New Findings


oTreatment of Chronic Delta Hepatitis with Pegylated Interferon
oEffect on the pregnant woman and fetus by multiple hepatitis virus infection
oVaried assembly and RNA editing efficiencies between genotypes I and II hepatitis D virus and their implications
oHepatitis B virus concentrations in serum determined by sensitive quantitative assays in patients with established chronic hepatitis delta virus infection
oThe conserved serine 177 in the delta antigen of hepatitis delta virus is one putative phosphorylation site and is required for efficient viral RNA replication

Treatment of Chronic Delta Hepatitis with Pegylated Interferon
We propose to treat between 10 and 20 patients with chronic delta hepatitis with pegylated alpha interferon for up to five years. Patients with chronic delta hepatitis with raised serum aminotransferases, HBsAg and HDV RNA in serum, and moderate-to-severe chronic hepatitis on liver biopsy with HDV antigen will be enrolled. Patients will be monitored for at least three months with regular testing for ALT levels and will undergo admission for a thorough medical evaluation and percutaneous liver biopsy before treatment. Pegylated interferon will then be started in a dose of 180 mcg weekly. At each clinic visit, patients will be questioned about side effects and symptoms and have blood taken for complete blood counts and routine liver test (ALT, AST, alkaline phosphatase, direct and total bilirubin, and albumin). At 12-24 week intervals patients will undergo a physical examination and be tested for HBsAg, anti-HBs, HDV RNA, and prothrombin time. The dose of pegylated interferon will be adjusted based upon side effects and changes in ALT levels, aiming for optimal suppression of ALT elevations with acceptable tolerance. At 48 weeks (one year) and every 96 weeks (two years) thereafter, patients will be readmitted to the NIH Clinical Center for repeat thorough medical evaluation and liver biopsy. The Primary endpoint of therapy will be improvements in hepatic histology on liver biopsy done after 3 years of pegylated alpha interferon therapy. Several secondary endpoints will be measured, including changes in HDV RNA, loss of HBsAg, HDV staining in the liver biopsy, ALT levels, quality of life, all at 1.3 and 5 years, and hepatic histology at 1 and 5 years. Patients will be maintained on pegylated interferon if it is adequately tolerated and there is an adequate "histological response," as defined by at least 3 point improvement in inflammatory score or 1 point improvement in fibrosis score of the HAI at each liver biopsy. Therapy will be stopped for: (1) intolerance to alpha interferon (which will be carefully defined), (2) lack of improvement in hepatic histology after 1, 3, or 5 years of therapy (histological nonresponse), or (3) a "complete response," i.e. loss of HDV RNA and HBsAg and development of anti-HBs.
August 2001

NIH Clinical Studies Info

Effect on the pregnant woman and fetus by multiple hepatitis virus infection

Zhonghua Fu Chan Ke Za Zhi 2001 Sep;36(9):523-6
Liu Y, Chang L.

Department of Obstetrics and Gynecology, Beijing Youan Hospital, Beijing 100054, China.

OBJECTIVE: To evaluate the effect on the pregnant woman and fetus by infection of multiple hepatitis virus during pregnancy. METHODS: Hepatitis virus A, hepatitis virus B, hepatitis virus C, hepatitis virus D and hepatitis virus E were determined in the pregnant women with abnormal liver function during 1994-1999. Patients diagnosed to be infected by single hepatitis virus or multiple hepatitis virus were divided into two groups and complications of the pregnant woman and fetus and their prognosis were evaluated. RESULTS: There were no significant differences in the levels of alamine transaminase (ALT), aspartama transaminase (AST) and total bilirubin (TBIL) between the multiple hepatitis virus infection group (multiple group) and the single hepatitis virus infection group (single group) (P > 0.05). The positive rate of HbeAg (35.7%) in multiple group was significantly lower than in single group (P < 0.05). However, the positive rate of HbeAb (57.1%) in multiple group was significantly higher than in single group (P < 0.01). There were no significant differences in incidences of pregnancy induced hypertension (PIH), postpartum hemorrhage, serious symptoms and mortality between the multiple hepatitis virus infection group and the single hepatitis virus infection group (P > 0.05). However, the incidences of premature rupture of membrane (PROM), premature delivery, 28.1%, 25.0% fetal distress and newborn infant asphyxia 31.3%, 25.0% in multiple hepatitis virus infection group were significantly higher than in single hepatitis virus infection group (P < 0.05, P < 0.01). CONCLUSIONS: Multiple hepatitis virus infection during pregnancy has no more serious effect on the pregnant woman, but has worse effect on fetus than single hepatitis virus infection. The obstetrician should pay more attention to the health care of the pregnant woman with the multiple hepatitis virus infection to prevent PROM and premature delivery, at the same time monitor fetus carefully and deal with labor actively to decrease the mortality of the fetus.

