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

Subject Category: Liver

Am J Gastroenterol 2012; 107:1388–1398; doi:10.1038/ajg.2012.137; published online 12 June 2012

Chihiro Morishima MD¹, Mitchell L Shiffman MD², Jules L Dienstag MD^3,4, Karen L Lindsay MD, MMM⁵, Gyongyi Szabo MD, PhD⁶, Gregory T Everson MD⁷, Anna S Lok MD⁸, Adrian M Di Bisceglie MD⁹, Marc G Ghany MD, MHSc¹⁰, Deepa Naishadham MA, MS¹¹, Timothy R Morgan MD^12,13 and Elizabeth C Wright PhD^10,14 for the HALT-C Trial Group¹⁵

1. ¹Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA
2. ²Liver Institute of Virginia, Bon Secours Health System, Newport News, Virginia, USA
3. ³Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
4. ⁴Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
5. ⁵Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
6. ⁶Department of Medicine, Division of Gastroenterology, Hepatology and Liver Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA
7. ⁷Section of Hepatology, Division of Gastroenterology and Hepatology, University of Colorado Denver School of Medicine, Aurora, Colorado, USA
8. ⁸Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan, USA
9. ⁹Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, Missouri, USA
10. ¹⁰Department of Health and Human Services, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
11. ¹¹New England Research Institutes, Watertown, Massachusetts, USA
12. ¹²Division of Gastroenterology, University of California—Irvine, Irvine, California, USA
13. ¹³Gastroenterology Service, VA Long Beach Healthcare System, Long Beach, California, USA
14. ¹⁴Department of Health and Human Services, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA

Correspondence: Chihiro Morishima, MD, Research Associate Professor, Department of Laboratory Medicine, University of Washington, Box 358050, 850 Republican Street, Seattle, Washington 98109, USA. E-mail: chihiro@u.washington.edu

¹⁵The HALT-C Trial was registered with clinicaltrials.gov (#NCT00006164).

Received 14 December 2011; Accepted 17 April 2012
Advance online publication 12 June 2012

Abstract

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.

Source

Effect of Maintenance Therapy With Low-dose Peginterferon for Recurrent Hepatitis C After Living Donor Liver Transplantation

From Journal of Viral Hepatitis

Y. Ueda; H. Marusawa; T. Kaido; Y. Ogura; F. Oike; A. Mori; K. Ogawa; A. Yoshizawa; E. Hatano; A. Miyagawa-Hayashino; H. Haga; H. Egawa; Y. Takada; S. Uemoto; T. Chiba

Authors and Disclosures

Posted: 02/07/2012; J Viral Hepat. 2012;19(1):32-38. © 2012 Blackwell Publishing

Abstract and Introduction

Abstract

Approximately 30% of patients who have recurrent hepatitis C after liver transplantation achieve sustained virological response (SVR) by taking a combination therapy of pegylated interferon and ribavirin. For the remaining non-SVR patients, an effective management treatment has not yet been established. In this study, efficacy of long-term peginterferon maintenance therapy for non-SVR patients was evaluated. Forty patients who had previously received the combination therapy for hepatitis C after living donor liver transplantation were classified into one of the following three groups: the SVR group (n = 11); the non-SVR-IFN group (n = 17), which received low-dose peginterferon maintenance therapy for non-SVR patients; and the non-SVR-Withdrawal group (n = 12), which discontinued the interferon treatment. We then compared histological changes among these three groups after 2 or more years follow-up. Activity grade of liver histology improved or remained stable in patients in the SVR and non-SVR-IFN groups, but deteriorated in half of the patients in the non-SVR-Withdrawal group. Fibrosis improved or remained stable in 10 of 11 SVR patients and in 13 of 17 non-SVR-IFN patients, but deteriorated in all non-SVR-Withdrawal patients. Mean changes in fibrosis stage between pretreatment and final liver biopsy were −0.18, +0.06 and +2.2 in the SVR, non-SVR-IFN and non-SVR-Withdrawal groups, respectively. Fibrosis stage deteriorated to F3 or F4 significantly more rapidly in the non-SVR-Withdrawal group than in the other two groups. In conclusion, continuing long-term maintenance therapy with peginterferon prevented histological progression of hepatitis C in patients who had undergone living donor liver transplantation.

Introduction

Cirrhosis and hepatocellular carcinoma caused by hepatitis C virus (HCV) infection is the leading indication for liver transplantation in Japan, the United States and western Europe. However, liver allograft infection with HCV following liver transplantation is universal, and almost all patients develop recurrent liver injury.^[1–6] The progression of recurrent hepatitis C is often accelerated and, without appropriate antiviral therapy, 10–25% of patients develop cirrhosis within 5 years after transplantation, resulting in poorer prognosis for HCV-positive recipients than HCV-negative recipients.^[7]

To prevent the progression of hepatitis C after liver transplantation, a combined therapy of pegylated interferon plus ribavirin is commonly administered.^[8,9] However, the efficacy of this combination therapy is limited: The mean sustained virological response (SVR) rate among patients with recurrent hepatitis C after liver transplantation was only 30% (range, 8–50%).^[10] Effective management of the remaining 70% of the patients who are unable to achieve SVR has not been established.^[11]

We recently reported the change in liver histology after combination therapy with interferon plus ribavirin in patients who have recurrent hepatitis C after living donor liver transplantations (LDLT). Among patients who did not achieve SVR, activity grade was not improved and fibrosis stage deteriorated. On the other hand, SVR was associated with reduced hepatic inflammation and suppression of liver fibrosis progression.^[12] Because the histological progression of non-SVR patients occurred mainly after interferon therapy was discontinued, we hypothesized that long-term, continuous interferon administration might be effective in slowing the progression of liver damage in these patients. Therefore, after our previous study, we prescribed a low-dose peginterferon maintenance therapy for non-SVR patients. Here, we evaluated the efficacy of this treatment by investigating long-term histological changes in these patients, as well as comparing them to the changes observed in SVR patients and non-SVR patients who did not receive maintenance treatment.

Methods

Eighty patients who had previously received the combination therapy with interferon and ribavirin (n = 40) or peginterferon and ribavirin (n = 40) for recurrent hepatitis C after LDLT at Kyoto University between January 2001 and April 2007 were retrospectively analysed.

Patients

Between March 1999 and December 2006, 141 patients with HCV-related liver diseases underwent LDLT at Kyoto University. Of these, 100 patients had been followed up for more than 6 months after LDLT in our hospital. Antiviral therapy was given to 80 patients with recurrent hepatitis C between January 2001 and April 2007. The remaining 20 patients did not receive the antiviral therapy because of no histological recurrence of hepatitis C in the follow-up period. To evaluate the histological progression caused by hepatitis C, patients who were diagnosed as having other causes of liver injury, such as biliary complications, chronic rejection, and de novo autoimmune hepatitis (AIH), were excluded. Patients who discontinued the treatment within 3 months because of worsening of liver function caused by hepatitis C were also excluded, because the rapid progression of these patients is not comparable to the long-term progression and inclusion of these patients would have led to overestimation of the progression in the patients who discontinued treatment. Patients were also excluded if they did not have a liver biopsy more than 2 years after the initiation of treatment, because this prevented an analysis of long-term histological changes.

