Early hepatitis B virus DNA reduction in hepatitis B e antigen–positive patients with chronic hepatitis B

Leung, Nancy; Peng, Chung-Kang; Hann, Hie Won; Sollano, José D.; Lao-Tan, Judy; Hsu, Chao‐Wei; Lesmana, Laurentius M. Adrianto; Yuen, Man Fung; Jeffers, Lennox J.; Sherman, Morris; Min, Albert D.; Mencarini, K.; Diva, Ulysses; Cross, Anne; Wilber, Richard B.; López-Talavera, Juan Carlos

doi:10.1002/hep.22658

Cited by 148 publications

(99 citation statements)

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“…[8][9][10] Entecavir is a more potent antiviral agent than lamivudine and adefovir. [11][12][13] Most entecavir-treated patients achieve maintained viral suppression and low Abbreviations: ALT, alanine aminotransferase; anti-HBe, antibody against hepatitis B e antigen; CHB, chronic hepatitis B; CI, confidence interval; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HR, hazard ratio; INR, international normalized ratio; MELD, model for end-stage liver disease; SBP, spontaneous bacterial peritonitis.…”

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confidence: 99%

Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients With liver cirrhosis

et al. 2013

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Entecavir is a potent antiviral agent with high genetic barrier to resistance, hence it is currently recommended as first-line antiviral therapy for chronic hepatitis B (CHB). The aim of this study was to investigate the efficacy of entecavir on clinical outcomes and deaths. It was a retrospective-prospective cohort study based on two cohorts of patients. The entecavir cohort included consecutive CHB patients who had received entecavir 0.5 mg/day for at least 12 months. The historical control cohort included untreated patients recruited since 1997 who underwent routine clinical care. The primary outcome was the 5-year cumulative probability of hepatic events, defined as any cirrhotic complications, hepatocellular carcinoma (HCC), and/or liver-related mortality. A total of 1,446 entecavir-treated patients (72% men; age, 51 6 12 years; follow-up, 36 6 13 months) and 424 treatment-naïve patients (65% men; age, 41 6 13 years; follow-up, 114 6 31 months) were studied. Overall, there was no difference in hepatic events between the entecavir and control cohorts. Among patients with liver cirrhosis (482 entecavir-treated, 69 treatment-naïve), entecavir-treated patients had reduced risks of all clinical outcomes when compared with treatment-naïve patients with cirrhosis after adjusted for model for end-stage liver disease score: hepatic events (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.34-0.78; P 5 0.002), HCC (HR, 0.55; 95% CI, 0.31-0.99; P 5 0.049), liver-related mortality (HR, 0.26; 95% CI, 0.13-0.55; P < 0.001), and all-cause mortality (HR, 0.34; 95% CI, 0.18-0.62; P < 0.001). Entecavir-treated patients with cirrhosis who failed to achieve undetectable hepatitis B virus DNA (105/482 [22%]) had comparable risk of hepatic events as the untreated patients. Conclusion: Entecavir therapy reduces the risks of hepatic events, HCC, liver-related and all-cause mortality of CHB patients with liver cirrhosis in 5 years, particularly among those who had maintained viral suppression. (HEPATOLOGY 2013;58:1537-1547 C hronic hepatitis B (CHB) is the leading cause of liver cirrhosis and hepatic events, including various cirrhotic complications and hepatocellular carcinoma (HCC) in Asia. 1 A high level of hepatitis B virus (HBV) DNA has been consistently shown to be an independent risk factor for the development of cirrhosis and HCC. 2,3 Antiviral therapy is effective in suppressing HBV DNA and reducing the risk of hepatic events and HCC. 4,5 Lamivudine, the first generation oral nucleoside analogue was shown to reduce the incidence of hepatic events in patients with advanced fibrosis or compensated cirrhosis by 50%. 6 However, the clinical benefit may be negated by lamivudine resistance and virologic relapse after cessation of treatment. 6,7 Therefore, lamivudine is no longer the firstline antiviral therapy for CHB. Instead, nucleos(t)ide analogues with high genetic barrier to resistancenamely, entecavir and tenofovir disoproxil fumarateare recommended by international guidelines. [8][9][10] Entecavir is a more potent ...

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Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients With liver cirrhosis

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“…Although adefovir effectively suppresses HBV replication, it has a slower suppressive effect on HBV replication and has been shown to be less potent than other oral NAs in randomized clinical trials [38][39][40]. Locarnini et al [41] Reprinted with permission from Liaw et al [6] rate of adefovir resistance and factors associated with adefovir resistance in a pooled analysis of more than 1,000 patients who received adefovir treatment with or without lamivudine for 48-192 weeks.…”

Section: Adefovir Dipivoxilmentioning

confidence: 99%

“…More recently, several studies have shown that serum HBV DNA levels at 24 weeks of adefovir are predictive of favorable outcomes in patients with CHB receiving adefovir [10,15,40]. In an adefovir-controlled, randomized, open-label trial of telbivudine involving 135 treatment-naive, HBeAg-positive adults with CHB, undetectable serum HBV DNA levels at week 24 were associated with high rates of virologic response at week 52 [40].…”

