Introduction
Hepatitis C virus (HCV), a hepatotropic RNA virus, is one of the leading causes of chronic liver disease. Hepatocellular carcinoma (HCC) is a major complication associated with HCV virus infection, with significant mortality and morbidity rates (Fig. 1). HCV-induced development of HCC is a gradual process and is affected by the duration of disease and viral genotype.1 The goal of HCV treatment is to eliminate the infection, decrease the rate of transmission to other individuals and reduce the risk of development of HCC.2 Direct-acting antiviral (DAA) agents have emerged as promising treatment options and are associated with high sustained virological response (SVR) rate.3 Despite the advent of highly effective treatment, the morbidity and incidence of HCV-related HCC remains high.
Epidemiology of HCV-related HCC
HCC is the fifth most common cancer and second leading cause of cancer-related death worldwide.4 Chronic HCV infection is the leading cause of HCC in the western countries, and accounts for about 34% of HCC cases in the USA.5 Risk of HCC in HCV-infected patients is increased by 15- to 20-fold, with annual incidence of HCC being estimated at 1% to 4% in cirrhotics over a 30-year period.6 In 2012, a total of 170000 new cancer cases, or approximately 7.8% of all new cancers, were attributable to HCV.7 Over the past decade, deaths from HCV-attributable HCC increased by 21.1%, during which time deaths from HCC secondary to causes other than HCV and alcohol remained stable.8
The incidence of HCV-related HCC varies with both geographic location and ethnicity. HCV is the leading etiology of HCC in the USA, Europe, Japan and South America, whereas hepatitis B virus (HBV) is the major cause of HCC in the majority of Asia and Africa.9 An estimated 2.5% of the world population (177.5 million) are infected with HCV.10 HCV infection became widespread in Japan in the 1920’s and in the USA in the 1960’s.11 HCV prevalence in Japan is around 3% and an estimated 85% of patients with HCC are infected with HCV.12 In contrast, the USA has a lower HCV prevalence of 1.8% of its population, with around 50–60% of patients with HCC being infected with HCV.13 Japan’s increased proportion of patients with HCC and HCV compared with the USA is influenced by the earlier onset of the HCV epidemic in Japan, suggesting that HCV-associated HCC incidence will continue to rise in the USA.14
Within the USA population, HCC varies by ethnicity and age group, with Hispanic patients and patients born between the years of 1945–1965 at highest risk of HCC.15 A large cohort study of 150000 USA veterans infected with HCV showed that Hispanic patients had the highest annual HCC incidence (at 7.8%), likely related to the higher incidence of nonalcoholic fatty liver disease in this patient population.16 In a similar cohort, HCC incidence was shown to increase 2.5-fold, with tripling of mortality since to 2001, despite the introduction of DAAs.17 The impact of DAA therapy on HCC incidence will be discussed later in this review.
Risk factors for development of HCC in chronic HCV infection
Approximately 20% of chronic HCV-infected individuals develop liver cirrhosis within 20–30 years and once cirrhosis is established, the rate of HCC development is 1–4% annually.18 The predominant risk factors for the development of HCC in chronic HCV infection include concurrent liver disease, viral genotype, lifestyle factors and the presence of obesity and diabetes mellitus. Coinfection with HBV and human immunodeficiency virus (HIV) significantly increases the risk of HCC in HCV-infected patients. In HBV-HCV coinfection, HBV replication status is the crucial factor affecting the risk for HCC. Coinfected patients with undetectable HBV DNA have HCC risk equal to that of patients only infected with HCV.19 On the other hand, HCV patients with active HBV replication have twice the risk of HCC and a 21% increase in mortality compared to those with latent HBV and HCV.19 Similarly, there is a substantial increase in HCC prevalence in HIV-HCV coinfected patients compared with HCV patients, with HCC occurring at a younger age in this population.20 This increase is attributed to amplified HCV replication, decreased immune response in HIV, and a more rapid progression to cirrhosis.21 In HIV-HCV coinfection, older age, cirrhosis, and low current CD4 cell count are associated with a higher incidence of HCC.22