Treatment Protocol and Definition of Responses to Treatment

After liver transplantation, patients with recurrent HCV liver disease underwent treatment with interferon–α–2b (3 or 6 mega units thrice weekly) plus ribavirin (400–800 mg/day orally) for the first 6 months. This was followed by interferon monotherapy for 6 months.^[12] This treatment protocol was employed between January 2001 through April 2004 inclusive. From May 2004 to April 2007, patients underwent combination antiviral therapy comprising peginterferon–α–2b (1.5 μg/kg body weight, weekly) and ribavirin (400–800 mg/day orally).^[13] Patients who became negative for serum HCV RNA within 12 months after initiating the treatment continued to receive the full (initial) dose for 8–22 months to achieve SVR; then, the treatment ended. Patients who were negative for serum HCV RNA for more than 6 months after completion of interferon therapy were defined as achieving SVR.

Patients who did not become negative for serum HCV RNA within 12 months of initiating the combination therapy, as well as patients who experienced a relapse after transient discontinuation of the treatment, continued to receive a low-dose peginterferon maintenance therapy (0.5–0.75 μg/kg of peginterferon-α-2b with or without ribavirin at 200 mg/day). Treatments occurred during the study period, May 2005–December 2009. During this time, the therapy was discontinued in patients with severe adverse events. Additionally, peginterferon treatments were discontinued when neutrophil and platelet counts fell below 500 and 30 000/μL, respectively, and ribavirin was discontinued when haemoglobin levels fell below 8 g/dL.

Histological Assessment

Liver biopsies were performed when patients' alanine aminotransferase (ALT) levels were more than twice the upper limit of normal, or at yearly intervals, with informed consent. Biopsy specimens were evaluated by two pathologists (H.H. and A.M.) with extensive experience in the pathology of liver transplantation. Necroinflammatory activity (A0–A3) and fibrosis stage (F0–F4) were assessed using METAVIR scores.^[14,15] Grading was defined as A0 (no activity), A1 (mild activity), A2 (moderate activity) or A3 (severe activity); staging was defined as F0 (no fibrosis), F1 (mild fibrosis), F2 (moderate fibrosis), F3 (severe fibrosis) or F4 (cirrhosis).^[14,15]

The following equations were used to analyse the histological changes:

1. Changes in activity grade = grade at final biopsy − grade at pretreatment biopsy, and
2. Changes in fibrosis stage = stage at final biopsy − stage at pretreatment biopsy.

Immunosuppression

Tacrolimus and low-dose steroid therapies were administered to induce immunosuppression.^[12,13,16] The lower limit of the target for whole blood tacrolimus level was 10–15 ng/mL during the first 2 weeks, 10 ng/mL during weeks 2–8 and 5–8 ng/mL thereafter. Four patients received cyclosporine microemulsions, rather than tacrolimus, to induce immunosuppression (Table 1). Steroid therapy was initiated at a dose of 10 mg/kg before graft reperfusion and then tapered from 1 mg/kg per day on the first day to 0.3 mg/kg per day until the end of the first month, followed by 0.1 mg/kg per day until the end of the third month. After that, steroid administration was terminated. Mycophenolate mofetil (MMF) was administered to patients who experienced refractory rejection or required reduction in tacrolimus or cyclosporine doses because of adverse events.

Virological Assays

Hepatitis C virus genotype was determined using a genotyping system based on polymerase chain reaction (PCR) of the core region using genotype-specific PCR primers.^[17] Serum HCV RNA load was evaluated once a month during treatment and 24 weeks after treatment, using PCR and an Amplicor HCV assay (Cobas Amplicor HCV Monitor; Roche Molecular Systems, Pleasanton, CA, USA).

Statistical Analysis

Wilcoxon and Kruskal–Wallis tests, chi-square tests and t-tests were used to analyse the continuous variables, categorical variables and histological changes, respectively. The Kaplan–Meier method was used to estimate the rates of patients who showed a progression of fibrosis to stage F3 or F4 after the initiation of the interferon therapy; log-rank tests were used to compare these rates among groups. Significance was defined as P < 0.05.

Results

Characteristics of Patients

Hepatitis C virus RNA concentrations and histological evidence were used to diagnose 80 patients with recurrent hepatitis C after LDLT. These patients were given one of two combination therapies: interferon and ribavirin (n = 40) or peginterferon and ribavirin (n = 40) at Kyoto University between January 2001 and April 2007. Thirty-one of the 80 patients who received the combination therapy achieved SVR (Fig. 1). Among the remaining 49 non-SVR patients, 23 (47%) received the low-dose peginterferon maintenance therapy, while 26 (53%) discontinued treatment within 12 months and did not receive low-dose peginterferon maintenance therapy as this was the patients' wish (n = 4), because of general fatigue (n = 4), recurrent hepatocellular carcinoma (n = 4), worsening of liver function (n = 3), biliary complications (n = 3), heart failure (n = 2), brain haemorrhage (n = 1), dementia (n = 1), sinusitis (n = 1), anaemia (n = 1), neutropenia (n = 1), and haemosputum (n = 1).

Figure 1. Flow diagram showing the outcome of interferon therapy for patients with recurrent hepatitis C after living donor liver transplantation and indicating the classification of patients in this study.

Of the 31 SVR patients, five were excluded because of chronic rejection (n = 3), biliary complications (n = 1) and de novo AIH (n = 1). Fifteen patients did not have liver biopsies more than 2 years after the initiation of the interferon therapy, mainly because liver function tests were normal. The remaining 11 patients were classified as the SVR group for analysis in this study. Among the 23 patients who received maintenance therapy, one patient with biliary complications and five patients who did not have liver biopsy more than 2 years after the initiation of therapy were excluded from the study. The remaining 17 patients were classified into the non-SVR-IFN group. Among the 26 patients who discontinued treatment within 12 months, three patients who initially experienced worsening of liver function were excluded because of the rapid progression of HCV; an additional three patients were excluded because of biliary complications. Eight patients were excluded because they had no liver biopsies taken more than 2 years after the initiation of the treatment. The remaining 12 patients were classified into the non-SVR-Withdrawal group. Cumulatively, we analysed the long-term histological changes of 40 patients: 11 in the SVR group (27.5% of the total), 17 in the non-SVR-IFN group (42.5% of the total) and 12 in the non-SVR-Withdrawal group (30% of the total).

There were no significant differences in the baseline characteristics among patients in the SVR, non-SVR-IFN, and non-SVR-Withdrawal groups (Table 1). The median age of patients at the beginning of therapy was 56.5 years (range, 15–70 years). The treatment started at a median of 9.5 months (range, 1.1–85.3 months) after LDLT. Thirty-five patients (88%) were infected with HCV genotype 1b. HCV genotypes of the remaining patients were 2a (n = 3), 2b (n = 1) and undetermined (n = 1). Median serum HCV RNA load was 2290 kIU/mL (range, 73.7–5000 kIU/mL); i.e. most patients had an extremely high viral load. Before the treatment, the necroinflammatory activity of all patients was A1 or greater, and 33 patients (83%) had a fibrosis score of F1 or greater. Among patients receiving tacrolimus for immunosuppression, the median serum trough level was 5.95 ng/mL (range, 3.3–10.9).

