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In This Issue:
• Continued Therapy after Rapid Response
• Meloxicam Reduces Neutropenia
• Chronic Hepatitis C in Children
• Hepatitis C Epidemiology
• Liver Fibrosis in HIV/HCV Coinfected Patients
• HIV Promotes HCV Replication
Continued Therapy after Rapid Response
Studies have shown that rapid virological response (RVR) to pegylated interferon plus ribavirin, or undetectable HCV RNA after four weeks, is a good predictor of sustained virological response (SVR) six months after completion of treatment. As reported in the April 2008 Journal of Viral Hepatitis, N. Napoli and colleagues examined different continuation regimens in 45 previously untreated genotype 1 chronic hepatitis C patients who started treatment with 1.5 mcg/kg/week pegylated interferon alfa-2b (PegIntron) plus 800-1200 mg/day weight-based ribavirin. After four weeks, 31 people (69%) achieved RVR and were randomly assigned to continue on either the same 1.5 mcg/kg/week or a lower 1.0 mcg/kg/week dose of PegIntron, staying on the same dose of ribavirin for the remaining 44 weeks. Similar proportions achieved SVR in both groups (94% with 1.5 mcg/kg/week, 93% with 1.0 mcg/kg/week). However, among four other patients who achieved early virological response between weeks 4 and 12, only 25% went on to achieve SVR. These finding confirm that RVR is an excellent predictor of SVR, and indicate that less intensive treatment may be feasible after this point.
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Meloxicam Reduces Neutropenia
Many patients treated with interferon-based therapy for hepatitis C experience difficult side effects including neutropenia, a reduced level of immune system white blood cells (neutrophils) that fight bacterial infections. In a study reported in the March 2008 issue of Hepatology Research, T. Kagawa and colleagues assessed whether the non-steroidal anti-inflammatory drug (NSAID) meloxicam could help prevent interferon dose reduction. In this study, 22 chronic hepatitis C patients were assigned to receive 10 mg once-daily oral meloxicam before starting 180 mcg/week pegylated interferon alfa-2a (Pegasys) and continuing for eight weeks, while 38 others were assigned to a control group receiving no meloxicam. Just 9% of patients in the meloxicam group required Pegasys dose reduction, compared with 45% in the control group. The dose was lowered due to neutropenia in 18% of the meloxicam group versus 32% of the control group. The researchers concluded that eight weeks of meloxicam “prevented dose reduction of pegylated interferon by relieving a decline of neutrophil count in the treatment of chronic hepatitis C.”
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Chronic Hepatitis C in Children
In the March 2008 issue of Hepatology, Z. Goodman and colleagues presented results from an analysis of liver histopathology in participants in the Peds-C trial, which tested the safety and efficacy of Pegasys plus ribavirin in children with chronic hepatitis C. Liver biopsy samples were obtained from 121 previously untreated children aged 2 to 16 years who had no other identifiable causes of liver disease. Overall, liver inflammation was minimal or absent in 42%, mild in 17%, moderate in 38%, and severe in 3%. Five children had bridging fibrosis and two had cirrhosis. More than half (56%) showed no evidence of liver steatosis (fat accumulation), 34% had minimal steatosis, 10% had mild steatosis, and none had moderate-to-severe steatosis. Fibrosis scores were higher in children with greater liver inflammation, but were not related to age, HCV genotype, body mass, or presence of steatosis. Overweight children, however, were more likely to have both fibrosis and steatosis. The researchers concluded that liver inflammation, fibrosis, and steatosis were milder in this cohort of children than in adults with chronic hepatitis C, but wrote that, “The positive correlation of inflammation with duration of infection and fibrosis, and of obesity with fibrosis, suggest that children with chronic hepatitis C will be at risk for progressive liver disease as they age and possibly acquire other comorbid risk factors.”
