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PegIFN+Adefovir Combination for HBV: cccDNA, seroconversion
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Reported by Jules Levin
Note from Jules Levin: there are two HCV protease inhibitors in patients in phase I, by Schering & Vertex. The successful development of these drugs are a major hope for improved therapy in the near future. As well, NM283 is further along in development but the protease inhibitors may be more potent. NM283 drops viral load by 1.1 log, in combination with peginterferon it looks like a 4.5 log reduction by week 24. The updated NM283 data will be presented Sunday here at EASL.
Author: J Peterson (University of Hamburg, Germany) reported these study results at EASL, April 13-17, 2005, Paris.
AUTHOR SUMMARY: 48 weeks of ADV & PegIFN therapy results in a -2.2 log decrease in hepatic cccDNA (ADV mono -0.8 log) and a high number of HBeAg and HbsAf seroconversion. Seroconverters (HBs & HBe) had higher ALT levels at baseline & during therapy and did not show lower baseline levels of cccDNA compared to non-seroconverters. HBsAg titers are positively correlated with cccDNA levels and confirm that ADV and PegIFN therapy reduces the reservoir of transcriptionally active viral cccDNA. Enhanced frequency observed of significant proliferative responses of CD4+ T-cells to HBc antigens during therapy. Immunostaining studies are ongoing to determine the evolution of the number of cells expressing viral antigens during ADV therapy.
AUTHOR PERSPECTIVES: Further studies are warranted to- (1) refine the model for cccDNA clearance in chronically infected HBC patients. (2) demonstrate that monitoring of cccDNA may provide an independent predictor of outcome. (3) investigate if HBsAg quantification might act as a noninvasive surrogate parameter for changes in cccDNA levels.
cccDNA in Chronic Hepatitis B
cccDNA is the viral reservoir responsible for persistent infection of hepatocytes during chronic hepatitis B (CHB)
--believed to be responsible for relapse after antiviral therapy
cccDNA serves as the transcriptional template foe mRNAs
--pregenomic RNA reverse transcription
--mRNA translated into viral proteins HBsAg, HBcAg, HBeAg, polymerase, and X protein.
Until recently, little information was available regarding cccDNA levels in CHB patients.
HBeAG+ patients have significantly more cccDNA and total intracellular HBV DNA than HBeAg- patients.
48 weeks of monotherapy with adefovir (ADV) resulted in a median 0.8 log reduction in cccDNA copies/ml (p<0.001).
ADV-associated changes in cccDNA were significantly and positively correlated with changes in HBsAg. (Werle et al, Gastrenterology, 2004; 126:1750-8)
Intrahepatic HBV cccDNA levels at the end of therapy with lamivudine (LAM) & PegIFN alfa-2b might act as a predictive marker for long-term viral response. (Sung et al, Gastroenterology 2005, In Press).
STUDY OBJECTIVES
To determine the virological, serological (blood/lab markers), and histologicaloutcome in CHB patients during 48 weeks of combination with 10 mg ADV and 1.5 ug/kg PegIFN alfa-2b followed by 96 weeks of ADV monotherapy.
Primary Endpoint
To monitor changes in cccDNA levels during antiviral combination therapy.
Secondary Endpoints
-to evaluate serum HBsAg titers
-to correlate changes in HBsAg titer with changes in cccDNA
-to investigate T-lymphocyte markers during therapy
The study is a mono center, open label trial, HBeAg+ and HBeAg- patients (n=26).
--Screening started inb April 03-Jan 04; baseline, biopsy #1.
--PegIFN a-2b +ADV started Nov 03-Jan 05
--week 48, biopsy #2- Nov 04-Jan 07; ADV administered.
--week 144. Biopsy #3, follow-up, July 07
Baseline Characteristics
Median age, years: 33 (18-60)
Male: 14
Caucasian: 21
Asian: 5
HBeAg+: 14
HBeAg-: 12
HBV DNA PCR: 5 x 106 (log copies/ml)
ALT: 3.1 x ULN
METHODS
Intrahepatocellular cccDNA and total intrahepatocellular DNA from needle biopsies were analyzed by real time PCR assay (Were et al, Gastrenterology 2004).
HBsAg titers were determined using a commercially available quantitative assay (Mono-Lisa Ag HBs ultra. Bio-Rad, and purified HBsAg, Hytest. Finland).
Elispot assays for the detection of HBV specific T cells against HBc (hepatitis B core) & HBs.
RESULTS at WEEK 48
ALT normalization: 12/25 (48%)
ALT improvement: 21/25 (84%)
Serum HBV DNA reduction: -4.7 log
Serum HBV DNA <100 copies/ml: 13/25 (52%)
Histology improved: (HAI): 16/25 (64%)
25/26 patients completed first year treatment, one patient changed place of residence (Kosova).
CTL Elispots
Enhanced frequency of significant proliferative responses of CD4+ T cells to HBc antigens.
Partial restoration of CD4+ T-cell response during antiviral ADV & PegIFN treatment.
(preliminary results)
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