Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine

Abstract

We determined the clinical outcome of hepatitis e antigen (HBeAg)-negative chronic hepatitis B patients treated with long-term nucleos(t)ide analog therapy starting with lamivudine. We evaluated 201 such patients treated for 3.8 ؎ 1.4 years and 2 historical similar cohorts: 1 treated with interferon-alfa (n ‫؍‬ 209) and 1 untreated (n ‫؍‬ 195). Virological or biochemical remission rate at 48 months under lamivudine was 34% or 36%, respectively, whereas adefovir was administered in 79 patients with virological-biochemical breakthroughs or no response. Of the lamivudinetreated patients, 4 died, 1 underwent a transplantation, and another 8 developed major events, all having advanced fibrosis at baseline and all but 1 having experienced breakthroughs or no response. At 5 years, survival was 96%, and major event-free survival was 93%. The major event-free survival was significantly better in patients with than in those without virological remission under lamivudine. At the end of follow-up, both survival and major event-free survival were independently associated with type of and response to treatment, being significantly better in patients under long-term antiviral therapy or interferon sustained responders than in interferon non-sustained responders or untreated cases (5-year survival: 96% or 98% vs. 88% or 90%, respectively). In conclusion, in HBeAg-negative chronic hepatitis B, long-term nucleos(t)ide analog therapy starting with lamivudine significantly improves survival and reduces the risk of major complications, compared with interferon non-sustained responders or untreated patients. In such patients with advanced fibrosis, close follow-up for lamivudine resistance and prompt onset of additional antiviral therapy is required or the ab initio use of agent(s) with low resistance rates should be considered. (HEPATOLOGY 2005;42:121-129.) H epatitis e antigen (HBeAg)-negative chronic hepatitis B (CHB) represents a rather late phase in the course of chronic hepatitis B virus (HBV) infection 1,2 usually associated with replication of HBV variants that are unable to produce HBeAg because of mutations either at the precore or basic core promoter region of the viral genome. 2,3 HBeAg-negative CHB is a potentially severe and progressive form of chronic liver disease with rare spontaneous remissions, frequent progression to cirrhosis, and increased risk of hepatocellular carcinoma (HCC). [4][5][6][7] The management of CHB has improved over the last years with the addition of lamivudine and more recently adefovir dipivoxil (ADV), but it is still suboptimal in achieving sustained off-therapy responses. [8][9][10][11] In particular in HBeAg-negative CHB, interferon-alfa (IFN␣), the first available effective therapeutic option in CHB, is the agent offering the higher chances for sustained-off therapy response ranging between 18% and 30%. 10-13 Conversely, both lamivudine and ADV, 2 oral, safe, and well-

Response predictors to treatment with pegylated interferon in chronic hepatitis B

“…In studies that analyzed treatment with lamivudine in HBeAgnegative patients or those with advanced liver fibrosis, sustained viral suppression was associated with the decrease in complications of cirrhosis and hepatocellular carcinoma. 11,19,20 A recent meta-analysis showed that the risk of hepatocellular carcinoma can be significantly decreased with viral suppression through antiviral therapy. 21 After NA withdrawal, relapse of viral infection can occur in most HBeAg-positive individuals that did not loose the HBeAg, as well as in HBeAg-negative individuals.…”

Five-year results of oral antiviral therapy in HBeAg-negative chronic Hepatitis B

“…These patients remained in remission after 5 years during a median follow-up period of 36 months, and virologic breakthrough associated with resistance was reported to be 33% in a median period of 15 months (17). George et al (23) reported HBV DNA suppression rates in 209 patients with HBeAgnegative chronic hepatitis B as 73.2% at the end of the first year, 52.3% at the end of 2 years, 40% at the end of 3 years, and 34% at the end of 4 years, whereas failure rates were approximately 46% within this period. In another study, Vito et al reported HBV DNA suppression rates that were 88.6% in the first year, 63% in the second year, 48% in the third year, and 39% in the fourth year in 616 patients with HBeAg negative chronic hepatitis B; the virologic failure rate was 33% under lamivudine (13).…”

Comment obtenir une efficacité optimale du traitement de l’hépatite chronique virale B ?

“…Cet analogue nucléosidique dont la tolérance est excellente a permis d'induire une réponse chez la majorité des malades [10,11]. Néanmoins, son utilisation a été rapidement limitée par l'émergence de mutations de résistance responsables d'une perte d'efficacité et d'une réactivation virale particulièrement sévère chez les malades atteints de cirrhose [11]. La fréquence de ces résistances augmentait de 20 % à la première année pour atteindre 70 % à la cinquième année de traitement [11].…”

“…Néanmoins, son utilisation a été rapidement limitée par l'émergence de mutations de résistance responsables d'une perte d'efficacité et d'une réactivation virale particulièrement sévère chez les malades atteints de cirrhose [11]. La fréquence de ces résistances augmentait de 20 % à la première année pour atteindre 70 % à la cinquième année de traitement [11]. Des études à long terme chez des malades à fibrose sévère ont montré que le traitement diminuait de façon significative par rapport à un placebo le risque d'évolution vers la cirrhose, la survenue de complications et de l'hépato-carcinome [12].…”