Piecing Together the Causes and Effects of HCV-Related HCC

The community of patients and practitioners associated with hepatitis C virus has grown accustomed to rapid development and ongoing breakthroughs. However, despite a long history and some new research, the pace of progress in understanding the relationship between HCV and hepatocellular carcinoma remains sluggish.

“Unfortunately, there have not been any major advances in current understanding of the relationship between HCV and HCC,” Bassam Estfan, MD, of the department of hematology and oncology at the Cleveland Clinic Cancer Center, told HCV Next. “The relation of HCV and HCC remains, for the most part, an indirect relation. While HCC due to HCV infection in a non-cirrhotic liver has been reported, and we have definitely seen such cases, it remains a rare occurrence.”

Although it is clear that inflammation is a cause of both diseases, researchers have yet to untangle the exact causative associations involved, or whether those causative associations exist at all. Recent data sets have explored various proteins implicated in HCV-related carcinogenesis, but experts are waiting to see how those findings will impact drug development and clinical practice.

Zobair M. Younossi, MD, MPH, chairman of the department of medicine, Inova Fairfax Hospital, and vice president for research of Inova Health System, laid out the fundamentals in an interview with HCV Next. “There are two probable causes of liver cancer,” he said. “In the United States, the most common causes of HCC are HCV and [nonalcoholic fatty liver disease] related to obesity.”

Jimmy J. Hwang, MD, the head of the gastrointestinal malignancies section from the Levine Cancer Institute, Carolinas HealthCare System, often sees HCV-associated HCC in practice.

“I am not aware of any theories that are specific to HCV’s association with HCC, though there are hypotheses that relate to oncologic effects from the virus, for example as we may see with hepatitis B, as well as others relating to inflammation. That is to say, the cirrhosis may have more to do with it than the virus per se,” he told HCV Next.

Beyond the mechanisms of action are the ever-present issues of how expanded screening protocols and the new direct-acting antiviral therapies will impact HCV-associated HCC. Patients with HCV or suspected HCV will continue to flood the health care system seeking a cure. Where they fall in terms of fibrosis, cirrhosis, disease stage or HCC status will dictate intervention strategies. Conversely, an HCV diagnosis may come as a result of a diagnosis of HCC.

Guilty Proteins

Younossi suggested that a number of mechanisms may be in play for HCV-associated HCC. “In general terms, because HCV causes a pro-inflammatory disease, inflammation could be the culprit,” he said. “There have also been associations with chemokines.”

A paper in the World Journal of Hepatology by Selimovic and colleagues provided a comprehensive overview etiology of the diseases at hand. “The drive of carcinogenesis during the infection with HCV is thought to result from the interactions of viral proteins with host cell proteins,” they wrote. “Thus, the induction of mutator phenotype, in liver, by the expression of HCV proteins provides a key mechanism for the development of HCV-associated hepatocellular carcinoma.”

Core, NS3, NS5A and NS5B are the HCV viral proteins with oncogenic potential, according to Selimovic and colleagues. They added that active cyclin-CDK complexes in genotype 1 results in the phosphorylation of pRb, p130 and p107, which they described as “the retinoblastoma family of proteins.”

They also discussed the role of inflammation in oncogenesis. Chemokines such as C-X-C motif chemokine 9 (CXCL9), CXCL10 and CXCL11, along with CCL5, are produced or elevated in HCV and may be involved in the carcinogenesis process. The role of transforming growth factor beta-1 (TGF-beta-1) in fibrosis may also play a role due to its involvement regulating major extracellular matrix proteins.

“Although ... advances [have been] made in the understanding of HCC pathogenesis, little is known about the molecular mechanisms of this malignancy,” Selimovic and colleagues wrote. “The most changes that occur in liver tissues are thought to result from either viral infection or the exposure to hepatotoxic agents leading to significant changes in the cellular signaling pathways and their target genes that are responsible in the regulation of tumor formation.” These pathways include Wnt/beta-catenin, p53, pRb, mitogen-activated protein (MAP) kinases, stress signaling, RAS, epidermal growth factor receptor, TGF-beta and JAK/STAT.

Emerging data have indicated that HCV-associated HCC incidence could also be dependent on HCV genotype, according to Younossi. “HCV genotype 1b and genotype 3 are both independently shown to increase risk of HCC,” he said.