Effect of Maintenance Interferon Therapy on Liver Histology

To evaluate the efficacy of long-term peginterferon therapy on histological changes, we compared scores between final biopsy samples (median, 44.0 months; range, 24.0–81.3 months) and those taken prior to treatment. Five patients in the non-SVR-IFN group discontinued maintenance therapy between 26.5 and 53.1 months after the initiation of the treatment because of the adverse events. For these patients, the biopsies taken just before or within 3 months after discontinuation of the treatment were analysed as final biopsies. Despite the variation in time between pretreatment and final biopsy sample collection, there were no significant differences in the duration among the three groups (P = 0.547). Median duration from initiation of interferon therapy to final liver biopsy was 41.9 months (range, 24.0–81.3 months) in the SVR group, 41.7 months (range, 26.5–68.4 months) in the non-SVR-IFN group and 46.5 months (range, 30.4–79.6 months) in the non-SVR-Withdrawal group.

There were no significant differences in baseline activity grades or fibrosis stages of patients in the three treatment groups when they were first diagnosed with recurrent hepatitis C (Table 1). However, there were noticeable differences among the three groups by the end of treatment (Fig. 2a). The activity grade of all patients in the SVR and non-SVR-IFN groups improved or remained stable, whereas it deteriorated in 6 (50%) of 12 patients in the non-SVR-Withdrawal group. The fibrosis stage deteriorated in all patients in the non-SVR-Withdrawal group; nine of these patients (75%) deteriorated by more than one stage. In contrast, only four patients (24%) in the non-SVR-IFN group deteriorated, all by only a single stage. Furthermore, three patients actually improved. In the SVR group, fibrosis stage decreased or remained stable in 10 of 11 patients (91%).

Figure 2. Effect of maintenance interferon therapy on liver histology: (a) Changes in activity grade (upper) and fibrosis score (lower) of individual patients before interferon therapy (Pre) and at final biopsy (final). (b) Mean changes of liver activity grade (left) and fibrosis stage (right) between pretreatment liver biopsy and the final liver biopsy in each of the three treatment groups. The error bars represent 2 SEs. (c) Kaplan–Meier estimates of the progression rates among patients whose fibrosis advanced to F3 or F4. The dashed line indicates the sustained virological response (SVR) group, the solid line indicates the non-SVR-IFN group and the dotted line indicates the non-SVR-Withdrawal group

In patients in the SVR and non-SVR-IFN groups, the mean activity grade was markedly reduced in the final biopsy, compared to the pretreatment biopsy (Fig. 2b). In contrast, patients in the non-SVR-Withdrawal group experienced an increase in activity grade. The differences between the non-SVR-Withdrawal group and both the SVR and the non-SVR-IFN groups were statistically significant (P <0.001). The mean changes in fibrosis stage in the SVR and non-SVR-IFN groups were −0.18 and +0.06, respectively, suggesting that fibrosis did not change during the follow-up period. However, there was an obvious increase (+2.2) among patients in the non-SVR-Withdrawal group, indicating marked progression of fibrosis.

The Kaplan–Meier analysis allowed us to investigate whether patients in the three treatment groups experienced different progression rates to late-stage fibrosis (Fig. 2c). No patient in the SVR group and only 1 patient (6%) in the non-SVR-IFN group developed fibrosis stage F3 or F4, whereas nine patients (75%) in the non-SVR-Withdrawal group progressed to these stages. The rates of fibrosis progression were significantly higher in the non-SVR-Withdrawal group than in the non-SVR-IFN and SVR groups (P = 0.0049 and P = 0.0086, respectively). There was no significant difference between the SVR group and the non-SVR-IFN group (P = 0.3980). Five-year progression rates to F3 or F4 were 0% in the SVR group, 14% in the non-SVR-IFN group and 54% in the non-SVR-Withdrawal group.

Safety and Tolerability of Maintenance Interferon Therapy

Five of 17 patients (29%) who received low-dose maintenance peginterferon treatment discontinued interferon therapy because of biliary complications (n = 2), neutropenia (n = 1), anaemia (n = 1) and de novo AIH (n = 1), between 26.5 and 53.1 months after its initiation. The biliary complications were not related to interferon therapy. Patients with neutropenia and anaemia recovered after discontinuing interferon therapy and were able to resume therapy within months (3 and 10, respectively). Steroid therapy alleviated the de novo AIH, but the patients did not resume interferon therapy.

Discussion

Studies have repeatedly shown the benefits of achieving SVR via interferon therapy after liver transplantation. For instance, the durability of the SVR is associated with improvements in hepatic inflammation and histological regression of fibrosis over the long-term.^[18–23] In contrast, efficacy of interferon therapy for non-SVR patients after liver transplantation had not previously been investigated. Here, we have demonstrated that long-term peginterferon maintenance therapy suppresses histological progression of recurrent hepatitis C after LDLT.

Maintenance interferon therapy was recently shown to have no influence on either histological or clinical outcomes in patients with nontransplant hepatitis C.^[24] This conclusion was drawn after observing that the rate of fibrosis progression was similar between treatment and control groups following a 3.5-year randomized controlled trial of low-dose peginterferon. As a large number of patients with advanced fibrosis were enrolled in the randomized controlled trial, it is difficult to compare with our study in which the number of patients studied is much smaller and patients with advanced fibrosis were not enrolled. In the current study after liver transplantation, however, we demonstrated that low-dose maintenance interferon therapy reduced necroinflammatory activity and fibrosis scores in non-SVR patients to levels similar to those in SVR patients. Furthermore, we found that non-SVR patients who discontinued treatment had significantly worse scores once no longer receiving therapy.

Although these results clearly suggest that low-dose peginterferon maintenance therapy is beneficial for non-SVR patients with recurrent hepatitis C after liver transplantation, the mechanism behind this positive response is unknown. Progression of hepatitis C and development of fibrosis after discontinuation of interferon treatment has been shown to proceed more rapidly in patients who have undergone liver transplantation.^[20,21] Our results, indicating that activity grade and fibrosis stage markedly deteriorated in non-SVR patients who discontinued maintenance treatment, support these previous findings. Thus, such a rapid progression of recurrent hepatitis C in patients who discontinued interferon therapy may have highlighted the beneficial effect of the low-dose peginterferon maintenance therapy.

Another issue is the tolerability and safety of long-term peginterferon maintenance treatment. In this study, five patients (29%) discontinued the treatment during the peginterferon maintenance treatment, but only three did so for reasons directly related to the treatment. While two of these patients recovered simply by discontinuing the treatment, the third did require steroid pulse therapy to treat de novo AIH. Overall, however, the maintenance therapy did not result in the incidence of major adverse events, suggesting that it is both a tolerable and a safe treatment method.

Our work shows that long-term, low-dose peginterferon administration is an effective method for inhibiting the progression of liver damage for recurrent hepatitis C after liver transplantation. Unfortunately, this was not a randomized control study, and only a small number of patients were eligible for research. Therefore, we recommend further work to more fully explore the effects of this treatment and to improve the outcomes for patients who do not achieve SVR.

