Current developments in nucleoside/nucleotide analogues for hepatitis B

Abstract

There had been remarkable development in nucleos(t)ide analogues (NAs) and evolution in treatment strategies in last 15 years. Currently, there are five NAs available for chronic hepatitis B treatment, namely lamivudine, telbivudine and entecavir (nucleoside analogues), adefovir dipivoxil and tenofovir disoproxil fumarate (nucleotide analogues). The advantages of relatively infrequent side effects and easy administration per oral make NAs popular treatment options. The major drawback of earlier generation NAs is the risk of emergence of drug resistance. Current international guidelines recommend the use of more potent agents with high genetic barriers to resistance including entecavir and tenofovir as first line chronic hepatitis B treatment. However, there is no consensus regarding the subsequent treatment regimens in patients with suboptimal responses to NAs. De novo combination therapy of two NAs, response-guided therapy and roadmap concept in NAs with subsequent switch or add-on therapy can also potentially improve treatment efficacy and avoid resistance.

Keywords::

• adefovir
• cost–effectiveness
• drug resistance
• entecavir
• HBV DNA polymerase
• lamivudine
• roadmap approach
• suboptimal responders
• telbivudine
• tenofovir disoproxil fumarate

Financial & competing interests disclosure

G Wong has served as an advisory committee member for Otsuka and Gilead. She has also served as a speaker for Bristol-Myers Squibb, Echosens, Furui and Otsuka. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The primary target of treatment for chronic hepatitis B (CHB) lies in prevention of disease progression into serious complications of decompensated cirrhosis, liver failure and hepatocellular carcinoma.

• Oral nucleos(t)ide analogs (NAs) have revolutionalized the CHB treatment by a daily oral dosing and few side effects.

• There are currently five NAs approved for CHB treatment: lamivudine, telbivudine and entecavir (nucleoside analogs), adefovir dipivoxil and tenofovir disoproxil fumarate (nucleotide analogs).

• NAs suppress hepatitis B virus (HBV) by targeting at the HBV DNA polymerase and thus intervene the replication of the virus.

• The latest internal guidelines recommend entecavir and tenofovir disoproxil fumarate as the preferred NAs.

• NA therapy has been proven to reduce the risk of hepatocellular carcinoma development and improve survival.

• De novo combination of NAs may achieve more complete viral suppression in the subgroup of patients with very high pre-treatment HBV DNA levels.

• Response-guided therapy for suboptimal responders to NAs, the roadmap approach, may improve the cost–effectiveness of NA therapy.

• Tenofovir alafenamide and besifovir are two promising NAs currently under investigations.

Notes