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Primary resistance, multidrug resistance, and cross-resistance pathways in HBV as a consequence of treatment failure.

ABSTRACT: Antiviral resistance is now the single most important factor in treatment failure using nucleos(t)ide analogues (NA). Primary drug resistance mutations refer to amino acid change(s) that result in reduced susceptibility to an antiviral agent. Secondary compensatory mutations restore replication defects associated with primary drug resistance and may be associated with low level reduced susceptibility. Several evolutionary pathways of drug resistant HBV have been observed in patients treated with NAs. It is possible that the drug resistance mutations selected with one agent may affect the efficacy of other NAs. Several major HBV-evolutionary NA-resistance pathways (rtM204I/V, rtN236T and rtA181T/V) have now been characterised. The rtM204V/I pathway is responsible for resistance to the L: -nucleosides, such as lamivudine (LMV), telbivudine (LdT) and clevudine (CLD), and also entecavir (ETV), whilst the rtN236T pathway is responsible for adefovir (ADV) and tenofovir (TFV) resistance. Both pathways are associated with clusters of secondary mutations that can affect subsequent treatment with NAs (rtT184G, rtS202I) such as ETV. The third pathway, rtA181T/V, is associated with resistance to LMV and ADV and is a potential multi-drug resistance pathway and will probably have an impact on TFV sensitivity, either alone or with the rtN236T. In naïve patients treated with ETV, atleast three mutations arising at the same time are required: rtL180M + rtM204V plus either one of rtT184, rtS202 or rtM250 codon changes. Finally, in highly drug-experienced patients, clusters of mutations such as rtA181T/I233V/N236T/M250L, all on the one dominant HBV genome, are being detected which are associated with multi-drug resistance. Sequential treatment with nucleos(t)ide analogue reverse transcriptase inhibitors (NRTI) promotes multidrug resistance. It is likely, therefore, that development of multi-drug resistance could be reduced by combination therapy optimised to individual viral phenotypes.

SUBMITTER: Locarnini S

PROVIDER: S-EPMC2716855 | biostudies-other | 2008 Jun

REPOSITORIES: biostudies-other

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Project description:OBJECTIVE:As the leading risk factor for the development of liver cancer, chronic infection with hepatitis B virus (HBV) represents a significant global health concern. Although an effective HBV vaccine exists, at least 240 million people are chronically infected with HBV worldwide. Therapeutic options for the treatment of chronic HBV remain limited, and none achieve an absolute cure. To develop novel therapeutic targets, a better understanding of the complex network of virus-host interactions is needed. Because of the central metabolic role of the liver, we assessed the metabolic impact of HBV infection as a means to identify viral dependency factors and metabolic pathways that could serve as novel points of therapeutic intervention. METHODS:Primary rat hepatocytes were infected with a control adenovirus, an adenovirus expressing a greater-than-unit-length copy of the HBV genome, or an adenovirus expressing the HBV X protein (HBx). A panel of 369 metabolites was analyzed for HBV- or HBx-induced changes 24 and 48?h post infection. Pathway analysis was used to identify key metabolic pathways altered in the presence of HBV or HBx expression, and these findings were further supported through integration of publically available gene expression data. RESULTS:We observed distinct changes to multiple metabolites in the context of HBV replication or HBx expression. Interestingly, a panel of 7 metabolites (maltotriose, maltose, myristate [14:0], arachidate [20:0], 3-hydroxybutyrate [BHBA], myo-inositol, and 2-palmitoylglycerol [16,0]) were altered by both HBV and HBx at both time points. In addition, incorporation of data from a transcriptome-based dataset allowed us to identify metabolic pathways, including long chain fatty acid metabolism, glycolysis, and glycogen metabolism, that were significantly altered by HBV and HBx. CONCLUSIONS:Because the liver is a central regulator of metabolic processes, it is important to understand how HBV replication and HBV protein expression affects the metabolic function of hepatocytes. Through analysis of a broad panel of metabolites we investigated this metabolic impact. The results of these studies have defined metabolic consequences of an HBV infection of hepatocytes and will help to lay the groundwork for novel research directions and, potentially, development of novel anti-HBV therapeutics.

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Primary resistance, multidrug resistance, and cross-resistance pathways in HBV as a consequence of treatment failure.

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