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In This Issue:
• Dramatic Declines in Viral Hepatitis
• Future Health Burden of Chronic Hepatitis C
• LDL Cholesterol and HCV
• Steatosis in Patients with Genotype 4 HCV
• Immune Response to HCV
• Autoimmune Hepatitis in Liver Transplant Recipients
Dramatic Declines in Viral Hepatitis
New hepatitis A, B, and C infections have decreased dramatically over the past decade, according to a new study by the Centers for Disease Control and Prevention (CDC). As reported in the March 16, 2007 issue of Morbidity and Mortality Weekly Report, A. Wasley and colleagues analyzed surveillance reports of new cases of HAV, HBV, and HCV infection in 2005. That year, there were 4,488 reported cases of acute symptomatic hepatitis A (1.5 per 100,000 persons, or 42,000 estimated total infections after accounting for asymptomatic cases and underreporting); 5,494 cases of acute symptomatic hepatitis B (1.8 per 100,000 persons, or 51,000 estimated total infections), and 671 confirmed cases of acute hepatitis C (0.2 per 100,000 persons, or 20,000 estimated total infections). New cases of acute hepatitis A decreased by 88% since 1995, hepatitis B declined by 79% since 1990, and hepatitis C declined by 92% since 1992 among individuals aged 25-39 years. The 2005 rates of new hepatitis A and B cases were the lowest ever recorded, attributable to the availability of effective vaccines. However, viral hepatitis surveillance data are limited by the fact that many acute infections are asymptomatic and never reported. The researchers concluded that, “Ongoing hepatitis B vaccination programs will ultimately eliminate domestic HBV transmission,” but added that, “Prevention of hepatitis C relies on identifying and counseling uninfected persons at risk for hepatitis C (e.g., IDUs) regarding ways to protect themselves from infection.”
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Future Health Burden of Chronic Hepatitis C
Despite the decrease in new infections, hepatitis C is a growing public health concern as people infected decades ago begin to develop complications of chronic liver disease, including cirrhosis and hepatocellular carcinoma (HCC). As reported in the February 2007 Journal of Viral Hepatitis, S. Dueffic-Burban and colleagues estimated the future burden of hepatitis C in the U.S. through the year 2030, using a back-calculation model based on epidemiological data from the CDC and World Health Organization. They estimated that HCV incidence peaked in 1984, with 350,000 new infections, then fell to about 77,000 new cases in 1998. HCV-related mortality rose from about 3,700 cases in 1998, and is expected to peak at about 13,000 in 2030. The researchers predicted that HCV-related deaths resulting from pre-1999 infections would likely continue to increase over the next 25 years, but could decline if there is improved access to treatment or more effective antiviral therapies are developed.
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LDL Cholesterol and HCV
The low-density lipoprotein (LDL) cholesterol receptor appears to plays a role in HCV infection, but the process is poorly understood. As reported in the March 2007 Journal of Hepatology, S. Molina and colleagues performed a laboratory study to assess expression and activity of the LDL receptor under various conditions. They exposed human liver cells to HCV in the absence or presence of LDL, high-density lipoprotein (HDL), LDL receptor peptides encompassing full-length or truncated LDL-binding domains, monoclonal antibodies against the full-length peptide, squalestatin (which up-regulates LDL receptor expression), and 25-hydroxycholesterol (which down-regulates expression). They found that LDL and the full-length LDL receptor peptide inhibited accumulation of HCV RNA in liver cells, regardless of genotype or viral load. In hepatocytes pre-treated with squalestatin or 25-hydroxycholesterol before HCV exposure, HCV RNA accumulation increased or decreased, respectively, in parallel with LDL receptor messenger RNA expression. The researchers concluded that, “LDL receptor is involved at an early stage in infection of normal human hepatocytes.”
In a related study reported in the March 2007 Journal of Hepatology, N. Akuta and colleagues found that patients who had an LDL level greater than 86 mg/dL were more likely to achieve both early and sustained virological response to pegylated interferon plus ribavirin, as were those who had HCV with certain amino acid substitutions (mutations) in the core region. Combining these two factors allowed the researchers to predict response to therapy with a high degree of sensitivity and specificity.
