Association of Alanine Aminotransferase Flares to Hepatitis B Surface Decline During Tenofovir Alone or With Pegylated Interferon Alfa.

INTRODUCTION: We aimed to determine whether the intensity of alanine aminotransferase (ALT) flares during antiviral therapy is associated with the level of hepatitis B surface antigen (HBsAg) decline. METHODS: Quantitative HBsAg was determined during tenofovir monotherapy or tenofovir plus peginterferon alfa-2a in 201 participants with hepatitis B e antigen-positive or -negative chronic hepatitis B. A multivariable analysis identified factors associated with a shorter time to reduction in HBsAg. RESULTS: Fifty flares occurred during treatment of which 74% were moderate (ALT >5-10 × upper limit of normal) or severe (ALT >10 × upper limit of normal). These flares were associated with greater HBsAg decline compared with no flares. Significantly faster times to HBsAg decline >1 log 10 IU ( P = 0.04) and to HBsAg level <100 IU/mL ( P = 0.01) were observed with severe flares. DISCUSSIONS: Flare severity is a potentially important factor associated with shorter time to HBsAg reduction. These findings can be useful when evaluating HBsAg response to evolving hepatitis B virus therapies.

Randomized Trial of Tenofovir With or Without Peginterferon Alfa Followed by Protocolized Treatment Withdrawal in Adults With Chronic Hepatitis B.

INTRODUCTION: Hepatitis B surface antigen (HBsAg) loss is associated with improved long-term outcomes of patients with chronic hepatitis B but is infrequently achieved with current monotherapies. We assessed whether combination strategies that included treatment withdrawal enhanced HBsAg loss. METHODS: A randomized (1:1) trial of tenofovir disoproxil fumarate (TDF) for 192 weeks with or without peginterferon (PegIFN) alfa-2a for the first 24 weeks, followed by withdrawal of TDF at week 192 with 48 weeks of off-treatment follow-up to week 240. The primary end point was HBsAg loss at week 240. RESULTS: Of 201 participants (52% HBeAg positive, 12%/6% genotype A/A2, 7% cirrhosis) randomized to TDF + PegIFN (n = 102) or TDF alone (n = 99), 6 participants had lost HBsAg at the end of the treatment phase (week 192), 5 (5.3%) in the combination group, and 1 (1.0%) in the TDF alone group ( P = 0.09). By week 240, 9 participants had cleared HBsAg, 5.3% in combination, and 4.1% in monotherapy arms ( P = 0.73). HBsAg decline and loss occurred earlier with TDF + PegIFN than TDF, with a ≥1-logIU/mL qHBsAg decline by week 24 in 28% in TDF + PegIFN compared with 6% in TDF ( P = 0.04). HBsAg loss occurred in 7 of 12 (58%) with hepatitis B virus subgenotype A2 (all HBeAg positive) compared with only 2 of 189 (1%) with other hepatitis B virus genotypes and in 8 of 93 (8.6%) HBeAg positive vs 1 of 87 (1.1%) HBeAg negative. DISCUSSION: PegIFN combined TDF followed by protocolized TDF withdrawal led to earlier but not higher percentages of HBsAg clearance. Pretreatment HBeAg positivity and subgenotype A2 were strongly associated with HBsAg clearance.

Entecavir and Peginterferon Alfa-2a in Adults With Hepatitis B e Antigen-Positive Immune-Tolerant Chronic Hepatitis B Virus Infection.