Certain HCV viral genotypes are associated with higher risk of HCC. Compared to genotype 1, genotype 3 was associated with an 80% higher risk of HCC in a large cohort of patients from the USA Veterans Affairs medical system.23 While less common in developed countries, HCV genotype 6 has also been shown to confer increased risk for development of HCC.24
HCC risk is also linked to lifestyle factors, such as smoking, alcohol use and coffee ingestion. Alcohol and smoking are associated with accelerated progression to HCC in HCV, likely via increased oxidative stress.25 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.25 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.26 Furthermore, studies suggest that even past heavy alcoholism in people who have since stopped drinking can contribute to liver disease progression, cirrhosis and liver cancer in HCV-infected patients, including those who attain an SVR.27,28 While drinking alcohol has shown to increase HCV-related HCC, coffee consumption may be protective. Several studies support a significant decrease in HCC mortality with consumption of greater than or equal to 1 cup of coffee daily.28,29 In fact, coffee has been associated with both a decrease in the rate of progression to hepatic fibrosis and a decreased risk of HCC.30
Diabetes and obesity in individuals with HCV contribute to an increased risk of HCC. HCV infection has high comorbidity with diabetes mellitus, which confers a 2- to 3-fold increase in HCC risk.31,32 Pathogenesis of diabetes mellitus-mediated HCC development likely involves elevated insulin levels and insulin resistance leading to increased inflammation, cellular proliferation, apoptosis inhibition and generation of tumor-causing mutations.33 Available data also suggests that there is a 1.5- to 4-fold increased risk of HCC in patients with obesity.34 Increased proinflammatory cytokines, adiponectin and insulin resistance are potential mediators of carcinogenesis in HCV-related HCC.35
Progression of HCV to HCC
HCC development due to HCV is a stepwise process spanning over 20 to 40 years (Fig. 2).36 HCV carcinogenesis is mediated by viral-induced factors and host-induced immunologic response. While evidence of a direct oncogenic effect of HCV on liver cells is limited to animal models, studies have shown that the HCV core protein may drive lipogenesis and impair oxidative stress metabolism.37 HCV viral proteins can act directly on cell signaling pathways to promote HCC by inhibiting tumor suppressor genes and cell cycle check points or by causing activation of signaling pathways that up-regulate growth and division.38 Specific tumor suppressor genes inhibited by HCV core protein include retinoblastoma protein and p53 tumor suppressor. The loss of p53 and retinoblastoma is synergistic, leading to a greater degree of carcinogenesis.39 HCV nonstructural protein genes also promote fibrosis and the development of HCC through inducing transforming growth factor-beta and activating hepatic stellate cells.40
Host-induced immunologic response is mediated by tumor necrosis factor, interferons (IFNs) and chronic inflammation secondary to HCV.41 Repeated cell cycles are associated with accumulation of mutations that may transform hepatocytes to malignant cells. Genes most commonly mutated in HCC are telomerase reverse transcriptase, tumor protein 53 and β-catenin.42 These mutations threaten telomere maintenance and lead to increased oxidative stress. Most cases of HCC arise from hepatocytes in cirrhotic nodules that have accumulated enough mutations to reenter the cell cycle, reactivate telomerase, and progress through cancer checkpoints.43 Additionally, oxidative stress on the hepatocytes induced by the virus and host immune response leads to cell death and regeneration, also leading to mutations in the hepatocytes and ultimately, the development of HCC.
