Persistent Hepatitis C Viremia Following Sofosbuvir/Velpatasvir During Bendamustine‐Rituximab Therapy for Follicular Lymphoma

ABSTRACT

This is a case of a 67‐year‐old female with follicular lymphoma who developed hepatitis C viremia during chemotherapy and failed treatment with a 12‐week course of sofosbuvir/velpatasvir. This highlights the possibility that chemotherapy may have contributed to failure to achieve sustained virologic response despite otherwise appropriate direct‐acting antiviral therapy.

Key Clinical Message.

The concurrent treatment of hepatitis C viremia while undergoing active treatment for lymphoma with bendamustine‐rituximab may increase the risk of incomplete virologic response. Thus, patients may benefit from more aggressive screening, alternative treatment regimens, and more frequent laboratory monitoring.

1. Introduction

Reactivation of chronic viral infections is a well‐recognized complication of immunosuppressive therapy, particularly in patients undergoing treatment for hematologic malignancies such as lymphoma. Although hepatitis B virus (HBV) reactivation is well characterized, increasing evidence demonstrates that hepatitis C virus (HCV) infection may undergo viral flare or marked increases in viral replication during chemotherapy, resulting in clinically significant hepatitis and interruption of oncologic treatment [1, 2, 3]. Unlike HBV, HCV does not establish true viral latency; however, chemotherapy‐induced immune dysregulation may permit uncontrolled viral replication [1].

Prior studies estimate that HCV reactivation occurs in approximately 23% of HCV‐infected patients receiving chemotherapy, with a substantial proportion developing hepatitis flares requiring chemotherapy delay or modification [2, 3, 4]. The introduction of direct‐acting antiviral (DAA) therapy, including sofosbuvir/velpatasvir (Epclusa), has transformed HCV treatment by providing high sustained viral response (SVR) rates with favorable safety profiles. We present a case of newly recognized HCV infection presenting with an acute hepatitis flare during chemotherapy for follicular lymphoma, accompanied by persistent viremia despite standard DAA therapy.

2. Case History

A 67‐year‐old female presented in January 2025 with a two‐month history of progressive abdominal pain, early satiety, and a 15‐pound unintentional weight loss. Imaging revealed a 12.6‐cm adnexal mass and bulky retroperitoneal lymphadenopathy. Diagnostic laparoscopy and biopsy performed in March 2025 confirmed Grade 3A follicular lymphoma, Stage II.

3. Methods

The patient in this case received systemic therapy for her follicular lymphoma with bendamustine‐rituximab (BR) initiated on April 23, 2025. The clinical course was complicated by Streptococcus pyogenes bacteremia in May 2025 and a maculopapular rash. Following the third cycle in July 2025, the patient developed malaise, fevers, and acute transaminitis. Her AST peaked at 62 U/L, ALT 56 U/L, alkaline phosphatase 100 U/L, total bilirubin 0.4 mg/dL, PT 12.4, and INR 0.9. Evaluation revealed a reactive HCV antibody and an HCV RNA PCR level greater than 100,000,000 IU/mL, genotype 1a. Evaluation for alternative causes of liver injury included hepatitis B serologies, medication review, and cross‐sectional imaging, which demonstrated no cirrhosis or biliary obstruction. Given her remote history of an HCV‐positive partner and absence of recent risk factors, the presentation was considered most consistent with either acute exacerbation of newly recognized chronic HCV infection or HCV reactivation during BR immunochemotherapy. Although pretreatment viral hepatitis testing is the standard of care, in this case, baseline HCV antibody testing was not performed precluding definitive differentiation between HCV reactivation and newly recognized HCV infection.

4. Conclusions and Results

Chemotherapy was briefly held, and sofosbuvir/velpatasvir was initiated for a 12‐week course. Cycle 4 of BR was resumed on October 1, 2025, and the remaining cycles were administered concurrently with DAA therapy. She completed the DAA therapy on December 5, 2025, and the BR protocol on December 9, 2025. Follow‐up PET/CT imaging performed on January 23, 2026, revealed a complete metabolic response to BR therapy. Her oncologist recommended ongoing surveillance without the need for rituximab maintenance therapy.

Although liver enzymes normalized during treatment, HCV RNA level remained elevated at 73,500,500 IU/mL when checked on February 27, 2026, consistent with persistent viremia. The patient reported adherence to medication, denied missed doses, and remained highly engaged in her medical care. She also denied recent HCV exposure and believed her infection was most likely related to her remote exposure many years earlier. Further investigation revealed no use of proton pump inhibitors, H₂ receptor antagonists, or herbal supplements during therapy. Resistance testing for NS5A‐associated substitutions was negative, and hepatic imaging revealed no cirrhosis. Given persistent viremia despite the absence of baseline resistance‐associated substitutions or significant drug–drug interactions, the patient was started on 12‐week salvage therapy with sofosbuvir/velpatasvir/voxilaprevir (VOSEVI) beginning on April 28, 2026.

