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Adefovir Reduced HBV Viral Reservoir & HBsAg in Parallel
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"REDUCTIONS IN SERUM HEPATITIS B SURFACE ANTIGEN (HBSAG) OCCUR IN PARALLEL WITH REDUCTIONS IN INTRAHEPATIC HBV COVALENTLY CLOSED CIRCULAR (CCC) DNA IN CHRONIC HEPATITIS B (CH-B) PATIENTS RECEIVING ADEFOVIR DIPIVOXIL (ADV):
Bettina Werle (INSERM 271, Lyon, France) and colleagues reported these study results at DDW May 2004 in New Orleans, LA. In an oral hepatitis B session.
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 (makes copies of the hepatitis B virus) for viral mRNAs: pregenomic RNA for reverse transcription; mRNA translated into viral proteins HBsAg, HBcAg, HBeAg, polymerase, and X protein. In this study the investigators found that 48 weeks of ADV therapy results in significant 73% decrease in serum HBsAg levels and reductions similar in magnitude to that of cccDNA (84%) and the two reductions were correlated. As well, ADV-associated changes in HBsAg are significantly and positively correlated with changes in total intracellular HBV DNA, and serum HBV DNA.
ADV-associated changes in HBsAg are significantly and positively correlated with changes in cccDNA, total intracellular HBV DNA, and serum HBV DNA.
Until recently, little information was available regarding cccDNA levels in CHB patients.
We previously demonstrated that 48 weeks of ADV therapy reduced intrahepatic HBV cccDNA by a median of 84% (p=0.002 vs. placebo) in CHB patients and was correlated with significant reductions in serum and intracellular HBV DNA (HEPATOLOGY 2002;36:296A).
Since HBV cccDNA is the transcriptional template for HBsAg, we investigated whether reductions in cccDNA translated into reductions in serum HBsAg titer.
The aim of this study was to determine if 48 weeks of ADV therapy reduced serum HBsAg titer in CH-B patients, and to determine if changes in HBsAg titer correlate with changes in intrahepatic cccDNA levels.
32 patients with HBeAg+ CHB received 48 weeks of therapy with ADV (n=22) or placebo (n=10). HBsAg was quantified in patient sera by ELISA using the Monolisa AgHBs plus kit (Biorad, France) with purified HBsAg as the standard (Hytest, Finland). Intrahepatic cccDNA was measured by DNA extraction from liver biopsies and real-time PCR under selective conditions as described previously.
Previous research has shown:
(1) By using a novel quantitative real-time PCR assay to measure cccDNA in biopsy it has been found that cccDNA persists through all phases of the natural history of CHB but at decreasing levels as HBV passes through these stages: HBeAg+, HBeAg-, inactive, HBsAg-. (Werle et al, Gastroenterology, In Press)
(2) Biopsies at baseline and after 48 weeks ADV therapy have been performed. 48 weeks of ADV therapy significantly reduced cccDNA (p=0.002) by 84% compared to patients who received placebo. (Werle et al, Gastroenterology, In Press)
THE STUDY
The objectives of this study were to determine if 48 weeks ADV therapy reduced serum HBsAg titer in CHB patients, and to determine if changes in HBsAg titer correlate with changes in intrahepatic cccDNA levels.
Baseline and week 48 sera from 32 HBeAg+, HBsAg+ patients from a phase III study of ADV (437) were available for analysis: 22 ADV treated patients & 10 placebo (PLB) patients.
HBsAg titer was determined using a commercially available quantitative assay (MonoLisa Ag HBs plus, Bio-Rad France). Statistical analysis were performed by Inveresk (Cary, NC) using SAS 8.1.
RESULTS
(1) 48 weeks of ADV therapy significantly reduces HBsAg in CHB patients:
Reduction in serum HBsAg during ADV therapy was significantly reduced compared to placebo (p<0.001), and compared to placebo (p<0.001).
At baseline, patients in the ADV and placebo groups had similar HBsAg titers (medians of 332,599 and 217,378 ng/mL, respectively, p=0.48). After 48 weeks, patients receiving placebo had a median -0.09 log10 change in HBsAg titer (p=0.85 vs. baseline). Patients receiving ADV therapy demonstrated a median 73% reduction in serum HBsAg (median change of -0.58 log10 ng/mL).
(2) ADV associated serum HBsAg reductions (-73%) are similar in magnitude to cccDNA reductions (-84%).
Changes in HBV markers from baseline:
--Change in cccDNA= -0.8 log10 copies/cell (84% reduction).
--serum HBV DNA declined about 4.5 log10 copies/cell(ml)
--total intracellular DNA declined about 1.75 log10 copies/cell(ml)
--change in serum HBsAg titer= -0.6 log10 copies/cell(ml) (73% reduction)
(3) Changes in HBsAg were significantly and positively correlated with changes in intrahepatic cccDNA (p<0.01), total intracellular HBV DNA (p<0.01), and serum HBV DNA (p<0.001).
The authors reported that HBV clearance from hepatocytes appears to be primarily non-cytolytic: decline in cccDNA (84%) and serum HBsAg (73%) is not paralleled by a similar decline in the number of HBcAg+ cells; this suggests cccDNA was depleted primarily by non-cytopathic mechanisms.
AUTHOR'S CONCLUSIONS
48 weeks of ADV therapy results in significant 73% decrease in serum HBsAg levels: reductions similar in magnitude to that of cccDNA (84%).
ADV-associated changes in HBsAg are significantly and positively correlated with changes in cccDNA, total intracellular HBV DNA, and serum HBV DNA.
HBV clearance from hepatocytes appears to be primarily non-cytolitic.
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