Hepatitis C virus pathogenesis and its natural history are characterized by several factors, among which those implicating immune system activity. This, in fact, involves regulatory and effector environments, since the acute phase of infection plays an important role [20]. In this latter case, the chronic infection underlies a persistent activity of the immune system, with a specific cytokines environment leading first to a liver necro-inflammation, and then to HCC onset (which may still occur over the years, as previously suggested) [21]. HCC onset, in particular, was recently related to a persistent inflammatory network mainly supported by IL-17, TGF-beta and deactivation of T Regulatory cells [22]. Based on these findings, one of the most important purposes of the antiviral treatment in persistent infection is represented by the virus eradication in order to prevent HCC occurrence.
Previously, in interferon-based regimens, the reduction of HCC incidence, but not its disappearance, had been associated with several factors, among which: the cirrhotic persistence stage, advanced age, presence of latent HCV mutations, presence of comorbidities such as diabetes [8, 9]. The approval of second wave DAA represents a recent event and still does not allow for a long-term assessment of SVR impact on HCC incidence [23].
Recently, two interesting studies have suggested some mechanisms as possible HCC inducers after DAA treatment. Debes et al. [24] identified, in patients who developed HCC de novo after DAA treatment, an higher value of 9 inflammatory cytokines, measured in serum before treatment (MIG, IL22, TRAIL, APRIL, VEGF, IL3, TWEAK, SCF, IL21), assuming a possible role in carcinogenesis.
Faillaci et al. [25] showed that the DAAs-mediated increase of VEGF favors HCC recurrence/occurrence in susceptible patients, i.e. who already have abnormal activation of neo-angiogenetic pathways in liver tissues, as showed by an increase in angiopoietin-2, studied in neoplastic and cirrhotic tissue.
This independent, real life study showed that the 61% of patients who developed a HCC had either a single small or 2–3 small nodules, while the remaining 39% were diagnosed with larger and infiltrative cancers. According to our data, early HCC occurrence seems to be associated with to well-known factors like diabetes, liver stiffness and advanced CTP stage. Furthermore, we also found that second wave HCV DAA therapy without a contemporary RBV treatment also seems to be related to an early HCC onset. Particularly, and more interestingly, this association with neoplasms onset seems strongly occurring among CTP A patients, hence suggesting that fibrosis might not represent the only factor possibly associated with HCC occurrence in this setting of patients.
Patients who showed HCC onset achieved SVR. Our data, according to previous findings, while proving that DAAs treatment does not increase the overall risk of HCC, also appear to demonstrate that the successful antiviral therapy is not able to prevent HCC onset even though patients achieve SVR [26]. More interestingly, this latter scenario, upon a multivariate analysis, seems to be more frequently related to SOF based regimens without Ribavirin, whose use, conversely, appears associated with a reduced HCC risk.
These data could be in part explained with the well-known immune-modulating activity of RBV, independently from the dosage, which may improve immune surveillance, while both boosting Th1 response and switching from Th2 to a Th1 CD4 pattern too [27]. Moreover, some kind of protective activity of RBV against HCC, when associated with Doxorubicin, most likely implicating the immune-surveillance, has also been recently demonstrated [28].
It could also be speculated that a rapid reduction in the HCV viral load may impact the tumor immunity, since it might affect the balance between pro-tumor and anti-tumor immune functions previously reported [29].
Nonetheless, despite this scientific evidence and the possible suggestion of a pathogenetic model, the related fine mechanisms still remain unclear and are most likely associated with several factors.
Further mechanisms that could explain these events may be related to the mitochondrial dysregulation these new drugs may induce, even though literature data regarding this issue are contradictory [30, 31].
Consistently with our data, the duration of therapy did not result significantly associated with HCC occurrence. Though a much higher percentage of HCC occurrence in the 24 weeks group versus the 12 weeks group, the stratification for duration of therapy did not affect the statistically significance between HCC onset and type of treatment.
It could be argued that our findings may be related to HCC micro nodules already placed in the liver before treatment, since the majority of nodules are bigger than 2 cm, as such rapid HCC growth seems really unusual. Of note, we found one patient having a 5 cm lesion at the onset of HCC. The possible reason of a close HCC onset after SVR and the difference in lesion size could be related not only to immune system but also intrinsically correlated to HCC. Indeed previously has been demonstrated that HCC size could explain phenotypic diversity within proliferative and non-proliferative HCCs and be associated to vascular invasion according to dimension [32]. Therefore patients with largest tumor are correlated to different metabolic path of tumor with related poor prognosis [33].
In addition, one of the major bias of the study is the limited number of cases and the short follow-up time, but early HCC occurrence was the primary endpoint of the study and, for that reason, long term assessment was not part of this research protocol.
These results seem to be corroborated by the absence of any statistically significant difference in clinical and laboratory results between patients who underwent 2D–3D based treatment compared to other antiviral regimens, as well as in the use of ribavirin in CTP class A and B.
Nevertheless, during the follow-up of our patients the aim was mainly focused on the early appearance of HCC after treatment and, fascinatingly, this event occurred at all times of this short term follow-up period. Therefore, our findings significantly underline that we still have no large data on the possible effect of some DAAs treatment schedule on physiopathology of HCC natural history and that Ribavirin, probably due to its immunomodulatory properties, may represents a protective factor on HCC risk.
In these patients, others rigorous studies on molecular mechanisms and immune system on are necessary to better elucidate and understand subtended mechanisms of early HCC occurrence in this cohort. In particular, a limitation of this study is the lack of an external validation cohort for confirming our results.