Treating hepatitis B virus (HBV) with
nucleoside/nucleotide antiviral drugs was associated with a lower risk of
developing hepatocellular carcinoma (HCC), the most common type of liver
cancer, according to studies presented last week at the AASLD Liver Meeting in Boston.
years or decades, chronic HBV infection can lead to liver cirrhosis, liver
failure and the development of liver cancer. Antiviral medications such as
tenofovir disoproxil fumarate (TDF, Viread),
tenofovir alafenamide (TAF, Vemlidy)
and entecavir (Baraclude) can suppress HBV replication indefinitely during
treatment, but they seldom lead to a cure, defined as clearance of
hepatitis B surface antigen (HBsAg). Nonetheless, viral suppression reduces
liver inflammation and slows liver disease progression.
Prof Young-Suk Lim of Asan
Medical Centre in Seoul, Korea, and colleagues evaluated long-term results from
a pair of phase III clinical trials comparing TDF and TAF for hepatitis B. TAF
is an updated version of TDF that produces higher levels of the active drug in
liver cells. This means TAF can be given at lower doses, leading to less drug
exposure for the kidneys and bones.
- decompensated cirrhosis
The later stage of
cirrhosis, during which the liver cannot perform some vital functions and
complications occur. See also ‘cirrhosis’ and ‘compensated cirrhosis’.
A test that uses
results from blood tests to predict liver damage.
- hepatocellular carcinoma (HCC)
Liver cancer. A long-term complication of chronic inflammation of the liver or cirrhosis.
Gilead Sciences' Study 108 included 579 people with
hepatitis 'e' antigen (HBeAg)-negative chronic HBV infection, while Study 110
included 1053 people with HBeAg-positive HBV. All had baseline HBV DNA levels
of 20,000 IU/ml or higher and elevated ALT liver enzyme levels. Some had
compensated liver cirrhosis, but none had been diagnosed with HCC at study
Participants were randomly assigned to receive TAF or
TDF for three years, followed by an open-label extension phase in which
everyone took TAF for up to eight years.
As previously reported, both drugs were about equally
effective. After 48 weeks of treatment, 94% of TAF recipients and 93% of TDF
recipients had suppressed HBV DNA in the HBeAg-negative study, and 64% and 66%,
respectively, did so in the HBeAg-positive study. Both drugs also led to
declines in ALT levels.
Researchers have also reported that people assigned to
take TAF were less likely to see detrimental effects on markers of kidney
function and bone loss than those randomised to TDF, and that patients who have
switched from TDF to TAF showed improvements in these
markers. Another study presented at The Liver Meeting showed that switching to TAF
was beneficial for people who had taken TDF for four years or longer.
At week 96 of treatment, participants in these studies
began receiving ultrasound scans every six months to screen for liver cancer.
Over three or five years of follow-up, 11 TAF
recipients (1.0%) and 10 TDF recipients (1.9%) developed HCC. This was about
equally like to occur during the initial randomised phase and in the open-label
extension phase. The median time to HCC diagnosis was 173 weeks for TAF
recipients and 81 weeks for TDF recipients, a difference that did not reach the
threshold for statistical significance. Seven cases were diagnosed in people
with cirrhosis and 14 in those without cirrhosis.
Overall, people who developed liver cancer were older than
those who did not (median 53 versus 39 years), more likely to be men (90% versus
65%), more likely to have cirrhosis (33% versus 9%) and had higher Fibrotest
fibrosis scores (median 0.64 versus 0.32). Characteristics were generally
similar between those who developed HCC while taking TAF and those who did so
while taking TDF.
After adjusting for other factors in a multivariate
analysis, male sex was associated with a more than sevenfold higher risk of
HCC (hazard ratio 7.57), lack of ALT normalisation at week 24 was associated
with a nearly sevenfold elevation (HR 6.90), and having cirrhosis was
associated with a more than fourfold high risk (HR 4.18), while a higher
baseline HBsAg level was associated with a decrease in HCC risk (HR 0.53).
Cumulative HCC incidence did not differ between people taking TAF and those
Although these studies did not directly compare HCC
risk in treated and untreated people, comparisons based on a prediction model known as REACH-B indicated that the number of liver
cancer cases among people treated with TAF or TDF was lower than would have
been expected among untreated individuals over the same time frame:
Calculating standardised incidence ratios of observed
versus predicted cases, the researchers concluded that antiviral therapy reduced
the risk of HCC across groups:
21 cases observed vs 50 predicted; 58% reduction (standardised incidence ratio
with cirrhosis: 7 observed vs 11 predicted; 37% reduction (SIR 0.63)
14 observed vs 38 predicted; 63% reduction (SIR 0.37)
- TAF recipients:
11 observed vs 32 predicted; 65% reduction (SIR 0.35)
recipients: 10 observed vs 18 predicted; 45% reduction (SIR 0.55).
"significant reduction in HCC incidence vs predicted rates by REACH-B was
seen for all cases and for patients with no cirrhosis at baseline," the
researchers concluded. "In patients treated with TAF, a significant
reduction in SIR was seen; for TDF there was a trend toward a significant