Because HCV genotype 3 is a metabolic virus, Younossi added that the buildup of fat can also cause cancer. “Obesity is also a pro-inflammatory state,” he said. “This can cause metabolic syndrome and type 2 diabetes. We are learning more and more that this relationship between the host and the HCV virus can contribute to the development of HCC.”

“The HCV core protein has been implicated in these cases, but this remains a controversial issue,” Estfan said. “What may support this theory is that certain HCV genotypes are associated with a higher risk of HCC in cirrhotic patients, such as genotype 1b.”

Catherine T. Frenette, MD, of the Department of Organ Transplantation at Scripps Green Hospital in San Diego, Calif., acknowledged reports and associations about genotype 1b yielding a higher incidence of HCC, but did not necessarily view that as a significant factor. “I do not generally think about the genotype in terms of risk,” she said. “We may see a bit more fatty liver in these patients, but we don’t screen them any differently, and we treat them the same.”

Screening Protocols

Ongoing campaigns from CDC and the U.S. Preventative Services Task Force have yielded increases in HCV screening uptake. However, the consequence of this is that many non-hepatologists are now screening for and treating HCV. Because they are not experts, mistakes can occur and one of the pieces that may be missed is HCC risk factors.

“We are seeing a lot of [infectious disease] doctors and primary care providers involved in treating HCV,” Frenette said. “My concern is that non-HCV specialists may not be looking as closely as necessary for cirrhosis. If there is cirrhosis, you have to screen them for HCC. Otherwise, patients may run the risk of not being staged appropriately.”

Estfan brought the issue back to educating those clinicians.

“The advice should go beyond the hepatologist or ID specialist to primary care physicians who have patients with HCV,” he said. “Unfortunately, we see many patients who were diagnosed with HCV many years ago but never underwent treatment, had initially ineffective treatment and were lost to follow up or were never referred to a hepatologist or ID specialist for either further treatment or surveillance of cirrhosis and HCC.”

Additionally, Frenette explained that many experts believe that despite recommendations, adherence to HCC screening protocols in patients with HCV is low. “We should be screening for HCC when people are infected with HCV, and screening when we cure them,” she said.

“Anyone who has advanced scarring of the liver should be on a screening program every 6 months,” Younossi said. “Even if you achieve cure in the setting of cirrhosis, you should continue to be screened.”

He added that a patient with highly suspicious levels of scarring should be referred to a specialist or tumor clinic. “A multidisciplinary team is best,” he said.

According to the AASLD practice guidelines on HCC, which were last updated in 2011, all patients with HCV and cirrhosis need surveillance.

“In the HALT-C study, the 5-year risk of non-cirrhotics developing HCC was 4.8%. Whether it is cost-effective for these subjects to undergo routine surveillance has not been determined, but on the basis of prior cost-effectiveness analyses, they would fall below the 1.5%/yr incidence cut-off value,” the guidelines state.

Though the guidelines discuss possible markers to indicate HCC development is imminent, such as platelet count, alpha 2-macroglobulin, apolipoprotein A1, haptoglobin, bilirubin, gamma-glutamyltranspeptidase, and the AST/ALT ratio, none have been validated enough for full recommendation. The HALT-C website, though, offers a calculator for HCC risk prediction.

As mentioned by the experts, reaching a cure in HCV does lower risk, so the guidelines state: “It is likely that the reduction in risk is not immediate, and probably increases with time. Thus it likely becomes cost-ineffective to provide surveillance for these patients at some point in time. However, since that point cannot be determined with any certainty, these patients should continue to undergo surveillance for HCC.”

The guidelines touch on the use of ultrasound for monitoring, but did not fully endorse at the time of publication, though another study released in 2011 suggested this was the best method when combined with serum alpha fetoprotein.

“The performance of ultrasound as a surveillance test depends on the experience of the examiner. It is reportedly less accurate in patients who are obese and those with a nodular liver,” the study states. “Cost-effectiveness of HCC surveillance is largely dependent on the receipt of potentially curative therapy. If treatment is not available, not given, or the patient is ineligible for treatment due to liver disease severity or other medical comorbidities, then HCC surveillance cannot be considered cost-effective.”

Despite all of these opinions, there has yet to be a prospective, randomized trial looking at HCC surveillance in patients with HCV.

