A framework for patient-centered telemedicine: Application and lessons learned from vulnerable populations.

Virtual technologies can facilitate clinical monitoring, clinician-patient interactions, and enhance patient-centered approaches to healthcare delivery. Telemedicine, two-way communication between a healthcare provider and a patient not in the same physical location, emphasizes patient preference and convenience by substituting the transportation of patients with information transfer. We present a framework for implementation of a comprehensive, dynamic, patient-centered telemedicine network deployed in 12 opioid treatment programs (OTP) located throughout New York State (NYS). The program aims to effectively manage hepatitis C virus (HCV) infection via telemedicine with co-administration of HCV and substance use medications. We have found that the Sociotechnical System model with emphasis on patient-centered factors provides a framework for telemedicine deployment and implementation to a vulnerable population. The issue of interoperability between the telemedicine platform and the electronic health record (EHR) system as well as clinical information retrieval for medical decision-making are challenges with implementation of a comprehensive, dynamic telemedicine system. Targeting telemedicine to a vulnerable population requires additional consideration of trust in the security and confidentiality of the telemedicine system. Our contribution is the valuable lessons learned from implementing a comprehensive, dynamic, patient-centered telemedicine system among an OTP network throughout NYS as applied to a vulnerable population that can be generalized to other difficult-to-reach populations.

Genetic Variation at IFNL4 Influences Extrahepatic Interferon-Stimulated Gene Expression in Chronic HCV Patients.

Polymorphisms at IFNL4 strongly influence spontaneous resolution and interferon therapeutic response in hepatitis C virus (HCV) infection. In chronic HCV, unfavorable alleles are associated with elevated interferon (IFN)-stimulated gene (ISG) expression in the liver, but extrahepatic effects are less well characterized. We used RNA sequencing (RNA-Seq) to examine whether IFNL4 genetic variation (rs368234815) modulates ISG expression in peripheral blood mononuclear cells (PBMC) during chronic HCV infection. ISG expression was elevated in unstimulated PBMC homozygous for the unfavorable ΔG IFNL4 variant; expression following IFN-α stimulation was comparable across genotypes. These findings suggest that lambda interferons may have broader systemic effects during HCV infection.

Fibrosis Progression in Patients With Chronic Hepatitis C Virus Infection.

BACKGROUND: Fibrosis progression varies markedly in hepatitis C virus (HCV)-infected individuals. We investigated factors that influence fibrosis progression in chronic HCV infection. METHODS: HCV-infected patients who underwent at least 2 liver biopsies were included in this study. Associations between fibrosis progression and epidemiologic, virologic, and disease-associated factors were analyzed using logistic regression and multistate Markov modeling. RESULTS: We analyzed 936 biopsy specimens obtained from 378 individuals. Mean age (±SD) at first biopsy was 48.3 ± 9.3 years, 59.3% of patients were male, 59.9% were white, and 86.7% were infected with HCV genotype 1. Fibrosis progression and cirrhosis occurred in 57.4% and 5.8%, respectively. Fibrosis progression between the first and last biopsies was associated with lower fibrosis in the first biopsy specimen (P < .001) and with the occurrence of at least 1 flare in the alanine aminotransferase (ALT) level (>200 U/L; P = .007). We found the highest fibrosis progression rate between stages 0 and 1 and the lowest between stages 2 and 3. Increased necroinflammation and higher ALT level were associated with faster progression. HCV genotype 3-infected patients were more likely to progress to cirrhosis (P < .001). CONCLUSIONS: Fibrosis progression in HCV is not linear but varies according to stage, with the highest progression in patients with the lowest fibrosis severity. Patients who experience flares in the ALT level are also more likely to progress.

Intrahepatic and Peripheral CXCL10 Expression in Hepatitis C Virus-Infected Patients Treated With Telaprevir, Pegylated Interferon, and Ribavirin.