Monotherapy with interferon or nucleoside analog is generally not recommended during the immune-tolerant (IT) phase of chronic hepatitis B virus (HBV) infection. Recognition that high HBV DNA levels are associated with hepatocellular carcinoma has increased interest in treating HBV in the IT phase. Small pediatric studies reported efficacy with combination nucleoside analog and interferon therapy. The aim of this study was to evaluate the safety and efficacy of the combination of entecavir and peginterferon in adults in the IT phase of chronic HBV infection. Hepatitis B e antigen (HBeAg)-positive adults with HBV DNA > 107 IU/mL and alanine aminotransferase (ALT) ≤ 1.5 times the upper limit of normal (ULN) (male: ≤ 45, female: ≤ 30 U/L) received entecavir 0.5 mg daily for 8 weeks followed by the addition of peginterferon alfa-2a 180 µg/week to entecavir for an additional 40 weeks. The primary endpoint was HBeAg loss and HBV DNA ≤ 1,000 IU/mL 48 weeks after end of treatment (EOT). Among 28 participants from 11 sites, the median age was 37.2 (range: 22-61) years, 54% were male, and 96% were Asian. Nearly all were infected with genotype C (64%) or B (32%). Median baseline HBV DNA was 8.2 log10 IU/mL, and ALT was 0.9 times the ULN. Although one (4%) participant cleared HBeAg, none met the primary endpoint of both HBeAg loss AND HBV DNA ≤ 1,000 IU/mL 48 weeks post-EOT. ALT elevations > 5 times the ULN occurred in eight (29%) participants, and none were associated with icterus. Forty-eight weeks posttreatment, HBV DNA rebounded to baseline levels in all participants, including the participant who lost HBeAg, and ALT values returned to near baseline levels in all but four participants. Conclusion: A lead-in strategy of 8 weeks of entecavir followed by combination peginterferon and entecavir therapy for 40 weeks had limited efficacy in adults in the IT phase of chronic HBV infection and cannot be recommended.

Effect of ribavirin on viral kinetics and liver gene expression in chronic hepatitis C.

OBJECTIVE: Ribavirin improves treatment response to pegylated-interferon (PEG-IFN) in chronic hepatitis C but the mechanism remains controversial. We studied correlates of response and mechanism of action of ribavirin in treatment of hepatitis C. DESIGN: 70 treatment-naive patients were randomised to 4 weeks of ribavirin (1000-1200 mg/d) or none, followed by PEG-IFNα-2a and ribavirin at standard doses and durations. Patients were also randomised to a liver biopsy 24 h before or 6 h after starting PEG-IFN. Hepatic gene expression was assessed by microarray and interferon-stimulated gene (ISG) expression quantified by nCounter platform. Temporal changes in ISG expression were assessed by qPCR in peripheral-blood mononuclear cells (PBMC) and by serum levels of IP-10. RESULTS: After 4 weeks of ribavirin monotherapy, hepatitis C virus (HCV) levels decreased by 0.5±0.5 log10 (p=0.009 vs controls) and ALT by 33% (p<0.001). Ribavirin pretreatment, while modestly augmenting ISG induction by PEG-IFN, did not modify the virological response to subsequent PEG-IFN and ribavirin treatment. However, biochemical, but not virological, response to ribavirin monotherapy predicted response to subsequent combination treatment (rapid virological response, 71% in biochemical responders vs 22% non-responders, p=0.01; early virological response, 100% vs 68%, p=0.03; sustained virological response 83% vs 41%, p=0.053). Ribavirin monotherapy lowered serum IP-10 levels but had no effect on ISG expression in PBMC. CONCLUSIONS: Ribavirin is a weak antiviral but its clinical effect seems to be mediated by a separate, indirect mechanism, which may act to reset IFN-responsiveness in HCV-infected liver.

What the infectious disease physician needs to know about pegylated interferon and ribavirin.

The treatment of chronic hepatitis C is rapidly evolving from triple therapy to regimens that do not require interferon or even ribavirin. However, pegylated interferon and ribavirin will remain the backbone of hepatitis C therapy for the time being. This review summarizes the pharmacokinetics of peginterferon and ribavirin with a particular emphasis on their side-effect profile and management. Finally, the continued role of peginterferon and ribavirin in future therapies will be discussed.

S-adenosyl methionine improves early viral responses and interferon-stimulated gene induction in hepatitis C nonresponders.

