At least 4 nucleos(t)ide analogs have been approved for the treatment of chronic hepatitis B: lamivudine, adefovir dipivoxil, entecavir, and telbivudine. The introduction of these drugs has radically changed the treatment of this disease. The advantages of these drugs are their oral administration, excellent tolerability and efficacy in all types of chronic hepatitis B (compensated and decompensated disease). The limitations are the need for prolonged treatments, which hampers adherence and can cause selection of HBV strains resistant to distinct drugs. The resistance rate differs for each of the drugs. Nucleotide analogs such as adefovir and tenofovir are useful in patients resistant to nucleoside analogs such as lamivudine, entecavir and telbivudine and vice versa. In cases of resistance to one of these drugs, combined treatment is advised.

There are remarkable advances in the treatment of chronic hepatitis B (CHB) in the last few years. Unfortunately, prolonged antiviral treatment is associated with increasing risk of drug resistance/viral breakthrough (VBT), which may lead to flare-up and rapid decompensation. We have designed this study to predict the pretreatment and on-treatment factors responsible for development of VBT.

This study was conducted during the period of February 2000 to November 2007. We have included 423 patients who received lamivudine (LAM) therapy for at least 1 year and at least 2 follow-ups at 6 months' interval. Follow-up period was 12-78 months. Chi-square test, student's t test, and logistic regression analysis were performed to prove the validity.

Of the 423 study cases, 367 (86.8%) were of male patients and 261 (61.7%) patients were HBeAg positive; the age of the patients was 30.8 +/- 12.9 years. Development of VBT was 4.4, 22.8, 45.3, and 74% at 1, 2, 3, and 4 or more years, respectively. Pretreatment high HBV DNA (P = 0.005) and female sex (P = 0.01) were associated with VBT and pretherapy ALT (P = 0.698), HBeAg status (P = 0.273), and age (P = 0.059) were not associated. Duration of treatment, failure to lose HBeAg at 1 year, and HBV DNA nonresponder at 6 months were significantly (P = 0.001) associated with development of VBT.

Persistence of HBeAg at 1 year and HBV DNA nonresponder at 6 months are good predictors of development of VBT.

The changing scenario of hepatitis B virus therapy has encouraged the organisation of a workshop, endorsed by three Italian scientific societies, aimed at defining the current recommendations for hepatitis B virus treatment. Liver histology and stage of disease remain fundamental for treatment decisions; interferon and nucleoside/nucleotide analogues-based therapy represent different strategies for different phases of the hepatitis B virus disease. The recommendations defined: new and lower cut-off of hepatitis B virus-DNA for eligibility to therapy according to disease stage, how to optimise the use of nucleoside/nucleotide analogues and to individualise the monitoring of response and what to do with treatment failures. Specific recommendations have also been given for cirrhosis patients, those immune suppressed and co-infected with HIV and other hepatitis viruses.

Lamivudine can select resistant hepatitis B virus (HBV) tyrosine-methionine-aspartate-aspartate aminoacid motif (YMDD) mutants, which usually disappear in few months after lamivudine withdrawal. We report an unusual case of a male adult patient who showed a prolonged persistence of the M204I mutation up to 24 months after lamivudine withdrawal followed by the emergence of new distinct YMDD mutants (namely M204V, V207L). Only 42 months after lamivudine withdrawal wild-type YMDD motif became dominant over the YMDD mutants. To our knowledge, a so prolonged persistence of a YMDD mutant and also the emergence of new YMDD mutants many months after drug withdrawal are unusual.

Chronic hepatitis B virus infection, a major cause of end-stage liver disease and hepatocellular carcinoma, is a worldwide health concern. While the past two decades have brought major advances in the availability of treatments to help delay or prevent these outcomes, treatment of chronic hepatitis B remains a serious challenge, not least due to the ability of the virus to remain in hepatocyte nuclei as a source of potential reactivation-hence the term chronic hepatitis B infection. This article reviews the current treatments available and suggests a framework for a rational approach to managing the disease.

