Long-term follow-up of patients with anti-HBe/HBV DNA-positive chronic hepatitis B treated for 12 months with lamivudine

Santantonio, T.; Mazzola, Michele; Iacovazzi, Tiziana; Miglietta, Antonio; Guastadisegni, A.; Pastore, Giuseppe

doi:10.1016/s0168-8278(00)80076-8

Cited by 222 publications

(183 citation statements)

References 25 publications

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“…The follow-up liver biopsies were performed within the first 6 months after the onset of biochemical breakthrough (median, 5.5 [range, 1-6] months) (early follow-up biopsies) in 8 patients and after the first 6 months (median, 9 [range, 7-15] months) (late follow-up liver biopsies) in the remaining 5 patients. The median grading score was significantly higher in the late than the early follow-up biopsies (11 [range, 10-12] vs. 6.5 [range, [4][5][6][7][8][9][10][11], P ϭ .02), while there was no significant difference in the staging score or serum ALT or HBV DNA levels between these 2 groups. In addition, grading or staging score as well as ALT and HBV DNA levels at follow-up biopsies were similar with baseline findings irrespective of the timing of the follow-up biopsies ( Table 2).…”

Section: Resultsmentioning

confidence: 91%

Course of virologic breakthroughs under long-term lamivudine in HBeAg-negative precore mutant HBV liver disease

et al. 2002

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We studied the course of virologic breakthroughs detected by a quantitative polymerase chain reaction (PCR) assay in 32 of 78 patients with hepatitis B e antigen (HBeAg)-negative precore mutant hepatitis B virus (HBV) chronic liver disease under long-term lamivudine monotherapy. Serum HBV DNA levels were measured every 3 months and on every biochemical breakthrough. YMDD mutants were detected in 30 of the 32 patients with virologic breakthroughs. Among these 32 patients, biochemical remission rate was 44% at 6 months, 21% at 12 months, and 0% at 24 months after the onset of virologic breakthrough. Development of biochemical breakthroughs was associated with a significant increase of serum HBV DNA levels, which exceeded 100,000 copies/mL in 19 of 20 patients (95%) with biochemical breakthroughs and in only 1 of 8 patients (12.5%) remaining in biochemical remission for at least 6 months after the onset of virologic breakthrough (P < .001). Alanine aminotransferase (ALT) level peaked within 0 to 3 months after the onset of biochemical breakthrough and decreased at 6 months but remained abnormal in all but 2 patients. Follow-up liver histologic lesions in patients with biochemical breakthroughs did not differ from baseline findings, although they were significantly improved in patients remaining in virologic and biochemical remission. In conclusion, the frequent emergence of viral resistance under long-term lamivudine monotherapy in HBeAg-negative precore mutant HBV chronic liver disease is followed by increasing viremia levels culminating in the development of biochemical breakthroughs in most cases. ALT activity peaks close to the onset of biochemical breakthrough, decreasing thereafter but remaining persistently abnormal with fluctuating levels. (HEPATOLOGY 2002;36:219-226.)

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Section: Resultsmentioning

confidence: 91%

Course of virologic breakthroughs under long-term lamivudine in HBeAg-negative precore mutant HBV liver disease

et al. 2002

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“…15,18,81 Improvement in liver necroinflammation is observed in a similar proportion of patients, but the relapse rate after stopping therapy is very high, even higher than that with IFN-␣ treatment. 18,81 Short-term courses of combination therapy with IFN-␣ and lamivudine may increase the ET response rate, but the number of relapses after discontinuation of treatment still remains very high. 108 Lamivudine administration for longer periods of time (Ͼ12 months) has been evaluated by several investigators.…”

Section: Managementmentioning

confidence: 99%

“…14 More recently, the new nucleoside analog, lamivudine, has been used to treat a sizeable number of patients with HBeAg-negative CHB, and important information on its efficacy and the development of resistance has been collected. [15][16][17][18] …”

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confidence: 99%

Hepatitis B e antigen–negative chronic hepatitis B

2001

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Thirty years ago, the diagnosis of chronic hepatitis B (CHB) was thought to require the presence of hepatitis B e antigen (HBeAg), as a reliable and sensitive marker of hepatitis B virus (HBV) replication. 1 Individuals positive for hepatitis B surface antigen (HBsAg) but negative for HBeAg were considered to have nonreplicative HBV infection, and if their liver enzymes were normal or nearly normal they were referred to as asymptomatic or healthy HBsAg or HBV carriers. 2 If, on the other hand, they displayed elevated serum aminotransferases and liver histology indicative of chronic hepatitis, they were generally thought to be suffering from other superimposed or complicating conditions such as hepatitis D virus infection, alcohol-induced, metabolic, autoimmune, drug-induced, or other forms of chronic liver disease. 3 In the early 1980s it became apparent that HBV could replicate in the absence of HBeAg. [4][5][6] Patients from the Mediterranean area, although negative for HBeAg and positive for antibodies to HBeAg (anti-HBe), were reported to have CHB with replicating HBV. 7 The term anti-HBe-positive or HBeAgnegative CHB was then proposed 4 and subsequently became widely accepted. In 1989 the molecular basis of this form of CHB was discovered 8,9 with the identification of HBV mutations preventing HBeAg formation from an otherwise normally replicating HBV. 10,11 With time, it became apparent that HBeAg-negative CHB, initially viewed as an atypical and rare form of CHB mainly restricted in the Mediterranean area, had a much wider geographical distribution and that its frequency was increasing. 12 Its molecular virology and immunology were found to be more complex than initially thought, 13 whereas the selection of precore HBV mutants was shown to be largely determined by the HBV genotype. 14 Mutations abolishing or diminishing HBeAg formation were identified along with changes in other parts of the HBV genome. 14 More recently, the new nucleoside analog, lamivudine, has been used to treat a sizeable number of patients with HBeAg-negative CHB, and important information on its efficacy and the development of resistance has been collected. [15][16][17][18] DEFINITION AND NOMENCLATUREThe term HBeAg-negative CHB defines the condition as disease caused by strains of HBV that are not producing HBeAg. 12 It does not specify the mutations responsible for the lack of HBeAg, i.e., a precore stop-codon mutation, 10 a double basic core promoter (BCP) mutation, or other, 14 and it says nothing about the level of HBV replication. The alternative term "precore mutant CHB," used by some investigators, also does not specify the nature of the precore mutation. In clinical practice, the term HBeAg-negative CHB is appropriate for patients with chronic HBV infection who test negative for HBeAg, are usually positive for anti-HBe, have increased alanine aminotransferase (ALT) levels and display detectable HBV DNA in serum by classical hybridization techniques. 12 Despite the fact that the identification of the underlying mutations in ...

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“…17,18 Approximately two thirds of the patients showed a virologic, biochemical, and histologic response at month 12; drug resistant variants with a mutation in the polymerase gene were observed in one fourth of the patients. 17,18 These studies highlight that therapy of precore/core promoter mutant infection is a critical issue. In this issue of HEPA-TOLOGY, two very interesting reports describe the evolution of precore/core promoter mutants during long-term lamivudine treatment and the evolution of the polymerase gene sequence during lamivudine treatment of HBeAg-negative chronic hepatitis B.…”

mentioning

confidence: 99%

“…These results are also in accordance with those of reports in the same patient population. 17,18 However, there is some independent evidence that suggests a higher frequency of ALT flares in patients infected with HBeAg-negative strains when drug-resistant mutants are selected, compared with HBeAgpositive patients. 22 Five patients showed the simultaneous selection of the double L528M ϩ M552V mutant, and the other 5 had the M552I mutant together with the L528M mutant in 3 of them.…”

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confidence: 99%