Review Article

Long-term Safety of Nucleoside and Nucleotide Analogues in HBV-monoinfected Patients

P. Lampertico; H. L. Y. Chan; H. L. A. Janssen; S. I. Strasser; R. Schindler; T. Berg


Aliment Pharmacol Ther. 2016;44(1):16-34. 

In This Article

Abstract and Introduction


Background Nucleos(t)ide analogues (NUCs) for chronic hepatitis B treatment achieve high rates of viral suppression and are generally well tolerated. Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are the currently preferred first-line agents. The safety of these agents in clinical practice is particularly relevant since long-term treatment is usually required.

Aim To summarise and critically discuss recent real-world evidence on the safety of treatment with ETV or TDF in hepatitis B virus (HBV)-monoinfected patients.

Methods PubMed and conference proceedings up to 15th June 2015 were searched using the terms ((((Hepatitis_B) OR HBV) AND ((tenofovir) OR entecavir)) AND (((lactic_acidosis) OR bone) OR renal)).

Results In selected populations included in registration studies, both ETV and TDF were well tolerated with no clinically significant renal toxicity or lactic acidosis. Growing 'real-world' clinical experience with these agents includes some reports of ETV-associated lactic acidosis and TDF-associated renal impairment; however, evidence from cohort studies appears to be conflicting. In the case of ETV-related lactic acidosis, a small number of cases have been reported, all in patients with decompensated cirrhosis. The degree of association between TDF treatment and changes in markers of renal function varies between studies: discrepancies may result from the use of different definitions and cut-offs for reporting renal toxicities, and differences in patient populations.

Conclusions Pre-treatment and on-treatment monitoring of eGFR and phosphorus, with prompt appropriate dose adjustment or treatment switch can minimise the impact of NUC renal toxicity. Standardisation of measures of renal impairment and identification of early molecular markers remain an unmet need.


The prevention and management of chronic hepatitis B virus (HBV) infection have dramatically improved over the past two decades, with vaccination programmes reducing the prevalence of HBV infection in younger populations in many regions to <1%; however, the global burden of chronic hepatitis B (CHB) remains high among individuals born before the introduction of vaccination.[1–3] The risk of disease progression and HBV-related hepatocellular carcinoma can be significantly reduced with effective anti-viral therapy.[4–6] Currently approved agents for the treatment of chronic HBV infection are interferons (IFNs) and nucleos(t)ide analogues (NUCs). Compared with IFNs, NUCs achieve not only higher rates of HBV DNA suppression but are also associated with a more favourable safety profile. Safety is particularly relevant since with NUCs, long-term, if not life-long, treatment is often needed.[4–6] Among the approved NUCs, entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are the currently preferred first-line agents for the treatment of chronic HBV infection and this review therefore focuses on these two options. Both these agents are potent anti-virals with favourable resistance profiles (minimal risk of resistance during long-term therapy).[4–6] In phase 3 registration studies and long-term clinical studies in NUC-naïve patients with compensated CHB, both ETV and TDF showed a favourable safety profile.[7–14] Both agents were also well tolerated in a phase 2 clinical study in NUC-naïve patients with chronic HBV infection and decompensated liver disease.[15] More recently there have been reports of specific adverse events (AEs) from real-life, long-term experience with these agents; mostly nephrotoxicity, which may be associated with Fanconi syndrome and reduced bone mineral density (BMD), and lactic acidosis. The aim of this review is to summarise and critically discuss recent real-world evidence on the safety of treatment with ETV or TDF in HBV-monoinfected patients.