Hepatitis C virus (HCV)–associated hepatocellular carcinoma (HCC) incidence in the United States is increasing, partly because of risk factors such as diabetes, fatty liver, hepatitis B virus, and human immunodeficiency virus coinfection. Achieving sustained virologic response (SVR) is the most significant factor in reducing HCV-associated HCC incidence. Improved SVR with the next generation of direct-acting antivirals brings hope for decreased HCC mortality. Nevertheless, surveillance for HCC remains important because HCC can still occur despite SVR, especially in cirrhotics. Individualized risk stratification through increased understanding of HCC pathogenesis and improved surveillance holds the promise for future reduction of HCC incidence.
Key points
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Hepatitis C virus (HCV)–associated hepatocellular carcinoma (HCC) incidence is increasing in the United States.
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HCV core promoter protein and microRNA pathways play key roles in HCC carcinogenesis.
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Sustained virologic response decreases the risk of HCV-associated HCC.
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Individualized risk stratification in patients with HCV holds hope for further HCC risk reduction.
Introduction
Hepatocellular carcinoma (HCC) is a leading cause of liver-related death and the third most common cause of cancer death worldwide. In the United States, the incidence of HCC is increasing, in part because of the growing impact of hepatitis C virus (HCV)–associated morbidity and mortality. Without effective intervention, the number of patients with HCV-related cirrhosis or HCC is estimated to double by 2020. This article reviews the latest efforts to discern the relationship of HCV with HCC, including virologic pathways to HCC, such as the role of the HCV core promoter protein and microRNA pathways. The impact of direct-acting antivirals (DAAs) on HCV-associated HCC and the persistent risk of HCC despite SVR are also reviewed with an emphasis on the need for individualized HCC risk stratification in patients with HCV.
Introduction
Hepatocellular carcinoma (HCC) is a leading cause of liver-related death and the third most common cause of cancer death worldwide. In the United States, the incidence of HCC is increasing, in part because of the growing impact of hepatitis C virus (HCV)–associated morbidity and mortality. Without effective intervention, the number of patients with HCV-related cirrhosis or HCC is estimated to double by 2020. This article reviews the latest efforts to discern the relationship of HCV with HCC, including virologic pathways to HCC, such as the role of the HCV core promoter protein and microRNA pathways. The impact of direct-acting antivirals (DAAs) on HCV-associated HCC and the persistent risk of HCC despite SVR are also reviewed with an emphasis on the need for individualized HCC risk stratification in patients with HCV.
Epidemiology
HCV is associated with a 15-fold to 20-fold increased risk of HCC. In patients with HCV, the annual incidence of HCC is estimated at 1% to 4% in cirrhotics compared with only 1% to 3% over a 30-year period in noncirrhotics. The incidence of HCC in the United States has nearly doubled, from 3.1 per 100,000 to 5.1 per 100,000 people between 1992 and 2005. This trend of increasing HCC in the United States is postulated to be reflective of the progression of chronic HCV to cirrhosis in the aging baby boomer population. As mortalities for HCC continue to increase, close monitoring of the state of HCC in the United States seems warranted.
Risk factors for hepatocellular carcinoma
HCC incidence is affected by many factors, including geographic location and ethnicity ( Table 1 ). For example, East Asia and West Africa have a high prevalence of HCV and the highest global prevalence of HCC, with more than 80% of cases. HCV prevalence in Japan is 1.9% to 3% and 80% to 90% of patients with HCC are infected with HCV, accounting for Japan’s high HCC prevalence. In contrast, in the United States, which has a lower HCV prevalence of 1.8%, only 30% to 50% of patients with HCC are infected with HCV. Japan’s greater proportion of patients with HCC who are infected with HCV compared with the United States is attributed to an earlier onset of the HCV epidemic in Japan, suggesting that HCV-associated HCC incidence will continue to grow in the United States.