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Hepatitis C Epidemiology
Two recent analyses looked at changes in the epidemiology of hepatitis C over the past decade. In the first, published in the March 21, 2008 Morbidity and Mortality Weekly Report Surveillance Summaries, A. Wasley and colleagues from the Centers for Disease Control and Prevention (CDC) examined the number of cases of hepatitis A, B, and C in the U.S. in 2006. In that year, the total number of reported cases of symptomatic acute hepatitis C was 802 (0.3 cases per 100,000 persons), up from 671 in 2005. After asymptomatic infections and underreporting were taken into account, the investigators estimated that there were approximately 19,000 total new HCV infections in 2006. Following a peak in the late 1980s, the incidence of acute hepatitis C declined through the 1990s, but it leveled off since 2003 and rose slightly in 2006. A majority of new hepatitis C cases occurred among adults, and injection drug use was the most common risk factor. By contrast, cases of acute hepatitis A and B both fell to the lowest rate ever recorded (1.2 and 1.6 cases per 100,000 persons, respectively), attributable to the implementation of routine childhood vaccination.
In a related analysis, published in the April 2008 issue of Hepatology, M. Wise and colleagues looked at changing hepatitis C mortality rates. A total of 56,409 hepatitis C-related deaths were identified during 1995-2004. The mortality rate increased 123% during this period, from 1.09 to 2.44 cases per 100,000 persons; however, average annual increases were smaller during 2000-2004 compared with 1995-1999. After peaking in 2002 at 2.57 cases per 100,000 persons, overall hepatitis C mortality rates declined slightly, to 2.44 cases. But mortality continued to increase among older individuals, rising by 376% in the 45-54 age group and by 188% in the 55-64 age group. Across all age categories, mortality increases were greater among men than women (144% vs 81%), and among blacks (170%) and Native Americans (241%) compared with whites (124%) and Hispanics (84%). The researchers estimated that the 7,427 deaths due to hepatitis C in 2004 represented 148,611 years of potential life lost.
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Liver Fibrosis in HIV/HCV Coinfected Patients
Studies have shown than HIV/HCV coinfected patients tend to experience more rapid liver fibrosis than HIV negative individuals with chronic hepatitis C. As reported in the March 1, 2008 issue of Clinical Infectious Diseases, F. Bani-Sadr and colleagues assessed the prevalence of and risk factors for fibrosis progression in the French RIBAVIC trial, which compared 1.5 mcg/kg/week PegIntron versus conventional interferon, both with 800 mg/day ribavirin. Overall, 27% of patients in the pegylated interferon arm achieved SVR – lower than similar trials, perhaps because RIBAVIC used a ribavirin dose that is now recognized as suboptimal for heavier patients. The latest analysis looked at 198 participants with paired pre- and post-treatment liver biopsy specimens. Just under one-fifth (17%) experienced worsening of fibrosis by two or more points, or from stage 5 to 6. Fibrosis progression was significantly associated with failure to achieve SVR and use of the anti-HIV drug ddI (Videx). The researchers suggested that mitochondrial toxicity due to antiretroviral agents such as ddI “seems to play a major role in worsening of fibrosis during HCV therapy,” confirming the recommendation that ddI should not be used by people taking ribavirin.
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HIV Promotes HCV Replication
Beyond antiretroviral-related drug toxicity, it is not fully understood how HIV coinfection might accelerate disease progression due to hepatitis C, since HIV does not directly infect hepatocytes. In a laboratory study described in the March 2008 issue of Gastroenterology, W. Lin and colleagues assessed whether circulating HIV or specific HIV proteins might contribute to HCV pathogenesis. They found that inactivated HIV and the HIV gp120 envelope glycoprotein were both associated with increased HCV replication. HCV-regulated transforming growth factor-beta-1 (TGF-beta-1) expression was higher in the presence of HIV and gp120, and TGF-beta-1 enhanced HCV replication. The effect of HIV and gp120 on HCV replication was neutralized by adding antibodies to the CCR5 or CXCR4 co-receptors, which HIV needs to enter cells. The effect was also blocked by a neutralizing antibody to TGF-beta-1. “These results suggest a novel mechanism by which HIV not only enhances HCV replication, but also contributes to progression of hepatic fibrosis,” the investigators concluded. This study adds to recent findings that HIV may also promote fibrosis by infecting hepatic stellate cells, which produces scar tissue in the liver.
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