For long-term lesion reversal, the most important aspect is the choice of drug. The following three factors must be taken into account when selecting a drug: effectiveness of drug therapy, safety, and occurrence of drug resistance. If the antiviral drug can consistently suppress viral replication and can prevent the development of drug resistance, long-term use of the drug will result in improved liver histology and delay the development of clinical endpoints such as cirrhosis and hepatocellular carcinoma. At the EASL Annual Meeting in Copenhagen, Denmark, April 22-26, 2009, a new concept in the treatment of chronic hepatitis B – “from halting the progression of hepatic histology to reversing it” – was brought to the attention of the participants. The goal of antiviral therapy for chronic hepatitis B is to prevent progression to cirrhosis, end-stage liver disease, hepatocellular carcinoma, and death, and to improve quality of life and survival; this can be achieved through long-term suppression of viral replication. Traditionally, liver fibrosis has been considered irreversible, while recent studies have shown that it can also be reversed. Possibility of reversal of liver lesions During HBV infection, sustained viral replication induces an immune response in the body, leading to chronic inflammation of the liver and activation of hepatic stellate cells. Hepatic stellate cells secrete large amounts of extracellular matrix and activate more stellate cells through an autocrine mechanism, creating a vicious cycle. Increased synthesis and decreased degradation of extracellular matrix results in massive matrix deposition, which promotes hepatic fibrosis, the development of cirrhosis. Traditionally, hepatic fibrosis was considered irreversible, but recent experimental data suggest that fibrosis is a dynamic process of injury healing, and cutting off the pathogenesis of hepatic fibrosis at multiple points may allow fibrosis to be reversed. Measures such as improving the hepatic inflammatory load by removing the cause (e.g., inhibiting HBV replication), inducing apoptosis or inactivating hepatic stellate cells, down-regulating matrix synthesis, and increasing matrix degradation may tip the balance between fiber formation and fibrolysis in favor of reversal of fibrosis. Long-term, effective antiviral therapy reverses liver lesions Improvement in liver histology represents the reversal of lesions and is the ultimate goal of antiviral therapy. Studies have shown that antiviral therapy not only reduces HBV DNA load, improves biochemical parameters, increases the chances of HBeAg seroconversion, and improves the HBsAg negative rate, but also, more importantly, achieves histologic improvement and prevents the development of complications. Avoidance of drug resistance: the key to lesion reversal Viral resistance to antiviral drugs reflects a decrease in viral susceptibility to drugs, which is caused by adaptive mutations in the genes of the HBV polymerase. The development of drug resistance can lead to virologic breakthrough, elevated ALT, reduced serologic conversion of HBeAg, integration of mutants into cccDNA, and escape of mutated virus from the protective effect of vaccines, and lead to progression of the lesion and the development of hepatic dysfunction and hepatocellular carcinoma. In contrast, cross-resistance reduces viral susceptibility to multiple antiviral agents and can influence future drug therapy choices. Studies have shown that antiviral therapy can be effective in reversing liver lesions, but the results of antiviral therapy are depleted when drug resistance occurs. It is clear that prevention of viral mutation and sustained suppression of viral replication over time are essential to achieve sustained improvement in liver histology. A key factor in the development of resistance is the resistance gene barrier, defined as the number of viral locus variants required to develop significant resistance to antiviral drugs. Lamivudine, telbivudine, and adefovir all require only one drug-specific variant site for resistance to occur, whereas entecavir resistance requires multiple point variants and is the drug with the highest barrier to resistance available. The 5-year genotypic resistance rates of lamivudine and adefovir are as high as 80% and 29%, respectively, while entecavir shows a very low cumulative resistance rate (5-year resistance rate of 1.2% in first-treated patients), which guarantees the long-term effective inhibition of viral replication. Safety of Long-Term Use Chronic hepatitis B may require several years of treatment, so it is important to examine long-term safety data for nucleoside analogs. Current nucleoside (acid) analogs are well tolerated, with the caveat that lactic acidosis or ALT relapse may occur during treatment. Monitoring of the drugs used is also needed, e.g., entecavir needs to be monitored for resistance in lamivudine-resistant (relapsed) patients; tibivudine should be watched for the risk of myopathy or myalgia; and blood creatinine levels need to be monitored for adefovir and tenofovir. For long-term lesion reversal, the most important aspect is the choice of drug. Three factors must be considered when choosing a drug: the effectiveness of the drug therapy, its safety, and the occurrence of drug resistance. Long-term use of antiviral drugs that consistently suppress viral replication and prevent the development of drug resistance will result in improved liver histology and delay the development of clinical endpoints such as cirrhosis and hepatocellular carcinoma.