| Prevalence of HCC | Region | Country | Incidence Rates (Cases per 100,000 Persons) |
|---|---|---|---|
| Very high prevalence | East Asia | Overall | 20 |
| Mongolia | 99 | ||
| Korea | 49 | ||
| Japan | 29 | ||
| West Africa | Mali Mozambique Gambia | 20 | |
| Moderately high prevalence | Southern Europe | Italy | 11–20 |
| Spain | 11–20 | ||
| Latin America | — | 10–20 | |
| Intermediate prevalence | Western Europe | France Germany | 5–10 |
| Low prevalence | North America | United States | 5.1 |
| Canada | <5 | ||
| Northern Europe | Scandinavia | <5 |
Within the US population, HCC varies by ethnicity, with Hispanic patients at highest risk of HCC compared with white people and African Americans. A large cohort study of 150,000 US veterans showed that Hispanic patients had the highest annual HCC incidence at 7.8%. The study postulated that a higher incidence of nonalcoholic fatty liver disease (NAFLD) in Hispanic patients could account for this higher HCC risk.
In addition to the impact of geographic region and ethnicity, many other risk factors affect the rates of HCC in patients with HCV. Major risk factors include concurrent liver disease, lifestyle, and viral factors.
Concurrent Liver Disease
At present, the literature suggests that NAFLD, diabetes, and obesity contribute to an increased risk of HCC. Diabetes has reportedly been linked to a 2-fold to 37-fold increased risk of HCC. Increased levels of homeostatic model assessment for Insulin resistance, which is an indicator for insulin resistance and a surrogate marker for the metabolic syndrome, have been measured in patients with HCC, suggesting that insulin resistance is associated with an increased risk of HCC. Additional studies suggest that obesity may independently increase HCC risk or have a synergistic effect with diabetes via a central HCC pathway of increased steatosis.
Similarly, coinfection with hepatitis B virus (HBV) increases the risk of HCC. In one small study, the cumulative lifetime incidence in coinfected men approached 38%, compared with 23% in monoinfected men. HBV replication status is the crucial factor affecting the risk for HCC in patients with HCV. In another study, patients coinfected with HBV/HCV without detectable HBV DNA had HCC risk equal to that of monoinfected patients with HCV. However, patients with active HBV replication had twice the risk of HCC and a 21% increase in mortality risk. The specific mechanism for this increased risk has not been fully elucidated, but has been attributed to the innate oncogenic potential of HBV covalently closed circular DNA during viral replication. At present there is no shortened HCC screening interval recommended in patients coinfected with HCV/HBV.
Although HCV prevalence in the general US population is 1.8%, the prevalence is much higher in the HIV population, at 16%. Improved survival of patients with HIV on antiretroviral therapy and the aggressiveness of HCV in patients with HIV has been associated with an increased risk of HCC. Between 1996 and 2009, there was a disproportionate 23-fold increase in HCC prevalence in coinfected patients compared with patients monoinfected with HIV. This increase is attributed to decreased immune response in HIV, increased HCV replication, and an expedited evolution to cirrhosis, along with improved overall HIV-related survival. The aggressive nature of HCV/HIV coinfection and increased HCC risk mandates identifying HCV coinfection in patients with HIV and rigorous HCC surveillance in this population.
Lifestyle Factors
HCC risk is also linked to lifestyle factors such as coffee, smoking, and alcohol use. Coffee has been associated with both a decrease in the rate of progression to hepatic fibrosis and a decreased risk of HCC. A large meta-analysis by Saab and colleagues reviewed multiple studies supporting a dose-dependent decrease in HCC risk with at least 1 cup of coffee daily. In addition, several studies support a significant decrease in HCC mortality with consumption of greater than or equal to 1 cup of coffee daily. Specifically, a study by Kurozawa and colleagues found a 69% reduction in HCC mortality in patients with HCV who drank 1 cup of coffee daily compared with non–coffee drinkers. At present, there are no randomized control trials on HCC and caffeine. Further, the previously mentioned cohort and case control studies have many potential confounders, including a higher incidence of alcohol use in coffee drinkers and lack of standardization regarding the volume and amount of caffeine in a cup of coffee.