BACKGROUND & AIMS: Less than half of patients infected with hepatitis C virus (HCV) achieve sustained viral clearance after pegylated interferon (peginterferon) and ribavirin therapy. S-adenosyl methionine (SAMe) improves interferon signaling in cell culture. We assessed the effect of SAMe on the kinetics of the early antiviral response and interferon signaling in nonresponders to previous antiviral therapy and investigated the mechanisms involved. METHODS: Nonresponders with HCV genotype 1 were given peginterferon alfa-2a and ribavirin for 2 weeks (course A, baseline/control). After 1 month, patients received SAMe (1600 mg daily) for 2 weeks and then peginterferon and ribavirin for 48 weeks (course B; completed by 21 of 24 patients). Viral kinetics and interferon-stimulated gene (ISG) expression in peripheral blood mononuclear cells (PBMCs) were compared between courses. RESULTS: The decrease in HCV RNA from 0 to 48 hours (phase 1) was similar with and without SAMe. However, the second phase slope of viral decline was improved with SAMe (course A, 0.11 ± 0.04 log(10) IU/mL/wk; course B, 0.27 ± 0.06; P = .009); 11 patients (53%) achieved an early virological response, and 10 (48%) had undetectable HCV RNA by week 24. Induction of ISGs in PBMCs was significantly greater during course B. In cultured cells, SAMe increased induction of ISGs and the antiviral effects of interferon by increasing STAT1 methylation, possibly affecting STAT1-DNA binding. CONCLUSIONS: The addition of SAMe to peginterferon and ribavirin improves the early viral kinetics and increases ISG induction in nonresponders to previous therapy. SAMe might be a useful adjunct to peginterferon-based therapies in chronic HCV infection.

Maintenance peginterferon therapy and other factors associated with hepatocellular carcinoma in patients with advanced hepatitis C.

BACKGROUND & AIMS: Interferon reportedly decreases the incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial showed that 4 years of maintenance therapy with pegylated interferon (peginterferon) does not reduce liver disease progression. We investigated whether peginterferon decreases the incidence of HCC in the HALT-C cohort over a longer posttreatment follow-up period. METHODS: The study included 1048 patients with chronic hepatitis C (Ishak fibrosis scores ≥ 3) who did not have a sustained virologic response (SVR) to therapy. They were randomly assigned to groups given a half-dose of peginterferon or no treatment (controls) for 3.5 years and followed up for a median of 6.1 (maximum, 8.7) years. RESULTS: Eighty-eight patients developed HCC (68 definite, 20 presumed): 37 of 515 who were given peginterferon (7.2%) and 51 of 533 controls (9.6%; P = .24). There was a significantly lower incidence of HCC among patients given peginterferon therapy who had cirrhosis, but not fibrosis, based on analysis of baseline biopsy samples. After 7 years, the cumulative incidences of HCC in treated and control patients with cirrhosis were 7.8% and 24.2%, respectively (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.24-0.83); in treated and control patients with fibrosis, incidences were 8.3% and 6.8%, respectively (HR, 1.44; 95% CI, 0.77-2.69). Treated patients with a ≥ 2-point decrease in the histologic activity index, based on a follow-up biopsy, had a lower incidence of HCC than those with unchanged or increased scores (2.9% vs 9.4%; P = .03). CONCLUSIONS: Extended analysis of the HALT-C cohort showed that long-term peginterferon therapy does not reduce the incidence of HCC among patients with advanced hepatitis C who did not achieve SVRs. Patients with cirrhosis who received peginterferon treatment had a lower risk of HCC than controls.

Reduction in Hepatic Inflammation Is Associated With Less Fibrosis Progression and Fewer Clinical Outcomes in Advanced Hepatitis C.

