Screening for HCC in the Post-SVR12 Setting

Direct-acting antiviral therapies reduce, but do not eliminate, hepatocellular carcinoma risk. As an increasing number of patients reach SVR12, the clinical community will face a myriad of individuals who are cured of HCV but who have sustained varying degrees of liver damage, either associated with HCV or not.

That damage may be the result of factors including alcohol use, fatty liver disease, non-alcoholic fatty liver disease, or of an entirely different etiology. Regardless of how it came about, these individuals are at risk for HCC. The question is: How do clinicians manage that risk? More specifically, clinicians face questions about how best to screen this population.

The key issues may lie beyond the clinic, according to Jeffrey A. Kahn, MD, associate professor of clinical medicine at the Keck School of Medicine of USC. “The most common problem we see is that these patients are cured of their HCV, and then they get lost in the community, thinking that they don’t have anything to worry about anymore,” he said. “These people are still at risk for HCC.”

For Kahn, educating both doctors and patients about the importance of HCC screening is critical, and should begin long before SVR12. “If somebody required screening or surveillance for HCC due to risk factors before treatment, then they need it lifelong,” he said.

But not all patients are clearly at risk before therapy, and not all patients have had accurate risk assessment before, during or after treatment with DAAs. In short, there are many patients whose risk for HCC is unknown, or at least uncertain.

The AASLD guidelines offer some recommendations, particularly in the form of screening protocols, according to Ramesh K. Batra, MBBS, MRCS, assistant professor of Surgery and transplant surgeon in the Department of Intra-Abdominal Transplantation at Loyola University Medical Center. “Screening for HCC is based on ultrasound and alpha fetoprotein monitoring at 6 months,” he said. “It is noteworthy that the HCV-positive patients are at almost 20-fold higher risk of HCC than the SVR patients, keeping in mind this risk is variable if the patient has cirrhosis or stage 3 fibrosis, in which case the risk of HCC development is higher.”

HCV Next spoke to several experts about this topic, and the consensus is that screening at 6-month intervals in high-risk patients is an optimal strategy. But the method of screening is debatable, with some preferring ultrasound and others also employing CT scan or MRI. Moreover, the interval at which to screen may also be uncertain. Patients with fewer risk factors, or no risk factors, may be screened less frequently.

There are other factors up for discussion, as well. Novel biomarkers and parameters of HCC risk are emerging, but whether they are ready for regular use in the clinic remains to be seen. The epidemiology of HCC among patients who have reached SVR12 should be considered, as should any potential drawbacks to overuse of HCC screening. Finally, with so many resources being diverted to DAA therapies, it is important to consider the cost–benefit ratio of all facets of HCC screening protocol in patients who have been successfully treated for HCV.

The Arguments

William D. Carey, MD, senior hepatologist in the department of gastroenterology at the Cleveland Clinic, emphasizes the need to tease out and consider separately HCV as an infection, and as a liver disease. “I look at the HCV infection, and I look at liver disease,” he said. “They are integrated, but they also can be talked about separately.”

Kahn was unequivocal in suggesting that if a patient has advanced stage 3 or 4 fibrosis or other risk factors, they should undergo imaging every 6 months. “For patients with less risk or no risk, surveillance should be on a case-by-case basis.,” he said. “Also, if the patient has little or no fibrosis on non-invasive testing, but I am suspicious that there is more fibrosis than meets the eye, I might consider a liver biopsy so that I can risk stratify patients for HCC. In terms of the modalities for HCC surveillance, alpha fetoprotein every 6 months, along with an imaging modality, is my strategy. Generally, ultrasounds are done every 6 months, but there may be circumstances where cross sectional contrast imaging, such as CT scan and MRI, may be utilized.”

A more concrete system of risk stratification may be necessary, according to Kahn. “It should be more clearly defined that high-risk patients should be screened one way and low-risk patients should be screened another way,” he said.

It is important to figure out the post-SVR screening protocol before the patient undergoes treatment, Kahn added. “It is always on a case-by-case basis, but I definitely do not wait until they have reached SVR12 before I decide how to deal with their HCC risk,” he said. “Either way, I never assume they don’t have a risk of cancer anymore, and stop screening. If there is any suspicion at all, I keep doing it. We have seen too many patients who came in for transplantation who were cirrhotic but not surveyed anymore and ended up with liver cancer.”

Despite Kahn’s warning that patients should be followed closely, even those with relatively low risk, Carey suggested that this group of patients may indeed be discharged with minimal follow-up. “There is good data that those with SVR12 and no hepatic fibrosis can be discharged fairly safely,” he said. “I discharge them and tell them to enjoy life.”

