Emergence of the rtA181T/sW172* mutant increased the risk of hepatoma occurrence in patients with lamivudine-resistant chronic hepatitis B

Abstract

BackgroundDevelopment of the hepatitis B virus (HBV) rtA181T/sW172* mutant could occur during prolonged lamivudine (LAM) therapy, conferring cross resistance to adefovir. Recent studies demonstrated an increased oncogenic potential of this mutant in NIH3T3 cells. In this study, we aimed to investigate the clinical significance of this finding.MethodsSerum samples from 123 LAM-resistant chronic hepatitis B patients were submitted for virological assays. A highly sensitive amplification created restriction enzyme site (ACRES) method was devised to detect small amounts of the rtA181T mutant in the serum. Virological factors including HBV-DNA level, genotype, precore G1896A, BCP A1762T/G1764A, rtM204I/V, rtA181T and pre-S internal deletion mutations as well as clinical variables including subsequent use of rescue drugs were submitted for outcome analysis.ResultsBy use of the highly sensitive ACRES method, the rtA181T mutant was detectable in 10 of the 123 LAM-resistant patients. During the mean follow-up period of 26.2 ± 16.4 months (range 2 to 108 months), 3 of the 10 (30.0%) rtA181T-positive patients and 2 of the 113 (1.8%) rtA181T-negative patients developed hepatocellular carcinoma (HCC). Kaplan-Meier analysis indicated that the presence of rtA181T mutation (P < 0.001), age > 50 years (P = 0.001), and liver cirrhosis (P < 0.001) were significantly associated with subsequent occurrence of HCC. All 5 HCC patients belonged to the older age and cirrhosis groups.ConclusionsEmergence of the rtA181T/sW172* mutant in LAM-resistant patients increased the risk of HCC development in the subsequent courses of antiviral therapy.

Clinical Predictors for Neutrophil–to–Lymphocyte Ratio Changes in Patients with Chronic Hepatitis B Receiving Peginterferon Treatment

“…In view of HCC prevention, peginterferon remains superior to nucleos(t)ide analogs (9). One possible reason for this is the emergence of HBV surface antigen truncation mutations, which had increased oncogenic potentials, in patients receiving long-term nucleos(t)ide analogue therapy (9)(10)(11) and the other is the immunomodulatory properties of peginterferon, which is believed to exert anticancer effect (12).…”

Monotherapy versus combinations of nucleos(t)ide in treatment-naive hepatitis B decompensated cirrhotic patients: A nested case-control study

“…Bae reported that 58.2% of patients show complete antiviral responses using LAM in decompensated HBV-related cirrhosis, which can improve the clinical prognosis (Bae et al, 2005). However, the failure of antiviral treatment or drug resistance are dangerous factors for liver disease progression and increase the incidence of liver cancer (Yeh et al, 2011;Zoulim, 2011). A single randomized double-blind controlled trial of LAM in patients with HBeAg and/or high serum HBV DNA levels showed that antiviral therapy prevented disease progression and reduced the incidence of HCC Nishida et al, 2008).…”

“…Some data supporting the benefit of antiviral therapy on the prevention of HCC in chronic hepatitis B patients has been shown in a few randomized controlled trials (Zhang et al, 2011;Jin et al, 2011;Lim et al, 2011;Tujios and Lee, 2012). Nonetheless, antiviral drug resistance is important in determining the success of long-term therapy for chronic hepatitis B patients (Yeh et al, 2011;Papatheodoridis et al, 2010). In recent clinical study data, the development of resistance to NUCs is associated with exacerbation of liver disease, including development of cirrhosis and HCC (Yeh et al, 2011), in addition, the risk of HCC remains high in HBV-related cirrhosis in patients who are treatment-naïve using NUCs (Papatheodoridis et al, 2010).…”

“…Nonetheless, antiviral drug resistance is important in determining the success of long-term therapy for chronic hepatitis B patients (Yeh et al, 2011;Papatheodoridis et al, 2010). In recent clinical study data, the development of resistance to NUCs is associated with exacerbation of liver disease, including development of cirrhosis and HCC (Yeh et al, 2011), in addition, the risk of HCC remains high in HBV-related cirrhosis in patients who are treatment-naïve using NUCs (Papatheodoridis et al, 2010). Decompensated cirrhosis is an end-stage characterized by high mortility and extremely high risk of HCC.…”

Possible Involvement of Multidrug-Resistant Hepatitis B Virus sW172* Truncation Variant in the ER Stress Signaling Pathway during Hepatocarcinogenesis

“…The presence of pre-S mutants in serum sample was reported to carry a high risk of developing HCC (27,28). The oncogenic potential of HBV sW172 * was also confirmed through its ability to transactivate the cMyc and SV40 promoters (12,29). There are still no reports on the oncogenic potential of this mutant in initiating ER stress and oxidative damage.…”