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In This Issue: Hepatitis C
• Sustained Response in a Clinical Setting
• 24-Week Treatment for Genotype 1 Rapid Responders
• Progression of Initially Mild Liver Disease
• Treating Fibrosis with Interferon Gamma
• Diabetes in Patients with Hepatitis B or C
• Natural History of HCV-Related Liver Disease
Sustained Response in a Clinical Setting
Various controlled clinical trials of pegylated interferon plus ribavirin have produced sustained virological response (SVR) rates of about 40%-80%, depending on genotype much higher than the 6%-20% rate obtained with conventional interferon monotherapy. However, response rates in actual clinical practice often don’t measure up to those observed in trials. As reported in the May 2006 Journal of Viral Hepatitis, C.P. Desmond and colleagues sought to determine SVR rates and durability of response in a clinical setting. They analyzed data from 175 chronic hepatitis C patients who received conventional interferon monotherapy, 96 who received conventional interferon plus ribavirin, and 73 who received pegylated interferon plus ribavirin, all for at least 12 weeks. For genotype 1 patients, SVR rates for the three regimens were 5%, 41%, and 47%, respectively; for genotype 2 or 3 patients, the corresponding rates were 25%, 73%, and 79%. All but one patient who achieved SVR (> 99%) still had undetectable HCV viral load after a mean follow-up period of 2.3 years (range 0.3-10.3). The authors concluded that advances in hepatitis C therapy have produced higher sustained response rates in the clinical setting. They also suggested that since this response appears durable, medium and long-term follow-up of patients with SVR is “of low yield and largely unnecessary.”
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24-Week Treatment for Genotype 1 Rapid Responders
Standard therapy for chronic hepatitis C consists of a 24-week course of pegylated interferon plus ribavirin for patients with genotype 2 or 3 HCV, and 48 weeks for those with genotype 1. However, as D.M. Jensen and colleagues reported in the May 2006 issue of Hepatology, the shorter course may be sufficient for genotype 1 patients who experience rapid virological response (RVR) after four weeks. In a randomized multinational trial, 51 out of 216 genotype 1 patients (24%) achieved SVR with 24 weeks of Pegasys plus ribavirin. The SVR rate was nearly five times higher among patients with RVR than without (89% vs 19%, respectively). Patients with baseline HCV viral load less than 200,000 IU/mL were more likely to achieve RVR, as were those with HCV subtype 1b. The authors concluded that while only a minority of genotype 1 patients will achieve RVR after four weeks of therapy, most who do can expect to ultimately achieve sustained response.
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Progression of Initially Mild Liver Disease
It can be difficult to decide whether patients with initially absent or mild fibrosis should receive treatment for hepatitis C, since it is unclear how often, or how rapidly, they will progress to more severe disease. As reported in the May 2006 Journal of Viral Hepatitis, S. Boccato and colleagues studied the rate and risk factors for fibrosis progression in 106 untreated patients with initially mild chronic hepatitis C who had minimal or no evidence of fibrosis on their first biopsy. After a mean follow-up period of about eight years, 60% showed evidence of fibrosis progression, including 49% of those who initially had no fibrosis (F0) and 65% of those with initial minimal fibrosis (F1); 36% of patients who started with stage F1 progressed to stage F3 (advanced fibrosis) or F4 (cirrhosis). Fibrosis progression was associated with older age, elevated alanine aminotransferase (ALT) levels, higher histological activity scores, presence of steatosis (fatty liver), and alcohol consumption. The authors concluded that fibrosis progression occurs in about two-thirds of patients with initially mild hepatitis C within 5-10 years, and that one-third of those with stage F1 fibrosis may develop advanced fibrosis or cirrhosis. Therefore, they recommended that antiviral therapy should be considered for patients with initially mild liver disease.
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Treating Fibrosis with Interferon Gamma
Long-term liver damage in patients with hepatitis C is primarily related to the build-up of fibrous tissue due to overproduction of extracellular matrix proteins by hepatic stellate cells. In the May 2006 Journal of Viral Hepatitis, A.J. Muir and colleagues reported on a study to assess the benefits of interferon gamma, a cytokine (chemical messenger) with anti-fibrotic effects. Twenty chronic hepatitis C patients who had failed or did not tolerate previous interferon-based therapy received 200 mcg interferon gamma three times weekly for 24 weeks. No serious adverse events were observed, and 18 patients completed therapy (one discontinued due to constitutional symptoms and another due to ALT elevation). Six patients (30%) had at least a 1% reduction in Ishak fibrosis score, and four patients (20%) experienced improvement in fibrosis after treatment. The researchers concluded that interferon gamma is safe and well-tolerated in patients with chronic hepatitis C. While they did not observe an overall reduction in fibrosis, interferon gamma did appear to improve fibrosis in certain patients, and the authors recommended further trials.
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Diabetes in Patients with Hepatitis B or C
Another study reported in the May 2006 Journal of Viral Hepatitis assessed the prevalence of diabetes in patients with hepatitis B or C and its association with liver fibrosis. G.V. Papatheodoris and colleagues collected epidemiological, somatomorphic (body shape), laboratory, and histological data from 260 patients with chronic hepatitis C and 174 with chronic HBeAg-negative hepatitis B. A total of 58 patients (13%) had diabetes, and the rates did not differ significantly between those with hepatitis C (13%) and hepatitis B (14%). Diabetes was significantly more common among individuals with more advanced fibrosis or cirrhosis: 7.7% among those with absent or minimal fibrosis (stages 0-2), 10.4% among those with stage 3-4 fibrosis, and 29.2% among those with severe fibrosis or cirrhosis (stages 5-6). Along with severe fibrosis and cirrhosis, diabetes was also independently associated with higher gamma-glutamyl transpeptidase (GGT) levels, high triglyceride levels, and the presence of steatosis. Among patients without cirrhosis, however, diabetes was significantly associated with older age and higher GGT levels, but not with extent of fibrosis. The authors concluded that diabetes is present in more than 10% of patients with chronic hepatitis B or C. They noted that the presence of diabetes is strongly associated with more severe liver fibrosis, and that this association may be related to the high prevalence of diabetes among patients with cirrhosis.
In a related study presented at the Digestive Disease Week 2006 meeting in Los Angeles in May, K. Ario and colleagues (abstract 553) found that inflammatory activity in patients with chronic hepatitis C is strongly related to insulin resistance (a precursor to type 2 diabetes), and suggested that treatment to improve insulin sensitivity - ranging from diet modification and weight loss to medications such as metformin (Glucophage) or rosiglitazone (Avandia) - might help reduce liver inflammation and ultimately slow fibrosis progression.
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Natural History of HCV-Related Liver Disease
A study published in the June 2006 issue of Hepatology provided further information about the long-term progression of liver cirrhosis in patients with hepatitis C. A. Sangiovanni and colleagues analyzed data from 214 patients with hepatitis C-related compensated cirrhosis who were prospectively followed for an average of 9.5 years. A total of 68 patients (32%) developed hepatocellular carcinoma (HCC), for an annual incidence rate of 3.9%. For most patients (72%), clinical status remained unchanged, but 21% progressed from Child-Pugh class A to B, and 7% progressed to class C. Symptoms included ascites in 50 patients (23%), jaundice in 36 patients (17%), upper gastrointestinal bleeding in 13 patients (6%), and hepatic encephalopathy in 2 patients (1%). HCC was the first complication to develop in about one-quarter of the subjects, and was the leading cause of mortality, responsible for 44% of deaths. The authors concluded that hepatitis C-related cirrhosis is a “slowly progressive disease that may be accelerated by other potential causes of liver disease.”
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