OBJECTIVES: During the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial, 3.5 years of maintenance peginterferon-alfa-2a therapy did not affect liver fibrosis progression or clinical outcomes among 1,050 previous interferon nonresponders with advanced fibrosis or cirrhosis. We investigated whether reduced hepatic inflammation was associated with clinical benefit in 834 patients with a baseline and follow-up biopsy 1.5 years after randomization to peginterferon or observation. METHODS: Relationships between change in hepatic inflammation (Ishak hepatic activity index, (HAI)) and serum alanine aminotransferase level, fibrosis progression and clinical outcomes after randomization, and hepatitis C virus (HCV) RNA decline before and after randomization were evaluated. Histological change was defined as a ≥ 2-point difference in HAI or Ishak fibrosis score between biopsies. RESULTS: Among 657 patients who received full-dose peginterferon/ribavirin "lead-in" therapy before randomization, year-1.5 HAI improvement was associated with lead-in HCV RNA suppression in both the randomized treated (P<0.0001) and control (P=0.0001) groups, even in the presence of recurrent viremia. This relationship persisted at year 3.5 in both the treated (P=0.001) and control (P=0.01) groups. Among 834 patients followed for a median of 6 years, fewer clinical outcomes occurred in patients with improved HAI at year 1.5 compared with those without such improvement in both the treated (P=0.03) and control (P=0.05) groups. Among patients with Ishak 3-4 fibrosis at baseline, those with improved HAI at year 1.5 had less fibrosis progression at year 1.5 in both the treated (P=0.0003) and control (P=0.02) groups. CONCLUSIONS: Reduced hepatic inflammation (measured 1.5 and 3.5 years after randomization) was associated with profound virological suppression during lead-in treatment with full-dose peginterferon/ribavirin and with decreased fibrosis progression and clinical outcomes, independent of randomized treatment.

Excess mortality in patients with advanced chronic hepatitis C treated with long-term peginterferon.

UNLABELLED: Chronic hepatitis C virus infection can cause chronic liver disease, cirrhosis and liver cancer. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial was a prospective, randomized controlled study of long-term, low-dose peginterferon therapy in patients with advanced chronic hepatitis C who failed to respond to a previous course of optimal antiviral therapy. The aim of this follow-up analysis is to describe the frequency and causes of death among this cohort of patients. Deaths occurring during and after the HALT-C Trial were reviewed by a committee of investigators to determine the cause of death and to categorize each death as liver- or nonliver-related and as related or not to complications of peginterferon. Rates of liver transplantation were also assessed. Over a median of 5.7 years, 122 deaths occurred among 1,050 randomized patients (12%), of which 76 were considered liver-related (62%) and 46 nonliver-related (38%); 74 patients (7%) underwent liver transplantation. At 7 years the cumulative mortality rate was higher in the treatment compared to the control group (20% versus 15%, P = 0.049); the primary difference in mortality was in patients in the fibrosis compared to the cirrhosis stratum (14% versus 7%, P = 0.01); comparable differences were observed when liver transplantation was included. Excess mortality, emerging after 3 years of treatment, was related largely to nonliver-related death; liver-related mortality was similar in the treatment and control groups. No specific cause of death accounted for the excess mortality and only one death was suspected to be a direct complication of peginterferon. CONCLUSION: Long-term maintenance peginterferon in patients with advanced chronic hepatitis C is associated with an excess overall mortality, which was primarily due to nonliver-related causes among patients with bridging fibrosis.

A prospective study of the rate of progression in compensated, histologically advanced chronic hepatitis C.

UNLABELLED: The incidence of liver disease progression among subjects with histologically advanced but compensated chronic hepatitis C is incomplete. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial was a randomized study of 3.5 years of maintenance peginterferon treatment on liver disease progression among patients who had not cleared virus on peginterferon and ribavirin therapy. Patients were followed subsequently off therapy. Because maintenance peginterferon treatment did not alter liver disease progression, we analyzed treated and control patients together. Among 1,050 subjects (60% advanced fibrosis, 40% cirrhosis), we determined the rate of progression to cirrhosis over 4 years and of clinical outcomes over 8 years. Among patients with fibrosis, the incidence of cirrhosis was 9.9% per year. Six hundred seventy-nine clinical outcomes occurred among 329 subjects. Initial clinical outcomes occurred more frequently among subjects with cirrhosis (7.5% per year) than subjects with fibrosis (3.3% per year) (P<0.0001). Child-Turcotte-Pugh (CTP) score≥7 was the most common first outcome, followed by hepatocellular carcinoma. Following occurrence of a CTP score≥7, the rate of subsequent events increased to 12.9% per year, including a death rate of 10% per year. Age and sex did not influence outcome rates. Baseline platelet count was a strong predictor of all clinical outcomes. During the 8 years of follow-up, death or liver transplantation occurred among 12.2% of patients with advanced fibrosis and 31.5% of those with cirrhosis. CONCLUSION: Among patients with advanced hepatitis C who failed peginterferon and ribavirin therapy, the rate of liver-related outcomes, including death and liver transplantation, is high, especially once the CTP score reaches at least 7.

