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In This Issue:
Long-term HCV Eradication
Sustained virological response (SVR), or undetectable HCV viral load 24 weeks after completion of treatment, is widely considered a “cure” for chronic hepatitis C. As reported in the September 2008 Gastroenterology, S. Maylin and colleagues performed long-term follow-up (median 3.3 years; range 0.5-18.0 years) of 344 patients who achieved SVR with interferon-based therapy, looking for residual HCV RNA in blood serum, peripheral blood mononuclear cells (PBMCs), and liver tissue. None of the patients (1300 total samples) experienced serum HCV rebound, nor was HCV RNA detected in any PBMC specimens. However, two of 114 liver specimens (1.7%) had detectable HCV. Analysis of 126 paired liver biopsy samples showed that fibrosis improved in 56%, remained stable in 32%, and worsened in 12%. A majority of patients with cirrhosis (9 of 14; 64%) experienced regression, and none progressed to decompensated disease, but three individuals developed hepatocellular carcinoma (HCC). “In this large cohort of chronic hepatitis C patients, SVR was durable up to 18 years after treatment cessation,” the researchers concluded. “The presence of residual HCV RNA was observed only in liver tissue (1.7%). This result strongly suggests that SVR may be considered to show eradication of HCV infection.”
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SVR Does Not Always Prevent HCC
Long-term studies indicate that most chronic hepatitis C patients who achieve SVR maintain HCV suppression, and successful treatment has been shown to reduce the risk of progression to severe fibrosis, cirrhosis or HCC. But sustained response is not a guarantee against liver cancer, according to a report by T.M. Scherzer and colleagues in the September 2008 Journal of Viral Hepatitis. The investigators described five patients who developed HCC during 3-6 years of follow-up after achieving SVR. All still had undetectable plasma HCV RNA during follow-up and at the time of HCC diagnosis; three individuals did not have cirrhosis at the start of treatment or at the time of HCC diagnosis. “Successful antiviral treatment in HCV patients does not prevent development of hepatocellular carcinoma even in non-cirrhotic livers,” the researchers concluded. “Long-term follow up of patients with SVR is mandatory and should include surveillance for hepatocellular carcinoma.”
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Warfarin May Slow Fibrosis Progression
Successful treatment of chronic hepatitis C can slow or halt liver disease progression, but since interferon-based therapy often does not produce sustained response, researchers are studying different types of therapies that directly interrupt fibrosis. According to a report in the August 2008 Journal of Thrombosis and Haemostasis, the anticoagulant (blood-thinning) drug warfarin – which is used to prevent blood clotting – might limit fibrosis, since coagulation triggers production of collagen and other substances that make up scar tissue; while this is crucial for wound healing, build-up of scar tissue in the liver can lead to impaired function. In a laboratory study, Q.M. Anstee and colleagues assessed liver fibrosis in mice with a prothrombotic (clot-promoting) factor V Leiden mutation, “anticoagulated” mice, and normal control mice exposed to a substance that causes liver damage. Warfarin significantly reduced fibrosis progression in normal mice, but was less effective in animals with the factor V Leiden mutation, which experienced worse liver fibrosis. Changes in fibrosis scores were associated with altered activation of hepatic stellate cells, which produce scar tissue material. These results “demonstrate that coagulation status has a strong influence on hepatic fibrogenesis” and “suggest a potential novel anti-fibrotic therapeutic approach for the future,” the investigators concluded. Based on these findings, they are starting a trial of warfarin in liver transplant recipients with hepatitis C.
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HCV Genotype 6
Chronic hepatitis C patients with HCV genotypes 2 or 3 respond better to interferon-based therapy than those with hard-to-treat genotypes 1 or 4, but less is known about genotype 6, which mainly occurs in Southeast Asia. In the September 15, 2008 Journal of Infectious Diseases, J. Fung and colleagues reported on a study of 42 patients in Hong Kong (half with genotype 1 and half with genotype 6) who were treated with pegylated interferon (20 with Pegasys; 22 with PegIntron) plus ribavirin for 48 weeks. There were no significant differences between the genotype 1 and genotype 6 groups in rates of early virological response (76% vs. 81%) or end-of-treatment response (71% vs. 81%), but genotype 6 patients had a significantly higher SVR rate (86%) than genotype 1 patients (52%). The researchers recommended further research to determine whether a shorter duration of therapy or lower drug doses might be appropriate for people with genotype 6.
