Hepatitis C Virus-Ribonucleic Acid: Comparison
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Please note this is a comparison between Version 2 by Rita Xu and Version 1 by Yutaka Tsutsumi.

The hepatitis C virus (HCV) is potentially associated with liver cancer, and advances in various drugs have led to progress in the treatment of hepatitis C and attempts to prevent its transition to liver cancer. Furthermore, reactivation of HCV has been observed in the treatment of lymphoma, during which the immortalization and proliferation of lymphocytes occur, which leads to the possibility of further stimulating cytokines and the like and possibly to the development of lymphoid malignancy.

  • hepatitis C virus (HCV)
  • Direct Acting Antivirals (DAA)
  • HCV-RNA

1. Introduction

HCV is a factor in the pathogenesis of hepatocellular carcinoma. Compared with healthy individuals, HCV is associated with a 23 to 35 times greater rate of liver cancer occurrence [1,2][1][2]. Control of HCV is thus considered to be important to suppress the pathogenesis of hepatocellular carcinoma. Meanwhile, the mechanism of how HCV is involved in the development of hepatocellular carcinoma is still not clear [2]. There have been reports since 2000 suggesting the involvement of HCV in lymphoproliferative disorders [3,4][3][4]. The mechanism of pathogenesis to lymphoid malignancy in HCV-infected cases is gradually becoming clear. However, there are still many areas that remain unelucidated [5]. Meanwhile, concerning lymphoma complicated with HCV infection, reactivation of HCV when rituximab is used has been reported [6,7][6][7]. The recurrence of non-Hodgkin’s lymphoma (NHL) with increasing HCV-RNA load has also been reported [8]. These cases suggest the possibility that an increase or eradication of HCV-RNA may affect the progression of HCV-positive lymphoid malignancy and its course of treatment.

