• Efficacy and Safety of Besifovir Dipivoxil Maleate in a Phase 3 Trial of Patients With Chronic HBV Infection

Efficacy and Safety of Besifovir Dipivoxil Maleate in a Phase 3 Trial of Patients With Chronic HBV Infection

The efficacy of 48 weeks treatment with besifovir dipivoxil maleate (BSV) for chronic hepatitis B virus (HBV) infection is comparable to that of tenofovir disoproxil fumarate (TDF), with durable effects for 96 weeks, researchers report in the August issue of Clinical Gastroenterology and Hepatology. BSV has a better safety profile than TDF, however, in terms of bone and renal outcomes.

Comparison of viral suppression between the BSV-BSV and TDF-BSV groups. (A) Proportion of patients with HBV DNA <69 IU/mL by study week. (B) Proportion of patients with HBV DNA <20 IU/mL by study week.

The ultimate goals of treatment of HBV infection the eradication of the virus and a functional cure.

Nucleos(t)ide analogues (NAs) are first-line therapies for chronic HBV infection and include entecavir, TDF, and tenofovir alafenamide monotherapy. However, these therapies are not ideal, because hepatic decompensation or hepatocellular carcinoma can still develop in some patients, despite a complete virologic response. In addition, patients on entecavir can develop drug resistance—particularly patients taking lamivudine.

TDF can cause nephrotoxicity and reduce bone mineral density (BMD). Patients at high risk for renal or bone-related diseases should be considered for entecavir or tenofovir alafenamide therapy, based on their lamivudine treatment history. New therapeutic agents are necessary, including newer NAs or drugs that can act on other steps in viral replication.

BSV, an acyclic nucleotide phosphonate (a guanosine monophosphate), has been studied in phase Ia and 2b studies and found to suppress HBV replication.

Sang Hoon Ahn et al performed a phase 3 trial to compare the antiviral efficacy and safety of 48 weeks of treatment with 150 mg BSV vs 300 mg TDF in 197 patients with chronic HBV infection. The authors then performed a 48-week extension study, to evaluate the long-term efficacy and safety of BSV treatment (BSV-BSV and TDF-BSV groups) at week 96.

The authors evaluated virologic responses to therapy (HBV DNA below 69 IU/mL or 400 copies/ml), BMD, and renal outcomes for safety analysis. The main efficacy endpoint was the proportion of patients with a virologic response at week 48. After 48 weeks, TDF was switched to BSV (150 mg) for an additional 48 weeks.

Ahn et al found a small difference in the proportion of patients who met the primary endpoint (80.9% in the BSV group and 84.9% in the TDF group. The proportion of patients with HBV DNA below 20 IU/mL after 48 weeks of treatment was 63.8% in the BSV group and 68.8% in the TDF group, which was not significantly different.

At week 96, 87.2% of the BSV-BSV group patients (75/86) and 85.7% of the TDF-BSV group patients (72/84) had an HBV DNA level below 69 IU/mL (no significant difference between the groups). Furthermore, 81.4% of the patients in the BSV-BSV group and 77.4% in the TDF-BSV group had an HBV DNA level below 20 IU/mL; the difference was not statistically significant at any time point throughout the 96 weeks (see figure).

Among HB e antigen (HBeAg)-positive patients, rates of HBeAg seroconversion were 5.7% in the BSV group and 2.0% in the TDF group (no significant difference). No patients in the BSV group had HBsAg loss, and only 1 patient in the TDF group (1.1%) had HBsAg loss after 48 weeks of treatment. No HBsAg loss was observed after the 96-week treatment in the BSV-BSV group, and only 1.3% of TDF-BSV group patients (1/77) had HBsAg loss.

The proportions of patients whose levels of alanine aminotransferase normalized after 48 weeks of treatment were 73.4% in the BSV group and 74.2% in the TDF group, with no significant difference between the groups.

There was no significant difference in the proportions of patients with a virologic breakthrough (5.3% in the BSV group and 5.4% in the TDF group). All patients with a virologic breakthrough had a transient increase in HBV DNA levels, which was subsequently reversed without any additional intervention. During the 96-week study period, 4.65% of BSV-BSV group patients (4/86) and 15.48% of TDF-BSV group patients (13/84) had a virologic breakthrough; all these patients recovered spontaneously without additional intervention. No antiviral resistance was detected in the virologic breakthrough.

There was no significant difference in the rates of overall adverse events between the 2 groups throughout the study period.

Ahn et al conclude that BSV is non-inferior to TDF in HBV suppression at week 48. BSV had a better safety profile than TDF, in terms of renal and bone parameters. There were no significant differences in the virologic response rates between the 2 groups, regardless of whether patients were positive or negative for HBeAg. In the extension study, the antiviral effects of BSV were maintained for up to 96 weeks without serious safety concerns.

TDF was reported to produce virologic response rates of 87% in HBeAg-negative patients and 71% in HBeAg-positive patients after 144 weeks. From this study, BSV treatment produced comparable rates of virologic response, regardless of HBeAg status, with antiviral effects of maintained throughout 96 weeks.

 

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