HCV and nonhepatic malignancy: Is pre‐emptive direct‐acting antiviral therapy indicated prior to treatment?
Authors: Michael Kriss, Matthew Burchill
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. See Articles on pages 36 and 48. With the advent of the direct‐acting antiviral (DAA) era, treatment of hepatitis C virus (HCV) patient cohorts previously felt to be untreatable with interferon‐based therapies has now become a routine reality. This clinical horizon has expanded to include HCV‐infected patients diagnosed with nonhepatic malignancy for whom multiple benefits of DAA treatment, both hepatologic and oncologic, exist. Potential benefits of eradication of HCV prior to cancer therapy include minimization of drug‐induced hepatotoxicity, avoiding detrimental dose reduction; prevention of cancer relapse or recurrence; avoidance of potentially decompensating hepatitis flares; and increased access to clinical trials for which HCV may have otherwise been an exclusionary criteria.1 Furthermore, DAA therapy in cancer patients has proven to be efficacious, durable, and with minimal drug–drug interactions.2 Despite these observations, prospective data are limited, and with the exception of patients being considered for bone marrow transplant, there are no current guidelines for the use of DAA therapy in HCV‐infected cancer patients. Clearly, there is a need for further clinical investigation to address two fundamental questions: Does cancer treatment impact chronic liver disease related to HCV infection and conversely, can treatment of HCV with DAAs impact oncologic outcomes in patients undergoing cancer treatment? Two articles in this month's issue of Hepatology address these complimentary concepts. Torres et al.3 report on a prospective observational study defining the incidence, clinical predictors, and associated outcomes of HCV reactivation (HCVr; ≥1 log10 IU/mL increase in viral load) in chronically infected patients undergoing chemotherapy. For the first time, this study prospectively demonstrates that HCVr occurred in 23% of patients, although it was only associated with a hepatitis flare (alanine aminotransferase ≥3 times upper limit of normal) in 43% of these patients. In multivariate analysis, the two statistically significant predictors of HCVr were use of rituximab (odds ratio 9.52) and high‐dose steroids (odds ratio 5.05). This paralleled the observation that HCVr was more common in hematologic malignancy, particularly lymphoma, for which these regimens are used. Interestingly, in patients with HCVr, there was a higher prevalence of genotype 2 and interleukin 28B CC genotype in those who developed hepatitis flare. While the presence of interleukin 28B CC genotype would intuitively confer a more robust inflammatory response to increased virus, the significance of genotype 2 remains unclear because this has previously been associated with slower disease progression.4 The degree and duration of lymphopenia were also greater in those with HCVr, supporting the recognized importance of lymphocytes, specifically T cells and natural killer cells, in viral control. While HCVr was not associated with increased risk of death, there was a trend toward increased discontinuation or dose reduction due to hepatitis flare in patients with HCVr (26% versus 10%; P = 0.08), potentially impacting oncologic outcomes. Taken together, these findings demonstrate that HCVr is common, particularly in rituximab‐treated patients, but does not detrimentally impact short‐term hepatologic or oncologic outcomes, although long‐term consequences remain unclear. In a separate study, Persico et al.5 report on a prospective historically matched cohort of genotype 1b HCV‐infected diffuse large B‐cell lymphoma patients treated concurrently with sofosbuvir/ledipasvir for 12 weeks and chemotherapy (70% of whom received rituximab). Concurrent DAA therapy was effective in these patients, with 100% sustained virological response at 12 weeks posttreatment reported. While there was no difference in overall survival, disease‐free survival (DFS) was significantly improved in DAA‐treated patients with an actuarial probability of DFS at 48 weeks being 95% versus 67.1% in the untreated historical controls. Excitingly, DAA treatment was the single greatest predictor of DFS in multivariate analysis (hazard ratio 0.277). This study highlights the potential for pre‐emptive DAA treatment to directly impact oncologic outcomes in carefully identified patient populations. Collectively, these two studies highlight the interrelationship between the clinical phenomena of HCVr (or conversely viral eradication with DAA therapy) and the underlying immunologic mechanisms that are determinants of both hepatologic and oncologic outcomes in HCV‐infected cancer patients (Fig. 1). As Torres et al. demonstrate, HCVr is associated with a more prolonged lymphopenia, suggesting that alterations in components of the immune