2. HCV Reactivation When Rituximab Is Administered

To trace the relationship between HCV and lymphoid malignancy, it is necessary to consider HCV reactivation during chemotherapy for HCV positive lymphoid malignancy. One model of the contribution to HCV reactivation is the decrease in B cells due to rituximab administration, which results in the decrease of antibody production and an increase in HCV load. Stamataki et al. reported cases of lysis of HCV-infected B cells when rituximab was used to treat cryoglobulinemia, resulting in the release of HCV and an increase in HCV viral load [9]. They posit that HCV loses its adherence to B cells when B cells are destroyed by rituximab administration, resulting in an increase in HCV viral load [10]. For chemotherapy of patients with B-cell NHL complicated with HCV infection, wresearchers have used rituximab alone or in combination with other drugs. In contrast to an increase in HCV viral load after rituximab administration, with chemotherapy alone, weresearchers have observed a decrease in HCV viral load after its increase, or a lack of increase in HCV viral load [11]. OurThe findings support the findings of Stamataki et al. However, it is difficult to explain the reason for the decrease in HCV viral load after its increase in peripheral blood when rituximab is not used. Because B cells do not recover for at least six to nine months after the use of rituximab, it is unlikely that B cells were reinfected [12,13][12][13]. It is very likely that the increased HCV in peripheral blood reenters the bloodstream and infects hepatocytes. As a result, cytotoxic T cells (CTL) are attacked, and hepatitis occurs [14]. On the other hand, there have been few reports of severe cases of hepatitis due to HCV reactivation. The reason is believed to be related to the fact that compared with the hepatitis B virus (HBV), HCV is more likely to become chronic. However, the mechanism remains unclear. It is known that after rituximab is administered, B cells not only decrease, but that changes in CD4- and CD8-positive T cells due to changes in cytokines and other factors also occur. As a result, CD8-positive T cells decrease, making it easier for HCV to proliferate like HBV. In the case of HBV, CD8-positive T cells are produced that target HBV antigens during CD8-positive T cell recovery. At the same time, memory T cells are impaired (they decrease). As a result, the phenomenon of HBV randomly attacking infected hepatocytes and causing hepatitis occurs. In such a case, the hepatitis tends to be more severe [15,16][15][16]. When HCV is reactivated, it is believed to produce hepatitis with a similar mechanism. However, it is known that HCV is not completely eliminated even though HCV-specific CTL in the host is produced [17,18][17][18]. These systems create escape mutation that allows HCV to slip past CTL recognition when HCV is reactivated after rituximab treatment, thus establishing immune tolerance to the host and promoting chronicity of HCV infection. At the same time, compared with HBV reactivation, severe hepatitis is prevented as a result. Many studies on HCV reactivation predate the use of rituximab, and few have actually evaluated HCV reactivation on a large scale. There have been scattered reports of HCV reactivation and resulting hepatitis, but few reports of large-scale occurrences [7,11,19,20,21,22][7][11][19][20][21][22]. These reports include cases of death resulting from post-HCV activation hepatitis [19,21][19][21]. Although there have been few large patient studies, in a representative study, Ennishi et al. reported that of the patients who were HCV-positive, 27% had hepatitis, compared with 3% of patients who were HCV-negative; furthermore, HCV-positive patients treated with transaminase had a higher rate of hepatitis [7]. Arcaini et al. reported that liver damage was observed in 17.9% of HCV-positive patients when R-CHOP was used [23]. Together with Ennishi et al.’s report, these findings show that liver damage occurs in about 15–30% of HCV-positive patients. In these reports, fatal hepatotoxicity in HCV-positive cases and delayed treatment due to liver damage caused the exacerbation of lymphoma [24]. On the other hand, no need to delay treatment even with the occurrence of liver damage has been reported [23,25,26][23][25][26]. In addition, HCV reactivation when rituximab is used is considered to be more frequent with genotype 2 HCVI, although the number of cases is small [19]. There has also been a report that the fatality rate is higher in patients with high initial HCV-RNA load [6]. It may be that the severity of hepatitis and the ease of reactivation depend on the HCV genome and viral load. However, there is a possibility that debate about HCV reactivation may be resolved with the development of direct-acting antivirals (DAA).

3. Epidemiology of HCV-Infected B-Cell Lymphoma

Like HCV’s involvement in hepatocellular carcinoma, whether HCV is involved in lymphoproliferative disorders has also been studied. Cryoglobulinemia has been reported to be strongly associated with HCV [27,28,29,30,31][27][28][29][30][31]. Because cases of cryoglobulinemia are rare in Japan, and NHL has been found to be associated with HCV, this revisewarch will focus on B-cell NHL. There have been reports stating an association between HCV and B-cell NHL [31[31][32][33][34][35][36][37],32,33,34,35,36,37], and in existing reports, the rate of HCV-positive lymphomas is considered to be approximately 0.5-25% [8,38,39][8][38][39]. The rate is also considered to depend on the type of lymphoma. Marginal zone lymphoma (MZL), diffuse large B cell lymphoma (DLBCL), and lymphoplasmacytic lymphoma have been reported to have a high association with being HCV-positive [40]. Nieters et al.’s study found HCV-infected patients were more likely to have DLBCL and unclassifiable B-cell lymphoma [41]. Dai Maso et al. conducted a meta-analysis of 15 studies on the association between HCV infection and NHL and found a 2–2.5 relative risk of lymphomagenesis in HCV-positive cases. Similar trends were found for various subtypes of NHL [32]. Meanwhile, in Japan there have been few epidemiological studies of B-cell lymphoma in HCV-infected patients. Ohsawa et al. reported on six-year (average) follow-ups of 2,162 HCV-positive patients [42]. Four cases of NHL were found, and although the association did not reach the dangerous level of hepatocarcinogenesis, they found a moderate association. Recently, Alkrekshi et al. compared the rate of B-cell lymphoma in HCV-positive and HCV-negative patients based on a database of 72 million patients from 2013 to 2020. They reported that there were 940 cases of NHL in 129,970 patients in the HCV group versus 107,480 cases of NHL in 37,961,970 patients in the control cohort (odds ratio (OR) 2.6, 95%, confidence interval (CI) 2.4–2.7). A positive association was observed for chronic lymphocytic leukemia, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma, Burkitt’s lymphoma, non-Hodgkin’s T-cell lymphoma, and primary cutaneous T-cell lymphoma. There were no differences in mantle cell lymphoma. They also reported that the increased risk of HCV-associated lymphoma was persistent across genders, between Caucasians and African-Americans, and across age groups. While the risk of NHL in the HCV-negative population was higher in Caucasians than African-Americans (OR 1.8, 95% CI 1.7–1.8), the risk of HCV-associated NHL was not different [43]. The researchers also found that there were few cases of NHL in patients under 40 years of age. In a prospective cohort study, Rabkin et al. analyzed 95 HCV-positive cases where B-cell lymphoproliferative disorder has developed. They reported the development of lymphoproliferative neoplasia a mean of 21 years after HCV infection [44]. These above findings indicate that a certain period of time is required after HCV infection before lymphoproliferative neoplasia develops.

