A case of entecavir resistance which is developed after complete viral suppression during entecavir treatment for nucleoside-naive chronic hepatitis B

Abstract

Entecavir (ETV) is a potent nucleoside analogue against hepatitis B virus (HBV), and the emergence of drug resistance is rare in nucleoside-naive patients because development of ETV resistance (ETVr) requires at least three amino acid substitutions in HBV reverse transcriptase. We observed a case of genotypic ETVr with viral and biochemical breakthrough during ETV treatment of nucleoside-naive patients with chronic hepatitis B (CHB). A 57-years-old HBeAg-positive man received ETV 0.5 mg/day for 145 weeks. HBV DNA was 7.7 log10 copies/ ml at baseline, decreased to below 2 at week 48, declined to a nadir of 0 (negative) at week 72, and rebounded to 2.2 log10 copies/ ml at week 90 and remained this level until 109 weeks and increased to 6.8 log10 copies/ ml at week 145. Alanine aminotransferase (ALT) level increased to 440 IU/ L at week 145. The ETVr-related substitution (rtS202P) and lamivudine resistance-related substitutions (rtL180M + rtM204V) were detected by DNA sequencing analysis at week 145. The patient discontinued ETV therapy at week 145, and then received 245 mg of tenofovir disoproxil fumarate (TDF). Afterwards, HBV DNA level dropped to below 2.6 log10 copies/ml and ALT level was normalized after 19 weeks of TDF dosing. The three substitutions associated with ETV and lamivudine resistance developed after complete viral suppression in a nucleoside-naive CHB patient during ETV treatment. In spite of the extremely rare chance of viral mutation during ETV treatment, nucleoside-naive patients should be carefully monitored for resistance even if complete suppression is present.

Entecavir resistance in a patient with treatment‑naïve HBV: A case report

“…Hence, ETV is a potent NA against HBV, and emergence of drug resistance is rare in NA-naïve patients (10)(11)(12). However, cases of ETVr, which developed in nucleoside-naïve patients, have been described in the literature (5,8,(11)(12)(13). The present report describes a NA-naïve patient with chronic HBV, who experienced ETVr and viral rebound during ETV treatment, when there was only one mutation present in the RT domain.…”

“…Among these therapies, the nucleos(t)ide analogues (NAs) are the treatment of choice (3). However, the efficacy of antiviral therapy for chronic hepatitis B virus (HBV) is impaired by emerging viral resistance (4,5). The selection of antiviral-resistant mutations depends on viral factors, such as the lack of a proofreading mechanisms during reverse transcription, which creates a large pool of HBV quasispecies that are better able to replicate due to their increased resistance levels (6,7).…”

“…Among the approved NA therapies for HBV, lamivudine (LVD), adefovir-dipivoxil and telbivudine (LdT) are associated with the highest rate of drug resistance in NA-naïve patients, as these offer a lower barrier to resistance exerting modest antiviral activity that incompletely suppresses viral replication providing the greatest opportunity for selecting drug-resistant virus, whereas entecavir (ETV) and tenofovir (either TAF or TDF) are associated with the lowest rate of drug resistance (5,6). Resistance to nucleoside/nucleotide antivirals arises through specific mutations in the HBV polymerase (pol) reverse transcriptase (RT) domain (5). The first cases of ETV resistance (ETVr) were observed in patients receiving ETV after failure of LVD.…”

“…The first cases of ETV resistance (ETVr) were observed in patients receiving ETV after failure of LVD. In fact, resistance to ETV appears to occur through a two-hit mechanism with primary LVD resistance (LVDr) substitutions (M204V/I with/without rtL180M) followed by amino acid substitutions at the rtI169, rtT184, rtS202 or rtM250 sites (5,6).…”