system dictate HCVr. In support of this hypothesis, they find that both rituximab and high‐dose steroids are significantly associated with HCVr in multivariate analysis. Rituximab induces the selective depletion of B cells through antibody‐dependent cellular cytotoxicity, and rituximab‐based regimens are associated with hepatitis B virus reactivation due to the critical role of B cells in controlling hepatitis B virus.6 However, the primary mechanism in which the immune system controls HCV infection is largely independent of B cells; therefore, it is surprising that rituximab would be associated with HCVr. It has been demonstrated that rituximab alters the functional capabilities of natural killer cells and disrupts T‐cell homeostasis, two cell types that are critical for control of HCV, establishing a mechanism by which rituximab may weaken HCV‐specific immunity.7 The data from Torres et al. demonstrate that care needs to be taken in monitoring HCVr in patients, particularly those receiving targeted immunotherapies that manipulate the components of the immune system that control HCV. Of particular interest is the effect of immune checkpoint inhibitors (i.e., programmed death 1 inhibitors) in HCVr and hepatic injury as these regimens would be expected to have differing effects on the control of HCV than treatment with rituximab.Figure 1: HCV immunity during chronic infection and cancer therapy. (A) HCV immunity in chronic infection. Chronic HCV results in activation of both NK cells and T cells to target HCV‐infected hepatocytes, resulting in direct cytotoxicity of infected cells for viral control. B cells are also activated, although the role of neutralizing antibody is felt to be minimal in viral control. HCV evades the immune system through multiple mechanisms that inhibit cytotoxic NK and T cells, and increased viral replication contributes to direct hepatotoxic effects of the virus itself. Concurrently, HCV protein leads to chronic antigenic stimulation of lymphocytes and is strongly associated with non‐Hodgkin's lymphoma (as is the case with B cells and DLBCL). (B) HCV immunity in cancer therapy. Cancer therapy (i.e., rituximab) can have deleterious effects on lymphocyte function, resulting in reduced viral control and increased viral replication. This can result in a lower threshold for drug hepatotoxicity and may impact long‐term liver‐related outcomes (i.e., fibrosis progression). Viral suppression with DAA therapy leads to restoration of NK‐cell and T‐cell function, negating deleterious proviral impact of chemotherapy, and may reduce the risk of hepatotoxicity requiring chemotherapy dose reduction. In addition, removal of viral antigen abrogates monoclonal B‐cell proliferation, reducing the risk of lymphoma and improving disease‐free survival in those diagnosed and receiving chemotherapy. Abbreviations: DLBCL, diffuse large B‐cell lymphoma; NK, natural killer; PD, programmed death; PDL, programmed death ligand.An unanswered question that remains is the duration and durability of HCVr in patients receiving chemotherapy and the long‐term consequences of elevated HCV viral loads. Interestingly, Torres et al. reported that in a single patient with HCVr, removal of immunomodulatory chemotherapy resulted in a rapid reduction of HCV viral loads, suggesting that HCV reactivation and hepatic flare could impact management of cancer therapy. These findings support the findings of Persico et al., suggesting that DFS is increased with concurrent DAA therapy, and highlight the pro‐oncogenic effect of HCV protein on B cells. Furthermore, while the findings reported by Torres et al. demonstrate that HCVr resulted in benign hepatic injury during the course of the study, the interpretation of these data are limited due to the short prospective following of patients in the study. While it has been reported that an increase in HCV viral load correlates with rapid progression to end‐stage liver disease, clinical and scientific consensus of this correlation has yet to be established. Therefore, it is imperative to determine if treatment of HCV with DAAs prior to or concurrent with chemotherapy are attractive options to prevent HCVr and long‐term liver‐related outcomes. The clinical implications of a sustained virological response in HCV‐infected cancer patients and their immunologic underpinnings warrant further prospective trials to identify patients for whom pre‐emptive therapy will provide optimal benefit. Expert opinion is evolving to more aggressively incorporate DAA therapy into cancer treatment regimens for HCV‐infected patients, and it will be critical to identify these patients for treatment, particularly as cancer immunotherapeutic options expand.10 It is likely that with additional information it will be oncologic predictors and not those solely related to liver disease that ultimately necessitate treatment of this, until now, difficult‐to‐treat HCV‐infected cohort.