December 7, 2010

Serum microRNA Profiles Serve as Novel Biomarkers for HBV Infection and Diagnosis of HBV-Positive Hepatocarcinoma

Cancer Res. 2010 Nov 23. [Epub ahead of print]

Li LM, Hu ZB, Zhou ZX, Chen X, Liu FY, Zhang JF, Shen HB, Zhang CY, Zen K.

Authors' Affiliations: Institute for Virology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Department of Epidemiology and Biostatistics, Cancer Center, Nanjing Medical University, and Clinical Laboratory, Nanjing Second Hospital, Nanjing, China; and Department of Virology, University of California School of Public Health, Berkeley, California.


Diagnosis of hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC), particularly HCC independent of cirrhosis etiology, presents a great challenge because of a lack of biomarkers. Here we test the hypothesis that expression profiles of microRNAs (miRNAs) in serum can serve as biomarkers for diagnosis of HBV infection and HBV-positive HCC. We recruited 513 subjects (210 controls and 135 HBV-, 48 hepatitis C virus (HCV)-, and 120 HCC-affected individuals) and employed a strategy of initial screening by Solexa sequencing followed by validation with TaqMan probe-based quantitative reverse transcription-PCR assay. First, because of a close link between chronic hepatitis B and HCC, we compared miRNA expression profiles in HBV serum with that in control serum and successfully obtained 13 miRNAs that were differentially expressed in HBV serum. This 13-miRNA-based biomarker accurately discriminated not only HBV cases from controls and HCV cases, but also HBV-positive HCC cases from control and HBV cases. Second, we directly compared miRNA expressions in HCC serum with those in controls and identified 6 miRNAs that were significantly upregulated in HCC samples. Interestingly, 2 of these miRNAs, miR-375 and miR-92a, were also identified by our first approach as HBV specific. When we employed 3 of these miRNAs (miR-25, miR-375, and let-7f) as biomarkers, we could clearly separate HCC cases from controls, and miR-375 alone had an ROC of 0.96 (specificity: 96%; sensitivity: 100%) in HCC prediction. In conclusion, our study demonstrates for the first time that serum miRNA profiles can serve as novel and noninvasive biomarkers for HBV infection and HBV-positive HCC diagnosis. Cancer Res; 70(23); 1-10. ©2010 AACR.

PMID: 21098710 [PubMed - as supplied by publisher]


Virologic Response Protects Against Death in Liver Transplant Patients With HCV

By: DIANA MAHONEY, Internal Medicine News Digital Network

BOSTON – Achieving sustained virologic response to antiviral therapy was highly protective against liver-related death in liver transplant patients with chronic hepatitis C, according to an analysis of data collected over a 20-year period from 12 liver transplant centers in Italy.

Patients with recurrent HCV who were unable to achieve sustained virologic response (SVR) were at a significantly higher risk of liver-related mortality than were those for whom the virus remained suppressed 6 weeks after treatment, Dr. Maria Rendina reported at the annual meeting of the American Association for the Study of Liver Diseases.

For the study, the investigators retrospectively analyzed data on 464 patients who underwent liver transplantation between 1989 and 2008. All of the patients had viral and histologic confirmation of HCV recurrence and all were treated with recombinant or pegylated interferon plus ribavirin at standard doses for at least 1 year, Dr. Rendina said. Of the study population, 35% achieved SVR, defined as undetectable HCV RNA 6 weeks after the end of treatment, and approximately 30% died during the mean 6.8 years of posttreatment follow-up. "Liver-related mortality was the cause of death in 73% of the patients who did not survive, and all of the liver-related deaths except for one were in the group of patients who did not attain [SVR]," she said.

A comparison of the SVR and non-SVR patient characteristics showed no differences in immunosuppressive strategies between the two groups, according to Dr. Rendina of the University of Bari in Italy. Overall, the SVR patients received livers from younger donors. They also had longer treatment durations, higher cumulative doses of interferon, lower dropout rates, and lower diabetes incidence, she said.

In univariate analysis, older donor age, viral genotypes 1 or 4, diabetes, and lack of SVR to antiviral therapy were significant risk factors for death, Dr. Rendina reported. In a multivariate analysis, after adjustment for donor, viral, and recipient variables including age, gender, genotype, immunosuppression, creatinine, hepatocellular carcinoma, and diabetes, failure to achieve SVR remained "significantly and independently associated with a very high risk of liver-related death," she said, noting that the hazard ratio for liver-related death in the non-SVR group was 3.3.

"Antiviral therapy should be strongly pursued in liver transplant patients with recurrent hepatitis C infection because of the protective role of [SVR]," she said.

The hesitancy to pursue antiviral therapy for HCV recurrence after liver transplantation stems, in large part, from the absence of data regarding the relationship between viral eradication and long-term clinical outcome, said Dr. Rendina. It is further exacerbated by the frequency and severity of adverse events associated with the pegylated interferon/ribavirin standard of care – most notably flulike symptoms, hemolytic anemia, neutropenia, depression, and neurologic symptoms, she said, noting that more than 25% of the patients in the current study stopped treatment because of intolerable side effects.

Despite the drawbacks, antiviral therapy holds the most promise for improving HCV-infected patients’ long-term outcome post transplantation and should be used in clinical practice, Dr. Rendina stated. At the same time, "further randomized trials aimed at exploring various treatment options and the efficacy of new antiviral drugs should be undertaken," she said.

Dr. Rendina disclosed having no financial conflicts of interest with respect to her presentation.