Faculty Bibliography

Initial reports analyzing dendritic cell (DC) function in patients with hepatitis C virus (HCV) infection have been controversial. Here, we enumerate and characterize the function of circulating myeloid and plasmacytoid DCs. The results show lower percentages of myeloid DCs (0.62 vs. 0.83; P = .05) and plasmacytoid DCs (0.11 vs. 0.34; P = .004) in patients with chronic HCV infection than in healthy, non-HCV-infected individuals. Despite the lower numbers of circulating myeloid DCs present, no phenotypic or functional defects were identified. The lower percentage of plasmacytoid DCs resulted in decreased absolute interferon (IFN)-alpha production; however, when analyzed on a per-cell basis, plasmacytoid DCs from HCV-infected patients generated levels of IFN-alpha equivalent to those generated by DCs from healthy, non-HCV-infected individuals. Contrary to data from previous models (which attributed HCV pathogenesis to defects in the DC compartment), our data reveal functional DC subsets in patients with chronic HCV infection. These results are encouraging for DC-based HCV immunotherapy trials

A significant number of patients with chronic hepatitis C relapse after treatment. As therapy for CHC has improved over the last decade, the issue of retreating patients who did not achieve a sustained virologic response with previous treatment regimens frequently arises. Several studies have assessed the efficacy of pegylated interferon (IFN) and ribavirin (RBV) combination therapy in IFN and RBV therapy relapsers. Patients who have relapsed after therapy have significantly higher SVR rates than those who are nonresponders to therapy and should be considered candidates for retreatment. Predictors of a favorable response to therapy in naive patients appear to also predict response to therapy in patients who have relapsed previously.

Clinicians may be concerned about prescribing statins to patients with chronic liver disease, but there is little evidence to suggest that drug-induced liver injury from statins is increased in these patients. Thus, we should prescribe statins for the same indications in patients with chronic liver disease as in patients without, but with closer monitoring. However, patients with acute liver disease (acute viral hepatitis, alcoholic hepatitis) should not take statins until they have recovered.

BACKGROUND/AIMS: In chronic hepatitis C (CHC) infection, a liver biopsy provides important information that guides treatment decisions, but is invasive, expensive and associated with possible complications. Extracellular matrix remodeling proteins may be useful non-invasive markers of fibrosis. The aim of this study was to evaluate the diagnostic accuracy of a panel of these markers in CHC patients, develop a predictive algorithm that differentiates no/mild (METAVIR F0-F1) from moderate/severe (F2-F4) fibrosis, and validate the model in external cohorts. METHODS: A combination of matrix markers were initially evaluated and optimized in 294 CHC patients from a single center, and validated in an external cohort of 402 patients. RESULTS: Hyaluronic acid, TIMP-1 and alpha2-macroglobulin were selected as having the best predictive accuracy for F2-F4 fibrosis (combined AUROC = 0.831). At an index cut-off >0.36 and prevalence for F2-F4 of 52%, results in all 696 patients indicated positive and negative predictive values of 74.3 and 75.8% with an accuracy of 75%. CONCLUSIONS: The three-marker panel may reliably differentiate CHC patients with moderate/severe fibrosis from those with no/mild fibrosis, although accurate delineation between stages was not possible. Prospective studies are required to determine the potential utility of the marker panel in guiding treatment decisions and following disease progression.

Certain populations with chronic hepatitis C face special challenges in attaining optimal adherence to antiviral therapy, including patients coinfected with human immunodeficiency virus, patients undergoing dialysis for end-stage renal disease, and liver transplant recipients. These patient groups may stand to gain particular benefit from the expanding use of hematopoietic growth factors to manage the cytopenic effects of antiviral therapy for hepatitis C. This article reviews the rationale, current evidence, and future prospects for the adjunctive use of growth factors in these special populations with hepatitis C.