Impact of newer DAA therapies on HCC
Viral eradication with the traditional IFN-based treatment strategy has been associated with reduced risk of HCC development in patients with chronic HCV infection.44,45 The advent of DAA therapy has revolutionized the treatment of HCV, with very high cure rates and excellent safety profile.46
Since the availability of DAAs, several observational studies have reported variable rates of occurrence of HCC.47 As experienced with IFN-based therapies, rates of occurrence of HCC were lower in two studies among patients achieving SVR after DAA therapy.48,49 However, in one study on patients with decompensated HCV-related cirrhosis who failed or were intolerant to IFN-based therapy, 5.4% of patients developed new onset of HCC.50 Although the incidence was higher among patients treated with a DAA regimen alone as compared to those with an IFN-based therapy, this was not statistically significant after adjusting for confounders.51 Studies comparing the occurrence of HCC in patients taking a DAA with or without IFN also showed no significant differences.52 Similar observations were made in another study reported from a single USA center.53 Data on recurrence of HCC after treatment with DAAs is also conflicting, with higher rates of up to 35% in some studies54 and no difference compared to untreated patients in other studies.55 Among those that received DAAs, time to recurrence was also longer.56 Studies comparing HCC recurrence in patients who received DAA versus IFN-based regimens did not show difference in the rates of recurrence.57
Studies on treatment of HCV infection in patients with HCC are even further limited. Although cure rates with DAA treatment have approached over 95% in most studies as well as in routine world practice experience,46 the rates remain low, at 52–62% among patients with active HCC.58 In one study, patients with active HCC were 8.5 times more likely to fail treatment.59 In another study, rate of radiological progression and exclusion from the liver transplant wait list was higher, although not by a statistically significant margin.60
Mechanisms of increased HCC rate after DAA treatment are not well understood. One speculated mechanism is altered immunological balance secondary to a rapid decrease in HCV viral load contributing to the tumor development occurrence and recurrence.61
Screening for HCC in HCV patients
High mortality associated with HCC makes it imperative for clinicians to commence screening for HCC early in the disease course. HCV-infected individuals with cirrhosis need systematic monitoring with liver ultrasound, possibly with adjunct serum alpha-fetoprotein (AFP) level.62–64 Ultrasound is the recommended imaging modality for screening, as it has higher sensitivity and specificity than AFP and is able to detect lesions 0.5–1 cm in diameter.65 The sensitivity of ultrasound is user-dependent, and the accuracy for detecting small nodules less than 0.5 cm is limited. Recently, computed tomography scan and magnetic resonance imaging have emerged as promising screening tools.66 Liver ultrasonography is mandatory prior to starting HCV treatment, within 12 weeks after its completion, and at 24-week intervals after that.62 Currently, AFP is only recommended to be used as an adjunctive screening tool when ultrasound is either not available or is of poor quality.67 However, in some cases the use of AFP alongside ultrasound imaging increased the sensitivity of HCC detection from 63% to 69%.68
Whereas most cases of HCV-associated HCC occur in the background of cirrhosis, occasionally it may occur in the setting of bridging fibrosis.69 As a result, the current recommendations for HCC surveillance (liver ultrasound with or without AFP twice per year) are recommended for patients with cirrhosis and F3 fibrosis.70 As alluded to in the previous section, the data remain controversial on the risk of developing HCC after treatment with DAA.
Lifelong surveillance for HCC in patients with fibrosis and cirrhosis is associated with considerable economic and psychological implications. With emerging advancements in treatment modalities, there is evidence that fibrosis regression can occur after achieving SVR.71 There is lack of evidence on correlation between regression in cirrhosis determined histologically and risk of HCC.72 Based on limited data, post-SVR liver biopsies are neither routinely performed nor are they clinically practical. At this point, it is difficult to determine if serial biopsies would provide sufficient data to discontinue HCC surveillance based on histological regression of fibrosis. Similarly, studies on noninvasive biomarkers for fibrosis are also inconclusive in determining the regression in fibrosis post-SVR.73 Based on current available data, physicians should perform twice yearly hepatic imaging indefinitely post-SVR in patients with advanced fibrosis and cirrhosis.
Conclusions
HCV-related HCC is increasing worldwide and is associated with high mortality. The risk of HCC is substantially reduced in patients who achieve viral eradication but is not completely eliminated, and patients with advanced fibrosis and cirrhosis require ongoing surveillance for HCC. Future research should be directed towards clarifying the role of DAA treatment on the development of HCC.
Abbreviations
- AFP:
alpha-fetoprotein
- DAA:
direct-acting antiviral
- HBV:
hepatitis B virus
- HCC:
hepatocellular carcinoma
- HCV:
hepatitis C virus
- HIV:
human immunodeficiency virus
- IFN:
interferon
- SVR:
sustained virologic response
Declarations
Acknowledgement
The work was supported by a faculty development grant to AKS by the American College of Gastroenterology.
Conflict of interest
The authors have no conflict of interests related to this publication.
Authors’ contributions
Review of literature and drafting of manuscript (PA, ZA, SR), critical revision of the manuscript (AKS).