Diagnosing, Managing HCC

In a 2014 study, Frenette, along with Ana Maria Crissien, MD, a gastroenterology and hepatology fellow in the Division of Gastroenterology of the Department of Medicine at Scripps, noted that HCC diagnoses are overwhelmingly made without liver biopsy. “Screening with ultrasound and alpha-fetoprotein at 6-month intervals is advised,” they wrote. “However, it is not adequate for patients on the orthotopic liver transplantation list.”

CT and MRI, along with the detection of AFP, AFP-L3%, and/or des-gamma-carboxy prothrombin, may be used to detect HCC, according to Frenette and Crissien.

Hwang said, “Oncologists use the same AASLD criteria as hepatologists, though we (or certainly those of us in more academic environments) probably are also interested in getting tissue diagnosis, in part so that we can explore potential chemotherapies or ‘targeted therapies.’”

Yet, despite a cross-section of treatment options, only surgery and transplantation may cure HCC, Frenette and Crissien wrote.

“Other treatment options include radiofrequency ablation, microwave ablation, percutaneous ethanol injection, transarterial chemoembolization, radioembolization, cryoablation, radiation therapy, stereotactic radiotherapy, systemic chemotherapy, and molecularly targeted therapies,” they wrote. “The management of HCC is based on tumor size and location, extrahepatic spread and underlying liver function. Given the complexity of the disease, patients are often best served in centers with experience in HCC management, where a multidisciplinary approach can take place.”

Younossi echoed this point. “Each cancer has a specific genomic or proteomic profile or signature,” he said. “The signature is important because it may provide targets for future precision treatment of HCC.”

Understanding the disease types may impact treatment approaches.

“We are in the process of developing biomarkers, finding targets, and figuring out how to treat them,” Younossi said. “As of right now, the treatment of liver cancer is basically surgical (resection, local ablation or liver transplantation). You could envision a time in the future when genomics, proteomics or other signatures can be defined by each individual.”

But Younossi noted that the treatment of HCC has not changed dramatically in recent years. “Transplant is still the only curative approach,” he said. “Resection can be effective, but since cirrhosis is still present, you still have cases at risk of developing de novo HCC. Even in the era of highly effective HCV treatments, curing cirrhotics reduces, but does not eliminate the risk.”

Prioritizing HCV, HCC

With HCV-associated HCV, it is still under debate as to which disease takes priority in treatment.

“Once a patient has HCC, my general rule is to get the cancer under control first and then treat the HCV,” Frenette said. “Hopefully, then treating them for HCV will reduce the risk of recurrence.”

Hwang agreed: “Generally, HCC, since it is the more immediately life-threatening disease. I say that not only because I am a medical oncologist, but I believe that our hepatologists believe that too, based both on our discussions in multidisciplinary HCC conferences and what I see in patients sent to me.”

Kanogawa and colleagues investigated whether interferon-based therapy after curing HCC improves the prognosis among individuals with HCV-associated HCC.

The study included 178 patients within the Milan criteria. The researchers compared time to beyond the Milan criteria and overall survival among 22 patients who achieved SVR with interferon, 19 patients who did not reach SVR on interferon and 82 patients who did not receive interferon-based therapy.

Patients who reached SVR with interferon experienced a significantly longer time to the Milan criteria than those in the non-SVR (P = .006) and the non-interferon (P < .001) groups.

Similar results were reported in terms of OS for the interferon/SVR group compared with the non-SVR (P = .029) and non-interferon (P < .001) groups.

Multivariable analysis results indicated that interferon-induced SVR decreased mortality risk by a factor of 0.096-fold compared with non-interferon controls (95% CI, 0.023-0.405).

“Elimination of HCV after curative treatment of patients with HCC within the Milan criteria inhibits recurrence and contributes to a preferential prognosis,” the researchers concluded.

Working from the other end, Estfan suggested that HCV treatment should be available and offered to anyone with known HCV infection, including those with HCC.

“This is important on several levels,” he said. “First, in noncirrhotic patients, HCV treatment can eliminate chronic inflammation of the liver and prevent progression to cirrhosis, which is the main reason for HCC in HCV-infected patients.”

Frenette cautioned that this is not a cure-all. “Even when we improve cirrhosis, the risk of liver cancer doesn’t completely go away,” she said. “We still have not completely defined this risk. ... But it drops risk so dramatically that we have seen reductions in overall mortality,” she said. “This is an argument for treating patients with HCV at an earlier stage.”

