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.

Review article: long‐term safety of oral anti‐viral treatment for chronic hepatitis B

“…18 On the other hand, all NAs are renally excreted. 2 Older generations of nucleotide analogues, that is, adefovir dipivoxil and TDF, are known to be associated with a small but non-negligible risk of …”

“…1 At present, six NAs have been approved as anti-viral therapy for CHB. These agents are classified according to their chemical structures: the three nucleoside analogues include lamivudine, telbivudine and entecavir, whereas the two nucleotide analogues include adefovir dipivoxil, tenofovir disoproxil fumarate (TDF), 2 and the newly approved tenofovir alafenamide (TAF). 3,4 NAs are well-known to effectively suppress hepatitis B virus (HBV) replication and reduce the risk of disease progression and hepatic events; 5 yet they cannot clear the replication template of HBV ie covalently closed circular DNA.…”

The progress and prospects of routine prophylactic antiviral treatment in hepatitis B-related hepatocellular carcinoma

“…However, long-term continuous treatment with NAs can cause drug resistance due to the HBV mutations [21]. International guidelines for antiviral treatment in hepatitis recommend more potent agents with high genetic barriers to resistance, including entecavir and tenofovir as first line CHB medications [22]. When drug resistance occurs, adding another drug that is effective against the drug-resistant mutants or switching to a new antiviral agent after the development of resistance seems to be the only efficacious strategy [23].…”

Combination therapy of interferon and nucleotide/nucleoside analogues for chronic hepatitis B

“…Compensatory mutations could also occur at position rt80 (rtL80V/I) and rt173 (rtV173L) . Common adefovir resistance mutations, which also lead to slower or suboptimal to tenofovir disoproxil fumarate, include rtN236T and rtA181T/V . Entecavir resistance requires at least three simultaneous mutations including rtL180M, rtM204V and one more mutations at rt184, rt202 or rt250 .…”