Gene Expression Profiles Predict Emergence of Psychiatric Adverse Events in HIV/HCV-Coinfected Patients on Interferon-Based HCV Therapy

Abstract

Background The efficacy of pegylated IFN-α and ribavirin (pegIFN/RBV) in the treatment of Hepatitis C infection is limited by psychiatric adverse effects (IFN-PE). Our study examined the ability of differential gene expression patterns prior to therapy to predict emergent IFN-PE among 28 HIV/HCV co-infected patients treated with pegIFN-α2b/RBV. Methods Patients dually infected with HIV and HCV were evaluated at baseline and during treatment by board-certified psychiatrists who classified patients into 2 groups: those who developed IFN-PE and those who did not (IFN-NPE). Gene expression analysis (Affymetrix HG-U133A) was performed using PBMCs before and after initiation of treatment. ANOVA, post hoc analysis based on pair-wise comparisons and functional annotation analysis identified differentially expressed genes within and between groups. Prediction Analysis for Microarrays was used to test the predictive ability of selected genes. Results Twenty-four genes (16 up- and 8 down-regulated) that were differentially expressed at baseline in patients who subsequently developed IFN-PE compared to the IFN-NPE group showed the ability to predict IFN-PE with an accuracy of 82%. In 16 patients with IFN-PE, 135 genes (117 up-; 18 down-regulated) were significantly modulated following treatment. Of these, 10 genes have already been shown to be associated with neuropsychiatric illnesses and were significantly modulated only in patients who experienced IFN-PE. Conclusions We describe a novel molecular diagnostic biomarker panel to predict emergent IFN-PE in HIV/HCV-co-infected patients undergoing pegIFN/RBV treatment, which may improve the identification of patients at greatest risk for IFN-PE and suggest candidate therapeutic targets for preventing or treating IFN-PE.

Interferon stimulated exonuclease gene 20 kDa links psychiatric events to distinct hepatitis C virus responses in human immunodeficiency virus positive patients

“…As previously reported, occurrence of toxicity to PegIFN‐α based therapy in subjects co‐infected with HIV and HCV is closely associated with achieving virologic suppression and effectiveness of therapy [Rasimas et al, ]. As consistent observations have been reported by other investigators in this regard [Loftis et al, ] a DNA microarray analysis was utilized to shed light on molecular mechanisms that could govern this crucial clinical interaction outcome.…”

“…Baseline characteristics of patients who developed toxicity and those who did not were similar with regards to age, sex, race, Body Mass Index, HCV genotype, HCV viral load, CD4 + T‐cell counts, HIV viral load, highly active antiretroviral therapy (HAART), underlying psychiatric history, and psychiatric medication prior to enrollment. (For details please see under Materials and Methods → Study inclusion and exclusion criteria and elsewhere [Rasimas et al, ]). In this study, the incidence of PegIFN‐α induced depression (29%) was lower than reported by other investigators [Laguno et al, ].…”

“…Finally, four gene subsets (including 22 probe IDs) involving 21 unique genes reached statistical significance based on the above criteria and exhibited significant enrichment in brain tissue or were associated with neuro‐psychiatric disorders based on DAVID [Huang da et al, ]. There were five genes that were common to previous work [Rasimas et al, ] (Supplementary ). STEP FOUR : Using expression data of those 21 unique genes, two‐way‐ANOVA was performed based on pair‐wise comparisons between three groups: patients with psychiatric toxicity who reached sustained virological response (N = 8, 28%) versus patients with psychiatric toxicity who did not (N = 10, 36%) versus patients who remained uneventful non‐responders (N = 10, 36%).…”

“…Previously, a diagnostic biomarker panel has been described as able to predict emergent psychiatric toxicity in patients co-infected with HIV and HCV undergoing PegIFN-a/RBV treatment [Rasimas et al, 2012]. This study was aimed to further explore the molecular basis of the clinical outcome observed in patients who experience a psychiatric toxicity and achieve sustained virologic response [Rasimas et al, 2012], similar to findings published using HCV monoinfected patients [Loftis et al, 2004]. To date, it is unclear if psychiatric adverse events are more commonly associated with a favorable therapeutic outcome.…”

Differences in gene expression and alterations in cell cycle of acute myeloid leukemia cell lines after treatment with JAK inhibitors

“…The pharmacotranscriptomic approach is believed to be an important part of individualized medicine (Wang, 2010). For example, changes in gene expression profile in patients have been shown to act as a biomarker of potential cardiovascular events or psychiatric events in response to antiviral therapy (Rasimas et al, 2012). We believe that similar research done in vitro, although in much greater scale and with the careful choice of models, could be translated into clinical effect by predicting potential adverse events that can arouse from different selectivity of the kinase inhibitors tested.…”