Caution needed about claims of increased risk of liver cancer recurrence with use of DAAs

Hepatitis C virus (HCV) infects the liver, causing inflammation. If left untreated, it also results in a gradual loss of healthy tissue and its replacement with useless scar tissue in a process called fibrosis. As more of the liver becomes scarred, it increasingly becomes dysfunctional. This leads to complications, serious infections and, ultimately, liver failure. As scar tissue accumulates, the risk for developing liver cancer also increases.

The arrival of potent all-oral anti-HCV therapy—called direct acting antivirals (DAAs)—has greatly increased the chances of people being cured from HCV infection. In clinical trials, cure rates with modern DAAs are generally around 95% or greater.

Results from observational studies in the United States and France suggest that after a person is cured of HCV there is a small and temporary residual risk for developing symptoms associated with cirrhosis, and in some cases there is also a small and temporary risk for developing liver cancer. These risks seem greatest for people who have cirrhosis. However, the risk for such serious complications declines after one has been cured and data so far suggest that it is extremely low two years after being cured.

Recently, reports have appeared at conferences and in journal articles suggesting that there is an unexpected increase in rates of recurrence of liver cancer. These reports have emerged from clinics in Barcelona and Vienna but may also appear from clinics in other cities in the future.

How should this news be interpreted? We urge our readers to treat these reports with caution. There are several reasons that could explain why such cancers have recurred and these are discussed later in this issue of TreatmentUpdate. The reports generally contain a dataset that is relatively small compared to clinical trials. Such small datasets are not likely to be broadly representative of people at high risk for liver cancer. For this and other reasons, the link that some researchers attempt to make between the use of DAAs and the onset of liver cancer recurrence is not robust and may even be due to chance.

Bear in mind that tumours do not usually appear suddenly. Cells generally slowly transform into an abnormal state, and even then, only some of those abnormal cells become cancers; some form benign tumours. Thus, liver cells that have been transformed into cancers take time to grow and form large tumours that can be detected with scans. Although ultrasound scans performed every six months are considered part of the basis of screening for liver tumours, such scans are imperfect and do not always detect tumours. Indeed no scanning technology that seeks to detect tumours in the liver is perfect. As a result, some people in the reports that we will present may have had cancer but it was not detected until much later. This could have confused some of the doctors when they attempted to link the development or recurrence of such cancers with exposure to DAAs. Also, liver cancer does not generally cause symptoms until it has become advanced, so some patients and their doctors may not be aware that cancer has formed and is growing.

It is also possible that reports from the smaller datasets in Barcelona and Vienna were inadvertently over-represented with people at very high risk for the recurrence of liver cancer. This elevated risk may stem from one’s medical history, the type of liver tumour(s) that they had previously been diagnosed with and, possibly, the type of anti-cancer therapy that they had received.

Collectively, all of the factors mentioned here weaken the association between the use of DAAs and risk for the recurrence of liver cancer.

Whatever the cause(s) of the apparent increased risk for the recurrence of liver cancer, there is no evidence that DAAs cause liver cancer or increase the risk for its recurrence. Though the reports from Barcelona and Vienna are interesting, they are based on relatively small numbers of patients and are not definitive. Doctors who have reviewed the reports from Barcelona and Vienna strongly suggest that people who are cured of HCV and who are at high risk for liver cancer because of cirrhosis or having had such cancer in the past undergo regular screening for liver cancer.

—Sean R. Hosein