There has been a significant advance in the treatment of chronic Hepatitis B virus (HBV) infection and the following drugs were approved for therapy: Conventional interferon (IFN), pegylated interferon alfa-2a (PEG IFN alpha2a), lamivudine, adefovir and entecavir. Compared to nucleoside analogues IFN induces higher rates of sustained remission and HBsAg loss. Conventional IFN in lower doses (1, 5-3 MIU) tiw for 4-6 mo has similar efficacy in comparison to "standard IFN therapy". Longer IFN treatment is a significant factor for long-term remission in HBeAg-negative CHB, but the higher actual IFN dose is not such a factor. PEG IFN is superior to conventional IFN. There is no significant difference between PEG IFN alpha2a at doses 90 mcg/wk and 180 mcg/wk in HBeAg-positive patients. These results provide a rational for further clinical trials with lower doses PEG IFN alpha2a given in prolonged course as maintenance or intermittent treatment. Serious new problems arose after the introduction of nucleoside/nucleotide analogues in clinical practice. The most important ones are drug-resistance and the high rates of relapse after treatment discontinuation. Therapy should only be recommended if the expected benefit exceeds significantly the abstain from treatment. The choice of therapy should take into account the patient's age, co-morbidity, severity of liver disease and the risk of drug-resistance. New antivirals significantly suppress HBV-replication, but have no effect on cccDNA in hepatocytes, and after the treatment discontinuation viral relapses occurs. At the present level of knowledge it is impossible "to eradicate the virus" The realistic treatment goal is to achieve durable response by clearance of HBeAg, sustained decrease of serum HBV DNA levels, normalization of ALT, improvement of liver histology and stopping of liver fibrogenesis. The competition between IFN based therapy and nucleoside or nucleotide analogues still remains. IFN can cure the liver disease while nucleotide analogues only suppress the viral replication during therapy and can reduce the liver fibrosis. Treatment should be prolonged for 24-mo or longer by using maintenance or intermittent treatment course with the lowest effective IFN and PEG IFN doses. Nucleoside/nucleotide analogues are a promising treatment option, but additional data for treatment duration and long-term post-treatment outcome are necessary.

The results of earlier studies on determinants for the emergence of tyrosine-methionine-aspartate-aspartate (YMDD) mutants (rtM204 I/V) were controversial. The aim was to evaluate the impact of viral factors, host factors, host-viral interaction and drug factor on the emergence of rtM204 I/V.

56 non-cirrhotic and 58 cirrhotic patients received lamivudine therapy for a median of 34 (12-60) months.

rtM204 I/V emerged in 37 noncirrhotic and 36 cirrhotic patients. Stepwise logistic regression analysis showed that baseline hepatitis B e antigen (HBeAg) status [odds ratio (OR), 7.728; 95% confidental interval (CI), 2.886-12.957; P=0.0026], HBV-DNA level (OR, 3.756; 95% CI, 1.058-5.089; P=0.0202), alanine transaminase (ALT) level (OR, 6.285; 95% CI, 1.057-11.990; P=0.00246) and treatment duration (OR, 19.88; 95% CI, 8.652-31.762; P<0.0004) were independent determinants for the emergence of rtM204 I/V. Further categorical analysis and correlation test disclosed that patients with HBeAg positivity, HBV-DNA>500 pg/ml and ALT <5x upper limit of normal had significantly higher mutation rates.

HBeAg status, HBV-DNA, ALT levels and treatment duration are the major determinants for the YMDD mutation during lamivudine therapy, and should be considered in designing the therapeutic strategy.

The emergence of drug-resistant virus in hepatitis B virus patients treated with lamivudine is well documented. However, its clinical impact in the long-term treatment of anti-HBe positive compensated cirrhotic patients is not well known. In this study, we treated 22 consecutive patients with anti-HBe compensated cirrhosis with lamivudine for a median period of 42 months. All patients responded to lamivudine, but viral breakthrough occurred in 13 patients (59%) between 9 and 42 months of therapy due to the emergence of a mutant strain. During the follow-up, 11 developed hepatocellular carcinoma. Of these, 10 occurred soon after the emergence of viral resistance, generally showing aggressive behaviour, and one in the nine long-term responder patients (P = 0.013). Lamivudine resistance was the only independent predictor of hepatocellular carcinoma development (risk ratio: 10.4; 95% CI: 1.3-84.9). Our study suggests that the occurrence of lamivudine resistance increases the risk of hepatocellular carcinoma in anti-HBe positive cirrhosis and warrants further research.