Relapse Rates in Chronic HBV After Stopping Antivirals
Relapse Rates in Chronic HBV After Stopping Antivirals
Registration studies show entecavir (ETV) to be effective and safe in NUC-naïve patients with chronic hepatitis B, but relapse rates after treatment discontinuation have not been well established. Relapse rates and predictors of relapse were evaluated in naïve HBeAg-positive and HBeAg-negative patients treated with ETV. Treatment duration was defined according to international guidelines. Virological relapse was defined as reappearance in serum of hepatitis B virus (HBV) DNA to >2000 IU/mL after discontinuation of treatment. A hundred and sixty-nine consecutive patients were treated for a median 181 weeks. 61% were HBeAg positive, 23% had cirrhosis, and mean HBV DNA level was 6.88 ± 1.74 log10 IU/mL. Ninety-two per cent became HBV DNA negative; 71% of HBeAg+ve patients became HBeAg negative and 68% anti-HBe positive; 14% became HBsAg negative and 13% anti-HBs positive. At the end of the study, 36 patients discontinued treatment: one due to breakthrough associated with resistant variants and 35 (20%) due to sustained virological response; 33 of these patients developed HBeAg seroconversion and 18 HBsAg seroconversion. Median off-treatment time was 69 weeks. Nine patients (26%), all HBeAg positive at baseline, developed virological relapse after a median 48 weeks off-treatment, 3 of them showed HBeAg reversion and 4 lost anti-HBe. No patient with HBsAg seroconversion relapsed. HBeAg clearance after week 48 of treatment was associated with an increase risk of relapse. After ETV discontinuation, HBsAg seroconversion was maintained in 100% of the patients, HBeAg seroconversion maintained in 90%, and virological relapse rate was 24%.
The hepatitis B virus (HBV) is estimated to have infected more than 2 billion people worldwide, of whom 400 million are chronically infected today and are at an increased risk of liver-related complications, including cirrhosis, liver failure, hepatocellular carcinoma (HCC) and death. In most regions of America, HBV prevalence is relatively low, with hepatitis B surface antigen (HBsAg) positivity ranging from <2% to 7% compared with Asia, Africa and the Middle East, where chronic hepatitis B prevalence rates reach 5–20% of the general population. Indications for treatment have been established by several international guidelines. Pegylated interferon alpha (PEG-IFN alpha), tenofovir (TDF) and entecavir (ETV) had been selected as the first-line therapy to initiate treatment in naïve chronic HBV-infected patients. Treatment end-points are complete viral suppression (undetectable levels of HBV DNA replication), HBeAg clearance and seroconversion in hepatitis B e antigen (HBeAg)-positive patients, and if possible, HBsAg clearance and development of anti-HBs antibody. Patients achieving these serological end-points may discontinue treatment, after an additional 6- to 12-month period of consolidation therapy, according to the cited guidelines. In HBeAg-negative patients, duration of treatment is not clear; it should be continued until HBsAg clearance is achieved.
However, the durability of sustained response after discontinuation of therapy appears to be variable, and some patients experience virological and/or serological relapse following treatment discontinuation. Most of the studies of long-term use of first-line nucleos(t)ide analogues (NUCs) and do not report relapse rates after treatment discontinuation. Older studies using lamivudine (LAM) report high relapse rates, but these studies do not follow current treatment recommendations. However, consolidation therapy with LAM decreased relapse rates. Studies reporting treatment with different NUCs obtained variable results, but high relapse rates were described. A study prolonging treatment with TDF for more than 3 years did not report discontinuation treatment or relapse rates. Experiences with long-term ETV and TDF treatment in clinical practice showed that patients achieved treatment end-points in a low rate; so few patients discontinued treatment, and their outcomes were not reported. In a randomized clinical trial, short-term treatment with ETV showed 76% virological and 22% serological relapse rates.
The aim of the current study was to evaluate the virological and serological relapse rates after discontinuation of long-term ETV treatment in chronic HBV naïve HBeAg-positive and HBeAg-negative patients.
