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In This Issue: Hepatitis C
• Long-Term Follow-Up of Nonresponders
• Treatment and Response in Black Patients
• Metabolic Abnormalities in HCV Patients
• Mother-to-Child HCV Transmission
Long-Term Follow-Up of Nonresponders
Three recent studies examined retreatment and long-term follow-up of previous nonresponders to interferon-based therapy. In the first study, published in the July 2006 Journal of Viral Hepatitis, C. Berg and colleagues administered pegylated interferon alpha-2a (Pegasys) plus ribavirin to 64 patients who relapsed after 24-week therapy with the same drugs. They found that 55% of the retreated patients achieved sustained virological response (SVR) (51% for genotype 1 and 63% for non-1 genotypes), leading them to conclude that, “Physicians should not hesitate to offer retreatment to patients who relapse after an initial, 24-week course of combination therapy.”
The second study, published in the June 16, 2006 online edition of the American Journal of Gastroenterology, suggested that nonresponders to suboptimal therapy who achieve SVR following retreatment may still relapse with longer follow-up. A. Ciancio and colleagues treated 97 previous nonresponders with various combinations of conventional interferon plus ribavirin. All patients achieved SVR 24 weeks after the completion of therapy, but during seven years of follow-up, 11% experienced HCV rebound. Among genotype 1 patients, late relapse was significantly more likely when patients were retreated with lower interferon doses for 24 weeks compared with higher doses for 48 weeks. The occurrence of late relapse suggests that for some patients, SVR does not truly represent a “cure,” and low levels of HCV may remain in the body.
A related study by V. Carreno and colleagues, published in the July 1, 2006 Journal of Infectious Diseases, found that HCV genetic material remained detectable in liver biopsy specimens from 10 out of 12 patients, and in peripheral blood mononuclear cells (PBMCs) from 6 out of 12 patients, who had normal ALT levels and undetectable serum viral load for at least 12 months. The researchers concluded that HCV may persist and continue to replicate in patients with undetectable serum HCV RNA, and that such individuals should receive ongoing follow-up.
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Treatment and Response in Black Patients
Several studies have shown that blacks do not respond as well as whites to interferon-based therapy for chronic hepatitis C, but the reasons are not well-understood. In the June 2006 Journal of Viral Hepatitis, C. Howell and colleagues reported on the safety profile of pegylated interferon alfa-2a (Pegasys) plus ribavirin in 78 black patients with genotype 1 HCV. Most (79%) completed 48 weeks of therapy, but 46% required pegylated interferon dose modification due to neutropenia and 40% required ribavirin dose reduction due to anemia. SVR rates were directly related to how much of the original planned therapy participants received: 30% for patients who took at least 60% of planned doses of both drugs, compared with 0% for those who received 60% or less of both medications. Patients of African descent have lower normal neutrophil counts and thus are more likely to develop neutropenia during interferon therapy; a greater need for dose reduction may contribute to poorer response rates in this population.
Another recent study, published in the August 2006 issue of Hepatology, showed that host immune activity against HCV in response to interferon therapy appears to differ by race. X. He and colleagues obtained PBMC samples from chronic hepatitis C patients before they started treatment, and incubated the cells with or without interferon in the laboratory. Expression of interferon-stimulated genes was greater among patients who went on to achieve SVR compared with nonresponders, and greater among white patients compared with blacks. Activation of one component of the JAK-STAT interferon-signaling pathway was significantly greater in whites, which may help explain their higher response rates.
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Metabolic Abnormalities in HCV Patients
Several recent studies have looked at metabolic conditions, including diabetes and elevated blood fat levels, in people with chronic hepatitis C. Research has yielded conflicting results regarding the association between insulin resistance or diabetes and fibrosis in hepatitis C patients. Insulin resistance – a condition in which cells do not respond properly to insulin – can progress to type 2 diabetes. In contrast with several past studies in HCV monoinfected individuals, M. Merchante and colleagues reported in the July 2006 Journal of Viral Hepatitis that they found no association between insulin resistance and advanced fibrosis or faster fibrosis progression in 79 HIV/HCV coinfected patients.
In a study of HCV monoinfected individuals with cirrhosis, published in the July 2006 American Journal of Gastroenterology, S. Sigal and colleagues found that hepatic encephalopathy was more common and more severe among cirrhotic patients with diabetes compared to non-diabetic individuals. This may happen because constipation can lead to elevated levels of ammonia produced by bacteria in the gut, and diabetes is associated with delayed gastrointestinal transit.
Steatosis, or fatty liver, is another metabolic condition linked to fibrosis progression in many studies. Research has shown that patients with chronic hepatitis C are more likely to develop steatosis, but most studies have focused on adults. As reported in the September 2006 Journal of Hepatology,A. Giannattasio assessed whether steatosis is also associated with HCV in children. They found that 25% of 64 children undergoing liver biopsies showed evidence of mild to moderate steatosis. While no significant differences in necroinflammatory or fibrosis scores were observed between children with and without steatosis, three of the 16 children (19%) with steatosis had fibrosis scores greater than 2, compared with just one of the 48 children (2%) without steatosis. Children with steatosis were also less likely to achieve SVR with interferon-based therapy (23% vs 53%). In adults, steatosis is more common in patients with genotype 3 HCV. Since only one child in this study had genotype 3, but one-quarter developed steatosis, the researchers suggested that, “Differently from adults, genotypes other than 3 may be associated with steatosis independently from classical metabolic risk factors.”
Finally, a study by K. Gopal and colleagues, published in the August 2006 issue of Hepatology, found that patients who had elevated total and low-density lipoprotein (LDL) cholesterol levels when starting interferon-based therapy were more likely to achieve end-of-treatment and sustained virological response. This may occur because HCV uses LDL receptors to enter host cells, and thus higher LDL levels may inhibit infection of cells through “competitive inhibition.” However, elevated LDL is associated with increased risk for cardiovascular disease, so much more research is needed before concluding that intentionally raising LDL might benefit people with hepatitis C.
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Mother-to-Child HCV Transmission
The overall rate of mother-to-child transmission of HCV is low – less than 5% – but factors including high maternal HCV viral load and coinfection with HIV can increase the risk. A study in the July 2006 Journal of Medical Virology suggested that maternal ALT levels during the year prior to pregnancy may also predict the risk of vertical transmission. G. Indolfi and colleagues studied 477 HCV positive mothers, 74 of whom transmitted the virus to their infants and 403 of whom did not. The women received two ALT measurements in the year before becoming pregnant, and were classified as having normal (both readings normal) or abnormal (either one or both readings elevated) ALT. Just over half (53%) of mothers who transmitted HCV had abnormal ALT levels, compared with 33% of mothers who did not transmit the virus; women with two elevated readings were more likely to transmit HCV than those with fluctuating ALT (one normal and one elevated reading). The authors concluded that elevated ALT may reflect more severe liver disease and higher HCV viral load, which is associated with increased risk of transmission. They added that the inexpensive ALT test may help to identify mothers at risk for vertical transmission in settings where more expensive HCV viral load tests are not readily available.
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