UNLABELLED: We assessed peripheral and liver CXCL10 levels in 15 patients treated with telaprevir/pegylated interferon/ribavirin. Induction of peripheral CXCL10 messenger RNA (mRNA) peaked (mean fold-induction [±SD], 3.1 ± 1.9) between treatment hour 6 and day 2, while induction of intrahepatic CXCL10 mRNA peaked (mean fold-induction [±SD], 1.3 ± 0.54) at hour 10 or day 4. Peripheral CXCL10 levels were higher at treatment hour 10 (P = .032) and day 2 (P = .009) in patients with undetectable virus 2 weeks after treatment initiation. Treatment hour 10 (P = .023) and peak (P = .034) intrahepatic CXCL10 levels were also higher in these patients. CXCL10 did not distinguish treatment responders from nonresponders. In conclusion, CXCL10 identified very rapid virological response in patients treated with a direct-acting antiviral. CLINICAL TRIALS REGISTRATION: NCT00892697.

Telaprevir-based treatment effects on hepatitis C virus in liver and blood.

UNLABELLED: Understanding hepatitis C virus (HCV) replication has been limited by access to serial samples of liver, the primary site of viral replication. Our understanding of how HCV replicates and develops drug-resistant variants in the liver is limited. We studied 15 patients chronically infected with genotype 1 HCV treated with telaprevir (TVR)/pegylated-interferon alpha/ribavirin. Hepatic fine needle aspiration was performed before treatment and at hour 10, days 4 and 15, and week 8 after initiation of antiviral therapy. We measured viral kinetics, resistance patterns, TVR concentrations, and host transcription profiles. All patients completed all protocol-defined procedures that were generally well tolerated. First-phase HCV decline (baseline/treatment day 4) was significantly slower in liver than in plasma (slope plasma: -0.29; liver, -0.009; P < 0.001), whereas second-phase decline (posttreatment days 4-15) did not differ between the two body compartments (-0.11 and -0.15, respectively; P = 0.1). TVR-resistant variants were detected in plasma, but not in liver (where only wild-type virus was detected). Based upon nonstructural protein 3 sequence analysis, no compartmentalization of viral populations was observed between plasma and liver compartments. Gene expression profiling revealed strong tissue-specific expression signatures. Human intrahepatic TVR concentration, measured for the first time, was lower, compared to plasma, on a gram per milliliter basis. We found moderate heterogeneity between HCV RNA levels from different intrahepatic sites, indicating differences in hepatic microenvironments. CONCLUSION: These data support an integrated model for HCV replication wherein the host hepatic milieu and innate immunity control the level of viral replication, and the early antiviral response observed in the plasma is predominantly driven by inhibition of hepatic high-level HCV replication sites.

FibroSURE as a noninvasive marker of liver fibrosis and inflammation in chronic hepatitis B.

BACKGROUND: Noninvasive markers of liver fibrosis have not been extensively studied in patients with chronic hepatitis B virus (HBV) infection. Our aim was to evaluate the capacity of FibroSURE, one of the two noninvasive fibrosis indices commercially available in the United States, to identify HBV infected patients with moderate to severe fibrosis. METHODS: Forty-five patients who underwent liver biopsy at a single tertiary care center were prospectively enrolled and had FibroSURE performed within an average interval of 11 days of the biopsy. RESULTS: Of the 45 patients, 40% were Asian, 40% were African American, and 13% were Caucasian; 27% were co-infected with HIV and 67% had no or mild fibrosis. We found FibroSURE to have moderate capacity to discriminate between patients with moderate to high fibrosis and those with no to mild fibrosis (area under receiver operating characteristic [AUROC] curve = 0.77; 95% confidence interval [CI] [0.61, 0.92]). When we combined the fibrosis score determined by FibroSURE with aspartate aminotransferase (AST) measurements and HIV co-infection status, the discriminatory ability significantly improved reaching an AUROC of 0.90 (95% CI [0.80, 1.00]). FibroSURE also had a good ability to differentiate patients with no or mild from those with moderate to high inflammation (AUROC = 0.83; 95% CI [0.71, 0.95]). CONCLUSIONS: FibroSURE in combination with AST levels has an excellent capacity to identify moderate to high fibrosis stages in chronic HBV-infected patients. These data suggest that FibroSURE may be a useful substitute for liver biopsy in chronic HBV infection.

Determinants of hepatitis C virus treatment completion and efficacy in drug users assessed by meta-analysis.

