• 3,010 patients from 4 randomized, controlled trials with "before" and "after" liver biopsies.
• Treatment with pegylated or non-pegylated interferon alfa, with or without ribavirin
• 69% genotype 1 (most difficult to treat).
• 56% of those with significant baseline fibrosis (F2, F3 or F4) had an improvement of at least one fibrosis stage (grade) after treatment.
• Mean fibrosis progression rate among sustained virologic responders with significant baseline fibrosis (F2, F3 or F4) after treatment was -0.6 units per year (i.e., regression).
• New "fibrosis index" might obviate the need for liver biopsies among some patients with chronic hepatitis C.

Thierry Poynard, MD of Hospital Pitie Salpetriere in Paris, France presented a new "meta-analysis" of 4 studies with 3,010 patients confirming that treatment for chronic hepatitis C improves fibrosis (scarring) in the liver. "Pre- and post-treatment" liver biopsies were analyzed by a pathologist "blinded" to (unaware of) patient treatment information. Fibrosis represents a prognostic liver abnormality that is associated with life-threatening complications of cirrhosis.

Among the 679 patients with paired biopsies, a baseline "METAVIR" fibrosis score of F2 ("few septa"), F3 ("many septa") or F4 (cirrhosis) and known duration of HCV infection, the fibrosis progression rate (FPR) decreased significantly from 0.137 to -0.49 units per year (p<0.001). Specifically, among those who had a sustained virologic response (undetectable HCV RNA 6 months after treatment), the FPR decreased from 0.139 pre-treatment to -0.591 after treatment, while non-responders had a less dramatic decrease in their FPR from a baseline of 0.135 pre-treatment to zero units annually after treatment.

Among the 1,900 patients with baseline fibrosis scores of F0-F1 (no fibrosis or only portal fibrosis), the FPR (fibrosis progression rate) also decreased significantly to zero units per year for both non-responders and sustained responders after treatment (p<0.001). In that group, the baseline FPR was 0.053 for virologic non-responders and 0.063 units per year for sustained responders.

In addition, among those 153 patients with cirrhosis at baseline (fibrosis score F4), 49% had regression of cirrhosis to a lower fibrosis score. In this smaller subset of patients, cirrhosis regression was significantly associated with combination therapy (versus monotherapy), younger age at baseline, a sustained virologic response and a "METAVIR" inflammation "activity" score of A0 or A1 after treatment (p=0.02, "univariate" statistical analysis).

In a statistical "proportional hazards regression" model, factors statistically associated with an absence of extensive fibrosis after 24 months (2,861 patients) included: a baseline fibrosis score of F0 or F1 ("odds ratio" or OR 0.12, p<0.001); sustained HCV virologic response (OR 0.36, p<0.001); age younger than 40 years (OR 0.51, p<0.001); "body mass index" (weight divided by height squared) less than 27 (OR 0.65, p<0.001); a baseline liver activity score of A0 or A1 (OR 0.70, P=0.02); and baseline HCV viral load less than 3.5 million copies per milliliter (OR 0.79, p=0.03).

Meta-Analysis of 4 Trials for Treatment of Chronic Hepatitis C:
3,010 Patients with Paired Liver Biopsies;
Changes in Liver Fibrosis and Inflammatory Activity

Dr. Poynard emphasized that chronic hepatitis C is both a viral infection and a liver "fibrotic" disease that is caused primarily by the former. The life-threatening complications of chronic hepatitis C (primary liver cancer, liver "insufficiency" or failure and internal bleeding) all need to be addressed when considering treatment. Therefore, looking in the blood at the virologic response to treatment is only one endpoint after therapy has finished-changes on liver biopsy (sampling) must also be considered. Loss of detectable HCV in blood plasma does not always correlate with changes on liver biopsy; however, in studies to date, there appear to be improvements in the liver not only in sustained virologic responders, but also, to a lesser degree in non-responders. Dr. Poynard also discussed the concept of "maintenance" therapy with interferon alfa or pegylated interferon alfa (after standard treatment with combination therapy) among virologic non-responders to prevent liver disease progression or to potentially induce regression of fibrosis (improvement).

The 4, pivotal, international, randomized, controlled studies have been previously published by Drs. Poynard, J. McHutchison, C. Trepo or M. Manns. A total of 4,493 treatment-naïve (no previous treatment) patients with chronic hepatitis C were included. Nine different treatment regimens were included in the meta-analysis: interferon alfa for 24 or 48 weeks; pegylated interferon alfa 2b (0.1, 0.5, 1.5 micrograms per kilogram once-weekly, PegIntron); interferon alfa 2b plus oral ribavirin for either 24 or 48 weeks; and pegylated interferon alfa 2b (0.5 or 1.5 mg/kg once weekly) plus oral ribavirin.

