Lower hepatoma risk with earlier ALT normalization during HBV treatment

Last Updated: 2020-01-17

By Will Boggs MD

NEW YORK (Reuters Health) - Earlier normalization of alanine aminotransferase (ALT) levels during treatment of chronic hepatitis B is independently associated with a reduced risk of hepatocellular carcinoma (HCC), researchers from South Korea report.

In previous studies of the natural course of chronic hepatitis B, normalization of ALT levels, marked decreases in HBV DNA, and hepatitis B e antigen (HBeAg) seroclearance have been associated with a reduced rates of HCC and mortality.

A recent study also suggested that ALT normalization at one year after direct-acting antiviral treatment was associated with a lower risk of hepatic events. But whether ALT normalization with therapy is associated with a lower risk of HCC remains unclear.

Dr. Young-Suk Lim of Asan Medical Center, University of Ulsan College of Medicine, in Seoul, and colleagues evaluated the impact of on-treatment surrogate endpoints on the risk of HCC in more than 4,600 treatment-naive adults with chronic hepatitis B who initiated treatment with entecavir or tenofovir disoproxil fumarate (TDF) from 2007 through 2016.

During a median follow-up of 5.6 years, 509 patients (11%) developed HCC, for an annual incidence rate of 1.99 per 100 person-years and cumulative HCC risks of 5.1% at three years, 9.2% at five years and 18.8% at 10 years.

During this interval, 220 patients died or underwent liver transplantation, with cumulative incidence rates of 1.9% at three years, 3.9% at five years and 8.0% at 10 years, the researchers report in The American Journal of Gastroenterology.

The cumulative rates of ALT normalization were 65.6% at one year, 81.9% at two and 90.9% at five; the cumulative viral response rates were 45.4%, 72.6%, and 86.8%, respectively; and the cumulative HBeAg seroclearance rates were 14.5%, 24.6% and 40.8%.

In multivariable analyses, earlier ALT normalization during the overall treatment period was independently associated with a 43% lower HCC risk (P<0.001).

Compared with ALT normalization within six months of treatment, the risk of HCC was 40% higher (P=0.02) with ALT normalization at six-12 months, 74% higher (P<0.001) with ALT normalization at 12-24 months, and 2.45-fold higher (P<0.001) with ALT normalization beyond 24 months.

In contrast, neither earlier viral response nor earlier HBeAg seroclearance was independently associated with a significantly lower HCC risk.

ALT normalization at one and two years of treatment was also significantly associated with a reduced risk of overall death or transplantation during follow-up.

Factors independently associated with early ALT normalization included male sex, lower HBV DNA at baseline, absence of fatty liver and treatment with TDF.

On the other hand, older age, female sex, cirrhosis, hyperbilirubinemia and the presence of fatty liver at baseline were independently associated with no normalization of ALT at two years of treatment.

"Although the biological mechanism that explains this association should be the subject of future studies, our results suggest that efforts should be made to achieve ALT normalization as early as possible during nucleos(t)ide analogue treatment to minimize the risk of HCC and mortality," the authors conclude.

Dr. Robert G. Gish of the University of Nevada Reno School of Medicine and the University of Nevada at Las Vegas, who provides consulting services to liver and liver-transplant programs and has researched various aspects of hepatitis B, told Reuters Health by email that he found it interesting "how much more closely linked the ALT was than the HBV DNA to HCC risk. This really points to inflammation as a major driver of HCC formation."

"Driving the ALT to normal is a key step, since all of the first-line meds have equal DNA-negativity rates," said Dr. Gish, who was not involved in the study.

He advised, "Treat NASH (non-alcoholic steatohepatitis) and stop alcohol use to help normalize ALT."

Dr. Lim did not respond to a request for comments.

SOURCE: https://bit.ly/2NmUqqR The American Journal of Gastroenterology, online January 2, 2020.