Section: Adefovir Dipivoxilmentioning

confidence: 99%

“…In an adefovir-controlled, randomized, open-label trial of telbivudine involving 135 treatment-naive, HBeAg-positive adults with CHB, undetectable serum HBV DNA levels at week 24 were associated with high rates of virologic response at week 52 [40]. Specifically, a higher proportion of patients with undetectable HBV DNA levels at 24 weeks had undetectable serum HBV DNA levels (90% vs. 25%), ALT normalization (90% vs. 83%), and HBeAg seroconversion (50% vs. 9%) at week 52 than the proportion of patients who had detectable HBV DNA levels at week 24 of adefovir treatment.…”

Section: Adefovir Dipivoxilmentioning

confidence: 99%

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On-treatment monitoring of HBV DNA levels: predicting response and resistance to oral antiviral therapy at week 24 versus week 48

Chang

2009

Hepatol Int

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The suppression of hepatitis B viral (HBV) load correlates with favorable histologic, biochemical, and serologic responses in clinical trials of patients with chronic hepatitis B (CHB). The ability to identify patients who will not experience durable viral suppression in response to a specific antiviral regimen affords the opportunity for early treatment modification to optimize outcomes and avoid the development of antiviral resistance. Substantial evidence demonstrates that on-treatment serum HBV DNA levels are predictive of virologic response and risk of resistance. Regional clinical practice guidelines for the management of CHB universally recommend monitoring serum HBV DNA levels at treatment week 24. However, the value of this time point as a predictor of long-term success may not be applicable to all types of antiviral therapy. Indeed, each oral nucleos(t)ide analog (NA) antiviral therapy has a unique profile of potency, genetic barriers to resistance, and viral kinetics that may affect the optimal time point for on-treatment monitoring. This review discusses available data for appropriate predictors for long-term response and antiviral resistance for patients receiving specific oral NA antiviral therapy. Guidelines for on-treatment monitoring are also discussed.

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“…Two phase III pivotal trials of entecavir 0.5 mg daily versus lamivudine 100 mg daily in 715 HBeAg-positive patients and 648 HBeAg-negative patients have shown that entecavir is superior to lamivudine at week 48 of treatment [15,16]. Entecavir has also been found to be superior to 10 mg of adefovir at week 48 of treatment in an open-label study of 69 treatment-naive, HBeAg-positive patients [17]. The superiority of entecavir to lamivudine becomes even more apparent in comparative studies at week 96, partly because of its potency but, more important, because of its very low rate of resistance development [18,19].…”

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confidence: 99%

The saga of entecavir

Lai

Yuen

2009

Hepatol Int

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And the communication I have got to make is, that (it) has great expectations. -Charles Dickens Great ExpectationsChronic infection by hepatitis B virus (HBV) affects approximately 400 million people worldwide and is estimated to cause 1 million deaths annually [1]. The treatment of chronic hepatitis B has been radically altered in the past decade as a result of two developments. First, there are important new findings concerning its natural history. Second, the oral nucleoside/nucleotide analogues are now firmly established as an excellent alternative mode of therapy.Studies of the natural history of chronic hepatitis B suggest that other than the traditional endpoint of hepatitis B e antigen (HBeAg) seroconversion, sustained suppression of HBV DNA to very low levels, preferably to below the detection limit of sensitive polymerase chain reaction (PCR) assays, is an even more important endpoint of treatment [2][3][4][5]. The availability of nucleoside/nucleotide analogues makes the ideal of sustained viral suppression a reality. The rate of HBeAg seroconversion is slower with nucleoside/nucleotide analogues than with interferon therapy because they lack the immunomodulatory effects of interferon. Unlike interferon, nucleoside/nucleotide analogues can be given orally, and, except for mild and reversible nephrotoxicity (approximately 3% in 5 years) with adefovir [6], are almost without side effects. Even a relatively short period of treatment with lamivudine has been shown to decrease the risk for the development of cirrhosis complications and hepatocellular carcinoma (HCC) both in patients with established cirrhosis and in patients with precirrhotic disease [7,8]. The problem with long-term nucleoside/nucleotide analogue therapy is of course the potential for the development of resistant mutants.One of the most promising nucleoside analogues for long-term viral suppression with low rate of development of resistance is entecavir. Entecavir is a deoxyguanosine analogue that is rapidly phosphorylated intracellularly into its active 5 0 -triphosphate form. It inhibits HBV replication at three important steps: protein-linked priming of the HBV polymerase, synthesis of the first negative strand of the HBV DNA by reverse transcription, and synthesis of the second positive strand [9]. Its efficient phosphorylation and its triple action in the inhibition of HBV replication may explain its potency in the suppression of HBV DNA in small doses of 0.5-1 mg licensed for use. It has been approved for use in the treatment of chronic hepatitis B in the United States in 2005, and since then in the European Union, China, and several other countries worldwide.In the current issue of the journal, Shindo et al.[10] report a randomized, double-blind phase II study of the antiviral activity of once-daily oral dose of entecavir 0.01, 0.1, or 0.5 mg, or lamivudine 100 mg, over 24 weeks in 137 nucleoside-naive Japanese adults. This study confirmed the results of an international study of 169 patients including Asians and Westerners publish...

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Early hepatitis B virus DNA reduction in hepatitis B e antigen–positive patients with chronic hepatitis B

Cited by 148 publications

References 29 publications

Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients With liver cirrhosis

Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients With liver cirrhosis

On-treatment monitoring of HBV DNA levels: predicting response and resistance to oral antiviral therapy at week 24 versus week 48

The saga of entecavir

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