Successful treatment by on-demand glecaprevir and pibrentasvir for hepatitis C flare during R-CHOP in patients with diffuse large B-cell lymphoma: a case report

Globally, hepatitis C virus (HCV) remains a major cause of hepatocellular carcinoma and liver-related deaths. HCV infection can cause extrahepatic disorders, including lichen planus, diabetes mellitus, renal dysfunction, and lymphoma [1].

Recently developed direct-acting antivirals (DAAs) have improved the efficacy and safety of anti-HCV therapy compared with interferon-based therapy. Several basic studies, clinical trials, and real-world studies have shown that DAA therapy is highly safe and effective, with minimal drug–drug interactions [2‐4]. However, anti-HCV treatment for patients with advanced malignancies remains controversial. DAA treatment is contraindicated in HCV-infected patients with uncontrolled malignancies [5]. In addition, there are no guidelines for the timing of DAA administration with respect to the individual anti-tumor treatment schedule in patients with HCV and cancer. Further, the indications for DAA treatment with these cases remain unknown [5].

HCV infection is associated with lymphoma, especially diffuse large B-cell non-Hodgkin lymphoma and HCV-associated indolent B-cell non-Hodgkin lymphomas [1, 6]. After HCV eradication by anti-HCV therapy, indolent B-cell non-Hodgkin lymphoma regression, especially in marginal zone lymphomas, is sometimes observed, suggesting a link between HCV and lymphoma progression [1, 6, 7]. Compared with non-HCV-positive diffuse large B-cell lymphoma (DLBCL) patients, HCV-positive DLBCL patients were reported to have different characteristics, including elevated LDH and old age [8, 9]. High HCV-RNA viral load is associated with a worse prognosis in patients with diffuse large B-cell lymphoma (DLBCL) [10] and HCV infection causes liver cirrhosis and hepatocellular carcinoma; thus, if possible, proper treatment is required. During standard therapies, including high rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) for DLBCL, a total of 14–28% of patients experienced grade 3–4 hepatic toxicity [9, 11]. Thus, patients with DLBCL and HCV infection administered with R-CHOP may require careful monitoring for hepatic toxicity, as well as proper management; however, to our best knowledge, no study has evaluated the more recent DAAs; glecaprevir and pibrentasvir for hepatitis C flares during R-CHOP.

Here, we describe successful HCV treatment by on-demand gearlever and pivrentasvir, which is initiated only when hepatic C flare is observed during R-CHOP therapy, in an HCV-infected patient with DLBCL.

Recently, several studies have reported the efficacy and safety of concurrent or subsequent anti-HCV therapy in immunochemotherapy (I-CT), including R-CHOP for patients with HCV and malignant lymphoma. Concurrent or upfront concomitant DAAs and I-CT are potential therapeutic approaches [12, 13]; however, a limited number of patients have been treated with I-CT and concurrent DAAs. In addition, anti-HCV treatment for patients with advanced malignancies remains controversial, and DAA treatment is contraindicated in patients with HCV and uncontrolled malignancies [5]. Thus, in general practice, R-CHOP is used without concurrent DAAs for HCV-infected patients with malignant lymphoma.

Administration of DAAs following I-CT—including R-CHOP—is highly safe and effective based on studies involving a relatively large number of patients [12, 13]. However, in the initial I-CT, 60% (23/38) and 18% (7/38) of patients experience any grade of hepatic toxicity and severe hepatic toxicity, respectively [13]. Similarly, Zaky et al. have reported that in HCV-infected patients with lymphoma, R-CHOP causes severe hepatic toxicity at a high rate of 28% (19/68) and that these hepatic toxicities lead to the modification and discontinuation of I-CT, resulting in poor responses to treatment [11]. Thus, the management of hepatic toxicity during R-CHOP in HCV-infected patients with malignant lymphoma is a crucial issue requiring clarification. To the best of our knowledge, the present case is the first evidence for the safety and efficacy of on-demand glecaprevir and pibrentasvir therapy for hepatitis C flare, thereby enabling further R-CHOP without hepatic toxicity. Thus, in addition to concurrent or upfront concomitant DAAs and I-CT, this “on demand” DAAs therapy might be promising approach.

