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Hepatitis B treatment may be linked to colorectal and cervical cancer

Liz Highleyman
10 June 2016
Grace Wong presenting at ILC 2016. Photo by Liz Highleyman,

People with hepatitis B who were treated with nucleoside/nucleotide antivirals did not have a higher rate of malignancies overall, but did show an increased incidence of colorectal and cervical cancer, underlining the need for regular screening, according to a study presented at the recent 2016 International Liver Congress in Barcelona.

Antiviral therapy using nucleoside/nucleotide analogues such as entecavir (Baraclude) or tenofovir (Viread) is the mainstay of treatment for chronic hepatitis B. While these drugs can effectively suppress hepatitis B virus replication during therapy, they usually do not lead to a cure, and thus often must be taken for a long period.

Grace Wong of the Chinese University of Hong Kong and colleagues analysed the incidence rates of various malignancies among antiviral-treated hepatitis B patients compared to untreated patients.



A type of tumour affecting the lymph nodes.

Prior studies have produced conflicting evidence about whether long-term nucleoside/nucleotide analogue therapy increases risk of various cancers, they noted as background. Entecavir, in particular, has been linked to cancer in some animal studies.

The researchers did a retrospective cohort study using the database of the Hospital Authority, which manages Hong Kong's public hospitals. Using diagnostic codes they identified 68,492 chronic hepatitis B patients diagnosed between 2000 and 2012. People with pre-existing malignancies at baseline and those co-infected with hepatitis C, hepatitis delta, hepatitis E or HIV were excluded.

The outcome of interest was incident or new malignancies other than hepatocellular carcinoma, a type of liver cancer known to be caused by hepatitis B virus. Participants were analysed after a cancer-free 'landmark period' of 2, 3 or 4 years after baseline and followed until death, 7 years or the end of the study in 2012.

Within this group, 44,949 participants were included in the 3-year landmark analysis. Of these, 4782 patients (about 11%) had been treated with nucleoside/nucleotide antivirals while 39,712 remained untreated. Demographics and laboratory biomarkers differed between the treated and untreated groups, so the groups were weighted to make them more similar. About 75% of the treated patients were men and the mean age was 46 years.

As expected, hepatocellular carcinoma was much more common among chronic hepatitis B patients compared to the Hong Kong general population: 300.0 vs 25.0 cases per 100,000 persons.

Incidence rates for other types of cancer were much lower. All gastrointestinal malignancies occurred at a rate of 21.2 cases per 100,000 hepatitis B patients. Incidence rates were 28.8, 11.8, and 6.2 per 100,000, respectively, for colorectal, gastric (stomach) and oesophageal cancer.

All other types of cancer occurred at a rate of 38.0 per 100,000 persons. Incidence rates were 74.4 per 100,000 for lung cancer, 24.1 for breast cancer, 20.0 for retroperitoneal malignancies, 1.0 for urinary or kidney malignancies, 18.5 for lymphoma, 18.0 for cervical cancer (females only) and 14.9 for brain cancer.

In an unweighted analysis, rates of lymphoma and cervical cancer were found to be higher among chronic hepatitis B patients compared to the general population.

Looking at the effect of nucleoside/nucleotide treatment, incidence of all malignancies, lung cancer, urinary/kidney cancer, breast cancer and lymphoma were statistically similar between treated and untreated hepatitis B patients.

However, treated hepatitis B patients had a significantly higher incidence of colorectal cancer and cervical cancer, with weighted hazard ratios of 2.17 (about twice the risk) and 7.33 (more than seven times the risk), respectively.

Similar findings were observed when results were analysed according to patient sex, age above or below 50 years, use of entecavir versus other nucleoside/nucleotides and consistency of antiviral treatment. Results were also similar in the 2-year and 4-year landmark analyses. The exception was that women with hepatitis B had a higher risk of colorectal cancer than men, but the number of cases was small.

"This large-scaled population-based study does not suggest an increased risk of all malignancies in [nucleoside/nucleotide analogue]-treated chronic hepatitis B patients," the researchers concluded.

However, they recommended, "colorectal and cervical cancer screening should be offered to those with risk factors," and added that "the risks of colorectal and cervical cancers in [nucleoside/nucleotide analogue]-treated female patients require independent confirmation."

"In light of these findings we strongly urge regular screening of these cancers to help prevent them from developing in patients taking [nucleoside/nucleotide analogue] treatment," Dr Grace stated in an European Association for the Study of the Liver (EASL) press release.

"This large-scale study determines an important link between [nucleoside/nucleotide analogue] treatment and cervical and colorectal cancer," added EASL vice secretary Tom Hemming Karlsen. "The results are important and could change cancer surveillance and management of patients treated for hepatitis B."


Wong GLH et al. Incidences of all malignancies in patients with chronic hepatitis B receiving long-term oral nucleos(t)ide analogue treatment  – a study of 45,299 subjects. International Liver Congress, Barcelona, abstract PS052, 2016.