CD3- CD56(+dim) natural killer (NK) cells, which are cytotoxic against virally infected cells, may be important in hepatitis C virus (HCV)-infected patients who are successfully treated with pegylated interferon (PEG-IFN)-alpha. We used flow cytometry to enumerate activated (CD69+) and apoptotic (annexin-V+) dim (CD3- CD56(+dim)) and bright (CD3- CD56(+bright)) NK cells obtained from HCV-infected patients before treatment (n=16) and healthy controls (n=15) in the absence and presence of pegylated interferon (PEG-IFN)-alpha-2b. A subset of HCV-infected patients, subsequently treated with PEG-IFN-alpha-2b in vivo, was determined to have a sustained virological response (SVR, n=6) or to not respond (NR) to treatment (n=5). In the absence of IFN, activated dim (CD3- CD56(+dim) CD69+) NK cells were significantly decreased (P=0.04) while activated apoptotic dim (CD3- CD56(+dim)CD69+ annexin-V+) NK cells tended to be increased (P=0.07) in SVR patients compared with NR patients. Activated bright (CD3-CD56(+bright)CD69+) and activated apoptotic bright (CD3- CD56(+bright)CD69+ annexin-V+) NK cells were significantly correlated (P=0.02 and P=0.01, respectively) with increasing hepatic inflammation. These findings suggest that in the absence of PEG-IFN, activated dim (CD3- CD56(+dim)CD69+) NK cell turnover may be enhanced in SVR compared with NR patients and that activated bright (CD3- CD56(+bright)CD69+) NK cells may play a role in liver inflammation.

OBJECTIVES: Most studies establishing the role of antiviral therapy in patients with chronic hepatitis C (CHC) excluded the patients with normal ALT levels. Small trials with interferon monotherapy suggested a limited efficacy and/or de novo ALT elevations. We sought to evaluate the efficacy of two doses of interferon alfa-2b (IFN) with ribavirin (RBV) in patients with normal ALT [correction]. METHODS: Patients with biopsy-proven CHC with detectable HCV RNA and at least two normal ALT levels three or more months apart were randomized to receive either 3 or 5 million units of IFN thrice a week plus RBV 1,000-1,200 mg. Therapy was stopped at 24 wk if HCV RNA remained detectable and continued for an additional 24 wk if HCV RNA was undetectable. A final HCV RNA level was obtained 24 wk after discontinuation of therapy. RESULTS: Fifty-six patients were randomized and received at least one dose of treatment. The overall rate of sustained virologic response (SVR) was 32%. SVR rates were higher in genotype 2 and 3 patients (80%) than in genotype 1 patients (24%, p = 0.002). There was a tendency toward higher SVR in genotype 1 patients treated with the higher IFN dose (36%vs 10%, p = 0.07). Five patients had mild, transient ALT elevations. No sustained ALT elevations were noted. CONCLUSIONS: Patients with normal ALT had a rate of SVR comparable to that reported in patients with elevated ALT. Higher dose of interferon tended to be more effective in genotype 1 infected patients. De novo ALT elevations were transient and not clinically significant. Patients with CHC should not be excluded from treatment on the basis of ALT alone. Combination therapy with pegylated interferon and ribavirin should be evaluated in these patients

SUMMARY: Coinfection with HIV and hepatitis C virus (HCV)-specific immune responses, increases hepatic inflammation, accelerates hepatic fibrosis, and is associated with deceased treatment responses. We quantified intrahepatic lymphocyte and hepatocyte phenotypes in HCV-infected patients with (n = 38) and without (n = 41) HIV infection. A single pathologist counted positive cells in 5 portal and 5 lobular areas. Coinfected patients had 6.81 +/- 1.9 fewer CD4 cells per portal field (10.58 +/- 1.12 vs. 4.97 +/- 1.09 cells/high-power field [HPF]; P < 0.001) and 0.48 +/- 0.15 more apoptotic lymphocytes per lobular field (0.16 +/- 0.06 vs. 0.64 +/- 0.15 cell/HPF; P = 0.002) than monoinfected patients. The number of portal CD4 cells was not associated with the peripheral CD4 cell number. Portal and lobular CD8 cells did not differ between the 2 groups. Portal proliferative hepatocytes were increased in coinfected patients with HIV RNA levels of >400 copies/mL (1.13 +/- 0.32 cells/HPF; P = 0.01) compared with those with undetectable HIV RNA (0.46 +/- 0.09 cell/HPF) and monoinfected patients (0.45 +/- 0.08 cell/HPF). In conclusion, HIV coinfection is associated with fewer portal CD4 cells and increased lobular lymphocyte apoptosis that may impact on the natural history of HCV infection