P. Opolon

Natural history of liver fibrosis progression in patients with chronic hepatitis C

BACKGROUNDnOur aim was to assess the natural history of liver fibrosis progression in hepatitis C and the factors associated with this progression.nnnMETHODSnWe recruited 2235 patients from the Observatoire de lHépatite C (OBSVIRC) population, the Cohorte Hépatite C Pitié-Salpétrière (DOSVIRC) population, and the original METAVIR population. All the patients had a biopsy sample compatible with chronic hepatitis C as assessed by the METAVIR scoring system (grades the stage of fibrosis on a five-point scale, F0 = no fibrosis, F4 = cirrhosis, and histological activity on a four-point scale, A0 = no activity, A3 = severe activity). No patient had received interferon treatment before the liver biopsy sample was obtained. We assessed the effect of nine factors on fibrosis progression: age at biopsy; estimated duration of infection; sex; age at infection; alcohol consumption; hepatitis C virus C (HCV) genotype; HCV viraemia; cause of infection; and histological activity grade. We defined fibrosis progression per year as the ratio between fibrosis stage in METAVIR units and the duration of infection (1 unit = one stage, 4 units = cirrhosis).nnnFINDINGSnThe median rate of fibrosis progression per year was 0.133 fibrosis unit (95% CI 0.125-0.143), which was similar to the estimates from previous studies (0.146 to 0.154). Three independent factors were associated with an increased rate of fibrosis progression: age at infection older than 40 years, daily alcohol consumption of 50 g or more, and male sex. There was no association between fibrosis progression and HCV genotype. The median estimated duration of infection for progression to cirrhosis was 30 years (28-32), ranging from 13 years in men infected after the age of 40 to 42 years in women who did not drink alcohol and were infected before the age of 40. Without treatment, 377 (33%) patients had an expected median time to cirrhosis of less than 20 years, and 356 (31%) will never progress to cirrhosis or will not progress for at least 50 years.nnnINTERPRETATIONnThe host factors of ageing, alcohol consumption, and male sex have a stronger association with fibrosis progression than virological factors in HCV infection.

Modeling the impact of interferon alfa treatment on liver fibrosis progression in chronic hepatitis C: A dynamic view

BACKGROUND & AIMSnImpact of hepatitis C treatment has never taken into account the dynamics of fibrosis progression. This study assessed the impact of interferon on liver fibrosis progression in patients with chronic hepatitis C according to 3-month aminotransferase activity response.nnnMETHODSnWe recruited 287 patients, 185 treated and 102 control, with paired biopsy specimens. Before follow-up, the fibrosis progression rate per year was estimated as the ratio between fibrosis stage in METAVIR units (1 U, 1 stage; 4 U, cirrhosis) and the duration of infection. During follow-up, fibrosis progression was assessed by the observed difference between stages divided by duration between biopsies.nnnRESULTSnThe median fibrosis progression rate in treated patients decreased compared with the rate before treatment from 0.103 F METAVIR U/yr (95% confidence interval [CI], 0.087-0.120) to 0.000 (95% CI, 0.000-0.000; P </= 0.0001). Among 91 treated responders, fibrosis stage worsened in 19 (22%), compared with 21 (22%) of 94 treated nonresponders and 57 of 102 controls (56%; P </= 0.0001 compared with treated patients), and improved in 26 (29%), 17 (18%), and 8 (8%; P = 0.0002 compared with 29% and P = 0.03 compared with 18%), respectively. These observed differences persisted after genotype, viremia, sex, age at infection, duration of infection, and alcohol consumption were taken into account.nnnCONCLUSIONSnInterferon treatment changes the natural fibrosis progression rate in patients with chronic hepatitis C independently of genotype and early response.

Flumazenil vs. placebo in hepatic encephalopathy in patients with cirrhosis: a meta-analysis

Randomized controlled trials testing flumazenil in hepatic encephalopathy have shown conflicting results.

Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C in naive patients: 1999 update.

