Tenofovir may lower the risk of liver cancer more than entecavir

People with hepatitis B who were treated with tenofovir disoproxil fumarate (TDF; Viread) were less likely to develop hepatocellular carcinoma (HCC) than those treated with entecavir (Baraclude) in a large observational study, according to results presented at the 2019 International Liver Congress last week in Vienna.

Although the analysis included nearly 30,000 people, only a small proportion of them used TDF. While the researchers attempted to control for other factors that might influence outcomes, it may be too early to conclude that TDF is a superior option for hepatitis B treatment. If further data confirm these findings, it could have public health implications because entecavir is off patent and less expensive than TDF and the newer tenofovir alafenamide (Vemlidy).

Over years or decades, chronic hepatitis B virus (HBV) infection can lead to liver cirrhosis, HCC and end-stage liver failure necessitating a transplant. Nucleoside/nucleotide antivirals such as TDF and entecavir can halt HBV replication during long-term treatment. These medications usually do not lead to a cure, but keeping the virus suppressed reduces the likelihood of developing of liver cancer.

Dr Terry Cheuk Fung Yip of the Chinese University of Hong Kong presented findings from an observational study of people with hepatitis B who were treated with either TDF or entecavir. Because this type of study does not randomly assign similar participants to different treatments – but rather observes what happens in real-world practice – people who receive different treatments could have other differences that affect outcomes.

TDF and entecavir are both potent and well-tolerated antivirals, and guidelines in many countries recommend them equally for first-line chronic HBV treatment, Yip noted. However, a recent Korean study found that TDF was associated with a 39% lower risk of HCC compared with entecavir.

Yip's analysis included adults with chronic hepatitis B seen at all public hospitals and clinics in Hong Kong who were treated with TDF or entecavir for at least six months between January 2008 and June 2018. People who already had HCC or other cancers at the start of the study were excluded. This was also the case for people with hepatitis C, hepatitis D or HIV co-infection and those previously treated with interferon or other nucleoside/nucleotide antivirals.

Of the more than 55,000 Hong Kong people treated with TDF or entecavir, 29,350 were included in this analysis. Most of the excluded individuals had pre-existing cancer, had co-infection with hepatitis C, had previously tried other HBV therapies, started treatment before 2008 or had less than six months of follow-up.

In the selected group, 1309 people – just under 5% – started treatment with TDF while 28,041 started with entecavir. People who used TDF were more likely to be female, were 10 years younger on average (43 versus 53 years) and had fewer other health problems including diabetes and hypertension. In addition, those taking TDF were less likely to have cirrhosis (3% vs 13%), less likely to be hepatitis B 'e' antigen (HBeAg) negative, had lower HBV DNA, lower ALT and more favourable biomarkers of liver function. However, similar proportions achieved HBV suppression on treatment.

During follow-up, eight people treated with TDF and 1386 treated with entecavir developed HCC. The cumulative five-year incidence was 1.1% in the TDF group versus 7.0% in the entecavir group. Looking at single factors in a univariate analysis, isolation, the biggest risk factors for HCC were male sex (hazard ratio 2.17) and having cirrhosis (hazard ratio 5.73).

In a multivariate analysis that accounted for several risk factors, people treated with TDF had about a third of the risk of developing HCC as those who used entecavir (adjusted hazard ratio 0.32).

The researchers attempted to control for differences between the populations using statistical techniques including imputation of missing data, propensity score weighting and competing risk analysis. Doing so brought the hazard ratio to 0.36, or about a 60% lower risk. A propensity score matching analysis, in which most TDF recipients were matched with an entecavir recipient with similar characteristics, yielded a hazard ratio of 0.42. Results were in the same range when considering only patients with cirrhosis.

Yip noted that another study presented at the conference, this one from the United States, showed that Asian patients who used TDF had about a 30% lower risk of HCC than those who used entecavir, while non-Asian people who took TDF actually had a higher liver cancer risk.

"Tenofovir was associated with a significantly lower risk of HCC than entecavir in this large population of adults with chronic HBV infection," Yip said in a conference press release. "Although we recognize the inherent limitations of observational data, our findings are consistent with those of the Korean group."