PMID: 11769663

Varied assembly and RNA editing efficiencies between genotypes I and II hepatitis D virus and their implications.

Hsu SC, Syu WJ, Sheen IJ, Liu HT, Jeng KS, Wu JC.

Institute of Microbiology and Immunology, National Yang-Ming University School of Medicine, Taipei, Taiwan, Republic of China.

The mechanisms that link genotypes of hepatitis D virus (HDV) with clinical outcomes have not yet been elucidated. Genotypic variations are unevenly distributed along the sequences of hepatitis delta antigens (HDAgs). Of these variations, the packaging signal at the C-terminus has a divergence of 74% between genotypes I and II. In this report, we address the issue of whether these high variations between genotypes affect assembly efficiency of HDV particles and editing efficiency of RNA. Viral package systems of transfection with expression plasmids of hepatitis B surface antigen and HDAgs or whole genomes of HDV consistently indicate that the package efficiency of genotype I HDV is higher than that of genotype II. Segment swapping of large-form HDAg indicates that the C-terminal 19-residue region plays a key role for the varied assembly efficiencies. Also, the editing efficiency of genotype I HDV is higher than that of genotype II. The nucleotide and structural changes surrounding the editing site may explain why genotype II HDV has a low RNA editing efficiency. The findings of in vitro assembly systems were further supported by the observations that patients infected with genotype II had significantly lower alanine transaminase (ALT) levels, more favorable outcomes (P <.05), and a trend to have lower serum HDV RNA levels as compared with those infected with genotype I HDV (P =.094). In conclusion, genotype II HDV secretes fewer viral particles than genotype I HDV does, which in turn may reduce the extent of infection of hepatocytes and result in less severe hepatic inflammation.

PMID: 11870382
Hepatitis B virus concentrations in serum determined by sensitive quantitative assays in patients with established chronic hepatitis delta virus infection.

Sakugawa H, Nakasone H, Nakayoshi T, Kawakami Y, Yamashiro T, Maeshiro T, Kinjo F, Saito A, Zukeran H.

First Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Okinawa, Japan. b987607@med.u-ryukyu.ac.jp

To clarify the correlation between hepatitis B virus (HBV) DNA levels and serum alanine aminotransferase (ALT) levels in patients with established chronic hepatitis delta virus (HDV) infection, sensitive HBV quantitative assays were used for the study. Thirty-four consecutive patients with chronic liver disease who were positive for both hepatitis B surface antigen (HBsAg) and antibody to HDV (anti-HDV), including 19 patients with chronic hepatitis, 8 patients with liver cirrhosis and 7 patients with hepatocellular carcinoma. All were negative for hepatitis Be antigen (HBeAg) and positive for antibody to HBeAg. HBV DNA was detected in 25 (73.5%) of the 34 patients using real-time detection PCR, and the HBV DNA levels of these patients were significantly lower compared with HBeAg status and ALT level-matched patients with chronic liver disease positive for HBsAg but negative for anti-HDV. There was no correlation between serum HBV DNA and ALT levels among the 34 patients with chronic liver disease positive for anti-HDV. Whereas serum ALT levels in anti-HDV-positive HBsAg carriers with HDV RNA were significantly higher than those without HDV RNA. Liver damage in patients with established chronic HDV infection may be caused mainly by ongoing HDV infection not by HBV replication. Copyright 2001 Wiley-Liss, Inc.

PMID: 11596082

The conserved serine 177 in the delta antigen of hepatitis delta virus is one putative phosphorylation site and is required for efficient viral RNA replication.

Mu JJ, Chen DS, Chen PJ.

Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.

Hepatitis delta virus (HDV) small delta antigen (S-HDAg) plays a critical role in virus replication. We previously demonstrated that the S-HDAg phosphorylation occurs on both serine and threonine residues. However, their biological significance and the exact phosphorylation sites of S-HDAg are still unknown. In this study, phosphorylated S-HDAg was detected only in the intracellular compartment, not in viral particles. In addition, the number of phosphorylated isoforms of S-HDAg significantly increased with the extent of viral replication in transfection system. Site-directed mutagenesis showed that alanine replacement of serine 177, which is conserved among all the known HDV strains, resulted in reduced phosphorylation of S-HDAg, while the mutation of the other two conserved serine residues (2 and 123) had little effect. The S177A mutant dramatically decreased its capability in assisting HDV RNA replication, with a preferential and profound impairment of the antigenomic RNA replication. Furthermore, the viral RNA editing, a step relying upon antigenomic RNA replication, was also abolished by this mutation. These results suggested that phosphorylation of S-HDAg, with serine 177 as a presumable site, plays a critical role in viral RNA replication, especially in augmenting the replication of antigenomic RNA.

PMID: 11533172
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