Long-term Maintenance Interferon Does Not Prevent Hepatocellular Carcinoma among Chronic Hepatitis C Patients in HALT-C Study

Current standard therapy for chronic hepatitis C virus (HCV) infection using pegylated interferon plus ribavirin produces a sustained virological response (SVR) in about half of treated patients, and researchers have explored other therapies that might slow, halt, or even reverse liver fibrosis progression and reduce the risk of cirrhosis and hepatocellular carcinoma (HCC) in people who do not clear the virus.

The HALT-C trial was designed to assess whether long-term, low-dose pegylated interferon maintenance monotherapy would improve outcomes in this population. While an interim analysis indicated that low-dose interferon produced improvements in ALT levels, HCV viral load, and necroinflammation, the study's primary analysis found no benefit with regard to reduced liver disease progression after 3.5 years.

HALT-C researchers also conducted several secondary analyses looking at specific aspects of disease progression. In the present study, published in the January 2009 issue of Gastroenterology, Anna Lok from the University of Michigan Medical Center and colleagues analyzed the HCC incidence rate and risk factors among HALT-C participants. (Results from a shorter duration of follow-up were previously presented at the April 2008 annual meeting of the European Association for the Study of the Liver [EASL]).

Briefly, HALT-C included more than 1000 participants with chronic hepatitis C and bridging fibrosis (Ishak stages F3-F4; 59%) or cirrhosis (stages F5-F6; 41%) at baseline. Those who did not achieve sustained response to standard combination therapy with pegylated interferon plus ribavirin were randomly assigned to receive either low-dose (90 mcg per week) pegylated interferon alfa-2a (Pegasys) monotherapy for 3.5 years or else no ongoing treatment. Most study participants (71%) were men, the mean age was 50 years, and 72% were white.

Results

• Over a median 4.6 years of follow-up (maximum 6.7 years), 48 out of 1005 patients (4.8%) developed HCC
• The cumulative 5-year HCC incidence rate was similar in the maintenance therapy and untreated observation arms, at 5.4% and 5.0%, respectively (P = 0.78).
• As expected, HCC was more likely to occur in patients with cirrhosis than in those with bridging fibrosis (7.0% vs 4.1%, respectively; P = .08).
• However, HCC developed in 8 patients (17%) whose serial biopsy specimens showed only simple (non-bridging) fibrosis.
• In a multivariate analysis, a model including older age, black race, lower platelet count, higher alkaline phosphatase level, presence of esophageal varices, and tobacco smoking was developed to predict the risk of HCC.
• Over 5 years, the researchers calculated that the expected rate of HCC would be < 1% for patients the model classified as low-risk, about 5% for those classified as intermediate-risk, and approximately 20% for those considered high-risk.

Based on these results, the study investigators concluded, "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."

In an accompanying editorial, Morris Sherman from the University of Toronto presented an overview of HCC epidemiology in individuals with chronic hepatitis C.

He noted that the incidence HCC was "unexpectedly high" in HALT-C participants who had advanced fibrosis but not yet cirrhosis. Until this report, he wrote, "HCC developing in a noncirrhotic hepatitis C patient was considered uncommon."

The HALT-C findings led to an algorithm that can identify patients at greatest risk who can then be targeted for surveillance. But, Sherman stated, "the intensity of surveillance in the United States has to increase to a level that exists elsewhere in the world before HCC surveillance will result in mortality reduction."

Recent data suggest that regular surveillance (e.g., with ultrasonography) every 6 months is associated with better survival than every 12 months, since the shorter interval improves the chances of detecting small tumors at an earlier, more treatable stage.

3/17/09

Reference

AS Lok, LB Seeff, TR Morgan, and others. Incidence of Hepatocellular Carcinoma and Associated Risk Factors in Hepatitis C-Related Advanced Liver Disease. Gastroenterology 136(1): 138-148. January 2009. (Abstract).