In addition, it is well known that alcohol and smoking are associated with accelerated progression to HCC in HCV, likely via increased oxidative stress. There is a synergistic effect between alcohol and HCV on HCC, with a 2-fold increase in individuals who drink more than 60 g of alcohol daily. Similarly, a recent meta-analysis has shown a significant increase in relative risk of HCC in smokers with HCV compared with nonsmokers with HCV, with relative risks of 23 and 7.9 respectively. This increased risk with smoking may be confounded by alcohol because some patients tend to smoke while they drink.
Inherent Viral Factors
Genotype 3 was associated with an 80% higher risk of HCC than genotype 1 in a large Veterans’ Affairs cohort of 100,000 patients controlled for age, body mass index, and viral therapy. There was no consistent evidence that viral load affects HCC risk. In addition, although cirrhosis and stage 4 fibrosis are well-established risk factors for HCC, recent data suggest that stage 3 fibrosis also presents increased risk, with as many as 20% of patients progressing to HCC. Additional data on these inherent viral factors are awaited.
Virology and pathogenesis
Both direct and indirect pathways of carcinogenesis are responsible for HCC development and understanding of these pathways will be key to devising new treatment strategies. Three major mechanisms of carcinogenesis have been proposed: direct pathways involving the HCV core protein, indirect injury from oxidative stress and steatosis leading to hepatocyte death, and microRNA (mi-RNA) instability.
HCV viral proteins can act directly on cell signaling pathways to promote HCC by inhibiting crucial cell cycle check points, inhibiting tumor suppressor genes and apoptosis regulators, or by causing activation of signaling pathways that upregulate growth and division ( Table 2 ). All these actions culminate in uncontrolled cell proliferation. The HCV core protein plays a key role in these deregulatory pathways by inhibiting the retinoblastoma protein (RB) and p53 tumor suppressor. Inhibition of RB causes dysfunction of important cell cycle check points involved in cell turnover and repair of faulty DNA sequences, resulting in uncontrolled proliferation of mutated HCV cells. Also, HCV NS5B can inhibit other apoptosis regulators, such as BCL-2, and cause abnormal activation of signaling pathways that promote growth, such as Wnt/beta catenin and mammalian target of rapamycin (mTOR). HCV core promoter protein also inhibits p53, which is the second most abundant tumor suppressor in the liver. It has been suggested that the loss of p53 and retinoblastoma could be synergistic, leading to a greater degree of carcinogenesis. HCV core protein may also indirectly facilitate HCC by increasing oxidative damage via increased steatosis, lipogenesis, and promotion of protein misfolding in the endoplasmic reticulum.
| Theory | Pathway | Direct or Indirect Effect | Basic Mechanism of Action | Deficiency of Function or Abnormal Activation | Specific Pathways or Molecules Involved |
|---|---|---|---|---|---|
| 1 | HCV core protein | Direct | Upregulates proliferation pathways | Activation | mTOR Wnt/Beta |
| 1 | HCV core protein | Direct | Inhibition of tumor suppressor genes (p53 and RB) | Deficiency | P53 Retinoblastoma |
| 1 | HCV core protein | Direct | Disables cell cycle checkpoints to allow continued division | Deficiency | G1-S |
| 1 | HCV core protein | Direct | Interferes with DNA repair via inhibiting retinoblastoma at G2-M cell cycle check point | Deficiency | G2-M |
| 1 | HCV core protein | Direct | Inhibits apoptosis regulators | Deficiency | BCL-2 |
| 1 | HCV core protein | Indirect | Increases stress and oxidative damage | Neither | — |
| 2 | Bystander effect | Indirect | Death of HCV-infected cells by immune system leads to rapid proliferation of new hepatocytes and increased risk for mutations to accumulate | Deficiency | No specific markers |
| 3 | MicroRNAs | unclear | Regulators of gene expression | Activating in some cases and deficiency in others | miR-22 miR-122 |
Other indirect pathways to HCC have been proposed, including the bystander effect. In the bystander effect, the immune system produces proapoptotic signals to fight the replicating HCV virus, causing death of HCV-infected hepatocytes. As a result of this widespread hepatocyte death, hepatocyte proliferation is enhanced to maintain hepatic synthetic function. In the midst of this rapid proliferation, uninfected bystander cells can accumulate mutations, which in an environment of oxidative stress can promote carcinogenesis. This theory has been partially shown in mouse studies, which show that stimulation of rapid hepatocyte turnover and apoptosis can serve as a driver for HCC.