BACKGROUND: Hepatitis C virus (HCV)-infected drug users (DUs) have largely been excluded from HCV care. We conducted a systematic review and meta-analysis of the literature on treatment completion and sustained virologic response (SVR) rates in DUs. We assessed the effects of different treatment approaches and services to promote HCV care among DUs as well as demographic and viral characteristics. METHODS: Studies of at least 10 DUs treated with pegylated interferon/ribavirin that reported SVR were analyzed. Heterogeneity was assessed (Cochran test) and investigated (meta-regression), and pooled rates were estimated (random effects). RESULTS: Thirty-six studies comprising 2866 patients were retrieved. The treatment completion rate among DUs was 83.4% (95% confidence interval [CI], 77.1%-88.9%). Among studies that included addiction-treated and untreated patients during HCV therapy, the higher the proportion of addiction-treated patients, the higher the HCV treatment completion rate (P < .0001). After adjusting for human immunodeficiency virus (HIV)/HCV coinfection, sex, and treatment of addiction, support services during antiviral therapy increased treatment completion (P < .0001). The pooled SVR rate was 55.5% (95% CI, 50.6%-60.3%). Genotype 1/4 (P = .0012) and the proportion of HIV-coinfected DUs (P = .0173) influenced the SVR rate. After adjusting for HCV genotype 1/4 and HIV/HCV coinfection, the SVR rate was positively correlated with involvement of a multidisciplinary team (P < .0001). CONCLUSIONS: Treatment of addiction during HCV therapy results in higher treatment completion. Our pooled SVR rate is similar to that obtained in registration trials in the general population. Treatment of addiction during HCV therapy will likely be important for HCV-infected DUs undergoing treatment with more complex regimens including direct-acting antivirals.

CXCL9 and CXCL10 chemokines as predictors of liver fibrosis in a cohort of primarily African-American injection drug users with chronic hepatitis C.

CXCL9 (monokine induced by IFN γ [Mig]) and CXCL10 (interferon [IFN] γ-inducible protein 10 [IP-10]) have been associated with hepatic fibrosis in predominantly white hepatitis C virus (HCV)-infected patients. We investigated their potential as noninvasive markers of hepatic fibrosis and fibrosis progression in African-American patients. Peripheral chemokine levels were measured in 115 HCV-infected patients within 4 months of liver biopsy; patients underwent a second biopsy after 3-5 years. CXCL10 levels appeared to be higher in patients with advanced fibrosis on the contemporaneous biopsy and were significantly higher in patients with advanced fibrosis compared with those with minimal fibrosis on the later biopsy (P = .0045). Therefore, CXCL10 has potential as a marker of fibrosis progression in African-American HCV-infected patients.

Induction of CXCR3- and CCR5-associated chemokines during acute hepatitis C virus infection.

BACKGROUND & AIMS: Characterization of inflammatory mediators, such as chemokines, during acute hepatitis C virus (HCV) infection might shed some light on viral clearance mechanisms. METHODS: Plasma levels of CXCR3 (CXCL9-11)- and CCR5 (CCL3-4)-associated chemokines, ALT, and HCV RNA were measured in nine injection drug users (median 26 samples/patient) before and during 10 acute (eight primary and two secondary) HCV infections. Using functional data analysis, we estimated smooth long-term trends in chemokine expression levels to obtain the magnitude and timing of overall changes. Residuals were analyzed to characterize short-term fluctuations. RESULTS: CXCL9-11 induction began 38-53days and peaked 72-83days after virus acquisition. Increases in ALT levels followed a similar pattern. Substantial negative auto-correlations of chemokine levels at 1 week lags suggested substantial week-to-week oscillations. Significant correlations were observed between CXCL10 and HCV RNA as well as ALT and CXCR3-associated chemokines measured in the preceding week, CCL3-4 expression levels did not change appreciably during acute HCV infection. CONCLUSIONS: Elevation of CXCR3-associated chemokines late during acute HCV infection suggests a role for cellular immune responses in chemokine induction. Week-to-week oscillations of HCV RNA, chemokines, and ALT suggest frequent, repeated cycles of gain and loss of immune control during acute hepatitis C.

Facilitating engagement of persons with opioid use disorder in treatment for hepatitis C virus infection via telemedicine: Stories of onsite case managers.

