We studied the long-term efficacy of adefovir dipivoxil (ADV) treatment in 42 HBeAgnegative patients with chronic hepatitis B (CHB) who had developed genotypical lamivudine (LAM) resistance with virological and clinical breakthroughs under long-term LAM treatment. Patients were allocated in 2 treatment groups. In the first (n ؍ 14), LAM was switched to ADV monotherapy whereas in the second (n ؍ 28) ADV was added to LAM. The two groups did not differ in patients' characteristics, all of them having HBV genotype D infection with the precore stop codon mutation. Within 12 months from start of ADV treatment, serum HBV DNA became nondetectable and ALT normalized in 71% and 90% of patients, respectively, with no difference between the 2 arms. Patients with baseline HBV DNA levels less than 10 7 copies/ml experienced a significantly earlier and more frequent decline in serum HBV DNA to nondetectable levels as compared with patients with greater than 10 7 HBV DNA copies/ml at baseline (P ؍ 0.0013) This response has hitherto been maintained (median treatment duration 40 months) in all patients with ADV added to LAM, whereas virological and biochemical breakthroughs due to development of ADV signature resistance mutations occurred in 3 of 14 patients (21%) on ADV monotherapy 15 to 18 months from start of treatment (P ؍ 0.0174). Conclusion: Adding ADV to LAM in HBeAgnegative CHB patients with LAM resistance effectively suppresses HBV replication in most of them and induces biochemical remission that can be maintained in all of them at least for 3 years without any evidence of development of resistance to ADV. (HEPATOLOGY 2007;45: 307-313.)See Editorial on Page 266 C hronic infection with the hepatitis B virus (HBV) represents a global health problem, being a major cause of liver disease, morbidity, and mortality. Effective long-term treatment of chronic viral B liver disease improves significantly patients' survival and reduces the risk of development of major complications. 1 Longterm nucleos(t)ide analog administration represents the first-line/first-choice therapy for most patients with chronic hepatitis B (CHB), particularly those with the hepatitis B e antigen (HBeAg)-negative type of the disease. [1][2][3][4][5] Lamivudine (LAM) is the first nucleoside analog approved in the treatment of CHB and, because of potency, safety profile, and relatively low cost, it has been and is still widely applied globally as first-choice therapy for CHB patients either HBeAg-positive or HBeAg-negative. 1 However, approximately 70% of CHB patients in long-term LAM therapy develop resistance to the drug within approximately 3 years of treatment and experience clinical relapses that may be severe and occasionally life threatening. 4,[6][7][8][9] Continuation of LAM therapy in patients who have developed virologic resistance is of no benefit to them. 7,10 LAM-resistant patients have been treated with adefovir dipivoxil (ADV) either in monotherapy or in combination with LAM without significant differences between the two regime...
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-
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