Two cases of development of entecavir resistance during entecavir treatment for nucleoside-naive chronic hepatitis B

Kobashi, Haruhiko; Fujioka, Shin; Kawaguchi, Mitsuhiko; Kumada, Hiromitsu; Yokosuka, Osamu; Hayashi, Norio; Suzuki, Kazuyuki; Okanoue, Takeshi; Sata, Michio; Tsubouchi, Hirohito; Sato, Chifumi; Kiyosawa, Kendo; Tanikawa, Kyuichi; Seriu, Taku; Ishikawa, Hiroki; Takaki, Akinobu; Iwasaki, Yoshiaki; Osawa, Toshiya; Takaki, Toshiyuki; Sakaguchi, Koichiro; Shiratori, Yasushi; Yamamoto, Kazuhide; Tenney, Daniel J.; Omata, Masao

doi:10.1007/s12072-008-9108-8

Cited by 23 publications

(19 citation statements)

References 27 publications

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“…In a Japanese case, the patient received 0.1 mg/day ETV for 52 weeks and developed three resistance substitutions. Suboptimal dosing of ETV may be a possible contributing factor to resistance [7]. Colonno et al [3] reported that the emergence of ETV resistance in nucleoside-naive patients would likely require the emergence of viruses containing at least three resistance substitutions in a very small sub-population of patients who harbor infected cells/cccDNA that simultaneously encode LAM-resistant/ETV-resistant viruses [3,7].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the American Association for the Study of Liver Diseases (AASLD) guidelines recommend ETV as the first-line antiviral agent for treatment-naive chronic hepatitis B (CHB) patients [6]. However, rare cases of ETV resistance have recently been reported in treatment-naive patients [7]. We also experienced one case of genotypic ETV resistance with viral rebound during ETV treatment of nucleoside-naive patients with CHB.…”

Section: Introductionmentioning

confidence: 99%

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Simultaneous Emergence of Entecavir Resistance Mutations in a Nucleoside-Naive Chronic Hepatitis B Patient

et al. 2012

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Background: Entecavir (ETV) has potent antiviral activity against hepatitis B virus (HBV), and the emergence of drug resistance is rare in nucleoside-naive patients. Resistance requires simultaneous appearance of three mutations which account for the very low resistance profile of ETV. We experienced one case of genotypic ETV resistance with viral rebound during ETV treatment of nucleoside-naive patients with chronic hepatitis B (CHB). Case: A 50-year-old HBV e antigen-positive man received ETV 0.5 mg/day for 120 weeks. The level of HBV DNA was 9.0 log₁₀ copies/ml at baseline, declined to a nadir of 2.7 at week 60 and then rebounded to 6.0 at week 108 and 7.5 at week 120. The serum alanine aminotransferase level did not increase during ETV treatment. The ETV resistance-related substitution (T184A) and lamivudine resistance-related substitutions (L180M and M204V) were detected by sequence analysis at week 96. Conclusions: The three substitutions associated with ETV and lamivudine resistance developed simultaneously without complete suppression in a nucleoside-naive CHB patient after extended therapy. In spite of the extremely rare chance of viral mutation during ETV treatment, treatment-naive patients with high pretreatment viral loads and detectable HBV DNA during treatment should be carefully monitored or undergo targeted surveillance for resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Simultaneous Emergence of Entecavir Resistance Mutations in a Nucleoside-Naive Chronic Hepatitis B Patient

et al. 2012

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“…Meanwhile, the results also suggested that NA treatment is the major selecting factor of primary drug-resistant mutations and that NA treatment promotes putative NAr mutations (Li et al, 2012). Moreover, several previous studies showed that primary NAr mutations occur in patients with no history of NA treatment (Han et al, 2009;Kobashi et al, 2009;Pastor et al, 2009). Recently, another paper also reported that HBV resistance mutations were identified in 5 % of treatment-naïve patients by using INNO-LiPA (Fujirebio) line probe analysis (Mirandola et al, 2011).…”

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confidence: 99%

Nucleotide analogue-resistant mutations in hepatitis B viral genomes found in hepatitis B patients