Although hepatitis C virus (HCV) infection has high prevalence and incidence in persons with opioid use disorder (PWOUD), their engagement in HCV care has been limited due to a variety of factors. In an ongoing multisite study at 12 opioid treatment programs (OTPs) throughout New York State (NYS), we have been evaluating telemedicine accompanied by onsite administration of direct acting antiviral (DAA) medications compared with usual care including offsite referral to a liver specialist for HCV management. Each site has a case manager (CM) who is responsible for all study-related activities including participant recruitment, facilitating telemedicine interactions, retention in care, and data collection. Our overall objective is to analyze CM experiences of clients' stories and events to understand how the telemedicine model facilitates HCV treatment. Hermeneutic phenomenology was used to interpret and to explicate common meanings and shared practices of the phenomena of case management, and a focus group with CMs was conducted to reinforce and expand on key themes identified from the CMs' stories. We identified three themes: (1) building trust, (2) identification of multiple competing priorities, and (3) development of personalized care approaches. Our results illustrate that trust is a fundamental pillar on which the telemedicine system can be based. Participants' experiences at the OTP can reinforce trust. Understanding the specific competing priorities and routinizing dedicated personalized approaches to overcome them are key to increasing participation in HCV care among PWOUD.

Peripheral CXCR3-associated chemokines as biomarkers of fibrosis in chronic hepatitis C virus infection.

BACKGROUND: CXCR3-associated chemokines CXCL9-CXCL11 promote histologic progression in chronic hepatitis C virus (HCV) infection, as indicated by elevated intrahepatic levels of messenger RNA in patients with advanced inflammation and fibrosis. We evaluated the potential of peripheral chemokine levels to discriminate among patients with chronic HCV infection who had different stages of fibrosis. METHODS: Peripheral levels of CXCR3-associated chemokines were measured by enzyme-linked immunosorbent assay of plasma samples obtained from 93 patients with chronic HCV infection. Of the subjects, 79 (85%) were white, and 68 (73%) were infected with HCV genotype 1. RESULTS: Expression of all 3 chemokines, when analyzed as a group, was significantly associated with intrahepatic inflammation and fibrosis. Plasma levels of CXCL10 were significantly elevated in patients with advanced fibrosis, whereas CXCL9 levels were significantly elevated in patients with advanced inflammation. By proportional odds multivariate modeling, we observed an association between fibrosis and CXCL10 (P< .002) as well as between fibrosis and inflammation (P<.001). Of the individual parameters, the CXCL10 level was most useful in identifying patients with more-severe (stage 3-4) fibrosis. Discriminatory ability was improved by the combination of CXCL10 and CXCL9. CONCLUSIONS: The strong association between CXCR3-associated chemokines and fibrosis suggests that they may have promise as noninvasive markers of hepatic fibrosis in a predominantly white HCV genotype 1-infected population.

Intrahepatic levels of CXCR3-associated chemokines correlate with liver inflammation and fibrosis in chronic hepatitis C.

UNLABELLED: Chemokines, chemotactic cytokines, may promote hepatic inflammation in chronic hepatitis C virus (HCV) infection through the recruitment of lymphocytes to the liver parenchyma. We evaluated the association between inflammation and fibrosis and CXCR3-associated chemokines, interferon-gamma (IFN-gamma)-inducible protein 10 (IP-10/CXCL10), monokine induced by IFN-gamma (Mig/CXCL9), and interferon-inducible T cell alpha chemoattractant (I-TAC/CXCL11), in HCV infection. Intrahepatic mRNA expression of these chemokines was analyzed in 106 chronic HCV-infected patients by real-time PCR. The intrahepatic localization of chemokine producer cells and CXCR3(+) lymphocytes was determined in selected patients by immunohistochemistry. We found elevated intrahepatic mRNA expression of all three chemokines, most markedly CXCL10, in chronic HCV-infected patients with higher necroinflammation and fibrosis. By multivariable multivariate analysis, intrahepatic CXCL10 mRNA expression levels were significantly associated with lobular necroinflammatory grade and HCV genotype 1. In the lobular region, CXCL10-expressing and CXCL9-expressing hepatocytes predominated in areas with necroinflammation. Strong CXCL11 expression was observed in almost all portal tracts, whereas CXCL9 expression varied considerably among portal tracts in the same individual. Most intrahepatic lymphocytes express the CXCR3 receptor, and the number of CXCR3(+) lymphocytes was increased in patients with advanced necroinflammation. CONCLUSION: These findings suggest that the CXCR3-associated chemokines, particularly CXCL10, may play an important role in the development of necroinflammation and fibrosis in the liver parenchyma in chronic HCV infection.

