Editorial Board: Emmet B. Keeffe, MD (Chair); Anna Lok, MD; Brian McMahon, MD; Albert Min, MD; Myron Tong, MD; Naoky Tsai, MD; Bruce Tung, MD
HBV Watch^™
Timely Information for Practicing Physicians

JANUARY 2005

COVALENTLY CLOSED CIRCULAR DNA (cccDNA)

Intrahepatic levels in chronic HBV infection. HBV covalently closed circular DNA (cccDNA) is a key intermediate in HBV replication and serves as the template for transcription of viral RNA. Intracellular cccDNA is the reservoir responsible for the persistence of chronic HBV infection and for reactivation of hepatitis B after stopping therapy. Technical constraints have hampered the direct study of cccDNA maintenance and clearance mechanisms in patients with chronic hepatitis B. The Invader assay, a signal amplification assay, was used by Danny Wong et al. to quantify HBV cccDNA in liver biopsies. They measured total HBV DNA and cccDNA using the Invader assay in DNA extracted from liver biopsies and in serum collected from 16 HBeAg(+) and 36 anti-HBe(+) chronic HBV patients. The median intrahepatic levels of total HBV DNA and cccDNA were significantly lower in anti-HBe(+) patients than HBeAg(+) patients. The absolute level of intrahepatic cccDNA correlated positively with the total intrahepatic HBV DNA level; however, the proportion of intrahepatic HBV DNA in the form of cccDNA was inversely related to the amount of total intrahepatic HBV DNA. It was also found that serum HBV DNA levels correlated positively with intrahepatic HBV DNA and cccDNA levels. These findings indicate that cccDNA becomes the predominant form of intrahepatic HBV DNA as total HBV DNA levels decrease during progression from the HBeAg(+) to the anti-HBe(+) phase of HBV infection. In a second study, Bettina Werle-Lapostolle and colleagues measured intrahepatic cccDNA in 98 liver biopsy samples from patients in different phases of the natural history of HBV infection. In addition, paired samples from 32 HBV patients receiving adefovir dipivoxil therapy were analyzed. Similar to Wong et al., they found intrahepatic cccDNA levels were strongly correlated with serum and intrahepatic HBV DNA levels. Intrahepatic cccDNA was detected in patients in all phases of HBV infection. Furthermore, 48 weeks of adefovir treatment was associated with a significant decrease in cccDNA copies/cell. The decrease in intrahepatic cccDNA correlated with a similar reduction in serum HBsAg titer; however, the number of HBV antigen-positive cells was not observed to decrease. These data demonstrate that cccDNA persists throughout the natural history of HBV infection and that long-term adefovir treatment can decrease, but not eradicate, intrahepatic cccDNA levels. (Wong DK-H, et al. Hepatology 2004; 40: 727-737 and Werle-Lapostolle B, et al., Gastroenterology 2004;126:1750-1758)

OCCULT HBV INFECTION

Occult HBV in hemodialysis patients. HBV infection continues to occur in adult hemodialysis patients, and a possible contributing factor is the presence of occult HBV infection (negative HBsAg, but positive HBV DNA). To document the prevalence of HBV infection in this population, Gerald Minuk and others screened 241 adult hemodialysis patients for occult HBV utilizing real-time PCR with 2 independent primer sets (core promoter and surface). Two patients (0.8%) were HBsAg(+). Among the remaining 239 HBsAg(-) patients, 9 patients (3.8%) had detectable levels of HBV DNA in the serum with viral loads ranging from10² to 10⁴ viral copies/mL. Seven of these 9 patients were nt 587 mutation (S-mutant) positive. No demographic factors were found to be predictive for occult HBV infection. These findings indicate the prevalence of occult HBV is 4-5 times higher than HBsAg testing would suggest and these infections are frequently associated with low viral loads and the S-mutant. A monoclonal based EIA was used for detection of HBsAg, which may have accounted for the failure to detect the S-mutant. Of the 228 individuals with information available regarding HBV vaccination status, only 202 (88.6%) had completed the course of vaccination, which may have contributed to the high rate of HBV infection. Additional studies are needed to further evaluate the clinical relevance of detection of HBV DNA with sensitive PCR-based assays, and whether or not screening dialysis patients and staff with these assays should be performed. (Minuk GY, et al. Hepatology 2004;40:1072-1077)

HBV VACCINATION

Long-term follow-up of a randomized trial. Man-Fung Yuen and colleagues from the University of Hong Kong tested long-term immunogenicity in 88 subjects who had participated in a HBV vaccination study 18 years earlier. The subjects had been randomized to receive 3 different HBV vaccination regimens: 2-dose recombinant; 3-dose recombinant; and 3-dose plasma-derived vaccines. The two 3-dose vaccine regimen groups had a significantly higher geometric mean titer of anti-HBs and a higher proportion of subjects with anti-HBs titers ≥10 mIU/mL than the 2-dose regimen group. No differences were found between subjects receiving the 3-dose recombinant and the 3-dose plasma-derived vaccine regimens. Anamnestic responses were documented in 70 subjects and no subject became HBsAg(+). Benign breakthrough HBV infection, indicated by isolated anti-HBc positivity, occurred in 3 patients. These findings showed that the 3-dose regimens were more effective than the 2-dose regimen and that a booster dose was not necessary for up to 18 years after the primary vaccination, but the number of subjects studied was small. (Yuen M-F, et al. Clin Gastroenterol Hepatol 2004;2:941-945)

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