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Background: As the era of interferon-alpha (IFN)-based therapy for hepatitis C ends, long-term treatment outcomes are now being evaluated., Aim: To more fully understand the natural history of hepatitis C infection by following a multisite cohort of patients., Methods: Patients with chronic HCV were prospectively enrolled in 1999-2000 from 11 VA medical centers and followed through retrospective medical record review., Results: A total of 2211 patients were followed for an average of 8.5 years after enrollment. Thirty-one percent of patients received HCV antiviral therapy, 15 % with standard IFN/ribavirin only, 16 % with pegylated IFN/ribavirin, and 26.7 % of treated patients achieved sustained virologic response (SVR). Cirrhosis developed in 25.8 % of patients. Treatment nonresponders had a greater than twofold increase in the hazard of cirrhosis and hepatocellular carcinoma, compared to untreated patients, whereas SVR patients were only marginally protected from cirrhosis. Nearly 6 % developed hepatocellular carcinoma, and 27.1 % died during the follow-up period. Treated patients, regardless of response, had a significant survival benefit compared to untreated patients (HR 0.58, CI 0.46-0.72). Improved survival was also associated with college education, younger age, lower levels of alcohol consumption, and longer duration of medical service follow-up-factors typically associated with treatment eligibility., Conclusions: As more hepatitis C patients are now being assessed for all-oral combination therapy, these results highlight that patient compliance and limiting harmful behaviors contribute a significant proportion of the survival benefit in treated patients and that the long-term clinical benefits of SVR may be less profound than previously reported., Competing Interests: All authors declare that they have no conflict of interest related to the data or interpretation of this study.

Background: Interferon α (IFN-α) and ribavirin can induce a sustained virologic response (SVR) in some but not all hepatitis C virus (HCV)-infected patients. The mechanism of effective treatment is unclear. One possibility is that IFN-α differentially improves the functional capacity of classic myeloid dendritic cells (mDCs) by altering expression of surface molecules or cytokines. Others have proposed that antigen-presenting cell activation could be paradoxically detrimental during HCV infection because of the production by monocytes of substances inhibitory or toxic to plasmacytoid dendritic cells., Methods: We examined responses to in vitro IFN-α treatment of peripheral blood leukocyte samples from a retrospective treatment cohort of nearly 200 HCV-seropositive patients who had undergone antiviral therapy with ribavirin and pegylated IFN. We analyzed the variable responses of antigen-presenting cell subsets to drug., Results: We found that patients achieving SVR were no more likely to have robust mDC activation in response to IFN-α than those who did not achieve SVR. Rather, patients achieving SVR were distinguished by restrained monocyte activation in the presence of IFN-α, a factor that was second in importance only to IL28B genotype in its association with SVR., Conclusions: These results suggest that interindividual variability in the response of monocytes to IFN-α is an important determinant of treatment success with IFN-α-based regimens.

Background: Many HCV-infected persons with recent or ongoing injection drug use (IDU) do not receive HCV treatment due to the perceived risk of HCV reinfection. There are few prospective studies investigating HCV reinfection among IDUs., Methods: Two hundred and twenty-four persons with past or ongoing IDU were followed from 1997 to 2007. Baseline and every 6-month follow-up data were collected including demographics, IDU, and sexual behaviors. Serum was tested for the presence of HCV antibody and serially for HCV RNA. Resolvers were defined as HCV antibody and RIBA positive and RNA negative at two consecutive time points or as becoming HCV RNA negative after HCV antiviral treatment. Reinfection was defined by the presence of HCV RNA at > or =2 visits., Results: One hundred and eighty-six persons had chronic HCV and 38 had resolved HCV. The resolvers were followed for a total of 214 person-years. Forty-two percent of resolvers reported ongoing IDU, representing 58 person-years of IDU. Only one reinfection occurred in the resolvers, for a reinfection rate of 0.47 cases/100 person-years of follow-up. The single reinfection, which occurred in a person who continued to inject drugs, represents a reinfection rate of 1.75 cases/100 person-years of IDU., Conclusion: These data suggest that despite ongoing IDU, persistent HCV reinfection is lower than previously published. This can be attributed to a more clinically relevant definition of reinfection. This information will better help clinicians make informed decisions regarding HCV treatment options for patients who may continue to inject illicit drugs.