Liver Disease and Fibrosis Assessment in Substance Use-Related Disorders.

Substance users have the highest prevalence of hepatitis C virus (HCV) infection but have rarely been treated, largely because of their mistrust of the health care system, misconceptions about the consequences of the infection, and concerns regarding interferon-related side effects. With the development of highly efficacious, interferon-free therapeutic regimens without significant side effects, the concept of colocating HCV and substance use treatment would appear to be highly feasible. This process has been further facilitated by widespread clinical adaptation of noninvasive assays for fibrosis assessment, which could be performed routinely in substance use treatment facilities. The most commonly used noninvasive fibrosis assessment methods are serum marker indexes and transient elastography, both of which are very accurate in detecting cirrhosis or the absence of fibrosis, but much less successful in identifying intermediate fibrosis stages. The effect of drugs of abuse on the liver is not completely understood or sufficiently studied. There are no indications that heroin and cocaine affect fibrosis progression, but some recreational drugs (eg, alcohol and cannabis) can induce hepatic injury. In addition, knowledge gaps exist on the effect of impaired liver function on metabolism or transport of agents used to treat substance disorders as well as their interactions with HCV antivirals.

Hepatitis C virus core antigen: A potential alternative to HCV RNA testing among persons with substance use disorders.

BACKGROUND: The hepatitis C virus (HCV) core antigen (HCVcAg) may be an alternative diagnostic method to HCV RNA especially in populations such as substance users, the homeless or in resource-limited settings. AIMS: To evaluate performance of HCVcAg test in patients with opioid use disorder (OUD) on methadone in order to document its performance characteristics in the target population and to ensure that its specificity remains consistent across different populations. METHODS: HCVcAg levels from 109 methadone-maintained patients were compared to HCV RNA levels. RESULTS: Mean age was 53.8±7.8years, 59.6% were male, 68.8% African American, and 44% HCV-infected. HCVcAg was detectable in 47 of 48 HCV-infected, and undetectable in all HCV RNA negative patients. The HCVcAg assay had sensitivity of 97.9% and specificity of 100%. Correlation with HCV RNA levels was excellent (r=0.88, 95% CI 0.76; 0.95, p<0.01). CONCLUSION: HCVcAg has excellent performance for the diagnosis of HCV infection in patients with OUD on methadone.

Improvements in HCV-related Knowledge Among Substance Users on Opioid Agonist Therapy After an Educational Intervention.

OBJECTIVES: Lack of knowledge about hepatitis C virus (HCV) is a principal barrier to substance users' engagement into care for the infection. As a step toward their increased engagement into HCV care, the objective of this study was to deliver an HCV-related educational intervention to substance users on opioid agonist therapy and to assess the change in HCV-related knowledge after the intervention. METHODS: We designed a comprehensive and interactive hepatitis C-related educational intervention, composed of two 30 to 60-minute sessions conducted during 2 consecutive weeks. Patients' knowledge about hepatitis C was assessed immediately before and after the intervention using a 7-item questionnaire. RESULTS: A total of 110 patients completed both educational sessions. Patients' mean age was 54.7 ±â€Š7.8 years, 58.7% were men, 70.4% African American, and 30% were Hispanic. We observed a significant increase in HCV-related knowledge after completion of the educational intervention. Whereas 65.45% of patients answered 5 or more questions correctly before the intervention, 83.64% had 5 or more questions answered correctly on the posteducational quiz (P < 0.001). Male sex, ever receiving an HCV diagnostic test before the educational intervention, and a higher level of HCV knowledge on the preeducational quiz were found to be significantly associated with HCV-related knowledge after the educational intervention. CONCLUSIONS: Patients' knowledge about hepatitis C was found to be significantly improved after the educational intervention. Therefore, HCV-related education could be the first step toward effective enrollment of patients on opioid agonist therapy into hepatitis C care.

