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AMSTERDAM -- Hepatitis C patients treated with direct-acting antiviral (DAA) therapy do not appear to have a higher risk of developing liver cancer than those treated with interferon, but the latest data leave some room for debate, according to studies presented here.

A meta-analysis of more than 40 studies found no evidence of a higher risk of new or recurring hepatocellular carcinoma (HCC) after DAA treatment, according to , from the Kirby Institute at the University of New South Wales in Sydney.

Dore's findings, along with those of several other studies of HCC following DAA treatment, were presented at the , the annual meeting of the .

Over years or decades chronic hepatitis C virus (HCV) infection can lead to serious liver disease including cirrhosis and hepatocellular carcinoma. Worldwide, liver cancer is a leading cause of cancer-related death.

Successful treatment of chronic hepatitis C is expected to reduce the risk of liver disease progression and development of HCC. But liver damage is not fully reversible, and people who already have cirrhosis when they start therapy remain at risk for liver cancer.

"I don't think there's any question that curing hepatitis C in people with compensated cirrhosis reduces the risk of HCC," Dore said. "The question is whether there's a differential risk between an interferon-based cure and a DAA-based cure."

To date there has been conflicting evidence about the likelihood of liver cancer occurring or recurring after treatment with DAAs versus interferon-based therapy.

A study presented at last year's EASL meeting provided the first suggestion that people cured with DAAs might be at greater risk for liver cancer. Italian researchers reported that patients with cirrhosis who were treated with DAAs had a higher likelihood of developing liver cancer, but the excess risk was limited to recurrence in people with a prior history of HCC. A higher than expected rate of HCC recurrence was also seen in a .

On the other hand, a study presented at the annual meeting last November showed that treatment with DAAs was not linked to higher HCC risk in a large Northern Italian cohort. But people treated with the new drugs appeared to experience more aggressive disease progression.

Dore and colleagues performed a systematic review and meta-analysis to compare the risk of HCC occurrence in people with cirrhosis who achieved sustained virological response -- undetectable HCV viral load 12 weeks after finishing treatment (SVR12) -- with DAAs versus interferon. They also compared HCC recurrence in patients who had received curative treatment for liver cancer.

Although the researchers started out with more than 4,000 studies, many had to be thrown out due to missing data or for other reasons, leaving 26 relevant studies of HCC occurrence and 15 studies of HCC recurrence. Together the 41 studies included a total of 13,875 patients.

Dore's team found that patients treated with DAAs were not the same as those treated with interferon, and these differences could explain the apparent divergence in liver cancer risk.

Without taking these factors into account, the rate of initial HCC occurrence was 3.09 per 100 person-years for DAA-treated patients compared to 1.14 for interferon-treated patients -- seemingly threefold higher. For HCC recurrence, the rates were 12.14 and 9.21 per 100 person-years, respectively.

But DAA-treated patients who initially developed liver cancer were older on average than those treated with interferon (60 versus 52 years) and had more severe liver disease.

"As you get older, even [among] people with cirrhosis, the risk of HCC goes up," Dore told reporters.

All patients treated with interferon had milder Child-Pugh Class A compensated cirrhosis, while a third of those treated with DAAs had more severe Class B or Class C decompensated disease.

Dore explained that people with more advanced liver disease often could not tolerate interferon and ribavirin, and interferon-based therapy was therefore considered unsuitable for the sickest patients.

Also, because the direct-acting drugs are so new, in both the initial occurrence and recurrence comparisons the follow-up time was much shorter for DAA-treated patients than for interferon-treated patients -- approximately one versus five years, on average.

This is important because many cases of initial and recurrent HCC occur soon after finishing treatment.

"As the follow-up period lengthens, the incidence of HCC comes down," Dore explained. "Often in the early period of follow-up those people at very high risk develop HCC, and as you extend the follow-up period the overall group becomes lower risk. If you only follow people for a short period of time, you can get these apparent high rates coming through."

Dore suggested that some people on DAAs might have had small tumors present before treatment that were only detected after they completed three months of therapy. In contrast, people treated with interferon had 6 or 12 months of therapy during which HCC progression could occur, making it more likely that cancer would be caught during rather than after treatment.

After adjusting the data for these factors in a statistical analysis, there was no significant difference in the rates of HCC occurrence or recurrence between DAA-treated and interferon-treated patients. In fact, Dore said, there was a hint that the DAA group may have a lower risk.

Other HCC studies

A conference session on hepatitis C post-SVR management featured several other studies of HCC among people treated with DAAs. , from Università degli Studi in Milan gave an overview of these presentations at an EASL press conference.

"The general theme is that we are dealing with a completely different patient population [in the DAA era] with respect to our previous experience with interferon -- more advanced and with a higher risk of having dormant cancer in the liver," Colombo told reporters.

In one of the studies, , and colleagues from Hospital Clinic Barcelona presented new findings, updating their 2016 Journal of Hepatology report, confirming a high rate of liver cancer recurrence among people treated with DAAs. Over a 12-month period, 31% saw their HCC come back, and nearly a third of those who were treated for liver cancer experienced HCC progression within 6 months.

"Our study offers further support to previous findings that there is an unexpected high recurrence rate of hepatocellular carcinoma associated with DAAs, and that this association may result in a more aggressive pattern of recurrence and faster tumor progression," Reig said in a statement.

But Reig's group stood virtually alone in reporting increased liver cancer risk associated with DAA treatment. Researchers from France, Scotland, Sicily, and China saw either similar rates of HCC after DAA therapy, or somewhat higher rates that could be attributed to differences in patient characteristics -- chiefly older age and more advanced liver disease. A Japanese study saw a lower incidence of liver cancer among people treated with DAAs.

These new studies were not part of Dore's meta-analysis, and their inclusion would likely strengthen his conclusion that the risk of HCC occurrence and recurrence is not significantly greater after treatment with DAAs.

Whatever the cause, the ongoing risk of HCC among people who have cirrhosis before starting treatment underscores the need for ongoing monitoring for liver cancer. The study findings also support early DAA treatment before people develop advanced liver disease.

"The best HCC prevention strategy and best way to reduce mortality is to scale-up DAA therapy as broadly and rapidly as you can," Dore told 番茄社区app. "I will be very surprised if survival following HCC in the DAA era is reduced rather than improved."