Rositsa B. Dimova

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

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‐γ (IFN‐γ)–inducible protein 10 (IP‐10/CXCL10), monokine induced by IFN‐γ (Mig/CXCL9), and interferon‐inducible T cell α 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. (Hepatology 2008.)

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.

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.

Integrated internist — addiction medicine — hepatology model for hepatitis C management for individuals on methadone maintenance

Summary.  Despite a high prevalence of hepatitis C virus (HCV) among drug users, HCV evaluation and treatment acceptance are extremely low among these patients when referred from drug treatment facilities for HCV management. We sought to increase HCV treatment effectiveness among patients from a methadone maintenance treatment program (MMTP) by maintaining continuity of care. We developed, instituted and retrospectively assessed the effectiveness of an integrated, co‐localized care model in which an internist‐addiction medicine specialist from MMTP was embedded in the hepatitis clinic. Methadone maintenance treatment program patients were referred, evaluated by the internist and hepatologist in hepatitis clinic and provided HCV treatment with integration between both sites. Of 401 evaluated patients, anti‐HCV antibody was detected in 257, 86% of whom were older than 40 years. Hepatitis C virus RNA levels were measured in 222 patients, 65 of whom were aviremic. Of 157 patients with detectable HCV RNA, 125 were eligible for referral to the hepatitis clinic, 76 (61%) of whom accepted and adhered with the referral. Men engaged in MMTP <36 months were significantly less likely to be seen in hepatitis clinic than men in MMTP more than 36 months (odds ratio = 7.7; 95% confidence interval 2.6–22.9) or women. We evaluated liver histology in 63 patients, and 83% had moderate to advanced liver disease. Twenty‐four patients initiated treatment with 19 completing and 13 (54%) achieving sustained response. In conclusion, integrated care between the MMTP and the hepatitis clinic improves adherence with HCV evaluation and treatment compared to standard referral practices.

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.

Common scientific and statistical errors in obesity research.

This review identifies 10 common errors and problems in the statistical analysis, design, interpretation, and reporting of obesity research and discuss how they can be avoided. The 10 topics are: 1) misinterpretation of statistical significance, 2) inappropriate testing against baseline values, 3) excessive and undisclosed multiple testing and “P‐value hacking,” 4) mishandling of clustering in cluster randomized trials, 5) misconceptions about nonparametric tests, 6) mishandling of missing data, 7) miscalculation of effect sizes, 8) ignoring regression to the mean, 9) ignoring confirmation bias, and 10) insufficient statistical reporting. It is hoped that discussion of these errors can improve the quality of obesity research by helping researchers to implement proper statistical practice and to know when to seek the help of a statistician.

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

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. (Hepatology 2014;60:1825–1836)

Information methods for model selection in linear mixed effects models with application to HCV data

In this paper, we derive a small sample Akaike information criterion, based on the maximized loglikelihood, and a small sample information criterion based on the maximized restricted loglikelihood in the linear mixed effects model when the covariance matrix of the random effects is known. Small sample corrected information criteria are proposed for a special case of linear mixed effects models, the balanced random-coefficient model, without assuming the random coefficients covariance matrix to be known. A simulation study comparing the derived criteria and several others for model selection in the linear mixed effects models is presented. We illustrate the behavior of the studied information criteria on real data from a study of subjects coinfected with HIV and Hepatitis C virus. Robustness of the criteria, in terms of the error distributed as a mixture of normal distributions, is also studied. Special attention is given to the behavior of the conditional AIC by Vaida and Blanchard (2005). Among the studied criteria, GIC performs best, while cAIC exhibits poor performance. Because of its inferior performance, as demonstrated in this work, we do not recommend its use for model selection in linear mixed effects models.

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.

Assessment of methadone clinic staff attitudes toward hepatitis C evaluation and treatment.

We used a 25-item, self-administered questionnaire to assess staffs perceived barriers and willingness to engage in onsite treatment of hepatitis C virus (HCV) at the Beth Israel Medical Center methadone maintenance treatment program (MMTP) at its Harlem sites. Of 80 participants, 50% were counselors and 24% were directly involved in referral or HCV testing. Although 92% of the MMTP staff indicated that they discuss HCV evaluation and treatment with patients at least annually, 70% believed that less than 25% of patients accept referral for HCV treatment and attend their initial appointment. Most staff (66%) supported onsite HCV evaluation and treatment, although support was higher among those with a bachelors degree or higher (p = 0.046). Lack of infrastructure was perceived as the greatest obstacle to onsite treatment. Educational interventions and skill building for staff to confidently engage and support MMTP patients in HCV treatment may be necessary prerequisites for onsite HCV management in MMTPs.