Hepatitis: Bläckberg J

Lindh M, Uhnoo I, Bläckberg J, Duberg AS, Friman S, Fischler B, Karlström O, Norkrans G, Reichard O, Sangfeldt P, Söderström A, Sönnerborg A, Weiland O, Wejstål R, Wiström J. · Department of Infectious Diseases, Sahlgrenska University Hospital, Göteborg, Sweden. · Scand J Infect Dis. · Pubmed #18584530 No free full text.

Abstract: The main goal for treatment of chronic hepatitis B is to prevent complications such as liver cirrhosis or hepatocellular carcinoma. Knowledge from population studies of the long-term risk of chronic HBV infection, as well as the recent introduction of pegylated interferon and additional nucleoside analogues has changed the therapeutic situation. Recently, a Swedish expert panel convened to update the national recommendations for treatment. The panel recommends treatment for patients with active HBV infection causing protracted liver inflammation or significant liver fibrosis, verified by liver histology. In general, pegylated interferon alpha-2a is recommended as first-line treatment, in particular for HBeAg-positive patients with HBV genotypes A or B. Among nucleoside analogues, entecavir is the first choice and adefovir or tenofovir can be used as alternatives. Lamivudine monotherapy is not recommended due to the high risk of resistance development. Combinations of nucleoside analogues such as tenofovir and lamivudine or emtricitabine are alternatives for patients with non-response or infection with resistant variants, or as first choice for patients with advanced liver disease. Nucleoside analogue treatment should be monitored to detect primary non-response and virological breakthrough. Special recommendations are given for HBV/HIV coinfected patients, immunosuppressed patients, children, and for treatment before and after liver transplantation. The present guideline is translated from Swedish, where it is published on the MPA and RAV websites (www.mpa.se and www.rav.nu.se) including 7 separate papers based on thorough literature search. The complete reference list can be received from the Medical Products Agency upon request.

Kidd-Ljunggren K, Holmberg A, Bläckberg J, Lindqvist B. · Department of Infectious Diseases, Lund University, Lund, Sweden. · J Hosp Infect. · Pubmed #17046105 No free full text.

Abstract: Chronic infection with hepatitis B virus (HBV) is a major global health problem. Transmission is mainly blood-borne, although the route of infection during horizontal transmission in childhood is unclear. Nosocomial outbreaks of HBV have been widely reported, but have mainly focused on blood-borne transmission. There is limited knowledge of the viral load levels in other body fluids. In the present study, chronic HBV carriers were tested for the presence of HBV DNA in serum, saliva, nasopharyngeal fluid, urine and tears by means of qualitative and quantitative polymerase chain reaction (PCR) methods. Twenty-five patients who were positive for HBV DNA with both PCRs were included. Low titres in real-time PCR corresponded with weak bands in the qualitative assay. HBV DNA was found in two urine samples, 10 saliva samples, five nasopharyngeal swabs and in tear fluid from four patients. One highly viraemic HBeAg-positive carrier with serum HBV DNA levels of 7 x 10(9) genome copies had high copy numbers detected in both saliva and nasopharyngeal fluid. These results demonstrate that highly viraemic HBV carriers may have high titres of HBV DNA in other body fluids. This has particular importance for infection control programmes and regulations, underlining the importance of aiming towards regular HBV DNA testing and thus infectivity assessment of chronic carriers in order to prevent transmission.

Carlsson T, Reichard O, Norkrans G, Bläckberg J, Sangfelt P, Wallmark E, Weiland O. · Division of Infectious Diseases, Karolinska University Hospital (Solna and Huddinge), Karolinska Institutet, Stockholm, Sweden. · J Viral Hepat. · Pubmed #16108761 No free full text.

