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

Lee, Hyun Woong; Kim, Hyung Joon; Hong, Sun; Ki, Bong; Chang, Heon-Young; Choi, Chang Hwan; Hyuk, Jae; Kim, Jae Gyu; Chang, Sae Kyung

doi:10.1159/000336561

Cited by 7 publications

(10 citation statements)

References 27 publications

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“…The cumulative rate of achieving VR was significantly higher in patients with HBV DNA at Ͻ5,000 copies/ml at year 1 than in patients with HBV DNA at Ն5,000 copies/ml at year 1 without treatment adaptation during prolonged ETV therapy (P ϭ 0.019). In accordance with a previously published article, (6) a Patient 1 was reported previously (14). b The upper limit of normal ALT levels is less than 40 IU/liter.…”

Section: Discussionsupporting

confidence: 74%

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Prolonged Entecavir Therapy Is Not Effective for HBeAg Seroconversion in Treatment-Naive Chronic Hepatitis B Patients with a Partial Virological Response

Lee

Kwon

et al. 2015

Antimicrob Agents Chemother

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The aims of this study were to investigate the efficacy of prolonged entecavir (ETV) therapy in treatment-naive chronic hepatitis B (CHB) patients and to determine whether continuous ETV therapy is feasible to achieve HBeAg seroconversion, particularly in patients with partial virological response (PVR). A total of 142 treatment-naive patients with CHB were enrolled. The mean duration of treatment was 65 (range, 26 to 90) months, and 86 patients (60.6%) were HBeAg positive. PVR was defined as detectable hepatitis B virus (HBV) DNA (>116 copies/ml) at year 1. The cumulative incidence of virological response (VR) increased from 54.9% at year 1 to 98.2% at year 7. HBeAg positivity (odds ratio [OR], 4.146; P ‫؍‬ 0.001) and initial alanine aminotransferase (ALT) (OR, 0.997; P ‫؍‬ 0.004) were independent risk factors for PVR. Among the 64 patients with PVR, 47 patients (73.4%) achieved VR within 4 years after prolonged ETV therapy without treatment adaptation. Three patients (2.1%) experienced virological breakthrough and HBV variants with genotypic resistance. The cumulative rate of HBeAg seroconversion was significantly higher in the patients with VR than in the patients with PVR (P ‫؍‬ 0.018). None of the PVR patients with HBV DNA at >5,000 copies/ml at year 1 ever experienced HBeAg seroconversion. Multivariate analysis identified VR at year 1 as the only determinant of HBeAg seroconversion (hazard ratio [HR], 3.009; P ‫؍‬ 0.010). In conclusion, although there were patients with PVR, prolonged ETV therapy showed excellent VR, with only 2.1% emergence of viral resistance during a 7-year follow-up. However, to achieve HBeAg seroconversion, drug modification is needed for HBeAg-positive patients with PVR (especially those with HBV DNA at >5,000 copies/ml at year 1). C urrently, treatment guidelines for both HBeAg-positive and HBeAg-negative chronic hepatitis B (CHB) patients recommend treatment with pegylated interferon or nucleos(t)ide analogs (NAs) (1-4). Although pegylated interferon has advantages, including a finite treatment duration and the absence of viral resistance, adherence to treatment is poor due to frequent side effects and the need for frequent subcutaneous injections (5). Given the increased risk of virological failure from poor adherence to pegylated interferon treatment, NAs have been widely used in clinical practice. Among several NAs, entecavir (ETV) and tenofovir (TDF) are especially potent inhibitors of hepatitis B virus (HBV) reverse transcriptase and DNA polymerase with minimal or no drug resistance (6-8). Therefore, ETV has been confidently used as a first-line therapy. Despite its efficacy, about 10 to 20% patients treated with ETV showed partial virological response (PVR) (9, 10). Unfortunately, HBV cannot be eradicated, and NAs must be continued until HBsAg seroclearance. Sustained viremia may ultimately result in HBV variants with genotypic resistance and clinical breakthrough. Therefore, it is related to subsequent therapeutic failure. In contrast to the frequently described genotypic re...

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Section: Discussionsupporting

confidence: 74%

“…The patients' baseline demographics and on-treatment responses are shown in Table 4. Patient 1 had been reported previously (14). Three patients were switched to adefovir (ADV) add-on therapy or TDF-based therapy (ETV plus TDF or TDF monotherapy).…”

Section: Figmentioning

confidence: 99%

Prolonged Entecavir Therapy Is Not Effective for HBeAg Seroconversion in Treatment-Naive Chronic Hepatitis B Patients with a Partial Virological Response

Lee

Kwon

et al. 2015

Antimicrob Agents Chemother

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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 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: 94%

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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“…Without lamivudine resistant mutations, mutations on rtM250, rtT184, or rtS202 by themselves do not exhibit significant resistance to entecavir. Although entecavir resistance is rare in treatment naive patients,16 simultaneous development of resistance to entecavir and lamivudine has been reported 24…”

Section: Introductionmentioning

confidence: 99%

Options for the management of antiviral resistance during hepatitis B therapy: reflections on battles over a decade

Yim

Hwang

2013

Clin Mol Hepatol

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Although much advancement has been achieved in the treatment of chronic hepatitis B, antiviral resistance is still a challenging issue. Previous generation antiviral agents have already developed resistance in a number of patients, and it is still being used especially in resource limited countries. Once antiviral resistance occurs, it predisposes to subsequent resistance, resulting in multidrug resistance. Therefore, prevention of initial antiviral resistance is the most important strategy, and appropriate choice and modification of therapy would be the cornerstone in avoiding treatment failures. Until now, management of antiviral resistance has been evolving from sequential therapy to combination therapy. In the era of tenofovir, the paradigm shifts again, and we have to decide when to switch and when to combine on the basis of newly emerging clinical data. We expect future eradication of chronic hepatitis B virus infection by proper prevention and optimal management of antiviral resistance.

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

Cited by 7 publications

References 27 publications

Prolonged Entecavir Therapy Is Not Effective for HBeAg Seroconversion in Treatment-Naive Chronic Hepatitis B Patients with a Partial Virological Response

Prolonged Entecavir Therapy Is Not Effective for HBeAg Seroconversion in Treatment-Naive Chronic Hepatitis B Patients with a Partial Virological Response

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

Options for the management of antiviral resistance during hepatitis B therapy: reflections on battles over a decade

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