Factors that determine the development and progression of gastroesophageal varices in patients with chronic hepatitis C.

BACKGROUND & AIMS: We aimed to identify the incidence and predictors of de novo gastroesophageal variceal formation and progression in a large cohort of patients with chronic hepatitis C and advanced fibrosis. METHODS: All participants in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial were offered an endoscopy before treatment and again after 4 years. Patients with varices at baseline also had an endoscopy at 2 years. Baseline laboratory and clinical parameters were analyzed as predictors of de novo variceal formation and variceal progression. RESULTS: De novo varices developed in 157 of the 598 (26.2%) patients. Most of the new varices were small (76.4%) and only 1% of patients developed variceal hemorrhage. The likelihood of developing varices was associated with subject race (Hispanic > Caucasian > African American; P = .0005), lower baseline levels of albumin (P = .051), and higher levels of hyaluronic acid (P < .001) with an area under the receiver operating characteristic curve = .70. Among 210 patients with existing gastroesophageal varices, 74 (35.2%) had variceal progression or bleeding during follow-up. Patients with higher baseline ratios of serum aspartate/alanine aminotransferase (P = .028) and lower platelet counts (P = .0002) were at greatest risk of variceal progression (area under the receiver operating characteristic = .72). Prolonged, low-dose peginterferon-alpha2a therapy and beta-blockers did not influence the risk of developing new or enlarging varices. CONCLUSION: Development of varices in patients with chronic hepatitis C is associated with patient race/ethnicity and laboratory markers of disease severity. Prolonged low-dose peginterferon-alpha2a therapy and beta-blockers do not reduce the risk of variceal development or progression.

Ribavirin improves early responses to peginterferon through improved interferon signaling.

BACKGROUND & AIMS: The therapeutic mechanisms of ribavirin for hepatitis C are unclear. Microarray analyses have shown that ribavirin increases induction of interferon-stimulated genes. We evaluated viral kinetics, serum cytokine expression, and viral mutagenesis during early stages of peginterferon therapy with and without ribavirin. METHODS: Fifty patients with chronic hepatitis C virus (HCV) infection genotype 1 were randomly assigned to groups that were given peginterferon alpha-2a, with or without ribavirin, for 4 weeks; all patients then received an additional 44 weeks of combination therapy. First- and second-phase viral kinetics were evaluated. Serum levels of interferon-gamma-inducible protein-10 (IP10), monokine induced by interferon-gamma, and monocyte chemoattractant protein 1 were quantified as measures of the interferon-stimulated genes response. NS5A and NS5B were partially sequenced, and mutation rates were calculated. RESULTS: The first-phase decrease in HCV RNA was similar between groups. Patients who received ribavirin had a more rapid second-phase decrease, compared with patients who did not receive ribavirin-particularly those with an adequate first-phase decrease (0.61 vs 0.35 log10 IU/mL/week; P = .018). At 12 hours, fold induction of serum IP10 was higher in patients given the combination therapy than those given peginterferon only (7.6- vs 3.8-fold; P = .01); however, the difference was greatest in patients with an adequate first-phase decrease in HCV RNA. IP10-induction correlated with first- and second-phase kinetics and with ribavirin serum concentrations on day 3. HCV mutation rates were similar between groups. CONCLUSIONS: Ribavirin improves the kinetics of the early response to therapy in patients with an adequate initial response to peginterferon. Induction of interferon-stimulated cytokines correlates with viral kinetics following ribavirin therapy, suggesting that ribavirin promotes interferon signaling.

Development and progression of portal hypertensive gastropathy in patients with chronic hepatitis C.