Estfan also advocated for treating HCC patients with HCV: “In addition, in those already with cirrhosis and HCC who are eligible for transplantation, complete treatment of HCV prior to transplant reduces risk of fibrotic and cirrhotic transformation in the transplanted liver.”

Hwang said he would certainly recommend a liver transplant in a patient who has achieved SVR of their HCV.

“If not yet treated, my sense is that these new therapies are effective enough that transplant should still be considered if the patient can undergo such therapies,” he added.

Impact of DAA Therapies

Today, DAA therapies come with new rewards, consequences and challenges. As stated above, achieving SVR with DAA therapy reduces the risk of cirrhosis and, therefore, the risk of developing HCC. Theoretically, the 90% and higher SVR rates should produce a reduction in the subsequently diagnosed HCC.

However, those expecting dramatic reductions in HCC incidence may have to wait.

“The initial stages of DAA therapy will have a moderate impact on HCC incidence, but there will not be an immediate, dramatic impact,” Frenette said. “The dramatic impact will not come for another 10 or 20 years when people are really using these drugs. It’s a matter of volume.”

One effect of the novel therapies and the direct-to-consumer advertising of their cure rates is that patients are seeking treatment for HCV. Yet, rather than finding a cure, they discover they have liver cancer.

The good news is most new DAA drugs have a good safety profile, but most experts believe that drug-drug interactions between HCV and HCC therapies will require ongoing investigation.

Moving Forward

Despite the dramatic advances in HCV therapies in recent years, Younossi stressed vigilance. “Incidence rates of most solid tumors are decreasing,” he said. “HCC is one of the few that is increasing. We need to be aware of this.”

Frenette said that HCV remains a major cause of liver cancer. “New therapies will improve much, but not all of this incidence,” she said. “When we cure the HCV, the HCC risk gets better, but it still does not go away.”

“The main mechanism in which HCV causes HCC is through chronic inflammation of the liver leading to fibrosis and cirrhosis, which is a similar mechanism to HCC development due to other causes of cirrhosis,” Estfan said. “This process takes place sometimes over decades from diagnosis, which is why early detection and treatment can play a major role of prevention.”

Frenette made an analogy to skin cancer. “It is not the sunburn you got last week, it is the sunburns you got 20 and 30 years ago that gave you skin cancer,” she said. “So it goes with HCC and HCV. Scar tissue building up for years causes the HCC risk.”

“This is a complicated disease, where there are two different life threatening diseases, and that requires coordinated multidisciplinary care, including interventional radiologists, surgical oncologists, hepatologists, medical oncologists and even radiation oncologists, in order to produce the best possible outcomes,” Hwang said. by Rob Volansky and Katrina Altersitz

• References:
• Crissien AM. J Gastroenterol Hepatol. 2014;10:153-161.
• El Sarag HB, et al. Therap Adv Gastroenterol. 2011; doi:10.1177/1756283X10385964.
• Kanogawa N, et al. J Gastroenterol Hepatol. 2015;doi:10.1111/jgh.12925.
• Lok AS, et al. Gastroenterology. 2009; 136(1):138-148.
• Nakaoka K, et al. Springerplus. 2015;doi:10.1186/s40064-015-0870-5.
• Selimovic D. World J Hepatol. 2012;doi:10.4254/wjh.v4.i12.342.

• For more information:
• Bassam Estfan, MD, can be reached at Cleveland Clinic Main Campus, Mail Code R35, 9500 Euclid Avenue, Cleveland, OH 44195; email: estfanb@ccf.org.
• Catherine T. Frenette, MD, can be reached at Scripps Clinic Torrey Pines, 10666 N. Torrey Pines Rd., LaJolla, CA 92037; email: Frenette.Catherine@scrippshealth.org.
• Jimmy J. Hwang, MD, can be reached at Carolinas HealthCare System, Levine Cancer Institute, 1021 Morehead Medical Drive, Charlotte, NC 28204; email: Jimmy.Hwang@carolinashealthcare.org.
• 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: Estfan reports no relevant financial disclosures. Frenette reports associations with Bayer, Gilead and Salix. Hwang reports serving as a consultant for Amgen, Bayer, Celgene, Lilly, Merrimack, Roche/Genentech and Taiho, and serving on the speaker’s bureau for Amgen, Celgene and Roche/Genentech. Younossi reports being a consultant for Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline and Intercept Pharmaceuticals.