4. Mechanisms of B-Cell Lymphomagenesis in HCV-Infected Patients

Marcucci et al. reviewed the possibility of HCV-induced lymphoma in the research literature and hypothesized the following mechanisms: (1) growth of lymphoma due to antigenic stimulation, (2) suppression of tumor immunity due to HCV infection, (3) co-infection with an unknown tumor virus, and (4) direct tumor antigenicity of HCV [45]. WResearchers first became aware of the association between HCV and lymphoma in a case of HCV-positive DLBCL where rapid increase in HCV-RNA was observed prior to recurrence [8]. Subsequently, wresearchers conducted staining of lymphoma specimens from cases of HCV-positive lymphoma with HCV-specific antibodies, and found that nonstructural protein 3 (NS3), an HCV antigen, stained positive, both strongly and weakly, in 76.9% of the cases. However, there was no significant correlation between the degree of HCV staining and the rate of recurrence or resistance to treatment [46]. While these findings suggest the possibility that HCV is associated with lymphoma, because not all pathology specimens from HCV-positive lymphoma were positive for NS3, it is inferred that HCV may not be necessarily directly involved in lymphoma in HCV-positive cases. A factor currently considered in the association of HCV with B-cell lymphomagenesis is the possibility of HCV infection of hepatocytes and lymphocytes due to the fact that both hepatocytes and lymphocytes share CD81 [47,48,49][47][48][49]. Furthermore, CD81 forms a stimulatory complex with CD19 and CD21, which results in the promotion of the activation and proliferation of B cells via the B-cell antigen receptor (BCR) [50]. In addition, CD81 upregulates chemokine receptor CXCR3, activating B cells [51]. On the other hand, intracellular viral replication is not necessarily required for tumorigenesis of those cells [52]. The reason is considered to be the possibility of the loss of viral genome from the nascent cell in the process of being inserted into the cell’s DNA or during cell replication [53]. Viral oncoproteins can also cause epigenetic dysregulation to genetically reprogram cellular gene expression. After determining these changes in the gene expression pattern, the viral genome may be lost completely. Thus, a hit-and-run mechanism may be sufficient to induce tumorigenesis of the host cell with the temporary acquisition of a complete or incomplete viral genome [53]. A hit-and-run mechanism has also been suggested for HCV, and some researchers have shown that in vitro, HCV can induce mutations in several genes associated with cellular replication, such as p53, bcl6, and beta-catenin [54,55][54][55]. However, the possibility that HCV produces phenotypes that increase mutation rates has not been confirmed in vitro or from lymphocytes obtained from chronically HCV-infected patients [56]. The involvement of chronic antigen stimulation in the pathogenesis of NHL has been shown in mucosa-associated lymphoid tissue (MALT) lymphoma, which arises from Helicobacter pylori (HP) infection [57]. It has been suggested that a certain period of time is required until lymphomagenesis [43,44][43][44]. It is believed that chronic antigen stimulation of B cells is mediated by CD81, causing oligoclonal expansion and finally monoclonal expansion of lymphocytes and leading to NHL pathogenesis. The HCV-E2 protein also causes the proliferation of B cells by activating the JNK pathway through binding to CD81 [51]. In addition, overexpression of anti-apoptotic protein bcl-2 is often observed in HCV-positive mixed cryoglobulinemia (MC). It is also considered to be a second hit for the transition of lymphocyte proliferation to lymphoma [58,59][58][59]. Interleukin 6 (IL6) has been reported to be involved in the transformation of MC to lymphoma. An increase in IL6 causes inflammation, bringing changes in host conditions, and may strongly stimulate tumorigenesis [60]. Thus, as surveyed above, mechanisms of the pathways of potential lymphomagenesis include active lymphocyte proliferation and replication by viruses, and associated with that, cytogenetic abnormalities; run-and-hit mechanism; and chronic antigen stimulation. These mechanisms may act singly or in combination to contribute to lymphoma pathogenesis.