In a related report in the October 2008 Journal of Medical Virology, X. Xia and colleagues described a new HCV subtype, designated 6u. The researchers performed full-length genome sequencing of three novel HCV isolates (DH012, DH014, and DH028) from HIV coinfected injection drug users in Dehong prefecture, Yunnan Province, China, which borders Myanmar. The three new strains were about 98% similar to one another, but only about 75% similar to 20 previously characterized genotype 6 reference strains (including 6a-6q and 6t), supporting classification as a new subtype.
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Kidney Disease in People with HCV and HIV/HCV Coinfection
Chronic hepatitis C is an important cause of liver disease in people with end-stage renal disease (ESRD), which includes kidney dialysis patients and kidney transplant recipients. E.J. Okoh and colleagues discussed HCV infection in patients with ESRD in the August 2008 American Journal of Gastroenterology. Given the shortage of donated kidneys, organs from HCV positive donors may be used for recipients who already have hepatitis C. This practice is associated with an increased risk of liver disease, “but when compared with continued hemodialysis, transplantation using these kidneys is associated with improved survival,” the authors wrote. Interferon-based therapy is effective in ESRD patients, but “tolerability continues to be troublesome.” Such individuals may receive reduced doses of ribavirin, but should undergo careful monitoring since impaired kidney function may cause slower ribavirin elimination leading to worse side effects.
In a related report published in the October 2008 Journal of Hepatology, P. Martin and F. Fabrizi presented an overview of HCV diagnosis and management in ESRD patients. Monotherapy with conventional interferon appears to be more effective in dialysis patients than in individuals with normal kidney function, probably because impaired clearance keeps drug concentrations high, but tolerance is also poorer. The authors wrote that interferon-based therapy after kidney transplantation “remains contraindicated” due to concerns about damage to the kidney graft. But pre-transplant treatment can produce a sustained response and may reduce HCV-related complications such as diabetes and glomerulonephritis.
Finally, in the September 12, 2008 issue of AIDS, C.M. Wyatt and colleagues described a meta-analysis of the impact of HCV coinfection on HIV-related kidney disease, which is particularly common among black patients. Searching medical databases for English-language citations from 1989 through July 2007, they identified 27 eligible studies of HIV-related kidney disease or nephrotoxicity due to antiretroviral drugs, with a total of more than 18,000 patents. The pooled incidence of chronic kidney disease was nearly 50% higher in patients with HIV/HCV coinfection than in individuals without hepatitis C (6.2% vs. 4.0%). Having HCV was associated with an increased risk of protein in the urine and acute kidney failure, and the likelihood of kidney toxicity related to the HIV protease inhibitor indinavir (Crixivan) was also higher. Based on these findings, the researchers concluded that, “Hepatitis C coinfection is associated with a significant increase in the risk of HIV-related kidney disease.”
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Ribavirin Doses in Coinfected Patients
Adequate doses of pegylated interferon plus ribavirin are important for sustained response to hepatitis C therapy, with ribavirin helping to prevent post-treatment relapse. As reported in the September 2008 Journal of Medical Virology, F. Nicot and colleagues assessed the relationship between treatment response and serum concentrations of pegylated interferon and ribavirin in 35 HIV/HCV coinfected patients in France. At week 12, pegylated interferon levels in responders and nonresponders were similar, but responders tended to have higher ribavirin concentrations (2322 vs. 1833 ng/mL). The difference was especially pronounced in patients with HCV genotypes 1 or 4 (2672 vs. 1758 ng/mL for responders and nonresponders, respectively). The researchers determined that a ribavirin concentration of 2300 ng/mL was the best threshold for predicting response, and recommended that “[m]onitoring ribavirin concentrations could help adapt ribavirin concentrations and improve the sustained virological response.”
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