Daryl T. Lau

Cytotoxic T lymphocyte responsiveness after resolution of chronic hepatitis B virus infection.

Clearance of the hepatitis B virus (HBV) during acute hepatitis is associated with a strong, polyclonal, multispecific cytotoxic T lymphocyte (CTL) response to the viral envelope, nucleocapsid and polymerase proteins that persists for decades after clinical recovery. In contrast, chronically infected patients usually fail to mount a strong CTL response to this virus. In this study we demonstrate that chronically infected patients who experience a spontaneous or interferon-induced remission develop a CTL response to HBV that is similar in strength and specificity to patients who have recovered from acute hepatitis. The results suggest that specific immunotherapeutic enhancement of the CTL response to HBV should be possible in chronically infected patients, and that it could lead to viral clearance in these individuals with resolution of chronic liver disease.

CHRONIC VIRAL HEPATITIS : BENEFITS OF CURRENT THERAPIES

Interferon alfa was approved as therapy for chronic hepatitis C in the United States in 1991 and for chronic hepatitis B in 1992. These approvals were based on the results of randomized, controlled...

Combination Therapy with Famciclovir and Interferon-α for the Treatment of Chronic Hepatitis B

Interferon-alpha (IFN-alpha) treatment results in long-term remissions in only 25%-40% of patients with chronic hepatitis B virus (HBV) infection. Famciclovir, the oral prodrug of penciclovir, inhibits HBV DNA replication. Five adults with chronic HBV infection in whom previous IFN-alpha therapy had failed were treated in a pilot study of overlapping IFN-alpha and famciclovir therapy totaling 20 weeks. HBV DNA levels decreased by 0.9 log units during the initial 4-week period of famciclovir alone, followed by a further decrease of 1.8 logs during the middle 12-week period of combination therapy. HBV DNA rose by 0.9 log during the final 4-week period of IFN-alpha alone. Two patients cleared HBV DNA, and their liver disease improved by clinical and histologic criteria. The combination of famciclovir and IFN-alpha appeared to be at least additive in suppressing HBV DNA. Efficacy trials of combination therapy with famciclovir and IFN-alpha are warranted.

Pegylated IFN-α regulates hepatic gene expression through transient Jak/STAT activation

The use of pegylated interferon-α (pegIFN-α) has replaced unmodified recombinant IFN-α for the treatment of chronic viral hepatitis. While the superior antiviral efficacy of pegIFN-α is generally attributed to improved pharmacokinetic properties, the pharmacodynamic effects of pegIFN-α in the liver have not been studied. Here, we analyzed pegIFN-α-induced signaling and gene regulation in paired liver biopsies obtained prior to treatment and during the first week following pegIFN-α injection in 18 patients with chronic hepatitis C. Despite sustained high concentrations of pegIFN-α in serum, the Jak/STAT pathway was activated in hepatocytes only on the first day after pegIFN-α administration. Evaluation of liver biopsies revealed that pegIFN-α induces hundreds of genes that can be classified into four clusters based on different temporal expression profiles. In all clusters, gene transcription was mainly driven by IFN-stimulated gene factor 3 (ISGF3). Compared with conventional IFN-α therapy, pegIFN-α induced a broader spectrum of gene expression, including many genes involved in cellular immunity. IFN-induced secondary transcription factors did not result in additional waves of gene expression. Our data indicate that the superior antiviral efficacy of pegIFN-α is not the result of prolonged Jak/STAT pathway activation in hepatocytes, but rather is due to induction of additional genes that are involved in cellular immune responses.

Hepatitis G Virus and Human Immunodeficiency Virus Coinfection: Response to Interferon-α Therapy

The prevalence and consequences of hepatitis G virus (HGV) infection were determined in 180 patients with human immunodeficiency virus (HIV) infection (predominantly male homosexuals) who participated in a trial that compared treatment with zidovudine versus interferon (IFN)-alpha versus the combination. HGV RNA levels were measured by branched DNA signal amplification assay. Initially, 66 (37%) had HGV RNA. Sexual transmission was the sole risk factor for infection in all but 4 subjects. Pretreatment clinical features were similar between HGV RNA-positive and -negative patients. After 6 months, only 5% treated with zidovudine became HGV RNA negative, compared with 95% who received IFN-alpha alone and 66% on combination therapy with low-dose IFN-alpha. After therapy, HGV RNA levels returned to baseline in most subjects. Thus, HGV infection is common among HIV-infected homosexual males but does not appear to influence clinical features in early HIV infection. HGV RNA levels are suppressed by IFN but not by zidovudine.

O47 PEGYLATED INTERFERON-ALPHA INDUCES SUSTAINED TRANSCRIPTIONAL RESPONSE IN LIVER INFILTRATING IMMUNE CELLS BUT NOT IN HEPATOCYTES IN THE LIVER OF PATIENTS WITH CHRONIC HEPATITIS C

O47 PEGYLATED INTERFERON-ALPHA INDUCES SUSTAINED TRANSCRIPTIONAL RESPONSE IN LIVER INFILTRATING IMMUNE CELLS BUT NOT IN HEPATOCYTES IN THE LIVER OF PATIENTS WITH CHRONIC HEPATITIS C M.T. Dill, Z. Makowska, G. Trincucci, A.J. Gruber, J.E. Vogt, M. Filipowicz, D. Calabrese, I. Krol, D.T. Lau, L. Terracciano, E. van Nimwegen, V. Roth, M.H. Heim. Department of Biomedicine, Hepatology Laboratory, University of Basel, Division of Gastroenterology and Hepatology, University Hospital Basel, Biozentrum and Swiss Institute of Bioinformatics, Computer Science Department, University of Basel, Basel, Switzerland; Liver Center, Beth Israel Deaconness Medical Center, Harvard Medical School, Boston, MA, United States; Institute of Pathology, University of Basel, Basel, Switzerland E-mail: michael.dill@unibas.ch