Histone deacetylase 1 represses the small GTPase RhoB expression in human nonsmall lung carcinoma cell line.

The dynamic balance between histone acetylation and deacetylation plays a significant role in the regulation of gene transcription. Much of our current understanding of this transcriptional control comes from the use of HDAC inhibitors such as trapoxin A (TPX), which leads to hyperacetylated histone, alters local chromatin architecture and transcription and results in tumor cell death. In this study, we treated tumor cells with TPX and HDAC1 antisense oligonucleotides, and analysed the transcriptional consequences of HDAC inhibition. Among other genes, the small GTPase RhoB was found to be significantly upregulated by TPX and repressed by HDAC1. The induction of RhoB by HDAC inhibition was mediated by an inverted CCAAT box in the RhoB promoter. Interestingly, measurement of RhoB transcription in approximately 130 tumor-derived cell lines revealed low expression in almost all of these samples, in contrast to RhoA and RhoC. Accumulating evidence indicates that the small GTPase Rho proteins are involved in a variety of important processes in cancer, including cell transformation, survival, invasion, metastasis and angiogenesis. This study for the first time demonstrates a link between HDAC inhibition and RhoB expression and provides an important insight into the mechanisms of HDAC-mediated transcriptional control and the potential therapeutic benefit of HDAC inhibition.

IFN-α-Induced Downregulation of miR-221 in Dendritic Cells: Implications for HCV Pathogenesis and Treatment.

Although interferon (IFN)-α is known to exert immunomodulatory and antiproliferative effects on dendritic cells (DCs) through induction of protein-coding IFN-stimulated genes (ISGs), little is known about IFN-α-regulated miRNAs in DCs. Since several miRNAs are involved in regulating DC functions, it is important to investigate whether IFN-α's effects on DCs are mediated through miRNAs as well. In this study, we examined miRNA expression patterns in myeloid DCs (mDCs) and plasmacytoid DCs after exposing them to IFN-α. We report that IFN-α downregulates miR-221 in both DC subsets via inhibition of STAT3. We validated proapoptotic proteins BCL2L11 and CDKN1C as miR-221 targets suggesting that IFN-α can induce DC apoptosis via miR-221 downregulation. In addition, we validated another miR-221 target, SOCS1, which is known to be a negative regulator of JAK/STAT signaling. Consistent with this, miR-221 overexpression in mDCs enhanced the secretion of proinflammatory cytokines IL-6 and TNF-α. In peripheral blood mononuclear cells (PBMCs) of HIV-1/HCV co-infected individuals undergoing IFN-α-based treatment the baseline miR-221 expression was lower in non-responders compared with responders; and miR-221 expression directly correlated with DC frequency and IL-6/TNF-α secretion. In addition to PBMCs, we isolated total liver cells and kupffer cells from HCV-infected individuals and individuals with alcoholic cirrhosis. We found that both total liver cells and kupffer cells from HCV-infected individuals had significantly higher miR-221 levels compared with individuals with cirrhosis. Overall, we demonstrate that IFN-α exerts both antiproliferative and immunomodulatory effects on mDCs via miR-221 downregulation; and IFN-miR-221 axis can play important role in HCV pathogenesis and treatment.

Transcription regulation by histone deacetylases.

Dynamic changes in the post-translational modification pattern of histories such as acetylation, deacetylation, phosphorylation, methylation and ubiquitination are thought to provide a code for correct regulation of gene expression by affecting chromatin structure and interaction with regulatory factors. Our studies focus on the role of histone deacetylases (HDACs) in transcriptional regulation and addressing functional differences of class I and class II HDACs. To identify genes that were transcriptionally regulated by specific HDACs, genome scale expression profiles were performed in cancer cells following the inhibition of three HDAC family members by specific oligonucleotides. The modulated genes identified in this study represented a wide range of modifications in different cellular pathways. In addition, treatment of cancer cells with a HDAC inhibitor was found to induce the expression of the small GTPase RhoB through an inverted CCAAT box in the RhoB promoter. These studies identified a specific transcription element involved in HDAC-mediated gene transcription and genes that are transcriptionally regulated by specific HDACs, providing important insight into the potential therapeutic benefit of HDAC inhibition.