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16. Ueda Y, Takada Y, Marusawa H et al. Clinical features of biochemical cholestasis in patients with recurrent hepatitis C after living-donor liver transplantation. J Viral Hepat 2010; 17(7): 481–487.
17. Ohno O, Mizokami M, Wu RR et al. New hepatitis C virus (HCV) genotyping system that allows for identification of HCV genotypes 1a, 1b, 2a, 2b, 3a, 3b, 4, 5a, and 6a. J Clin Microbiol 1997; 35(1): 201–207.
18. Abdelmalek MF, Firpi RJ, Soldevila-Pico C et al. Sustained viral response to interferon and ribavirin in liver transplant recipients with recurrent hepatitis C. Liver Transpl 2004; 10(2): 199–207.
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Source

Maintenance Therapy With Peginterferon Alfa-2b Does Not Prevent Hepatocellular Carcinoma in Cirrhotic Patients With Chronic Hepatitis C

Gastroenterology
Volume 140, Issue 7 , Pages 1990-1999, June 2011.

Jordi Bruix, Thierry Poynard, Massimo Colombo, Eugene Schiff, Kelly Burak, Elizabeth J.L. Heathcote, Thomas Berg, Jorge–Luis Poo, Carlos Brandao Mello, Rainer Guenther, Claus Niederau, Ruben Terg, Pierre Bedossa, Navdeep Boparai, Louis H. Griffel, Margaret Burroughs, Clifford A. Brass, Janice K. Albrecht, EPIC3 Study Group

Received 1 October 2010; accepted 4 March 2011. published online 18 March 2011.

Abstract

Background & Aims

Several studies have reported that low doses of interferon can delay the development of hepatocellular carcinoma (HCC) and progression of chronic hepatitis C. We investigated the incidence of clinical events among participants of the Evaluation of PegIntron in Control of Hepatitis C Cirrhosis (EPIC)3 program.

Methods
Data were analyzed from an open-label randomized study of patients with chronic hepatitis C who had failed to respond to interferon alfa plus ribavirin. All patients had compensated cirrhosis with no evidence of HCC. Patients received peginterferon alfa-2b (0.5 μg/kg/week; n = 311) or no treatment (controls, n = 315) for a maximum period of 5 years or until 98 patients had a clinical event (hepatic decompensation, HCC, death, or liver transplantation). The primary measure of efficacy was time until the first clinical event.

Results
There was no significant difference in time to first clinical event among patients who received peginterferon alfa-2b compared with controls (hazard ratio [HR], 1.452; 95% confidence interval [CI]: 0.880–2.396). There was no decrease in the development of HCC with therapy. The time to disease progression (clinical events or new or enlarged varices) was significantly longer for patients who received peginterferon alfa-2b compared with controls (HR, 1.564; 95% CI: 1.130–2.166). In a prospectively defined subanalysis of patients with baseline portal hypertension, peginterferon alfa-2b significantly increased the time to first clinical event compared with controls (P = .016). There were no new safety observations.

Conclusions
Maintenance therapy with peginterferon alfa-2b is not warranted in all patients and does not prevent HCC. However, there is a potential clinical benefit of long-term suppressive therapy in patients with preexisting portal hypertension.

Keywords: Liver Cancer, Evaluation of PegIntron in Control of Hepatitis C Cirrhosis Program, EPIC3 Program, Clinical Trial

Source

Retreatment of patients with chronic hepatitis C relapsers to a previous antiviral treatment

Eur J Gastroenterol Hepatol. 2011 Jun 4. [Epub ahead of print]

 

Floreani A, Cazzagon N, Furlan P, Baldovin T, Egoue J, Antoniazzi S, Baldo V, Minola E.

 

aDepartment of Surgical and Gastroenterological Sciences, University of Padova bDepartment of Hygiene and Public Health, University of Padova, Padova cDepartment of Infectious Disease, Bergamo Hospital, Bergamo, Italy.

Abstract

BACKGROUND:

The efficacy of retreatment with pegylated interferon (PEG-IFN) plus ribavirin for patients relapsing after a previous treatment remains to be fully elucidated, although extended treatment seems to be the best option in such cases.

AIM:
To evaluate the efficacy of two extended protocols in patients with genotypes 1 or 4, or those with genotypes 2 or 3.

METHODS:
A total of 181 patients who had relapsed after a previous antiviral treatment with PEG-IFNα2a plus weight-based ribavirin were offered retreatment with the same dose of both PEG-IFN plus ribavirin, to be continued for 48 weeks in those with genotypes 2 or 3 (group 1), and for 72 weeks in those with genotypes 1 or 4 (group 2).

RESULTS:
A total of 59 patients (32.5%) refused the retreatment, while 122 (78 men, 44 women) patients were enrolled in the study: 41 were allocated in group 1 and 81 in group 2. Cirrhosis at baseline (staging 5/6 according to Ishak's score was recorded in 11 patients, six in group 1 and five in group 2). Nine patients (7.3%) in group 2 discontinued the treatment (due to lack of response). The remaining patients completed the treatment and were followed-up for at least 12 months after the treatment. Sustained virological response (SVR) rate was 82.9% in group 1 and 50.6% in group 2.

CONCLUSION:
Patients with chronic hepatitis C with 'easy genotypes' relapsers to a previous antiviral treatment have more than 80% probability of achieving a SVR with a 48-week retreatment. Patients with 'difficult genotypes' have more than 50% chance of a SVR after a 72-week extended treatment.

Source

Maintenance Therapy With Peginterferon Alfa-2b Does Not Prevent Hepatocellular Carcinoma in Cirrhotic Patients With Chronic Hepatitis C

Gastroenterology. 2011 Mar 16. [Epub ahead of print]

Bruix J, Poynard T, Colombo M, Schiff E, Burak K, Heathcote EJ, Berg T, Poo JL, Mello CB, Guenther R, Niederau C, Terg R, Bedossa P, Boparai N, Griffel LH, Burroughs M, Brass CA, Albrecht JK; EPIC(3) Study Group.

BCLC Group; Liver Unit, Hospital Clinic of Barcelona, University of Barcelona; IDIBAPS, Centro de Investigación Biomédica en Red de Hepatología y Enfermedades Digestivas, Barcelona, Spain.

Abstract

BACKGROUND & AIMS: Several studies have reported that low doses of interferon can delay the development of hepatocellular carcinoma (HCC) and progression of chronic hepatitis C. We investigated the incidence of clinical events among participants of the Evaluation of PegIntron in Control of Hepatitis C Cirrhosis (EPIC(3)) program.

METHODS: Data was analyzed from an open-label randomized study of patients with chronic hepatitis C who had failed to respond to interferon alfa plus ribavirin. All patients had compensated cirrhosis with no evidence of HCC. Patients received peginterferon alfa-2b (0.5 μg/kg/week; n = 311) or no treatment (controls, n = 315) for a maximum period of 5 years, or until 98 patients had a clinical event (hepatic decompensation, HCC, death, or liver transplantation). The primary measure of efficacy was time until the first clinical event.

