Serum microRNA signature a biomarker of HBV infection status
An index of three liver-specific microRNAs (the MiR-B Index) could serve as a biomarker of spontaneous or treatment-induced transition from active to inactive chronic hepatitis B virus (HBV) infection, facilitating disease monitoring and testing of new antivirals, according to Dr Mauricia Brunetto from the University of Pisa, Italy, who spoke recently at the Asian Pacific Digestive Week (APDW) 2017 in Hong Kong.
“The primary efforts in chronic hepatitis B are focusing on new therapeutics that could completely stop HBV replication, eliminate or inactivate covalently closed circular DNA [cccDNA, the nuclear form of the HBV genome], and activate the host immune response,” said Brunetto. “Molecular biology testing is needed to monitor the virus-host interplay and the response to antiviral therapy.”
Current treatments for HBV infection provide sustained suppression of HBV replication and clinical benefits in most patients. However, HBV usually rebounds upon treatment discontinuation because of the drugs’ inability to eliminate cccDNA and restore the dysfunctional host antiviral immune response.
“Unfortunately, cccDNA detection has many pitfalls. It requires liver biopsy, an invasive procedure that is difficult to use for monitoring,” she said. “Moreover, it cannot distinguish between transcriptionally activated or quiescent cccDNA.”
MicroRNAs play a pivotal role in virus-host interactions and are detected in both serum and hepatitis B surface antigen (HBsAg) particles. Serum HBV RNA can be detected in both overt and occult HBV infection and is related to hepatitis B e-antigen (HBeAg) and alanine aminotransferase (ALT) levels. “HBV-RNA was detected within enveloped particles from infected cell supernatant and sera of infected patients,” noted Brunetto. “In 62 HBsAg-positive patients treated with a nucleos(t)ide analogue for 30 months, HBV RNA decline at months 3 and 6 was the strongest predictor of HBeAg seroconversion.” [Clin Cancer Res 2001;7:2005-2015; Hepatology 2015;61:66-76]
Brunetto and colleagues studied microRNA levels during different phases of chronic HBV infection and antiviral treatment. Two cohorts of HBsAg carriers were followed up for a median of 34–52 months: a) a training panel of 141 sera and HBsAg particles from 61 HBsAg carriers, and b) a validation panel of 136 sera from 84 carriers. [PLoS ONE 2014;9(10): e110782]
“Thirty-one microRNAs were differentially expressed in inactive carriers [IC] and chronic hepatitis B [CHB], with the largest difference for miR-122-5p, miR-99a-5p and miR-192-5p [liver-specific microRNAs], which were overexpressed in both sera and HBsAg particles of CHB,” she reported. “They were significantly downregulated during and after treatment in sustained virological responders [SVR].”
Liver-specific microRNAs were combined with three additional microRNAs as internal control to form the MiR-B Index. Using a cutoff value of -1.7, IC were identified with a 100 percent sensitivity and 83.3 percent specificity. The index also correlated with ALT, HBV DNA and HBsAg. “In SVR to pegylated interferon or nuclos(t)ide analogs, the MiR-B Index improved during and after treatment, reaching IC values and indicating sustained HBV immune control earlier than HBsAg decline,” noted Brunetto. “The MiR-B Index might be a useful biomarker for early identification of sustained switch from CHB to inactive HBV infection in patients treated with antivirals.”