: The Role of Curated Databases

Nadkarni

Wiepert

2005

Pharmacogenomics

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“…Antiretroviral drugs have been the basis of HIV treatment since the first nucleoside reverse transcriptase inhibitor was introduced in 1987 [8], followed by other antiretrovirals, and in 1996 by combined Antiretroviral Therapy (cART) [9]. Furthermore, new methods to monitor plasma HIV RNA as well as drug resistance tests on viruses have greatly facilitated treatment-related decisions [10,11]. At the present time newly infected HIV-positive individuals who enjoy good health care can have a comparable life expectancy to those in the same age group in the general population [12,13].…”

Section: Introductionmentioning

confidence: 99%

Long Term Nationwide Analysis of HIV and AIDS in Iceland, 1983-2012

Gudmundsson¹

2014

J AIDS Clin Res

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Introduction: Iceland is well suited for epidemiological research due to well-kept patient records, easy followup of patients and nation-wide health care databases. This study provides a nationwide 30-year epidemiological overview of the HIV epidemic in the country. Materials and methods:Retrospective study on all HIV positive individuals in Iceland, 1983Iceland, -2012. Clinical data, CD4 + T-cell counts, plasma HIV RNA, proportion of late presenters and effectiveness of combined antiretroviral therapy (cART) were compared by different time intervals. Results:In total, 313 were diagnosed with HIV in 1983-2012, thereof 222 (71%) men and 91 (29%) women. Most infections (65%) were acquired outside the country. Mean incidence of HIV was 3.7/100,000 inhabitants/year, with a significant increase in 2010-2012 (p=0.0113), related to misuse of the prescription drug methylphenidate among intravenous drug users. Official prescriptions for this drug increased from 3.5 in 2002 to 17.4 defined daily doses/ 1,000 inhabitants/day in 2012. Mortality decreased by 70% during the study period (p=0.0275). Proportion of late presenters decreased from 74% in the first decade to 36% during the third (p=0.0001). After 6 months of ART, CD4 + T-cells increased by only 26 cells/µl on average during the monotherapy era (1987-1995; p=0,174), by 107 cells/µl during the early-cART era (1996-2004; p<0.0001) and by 159 cells/µl during the late-cART era (2005-2012; p<0,0001). Similarly, progressively greater reductions in plasma HIV RNA were observed from 1996-2004 to 2005-2012 (p<0.0001).Conclusions: HIV incidence remained relatively low in Iceland until 2010, when it increased significantly due to spread among IDUs. The majority of HIV infections diagnosed in Iceland were imported. With ever more effective drug treatments on CD4+ T-cells and plasma HIV RNA, the number of AIDS diagnoses and deaths has decreased dramatically.

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“…While personalized medicine guided by genomics is still in early stages of development, individuals' genetic profiles are already starting to be used to guide patient care. As some examples, clinicians can obtain gene expression profiles of breast cancer samples to guide management [Paik et al 2006], genotypes of HIV samples to identify the optimal antiretroviral regimen [Blum et al 2005], and genetic profiles of patients' cytochrome P450 drug metabolizing system to guide the selection and dosing of pharmacotherapies [de Leon et al 2006]. However, it is the proteins that form the actual cell signaling and metabolic networks within the cell.…”

Section: Introductionmentioning

confidence: 99%

Homologous control of protein signaling networks

Napoletani

Signore

Sauer

et al. 2011

Journal of Theoretical Biology

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In a previous paper we introduced a method called augmented sparse reconstruction (ASR) that identifies links among nodes of ordinary differential equation networks, given a small set of observed trajectories with various initial conditions. The main purpose of that technique was to reconstruct intracellular protein signaling networks. In this paper we show that a recursive augmented sparse reconstruction generates artificial networks that are homologous to a large, reference network, in the sense that kinase inhibition of several reactions in the network alters the trajectories of a sizable number of proteins in comparable ways for reference and reconstructed networks. We show this result using a large in-silico model of the epidermal growth factor receptor (EGF-R) driven signaling cascade to generate the data used in the reconstruction algorithm. The most significant consequence of this observed homology is that a nearly optimal combinatorial dosage of kinase inhibitors can be inferred, for many nodes, from the reconstructed network, a result potentially useful for a variety of applications in personalized medicine.

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HIV resistance testing in the USA – a model for the application of pharmacogenomics in the clinical setting

Cited by 9 publications

References 43 publications

Translating Pharmacogenomics Discoveries into Clinical Practice: The Role of Curated Databases

Translating Pharmacogenomics Discoveries into Clinical Practice: The Role of Curated Databases

Long Term Nationwide Analysis of HIV and AIDS in Iceland, 1983-2012

Homologous control of protein signaling networks

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