In addition, HCC carcinogenesis is affected by mi-RNAs, a group of complex gene regulators that control expression of apoptosis, proliferation, and differentiation of cells. Alterations in the expression of various mi-RNAs are associated with HCC. For example, silencing miR-122, which is crucial for HCV replication, has been associated with an antiviral effect in monkeys. In addition, inhibiting miR-21 in cultured HCC cells leads to decreased tumor proliferation and invasion. Elucidating the relationship of these various mi-RNAs may offer promising therapeutic targets.
Although progress has been made in understanding these pathways, significant obstacles remain in identifying potential viral targets for treatment and HCC risk reduction.
Impact of antiviral therapy on hepatocellular carcinoma
Impact of Interferon Therapy
Interferon (IFN) is successful in reducing the risk of HCC as long as SVR is achieved. SVR decreases the risk of HCC because of improvement in fibrosis and reduction in inflammation. Compared with nonresponders, achievement of SVR resulted in an 11% risk reduction and 4.6% absolute risk reduction. Even without SVR, patients with HCV relapse are 2 times less likely to develop HCC than nonresponders. Five-year HCC incidence rates were significantly lower in patients with transient virologic response (3%) compared with nonresponders (7.9%; P = .03) Although SVR is the optimal outcome, these findings suggested that even a temporary period of decreased inflammation by HCV treatment may be beneficial.
Although SVR reduces the risk of HCC, the risk of HCC persists, especially in patients with advanced fibrosis. Ikeda and colleagues observed that HCC risk gradually increased over a 9-year period despite achieving SVR. Specifically, 5-year and 10-year incidence rates after SVR in chronic HCV were 1.2% and 4.3%, respectively compared with a 5-year incidence of 20% in patients with HCV cirrhosis. Morgan and colleagues compared the risk of HCC in cirrhotics to that in patients with all stages of fibrosis and discovered that, despite achieving SVR, 4.2% of cirrhotics developed HCC as opposed to 1.5% of those with all stages of fibrosis.
In addition, HCV treatment after ablation or resection of HCC is effective in reducing new HCC foci and mortality in patients who achieve SVR. Improved survival is seen, with a 5-year survival of 76% compared with 60% in those not treated with IFN. However, even with SVR, there is still a 35% risk of HCC recurrence in these patients.
There are studies that reported that IFN therapy was unsuccessful in decreasing HCC risk. However, patients in these studies did not achieve SVR, had a short follow-up period, or had confounding variables that could increase the risk of HCC, such as a high proportion of subjects with diabetes or decompensated cirrhosis. On the whole, it seems that, with achievement of SVR, IFN is successful in decreasing the risk of HCC.
Impact of Direct-acting Antivirals
Given the recent approval of DAAs such as NS3/4A protease inhibitors, NS5B polymerase inhibitors, and NS5A complex inhibitors, there are limited data on their impact on HCC risk reduction. Based on the data from the IFN era, it is intuitive that achievement of SVR by IFN or DAA treatment would lead to similar HCC risk reduction. Significantly higher SVR rates of greater than 90% in DAAs, reported even in challenging HCV populations at increased risk of HCC, should result in reduced HCC risk that will be evident with time as these treatments are widely adopted into clinical practice. Specific data are awaited to confirm these strong hypotheses.
Predictors of Hepatocellular Carcinoma After Sustained Virologic Response
Because a reduced but durable risk of HCC persists despite SVR, there has been interest in identifying risk factors for HCC development after SVR. These risk factors are identical to initial HCC risk factors such as cirrhosis, duration of HCV infection, and comorbid conditions such as diabetes mellitus and HBV. Other factors include male gender, exposure to multiple IFN treatments, age, and surrogate markers for advanced fibrosis, such as albumin level, platelet count, and increased aspartate aminotransferase level. At this point, there are insufficient data to guide HCC risk stratification and surveillance intervals in patients with HCV who have achieved SVR. Ongoing HCC surveillance should continue for those with advanced fibrosis despite achieving SVR.
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