RESULTS: There was no significant difference in time to first clinical event among patients who received peginterferon alfa-2b, compared with controls (hazard ratio [HR], 1.452; 95% confidence interval [CI], 0.880-2.396). There was no decrease in the development of HCC with therapy. The time to disease progression (clinical events or new or enlarged varices) was significantly longer for patients who received peginterferon alfa-2b, compared with controls (HR, 1.564; 95% CI, 1.130-2.166). In a prospectively defined subanalysis of patients with baseline portal hypertension, peginterferon alfa-2b significantly increased the time to first clinical event, compared with controls ( P =.016). There were no new safety observations.

CONCLUSIONS: Maintenance therapy with peginterferon alfa-2b is not warranted in all patients and does not prevent HCC. However, there is a potential clinical benefit of long-term suppressive therapy in patients with preexisting portal hypertension.

Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

PMID: 21419770 [PubMed - as supplied by publisher]

Source

Maintenance Peginterferon Therapy and Other Factors Associated with Hepatocellular Carcinoma in Patients with Advanced Hepatitis C

Download the PDF here

Article in Press

Gastroenterology Dec 2010

Anna S. Lok, 1 James E. Everhart, 2 Elizabeth C. Wright, 3 Adrian M. Di Bisceglie, 4 Hae-Young Kim, 5 Richard K. Sterling, 6 Gregory T. Everson, 7 Karen L. Lindsay, 8 William M. Lee, 9 Herbert L. Bonkovsky, 10,11 Jules L. Dienstag, 12,13 Marc G. Ghany, 14 Chihiro Morishima, 15 Timothy R. Morgan, 16,17 and the HALT-C Trial Group

FROM JULES of NATAP: this was presented at AASLD where I went to the mic after Dr Lok presented the data and reminded the large audience I previously questioned and doubted the original findings that peg maintenence therapy was not useful when they were first presented several years ago. My questioning of their original findings were not well received but now upon further followup it appears maintenance therapy can provide benefit for patients with cirrhosis. The utility of maintenance therapy may still have application for patients who are nonresponders to the new HCV oral protease inhibitors expected to be approved in 2011, to prevent further disease progression until better, more effective multi-drug oral therapy combinations become available.

"extended follow-up of the HALT-C Trial cohort showed a modest benefit of long-term peginterferon therapy in reducing the incidence of HCC in patients with hepatitis C and cirrhosis but not in those with advanced precirrhotic fibrosis, an effect that took several years after completion of therapy to become apparent. Although the results were corroborated in multiple sub-analyses, the clinical implications are not clear. Given the marginal beneficial effect and its restriction to only part of the HALT-C Trial cohort, that no overall long-term benefit on mortality was observed in this cohort,29 and given the side effects of peginterferon, necessitating dose reduction or discontinuation in a substantial number of patients, the utility of maintenance peginterferon therapy to prevent HCC in patients with HCV-related cirrhosis is doubtful.....When patients with cirrhosis at baseline were analyzed separately, however, significantly fewer of those randomized to receive peginterferon had a diagnosis of HCC than those randomized to no treatment, 6.8% (14/207) vs.15.5% (34/220), respectively (HR for HCC in patients randomized to receive peginterferon 0.45 [95% CI 0.24-0.83], P = 0.01). Interferon has been shown to have antitumor effects in some malignancies and may have other beneficial effects including antiproliferative and antiangiogenic effects.19, 20 Chronic inflammation has been postulated to play a role in hepatitis B virus- (HBV) and HCV-related HCC. The observation that reduction in HCC incidence in the HALT-C Trial cohort was greater among the treated patients experiencing a reduction in HAI suggests that interferon may have acted through this pathway"

"The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial.......Analysis of the HALT-C Trial results after 3.5 years of treatment revealed that peginterferon did not reduce the overall risk of liver disease progression.4 A subsequent report focusing on HCC development also showed no difference between the treated and control groups during and immediately after the period of maintenance peginterferon therapy.5 We continued to follow the HALT-C Trial cohort off therapy for a total of up to 8.7 years to monitor for the development of decompensated liver disease and HCC. During the extended follow-up period, the number of patients with HCC increased progressively......

.......Although treated patients were less likely to have HCC than controls, 7.2% (37/515) vs. 9.6% (51/533), this difference was not statistically significant (hazard ratio [HR] for HCC in patients randomized to peginterferon treatment 0.77, 95% confidence interval [CI] 0.51-1.18, P = 0.24) (Figure 1A). ......When patients with cirrhosis at baseline were analyzed separately, however, significantly fewer of those randomized to receive peginterferon had a diagnosis of HCC than those randomized to no treatment, 6.8% (14/207) vs.15.5% (34/220), respectively (HR for HCC in patients randomized to receive peginterferon 0.45 [95% CI 0.24-0.83], P = 0.01). The cumulative incidence of HCC at 3, 5 and 7 years in the peginterferon group was 2.6%, 5.1%, and 7.8%, and, in the untreated control group, 4.0%, 11.1%, and 24.2%, respectively (log-rank test, P = 0.009). The absolute risk difference was 1.5% (95% CI -2.1%-5.0%) at 3 years, 6.1% (95% CI 0.4%-11.7%) at 5 years, and 16.4% (95% CI 2.3%-24.1%) at 7 years; the incidence of HCC in the two treatment groups did not diverge until after year 4 (Figure 1B)."

.......Because of the unexpected difference among patients with cirrhosis between our previous and the current findings, we performed additional analyses to verify the consistency of the results. A beneficial effect of peginterferon was observed even when the analysis was restricted to patients with definite HCC (i.e., after exclusion of 20 patients with presumed HCC as defined by the protocol). In addition, a dose-response effect of peginterferon was apparent, as suggested by three findings. First, among patients randomized to receive peginterferon, multivariate analysis showed that those who stopped treatment before 2 years did not have a reduction in the risk of HCC after adjusting for laboratory markers of advanced liver disease. Second, among patients receiving peginterferon, those experiencing a ≥2-point reduction in HAI had an approximately 3-fold reduction in HCC compared to those who did not have a reduction in HAI on follow-up liver biopsy. Third, in a regression analysis of factors associated with the development of HCC, including treatment assignment, peginterferon therapy was associated with an approximate 50% reduction in the incidence of HCC over a median of 6.1 year observation period among patients with cirrhosis at baseline even when adjusted for other risk factors including age, race, smoking history, and laboratory tests associated with advanced liver disease. Nevertheless, while analysis by the two pre-specified strata of histological severity (bridging fibrosis and cirrhosis) was warranted, why the effect of peginterferon was confined to patients with cirrhosis is unclear, and the possibility that this is a chance finding cannot be excluded."

Abstract

Background & Aims

Interferon reportedly decreases the incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. The Hepatitis C anti-viral long-term treatment against cirrhosis (HALT-C) trial showed that 4 years of maintenance therapy with peginterferon does not reduce liver disease progression. We investigated whether peginterferon decreases the incidence of HCC in the HALT-C cohort over a longer post-treatment follow-up period.

Methods

The study included 1,048 patients with chronic Hepatitis C (Ishak fibrosis scores ≥3) who did not have a sustained virological 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 for a median 6.1 (maximum 8.7) years.