However, Carey acknowledged that advancing levels of fibrosis comes with HCC risk. “Those with significant fibrosis need to be in a screening program forever, one that follows AASLD or EASL guidelines,” he said.

“They need to be in a screening program forever, one that follows AASLD or EASL guidelines,” he said.

Data support this, as well. In an abstract presented at The Liver Meeting last month, Janiua and colleagues evaluated the impact of SVR12 on HCC risk in a cohort of about 1.5 million individuals tested for HCV in Canada between 1990 and 2013. Patients treated during the interferon era were followed until Dec. 31, 2012.

Researchers assessed patients based on whether they did or did not reach SVR12. The initial cohort included 8,147 individuals who initiated therapy, of whom 57% reached SVR. In the SVR12 group, the HCC incidence rate was 1.1 per 1,000 person-years, compared with 7.2 per 1,000 person-years in the non-SVR group.

Patients with cirrhosis at treatment were more likely to acquire HCC (6.4 per 1,000 person-years in the SVR group vs. 21 per 1,000 person-years in the non-SVR group). After treatment, the cumulative increase of HCC incidence was steeper among non-SVR individuals than among SVR individuals.

Multivariate analysis results indicated that SVR was associated with a reduction in HCC risk (HR = 0.2; 95% CI, 0.1-0.3). Cirrhosis increased HCC risk (HR = 2.61; 95% CI, 1.68-4.04), as did genotype 1 vs. genotype 3 disease (HR = 1.85; 95% CI, 1.25-2.73) and alcohol consumption (HR = 1.46; 95% CI, 1-2.15). In the SVR arm, the association between cirrhosis and HCC risk persisted (HR = 3.16).

“SVR reduces but doesn’t eliminate HCC risk,” Zobair M. Younossi, MD, MPH, chairman of the department of medicine at Inova Fairfax Hospital and vice president for research at Inova Health System in Falls Church, Va., said in an interview. “We know this. What this data set actually tells us is it is the associated risks in these patients that put them at risk for HCC. Cirrhosis, older age, drinking alcohol, male sex. All of these will continue to pose risks even if you achieve cure.”

Younossi regularly uses alpha fetoprotein in his practice, but Carey is more skeptical. “I’m not much of a believer in alpha fetoprotein,” Carey said. “It doesn’t add much to this screening mode. I would not stand in the way of it, but the evidence for its value as a liver cancer screening tool is on the thin side.”

Like many clinicians, Carey relies primarily on ultrasound. However, he was measured in his opinions on this approach. “The problem with ultrasound imaging is that it doesn’t have the resolution power of CT scans and MRIs,” he said. “We give up a little using ultrasound, but over a lifetime, CT scanning has too much radiation exposure risk and MRI is very expensive.”

Some evidence indicates that CT scanning is more sensitive but not as cost-effective as ultrasound, according to Batra. “Combining ultrasound with alpha fetoprotein increases the sensitivity and specificity for HCC surveillance, keeping in mind the studies comparing CT scan to plain ultrasound were done in Asia, where hepatitis B is the leading cause for cirrhosis. Hepatitis C is the leading cause in United States. Furthermore, CT scan adds value in surveillance when done in four phases, which increases continued and increased radiation exposure, therefore the value is not that great.”

False Positives, Associated Risks

In another study presented at AASLD, Verma and colleagues found that indeterminate nodules were observed via ultrasound in 25% of patients with cirrhosis during HCC surveillance in the U.S. However, 77% of those patients were not diagnosed with HCC.

“Despite multiple CT/MRI, the nature of [indeterminate nodules] could not be resolved in 35 patients,” the researchers concluded. “Predictive tools are necessary to better risk stratify patients with [indeterminate nodules] to minimize unnecessary testing and patient anxiety.”

“One problem with doing any test is finding things that are not cancer but may look like it,” Carey said. “A nodule on the liver does not necessarily mean cancer. These are unintended findings that cost money, anxiety, resource utilization.”

Despite these findings, Carey noted that ultrasound “is probably the best tool we have,” he said. “False positives are just something we are going to have to deal with. If you are using a screening test, it’s ok to cast a wide net. It’s ok to catch something you are not looking for, rather than missing a lot of cancers. This is just the cost of doing business.”

Regarding MRI, Carey suggested that the sensitivity of such a test may not be worth the tradeoff of the cost. “I’m not sure I am interested in finding a lesion that is 0.5 cm,” he said. “The cost of MRI is much more than that of an ultrasound. A lot of insurance companies won’t pay for it. It is true that there isn’t any ionizing radiation involved, but the cost–benefit ratio is still unfavorable.”

