Chronic HCV infection has been identified as an important cause of liver cancer, but in a Veterans Health Administration (VHA) cohort with widespread access to effective direct-acting antiviral therapies, a nearly 30% decline in the incidence of hepatitis-related liver cancer was observed during a 3-year period following the introduction of effective treatment.
Conversely, the incidence of non–HCV-related liver cancer increased during the same time period.
“I think the main message is that HCV treatment is associated with a greatly reduced rate of HCV-related hepatocellular carcinoma within a relatively short time horizon,” said lead author Lauren Beste, MD, MSc, director of HIV, Hepatitis C, and Related Conditions Data and Analysis Group, US Dept of Veterans Affairs, Seattle, Washington.
Beste and coauthors, however, pointed out that this observational study cannot prove causation.
“I was very impressed that we saw a downtrend in cancers within just a few years,” Beste told Medscape Medical News. “This message is extremely relevant to the world beyond the VA because it shows that HCV treatment has benefits on a population level.”
This comment was a reference to the fact that the incidence of liver cancer has been steadily rising in the US during the past two decades.
An independent expert placed the VHA’s efforts and the new study, which was published online September 8 in the Journal of the American Medical Association, in an international context
“There are countries, such as Japan, that have initiated programs to eliminate HCV,” said Jing-Hsiung James Ou, PhD, professor of molecular microbiology and immunology at the University of Southern California in Los Angeles, who was asked for comment. “However, the high cost of the drugs is preventing this from taking place in the US.”
Rising and Falling
Previous research has shown that treatment with direct-acting antivirals appears to reduce the risk for death and liver cancer among patients with chronic HCV infection, including those with cirrhosis. As previously reported by Medscape Medical News, one prospective cohort study that included more than 10,000 adult patients with HCV, the risk for all-cause mortality, liver-related mortality, non–liver-related mortality, and liver cancer was significantly reduced among those who received direct-acting antiviral medications as compared with those who did not.
Liver cancer is now a leading cause of cancer-related death in the United States. Virtually all cases (>90%) of liver cancer are diagnosed in patients with cirrhosis, which tends to be the end result from any chronic liver disease, including HCV, hepatitis B (HBV), alcohol-related liver disease, and nonalcoholic fatty liver disease (NAFLD).
However, uptake of the direct-acting antiviral therapies has been less than optimal, note Beste and colleagues. Available since 2013, the direct-acting antivirals appear to be underused in the United States, as there has only been a 14% cure rate for HCV patients (as of 2016).
In contrast, the VHA, which is the largest integrated healthcare system in the US, provides its patients with unrestricted access to HCV treatments; about 85% of cases have been cured.
“The VA is the only national system I’m aware of that is offering HCV treatment nationally,” said Beste. “Outside the VA world, medication cost and lack of trained providers have been the major bottlenecks in the past.”
Decline in HCV-Related Liver Cancer
In this study, the authors used data from the VHA to examine trends in liver cancer incidence from 2002 to 2018, according to HCV status, and then looked to see if the cancer incidence had changed following widespread HCV treatment. They categorized patients into three groups as of the time of HCC diagnosis:
HCC/HCV viremic (latest HCV RNA before HCC diagnosis was positive
HCC/HCV cured (HCV eradicated before HCC diagnosis)
HCC/non-HCV (no positive lifetime HCV RNA)
The population of veterans ranged from 4.2 million in 2002 to 6.1 million in 2018. The overall incidence of HCC/HCV within the VHA increased from 2000 to 2015 and reached a peak in 2015 at 31.0 per 100,000 patients. It then began to trend downward, and by 2018 the incidence had declined by 30% to 21.8 per 100,000 patients.
In the group of patients with a history of HCV, liver cancer incidence peaked in 2015 (1061 per 100,000 patients) and then declined 27.2% to 773 per 100,000 by 2018. Further analysis showed that the incidence for both HCC/HCV total and all-cause HCC (P < .001) decreased after 2015 but increased for HCC/non-HCV (P = .002).
The incidence of HCC/HCV patients who were cured increased and the incidence of HCC/HCV viremic declined after 2013, when the direct-acting antivirals became available. By 2018, the number of patients with HCC/HCV who were cured began to exceed the number who were viremic. Among patients who were cured and diagnosed with HCC in 2018, cancer diagnosis occurred a mean of 2.8 years after HCV therapy. The annual HCV antiviral treatments peaked at 42,031 in 2016.
The authors note that antiviral treatment does not completely eliminate residual HCC risk, especially among patients with advanced fibrosis. And for those with HCC/HCV who were cured, because a cancer diagnosis was made about 2.8 years after HCV therapy, this further suggests that “HCV will continue to be an important cause of HCC even after managing the majority of HCV infections.”
USC’s Ou noted that even though the study was conducted in a VHA population, it is still very relevant to the US population as a whole.
“HCV patients who are using direct-acting antivirals can still be reinfected,” he said. “They still have an increased risk for hepatocellular carcinoma and the degree of risk is positively correlated with the degree of liver damage at the time of cure.”
Ou also pointed out that even though HCV-related HCC incidence is declining as more and more HCV patients are cured, HCC caused by other factors such as non-alcoholic fatty liver disease is increasing.
The study was supported in part by grants from the National Institutes of Health/National Cancer Institute and the Veterans Affairs Clinical Science Research and Development. The authors and Dr Ou have disclosed no relevant financial relationships
JAMA. Published online September 8, 2020. Research Letter