OBJECTIVES: The objective of this study was to determine the incidence and risk factors associated with new-onset and worsening portal hypertensive gastropathy (PHG) in patients with chronic hepatitis C (CHC). METHODS: A total of 831 CHC patients with bridging fibrosis or cirrhosis at the time of entry were prospectively monitored for clinical and histological liver disease progression while receiving either low-dose peginterferon α2a or no antiviral therapy in the HALT-C (Hepatitis C Antiviral Long-term Treatment against Cirrhosis) trial. Upper endoscopy with grading of PHG was performed at baseline and at year 4 of the study. The presence and severity of PHG were determined using the NIEC (New Italian Endoscopy Conference) criteria, and worsening PHG was defined as a score increase of ≥1 point. RESULTS: During a median follow-up of 3.85 years, 50% of 514 subjects without PHG developed new-onset PHG, whereas 26% of 317 patients with baseline PHG had worsening PHG. Independent predictors of new-onset PHG included higher alkaline phosphatase and being diabetic, whereas predictors of worsening PHG were Caucasian race, lower albumin, as well as higher serum aspartate transaminase/alanine transaminase ratio and homeostatic model assessment levels. New-onset and worsening PHG were significantly associated with clinical and histological progression. They were also associated with new-onset and worsening gastroesophageal varices. CONCLUSIONS: New-onset and worsening PHG develop at a rate of 12.9% per year and 6.7% per year, respectively, in non-responder CHC patients with advanced fibrosis. If confirmed in other studies, endoscopic surveillance for PHG may need to be tailored to individual patient risk factors.

Outcome of sustained virological responders with histologically advanced chronic hepatitis C.

UNLABELLED: Retrospective studies suggest that subjects with chronic hepatitis C and advanced fibrosis who achieve a sustained virological response (SVR) have a lower risk of hepatic decompensation and hepatocellular carcinoma (HCC). In this prospective analysis, we compared the rate of death from any cause or liver transplantation, and of liver-related morbidity and mortality, after antiviral therapy among patients who achieved SVR, virologic nonresponders (NR), and those with initial viral clearance but subsequent breakthrough or relapse (BT/R) in the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) Trial. Laboratory and/or clinical outcome data were available for 140 of the 180 patients who achieved SVR. Patients with nonresponse (NR; n = 309) or who experienced breakthrough or relapse (BT/R; n = 77) were evaluated every 3 months for 3.5 years and then every 6 months thereafter. Outcomes included death, liver-related death, liver transplantation, decompensated liver disease, and HCC. Median follow-up for the SVR, BT/R, and NR groups of patients was 86, 85, and 79 months, respectively. At 7.5 years, the adjusted cumulative rate of death/liver transplantation and of liver-related morbidity/mortality in the SVR group (2.2% and 2.7%, respectively) was significantly lower than that of the NR group (21.3% and 27.2%, P < 0.001 for both) but not the BT/R group (4.4% and 8.7%). The adjusted hazard ratio (HR) for time to death/liver transplantation (HR = 0.17, 95% confidence interval [CI] = 0.06-0.46) or development of liver-related morbidity/mortality (HR = 0.15, 95% CI = 0.06-0.38) or HCC (HR = 0.19, 95% CI = 0.04-0.80) was significant for SVR compared to NR. Laboratory tests related to liver disease severity improved following SVR. CONCLUSION: Patients with advanced chronic hepatitis C who achieved SVR had a marked reduction in death/liver transplantation, and in liver-related morbidity/mortality, although they remain at risk for HCC.

Clearance of pegylated interferon by Kupffer cells limits NK cell activation and therapy response of patients with HBV infection.