Fan

Zhang

Xiong

et al. 2015

Journal of General Virology

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Chronic hepatitis B (CHB) is treated with nucleos(t)ide analogues (NAs). The reverse transcriptase (RT) region in the hepatitis B virus (HBV) genome mutates to resist NA treatment, yet the RT mutations have not been well characterized. Furthermore, the HBV genotype might influence RT sequence evolution, NA resistance (NAr) mutation patterns and drug resistance development. We examined 42 NAr mutation sites in 169 untreated and 131 NA-treated CHB patient samples. Patients were identified with HBV-B and HBV-C genotype infections, with a higher prevalence and mutation frequency of HBV-C than HBV-B. Seventeen reported NAr mutation sites and 13 novel mutations were detected. NAr-related mutation prevalence was significantly higher in NA-treated versus untreated patients. Primary antiviral-resistant mutants only existed in NA-treated patients. Sequencing data revealed seven HBV-C-specific mutations and three HBV-B-specific mutations. In conclusion, NA treatment and HBV genotype might constitute the selection basis and promote NA-resistant HBV strain evolution under antiviral therapy.Chronic hepatitis B (CHB), a life-threatening liver disease, is a global public health concern, caused by hepatitis B virus (HBV) (Chen et al., 2012;Franco et al., 2012;Zhao et al., 2010). IFN and nucleos(t)ide analogue (NAs) CHB treatments have been approved in China, including lamivudine (LAM), adefovir dipivoxil (ADV), entecavir and telbivudine (Pan et al., 2013;Shaw et al., 2006). NA treatment is more convenient than IFN-based therapy, has fewer side effects and more quickly reduces HBV DNA levels. NA therapy inhibits HBV DNA polymerase activity and DNA replication by targeting HBV-encoded reverse transcriptase (RT) (Leung et al., 2001;Locarnini & Mason, 2006;Locarnini et al., 2004). However, NA therapy is challenged by several conditions: viral persistence in infected hepatocytes, limited NA availability and antiviral NA resistance (NAr) mutations during long-term NA treatment (Fung et al., 2011;Liaw et al., 2004;Locarnini & Mason, 2006), which are the most important factors responsible for treatment failure (Locarnini, 2008; Lok et al., 2007b). Therefore, it is important to understand the mechanism underlying drug-resistant mutation evolution to prevent and control drug resistance (Khudyakov, 2010).A previous study analysed amino acid substitutions at 42 potential NAr mutation sites in the HBV full-length RT sequence (Baldick et al., 2008;Bartholomeusz et al., 2004;Ghany & Doo, 2009;Keeffe et al., 2008;Liu et al., 2010). NAr-associated mutations within the HBV RT region can be classified into five categories : primary drug-resistant mutations (category 1), compensatory mutations (category 2), putative NAr mutations (category 3), pre-treatment mutations (category 4) and new mutations (category 5) (Table S1, available in the online Supplementary Material).Recent studies demonstrated that the HBV genotype contributes to drug-resistant mutant evolution and selection . Moreover, HBV genotypes differ in LAM-resistant mutation patterns, as...

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“…Recently, however, rare cases of ETVr, which developed in nucleoside-naive patients, have been reported (14)(15)(16). We also observed one patient who developed ETVr-associated HBV RT substitutions, followed by virologic and biochemical breakthrough after complete viral suppression in longterm ETV treatment of nucleoside-naive CHB patients.…”

Section: Introductionmentioning

confidence: 54%

“…In that report, ETVr developed in a nucleoside-naive patient with genotype H of HBV, which did not achieve undetectable HBV DNA levels. In another report, ETVr have been emerged in two Japanese nucleoside-naive CHB patients after prolonged therapy and incomplete suppression (15). Finally, in a recent report, the three substitutions associated with ETV and LVD resistance has been developed simultaneously without complete suppression in a nucleoside-naive CHB patient after extended therapy (16).…”

Section: Treatment Of Chb Has Evolved Markedly With the Introduction mentioning

confidence: 95%

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

Doğan

Öztürk²,

Akın³

et al. 2015

Turk J Gastroenterol

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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.

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Two cases of development of entecavir resistance during entecavir treatment for nucleoside-naive chronic hepatitis B

Cited by 23 publications

References 27 publications

Simultaneous Emergence of Entecavir Resistance Mutations in a Nucleoside-Naive Chronic Hepatitis B Patient

Simultaneous Emergence of Entecavir Resistance Mutations in a Nucleoside-Naive Chronic Hepatitis B Patient

Nucleotide analogue-resistant mutations in hepatitis B viral genomes found in hepatitis B patients

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

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