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Steatosis in Patients with Genotype 4 HCV
Liver steatosis (fatty liver) is associated with accelerated fibrosis progression and poorer response to interferon-based therapy. Past studies have shown that in patients with genotype 1 HCV, steatosis is primarily due to metabolic factors such as obesity, while viral factors play a more important role in those with genotype 3. As reported in the March 2007 American Journal of Gastroenterology, E. Tsochatzis and colleagues analyzed factors associated with steatosis in 350 Greek patients with chronic hepatitis C. Overall, 73% had some degree of steatosis, with no significant differences in prevalence according to genotype. However, patients with genotype 3 were more likely to have moderate-to-severe fibrosis than those with genotype 4. Among non-diabetic, non-obese individuals, advanced steatosis was observed in 15% of genotype 1 patients, 11% of genotype 4 patients, and 40% of genotype 3 patients. Moderate-to-severe steatosis was associated with greater body mass index in genotype 4 patients and with higher GGT levels in genotype 3 patients. The researchers concluded that liver steatosis in genotype 4 patients is mostly associated with metabolic factors, as is the case with genotype 1.
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Immune Response to HCV
HCV infection becomes chronic in most patients, and the immunological factors associated with spontaneous clearance are not well understood. In the February 2007 issue of Gastroenterology, D. Kaplan and colleagues reported on a study of HCV-specific CD4, CD8, and neutralizing antibody responses in patients with acute and chronic infection. HCV-specific CD8 T-cell responses were readily detected in patients with acute HCV infection, regardless of CD4 T-cell responses or ultimate outcome. In contrast, HCV neutralizing antibodies were detected in subjects with impaired HCV-specific CD4 T-cell responses and chronic infection, but not in those with robust CD4 T-cell responses who spontaneously cleared the virus. The researchers concluded that, “The outcome of acute hepatitis C is associated with efficient virus-specific CD4 T-cell response(s) without which HCV-specific CD8 T-cell and heterologous neutralizing antibody responses may develop but fail to clear viremia.”
A related study, published in the March 15, 2007 Journal of Infectious Diseases, looked at HCV-specific antibody responses in patients coinfected with HIV. HIV-positive individuals are more likely to develop chronic HCV infection, especially if they have low CD4 cell counts; CD4 T-cells regulate the activity of B-cells, which produce antibodies. D. Netski and colleagues compared levels and types of antibodies in 29 HCV-infected patients before and after they acquired HIV. They found that declining CD4 cell count was strongly associated with decreasing titers of HCV-specific antibodies, and that antibody levels were lower in patients who had been infected with HIV for a longer duration. The authors concluded that, “HCV-specific antibody production is impaired by HIV infection, and loss of antibody production depends on CD4 T-cell depletion.” However, they noted that decreases in antibody titers was less marked in active injection drug users.
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Autoimmune Hepatitis in Liver Transplant Recipients
After liver transplantation, HCV usually reinfects the new graft, which can lead to severe inflammation and organ rejection. Post-transplant treatment with interferon-based therapy is under study, but side effects may be intolerable in such patients, including the potential for autoimmune reactions triggered by interferon. As reported in the February 2007 issue of Gut, S. Berardi and colleagues studied 44 HCV-infected liver transplant recipients who received pegylated interferon alpha-2b (PegIntron) plus ribavirin for at least six months to treat HCV recurrence. Nine patients developed allograft dysfunction, including eight who did so despite HCV clearance. All nine had laboratory values suggesting probable autoimmune hepatitis, and three also developed other autoimmune disorders. Other causes of allograft dysfunction (such as infections, blood vessel complications, and organ rejection) were ruled out. The researchers concluded that, “De novo autoimmune hepatitis should be considered in differential diagnosis along with rejection in liver transplanted patients developing graft dysfunction while on interferon treatment.”
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