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Long term nucleos(t)ide analogue therapy reduced the extent of HBV DNA integration in chronic hepatitis B patients
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NUCs May Prevent HCC by Reducing HBV DNA Integration
AASLD The Liver Meeting Digital Experience, November 13-16, 2020
Mark Mascolini
Ongoing nucleos(t)ide analog (NUC) therapy "drastically reduced" HBV DNA integration into chromosomes of people with chronic hepatitis B virus (HBV) infection, according to a detailed 28-person analysis [1]. University of Hong Kong researchers suggested this anti-integration activity could explain why NUC therapy lowers the risk of hepatocellular carcinoma (HCC) in people with HBV.
Research links chromosomal integration of HBV DNA in people with chronic HBV infection to HCC development. This integration happens early in the course of chronic HBV. But because currently used anti-HBV NUCs rein in HBV replication, lower HBV DNA in blood and liver, and trim HCC risk, the Hong Kong team asked whether they might cut cancer risk by reducing HBV DNA integration.
To answer that que¬¬stion the researchers studied 28 people who took NUCs for chronic HBV infection. Everyone had a liver biopsy before NUC therapy began (baseline) and after 1 year of treatment. Five people (18%) had a third biopsy 10 years after HBV therapy began. The investigators used inverse PCR to detect HBV DNA integration in chromosomes and expressed extent of integration as hepatocyte clone size.
Twenty-one of the 28 participants were men and age averaged 40 years at baseline. Fourteen people were HBeAg-positive (indicating actively replicating HBV) and 14 were HBeAg-negative. Eleven people took lamivudine, 10 entecavir, and 7 telbivudine.
From baseline to treatment year 1, several median HBV measures dropped significantly: serum HBV DNA (6.36 to 1.3 log IU/mL, P = 0.009), HBcrAg (3.56 to 2.71 kU/mL, P = 0.016), intrahepatic total HBV DNA (185.3 to 3.87 copies/cell, P = 0.007), and intrahepatic cccDNA (4.21 to 0.70 copies/cell, P = 0.007). The last three measures continued to fall in the 5 people who had 10 years of follow-up. HBsAg did not drop significantly in the first year of treatment (3.49 to 3.30 log IU/mL) but continued drifting downward in the next 9 years (to 2.56 log IU/mL) (P = 0.247 for trend).
Before treatment began, all participants had detectable HBV DNA integration at a median hepatocyte clone size of 1.40 x 10(5). Integration could be detected randomly across the whole genome, in all chromosomes except Y. Initial hepatocyte clone size did not correlate with age, HBeAg status, or virologic parameters.
After 1 year of NUC therapy median hepatocyte clone size dropped by 42.5% to 6.72 x 10(4), a significant decline (P = 0.003). Three of 5 people with a biopsy 10 years after therapy began had no detectable HBV DNA integration into chromosomes. In these 3 study participants median hepatocyte clone size fell significantly from before NUC therapy to year 1 and to year 10 (4.54 x 10(4) to 2.62 x 10(4) to <1.00 x 10(2), P = 0.015). In the 5 people with 3 biopsies across 10 years, HBV DNA in the liver fell by 1.5 log (about 32-fold) after 1 year of NUC therapy and by 3.0 log (1000-fold) after 10 years.
Falling HBV measures in serum and the liver did not correlate significantly with declining hepatocyte clone size.
The researchers concluded that NUC therapy significantly lowered clone size of infected liver cells, and that long-term therapy "drastically reduced" HBV DNA integration. Why NUCs have these effects remains unclear. The investigators see a need for further study on how HBV DNA integration may differ by therapeutic agent or patient subgroup.
Reference
1. Chow N, Wong DKH, Mak LY, et al. Long term nucleos(t)ide analogue therapy reduced the extent of HBV DNA integration in chronic hepatitis B patients. AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 22.
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