There have been recent reports of HCV reactivation in patients receiving anti-malignancy therapy. In a prospective study, HCV reactivation occurred in 23% (23/100) of patients with HCV infection who were treated with anti-cancer therapy. In addition, of 23 patients with HCV reactivation, 10 patients experienced hepatitis flare, in some cases requiring the discontinuation of the anti-cancer treatment. A multivariate analysis revealed that rituximab and high-dose steroids are significantly associated with HCV reactivation [14]. Thus, R-CHOP, which involves rituximab and high-dose steroids, is considered a high-risk anti-cancer treatment. Moreover, Zaky et al. reported that in patients with DLBCL and HCV infection, R-CHOP is associated with severe hepatic toxicity and shows a high rate of discontinuation. In addition, significantly higher serum HCV-RNA levels after treatment initiation have been observed in patients treated with R-CHOP compared to those treated with CHOP [11].

As described previously, although Deming et al. proposed that DAA treatment is contraindicated in patients with HCV and uncontrolled malignancies, they recommended it in patients with stable cancers or those in remission for at least 3–6 months after cancer treatment [5]. Insufficient cancer therapy might cause poor outcomes; thus, to avoid discontinuation or dose reduction of cancer therapy, we hypothesized that on-demand glecaprevir and pibrentasvir are potential options. Recent favorable treatment outcomes of concurrent DAAs and I-CT for patients with malignant lymphoma and HCV infection [12, 13, 15] support this strategy. Glecaprevir and pibrentasvir are more recent DAAs and approved in many countries (Supplementary Table 1). In Japan, the combined administration of vincristine and glecaprevir and pivrentasvir is not a “precaution for co-administration” and “contraindication for concomitant use” refer to its package insert (https://​aconnect.​abbvie.​co.​jp/​/​media/​assets/​pdf/​products/​maviret/​Maviret_​tmpDocument.​pdf); however, vincristine is a substrate of P-glycoprotein (P-gp) and concentrations may increase due to inhibition of Pgp by glecaprevir and pivrentasvir and might cause adverse events. Additionally, there is no study regarding combined administration of vincristine and glecaprevir and pivrentasvir; thus, to ensure its safe use, further analysis is warranted. Merli et al. reported nine cases of concurrent administration of DAAs and I-CT. The DAAs regimen of the nine cases consisted of one case of sofobuvir and ribavirin, three cases of sofosbuvir and ledipasvir, and five cases of sofosbuvir and daclatasvir [13]. The safe use of sofosbuvir-based therapies has been reported; thus, these therapies could be used as alternatives for gelcaprevir and pibrentasvir. However, these therapies are adapted to limited HCV genotypes and required longer treatment duration than glecaprevir and pibrentasvir. Thus, further study is warranted.

Several reports have shown that anti-HCV therapy with both IFN and DAAs could improve overall survival or disease-free survival in HCV-infected patients with malignant lymphoma, and HCV infection cause liver cirrhosis and hepatocellular carcinoma [15‐17]. Thus, DAA therapy for HCV-infected patients with malignant lymphoma should be considered, with cost and insurance issues varying in each country.

In the present case, after one course of R-CHOP, increases in ALT and HCV-RNA were observed. HCV-RNA increased 1000-fold over baseline levels 9 days after treatment initiation. An immune response to virus-infected hepatocytes is a common cause of viral hepatitis. However, our previous in vitro and in vivo analyses had shown that rapid increases in HCV cause hepatic toxicity [18]. Thus, in this case, in addition to an immune response to virus-infected hepatocytes, as a potential hypothesis, a rapid increase in HCV might cause hepatic toxicity.

After 2 days of glecaprevir and pibrentasvir administration, our patient’s HCV-RNA levels decreased rapidly (a nearly 2.5 decrease); thus, glecaprevir and pibrentasvir showed immediate suppressive effects on HCV replication. This might result in immediate attenuation of hepatic toxicity. Glecaprevir or pibrentasvir monotherapy could decrease HCV-RNA levels by nearly 3 log 24 h after treatment initiation [19]; thus, our patient’s clinical course might be reasonable. Glecaprevir and pibrentasvir have a highly potent anti-HCV ability and induce a shorter treatment duration than previous DAA treatments; this combination might be suitable in R-CHOP-induced HCV flare and subsequent hepatitis.

This case report has a few limitations. Some clinical data, including fibroscan data, were lacking. Additionally, the safety regarding drug-drug interaction between R-CHOP and glecaprevir and pibrentasvir remains unclear. Thus, these should be considered when interpreting the case report results, and a prospective study with a large sample is required to validate the findings.

In conclusion, on-demand glecaprevir and pibrentasvir for hepatitis C flare during R-CHOP in HCV-infected patients with malignant lymphoma might be safe and effective.