Carey said that CT scan should not be used for screening because of the cumulative dose of ionizing radiation over time. “Some people alternate ultrasound with CT or MRI, which I suppose is a fine approach, but it is not what I do,” he said.

Zeroing in on patients with SVR12, Carey acknowledged that there are no easy answers and that as we acquire more experience cancer screening may evolve. “The liver is an elastic, moldable organ,” he said. “Fibrosis regresses in some patients who are successfully treated. If it regresses, maybe they don’t need to be screened. I’d caution to be very careful about this, but it’s possible. We may need to look more closely at ways of measuring the elastography of the liver.”

For Younossi, it is a matter of both trusting the current guidelines and updating them as new information comes to light. “We have to appropriately screen, and we can do so because we have guidelines for these patients,” he said. “We have a living document that guides our practice. If we follow the guidance document, it will be cost-effective. I don’t think we are over-screening. In fact, we may be under-screening, because often patients are not followed up or lost in the system.”

Patients with Cirrhosis

Romano and colleagues suggested that recent data indicate that HCC risk may be increased during and after DAA therapy in patients with HCV and advanced liver disease. They analyzed the incidence of de novo HCC in a cohort of 2,279 patients with HCV treated with DAA therapies in Italy.

The cohort included 85.7% of patients with cirrhosis, while a history of HCC was an exclusion criterion. The mean follow-up from initiation of therapy was 305 days. There were 41 cases of HCC reported in this interval, for an incidence rate of 1.64 per 100 patient-years, a rate co-author Alfredo Alberti, MD, said was not significantly different from historical untreated controls.

“However, a subset of patients may go on to develop an aggressive tumor during or directly following treatment,” he said at a press conference at The Liver Meeting. “This suggests that the immunological and molecular changes in the liver microenvironment could support the growth and spread of microscopic, and initially invisible, HCC. Further studies are needed to clarify these issues and identify predictive markers. ... Meanwhile, patients treated with direct-acting antiviral agents with advanced liver disease should continue to be closely monitored for HCC.”

“If you treat with DAAs, and if you have an SVR12, the risk of liver cancer may not be diminished as much in cirrhotic patients,” Younossi said. “Interferon has an anti-neoplastic impact that may augment the HCV cure.”

This paper is limited by a short follow-up duration, Younossi added. “These findings do not convince me that DAAs will be any worse than interferon.”

Potential Biomarkers

While there is much agreement about screening protocols in cirrhotic patients, there is much less agreement about a host of novel biomarkers that may potentially predict HCC risk in this population.

Atta and colleagues aimed to evaluate whether vascular endothelial growth factor (VEGF) plays a role in HCV-associated HCC. The study included 90 individuals, 60 of whom had HCV. The researchers further stratified the HCV group into 30 patients with HCC and 30 patients without HCC. Results showed increased plasma VEGF levels were significantly higher in the HCC group than in the non-HCC group, while both groups demonstrated significantly higher VEGF levels than controls. The researchers also reported that liver tissue VEGF was significantly higher in patients with HCC compared with those without HCC. They observed a positive correlation between plasma VEGF levels and a patient’s age, AST and alpha fetoprotein levels, the presence of portal vein thrombosis and the number of hepatic focal lesions among patients with HCC. “Plasma levels of VEGF may be a useful diagnostic and prognostic marker for HCC in patients who have been diagnosed with [HCV],” the researchers concluded.

“AASLD still recommends ultrasound combined with alpha fetoprotein, as the newer biomarkers are yet to be fully explored in their strengths or even their synergistic value as a screening tool,” Batra said.

Fiorino and colleagues investigated possible associations between microRNAs (miRNAs) and viral hepatitis-related liver disease. They suggested that miR-21, miR-122, mi-125a/b, miR-199a/b, miR-221, miR-222, miR-223, miR-224 may be biomarkers for early diagnosis or prognosis of HCC. However, they acknowledged that no definitive findings have emerged.

“The new biomarkers, most of them focus on early detection of HCC,” Batra said. “From a liver transplant perspective that doesn’t provide much help as if the lesion is large it will be picked up by ultrasound or CT or MRI, which will be large enough to get MELD exception points towards a liver transplant. If the novel biomarkers pick up a small lesion it won’t help in current times.”

