BACKGROUND & AIMS: Long-term ursodeoxycholic acid (UDCA) therapy slows the progression of primary biliary cirrhosis. This study examined the effect of UDCA therapy on survival free of liver ...transplantation in a large group of patients.
METHODS: Data from three clinical trials were combined in which patients with primary biliary cirrhosis were randomly assigned to receive UDCA (n = 273) or placebo (n = 275). After 2 years, patients from French and Canadian studies received UDCA for up to 2 years. Patients from the American study remained on their assigned treatment for up to 4 years.
RESULTS: Survival free of liver transplantation was significantly improved in the patients treated with UDCA compared with the patients originally assigned to placebo (P < 0.001; relative risk, 1.9; 95% confidence interval, 1.3-2.8). Subgroup analyses showed that survival free of liver transplantation was significantly improved in medium- and high-risk groups (serum bilirubin level, 1.4 to 3.5 or > 3.5 mg/dL; P < 0.0001 and P < 0.03, respectively) and histological stage IV subgroup (P < 0.01).
CONCLUSIONS: Long-term UDCA therapy improves survival free of liver transplantation in patients with moderate or severe disease. An effect in patients with mild disease is probably not found because they do not progress to end-stage disease in 4 years. (Gastroenterology 1997 Sep;113(3):884-90)
Primary biliary cirrhosis (PBC) is a presumed autoimmune disease of the liver, which predominantly affects women once over the age of 20 years. Most cases are diagnosed when asymptomatic (60%). The ...antimitochondrial antibody is present in serum in most, but not in all, patients with PBC. The disease generally progresses slowly but survival is less than an age‐ and gender‐matched general population. The symptomatic patient may have fatigue, generalized pruritus, portal hypertension, osteoporosis, skin xanthomata, fat soluble vitamin deficiencies, and/or recurrent asymptomatic urinary tract infections. Many nonhepatic autoimmune diseases are found in association with PBC and may prompt initial presentation. To date, immunosuppressive therapy has not been shown to prolong survival in PBC. The hydrophilic bile acid, ursodeoxycholic acid (UDCA), has been shown when given in a dose of 13 to 15 mg/kg daily for up to 4 years to delay the time to liver transplantation or death. This therapy also causes a significant improvement of all the biochemical markers of cholestasis but has no beneficial effects on any of the symptoms or associated disorders. Treatment with UDCA does not obviate the need for liver transplantation. Therapies to prevent complications arising from malabsorption, portal hypertension, and/or osteoporosis are required as well. Good control of pruritus can be achieved in most patients. PBC is diagnosed with increasing frequency, but the agent(s) responsible for this slowly progressive destruction of the interlobular bile ducts remains elusive and hence a specific therapy remains unavailable.
In the second phase of a randomized, placebo-controlled trial of adefovir dipivoxil for the treatment of hepatitis B e antigen (HBeAg)–negative chronic hepatitis B, patients who had been treated with ...adefovir during the initial 48 weeks of the trial were randomly assigned to be switched to placebo or to continue to receive adefovir. Patients who were switched to placebo lost the benefits that had been gained during the initial 48 weeks of treatment, and patients randomly assigned to continue adefovir therapy maintained a response. Resistance mutations developed in 6 percent of the patients treated with adefovir dipivoxil for 144 weeks.
Patients who were switched to placebo after 48 weeks lost the benefits that had been gained during initial treatment, and patients randomly assigned to continue adefovir therapy maintained a response.
An estimated 400 million people worldwide are chronically infected with hepatitis B virus (HBV). One million die each year from complications of infection, including cirrhosis, hepatocellular carcinoma, or both.
1
Hepatitis B e antigen (HBeAg)–negative chronic hepatitis B represents a late phase in the course of HBV infection.
2
Mutations in the precore promoter regions, core promoter regions, or both, which prevent the formation of HBeAg, are selected during or after HBeAg loss and seroconversion to antibody to HBeAg (anti-HBe). HBeAg-negative chronic hepatitis B infection is characterized by intermittent periods of exacerbation and quiescence. It frequently follows an aggressive disease course, with . . .