The aim of this study was to update our previous meta‐analysis of interferon (IFN) in the treatment of hepatitis C and to analyse new factors, namely, HCV RNA end‐point, patients with cirrhosis and patients with normal ALT. We use the Der Simonian and Laird method, with heterogeneity and sensitivity analyses. Seventy‐six randomized control trials (RCTs) in naive patients were found but we focused our analysis on 59 RCTs with chronic hepatitis C (26 vs. controls and 33 comparing different regimens) and on seven RCTs in acute hepatitis. Interferon‐α (IFN‐α) at 3 MU thrice weekly (TIW) for 12u2003months exhibited 39% of virological end‐of‐treatment response (ETR) and 17% of virological sustained response (SR), respectively, vs. 1% and 3% in untreated controls (all Pu2003<u20030.001). There was a significant dose effect (in favour of 6 vs. 3 MU TIW): the virological SR at 6u2003months were 35% in the 6 MU group (95% CI: 24–47) and 16% in the 3 MU group (95% CI: 8–27) and were at 12u2003months 43% in the 6 MU group (95%CI: 31–56) and 25% in the 3 MU group (95% CI: 16–37). There was a significant duration effect (12 vs. 6u2003months) upon the virological SR rate both at 3 and 6 MU: 3 MU provided 14% of virological SR (95% CI: 11–19) in the 12u2003months group vs. 7% (95% CI: 5–11) in the 6u2003months group and 6 MU provided 22% (95% CI: 17–29) and 16% (95% CI: 11–22) virological SR in the 12 and 6u2003months groups, respectively. Cirrhotic treated patients had 17% of virological SR (95 CI: 9–24%; Pu2003<u20030.001) vs. 0% in controls and provided a 20% reduction rate (95 CI: −2% to −37%, P=0.03) in hepatocellular carcinoma incidence. In acute hepatitis C, a 3‐month treatment with IFN‐α showed significant efficacy vs. controls upon the virological SR rate (32% vs. 4%, Pu2003<u20030.001). In conclusion, we confirm the dose and duration effect of IFN in chronic hepatitis C, and the efficacy of IFN‐α in the treatment of acute hepatitis and in cirrhotic patients.

Interferon for interferon naive patients with chronic hepatitis C

BACKGROUNDnA previous meta-analysis of interferon therapy in naive patients with chronic hepatitis C has documented its efficacy in achieving virologic clearance, and improving liver biochemistry and histology; however, since its publication additional trials have been reported.nnnOBJECTIVESnTo evaluate the response to interferon in interferon naive patients with chronic hepatitis C. The effect of treatment dose and duration, and the response in patients with cirrhosis and those with normal aminotransferases was also investigated.nnnSEARCH STRATEGYnThe Cochrane Controlled Trials Register (Cochrane Library Issue 1, 1999), MEDLINE (January 1966 to December 1999), and reference lists were searched, and pharmaceutical companies were contacted for unpublished trials.nnnSELECTION CRITERIAnRandomised clinical trials comparing interferon with placebo, no treatment, or different regimens of interferon were selected. Abstracts were excluded.nnnDATA COLLECTION AND ANALYSISnThe primary outcome measure was sustained disappearance of serum HCV RNA (virologic sustained response (SR)). Biochemical and end of treatment responses, liver histology, and adverse events were also recorded. Assessment of drug efficacy used the methods of Peto and Der Simonian and Laird.nnnMAIN RESULTSnFifty-four trials enrolling 6545 patients were included. Compared with no treatment, interferon 3 MU thrice weekly for 12 months increased the probability of a virologic SR (Peto odds ratio (OR) 4.60; 95% confidence interval (CI) 1.53 to 13.85). At this dosage and duration of therapy, the rate of virologic SR was 17% (95% CI 10 to 28%) in interferon-treated patients versus 3% (95% CI 1 to 10%) in controls. A dose of 6 MU was more effective than 3 MU thrice weekly (OR for 12 months treatment, 2.21; 95% CI 1.10 to 4.45), as were durations of 12 months or greater versus six months (OR 1.87; 95% CI 1.30 to 2.67). Adverse events were more common with higher doses and prolonged durations of treatment. Compared with no therapy, interferon increased the probability of histologic improvement (OR 9.22; 95% CI 5.69 to 14.94). The response to interferon in cirrhotic patients (virologic SR, 17%; 95% CI 11 to 26%) was similar to that in non-cirrhotic patients. However, interferon was no more effective than control in patients with normal aminotransferases.nnnREVIEWERS CONCLUSIONSnInterferon is effective in achieving viral clearance and improving liver biochemistry and histology in interferon naive patients with chronic hepatitis C. Higher doses and prolonged durations are more effective, but associated with more frequent adverse events. Interferon is associated with similar benefits in patients with cirrhosis, but the efficacy in patients with normal aminotransferases is unproven.

Impact of human immunodeficiency virus infection on the histological features of chronic hepatitis C: A case-control study*

Hepatitis C virus (HCV) is frequently encountered in human immunodeficiency virus (HIV)-infected patients because of common routes of transmission. Previous studies suggested that HIV infection impaired the natural course of chronic hepatitis C, with a more rapid progression to cirrhosis. However, these studies did not assess the HIV infection impact on chronic hepatitis C by taking into account the risk factors for liver fibrosis progression: alcohol, sex, age at the contamination, and duration of HCV infection. We studied liver biopsy specimens of 2 groups of 58 patients that were infected by both HCV and HIV or by HCV alone. The 2 groups were matched according those risk factors, and liver biopsy responses were evaluated with the METAVIR items. The METAVIR activity was higher in HIV-positive than HIV-negative patients. Cirrhosis was more frequent: (1) in HIV-positive patients with CD4 < or = 200 cells/microL (45%) than in HIV-negative patients (10%) (P = .003), (2) in HIV-positive patients with CD4 < or = 200 cells/microL (45%) than in HIV-positive patients with CD4 > 200 cells/microL (17%) (P = .04). These differences, which were linked to HIV status, might be related to the enhanced HCV replication during HIV infection or other immune mechanisms that need further studies.