Abstract and Introduction
Abstract
Registration studies show entecavir (ETV) to be effective and safe in NUC-naïve patients with chronic hepatitis B, but relapse rates after treatment discontinuation have not been well established. Relapse rates and predictors of relapse were evaluated in naïve HBeAg-positive and HBeAg-negative patients treated with ETV. Treatment duration was defined according to international guidelines. Virological relapse was defined as reappearance in serum of hepatitis B virus (HBV) DNA to >2000 IU/mL after discontinuation of treatment. A hundred and sixty-nine consecutive patients were treated for a median 181 weeks. 61% were HBeAg positive, 23% had cirrhosis, and mean HBV DNA level was 6.88 ± 1.74 log10 IU/mL. Ninety-two per cent became HBV DNA negative; 71% of HBeAg+ve patients became HBeAg negative and 68% anti-HBe positive; 14% became HBsAg negative and 13% anti-HBs positive. At the end of the study, 36 patients discontinued treatment: one due to breakthrough associated with resistant variants and 35 (20%) due to sustained virological response; 33 of these patients developed HBeAg seroconversion and 18 HBsAg seroconversion. Median off-treatment time was 69 weeks. Nine patients (26%), all HBeAg positive at baseline, developed virological relapse after a median 48 weeks off-treatment, 3 of them showed HBeAg reversion and 4 lost anti-HBe. No patient with HBsAg seroconversion relapsed. HBeAg clearance after week 48 of treatment was associated with an increase risk of relapse. After ETV discontinuation, HBsAg seroconversion was maintained in 100% of the patients, HBeAg seroconversion maintained in 90%, and virological relapse rate was 24%.
Introduction
The hepatitis B virus (HBV) is estimated to have infected more than 2 billion people worldwide, of whom 400 million are chronically infected today and are at an increased risk of liver-related complications, including cirrhosis, liver failure, hepatocellular carcinoma (HCC) and death. In most regions of America, HBV prevalence is relatively low, with hepatitis B surface antigen (HBsAg) positivity ranging from <2% to 7% compared with Asia, Africa and the Middle East, where chronic hepatitis B prevalence rates reach 5–20% of the general population. Indications for treatment have been established by several international guidelines. Pegylated interferon alpha (PEG-IFN alpha), tenofovir (TDF) and entecavir (ETV) had been selected as the first-line therapy to initiate treatment in naïve chronic HBV-infected patients. Treatment end-points are complete viral suppression (undetectable levels of HBV DNA replication), HBeAg clearance and seroconversion in hepatitis B e antigen (HBeAg)-positive patients, and if possible, HBsAg clearance and development of anti-HBs antibody. Patients achieving these serological end-points may discontinue treatment, after an additional 6- to 12-month period of consolidation therapy, according to the cited guidelines. In HBeAg-negative patients, duration of treatment is not clear; it should be continued until HBsAg clearance is achieved.
However, the durability of sustained response after discontinuation of therapy appears to be variable, and some patients experience virological and/or serological relapse following treatment discontinuation. Most of the studies of long-term use of first-line nucleos(t)ide analogues (NUCs) and do not report relapse rates after treatment discontinuation. Older studies using lamivudine (LAM) report high relapse rates, but these studies do not follow current treatment recommendations. However, consolidation therapy with LAM decreased relapse rates. Studies reporting treatment with different NUCs obtained variable results, but high relapse rates were described. A study prolonging treatment with TDF for more than 3 years did not report discontinuation treatment or relapse rates. Experiences with long-term ETV and TDF treatment in clinical practice showed that patients achieved treatment end-points in a low rate; so few patients discontinued treatment, and their outcomes were not reported. In a randomized clinical trial, short-term treatment with ETV showed 76% virological and 22% serological relapse rates.
The aim of the current study was to evaluate the virological and serological relapse rates after discontinuation of long-term ETV treatment in chronic HBV naïve HBeAg-positive and HBeAg-negative patients.
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