Hepatitis B Virus Resistance to Nucleos(t)ide Analogues

Zoulim, Fabien; Locarnini, Stephen

doi:10.1053/j.gastro.2009.08.063

Cited by 628 publications

(694 citation statements)

References 119 publications

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“…In this study, mutations rtL80I and rtL80V were detected in three out of four viral breakthrough patients, emphasizing the importance of rtL80I and rtL80V in the development of LDT resistance. It was generally believed that the complementary mutations were co-selected or subselected with primary resistance mutations and the complementary mutations were maintained after development (Allen et al, 1998;Delaney et al, 2003;Locarnini, 2008;Ono et al, 2001;Pallier et al, 2006;Tenney et al, 2004;Warner et al, 2007;Zoulim & Locarnini, 2009). Interestingly, in this study, we found that rtL80I and rtL80V were detected earlier than (patients O and Y) or at the same time as (patient J) the primary mutation rtM204I, and rtL80I and rtL80V mutation might or might not be maintained after the dominance of rtM204I (Fig.…”

Section: Resistant Mutations and Hbv Quasispecies In Ldt Therapysupporting

confidence: 51%

Resistant mutations and quasispecies complexity of hepatitis B virus during telbivudine treatment

Yin

Wei

et al. 2015

Journal of General Virology

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Ultra-deep pyrosequencing (UDPS) was used to analyse the dynamics of quasispecies and resistant mutations during telbivudine (LDT) treatment of hepatitis B patients. Twenty-six HBeAg-positive chronic hepatitis B patients were treated with LDT for a period of 104 weeks and were characterized as 16 responders, six partial responders and four viral breakthrough patients based on hepatitis B virus (HBV) DNA levels. The plasma samples were subjected to UDPS of the reverse transcriptase (RT) region of HBV. Mutations rtM204I, rtL80I and rtL80V were detected in at least three of the four viral breakthrough patients, indicating the significant roles of the mutations in resistance to LDT. The degree of complexity of viral quasispecies remained in a steady state in the absence of selection pressure, but increased after the LDT treatment. The complexity in the responder group at week 12 was significantly higher than that in the group comprising partial responders and viral breakthrough patients. In vitro replication efficiency analyses showed that the RT mutations had different impacts on HBV replication, with a tendency of rtM204I.rtL80V.rtL80I. Furthermore, double mutations rtL80I/M204I and rtL80V/M204V had replication efficiency similar to that of rtL80I and rtL80V, respectively. Consistent with previous studies, mutation rtM204I was found to be highly resistant to LDT. However, in contrast with their sensitivity to lamivudine, rtL80I and rtL80V were moderately resistant to LDT. Our results indicated that rtL80I and rtL80V may not only serve as replication complementary mutations to rtM204I, but also directly contribute to the LDT resistance.

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Section: Resistant Mutations and Hbv Quasispecies In Ldt Therapysupporting

confidence: 51%

Resistant mutations and quasispecies complexity of hepatitis B virus during telbivudine treatment

Yin

Wei

et al. 2015

Journal of General Virology

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“…Furthermore, a study has demonstrated that adult patients with CHB need over 2 years of NUC treatment to reduce risk of cirrhosis, HCC or CHB-related death [14]. In order to achieve and maintain virologic suppression, avoid virologic breakthrough, and attain undetectable levels of HBV DNA, optimal medication adherence is essential [15]. Antiviral therapy functions to prevent, delay, and reverse disease progression, leading to improved disease management and ultimately result in better survival [16].…”

Section: Introductionmentioning

confidence: 99%

Adherence and perceived barriers to oral antiviral therapy for chronic hepatitis B