Background and aimsSecond-generation direct-acting antivirals (2G DAA) to cure HCV have led to dramatic clinical improvements. HCV-associated hepatocellular carcinoma (HCC), however, remains common. Impaired immune tumor surveillance may play a role in HCC development. Our cohort evaluated the effects of innate immune types and clinical variables on outcomes including HCC.MethodsParticipants underwent full HLA class I/KIR typing and long-term HCV follow-up.ResultsA total of 353 HCV+ participants were followed for a mean of 7 years. Cirrhosis: 25% at baseline, developed in 12% during follow-up. 158 participants received 2G DAA therapy. HCC developed without HCV therapy in 20 subjects, 24 HCC after HCV therapy, and 10 of these after 2G DAA. Two predictors of HCC among 2G DAA-treated patients: cirrhosis (OR, 10.0, p = 0.002) and HLA/KIR profiles predicting weak natural killer (NK) cell-mediated immunity (NK cell complementation groups 6, 9, 11, 12, OR of 5.1, p = 0.02). Without 2G DAA therapy: cirrhosis was the main clinical predictor of HCC (OR, 30.8, p < 0.0001), and weak NK-cell-mediated immunity did not predict HCC.ConclusionCirrhosis is the main risk state predisposing to HCC, but weak NK-cell-mediated immunity may predispose to post-2G DAA HCC more than intermediate or strong NK-cell-mediated immunity.

The contribution of the host immune system to the efficacy of new anti-hepatitis C virus (HCV) drugs is unclear. We undertook a longitudinal prospective study of 33 individuals with chronic HCV treated with combination pegylated IFN-α, ribavirin, and telaprevir/boceprevir. We characterized innate and adaptive immune cells to determine whether kinetics of the host response could predict sustained virologic response (SVR). We show that characteristics of the host immune system present before treatment were correlated with successful therapy. Augmentation of adaptive immune responses during therapy was more impressive among those achieving SVR. Most importantly, active memory T cell proliferation before therapy predicted SVR and was associated with the magnitude of the HCV-specific responses at week 12 after treatment start. After therapy initiation, the most important correlate of success was minimal monocyte activation, as predicted by previous in vitro work. In addition, subjects achieving SVR had increasing expression of the transcription factor T-bet, a driver of Th1 differentiation and cytotoxic effector cell maturation. These results show that host immune features present before treatment initiation predict SVR and eventual development of a higher frequency of functional virus-specific cells in blood. Such host characteristics may also be required for successful vaccine-mediated protection.

The immune function test is an integrated measure of total mitogen-inducible CD4(+) T cell metabolic activity in the peripheral blood, and it is used to guide the dosing of immunosuppressive medications after solid organ transplantation. Recently, low CD4(+) T cell metabolic activity due to pharmacologic immunosuppression has been linked to rapidly progressive cirrhosis in hepatitis C virus (HCV)-infected liver transplant recipients. We speculate that either cirrhosis or HCV might adversely affect the CD4(+) T cell reactivity even in the absence of immunosuppressive medications. We thus performed this assay on a cohort of untransplanted hepatology patients who were not taking immunomodulatory drugs. Low mitogen-stimulated CD4(+) T cell metabolic reactivity was more commonly seen in untransplanted patients with HCV cirrhosis or with cirrhosis due to other causes but not in control patients or in those with chronic HCV in the absence of cirrhosis. The lowest mean CD4(+) T cell reactivities were seen in patients with both cirrhosis and HCV. Caution should be exercised when immune function test results are used to guide immunomodulatory therapy in transplant recipients with suspected cirrhosis, as low immune function test results may be a consequence of hepatic cirrhosis or of pharmacologic immunosuppression.

Background: The long-term consequences of unsuccessful interferon-α based hepatitis C treatment on liver disease progression and survival have not been fully explored. Methods and Findings: We performed retrospective analyses to assess long-term clinical outcomes among treated and untreated patients with hepatitis C virus in two independent cohorts from a United States Veterans Affairs Medical Center and a University Teaching Hospital. Eligible patients underwent liver biopsy during consideration for interferon-α based treatment between 1992 and 2007. They were assessed for the probability of developing cirrhosis and of dying during follow-up using Cox proportional hazards models, stratified by pretreatment liver fibrosis stage and adjusted for known risk factors for cirrhosis and characteristics affecting treatment selection. The major predictor was a time-dependent covariate for treatment outcome among four patient groups: 1) patients with sustained virological response to treatment; 2) treatment relapsers; 3) treatment nonresponders; and 4) never treated patients. Treatment nonresponders in both cohorts had a statistically significantly increased hazard of cirrhosis compared to never treated patients, as stratified by pretreatment liver fibrosis stage and adjusted for clinical and psychosocial risk factors that disproportionately affect patients who were ineligible for treatment (Veterans Affairs HR = 2.35, CI 1.18–4.69, mean follow-up 10 years, and University Hospital HR = 5.90, CI 1.50–23.24, mean follow-up 7.7 years). Despite their increased risk for liver disease progression, the overall survival of nonresponders in both cohorts was not significantly different from that of never treated patients. Conclusion: These unexpected findings suggest that patients who receive interferon-α based therapies but fail to clear the hepatitis C virus may have an increased hazard of cirrhosis compared to untreated patients. [ABSTRACT FROM AUTHOR]