Abstract: SUMMARY: To optimize treatment of chronic hepatitis C early identification of patients who will not achieve a sustained virological response (SVR) is desirable. We investigated hepatitis C virus (HCV) RNA kinetics at day 1 (in 15 patients; genotypes 1 and non-1, 9 and 6 respectively) at weeks 1, 4 and 12 (in 53 patients; genotypes 1 and non-1, 19 and 34, respectively) during treatment with pegylated interferon alpha-2a and ribavirin. Patients with SVR had a significantly more pronounced mean log10 decline from baseline in HCV RNA levels at weeks 1 and 4 compared with patients who failed to achieve SVR (1.99 vs 0.85 at week 1, P = 0.0003 and 2.89 vs 1.72 at week 4, P = 0.0159), whereas no difference was noted after day 1. For patients with a 2-log10 decrease in HCV RNA levels at day 7, the positive predictive value (PPV) for a SVR was 92%, whereas week 12 was the best time point for predicting a later nonresponse [negative predictive value (NPV) 92%] in patients failing to achieve a 2-log10 drop. For patients with genotype non-1 and a 2-log10 decrease in HCV RNA levels the PPV for a SVR was 89% week 1, and 79% weeks 4 and 12. The corresponding NPV for patients with genotype non-1 were 43, 40 and 100% respectively. During treatment with pegylated interferon alpha-2a plus ribavirin the HCV RNA decline at week 1 was an accurate predictor of SVR in patients who had achieved a 2-log10 drop in HCV RNA levels, whereas the lack of such decline week 12 was an accurate marker of a nonresponse.

Kidd-Ljunggren K, Myhre E, Bläckberg J. · Division of Infectious Diseases, Department of Medical Microbiology, Dermatology and Infection, Lund University, SE-221 85 Lund, Sweden. · J Clin Microbiol. · Pubmed #15583320 links to  free full text

Abstract: Hepatitis B virus (HBV) has eight genotypes which have distinct geographical distributions. Studies comparing differences in the clinical outcomes of infections caused by strains with genotype-related variations in the HBV genome have largely compared genotypes B and C and genotypes A and D but not all four genotypes. The present study included 196 HBV-infected patients attending an infectious diseases outpatient clinic in Sweden. The age and geographic origin, liver function, HBeAg and anti-HBe status, and the presence or absence of HBV DNA were analyzed for each patient. HBV DNA was detected in 144 patients, and the HBV genotype and the core promoter and precore sequences were determined for the isolates from 101 of these patients. Among the patients who might be considered most likely to be nonviremic, namely, anti-HBe-positive HBV carriers with normal alanine aminotransferase (ALT) levels, 65% had detectable HBV DNA and were thus viremic. Among the viremic patients, HBeAg-positive patients were more likely to have elevated ALT levels than anti-HBe-positive patients. HBV genotypes A to F were represented in the study, and their distributions coincided accurately with the origin of the patient. A significantly higher number of genotype D-infected patients were anti-HBe positive and had elevated ALT levels (42% of genotype D-infected patients but 0% of patients infected with genotypes B and C). Genotype D strains with mutations in the core promoter and precore regions were significantly correlated with elevated ALT levels in the patients. The differences were not age related. Therefore, in this large-scale cross-sectional study, genotype D appears to be associated with more active disease.

Bläckberg J, Kidd-Ljunggren K. · Department of Infectious Diseases, Lund University, Lund, Sweden. · J Med Virol. · Pubmed #12858404 No free full text.

Abstract: Chronic hepatitis B infection is a major cause of hepatocellular cancer (HCC). The pathogenesis of the carcinogenesis is not fully understood. Viral proteins such as the X protein and the truncated middle S protein have been implicated to be transactivators. In order to investigate whether any mutations within relevant parts of the hepatitis B virus (HBV) genome could be associated with the development of HCC, the genomes of 16 HBV strains from chronic HBV carriers with HCC were studied. Serum samples were subjected to PCR and the HBV DNA sequenced subsequently. Genotypes A-D were represented. The sequence analysis showed that an especially high proportion, 50% (CI 95%, 25-75%), of the patients with HCC carried HBV mutants with deletions or insertions in the N-terminal half of the pre-S2 region or had a point mutation in the start codon of pre-S2 compared with controls with chronic HBV infection, 21% (CI 95%, 3-39%). A high proportion (69%) also had mutations at position 1762 (A --> T) and/or 1764 (G --> A) in the core promoter region, but the proportion of core promoter mutations was no different from what was found in a control group of HBV carriers without HCC (68%). The pre-S2 variants, which involve deletions of immunogenic regions, may have a survival advantage as they are mostly found in long-standing HBV infection. There were no other mutations found frequently within the region coding for the X protein.

