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J.A. Romijn

Bio: J.A. Romijn is an academic researcher. The author has contributed to research in topics: Mitochondrial toxicity & Nucleoside analogue. The author has an hindex of 1, co-authored 1 publications receiving 23 citations.

Papers
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01 Jan 1999
Abstract: Highly active antiretroviral therapy (HAART) can induce a characteristic lipodystrophy syndrome of peripheral fat wasting and central adiposity. HIV-1 protease inhibitors are generally believed to be the causal agents, although the syndrome has also been observed with protease-inhibitor-sparing regimens. Here, we postulate that the mitochondrial toxicity of the nucleoside-analogue reverse-transcriptase inhibitors plays an essential part in the development of this lipodystrophy, similar to the role of mitochondrial defects in the development of multiple symmetrical lipomatosis.

28 citations


Cited by
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01 Jan 2005
TL;DR: Lipodystrophy following treatment with NRTI-containing HAART is associated with a decrease in adipose tissue mtRNAs, andND1, CYTB and ND6 expression was significantly reduced in HIV+ lipodystrophic patients.
Abstract: Background Damage to mitochondria (mt) is a major side effect of highly active antiretroviral therapy (HAART) that includes a nucleoside reverse transcriptase inhibitor (NRTI). Such damage is associated with the onset of lipodystrophy in HAART-treated HIV+ patients. To further investigate mt changes during this syndrome, we analysed the expression of mtRNA in adipocytes from lipodystrophic HIV+ patients taking NRTI-containing HAART and compared it with similar cells from healthy individuals. Materials and methods Total RNA was extracted from adipocytes collected from different anatomical locations of 11 HIV+ lipodystrophic patients and seven healthy control individuals. RNA was reverse transcribed and Taqman-based real-time PCR was used to quantify three different mt transcripts (ND1, CYTB and ND6 gene products). mtRNA content was normalized versus the housekeeping transcript L13. Results ND1, CYTB and ND6 expression was significantly reduced in HIV+ lipodystrophic patients. HIV+ men and women did not differ in a statistically significant way regarding the levels of ND1 and ND6, whereas the opposite occurred for CYTB. Conclusions Lipodystrophy following treatment with NRTI-containing HAART is associated with a decrease in adipose tissue mtRNAs.

27 citations

Journal Article
TL;DR: The predictive value of resistance testing is currently being examined in patients who have failed their first therapy, and further developments include vaccine, cytokine-, and gene therapy-based treatment strategies.

22 citations

01 Jan 2016
TL;DR: An integrated model of in vivo viral dynamics incorporating drug-specific mutation schemes learned from clinical data is developed and can be modified to incorporate recently elucidated mechanisms of drug action including molecules that target host factors.
Abstract: The human immunodeficiency virus (HIV) has resisted nearly three decades of efforts targeting a cure. Sustained suppression of the virus has remained a challenge, mainly due to the remarkable evolutionary adaptation that the virus exhibits by the accumulation of drug-resistant mutations in its genome. Current therapeutic strategies aim at achieving and maintaining a low viral burden and typically involve multiple drugs. The choice of optimal combinations of these drugs is crucial, particularly in the background of treatment failure having occurred previously with certain other drugs. An understanding of the dynamics of viral mutant genotypes aids in the assessment of treatment failure with a certain drug combination, and exploring potential salvage treatment regimens. Mathematical models of viral dynamics have proved invaluable in understanding the viral life cycle and the impact of antiretroviral drugs. However, such models typically use simplified and coarse-grained mutation schemes, that curbs the extent of their application to drug-specific clinical mutation data, in order to assess potential next-line therapies. Statistical models of mutation accumulation have served well in dissecting mechanisms of resistance evolution by reconstructing mutation pathways under different drug-environments. While these models perform well in predicting treatment outcomes by statistical learning, they do not incorporate drug effect mechanistically. Additionally, due to an inherent lack of temporal features in such models, they are less informative on aspects such as predicting mutational abundance at treatment failure. This limits their application in analyzing the pharmacology of antiretroviral drugs, in particular, time-dependent characteristics of HIV therapy such as pharmacokinetics and pharmacodynamics, and also in understanding the impact of drug efficacy on mutation dynamics. In this thesis, we develop an integrated model of in vivo viral dynamics incorporating drug-specific mutation schemes learned from clinical data. Our combined modelling approach enables us to study the dynamics of different mutant genotypes and assess mutational abundance at virological failure. As an application of our model, we estimate in vivo fitness characteristics of viral mutants under different drug environments. Our approach also extends naturally to multiple-drug therapies. Further, we demonstrate the versatility of our model by showing how it can be modified to incorporate recently elucidated mechanisms of drug action including molecules that target host factors. Additionally, we address another important aspect in the clinical management of HIV disease, namely drug pharmacokinetics. It is clear that time-dependent changes in in vivo drug concentration could have an impact on the antiviral effect, and also influence decisions on dosing intervals. We present a framework that provides an integrated understanding of key characteristics of multiple-dosing regimens including drug accumulation ratios and half-lifes, and then explore the impact of drug pharmacokinetics on viral suppression. Finally, parameter identifiability in such nonlinear models of viral dynamics is always a concern, and we investigate techniques that alleviate this issue in our setting.

10 citations

DissertationDOI
01 Apr 2014
TL;DR: This chapter discusses changes of cART Regimens and Guidelines and its impact on HIV Survival, as well as background, disease progression, and progress in HIV Treatment.
Abstract: .................................................................................................................................................. 4 Dedication ............................................................................................................................................... 5 Acknowledgement .................................................................................................................................. 6 List of Figures ....................................................................................................................................... 13 List of Tables ........................................................................................................................................ 16 Abbreviations and Acronyms ............................................................................................................. 18 Chapter 1 Introduction ..................................................................................................................... 20 1.1 Background ............................................................................................................................ 21 1.2 Natural History and Disease Progression of HIV .................................................................. 22 1.3 HIV Treatment ............................................................................................................................. 24 1.3.1 HIV Life Cycle ..................................................................................................................... 24 1.3.2 Antiretroviral Drugs ....................................................................................................... 27 1.3.2.1 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) .............................................. 28 1.3.2.2 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) ................................... 28 1.3.2.3 Protease Inhibitors (PIs) ............................................................................................. 28 1.3.2.4 Fusion Inhibitors ........................................................................................................ 28 1.3.2.5 Entry Inhibitors .......................................................................................................... 30 1.3.2.6 Integrase Strand Transfer Inhibitors........................................................................... 30 1.4 Progress in HIV Treatment .......................................................................................................... 30 1.4.1 From Monoto Triple Therapy and its Impact on HIV Survival .......................................... 30 1.4.2 Changes of cART Regimens and Guidelines ........................................................................ 32

8 citations