Sirs, We have read with great interest the recent paper by Chen et al. on lamivudine monotherapy in chronic hepatitis B (CHB) patients, where it was concluded that appearance of IgM anti-HBc in patients with acute exacerbation (AE) is a predictor of poor response.1 While this is an interesting finding, and clinically relevant to the decision-making in treating CHB patients with AE, no definitive explanations were fully discussed regarding mechanisms of poor therapy response nor did they specify alternate antiviral strategies. Previous data have demonstrated that, during interferon alfa (IFN-α) treatment of CHB patients, a rise in serum class IgM anti-HBc levels is associated with alanine aminotranspherase (ALT) flare-ups and subsequent HBeAg clearance; thus, this serological phenomenon is considered a predictor of beneficial response to IFN-α therapy. 2, 3 Chen et al.1 stated that the reason for these contradictory results is not fully understood, and a putative explanation is based on the fact that IFN-α may exert regulatory effects on cellular and humoral immune responses.4, 5 However, it is also well known that cell-mediated immune responses play a decisive role in successful lamivudine therapy of patients with CHB.6-8 We have evaluated, in a retrospective way, the rate of response to lamivudine monotherapy in a cohort of 52 consecutive patients with CHB, analysing the possible predictive factors for a favourable response to treatment. All 52 patients (39 men, mean age 45 ± 14 years) were of Spanish ethnic origin, had acquired hepatitis B virus infection during adult life, and presented without coinfection by other viruses. Standard biochemical and virological profile analyses were conducted, detecting an elevate ALT and positive viremia (HBV DNA) in all patients. Twenty of them (39%) had HBeAg positivity while the remaining 32 (62%) were anti-HBeAg positive; seven patients (14%) had histological proven liver cirrhosis. A daily dose of 100 mg of lamivudine was administered during a minimum of 12 months to each patient, determining clinical, biochemical and virological parameters every 2 months. During the study, an ALT flare-up compatible with AE was observed in five (10%) of patients, presenting with a rebound in HBV DNA serum levels and anti-HBc reappearance of IgM subclass. No patients suffered from concomitant hepatic decompensation and lamivudine therapy was not discontinued. After treatment completion and a follow-up period of 6 months, the rates of sustained response were clearly divergent: a favourable response was found in 100% (all five patients) of the IgM anti-HBc positivity group vs. 28% (12 out of 47 patients) for treated cases, which did not present an AE and without reappearance of class IgM anti-HBc. The main conclusion of our results was that in occidental patients the presence of an AE with appearance of serum IgM anti-HBc in CHB is not a predictor of poor response to lamivudine monotherapy. Evidence exists that CHB patients with AE and higher pre-treatment serum ALT levels may achieve a rate of up to 60% of sustained HBeAg negativity response to lamivudine.9, 10 According to the provocative new data by Chen et al.,1 the scientific community involved in CHB patients management has to face some important new challenges: (i) to define the epidemiological clinical, serological and virological characteristics of treated patients with AE and class IgM anti-HBc appearance; (ii) to analyze differences in treatment responses in a clear heterogeneous population of patients; (iii) to dissect the pathogenic mechanisms involved in different treatment outcomes in patients receiving IFN-α or lamivudine; and (iv) to establish a consistent treatment alternative, demonstrated by multicentre, prospective investigations, for CHB patients with AE and IgM anti-HBc positivity.