Pegylated interferon-α (PEG-IFN-α), where IFN-α is attached to polyethylene glycol (PEG), is an approved treatment for chronic hepatitis B virus (HBV) infection, a disease that causes liver-related morbidity and mortality in 257 million people worldwide. It is unknown why only a minority of patients respond to PEG-IFN-α. Using sequential blood samples and liver biopsies of patients with chronic HBV infection before, during, and after PEG-IFN-α treatment, we find that patients with early natural killer (NK) cell activation after PEG-IFN-α injection experienced greater liver inflammation, lysis of HBV-infected hepatocytes, and hepatitis B surface antigen (HBsAg) decline than those without. NK cell activation was associated with induction of interferon-stimulated genes and determined by PEG-IFN-α pharmacokinetics. Patients with delayed increases in PEG-IFN-α concentrations had greater amounts of PEG-specific immunoglobulin M (IgM) immune complexes in the blood and more PEG and IgM detected in the liver than patients with rapid increase in PEG-IFN-α concentration. This was associated with reduced NK cell activation. These results indicate that the immunomodulatory functions of PEG-IFN-α, particularly activation of NK cells, play a pivotal role in the response to treatment and further demonstrate that these functions are affected by PEG-IFN-α pharmacokinetics. Accelerated clearance of antibody-complexed pegylated drugs by Kupffer cells may be important beyond the field of HBV therapeutics. Thus, these findings may contribute to improving the efficacy of pegylated drugs that are now being developed for other chronic diseases and cancer.

Management of untreated and nonresponder patients with chronic hepatitis C.

Hepatitis C infection has evolved in the past quarter century from a newly recognized entity without a known pathogen (non-A, non-B hepatitis) to one of the world's most prevalent causes of liver disease, an important source for hepatocellular carcinoma, and the major indication for liver transplantation. It is caused by a virus with a complex replication cycle that occurs in multiple genotypes, of which the four most prevalent (1, 2, 3, and 4) exhibit differences in clinical behavior and responses to therapy. Chronic hepatitis C virus (HCV) in particular has evolved from a disease with no known treatment to one with several primary treatment options, none of which is uniformly effective, and a growing list of secondary treatment options for those who have failed to respond to, or relapsed after initial therapy. As treatment is often associated with significant side effects, it is now a disease that presents clinicians with multiple important decisions: whom to treat, when and with what to treat them initially, and how to manage patients who have failed during initial therapy to achieve a sustained virological response, the gold standard of effective therapy. This review examines each of these important decisions, presenting evidence to help guide clinicians in their choices. The decisions are addressed sequentially as they arise during the initial evaluation and subsequent treatment of a typical, newly recognized patient with chronic HCV, and the considerations facing the clinician when the patient has failed to achieve an SVR.

Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease.

BACKGROUND & AIMS: Although the incidence of hepatocellular carcinoma (HCC) is increasing in the United States, data from large prospective studies are limited. We evaluated the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) cohort for the incidence of HCC and associated risk factors. METHODS: Hepatitis C virus-positive patients with bridging fibrosis or cirrhosis who did not respond to peginterferon and ribavirin were randomized to groups that were given maintenance peginterferon for 3.5 years or no treatment. HCC incidence was determined by Kaplan-Meier analysis, and baseline factors associated with HCC were analyzed by Cox regression. RESULTS: 1,005 patients (mean age, 50.2 years; 71% male; 72% white race) were studied; 59% had bridging fibrosis, and 41% had cirrhosis. During a median follow-up of 4.6 years (maximum, 6.7 years), HCC developed in 48 patients (4.8%). The cumulative 5-year HCC incidence was similar for peginterferon-treated patients and controls, 5.4% vs 5.0%, respectively (P= .78), and was higher among patients with cirrhosis than those with bridging fibrosis, 7.0% vs 4.1%, respectively (P= .08). HCC developed in 8 (17%) patients whose serial biopsy specimens showed only fibrosis. A multivariate analysis model comprising older age, black race, lower platelet count, higher alkaline phosphatase, esophageal varices, and smoking was developed to predict the risk of HCC. CONCLUSIONS: We found that maintenance peginterferon did not reduce the incidence of HCC in the HALT-C cohort. Baseline clinical and laboratory features predicted risk for HCC. Additional studies are required to confirm our finding of HCC in patients with chronic hepatitis C and bridging fibrosis.

Effect of HCV RNA suppression during peginterferon alfa-2a maintenance therapy on clinical outcomes in the HALT-C trial.