Batra outlined a direction for research. “UNOS guidelines should be modified in light of successful co-relation with the advent of biomarkers,” he said. “Secondly, we need good markers to separate bad tumor biology in terms of metastatic potential as there is increased risk of recurrence of cancer post liver transplant. Sadly, this comes to light in the pathology of the explanted liver, by which time it is already too late, as in the liver transplant has already taken place.”

Lu and colleagues investigated mass spectrometry as a method of diagnosing cancer in patients with HCV. They used multiplex peptide stable isotopic labeling and immobilized metal affinity chromatography to enrich and quantify the phosphoproteome of HCC in an HCV setting and in a non-HCV setting. Raw data were used to identify protein targets based on expression. Abundance groups were used for comprehensive functional analysis, according to the results. “Analysis of functional differences highlighted deregulated phosphoprotein networks,” the researchers wrote. “This uncovered additional candidates that could be directly derived from the MS data. Cellular processes and pathways that may differ with HCV infection include: cytoskeletal dynamics, insulin response, gene expression, and PI3K/AKT oncogenesis.” They added that this information may be useful in the liver cancer research arena and in developing targets for therapy.

“There is plenty of research looking at parameters that show the likelihood of developing HCC,” Kahn said. “We just don’t know where those parameters are headed.”

In another study, Moreira and colleagues investigated the Interferon lambda polymorphisms, including genotypes rs8099917, rs12979860 and rs12980275, and HCV core protein mutations in a cohort of 59 patients with HCC. A comparator cohort included 50 patients with cirrhosis but no HCC. An association between HCC and the rs12980275-AG genotype was observed in an age-adjusted analysis (OR = 2.42; 95% CI, 1.03-5.69). The researchers also observed core substitutions R70Q and L91M, primarily in genotype 1b isolates. They also observed a mild association in the presence of amino acid Glutamine (Q) in the position 70 and IFNL3 genotype AG (P = .054), according to the results. “The screening of these polymorphisms and functional studies would be useful in clinical practice for identifying groups at high risk of HCC development,” the researchers concluded.

“We may use information like this to find that people have low risk or no risk,” he said. “These individuals would be worth studying further.”

Overall, though, Kahn was measured in his assessment of any of these parameters and biomarkers. “They are not yet clinical tools at all,” he said. “These are tools that may help predict the development of cancer, and they may be useful as we head to individualized patient care, but they are not even near clinical use.”

Younossi summed up this line of research. “These are interesting abstracts, but it is too early to apply them on a large scale,” he said. “These biomarkers have to be developed and validated. They have to show that they are cost-effective.”

Mathematical Modeling

Zheng and colleagues conducted a case-control study to determine risk factors for HCC after SVR. The aim was to develop a model for predicting risk in this population. Multivariate model results showed that an initial diagnosis of compensated cirrhosis was associated with 21.7-fold (95% CI, 4.2-112.3) increase in HCC risk, while a post-SVR albumin reduction of 1 g/L yielded 1.3-fold (95% CI, 1.1-1.7; P = .004) increase in HCC risk. The researchers developed a predictive model based on these findings that had an area under the curve of 0.88, a sensitivity of 0.833, a specificity of 0.896, and a negative predictive value of 0.956, according to the results. “An initial diagnosis of compensated cirrhosis combined with a post-SVR albumin value of [36 g/L or less] predicts the occurrence of HCC after SVR in patients with [HCV],” the researchers concluded.

For Kahn, the transient nature of this scientific research poses a concern. “The problem is that so many of these things come and go, and we always end up in the same place: with ultrasounds and alpha proteins,” he said. “I have looked at a lot of these biomarkers and models and tests, and so I wouldn’t want to speculate about these current markers until we see more data.”

Having said that, Kahn does not rule out the possibility that they may have clinical use, and he cites trends in other cancers as a possible reason. “In ovarian or breast cancer, we are moving to a place where we are not looking at the name or location of the tumor, but at specific characteristics of it, the receptors and other such information” he said. “We may get there in liver cancer, as well. You look at certain characteristics of a patient, including some of these markers that indicate risk for HCC. But we’re just not there yet.”

Screening Rates

Another area of study that may prove important moving forward are the hard numbers on who is being screened for HCC. Moore and colleagues aimed to describe the relationship between viral hepatitis and HCC in a cohort of 8,827 residents of New York City who were diagnosed with HCC between 2001 and 2012.

Of that group, 38.4% had HCV, 17.9% had HBV and 2.2% had both infections. The median survival time for individuals with HBV-associated HCV was 22.3 months, compared with 13.1 months for those with HCV and 6.9 months for those who had neither infection. Five-year survival rates were 37.5% in the HBV group, 20% for the HCV group and 29.5% in the coinfected group. The 5-year survival rate was 16.1% for those with no viral hepatitis.