Although the natural history of autoimmune hepatitis (AIH) has been characterized, little is known about patients who present asymptomatically. Consequently, whether they require immunosuppressive ...therapy with its associated complications is unclear. To compare the natural history of asymptomatic AIH with symptomatic AIH, a large cohort of patients from a single center was examined. All patients with a clinical diagnosis of AIH were reassessed using the revised criteria of the International Autoimmune Hepatitis Group. Liver histology, response to therapy, and survival were assessed. Patients asymptomatic at presentation (n = 31) had lower serum aminotransferase, bilirubin, and immunoglobulin G (IgG) values at baseline. Half of the asymptomatic patients received no therapy, and their survival was no different from that of the total cohort. Ten-year survival was 80.0% (62.5%-97.5%) in the asymptomatic group and 83.8% (75.1%-92.6%) in the symptomatic patients (P = NS). Survival to liver-related endpoints at 10 years was similar in both groups: 89.5% (75.7%-100%) asymptomatic and 83.8% (75.1%-92.6%) symptomatic patients (P = NS). Patients with cirrhosis at baseline had poorer 10-year survival (61.9% CI 44.9%-78.9%) than those without cirrhosis at presentation (94.0% CI 87.4%-100%) (P = .003) regardless of whether they presented with symptoms or whether they received immunosuppressive therapy. In conclusion, patients with AIH who are asymptomatic at presentation have a good prognosis and may not require immunosuppressive therapy. Cirrhosis on initial liver biopsy portends a poor prognosis in all patients with AIH.
Hepatitis B e antigen (HBeAg)–negative chronic hepatitis B is associated with progressive liver injury and is likely to require long-term therapy. In this trial, histologic liver abnormalities ...improved after 48 weeks of therapy with adefovir dipivoxil, and no resistance mutations were found.
Separate reports show that adefovir dipivoxil is effective in both HBeAg-positive and HBeAg-negative disease.
More than 350 million people worldwide are chronically infected with hepatitis B virus (HBV). Complications of chronic hepatitis B, such as cirrhosis, hepatocellular carcinoma, and end-stage liver disease, account for approximately 1 million deaths each year.
1
Liver injury seems to be particularly severe and rapidly progressive in patients with chronic hepatitis B who are negative for serum hepatitis B e antigen (HBeAg) and positive for antibodies against HBeAg (anti-HBe), but in whom clinically significant HBV replication persists.
2
For the most part, HBeAg-negative chronic hepatitis B is due to HBV mutations that suppress synthesis of HBeAg. Most patients with HBeAg-negative, anti-HBe–positive, . . .
Background & aims:
Data on thelong-term safety of lamivudine are limited. The aim of this analysis was to determine the incidence of hepatitis flares, hepatic decompensation, and ...liver-disease-related (LDR) serious adverse events (SAE) during long-term lamivudine treatment.
Methods:
We reviewed data on 998 patients with HBeAg-positive compensated chronic hepatitis B who received lamivudine for up to 6 years (median, 4 years) and 200 patients who received placebo for 1 year.
Results:
Hepatitis flares occurred in 10% of thelamivudine-treated patients in year 1 and in 18%–21% in years 2–5. A temporal association between hepatitis flares and lamivudine-resistant mutations increased from 43% in year 1 to >80% in year 3. Ten hepatic decompensation events occurred in 8 (<1%) lamivudine-treated patients. Fifty-three (5%) lamivudine-treated patients experienced a total of 60 LDR SAEs. Four patients died, 2 from liver-related causes. The proportion of patients with a documented lamivudine-resistant mutation increased from 23% in year 1 to 65% in year 5. During each year of the study, patients with lamivudine-resistant mutations experienced significantly more hepatitis flares than patients without lamivudine-resistant mutations (
P < 0.005). The occurrence of hepatic decompensation (0%–2%) and LDR SAEs (1%–10%) among patients with lamivudine resistance remained stable during the first 4 years with mutations and increased afterward to 6% (
P = 0.03) and 20% (
P = 0.009), respectively.
Conclusions:
This study demonstrated that lamivudine treatment for up to 6 years has an excellent safety profile in patients with HBeAg-positive compensated liver disease, but patients with long-standing lamivudine-resistant mutations may experience worsening liver disease.
