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Micro RNA-122 and the Clinical Course of Patients With Chronic Hepatitis C

2014-07-23 21:12:44 | BioPortfolio

Summary

Combination therapy with peginterferon plus ribavirin has become the current standard of care for chronic hepatitis C (CHC) patients, with an overall sustained virologic response (SVR) rate of 54-63%. Based on the ample evidence, a 48-week course of peginterferon plus weight-based ribavirin therapy is widely recommended to treat HCV genotype 1 infection in different parts of the world. Despite the increased SVR rates with the improved medical therapies, about 25-50% and 10-20% of HCV genotype 1 and HCV genotype 2/3 patients may experience relapse after the cessation of therapy with undetectable HCV viremia at the end of treatment. Moreover, combination therapy is costly and may cause various adverse events. Therefore, individualized therapy based on outcome analysis should be adopted to save medical cost as well as to lessen inadequate treatment. Few studies are aimed to evaluate the host responses of micro RNA regulation during interferon-based therapy and its relationships to the overall treatment responses.

Micro RNA (miRNA) is a single-stand RNA composed of 21-23 nucleotides, which may regulate the function of messenger RNA (mRNA). The regulating mechanisms involving micro RNA between the hosts and the HCV virus include (1) auto-regulation of HCV mRNA by HCV miRNA; (2) regulation of host mRNA by HCV miRNA; and (3) regulation of HCV mRNA by host miRNA. MiR-122 is the abundant liver-specific miRNA which is crucial for efficient HCV replication in culture Huh7 cells stably expressing HCV replicons. Recently, an in vivo study for hepatic miR-122 of 42 patients with CHC who received IFN-based therapy showed that patients who did not respond to IFN therapy had markedly decreased pretreatment miR-122 levels. Although miR-122 is abundant in the liver, liver biopsy is still considered an invasive procedure, which prevents its widespread use in routine clinical practice. The miRNA can be detected in the sera and is stable after 24 hours of room temperature store or repeated freezing and de-freezing. The serum miR-122 levels can reflect the severity of liver injuries in a rat acetaminophen toxicity model. Because miR-122 is liver specific and the miRNA is stable in the sera, the investigators aimed to evaluate the role of serum and hepatic miR-122 on the viral kinetics and the treatment responses and in HCV patients receiving peginterferon and ribavirin combination therapy.

Description

Hepatitis C virus (HCV) infection, a leading cause of cirrhosis, hepatocellular carcinoma (HCC) and liver transplantation, affects approximately 170 million individuals worldwide. In Asian-Pacific regions, the prevalence of HCV infection ranges from 0.3-12%, with a geographical variation. Therefore, prevention of HCV transmission and early intervention of HCV infection are urgently needed to reduce or halt the liver-related morbidity and mortality.

Combination therapy with peginterferon plus ribavirin has become the current standard of care for chronic hepatitis C (CHC) patients, with an overall sustained virologic response (SVR) rate of 54-63%. Treatment with weekly peginterferon and weight-based ribavirin for 48 weeks had a significantly higher SVR rate than that for 24 weeks in Caucasian patients with HCV genotype 1 infection (52% to 42%). Based on ample evidence from Western countries, a 48-week course of peginterferon plus weight-based ribavirin therapy is widely recommended to treat HCV genotype 1 infection in different parts of the world. However, recent studies for Asian CHC genotype 1 patients showed favorable treatment response to Caucasian patients with either 24 or 48 weeks of peginterferon plus weight-based ribavirin therapy (50 to 60% for 24 weeks; 75 to 80% for 48 weeks). In contrast, the overall SVR rates were similar across different ethnicity in patients with HCV genotype 2/3 infection.

Despite the increased SVR rates with the improved medical therapies, about 25-50% and 10-20% of HCV genotype 1 and HCV genotype 2/3 patients may experience relapse after the cessation of therapy with undetectable HCV viremia at the end of treatment. Moreover, combination therapy is costly and may cause various adverse events. Therefore, individualized therapy based on outcome analysis should be adopted to save medical cost as well as to lessen inadequate treatment. Currently, HCV viral kinetics is considered to predict treatment response. Patients with rapid virologic response (RVR) are good predictors of SVR; those who fail to achieve RVR but achieve complete or partial early virologic response (cEVR or pEVR) should be put on prolonged therapy; those who fail to achieve EVR should be considered for treatment discontinuation because of low chance for SVR. Various host and viral factors, including race, gender, body weight, baseline viral load, and viral genotype, were considered to predict RVR. However, few studies are aimed to evaluate the host responses of micro RNA regulation during interferon-based therapy and its relationships to the overall treatment responses.

