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A Bi-Monthly Publication of the Hepatitis Support Project

December 5 , 2006
Volume 3, Issue 21

Liz Highleyman

To download pdf version click here

In This Issue:

Hepatitis C

• Treatment of Nonresponders

• Liver Steatosis in Children

• Kidney Transplantation

• Signaling Pathways for Hepatitis B and C

• Coinfection Increases T-Cell Death

• Histological Response in Coinfected Patients

Treatment of Nonresponders
Since many people with hepatitis C do not respond to an initial course of interferon-based therapy – especially suboptimal therapy with conventional interferon or with pegylated interferon monotherapy – retreatment is an issue of considerable interest. In the November 2006 issue of Gut, M. Sherman and colleagues reported on an open-label study to evaluate the efficacy and safety of 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 800 mg/day ribavirin in 212 previous nonresponders (87% with genotype 1) and 100 relapsers (69% with genotype 1). Most (91%) were treated for 48 weeks, while the remainder received 24 weeks of therapy. The overall sustained virological response (SVR) rates were 23% for prior nonresponders and 41% for prior relapsers. By genotype, the combined nonresponder/relapser SVR rates were 24% for patients with genotype 1 and 47% for those with genotypes 2 or 3. “These ‘real world’ results in a large patient cohort demonstrate that it is possible to cure a proportion of previous nonresponders and relapsers by re-treating with [pegylated interferon] plus ribavirin,” the authors concluded.

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Liver Steatosis in Children
In the November 2006 American Journal of Gastroenterology, M. Guido and colleagues reported on a study of the prevalence and severity of steatosis (fat accumulation in liver cells) in children with chronic hepatitis C. The researchers obtained liver biopsy results from 66 Italian and Spanish children (88% with genotype 1). They found that 18 children (27%) had some degree of steatosis, and that the rate was higher among those with genotype 1. Interestingly, about half the Italian children had steatosis, compared with about 16% of the Spanish children. Body mass index (BMI) percentile for age was significantly correlated with both the presence and severity of steatosis. Steatosis was also directly associated with serum triglyceride levels. “Steatosis is associated with BMI in children with chronic hepatitis C due mainly to genotype 1, and with no confounding hepatotoxic factors (alcohol or drugs),” the researchers concluded. “This may reflect its metabolic rather than viral origin and raise new issues in the management of children with hepatitis C.”

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Kidney Transplantation
Research has shown that survival is reduced in kidney transplant recipients with hepatitis C, in part because immunosuppressive drugs used to prevent organ rejection can lead to increased HCV viral load. N. Kamar and colleagues reviewed hepatitis C treatment in patients receiving kidney dialysis and outcomes after kidney transplantation in the October 15, 200 issue of Transplantation. For dialysis patients, the only recommended anti-HCV treatment is conventional interferon monotherapy. Pegylated interferon is under study in this population, but ribavirin is considered contraindicated because it can cause severe anemia. While sustained response rates with interferon monotherapy are generally low, outcomes are promising in patients who do respond. “When HCV positive dialysis patients with a sustained virological response undergo successful renal transplantation, very few suffer a virological relapse, thus emphasizing that these patients were cured,” the researchers concluded.

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Signaling Pathways for Hepatitis B and C
Chronic hepatitis B and C can both cause liver cirrhosis and hepatocellular carcinoma, but their pathogenic mechanisms appear to differ, according to a study in the November 2006 issue of Hepatology. M. Honda and colleagues assessed signaling pathways associated with HBV and HCV infection by analyzing gene expression profiles of liver tissue from 24 patients with chronic hepatitis B and 23 with chronic hepatitis C. They found that gene expression was correlated more closely with the infecting virus than with clinical parameters such as histological stage or disease activity. Pro-apoptotic (promoting cell death) and DNA repair responses were predominant in tissue from people with hepatitis B, while inflammatory and anti-apoptotic gene profiles were predominant in those with hepatitis C. “These differences would evoke different oncogenic factors in chronic hepatitis B and chronic hepatitis C,” the researchers concluded. “The results might be useful in guiding therapeutic strategies to prevent the development of hepatocellular carcinoma in cases of chronic hepatitis B and chronic hepatitis C.”

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Coinfection Increases T-Cell Death
Several studies suggest that HIV/HCV coinfected people experience faster liver disease progression than those with HCV alone, and also may have greater CD4 cell depletion and “blunted” (less extensive) CD4 cell recovery after starting antiretroviral therapy for HIV. In the November 1, 2006 issue of Clinical Infectious Diseases, M. Nunez and colleagues reported on an analysis of the impact of HCV on T-cell apoptosis (programmed cell death) in 31 HIV monoinfected and 30 HIV/HCV coinfected patients not receiving antiretroviral therapy. After adjusting for age, CD4 cell count, and HIV viral load, HIV/HCV coinfected patients had significantly higher levels of apoptosis of naive CD4 cells, naive CD8 cells, and memory CD8 T-cells. However, plasma HCV RNA levels were not associated with degree of apoptosis of CD4 or CD8 T-cells. The researchers noted that since both HIV and HCV can cause T-cell death, the two viruses appear to act synergistically in killing these cells. Death of T-cells may allow HCV to evade the body’s immune responses, which could help explain the lower likelihood of spontaneous HCV clearance in HIV positive individuals. “HCV coinfection is associated with increased apoptosis of T-lymphocytes in HIV-infected patients,” the researchers concluded. “This effect could have a negative impact on CD4+ T-cell homeostasis in HCV/HIV coinfected patients, explaining the more pronounced decreases in the CD4+ cell count and blunted CD4+ cell count recoveries observed while patients are receiving HAART, as well as facilitating HCV immune escape in this population.”

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Histological Response in Coinfected Patients
In the November 2006 issue of AIDS, E. Lissen and colleagues reported on a study of histological response (improved liver tissue health) following treatment with Pegasys plus ribavirin in the APRICOT trial. APRICOT demonstrated that Pegasys plus ribavirin produced higher SVR rates in HIV/HCV coinfected patients than either Pegasys monotherapy or conventional interferon plus ribavirin (40%, 20, and 12%, respectively). The researchers analyzed paired liver biopsies from 401 subjects to assess whether virological response was associated with histological response. The rate of histological response (defined as a 2-point or greater reduction in the histological activity index score) was significantly higher in patients receiving Pegasys plus ribavirin (57%) than in those receiving either Pegasys monotherapy (39%) or conventional interferon plus ribavirin (41%). The histological response rate ranged from 62% to 74% among subjects who achieved SVR, compared with 32%-43% in patients without SVR. “The histological response rate was significantly higher in HIV/HCV coinfected patients who received [Pegasys] plus ribavirin than in those receiving [Pegasys] plus placebo or [conventional interferon] plus ribavirin,” the researchers concluded. “Histological response was correlated with virological response, although a substantial proportion of patients who did not achieve an SVR experienced histological improvement.”

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