Results

Eighty-eight patients developed HCC (68 definite, 20 presumed): 37/515 that were given peginterferon (7.2%) and 51/533 controls (9.6%; P=0.24). 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]: 0.24Ð0.83); in treated and control patients with fibrosis they were 8.3% and 6.8%, respectively (HR=1.44; 95% CI: 0.77Ð2.69). 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=0.03).

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 for HCC than controls.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer death in the world.1 In the United States, hepatitis C is the greatest contributor to both the occurrence of HCC and its observed increased incidence over the last 20 years. Among persons with chronic hepatitis C, risk factors for the development of HCC are incompletely understood. HCC has been found primarily, but not exclusively, in patients with cirrhosis. In addition to the degree of liver fibrosis, biochemical markers of advanced liver disease (e.g., low platelet count, low albumin), presence of esophageal varices, diabetes, obesity, and use of tobacco and excessive alcohol have been associated with an increased risk for HCC. The risk of HCC is decreased in patients with chronic hepatitis C who achieved a sustained virological response (SVR) to interferon/ribavirin treatment;2, 3 however, the effectiveness of interferon therapy in reducing HCC among patients with hepatitis C virus (HCV)-related cirrhosis who did not achieve an SVR is unclear.

The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial was a randomized, multi-center trial to determine whether 3.5 years of half-dose pegylated interferon (peginterferon) treatment reduced liver disease progression among patients with hepatitis C and advanced fibrosis who were nonresponders to peginterferon and ribavirin. Analysis of the HALT-C Trial results after 3.5 years of treatment revealed that peginterferon did not reduce the overall risk of liver disease progression.4 A subsequent report focusing on HCC development also showed no difference between the treated and control groups during and immediately after the period of maintenance peginterferon therapy.5 We continued to follow the HALT-C Trial cohort off therapy for a total of up to 8.7 years to monitor for the development of decompensated liver disease and HCC. During the extended follow-up period, the number of patients with HCC increased progressively. The aims of the current analysis were: 1) to determine the incidence of HCC among the HALT-C Trial cohort after a longer duration of follow-up, 2) to identify factors associated with the development of HCC in the HALT-C Trial cohort, and 3) to ascertain whether maintenance peginterferon therapy had any delayed, post- treatment effect in preventing HCC.

DISCUSSION

Previously, we reported that maintenance peginterferon in the HALT-C Trial was not effective in preventing clinical or histological outcomes.4 It has been suggested that the limited duration of follow-up in these reports may not have been sufficient to observe a clinical benefit of peginterferon as chemoprevention for HCC;8 in this vein, retrospective studies have suggested that a benefit of interferon in reducing the occurrence of HCC may not be observed for 5 years or more.9 Supporting this notion is a recent meta-analysis demonstrating that patients with hepatitis C who received interferon therapy had a significantly lower incidence of HCC but significant heterogeneity in the results limited confidence in this conclusion, and the duration of follow-up was an independent contributor to the heterogeneity.3 The process of hepatocarcinogenesis is well recognized to take place over many years, and, even after HCC has developed, many months to years may elapse before the tumor can be detected clinically. The HALT-C Trial investigators acknowledged the possibility that the initially planned follow-up period of 4 years from randomization (6 months after completion of randomized treatment) may have been too short to detect a benefit.10 Therefore, the protocol was amended to extend the duration of follow-up.

With continued observation of this large cohort of patients with advanced hepatitis C for up to 8.7 (median 6.1) years, we found that the number of patients with HCC increased to 88 from 53 (including 5 prevalent cases diagnosed in the first year) in an earlier report.5 Continued follow-up of the HALT-C Trial cohort for up to 5 years after the end of therapy did not show a statistically significant benefit of low dose peginterferon in reducing the incidence of HCC in patients with advanced hepatitis C who did not achieve SVR. In sub-group analysis, however, patients with cirrhosis at baseline assigned to treatment had lower risk of HCC.

Because of the unexpected difference among patients with cirrhosis between our previous and the current findings, we performed additional analyses to verify the consistency of the results. A beneficial effect of peginterferon was observed even when the analysis was restricted to patients with definite HCC (i.e., after exclusion of 20 patients with presumed HCC as defined by the protocol). In addition, a dose-response effect of peginterferon was apparent, as suggested by three findings. First, among patients randomized to receive peginterferon, multivariate analysis showed that those who stopped treatment before 2 years did not have a reduction in the risk of HCC after adjusting for laboratory markers of advanced liver disease. Second, among patients receiving peginterferon, those experiencing a ≥2-point reduction in HAI had an approximately 3-fold reduction in HCC compared to those who did not have a reduction in HAI on follow-up liver biopsy. Third, in a regression analysis of factors associated with the development of HCC, including treatment assignment, peginterferon therapy was associated with an approximate 50% reduction in the incidence of HCC over a median of 6.1 year observation period among patients with cirrhosis at baseline even when adjusted for other risk factors including age, race, smoking history, and laboratory tests associated with advanced liver disease. Nevertheless, while analysis by the two pre-specified strata of histological severity (bridging fibrosis and cirrhosis) was warranted, why the effect of peginterferon was confined to patients with cirrhosis is unclear, and the possibility that this is a chance finding cannot be excluded.

A small randomized controlled trial by Nishiguchi et al11 was the first to suggest that interferon may reduce the risk of HCC in patients with HCV-related cirrhosis. This report was followed by many other reports, mostly from Japan and Europe. The majority of these studies were retrospective or cohort studies comparing the incidence of HCC in patients who had received interferon for 6-12 months with historical or concurrent patients who had not received treatment. The median duration of follow-up ranged from 2 to 15 years. Most studies showed a benefit of treatment, although the effect was predominantly seen in patients who achieved SVR. In addition, three independent meta-analyses suggested that interferon therapy decreased the incidence of HCC in patients with chronic hepatitis C3, 12, 13 In the most recent of these meta- analyses, the relative risk (RR) of HCC for treated vs. untreated patients was 0.43 (95% CI 0.33-0.56, P<0.00001) and for patients with SVR vs. without SVR was 0.35 (95% CI 0.26-0.46, P<0.0001); however, only four of the studies included were randomized controlled trials.

Few studies have compared the incidence of HCC in interferon nonresponders and untreated patients. In two large retrospective studies, the incidence of HCC in these two groups was similar. HCC developed in 14% (20/148) of nonresponders and 12% (19/144) of untreated patients in the study by Imai et al14 and in 11% (39/342) of nonresponders and 10% (54/562) of untreated patients in the study by Yu et al.15 As was true for the 3.5-year randomized phase of the HALT-C Trial, two other studies of long-term, low-dose peginterferon (COPILOT and EPIC3) in patients with advanced fibrosis or cirrhosis showed no benefit of treatment on overall clinical outcomes or HCC.16, 17 To date, however, only preliminary data on outcomes up to 4 years have been reported in these two studies.