Micro RNA (miRNA) is a single-stand RNA composed of 21-23 nucleotides, which may regulate the function of massager RNA (mRNA). The regulating mechanisms involving micro RNA between the hosts and the HCV virus include (1) auto-regulation of HCV mRNA by HCV miRNA; (2) regulation of host mRNA by HCV miRNA; and (3) regulation of HCV mRNA by host miRNA. MiR-122 is the abundant liver-specific miRNA which is crucial for efficient HCV replication in culture Huh7 cells stably expressing HCV replicons. This observation raised much interest in the role of mir-122 in HCV infection and its potential as a therapeutic target. It was recently reported that the levels of miR-122 and several other miRNAs are regulated by IFN in Huh7 cells and primary mouse hepatocytes and that miRNAs might mediate at least some effects of IFN on HCV RNA replication in vitro. Recently, an in vivo study for hepatic miR-122 of 42 patients with CHC who received IFN-based therapy showed that patients who did not respond to IFN therapy had markedly decreased pretreatment miR-122 levels. Although miR-122 is abundant in the liver, liver biopsy is still considered an invasive procedure, which prevents its widespread use in routine clinical practice. Considering the abundant blood flow through the liver, we speculated that miR-122 can be detected in the sera, and can be used for screening and monitoring the responses by serial blood tests. The miRNA can be detected in the sera and is stable after 24 hours of room temperature store or repeated freezing and de-freezing. In addition, miRNA is resistant to RNase and can be sustained for more than 10 years after adequate freezing. Recent studies have shown the serum miRNA was potentially useful for the detection of cancer and its treatment responses. Furthermore, the serum miR-122 levels can reflect the severity of liver injuries in a rat acetaminophen toxicity model. Because miR-122 is liver specific and the miRNA is stable in the sera, the investigators aimed to evaluate the role of serum and hepatic miR-122 on the viral kinetics and the treatment responses and in HCV patients receiving peginterferon and ribavirin combination therapy.

Study Design

Observational Model: Case Control, Time Perspective: Cross-Sectional

Conditions

Hepatitis C

Location

National Taiwan University Hospital, Yun-Lin Branch
Douliou
Taiwan
10002

Status

Recruiting

Source

National Taiwan University Hospital

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-07-23T21:12:44-0400

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Medical and Biotech [MESH] Definitions

INFLAMMATION of the LIVER in humans due to infection by VIRUSES. There are several significant types of human viral hepatitis with infection caused by enteric-transmission (HEPATITIS A; HEPATITIS E) or blood transfusion (HEPATITIS B; HEPATITIS C; and HEPATITIS D).

A family of hepatotropic DNA viruses which contains double-stranded DNA genomes and causes hepatitis in humans and animals. There are two genera: AVIHEPADNAVIRUS and ORTHOHEPADNAVIRUS. Hepadnaviruses include HEPATITIS B VIRUS, duck hepatitis B virus (HEPATITIS B VIRUS, DUCK), heron hepatitis B virus, ground squirrel hepatitis virus, and woodchuck hepatitis B virus (HEPATITIS B VIRUS, WOODCHUCK).

A species in the genus HEPATOVIRUS containing one serotype and two strains: HUMAN HEPATITIS A VIRUS and Simian hepatitis A virus causing hepatitis in humans (HEPATITIS A) and primates, respectively.

INFLAMMATION of the LIVER in humans caused by HEPATITIS DELTA VIRUS, a defective RNA virus that can only infect HEPATITIS B patients. For its viral coating, hepatitis delta virus requires the HEPATITIS B SURFACE ANTIGENS produced by these patients. Hepatitis D can occur either concomitantly with (coinfection) or subsequent to (superinfection) hepatitis B infection. Similar to hepatitis B, it is primarily transmitted by parenteral exposure, such as transfusion of contaminated blood or blood products, but can also be transmitted via sexual or intimate personal contact.

INFLAMMATION of the LIVER in humans caused by HEPATITIS C VIRUS, a single-stranded RNA virus. Its incubation period is 30-90 days. Hepatitis C is transmitted primarily by contaminated blood parenterally, and is often associated with transfusion and intravenous drug abuse. However, in a significant number of cases, the source of hepatitis C infection is unknown.

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