Sustained response to HCV antivirals boosts liver cancer survival

People with liver cancer who achieved a sustained virological response (SVR) to direct-acting antiviral (DAA) therapy for hepatitis C saw a reduction in both liver-related and all-cause mortality over five years, according to research presented last week at the AASLD Liver Meeting in Boston.

Over years or decades, chronic hepatitis C virus (HCV) infection can lead to liver cirrhosis, hepatocellular carcinoma (HCC, the most common type of liver cancer) and the need for a liver transplant. Prior studies have shown that successful hepatitis C treatment reduces the risk of developing HCC, and it may also improve outcomes among those who already have liver cancer.

HCC is often detected late and is difficult to treat. Surgery to remove the cancer and local therapies to destroy tumours may be possible at earlier stages. Systemic therapies are used at later stages, but this cancer does not respond well to traditional chemotherapy. A variety of targeted therapies and immunotherapies are now approved, but survival typically remains short for most people with unresectable HCC.

"Patients with HCC have such dismal prognosis, especially those who are not candidates for curative treatment, and unfortunately, these are the majority of the HCC population," Prof Mindie Nguyen of Stanford University in California said in an AASLD press release. "[Patients with SVR] following treatment with very safe and well-tolerated DAAs could increase their survival rates by a median of 18 months, [which is] considerable progress compared to other currently available systemic therapies for HCC."

Prof Nguyen and colleagues compared survival rates among people with HCV-related liver cancer who either were not treated with DAAs for hepatitis C or were treated and achieved SVR, defined as continued undetectable HCV RNA (< 25 IU/ml) at three months after completion of treatment, which is considered a cure.

The researchers conducted a retrospective chart review of medical records from two groups of people with HCV and HCC in the United States, Japan, South Korea and Taiwan followed between 2005 and 2017. Individuals with hepatitis B or HIV co-infection or other cancers besides HCC were excluded. This was also the case for people who did not achieve SVR on HCV treatment, those who were treated and achieved SVR more than six months prior to liver cancer diagnosis and those never treated for liver cancer.

Participants could have received ether curative or palliative liver cancer treatment. A majority underwent transarterial chemoembolisation (TACE), a method of blocking blood flow to liver tumours, according to Prof. Nguyen. Few patients received the targeted therapy sorafenib (Nexavar) and none received immunotherapies like nivolumab (Opdivo) or pembrolizumab (Keytruda), which have only recently been approved for HCC.

After these exclusions, the remaining study population included 1239 people who were not treated for hepatitis C and 437 who were successfully treated with interferon-free DAA regimens.

The untreated and cured groups were demographically similar. About 60% were men, about 70% were Asian, the median age was approximately 66 years and just over 80% had cirrhosis. However, those who were not treated for hepatitis C had significantly worse liver function and more advanced HCC than those who achieved SVR (44% vs 27% with Child-Pugh class B or C; 43% vs 20% with BCLC stage B/C/D; MELD score 8.74 vs 8.19, respectively). Those not treated for HCV were more likely to receive palliative therapy rather than curative treatment for HCC, while the opposite was true in the SVR group.

The researchers therefore matched the two groups by age, sex, country, cirrhosis status, HCC severity, type of HCC treatment and other factors, leaving a propensity-score matched cohort of 321 untreated and 321 cured participants who were more closely balanced with no significant differences between them.

In the propensity-matched cohort, those successfully treated for hepatitis C had a higher five-year survival rate than those who did not receive HCV treatment when assessing only liver-related mortality, 90.9% vs 68.8%, respectively. The same pattern was observed for overall survival rates, 87.8% vs 66.0%, respectively. Median survival durations were 26 months and 44 months – an 18-month improvement.

After adjusting for other factors, achieving SVR with DAAs was associated with a 66% lower risk of five-year liver-related mortality and a 63% reduction in five-year all cause mortality, both of which were statistically significant.

In well-matched patients with HCV-related HCC, SVR with interferon-free DAA therapy was associated with a 60 to 70% improvement in both all-cause and liver-related five-year survival compared to untreated patients, the researchers concluded. Thus, "HCV-related HCC patients who are candidates for HCC therapy should also be considered for DAA therapy," they advised.

"Our results clearly showed that SVR by DAA therapy is associated with improved overall survival, which is the most important endpoint for patients with a cancer," said study co-author Hidenori Toyoda, MD, PhD, of Ogaki Municipal Hospital in Japan. "Next, we should elucidate how SVR by DAA contributes to improved survival of patients with HCC, whether through the improvement of liver function which, in turn, provides patients with more hepatic reserve [and] more opportunities to get HCC treatment, through both initial and repeat treatment, or through more direct effects that suppress the recurrence and/or progression of HCC."

Speaking at an AASLD press conference, Prof Nguyen added that DAA therapy should be considered even for those with advanced stages of liver cancer, as even high-stage patients had a survival benefit, and DAA therapy has a high cure rate in those with advanced HCC. "I don't think poor [liver] function should be excluded," she said. "Those patients could benefit even more."