A new hepatitis B virus strain in patients with severe anti-HBe positive chronic hepatitis B* M.R. Bmnetto’, M. Stemle?, F. Bonino’, F. Schodel’, F. Oliveri’, M. Rizzettol, G. Verne’ and H. WilI* In hepatitis B virus carriers who are anti-H& positive despite ongoing viral replication (HBcAg in liver and HBV-DNA in serum) the natural course of hepatitis is severe and the response to interferon is low. We investigeted whether a new hcp aids B virus (HBV) strain could be involved. A translational termination wdon at the carboxytermioel end of the pre+C region responsible for the lack of HBeAg secretion was found in 18 of 19 HBV clones isolated from seven pedigreed pa- tients with this clinical syndrome. The seme findings were cootinned by direct sequencing. One of these patientl under. weot a liver transplant and HBV infection of the new liver resulted in high titered viremia and intmkepatic expressiott of HBcAg, without detectable HBeAg in serum. Another patient ~88 suprinfected by hepatitis delta vhw (HDV) and de- veloped high titres of total and IgM anti4J.D. In spite of this, chronic hepatitis nmained unchanged during 7 years of fol- low-up. These data strongly suggest that e viable precore minus mutant of hepatitis B virus is responsible for tbe last of HBeAg in the serum of these patients. The HBV variant may explain the peculiar geographii distribution of ant&HBe pok itive hepatitis. The variations in the virus genome sequence may cause the mere severe form of liver di?.ee.?a and modify the pathogenicity in the case of HDV superinfection. Despite a vaccine and partially effective therapy, hep- atitis B virus (HBV) infection is still a major world health problem with more than 200 million chronic carriers worldwide (1). There are two subsets of auriers with on- going viral replication: one, a highly viremic and hepatitis ‘e’ antigen (HBeAg) positive while the other has lower vi- remia and is HBeAg negative (2-10). In the Mediterra- neen countries and East Asia, patients zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFE with e severe case of the diseaw, rare spontaneous remission and a poor re- sponse to interferon are frequentb HBeAg negative, but have antibodies to HBeAg (anti-HBe) (3-8.10). HBeAg, a non-structural, secreted protein, encoded by the C-gene of HBV, is found only in patients with active viral repli- cation (11.12). It is synthesized es a precursor c~recore) protein and its signal (pre-C) and carboxytemdnal-se- quences we cleaved off during maturation and secretion (13-15). ‘Iix nucleocapsid protein (HBcAg) is also eo- coded in the C-gene, buttranslation initiates at the second ATG of the C-gene (15). We identified a HBV variant with a translational termination codon at the carboxyter- minal end of the precore region in sera of two Italian, enti- HBe positive patients with chronic hepatitis (16). Sobse- quendy the seme ptemre mutation that prevents we- tion of HBeAg was found in HBV isolates from 16 other (Greek and French) patients (17,18). To investigate whether ant&HBe positive patients with chronic hepatitis are infected with a different HBV strain, the viral DNA was amplified from serum of 7 such patients using inde- pendent polymerase chain reactions and it was character- ized by direct sequencing and sequencing after cloning.