Published online Feb 28, 2021. doi: 10.3748/wjg.v27.i8.666
Peer-review started: October 21, 2020
First decision: December 3, 2020
Revised: December 25, 2020
Accepted: January 21, 2021
Article in press: January 21, 2021
Published online: February 28, 2021
Processing time: 127 Days and 18.1 Hours
Chronic hepatitis B virus (HBV) infection (CHB) is a public health concern worldwide. Current therapies utilizing nucleos(t)ide analogs (NA) have not resulted in a complete cure for CHB. Furthermore, patients on long-term NA treatment often develop low-level viremia (LLV). Persistent LLV, in addition to causing the progression of liver disease or hepatocellular carcinoma, may shed light on the current plight of NA therapy. Here, we review the literature on LLV, NA treatment, and various doses of entecavir to find a strategy for improving the efficacy of this antiviral agent. For LLV patients, three therapeutic options are available, switching to another antiviral monotherapy, interferon-α switching therapy, and continuing monotherapy. In real-world clinical practice, entecavir overdose has been used in antiviral therapy for CHB patients with NA refractory and persistent LLV, which encouraged us to conduct further in-depth literature survey on dosage and duration related entecavir studies. The studies of pharmacodynamics and pharmacokinetics show that entecavir has the maximal selected index for safety, and has great potential in inhibiting HBV replication, in all of the NAs. In the particular section of the drug approval package published by the United States Food and Drug Administration, entecavir doses 2.5-20 mg/d do not increase adverse events, and entecavir doses higher than 1.0 mg/d might improve the antiviral efficacy. The literature survey led us to two suggestions: (1) Increasing entecavir dose to 1.0 mg/d for the treatment of NA naïve patients with HBV DNA >2 × 106 IU/mL is feasible and would provide better prognosis; and (2) Further research is needed to assess the long-term toxic effects of higher entecavir doses (2.5 and 5.0 mg/d), which may prove beneficial in treating patients with prior NA treatment, partial virological response, or LLV state.
Core Tip: Persistent low-level viremia (LLV), in addition to causing the progression of liver disease or hepatocellular carcinoma, may shed light on the current plight of nucleos(t)ide analog (NA) therapy. Since 2006, the authors focused on NA-refractory and participated in treating LLV patients. We presented the interferon-α switching therapy to treat LLV patient with failure of combined nucleoside plus nucleotide therapy. The current study scoured the literature to shed light on the possibility of improving the antiviral effect of entecavir by increasing the dose. Here, we recommend that clinical trials involving entecavir should trial doses over more 1.0 mg/d for treating NA-refractory patients.