Dickens Theodore

Hepatic gene expression during treatment with peginterferon and ribavirin: Identifying molecular pathways for treatment response.

The reasons for hepatitis C treatment failure remain unknown but may be related to different host responses to therapy. In this study, we compared hepatic gene expression in patients prior to and during peginterferon and ribavirin therapy. In the on‐treatment group, patients received either ribavirin for 72 hours prior to peginterferon alpha‐2a injection or peginterferon alpha‐2a for 24 hours, prior to biopsy. The patients were grouped into rapid responders (RRs) with a greater than 2‐log drop and slow responders (SRs) with a less than 2‐log drop in hepatitis C virus RNA by week 4. Pretreatment biopsy specimens were obtained from a matched control group. The pretreatment patients were grouped as RRs or SRs on the basis of the subsequent treatment response. Gene expression profiling was performed with Affymetrix microarray technology. Known interferon‐stimulated genes (ISGs) were induced in treated patients. In the pretreatment group, future SRs had higher pretreatment ISG expression than RRs. On treatment, RRs and SRs had similar absolute ISG expression, but when it was corrected for the baseline expression with the pretreatment group, RRs showed a greater fold change in ISGs, whereas SRs showed a greater change in interferon (IFN)‐inhibitory pathways. The patients pretreated with ribavirin had heightened induction of IFN‐related genes and down‐regulation of genes involved in IFN inhibition and hepatic stellate cell activation. Conclusion: These data suggest that ISG inducibility is important for the treatment response and that ribavirin may improve outcomes by enhancing hepatic gene responses to peginterferon. Collectively, these mechanisms may provide a molecular basis for the improved efficacy of combination therapy. (HEPATOLOGY 2007.)

Immune recovery is associated with persistent rise in hepatitis C virus RNA, infrequent liver test flares, and is not impaired by hepatitis C virus in co-infected subjects.

Objectives: The impact of highly active antiretroviral therapy (HAART) on hepatitis C virus (HCV) is unknown. We analysed changes in HCV RNA and the frequency of hepatotoxicity in co-infected patient enrolling in AIDS Clinical Trials Group trials, and determined whether HCV impairs successful immune reconstitution in these populations. Design/methods: In a prospective analysis of co-infected patients completing at least 16 weeks of HAART in four trials, and co-infected patients with available stored plasma from two other completed HAART trials, HCV RNA was measured at baseline and to week 48. A retrospective analysis of immune recovery in 40 HCV-RNA-positive and 129 HCV-RNA-negative patients from a single trial was performed. Results: Prospective analysis: 60 patients completed at least 16 weeks of HAART. The mean HCV-RNA level increased 0.35 log10 IU/ml at week 16 and 0.43 log10 IU/ml at week 48. When stratified by baseline CD4 cell count, subjects’ HCV-RNA levels increased 0.43 and 0.59 log10 IU/ml at weeks 16 and 48 for entry CD4 cell counts < 350 cells/mm3, but only 0.26 and 0.1 log10 IU/ml at weeks 16 and 48 for entry CD4 cell counts > 350 cells/mm3. Severe alanine aminotransferase elevations occurred in only 3.3%. Retrospective analysis: HCV co-infection had no effect on the overall mean CD4 cell increase at weeks 16 or 48 compared with uninfected controls. Conclusion: In HCV-co-infected patients undergoing HAART, immune recovery is associated with a persistent increase in HCV RNA, especially with baseline CD4 cell counts < 350 cells/mm3. HCV co-infection did not antagonize the CD4 cell response to HAART.

Social stigmatization and hepatitis C virus infection.

Goal Our aim was to assess stigmatization by evaluating the impact of hepatitis C virus (HCV) on social interactions, feelings of rejection, internalized shame, and financial insecurity, and behavior. Background HCV patients suffer from slowly progressive disease. Although much research has improved the long-term prognosis of chronic HCV, quality of life may be affected by perceived social stigmatization. Study In a cross-sectional study, HCV patients without cirrhosis or significant comorbidities were recruited from the University of North Carolina viral hepatitis clinic. Subjects completed a questionnaire administered by a trained interviewer that assessed changes in sexual behavior, personal hygiene habits, social function, and interactions. Additionally, subjects completed validated, standardized questionnaires, the Health Status Questionnaire, and the SCL-90-R. Frequencies were calculated for the prevalence of stigmatization and altered social interaction. Correlations between education and behavior changes were assessed. A series of multivariate analyses controlling for age, sex, and education were performed to assess the association between HCV acquisition risk and stigmatization. Results One hundred seventy-five of 217 potential subjects (81%) participated in the survey. The average age was 45.2±7.7 years. Fifty-five percent were men and 53% were single. Twenty-nine percent had some college education. Risk factors for HCV acquisition included transfusion (21%) and injection drug use (29%), whereas 32% had an unknown mode of infection. Among common activities, 47% were less likely to share drinking glasses, 14% were less likely to prepare food, and one-third of subjects were less likely to share a towel. Thirty-five percent of respondents reported changes in their sexual practices. Decreased frequency of kissing and sexual intercourse was reported in 20% and 27% of individuals, respectively. Almost half of the single subjects reported increased use of condoms compared with only 20% among married couples. The majority of subjects perceived financial insecurity, internalized shame, and social rejection. Only 39% reported health impairment. Education level did not influence behavior change. Conclusion The majority of HCV subjects alter common behaviors and report financial insecurity, internalized shame, and social rejection, regardless of the method of HCV acquisition or socioeconomic status. These findings indicate that all HCV individuals be counseled and encouraged to participate in educational programs at the time of diagnosis to reduce unnecessary behavioral changes and stigmatization perceptions to improve quality of life.

Intensive interferon therapy does not increase virological response rates in African Americans with chronic hepatitis C.

To determine if an intensive regimen of daily, high-dose interferon would improve the initial response rates to therapy for hepatitis C genotype 1 among African American and Caucasian patients, we conducted a retrospective analysis of a treatment trial conducted between October 1995 and June 1997. Patients were randomized to 24 weeks of therapy with interferon −α-2b at either 5 MU daily or 3 MU three times a week. On the standard interferon regimen (3 MU three times a week) African Americans and Caucasians had similar initial response rates. However, unlike Caucasians, African Americans did not have an increased initial virological response when treated with an intensive, daily dose regimen. Levels of HCV RNA decreased more slowly during the first 12 weeks of therapy among African Americans. Nelson-Aalen cumulative hazard estimates for the different race and dose combinations revealed that Caucasians who received daily interferon were most likely to have an initial response (logrank, P < 0.001).

Correlation of single photon emission computed tomography parameters as a noninvasive alternative to liver biopsies in assessing liver involvement in the setting of HIV and hepatitis C virus coinfection: A multicenter trial of the adult aids clinical trials group

Performing a liver biopsy in patients infected with HIV and hepatitis C virus (HCV) is considered the standard of practice to assess hepatic involvement but carries risks to patients. This pilot study was designed to identify single photon emission computed tomography (SPECT) parameters that correlate with liver disease stage. HIV-coinfected and HCV-coinfected individuals undergoing a liver biopsy had a SPECT scan performed. The results showed that a number of SPECT parameters were associated with histologic changes in architecture, fibrosis, and cirrhosis, of which two SPECT parameters, the minimum pixel count for spleen region of interest and maximum pixel count for right hepatic lobe, correctly classified 39 of 46 SPECT/biopsy pairs. In conclusion, this pilot trial identified SPECT parameters that correlated with liver histology changes. A larger study is needed to demonstrate whether SPECT parameters alone or with other markers can provide information on fibrosis with the clinical significance obtained through liver biopsy.