A 57-year-old Caucasian man was diagnosed with genotype 1A HCV cirrhosis in 1996 and was treated with 24 weeks of sofosbuvir/simeprevir ~8 years later. He relapsed after completing therapy and received 24 weeks of ledipasvir/sofosbuvir, achieving SVR after 6 weeks of therapy (Figure 1B). Two months after completing therapy, he underwent surveillance abdominal ultrasound that showed a new right hepatic lobe lesion. MRI of the abdomen at that time confirmed two separate masses in segments II and III measuring 2.0 and 3.0 cm, respectively, concerning for multifocal HCC, with associated abnormal nonmass-like arterial enhancement and washout seen throughout the right hepatic lobe (Figure 2A). He was referred to medical oncology for the consideration of liver-directed therapies; however, a pretreatment MRI was obtained and demonstrated interval resolution of the abnormal findings (Figure 3B), now 5 months after completing DAA therapy for HCV. He has remained on active surveillance for the last 20 months with four additional MRIs showing no radiographic evidence of HCC.
(To view a larger version of Figure 3, click here.)
There are various proposed mechanisms by which HCV induces HCC. It is well known that HCV leads to chronic inflammation, causing fibrosis and liver cell proliferation. In addition to the chronic inflammatory milieu created by the HCV, several oncogenic mechanisms have been studied and are well established. The basic mechanism of cancer development is related to an increase in liver cell turnover and oxidative damage, facilitating genetic alterations. These mutations have an array of effects, including activation of oncogenes and proliferation pathways, activation of telomerase, overexpression of growth factors, increased angiogenesis, and inactivation of tumor suppressor genes.4–9 The most well studied of these pathways include alterations of phospho-retinoblastoma (pRB), p53, transforming growth factor-beta, and beta-catenin pathways. Various viral proteins, most notably nucleocapsid core protein, NS3, and NS5A, have been implicated in oncogenesis and tumor progression.
There is much to be learned about the effect of treating chronic HCV in patients with concurrent HCC, and there is debate about the effect that achieving SVR has on the biology of existing and recurrent HCC.10–13 The study by Conti et al of patients with HCV–cirrhosis treated with DAA reported an increase in de novo HCC occurrence and recurrence rates in the 24 weeks following the achievement of SVR when compared with patients who did not undergo treatment with DAA. The authors postulate that although the presumed etiology for cirrhosis and HCC was HCV, curing HCV decreases the level of immune surveillance in the liver, leading to a paradoxical increased risk of developing HCC.12 A second study by Reig et al also reports an unexpectedly high rate of tumor recurrence in patients with treated HCC (with resection, ablation, or chemoembolization) who achieved SVR with DAA.13 Of the 58 patients included in this retrospective analysis, ~28% developed radiographic evidence of recurrence. A key distinction between these published reports and our two cases is that these publications studied de novo occurrence or recurrence rates of HCC after HCV treatment, not the impact of HCV viral clearance on existing HCC. Moreover, other studies have called into question whether SVR truly increases the risk of HCC occurrence or recurrence.3,14–16
The two cases described in our report that of decreasing tumor burden and even resolution of presumed pulmonary metastasis with the treatment of HCV raises the possibility that with the clearance of HCV, there is inhibition of HCC oncogenesis. Although there is debate about how HCV SVR mechanistically impacts the biology of HCC, these cases raise an interesting question regarding the role of immunosurveillance in liver cancer. The theory of immunosurveillance is based on the complex ways in which the immune system and tumor cells interact, described in more detail as the following “Three E’s” model: “elimination” of the cancer cells by the immune system, “equilibrium” during which the immune system and cancer cells coexist, and then, “escape” of the cancer with overt tumor progression.17 Chronic HCV infection is characterized by an activation of the innate immune system (as evidenced by increased natural killer [NK] cells and interferon stimulated genes) as well as a decrease in the adaptive immune system with suppressed CD8+ T cells.18 Treatment of HCV patients with DAA has been shown to modulate the composition of immune cells both in the liver and in circulation with the normalization of NK cell function and restoration of virus-specific CD8+ memory T cells.19,20Expression of CD8+ T cells has been reported as a positive prognostic factor in HCC with high intratumoral densities correlating with lower rate of recurrences and longer disease-free survival times.21 Thus, curing a patient of SVR and reversing the inhibition of T-cell function potentially augment immune surveillance for HCC.