5. Discussion

Patients receiving lymphoma‐directed immunochemotherapy appear to be at particularly high risk for HCV viral flare and clinically significant hepatitis. Rituximab‐containing regimens have consistently emerged as strong predictors of elevated HCV RNA levels, and the BR combination may represent one of the highest‐risk regimens reported to date [2]. The proposed mechanism relates to profound and prolonged immunosuppression. Rituximab induces prolonged B‐cell depletion, whereas bendamustine causes sustained CD4+ and CD8+ T‐cell lymphopenia that may persist for months after completion of therapy [5].

These immunologic effects may be particularly relevant in HCV infection as B‐lymphocytes have been identified as potential extrahepatic reservoirs for HCV, and rituximab‐induced lysis of infected B‐cells may contribute to abrupt increases in circulating viral burden [6]. Simultaneously, depletion of CD4+ and CD8+ T‐cell populations may impair immune‐mediated viral control, as effective clearance of HCV depends heavily on intact host cellular immunity [5]. This combination of increased viral release and impaired immune surveillance may explain the extraordinarily high viral load observed in our patient during BR therapy.

The introduction of DAA has significantly transformed the management of HCV infection. Sofosbuvir/velpatasvir is a pan‐genotypic regimen associated with SVR rates exceeding 95% in treatment‐naive patients [7, 8, 9]. Current evidence suggests that DAAs can be safely administered before, during, or after chemotherapy, although optimal timing remains individualized based on malignancy urgency, liver function, and potential drug–drug interactions [7, 8].

Interestingly, some HCV‐associated lymphomas, specifically low‐grade indolent B‐cell non‐Hodgkin marginal‐zone lymphomas may respond favorably to DAA therapy [10]. Some authorities recommend prescribing DAA therapy first as the primary lymphoma treatment, then reassessing for both HCV clearance and lymphoma response [11].

Failure of sofosbuvir/velpatasvir in treatment‐naive patients without cirrhosis remains uncommon (less than 2%) [9]. Potential explanations include pharmacokinetic interactions, impaired absorption, viral resistance‐associated substitutions, or difficult‐to‐treat genotypes. In this case, these possibilities were systematically evaluated and considered unlikely. No clinically significant pharmacokinetic interactions between bendamustine, rituximab, and sofosbuvir/velpatasvir have been identified in currently available interaction databases or prescribing information [12].

Given the absence of traditional predictors of DAA failure, this case raises the possibility that profound immunosuppression from BR therapy may have contributed to persistent HCV viremia despite otherwise appropriate antiviral treatment. Although DAAs directly inhibit viral replication, successful clearance of residual virus may still depend, in part, on recovery of host immune function. Severe and prolonged depletion of both B‐cell and T‐cell populations during BR therapy may therefore impair complete viral clearance and facilitate persistent viremia despite suppression of viral replication.

Current guidelines and recommendations from the 9th European Conference on Infections in Leukemia suggest that concurrent DAA treatment may be preferable to delayed therapy in many patients receiving cancer treatment provided that drug–drug interactions are carefully reviewed [11]. To our knowledge, few reports have described persistent high‐level viremia following completion of sofosbuvir/velpatasvir in a treatment‐naïve, non‐cirrhotic patient receiving BR immunochemotherapy. Thus, this case highlights several important clinical considerations. First, patients receiving BR therapy may represent a uniquely high‐risk population for HCV viral flare during chemotherapy. Second, these patients may benefit from pre‐chemotherapy HCV screening and treatment, consistent with current recommendations. Third, standard‐duration DAA therapy may be insufficient in selected patients receiving highly lymphocyte‐depleting regimens; however, whether extended DAA therapy is beneficial in this population remains unknown and warrants future investigation. Fourth, initiation of DAA therapy before or after immunochemotherapy, rather than concurrently, may be considered in selected patients. Fifth, considering that viral clearance may be impaired, patients with profound immunosuppression may benefit from additional HCV RNA monitoring beyond the standard 12‐week assessment until further evidence becomes available. Finally, persistent viremia after DAA therapy in this setting should prompt repeat genotype testing and resistance evaluation.

6. Conclusion

This case suggests that profound BR‐induced immune depletion may have contributed to persistent HCV viremia despite otherwise appropriate DAA therapy. As a single case report, this observation demonstrates only a temporal association and cannot establish a causality. Nevertheless, the case presents an important clinical hypothesis that warrants further investigation.

Author Contributions

Chisom J. Orakwue: conceptualization, writing – original draft, writing – review and editing, investigation. Rade N. Pejic: conceptualization, writing – original draft, writing – review and editing, supervision, investigation.

Funding

The authors have nothing to report.

Consent

Written informed consent was obtained from the patient for publication of this case report.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.