“In NYC, most persons with HCC have viral hepatitis; the majority of viral hepatitis infections are due to HCV,” the researchers concluded. “Survival for persons with HCC differs widely by viral hepatitis status. This study highlights the importance of viral hepatitis prevention and treatment and HCC screening.”

Batra underscored these results. “There are no drawbacks for HCC screening,” he said. “There is data to suggest that needle track seeding in cases of biopsy for an HCC is a drawback. However, per the UNOS policy, certain classical radiological findings are sufficient to define HCC to gain the MELD exception points and a tissue biopsy is not required.”

Back to Basics

While the war against HCC rages on, many believe that because of the overwhelming effectiveness of DAA therapies, it is only a matter of time before the battle against HCV is won. Younossi cautioned against such thinking. “We still have millions of people with HCV in the world, and this includes millions who are not diagnosed,” he said. “If they are not diagnosed, they are not treated. Even if we do find these patients, they are still coming in with advanced disease, and therefore they are at risk for HCC.”

So, for Younossi, screening for HCV is as important as screening for HCC. “From there, it is back to basics,” he said. “Link them to HCV care, make sure they don’t have a second form of liver disease. If they use alcohol, we need to advise them about excessive use. If you achieve cure, you have to continue to check for advanced fibrosis or cirrhosis. We need to make sure they are linked to care with us, but also with their primary provider to stay on top of all of these HCC risk factors.”

Carey noted that the possible benefit of statins in this population may come to light in time, with further research. “They look like they are good for just about everything in liver disease,” he said. “People who take statins don’t die as often or as quickly, and there is considerable evidence of their benefit in reducing the risk of development of liver cancer. This should be something to consider in revised guidelines.”

But the entire discussion may ultimately come down to how many people are screened, according to Carey. He cited data from Parikh and colleagues that were presented at AASLD showing, simply, that HCC surveillance with ultrasound was associated with improved survival. However, he noted that only around 11% of individuals who should have been screened were being screened. “Patients need to be screened, and it is not getting done,” he said. “We have to do better.”

• References:
• Atta MM, et al. J Hepatocell Carcinoma. 2016;doi:10.2147/JHC.S86708.
• Fiorino S, et al. World J Gastroenterol. 2016;doi:10.3748/wjg.v22.i15.3907.
• Janiua NZ, et al. Abstract 175. Presented at: The Liver Meeting; Nov. 11-15, 2015; Boston.
• Lu NT, et al. Cancer Genomics Proteomics. 2016;13:339-357.
• Lu M, et al. Abstract 180. Presented at: The Liver Meeting; Nov. 11-15, 2015; Boston.
• Moore MS, et al. Clin Infect Dis. 2016;pii:ciw605.
• Moreira JP, et al. Virology. 2016;doi:10.1016/j.virol.2016.03.008.
• Parikh ND, et al. Abstract 442. Presented at: The Liver Meeting; Nov. 11-15, 2015; Boston.
• Romano A, et al. Abstract 19. Presented at: The Liver Meeting; Nov. 11-15, 2015; Boston.
• Verma P, et al. Abstract 434. Presented at: The Liver Meeting; Nov. 11-15, 2015; Boston.
• Zheng QL, et al. Gut Liver. 2016;doi:10.5009/gnl15321.
• Zhu RX, et al. Gut Liver. 2016;doi:10.5009/gnl15257.

• For more information:
• Ramesh K. Batra, MBBS, can be reached at Loyola University Medical Center, Maywood, IL 60153; email: THOMS@lumc.edu.
• William D. Carey, MD, can be reached at Mail Code A-51, 9500 Euclid Avenue, Cleveland, OH 44195; email: AUGERC@ccf.org.
• Jeffrey A. Kahn, MD, can be reached at 1975 Zonal Ave., Los Angeles, CA 90033; email: Cynthia.Smith@med.usc.edu.
• Zobair M. Younossi, MD, MPH, can be reached at Inova Fairfax Medical Campus, Center for Liver Diseases, 3rd Floor Claude Moore Building, 3300 Gallows Road, Falls Church, VA 22042; email: zobair.younossi@inova.com.

Disclosures: Batra and Carey report no relevant financial disclosures. Kahn reports no relevant financial disclosures. Younossi reports financial relationships with AbbVie, Bristol-Myers Squibb, Conatus, Gilead, Intercept, Janssen Therapeutics, Merck and Salix.