Comprehensive evaluation of hepatitis B virus reverse transcriptase substitutions associated with entecavir resistance

Abstract

Virologic resistance emerging during entecavir (ETV) therapy for hepatitis B virus (HBV)requiresT he genetic changes that impart resistance to the four approved nucleoside analogs used for the treatment of chronic hepatitis B virus (HBV) have been described (Table 1). Lamivudine (LVD) resistance (LVDr) arises from substitutions of the methionine (rtM204) to valine (rtM204V), isoleucine (rtM204I), or rarely serine (rtM204S) in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of the HBV reverse transcriptase (RT). The rtM204V change is always accompanied by an rtL180M growth adaptive substitution, 1 whereas the rtM204I substitution is found with or without rtL180M. Additionally, the rtV173L substitution has been found in some LVDr isolates and increases HBV replication capacity in vitro. 2 Resistance to telbivudine also arises from changes of the YMDD motif rtM204. 3 In contrast, resistance to adefovir (ADV) arises through rtN236T or rtA181V changes, whereas recent studies indicate that the rtA181T change often associated with ADV is more likely related to LVD therapy. 4,5 Entecavir (ETV), a novel deoxyguanosine analog, has demonstrated efficacy for treating HBV patients infected with wild-type or LVDr HBV. [6][7][8][9] Comprehensive resistance monitoring during clinical studies has revealed less than 1% viral resistance in nucleoside-treatment-naive (nucleoside-naive) patients through four years of therapy, reflecting a high genetic barrier to resistance that likely

Efficacy and resistance of entecavir following 3 years of treatment of Japanese patients with lamivudine-refractory chronic hepatitis B

“…In nucleoside-naive patients, emergence of entecavir resistance is rare because of entecavir's potent viral load reduction and high genetic barrier to resistance [49,50]. Substitutions at M204 ± L180 were detected at baseline for all patients described in this report and have been shown in previous studies to reduce in vitro susceptibility to entecavir by approximately eightfold [51]. Resistance to entecavir requires the presence of the rtM204V/I lamivudine-resistance substitution plus at least one additional amino acid substitution at rtT184, rtS202, or rtM250.…”

Resistance mutations of hepatitis B virus in entecavir‐refractory patients

“…Because these NAs share a common target for the viral reverse transcriptase (RT), resistance mutations to these reagents have been reported only in RT domains. Among these NAs, ETV is one of the most potent anti‐HBV reagents; it has a very low resistance rate in treatment‐naive patients7, 8, 9, 10, 11 and has long been used as a first‐line reagent. To date, a limited number of ETV‐resistant mutations have been reported.…”

“…To date, a limited number of ETV‐resistant mutations have been reported. They include the LAM‐resistant‐associated amino acid mutations at rt180 and rt204 and require additional mutations at rt169, rt184, rt202, or rt250 8, 12. Mutations of rtI163V and rtA186T in addition to the LAM‐resistant mutations have been reported to confer ETV resistance 13…”

Estudos moleculares sobre o vírus da hepatite B

“…Entretanto o papel dessas mutações na resistência a esses AN não está estabelecido, em alguns casos os estudos ainda são escassos e em outros os resultados apresentados por diferentes estudos são contraditórios. Algumas dessas mutações tem sido confirmadas como polimorfismos de determinados genótipos como é o caso da rtL217R, que é encontrada em praticamente todas as cepas de A2 (182) e das mutações na posição rt215, que são encontradas com frequência bem maior nas cepas genótipo D (240).…”