There were 3,010 patients (67%) who had paired liver biopsies for the meta-analysis. Baseline information showed that they were: 66% male, mean age 43 years, mean weight 80 kilograms (176 pounds), 53% history of injection drug use, 69% genotype 1 (the most difficult to treat), 28% genotypes 2 or 3, mean duration of HCV infection of 18 years (information available for 83%), mean duration between liver biopsies of 20 months, mean size of liver biopsies of 16 mm (inaccurate information if biopsy size is too small), and with a mean baseline HCV RNA of 4.1 million copies/mL. The baseline liver biopsies showed 2% with METAVIR fibrosis scores of F0 (no fibrosis), 73% with F1 (portal or mild fibrosis), 13% with F2 (few septa or moderate fibrosis), 7% with F3 (many septa or severe fibrosis), and 5% with F4 (frank cirrhosis). The mean METAVIR fibrosis stage was 1.4. The METAVIR inflammation "activity" scores on liver biopsy at baseline showed 2% with A0, 21% with A1 (mild), 39% with A2 (moderate), and 38% with A3 (severe). The mean METAVIR activity score was 2.2.

Dr. Poynard had previously published a similar meta-analysis involving a subset of the current, new analysis. He and his colleagues also previously had published the concept of the fibrosis progression rate, based upon using the results of one liver biopsy and an estimated duration of HCV infection. Using a METAVIR 5-point fibrosis scale (F0-F4), the units of fibrosis progression per year can be estimated. Among 2,235 untreated patients with chronic hepatitis C, the median (average, half above, half below) fibrosis progression rate was 0.133 units per year. Three factors associated with a faster progression were: age greater than 40 years at the time of HCV infection, male sex and daily alcohol consumption greater than 50 grams. One limitation of the fibrosis progression rate is the assumption that progression is fixed and constant with time, without periods of faster or slower progression: with only one biopsy, this is difficult to prove.

Dr. Poynard also briefly mentioned newly published research about a "fibrosis index," that uses five blood tests to predict the likelihood of fibrosis being present on liver biopsy among patients with chronic hepatitis C. Those tests are: "alpha 2 macroglobulin, alpha 2 globulin (or haptoglobin), gamma globulin, apolipoprotein A1, gamma glutamyltranspeptidase (GGT), and total bilirubin." Using the fibrosis index, half of liver biopsies in patients with chronic hepatitis C might be avoided, according to the new research that is available at www.FibroTest.com and were published in the April 7th issue of Lancet, Dr. Poynard said that virologic responders to interferon alfa had a lower fibrosis index after 18 months of follow-up than did virologic relapsers, who, in turn, had a lower index than virologic non-responders (for the full text of the Lancet article, here's the link.)

(Editorial note from Jules Levin: in the Lancet article, the authors report that "with the best index, a high negative predictive value (100% certainty of absence of F2, F3, or F4) was obtained for scores ranging from zero to 0.10 (12% [41] of all patients), and high positive predictive value (>90% certainty of presence of F2, F3, F4) for scores ranging from 0.60 to 1.00 (34% [115] of all patients). On the FibroTest.com web site Poynard says "for scores ranging from 0 to 0.10 the probability of significant fibrosis is below 10% and treatment is usually not recommended in the absence of symptoms or risk of dissemination". In the Lancet article he also says his study results need to be repeated by another centre, but he thinks that the number of biopsies in the management of HCV could be reduced by up to 46%. My take is that this approach needs considerable research to confirm these findings. Additionally, strong confirmation of the cut-offs and margins of error are needed. Still, biopsy remains, in my opinion, the only sure way to evaluate the liver.)

References
www.FibroTest.com

Imbert-Bismut F Poynard T and others. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet 2001 Apr 7;357(9262):1069-75

Manns MP and others. Peginterferon alfa-2b plus ribavirin compared to interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C: 24-week treatment analysis of a multicenter, multinational, phase III, randomized, controlled trial. Oral presentation (Presidential Plenary Session II) and abstract 552 at the 51st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), October 27-31, 2000; Dallas, Texas. Hepatology 2000;32:297A.

McHutchison JG and others. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. New England Journal of Medicine. 1998 November 19;339(21):1485-92.

Poynard T. Impact of peginterferon alfa-2b and ribavirin on progression of liver fibrosis in patients with chronic hepatitis C. Oral presentation at "Optimizing Response Rates with Weight Adjusted Combination Peginterferon Alfa-2b and Ribavirin Therapy," satellite symposium at the 36th Annual Meeting of the European Association for the Study of the Liver (EASL 2001); April 18-22, 2001

Prague, Czech Republic

Poynard T and others. Randomized trial of interferon alpha-2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet. 1998 October 31;352(9138):1426-32.

Poynard T and others. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups.

Lancet. 1997 March 22;349(9055):825-32.

Poynard T and others. Impact of interferon alfa-2b and ribavirin on progression of liver fibrosis in patients with chronic hepatitis C. Hepatology 2000 November;32(5):1131-7

Trepo C and others. Journal of Hepatology 2000;32(suppl 2):29. (35th EASL 2000)