Bläckberg J, Kidd-Ljunggren K. · Department of Infectious Diseases, Lund University, Sweden. · J Hepatol. · Pubmed #11131464 No free full text.

Abstract: BACKGROUND/AIMS: After acute self-limited hepatitis B virus (HBV) infection, serological loss of viral antigens and appearance of anti-HBs is generally believed to signify viral clearance. Latent and occult HBV infection appearing decades after self-limited hepatitis B has not been reported, nor has the evolutionary rate of HBV DNA over the same observation period. METHODS: DNA from serum and leukocytes from 16 patients with acute self-limited hepatitis B 30 years earlier was tested by polymerase chain reaction and positive samples were sequenced. Liver tissue from four patients was also tested. Additionally, another 10 HBV strains isolated from acute HBV cases in 1969-72 were compared to 11 strains isolated from acute cases in 1998-99 in the same community. RESULTS: HBV DNA was detected in liver from two patients, but not in serum or leukocytes. The HBV strains detected in liver showed complete homology, in the sequences analyzed, to the strains originally infecting these patients. Ten strains from 1998-99 were identical in pre-S and core promoter/precore regions to strains from the same community isolated 30 years earlier. CONCLUSIONS: HBV can persist as an occult infection three decades after acute, apparently self-limited hepatitis B, and both the mutation and evolutionary rates of HBV DNA are low.

Bläckberg J, Braconier JH, Widell A, Kidd-Ljunggren K. · Department of Infectious Diseases, University Hospital, Lund, Sweden. · Eur J Clin Microbiol Infect Dis. · Pubmed #10706175 No free full text.

Abstract: The objective of this study was to investigate the epidemiology, etiology, and long-term outcome of an extended outbreak of acute hepatitis that occurred in an area of Sweden between 1969 and 1972. The outbreak was analyzed retrospectively by retesting stored frozen serum samples for the presence of hepatitis A, B and C markers. The results were compared with the diagnoses that had been determined during the outbreak. Of 180 patients, 29 (16%) had acute hepatitis A, 126 (70%) had acute hepatitis B, and eight (4.4%) had acute hepatitis C. The Australia antigen test used during the outbreak had failed to identify 21 patients with acute hepatitis B virus infection. Genotyping of the hepatitis B virus strains showed that genotype D was the most prevalent, irrespective of the transmission route. An attempt was made to follow up patients with unresolved hepatitis B virus infection, 25-27 years after the acute infection. None of the 100 patients with acute hepatitis B infection who were traced had become chronic carriers. In ten patients with hepatitis C virus infection, the follow-up showed considerable variation in the outcome, ranging from spontaneous resolution to death through liver cirrhosis. Intravenous drug users had a high prevalence of hepatitis C virus infection, with 52% testing positive for hepatitis C antibodies.

Bläckberg J, Kidd-Ljunggren K. · Department of Infectious Diseases, University Hospital, Lund, Sweden. · J Med Virol. · Pubmed #10596007 No free full text.

Abstract: Hepatitis B virus (HBV) strains from anti-HBe positive patients often show specific mutations in the precore gene, the core promoter region, or both. The dynamics of seroconversion in relation to the appearance of these mutations has not been studied and compared between defined HBV genotypes. Samples from patients followed during seroconversion from HBeAg to anti-HBe were amplified by polymerase chain reaction (PCR), sequenced and genotyped. Among 16 sets of samples, 6 belonged to genotype A, 6 to genotype D, 2 to genotype B, 1 to genotype C, and 1 to genotype E. Whereas strains from genotypes B, C and E showed changes in the core promoter, precore codon 28 or both, genotype A and D strains displayed a different pattern. In 4 of 6 anti-HBe positive samples from genotype A, the precore had a wild-type sequence while the core promoter sequence showed a specific TGA mutation. In another genotype A strain a precore stop mutation was preceded by a mutation in codon 15, thus conserving base-pairing at the pregenomic RNA level in this region. In contrast, all genotype D strains showed wild-type sequences in both the core promoter and precore codon 28 in pre- and post-seroconversion samples. Thus, in 8 patients with a mean follow-up time of 17 months, wild-type sequences in both the core promoter and precore codon 28 were found after seroconversion to anti-HBe. This study also confirmed, for genotype D, that HBeAg seroconversion often occurs earlier than genomic conversion.