Management of hepatitis C

Chronic hepatitis C is a major health care problem throughout the world. The disease may progress to cirrhosis, with complications such as hepatocellular carcinoma. The usual primary goal of therapy is viral eradication, as patients with long‐term remission are generally regarded as unlikely to develop cirrhosis or hepatocellular carcinoma. Another primary goal should be the reduction in liver fibrosis progression. Interferon‐α (IFN‐α) is the only drug approved for the treatment of hepatitis C in Europe and North America. Its effectiveness appears to be related to dose and duration of therapy. The best efficacy/risk ratio seems to be in favour of 3 million units (MU) IFN‐α three times per week on a 12‐month schedule. With this regimen, a sustained alanine aminotransferase (ALT) response is achieved in nearly 35% of patients. Ribavirin has emerged as potentially the second most effective drug. While it appears unsatisfactory when given alone, it seems much more effective in combination with IFN. Combining them seems to exert a synergistic effect between the two drugs and sustained remission might be achieved in nearly 50% of patients with combination therapy. Controversy persists concerning the long‐term benefit of therapy in transient responders and non‐responders. It is possible that IFN therapy, in comparison to natural history, might reduce liver fibrosis progression and prevent hepatocellular carcinoma, even in non‐responders, and have greater efficacy if used in long‐term treatment. Whatever the treatment schedule, prolonged viral eradication may not be achieved in all patients and new drugs should be sought to improve the results of therapy.

Effects of interferon therapy in "non responder" patients with chronic hepatitis C.

We reviewed the impact of interferon treatment on viral load, transaminase serum activity and histological features in patients with chronic hepatitis C in whom treatment did not result in a sustained virus eradication. As patients with cirrhosis are often called non responders, we also reviewed the impact of interferon on these end points as well as on hepatocellular carcinoma incidence and survival. This overview provides evidence that interferon in patients who have not cleared hepatitis C virus (HCV) significantly reduces viral load, serum ALT activity, improves histological activity and blocks progression of fibrosis compared to the natural history of the disease. Thus, patients who still have a positive HCV PCR should no longer be called non responders to interferon. Although the number of randomized trials is limited, there is also cumulative data suggesting that interferon could reduce the incidence of hepatocellular carcinoma incidence and mortality.

Chronic liver dysfunction in heart transplant recipients, with special reference to viral B, C, and non-A, non-B, non-C hepatitis. A retrospective study in 80 patients with follow-up of 60 months.

In order to assess the prevalence, causes, and severity of chronic liver dysfunction (LD) in heart transplant patients, 80 transplanted patients followed for 60 months (median; range, 1.5–98 months) were reviewed. Sustained liver dysfunction was found in 50 patients, occurring during the first year after heart transplantation in 42 (84%) of them. Most patients were asymptomatic (80%). Causes for the liver dysfunction included non-A, non-B hepatitis in 16 cases (32%), viral B hepatitis in 13 (26%), delta hepatitis in one (2%), drug-induced hepatitis in six (12%), and cardiac failure in seven (14%). Anti-HCV antibodies were found in 56.2% of patients with non-A, non-B hepatitis and in 22% of patients with HBV hepatitis. It was found neither in patients with drug-induced hepatitis cardiac failure nor in patients with normal liver tests. This study outlines a high prevalence of LD (62.5%) in heart transplant patients, the high frequency of viral-related chronic LD (usually of moderate severity), and high incidence of HCV and HBV hepatitis.

Long-term effects of interferon-α in five HIV-positive patients with chronic hepatitis B

Summary. Chronic hepatitis B viral infection is common in human immunodeficiency virus (HIV) carriers, but the effectiveness of interferon therapy is still unknown. We report the results of a long‐term pilot study of five patients, who were infected with HIV and chronic hepatitis B, treated by interferon. Five males co‐infected with HIV and hepatitis B virus (HBV) (mean age 2 7 years) were given a 6‐month course of interferon (IFN)‐α2b 5 million units (MU) three times weekly. On initiating the treatment, their CD4 lymphocyte count was 340–553 mm‐3, their CDC stage was IIa‐III; all had histologically proven chronic hepatitis, with Knodells score ranging from 6–10, and active HBV replication (HBV DNA and hepatitis B e antigen (HBeAg) were detectable). There was no associated hepatitis δ virus (HδV) or hepatitis C virus (HCV) infection. Follow‐up was for 53 months on average (24–74 months). After the treatment, hepatitis B e antibody (HBeAb) and hepatitis B s antibody (HBsAb) sero‐conversion was observed in one patient, HBeAb seroconversion alone in two patients, HBV DNA was absent from serum in three patients, and HBV DNA significantly decreased in one patient. The serum alanine aminotransferase (ALT) activity was normal in four patients. Histological improvement was obtained in four patients. The HIV stage remained unchanged in all patients during the whole follow‐up. These preliminary results suggest that interferon can be successfully used in immunocompetent HIV carriers with chronic hepatitis B as well as in HIV‐negative patients.