DDW 2008: Higher HBV DNA Levels Linked to Increased Risk of Liver Cirrhosis in People with Chronic Hepatitis B

In a study presented at the Digestive Disease Week 2008 conference last month in San Diego, researchers investigated the relationship between HBV DNA levels and progression to cirrhosis over a longer follow-up period.

Read more:

Older Donor Liver Grafts May Be Suitable for Chronic Hepatitis C Patients Requiring Transplantation

Liver transplantation is the only effective treatment for end-stage liver failure due to chronic hepatitis C virus (HCV) infection, but the availability of the procedure is severely hampered by the shortage of donor organs. Surgeons have traditionally preferred to use livers from young donors, but increasing the age of acceptable donors could significantly expand the available liver supply. 

Read more:

CROI 2008: Rapid Liver Fibrosis Progression in HIV Positive Men with Acute HCV Infection

In recent years there have been reports of several outbreaks of apparently sexually transmitted acute hepatitis C among mostly HIV positive men who have sex with men (MSM) in European cities and Australia. These cases are notable because the patients were known to already be infected with HIV when they acquired HCV (typically HCV is acquired first).

Several studies have shown that HIV-HCV coinfected individuals with chronic hepatitis C tend to experience more rapid liver fibrosis progression. But little is known about the effect of HIV on liver disease in people with acute HCV infection.

At the 2007 Conference on Retroviruses and Opportunistic Infections (CROI) last February, Daniel Fierer and colleagues from Mt. Sinai School of Medicine in New York City presented early data from a prospective study of HIV positive MSM with acute HCV infection, defined as the first 6 months after HCV infection. The researchers considered a combination of 3 criteria as indicators of acute hepatitis C: recent seroconversion to HCV antibody positive status, marked elevations in serum alanine aminotransferase (ALT) level, and wide fluctuations in HCV viral load.

Study participants underwent liver biopsy within 4 months of the first-noted ALT elevation. Fibrosis was staged using the Scheuer system, on a scale of 0 to 4. Fibrosis progression rate (FPR) was calculated by dividing the fibrosis stage by the interval between the dates of the recent ALT elevation and the biopsy.

As previously reported, among the first 5 enrolled patients, 4 already had moderate portal fibrosis during acute hepatitis C. At this year’s CROI, taking place this week in Boston, the researchers presented a poster describing further data from more study participants.

Results

• Of the 11 patients who underwent liver biopsy, 9 did so within 4.5 months of detection of ALT elevation, and 2 within 16 months.
• Despite the short duration of HCV infection, 9 of the 11 (82%) had stage 2 fibrosis and 1 had stage 1 fibrosis.
• The mean FPR in these 11 patients was 4.5 (± 3.3) units per year.
• No causes of liver damage other than acute HCV infection were identified.
• In the analysis of risk factors for HCV acquisition, only 4 patients reported even a single episode of intravenous drug use.
• However, non-injection drug use and high-risk sexual behavior were common.
• 7 reported club drug (including methamphetamine) use and 10 reported unprotected anal intercourse with multiple partners.

Based on these findings, the researchers concluded, “Acute HCV infection of MSM with underlying HIV infection resulted in early and rapid progression of liver fibrosis, with FPR rates far in excess of other settings of HCV infection.”

“Many of these HIV-infected men with acute HCV used non-injection drugs and had unprotected sex with multiple partners,” they continued. “Some appear to have become HCV-infected via sexual activity.”

The investigators recommended that, “More intensive prevention and screening strategies for acute HCV in MSM are needed,” and “further research is needed to identify the disease processes leading to this highly accelerated liver injury.”

Mt Sinai School of Medicine, New York, NY.

2/5/08

Reference

D Fierer, A Uriel, D Carriero, and others. An Emerging Syndrome of Rapid Liver Fibrosis in HIV-infected Men with Acute HCV Infection. 15th Conference on Retroviruses and Opportunistic Infections. Boston, MA. February 3-6, 2008. Abstract 1050.