No effective medical therapy is available for all patients with nonalcoholic steatohepatitis (NASH). Ursodeoxycholic acid (UDCA) has been suggested to be of benefit based on open label clinical ...studies. We randomized 166 patients with liver biopsy–proven NASH to receive between 13 and 15 mg/kg/d of UDCA or placebo for 2 years. End points included changes in liver test results and liver histology at 2 years of therapy. The treatment groups were comparable at entry with regard to age, gender, risk factors for NASH, serum liver biochemistries, and baseline liver histology. A total of 126 patients completed 2 years of therapy. Pre‐ and posttreatment liver biopsies were available in 107 patients for review at the end of the study. UDCA was well tolerated and body weight was stable during the study duration. Serum liver biochemistries were stable or improved in both the UDCA and placebo‐treated groups. Changes in the degree of steatosis, necroinflammation, or fibrosis that occurred with therapy were not significantly different between the UDCA and placebo groups. In conclusion, 2 years of therapy with UDCA at a dose of 13 to 15 mg/kg/d, although safe and well tolerated, is not better than placebo for patients with NASH. (HEPATOLOGY 2004;39:770–778.)
Histological outcome during long-term lamivudine therapy Dienstag, Jules L.; Goldin, Robert D.; Heathcote, E.Jenny ...
Gastroenterology (New York, N.Y. 1943),
January 2003, 2003, 2003-Jan, 2003-1-00, Letnik:
124, Številka:
1
Journal Article
Recenzirano
Background & Aims: One year of lamivudine for chronic hepatitis B results in histologic improvement. We aimed to assess the histological impact of longer-term treatment. Methods: Sets of 3 liver ...biopsies, from 63 patients before and after 1 year of randomized lamivudine treatment and after 2 years of further open-label treatment, were assigned Histologic Activity Index scores under code. Results: At the end of year 1, 36/63 (57%) showed ≥2 point improvement and 24/63 (38%) no change in necroinflammatory activity; after 2 additional years of lamivudine, 38/63 (60%) remained stable and 12/63 (19%) continued to improve. Worsening occurred in similar proportions of patients with and without YMDD (tyrosine, methionine, aspartate, aspartate) variants. After all 3 years of lamivudine treatment, 35/63 (56%) of patients showed improvement, 21/63 (33%) no change, and 7/63 (11%) worsening. Those without, compared with those with, YMDD variants were more likely to improve (17/22 77% vs. 18/41 44%) and less likely to deteriorate (1/22 5% vs. 6/41 15%). Patients with YMDD variants for >2 years were least likely to improve (8/22 36%). Bridging fibrosis improved by ≥1 level in 12/19 (63%), and cirrhosis improved (score of 4 to ≤3) in 8/11 (73%). Only 1/52 2%) showed progression to cirrhosis, and 3/34 (9%) showed progression to bridging fibrosis (all with YMDD variants). Conclusions: Three years of lamivudine therapy reduces necroinflammatory activity and reverses fibrosis (including cirrhosis) in most patients. The emergence of YMDD variants blunts histologic responses; therefore, extended-duration YMDD variants may require additional therapies to maintain the histological benefit of treatment.
GASTROENTEROLOGY 2003;124:105-117
The incidence of hepatocellular carcinoma (HCC) is increasing in North America, Europe, and Japan, caused largely by the high rates of chronic hepatitis C virus (HCV) infection. In such individuals, ...the risk factors for developing HCC are advancing age, male gender, worsening hepatic fibrosis (particularly cirrhosis), and greater degrees of hepatic inflammation. Additional, potentially modifiable risk factors include coinfection with hepatitis B, excessive alcohol use, iron overload, and diabetes/obesity. Thus, approaches to preventing HCC should focus on eradicating HCV infection, responsible for the inflammation and fibrosis, and also on treating or reducing the modifiable risks, such as through hepatitis B vaccination, decreasing alcohol use, phlebotomy for iron overload, and weight control and diabetes prevention. These approaches have yet to be proven effective. Meta-analyses of standard interferon monotherapy trials in patients with HCV-related cirrhosis suggest that interferon has a small but significant effect on reducing HCC risk, particularly in those who achieve a sustained response. Other studies indicate that the reduction in HCC is greatest if a response is achieved before cirrhosis develops. Secondary prevention when HCC has been ablated or resected may be partially effected with interferon treatment or oral polyprenoic acid. No long-term studies of the effect of the currently recommended regimen of peginterferon and ribavirin have been reported, and no current trials include untreated control groups. Studies of maintenance peginterferon therapy in virological nonresponders are under way in the hope of proving that this approach is effective in decreasing the risk of HCC.
PDF
