Ask the Experts: Do cccDNA Levels Have a Role in Predicting Response to Treatment in Hepatitis B?

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From Medscape Gastroenterology

Ask the Experts about Liver Disease

Do cccDNA Levels Have a Role in Predicting Response to Treatment in Hepatitis B?

Posted 09/11/2008

, MD, FACP; Hui Hui Tan, MBS, MRCP (UK)

Author Information

Question

Does cccDNA have any role in predicting response to therapy with the oral

antiviral agents in hepatitis B?

Response from , MD, FACP, and Hui Hui Tan, MBS, MRCP (UK)

, MD, FACP, Professor of Medicine and Chief, Division of Hepatology,

Center for Liver Disease, University of Miami School of Medicine, Miami, Florida

Hui Hui Tan, MBS, MRCP (UK), Associate Consultant, Department of

Gastroenterology and Hepatology, Singapore General Hospital, Singapore

Covalently closed circular DNA (cccDNA) is a crucial intermediate in the

replication of the hepatitis B virus (HBV). In the host nucleoplasm, it acts as

a template for continued virion production in chronically infected patients.

Viral transcripts are transported from the nucleus into the cytoplasm, where

they are translated into the various HBV proteins. Pregenomic RNA is then

encapsidated and reverse-transcribed into new partially double-stranded viral

genomes. cccDNA remains in the nucleus as long as the infected hepatocyte

survives, maintaining a viral ¡ìpool¡ì in chronic infection. Because

cccDNA does not circulate in the blood, measurement of its levels requires

hepatic tissue (cccDNA is quantified by polymerase chain reaction [PCR]

assay),[1] whereas serum hepatitis B surface antigen concentration provides an

indirect assessment of its concentration in the hepatocyte.[2]

It is unclear whether currently approved treatments for HBV infection are able

to eliminate cccDNA in the absence of hepatocyte lysis. Return of HBV

replication after apparently successful treatment with suppression of viral

replication, is attributed to remnant intrahepatic cccDNA. Recent studies have

attempted to correlate cccDNA levels with treatment outcomes. To date, human

studies have been small (n < 80), although results appear promising. Most

studies have found pre-treatment cccDNA load or intrahepatic total HBV viral

load (quantified with PCR) to be inversely proportional to hepatitis B e antigen

(HBeAg) clearance rates and to sustained virologic response rates. A German

study of 26 HBeAg-positive patients treated with 48 weeks of combination

pegylated interferon alfa-2b and adefovir reported a correlation between cccDNA

reduction during the treatment period and treatment response.[3] Another study

of 47 Chinese patients found that log cccDNA levels were significantly lower

among subjects who achieved durable virologic responses (defined as durable

HBeAg seroconversion plus serum HBV DNA < 500,000 copies/mL from

end-of-treatment until week 52 after treatment) and concluded that both cccDNA

and intrahepatic total HBV DNA levels at end of therapy (with combination

pegylated interferon and lamivudine or lamivudine monotherapy) were superior to

serum HBV DNA as surrogates of virologic response.[4]

There are no human data correlating cccDNA levels with prediction of treatment

response to the newer nucleos[t]ide analogues yet. There has been no correlation

reported between cccDNA levels and treatment response in HBeAg-negative chronic

HBV patients yet either. Although current data on the use of cccDNA to predict

treatment response in HBV infection are limited, the initial results appear

promising and it is likely that baseline levels or degree of reduction during

treatment do predict treatment response. However, larger studies will be needed

before cccDNA levels can be validated and recommended as a tool to assess or

predict response to treatment in hepatitis B.