Hepatitis B antiviral drugs reduce liver cancer risk

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.

Over 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.

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 entry.

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 taking TDF.

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:

• Overall: 21 cases observed vs 50 predicted; 58% reduction (standardised incidence ratio 0.42)
• People with cirrhosis: 7 observed vs 11 predicted; 37% reduction (SIR 0.63)
• Non-cirrhotic: 14 observed vs 38 predicted; 63% reduction (SIR 0.37)
• TAF recipients: 11 observed vs 32 predicted; 65% reduction (SIR 0.35)
• TDF recipients: 10 observed vs 18 predicted; 45% reduction (SIR 0.55).

A "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 reduction."

In a related study, Prof Stanislas Pol and colleagues with the French ANRS/AFEF Hepather Collaboration looked at the occurrence of liver cancer among people treated with TDF or entecavir.

As background, the researchers noted that the prior REVEAL study showed that higher HBV DNA is associated with an increased risk of cirrhosis independent of age, sex, HBeAg status, ALT levels and smoking or alcohol consumption. As such, EASL guidelines recommend nucleoside/nucleotide antivirals for people with chronic hepatitis B to prevent progression to cirrhosis and hence development of HCC.

This analysis included 2436 people with current or past HBV infection at more than 30 centres in France who were treated with antivirals upon entry into the Hepather cohort. Those with hepatitis C or hepatitis delta co-infection were excluded. Of these, 1075 received TDF and 885 received entecavir.

TDF recipients were slightly younger on average (47 versus 50 years), less likely to be men (68% versus 73%) and less likely to be treatment-naive (48% versus 64%), but otherwise they were generally similar. More than two-thirds (36%) were of African origin, 21% were Asian and 32% were European. At study entry, 8% had advanced fibrosis (stage F3) and about 16% had cirrhosis (stage F4). Few had a prior history of HCC (3%) or decompensated cirrhosis (4%).

Over a median follow-up period of 45 months, 12 TDF recipients and 12 entecavir recipients were diagnosed with HCC (incidence rates of 3.3 and 3.0 per 1000 person-years [PY]). Seven and six, respectively, developed decompensated cirrhosis (1.8 and 1.7 per 1000 PY), and ten and four, respectively, died from liver-related causes (1.9 and 2.5 per 1000 PY). None of these differences were statistically significant. Liver transplantation rates were also similar.

Factors associated with the development of liver cancer included older age (HR 5.49 for < 50 vs 56-64; HR 4.10 for < 50 vs > 64) and having advanced fibrosis or cirrhosis compared with absent, mild or moderate fibrosis (HR 10.78 for F3 vs F0-F2; HR 11.38 for F4 vs F0-F2).

These results conflict with those from a previous study of an Asian cohort study in Hong Kong suggesting that TDF might be associated with a lower risk of liver cancer compared with entecavir.