The mechanisms by which peginterferon might prevent HCC are not clear. Certainly, achieving an SVR is associated with a reduction in HCC. Indeed, patients in HALT-C trial who achieved SVR after 48 weeks of combination therapy had lower risk of HCC compared to lead-in phase nonresponders, HR 0.19, 95% CI 0.04-0.80.18 Patients who had >2 log decline in HCV RNA after 1.5 years of low-dose peginterferon also had a lower incidence of HCC compared to those with <2 log decline but the difference was not significant and only 15.4% of the patients receiving low-dose peginterferon had >2 log decrease in HCV RNA after 18 months of treatment. Interferon has been shown to have antitumor effects in some malignancies and may have other beneficial effects including antiproliferative and antiangiogenic effects.19, 20 Chronic inflammation has been postulated to play a role in hepatitis B virus- (HBV) and HCV-related HCC. The observation that reduction in HCC incidence in the HALT-C Trial cohort was greater among the treated patients experiencing a reduction in HAI suggests that interferon may have acted through this pathway; however, absence of benefit among control patients with a reduction in hepatic inflammation indicates that interferon may exert its effects through other mechanisms and that a reduction in HAI on follow-up biopsies in interferon-treated patients may be a surrogate of other interferon effects.

The reasons for the apparent delay in the chemopreventive effect of peginterferon are also not known, but we speculate that the delay is related to the slow growth rate of HCC, estimated to have a median doubling time of 117 days.21 In fact, the Gompertzian model would predict that an HCC may have been present for several years before reaching a detectable size.22 Therefore, the HCCs diagnosed in the first 3 to 5 years may well have been present at enrollment into the HALT-C Trial. If, indeed, peginterferon prevented HCC, several years would have been required to detect this effect. In this study, the divergence in HCC incidence between the treated and control patients with cirrhosis at baseline was not apparent until after year 4. Unfortunately, with the termination of this study, we could not determine whether the protective effect disappears or increases with longer follow-up.

Several other interesting observations emerged during this study. Severity of liver disease and portal hypertension, as reflected by more abnormal biochemical tests, lower platelet counts, and presence of esophageal varices were associated with an increased risk of HCC. On the other hand, several studies have shown that patients with increased BMI have a higher rate of HCC;23, 24 while patients in the HALT-C Trial with higher BMI had a significantly lower incidence of HCC. An association between obesity and HCC in other studies may be related to the inclusion of patients with cirrhosis secondary to non-alcoholic fatty liver disease or the inclusion of patients with earlier stage liver disease in whom obesity and steatosis may have accelerated fibrosis progression thereby increasing the risk of HCC. The HALT-C Trial excluded patients with severe steatohepatitis and all patients had advanced fibrosis or cirrhosis. Alcohol and smoking have been reported to be associated with HCC. In the HALT-C Trial, although the average life-time alcohol consumption prior to entry into the HALT-C Trial was high, neither duration of regular alcohol consumption nor life-time alcohol consumption was associated with an increased risk of HCC. Smoking is a risk factor for many cancers, but its association with HCC is not as well described. Several prior reports suggested an association between smoking and histological severity of liver disease,25 and a few reports have appeared of an association between smoking and HCC.24, 26 In this study, smoking was a significant risk factor for HCC, even after adjustment for other risk factors. These data highlight the importance of counseling patients with liver disease on smoking cessation. Esophageal varices and more recently increase in hepatic venous pressure gradient had been shown to be predictors of HCC.27, 28 We found that both presence of varices at baseline and incident varices were associated with increased risk of HCC underscoring the need to evaluate for portal hypertension in patients with advanced liver disease.

In an earlier analysis of the incidence of HCC in the HALT-C Trial cohort, we found that 17% of patients with HCC had no evidence of cirrhosis on serial histology.5 In the current analysis, 8% of HCC developed in patients who had no evidence of cirrhosis. The lower rate of HCC in noncirrhotic patients in the current analysis is related to the subsequent finding of cirrhosis on explant livers in some of the earlier patients and a higher probability that patients diagnosed with HCC during the last two years of the HALT-C study had progressed from bridging fibrosis to cirrhosis. These data confirmed that HCC can occur in non-cirrhotic patients but the rate is low and the cost-effectiveness of HCC surveillance in these patients is unclear.

In conclusion, extended follow-up of the HALT-C Trial cohort showed a modest benefit of long-term peginterferon therapy in reducing the incidence of HCC in patients with hepatitis C and cirrhosis but not in those with advanced precirrhotic fibrosis, an effect that took several years after completion of therapy to become apparent. Although the results were corroborated in multiple sub-analyses, the clinical implications are not clear. Given the marginal beneficial effect and its restriction to only part of the HALT-C Trial cohort, that no overall long-term benefit on mortality was observed in this cohort,29 and given the side effects of peginterferon, necessitating dose reduction or discontinuation in a substantial number of patients, the utility of maintenance peginterferon therapy to prevent HCC in patients with HCV-related cirrhosis is doubtful.

RESULTS

Patient Characteristics

Of the 1,050 patients randomized, 90 met predefined criteria for HCC (presumed or definite), but two were excluded because they only met criteria for presumed HCC at the time of HCC diagnosis, did not receive HCC treatment, and did not meet criteria for definite HCC after more than 2 years of follow-up. Therefore, 1,048 patients were included in this analysis. The median duration of follow-up from randomization was 6.1 (range 0-8.7) years.

Table 1 summarizes the characteristics of the patients at the time of enrollment into the HALT-C Trial. Compared to patients without HCC, those in whom HCC subsequently developed were older, had lower body mass index (BMI), had laboratory values indicating more advanced liver disease, higher AFP, higher HAI, and higher fibrosis score, and were more likely to have esophageal varices and to have been smokers.

Incidence of HCC

Of the 88 patients who met HALT-C Trial criteria for HCC, 68 had definite HCC (66 were histologically confirmed), while 20 had presumed HCC (Table 2). Sixty-six (75%) of these 88 patients had stage 1 or 2 HCC according to the United Network of Organ Sharing classification. Although treated patients were less likely to have HCC than controls, 7.2% (37/515) vs. 9.6% (51/533), this difference was not statistically significant (hazard ratio [HR] for HCC in patients randomized to peginterferon treatment 0.77, 95% confidence interval [CI] 0.51-1.18, P = 0.24) (Figure 1A).

When patients with cirrhosis at baseline were analyzed separately, however, significantly fewer of those randomized to receive peginterferon had a diagnosis of HCC than those randomized to no treatment, 6.8% (14/207) vs.15.5% (34/220), respectively (HR for HCC in patients randomized to receive peginterferon 0.45 [95% CI 0.24-0.83], P = 0.01). The cumulative incidence of HCC at 3, 5 and 7 years in the peginterferon group was 2.6%, 5.1%, and 7.8%, and, in the untreated control group, 4.0%, 11.1%, and 24.2%, respectively (log-rank test, P = 0.009). The absolute risk difference was 1.5% (95% CI -2.1%-5.0%) at 3 years, 6.1% (95% CI 0.4%-11.7%) at 5 years, and 16.4% (95% CI 2.3%-24.1%) at 7 years; the incidence of HCC in the two treatment groups did not diverge until after year 4 (Figure 1B).