BACKGROUND & AIMS: The Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) trial demonstrated that low-dose peginterferon maintenance therapy was ineffective in preventing clinical outcomes in patients with chronic hepatitis C, advanced fibrosis, and failure to achieve a sustained virologic response during lead-in phase treatment with standard dose peginterferon/ribavirin. This analysis was performed to determine whether suppressing HCV RNA during the trial was associated with a reduction in clinical outcomes. METHODS: Seven hundred sixty-four patients treated during the lead-in phase of HALT-C trial were randomized to either peginterferon alfa-2a (90 microg/week) maintenance therapy or no treatment (control) for 3.5 years. Clinical outcomes included an increase in Child-Turcotte-Pugh score, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal hemorrhage, hepatocellular carcinoma, and mortality. RESULTS: During the lead-in, >or=4-log(10) decline in serum HCV RNA occurred in 178 patients; 82% of whom lost detectable HCV RNA and later broke through or relapsed. These patients had significantly (P = .003) fewer clinical outcomes whether randomized to maintenance therapy or control. Following randomization, serum HCV RNA increased significantly in all 90 control patients and in 58 of 88 receiving maintenance therapy. Only 30 patients had persistent suppression of HCV RNA by >or=4 log(10) during maintenance therapy. No significant reduction in clinical outcomes was observed in these patients. CONCLUSIONS: Viral suppression by >or=4 log(10) with full-dose peginterferon/ribavirin is associated with a significant reduction in clinical outcomes. Continuing low-dose peginterferon maintenance therapy, even in patients with persistent viral suppression, does not lead to a further decline in clinical outcomes.

Editorial: Treatment of patients with HCV-related cirrhosis with peginterferon and ribavirin: Swinging the pendulum toward treatment.

Patients with hepatitis C virus-related cirrhosis are at increased risk for hepatic decompensation and hepatocellular carcinoma (HCC). They also responded less well to standard therapy compared with those without cirrhosis. Several recent studies have demonstrated that patients with cirrhosis can be safely treated and those who achieve a sustained virological response have better clinical outcomes compared with nonresponders. These results support treatment for patients with compensated cirrhosis. In addition, cirrhotic patients should be monitored after a sustained virological response is obtained, because some patients remain at risk for complications of liver disease, particularly HCC. Newer, more effective therapy is needed for patients with cirrhosis.

Evolution of hepatic steatosis in patients with advanced hepatitis C: results from the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial.

UNLABELLED: Hepatic steatosis is a common histologic feature in patients with chronic hepatitis C (CHC) but there are no large longitudinal studies describing the progression of steatosis in CHC. We examined changes in steatosis on serial biopsies among CHC patients participating in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial. All 1050 patients in the trial had advanced fibrosis at baseline biopsy and were documented not to have had a sustained virological response to peginterferon and ribavirin. Most (94%) patients had genotype 1 infection. At least one protocol follow-up biopsy was read on 892 patients, and 699 had the last biopsy performed 3.5 years after randomization. At enrollment, 39% had cirrhosis and 61% had bridging fibrosis; 18%, 41%, 31%, and 10% had steatosis scores of 0, 1, 2, and 3 or 4, respectively. The mean steatosis score decreased in the follow-up biopsies in both the interferon-treated patients and controls with no effect of treatment assignment (P = 0.66). A decrease in steatosis score by > or =1 point was observed in 30% of patients and was associated with both progression to cirrhosis and continued presence of cirrhosis (P = 0.02). Compared to patients without a decrease in steatosis, those with a decrease in steatosis had worse metabolic parameters at enrollment, and were more likely to have a decrease in alcohol intake, improvement in metabolic parameters, and worsening liver disease (cirrhosis, esophageal varices, and deterioration in liver function). CONCLUSION: Serial biopsies demonstrated that in patients with CHC, steatosis recedes during progression from advanced fibrosis to cirrhosis. Decreased alcohol intake and improved metabolic parameters are associated with a decline in steatosis and may modulate hepatitis C progression.