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HBV nucleos(t)ide reverse transcriptase inhibitors (NrtIs) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs. This phase II trial (NCT03576066) evaluated the efficacy and safety of the investigational core inhibitor, vebicorvir (VBR), in virologically- suppressed patients on NrtIs.Non-cirrhotic, NrtI-suppressed patients with chronic HBV were randomised to VBR 300 mg once daily or matching placebo (PBO) for 24 weeks. Treatment was stratified by hepatitis B e antigen (HBeAg) status. The primary endpoint was change from Baseline in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks.Of 73 patients enrolled, 47 were HBeAg positive and 26 were HBeAg negative. In HBeAg-positive and -negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel, high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline achieved undetectable HBV DNA at Week 24 in the VBR+NrtI vs. PBO+NrtI group. In HBeAg-positive patients, a greater change from Baseline in HBV pregenomic (pg)RNA was observed at Week 24 with VBR+NrtI vs. PBO+NrtI. Treatment-emergent adverse events (TEAEs) in VBR+NrtI patients included upper respiratory tract infection, nausea, and pruritus. No serious adverse events, Grade 4 TEAEs, or deaths were reported.In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was demonstrated by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone.NCT03576066.Core inhibitors represent a novel approach for the treatment of chronic hepatitis B virus (HBV) infection, with mechanisms of action distinct from existing treatments. In this study, vebicorvir added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated.

Background The incidence and risk factors for adefovir-resistant HBV have not been clearly defined. Aims To characterize the virologic response to adefovir, to determine the rate of adefovir resistance and to explore factors associated with initial virologic response (IVR) and adefovir resistance. Methods All hepatitis B patients who received adefovir for ≥6 months at our center were prospectively monitored for virologic response and adefovir resistance. Results Forty three patients were included; mean treatment duration was 18 months (range 6–45). Thirty four (79%) patients had prior lamivudine. IVR was observed in 44% patients and associated with higher pretreatment ALT ( P =0.05) and the absence of HBeAg ( P =0.02). Six (14%) patients were found to have adefovir-resistant mutations. The cumulative probability of genotypic resistance to adefovir at month 24 was 22%. Patients with adefovir resistance were more likely to have been switched from lamivudine to adefovir monotherapy ( P =0.01), to be older ( P =0.04), and to be infected with HBV genotype D ( P =0.02). Conclusions Roughly 50% of patients failed to achieve IVR on adefovir. The cumulative probability of adefovir resistance at 2 years was 22%. Our data suggest that combination of lamivudine and adefovir may prevent emergence of adefovir resistance in patients with lamivudine-resistant HBV.

Approximately 350 million people worldwide are chronically infected with hepatitis B virus (HBV). If left untreated, approximately 20% will develop cirrhosis and complications of end-stage liver disease [1,2]. Antiviral therapy may decrease the progression to cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC). Until recently, the only treatment for chronic hepatitis B was standard interferon (IFN). Interferon has limited efficacy, and may be associated with severe sepsis and worsening of hepatic failure in patients with decompensated cirrhosis [3,4]. The availability of oral antiviral agents with a better safety profile has significantly changed the management of end-stage liver disease caused by HBV. Lamivudine has been shown to suppress HBV replication, and to improve or stabilize liver function in patients with compensated as well as in those with decompensated cirrhosis [5,6]. Adefovir dipivoxil has also demonstrated efficacy in patients with decompensated cirrhosis and lamivudine-resistant HBV [7]. Oral nucleos(t)ide agents have delayed or obviated the need for liver transplantation in some patients, but transplantation is still required for those who present with advanced liver failure [8,9]. This article will focus on the use of antiviral agents for the treatment of HBV-cirrhosis.

Chronic hepatitis B infection continues to be a major public health concern worldwide. The natural history of the disease can be divided into 4 different phases: immune tolerance, immune clearance, inactive carrier, and reactivation. The goals of treatment are sustained viral suppression, normalization of ALT, and improvement in liver histology. Antiviral agents in current use include standard interferon-alpha, lamivudine, and adefovir. With an improved understanding of the natural history of the disease and a growing repertoire of antiviral drugs, the important questions are: who should receive treatment, what is the best agent to use, and what is the optimal duration of therapy? Treatment is indicated for patients in the immune clearance and reactivation phases. Patients with high pretreatment ALT level, detectable HBV DNA in the serum, and active inflammation on liver biopsy are predicted to have the highest chance of response to treatment. The choice of a particular agent must balance long-term benefits such as the likelihood of a sustained response against long-term risks such as drug resistance. Interferon treatment leads to a more durable response but is associated with unpleasant side effects. Lamivudine is effective and well tolerated but requires long-term therapy and is associated with drug resistance. Adefovir has proven efficacy and a very low rate of drug resistance but is associated with a small risk of reversible nephrotoxicity. For HBeAG-positive chronic hepatitis B and HBeAG-negative chronic hepatitis B, the duration of interferon therapy is 4-6 months and 12 months, respectively. Duration of treatment is at least 1 year with lamivudine and adefovir; longer duration of treatment is needed in most patients, but the optimal duration of treatment and the criteria for stopping treatment have not been established.