Among patients with noncirrhotic fibrosis at baseline, similar numbers of treated and control patients were found to have a diagnosis of HCC, 7.5% (23/308) vs. 5.4% (17/313), respectively (HR for HCC in these patients randomized to receive peginterferon 1.44 (95% CI, 0.77-2.69, P = 0.26). Seven of these 40 patients had no evidence of cirrhosis on any of the follow-up biopsies, surgically resected tumors or liver explants. In noncirrhotics, the cumulative incidence of HCC at 3, 5 and 7 years in the peginterferon group was 2.1%, 6.4%, and 8.3% and in the control group, 1.4%, 2.9%, and 6.8%, respectively; the incidence of HCC in the two treatment groups was similar throughout the duration of the study (Figure 1B). Cox regression with interaction confirmed an interaction between treatment group and fibrosis stratum (P = 0.01).

To determine whether the observed results could have been related to uneven distribution of patients with presumed HCC in the two treatment groups, we repeated the analysis after exclusion of the 20 patients who only met criteria for presumed HCC. The results were similar, HR for HCC in the treated group 0.43 (95% CI 0.21-0.89, P = 0.02) for patients with cirrhosis at baseline and 1.86 (95% CI 0.91-3.78, P = 0.09) for patients with bridging fibrosis at baseline.

Because a beneficial effect of peginterferon was not observed during the first 4 years, we repeated the analysis on 994 patients who were still alive, had not undergone liver transplantation, and did not have HCC up to 1400 days after randomization (roughly 3 months after completion of the randomized treatment phase or 3.75 years from randomization). The cumulative incidence of HCC at 5 and 7 years in the peginterferon vs. control groups was significant, 0.7% vs. 4.0% and 3.6% vs. 18.1%, respectively (log-rank test, P = 0.01) among patients with baseline cirrhosis and insignificant, 2.5% vs. 0.8% and 4.4% vs. 4.8%, respectively (log-rank test, P = 0.69) among patients with baseline bridging fibrosis (Figure 1C). The hazard ratios were 0.33 (95% CI 0.13-0.83, P = 0.02) for patients with baseline cirrhosis and 1.19 (95% CI 0.52-2.69, P = 0.69) for patients with baseline bridging fibrosis. For all patients combined, the HR was 0.64 (95% CI 0.36-1.14; P = 0.13).

Patients might succumb from a liver-related death or undergo liver transplantation and no longer be at risk for HCC; therefore, a competing risk analysis to estimate the effect of liver transplantation or liver-related death on the incidence of HCC was conducted. Similar numbers of patients in the peginterferon and control groups underwent liver transplantation or had liver- related deaths (31 and 35 among patients with cirrhosis at baseline and 14 and 13 among patients with bridging fibrosis at baseline, respectively). The differences in the incidence of HCC between the peginterferon and control groups did not change after adjusting for these competing risks (HR 0.45, 95% CI 0.24-0.83, P = 0.01 for patients with cirrhosis at baseline and HR 1.44, 95% CI 0.77-2.69, P = 0.26 for patients with bridging fibrosis at baseline).

Impact of Duration of Peginterferon Treatment on Incidence of HCC

To further confirm the potential beneficial effect of peginterferon in reducing the incidence of HCC, we assessed the association between adherence to maintenance peginterferon and the incidence of HCC. For this analysis, treated patients were stratified into two groups: patients who were still receiving peginterferon (regardless of dose) ≥2 years after randomization and those who had stopped peginterferon <2 years after randomization but continued to be followed. Patients who received peginterferon for ≥2 years had a significantly lower incidence of HCC compared to those who were treated for <2 years (HR 0.36, 95% CI 0.16-0.82, P = 0.02) (Table 3); however, this difference was observed only in the patients with cirrhosis at baseline (HR 0.10, 95% CI 0.03-0.44, P = 0.002). Because patients who tolerated peginterferon treatment had less advanced liver disease (supplementary table), we performed a multivariate analysis to determine whether the duration of peginterferon treatment was associated, independent of disease severity, with a reduced risk of HCC, which was, in fact, the case (see below).

Viral Suppression and Incidence of HCC

Of the 468 patients randomized to maintenance peginterferon and were evaluated for virologic response at year 1.5, 30/396 (7.6%), 1/36 (2.8%), and 1/36 (2.8%) patients with <2 log, 2-4 log, and ≥4 log decrease in HCV RNA were subsequently diagnosed to have HCC, HR for the patients with ≥2 vs. <2 log decrease in HCV RNA 0.38 (95% CI 0.09-1.59, P = 0.18).

Association of Decrease in HAI with Decreased Incidence of HCC

In an earlier analysis of the HALT-C Trial data, we showed that maintenance peginterferon reduced HAI compared to no treatment.4 To determine whether the effect of peginterferon on prevention of HCC was related to its effect in decreasing hepatic inflammation, we analyzed 426 patients in the peginterferon group and 416 in the control group who had repeat liver biopsies at 1.5 years. Treated patients who had an unchanged or increased HAI had a higher incidence of HCC than those who had a decrease in HAI by ≥2 points on the year-1.5 biopsy: 9.4% vs. 2.9% (HR 2.98 and 95% CI 1.14-7.81, P = 0.03) (Table 4). The incidence of HCC in the control group was similar regardless of changes in HAI on the year-1.5 biopsy and comparable to that in the treatment group that did not have a decrease in HAI.

Multivariate Analyses for Predictors of HCC

We undertook stepwise Cox regression analysis to determine whether maintenance peginterferon had an independent effect in preventing HCC. Selected factors that were significant on univariate analysis: age, BMI, platelet, albumin, AST, alkaline phosphatase, total bilirubin, prothrombin time, esophageal varices, HAI, having ever smoked cigarettes, and other relevant factors including gender, black race, cirrhosis on baseline biopsy and treatment assignment were included in the model. To avoid over-fitting, several related laboratory markers that were significant on univariate analysis (Table 1) were not included in the model. Patients with cirrhosis on baseline biopsy assigned to peginterferon treatment had half the rate of HCC outcomes as those randomized to no treatment (HR 0.50, 95% CI 0.27-0.95) (Table 5). In contrast, the rate of HCC outcomes in patients with fibrosis on baseline biopsy, when analyzed separately, was similar regardless of treatment assignment (p = 0.38). Older age, lower BMI, lower platelet, higher AST, higher alkaline phosphatase, and history of smoking were also associated with increased risk of HCC. When the analysis was limited to patients in the treatment group, ability to remain on low-dose peginterferon for ≥2 years was an independent predictor that HCC would not develop (HR 0.39, 95% CI 0.16-0.92).

Because presence of esophageal varices at randomization was a strong risk factor for HCC in a previous analysis of HALT-C Trial outcomes,5 we examined the effect of their presence and development more closely, based on results from the baseline and year-3.5 upper endoscopies. Of the 781 patients who underwent a second endoscopy, 185 had varices noted at randomization, 148 had varices first noted at the second endoscopy (incident varices), and 448 did not have varices on either examination. Relative to patients without varices on either examination, subsequent HCC was more likely for patients with varices at randomization (HR 2.54, 95% CI 1.32-4.88) and for patients with incident varices (HR 2.68, 95% CI 1.35-5.32).

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