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

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


September 11, 2008

Does cccDNA have any role in predicting response to therapy with the oral antiviral agents in hepatitis B?

Response from Paul Martin, MD, FACP, and Hui Hui Tan, MBS, MRCP (UK)
Paul Martin, 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 ′pool′ 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.


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