Liu

Farazi

et al. 2018

Global Health Action

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Background: Globally, of the 248 million people chronically infected with the hepatitis B virus (HBV), 74 million reside in China. Five oral nucleot(s)ide analogs (NUCs) have been approved for the treatment of chronic hepatitis B (CHB) in China. Objectives: The aims of this study were to determine rates of adherence to NUC therapy in patients with CHB, to identify the self-perceived barriers to adherence, and to examine the factors associated with adherence. Methods: Questionnaire-based interviews were administered among Chinese patients with CHB at hepatology clinics of a tertiary hospital in the city of Wuhan, China. Adults aged 18 years or older prescribed with NUCs were recruited and interviewed to complete a 27-item questionnaire in a private setting, and adherence was measured using the Morisky Medication Adherence Scale (MMAS-8). Results: Among 369 participants, only 16.5% had high adherence (score of 8), 32.2% had medium adherence (score of 6 to <8), and 51.2% were measured with low adherence (score of <6). A logistic regression model was used to determine the factors associated with medication adherence. Significant predictors of high adherence consisted of urban residency, non-cirrhotic status, not using prescribed pills other than HBV medications, and reminders from family members. The five most common reasons for skipping NUCs were that medication(s) are expensive (48.7%), forgetfulness (45.1%), have experienced or worry about potential side effects (19.8%), do not want others to know about my medication(s) usage (18.5%), and ran out of pills and do not have time to refill (15.9%). Conclusions: This study revealed that adherence rates to oral antiviral therapy were far from optimal. This finding should generate public attention, and it would be beneficial for interventional programs to target Chinese patients from rural regions, as well as patients with low socioeconomic status, cirrhosis, and taking multiple medications.

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“…However, a high rate of LAM resistance (LAM-R) was reported; LAM-R progressively increased during treatment at rates of 14-32% annually, exceeding 70% after 5 years [6][7][8]. LAM-R development is responsible for the treatment failure and may confer crossresistance to all L-nucleosides, and might determine a reduced efficacy of other nucleos(t)ide analogue (NA) groups, thus limiting successive treatment options [9]. Therefore, LAM is not recommended by current guidelines for first-line monotherapy and has been substituted by the most potent NAs (entecavir or tenofovir) with a higher resistance barrier [10,11].…”

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confidence: 99%

HBV DNA suppression and HBsAg clearance in HBeAg negative chronic hepatitis B patients on lamivudine therapy for over 5years

Fasano

Lampertico

Marzano

et al. 2012

Journal of Hepatology

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Background & Aims: In long-term responder patients, it is unclear whether lamivudine (LAM) monotherapy should be continued or switched to a high-genetic-barrier analogue. This study aims at assessing LAM efficacy over a 5-year period and the residual risk of drug resistance. The rate of HBsAg clearance and LAM longterm safety profile were also evaluated. Methods: One hundred and ninety-one patients with chronic HBeAg-negative hepatitis B successfully treated with LAM monotherapy for at least 5 years were included. Biochemical and virological tests were assessed every 3 months in all patients and HBsAg quantification was performed in 45/191. Reverse-transcriptase (RT) region was directly sequenced in virological breakthrough patients. Results: One hundred and ninety-one patients (148 males, median age 53 years, 72 with compensated cirrhosis) responding to 60-month LAM monotherapy continued to receive LAM monotherapy beyond the initial 5 years and were followed for an additional 36-month median period (range 1-108). Virological response was maintained in 128/191 patients (67%) and HBsAg clearance was observed in 15/128 (11.7%) after a 32-month median period (range 1-65). The 63 remaining patients (33%) showed virological breakthrough after a 15-month median treatment (range 1-78). RT region analysis was performed in 38/63 breakthrough patients and LAM resistant mutations were found in 37/38. No significant side effects were observed. Conclusions: In long-term responder patients, continuation of LAM monotherapy resulted in persistent viral suppression in most cases with undetectable HBV DNA by real-time PCR; moreover, 11.7% of these patients cleared HBsAg. Selection of LAM resistance, however, can still occur even after successful longterm therapy, thus emphasising the importance of a careful virological monitoring. Ó

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Hepatitis B Virus Resistance to Nucleos(t)ide Analogues

Cited by 628 publications

References 119 publications

Resistant mutations and quasispecies complexity of hepatitis B virus during telbivudine treatment

Resistant mutations and quasispecies complexity of hepatitis B virus during telbivudine treatment

Adherence and perceived barriers to oral antiviral therapy for chronic hepatitis B

HBV DNA suppression and HBsAg clearance in HBeAg negative chronic hepatitis B patients on lamivudine therapy for over 5years

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