5. Prognosis of HCV-Positive Lymphoma

There have only been retrospective analyses when it comes to examining the prognosis of HCV-positive B-cell malignant lymphoma and HCV-negative B-cell lymphoma. Some reports find poor prognosis of HCV-positive lymphoma [23[23][38],38], whereas other reports find no difference in prognosis [8,20][8][20] or good prognosis [25]. In these reports, the prognosis cannot be stated with certainty because of noticeable variations in the cases. For example, the good prognosis group had many young patients and patients with low-grade lymphoma and the poor prognosis group had many patients with high LDH [39]. In the retrospective study wresearchers conducted in 2011, weresearchers found that patients with HCV-positive lymphoma tended to have poor prognosis. However, the difference in prognosis was not significant because of the small number of cases [46]. Studying prognostic factors, Merli et al. analyzed prognostic factors of HCV-positive malignant lymphoma in 535 patients given an anthracycline-based therapy. They found that ECOG performance status of 2 or over, serum albumin below 3.5 g/dL, and HCV-RNA viral load over 1000 KIU/mL were significant prognostic factors. The researchers proposed a way to stratify patients into three risk categories with different overall and progression-free survival (low = 0; intermediate = 1; high-risk ≥ 2 factors) by combining the three prognostic factors into a new prognostic score [61]. Recently, Elbedewy et al. analyzed the prognosis of HCV-positive DLBCL in Egypt and reported that compared to uninfected cases, HCV infection was independently associated with poor prognosis [62]. They also reported that although it had been suggested that antiviral therapy may improve prognosis, it was not an independent prognostic factor. Regarding these prognostic factors, Zhang et al. reviewed and analyzed previous reports on HCV-positive NHL [63]. They found that the overall survival (OS) and progression free survival (PFS) were both significantly shorter for HCV-positive NHL, which also showed poorer response to treatment. HCV-positive NHL patients also exhibited an advanced disease stage, elevated LDH level, high-intermediate or high international prognosis index (IPI) and follicular lymphoma international prognosis index (FLIPI) scores, as well as spleen and liver involvement [63]. They also found that antiviral therapy against HCV improved OS and PFS, and furthermore, combination with rituximab led to good results for HCV-positive NHL. However, patients with low albumin levels and hepatic cirrhosis still had a poor prognosis [63]. Synthesizing the above findings, it can be considered that for HCV-positive NHL, prognosis is still poor compared to HCV-negative NHL unless antiviral therapy is provided. Reasons include the progression of hepatic cirrhosis, IPI and FLIPI risk factors, low albumin, and the maintenance of a certain level of HCV-RNA.

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