Relapse Rate and Associated-Factor of Recurrence after Stopping NUCs Therapy with Different Prolonged Consolidation Therapy in HBeAg Positive CHB Patients

Pan, Xingfei; Zhang, Ka; Yang, Xiaoàn; Liang, Jian; Sun, Hongru; Li, Xuejun; Zou, Yong; Xu, Quan; An, Geng; Li, Gang; Xu, Qi-Huan

doi:10.1371/journal.pone.0068568

Cited by 23 publications

(34 citation statements)

References 23 publications

(28 reference statements)

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“…The off‐treatment durability in HBeAg‐negative patients seems to be not as good as that in HBeAg‐positive patients. Moreover, there are few head‐to‐head studies comparing the differences between patients with different pretreatment HBeAg status, mainly because of their small sample sizes . On the other hand, although the patients mostly relapse within 3 years, longer follow‐up periods are necessary to identify relapses and to evaluate clinical outcomes.…”

Section: Introductionmentioning

confidence: 99%

Varying 10‐year off‐treatment responses to nucleos(t)ide analogues in patients with chronic hepatitis B according to their pretreatment hepatitis B e antigen status

Liu

et al. 2018

J of Digest Diseases

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Section: Introductionmentioning

confidence: 99%

Varying 10‐year off‐treatment responses to nucleos(t)ide analogues in patients with chronic hepatitis B according to their pretreatment hepatitis B e antigen status

Liu

et al. 2018

J of Digest Diseases

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“…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.…”

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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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“…A recent study by Pan et al [16] showed that the cumulative rate of relapse for subjects exposed to prolonged consolidation therapy was significantly lower than for a group who met current standards for cessation of NUC therapy (recommended by the 2005 APASL). This suggests that a sustained response persisting for >48 weeks is a predictive marker for a longer-term sustained response follow- ing discontinuation of NUCs.…”

Section: Discussionmentioning

confidence: 96%

Long-term outcomes after nucleos(t)ide analogue discontinuation in HBeAg-positive chronic hepatitis B patients

Guo

Zhu

et al. 2014

Clinical Microbiology and Infection

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Nucleos(t)ide analogue (NUC) resistance is an important clinical risk resulting from long-term therapy in chronic hepatitis B (CHB) management. Discontinuation of NUCs is a feasible strategy to reduce resistance. We aimed to observe the outcomes after NUC withdrawal in HBeAg-positive CHB patients. A total of 97 patients (11 patients with HBsAg loss and 86 patients with sustained HBeAg seroconversion) were enrolled. HBV DNA levels and alanine aminotransferase (ALT) levels were monitored regularly after discontinuation. Relapse was defined as HBV DNA levels >2000 IU/mL in at least two determinations more than 4 weeks apart. HBeAg seroconversion was achieved within 48 weeks (interquartile range (IQR), 24-72 weeks). The time on consolidation therapy was 96 weeks (IQR, 84-144 weeks). No relapses occurred for HBsAg loss patients. Evidence of relapse was observed in 9.3% of HBeAg seroconversion patients. All relapse cases occurred within 48 weeks after discontinuation. The time to relapse was 33 ± 15 weeks. Elevation of HBV DNA and ALT levels over baseline were only observed in 12.5% of relapse patients. There were no significant differences in baseline characteristics (sex, HBV genotype, age or ALT levels) or time on consolidation therapy between patients with relapse or sustained response. NUC discontinuation in HBeAg-positive CHB patients is feasible after achieving HBeAg seroconversion at a minimum of 24 weeks. There is further benefit to prolonging the time on consolidation therapy to reduce relapse. More than 48 weeks of sustained response is a predictive marker for long-term sustained response.

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Relapse Rate and Associated-Factor of Recurrence after Stopping NUCs Therapy with Different Prolonged Consolidation Therapy in HBeAg Positive CHB Patients

Cited by 23 publications

References 23 publications

Varying 10‐year off‐treatment responses to nucleos(t)ide analogues in patients with chronic hepatitis B according to their pretreatment hepatitis B e antigen status

Varying 10‐year off‐treatment responses to nucleos(t)ide analogues in patients with chronic hepatitis B according to their pretreatment hepatitis B e antigen status

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

Long-term outcomes after nucleos(t)ide analogue discontinuation in HBeAg-positive chronic hepatitis B patients

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