Three lymphoma patients suffering from immune suppression caused by anti-CD20 antibody treatment experienced long-lasting COVID-19 infections that continually returned despite treatment with remdesivir, and every single case only saw recovery following a transition to ensitrelvir, an oral antiviral agent that inhibits the SARS-CoV-2 3-chymotrypsin-like protease.
Persistent COVID-19 in immunocompromised patients creates a difficult therapeutic challenge because impaired humoral immunity—specifically a lack of functional B-cells—prevents adequate viral clearance.
Antivirals Target Different Viral Mechanisms
- Different Targets: Remdesivir stops the virus by blocking its RNA polymerase (copying machine). Ensitrelvir works differently by blocking the 3CL protease (an enzyme the virus needs to process its proteins).
- B-Cell Depletion: Patients treated with anti-CD20 therapies like rituximab or obinutuzumab lose the B-cells that normally manufacture antibodies, leaving them vulnerable to long-lasting viral infections.
- Salvage Therapy: Switching to an antiviral with a completely different mechanism of action offers a potential fallback option when standard treatments fail to clear the infection.
Clinical Profiles and Treatment Failures in Follicular Lymphoma Patients
The case series, published in Respirology Case Reports, details three men with follicular lymphoma who experienced persistent SARS-CoV-2 infections following anti-CD20 therapy. The first patient, a 65-year-old man, received multiple rounds of rituximab regimens for Grade 2 follicular lymphoma. He contracted COVID-19 in March 2024. Although an initial course of remdesivir paired with prednisolone temporarily resolved his upper respiratory symptoms, his illness relapsed repeatedly. On Day 63, during his third relapse, clinicians administered ensitrelvir, leading to complete resolution.
The second patient, an 81-year-old man with advanced follicular lymphoma that transformed to Grade 3B, had previously received bendamustine and obinutuzumab. In October 2023, he developed an XBB.1 lineage infection that progressed to respiratory failure by Day 31. Remdesivir, steroid pulse therapy, and azithromycin provided only transient relief. Ensitrelvir was administered at his third relapse on Day 83, preventing further recurrences.
The third patient, a 59-year-old man with Grade 3A follicular lymphoma, was undergoing obinutuzumab maintenance therapy when he contracted COVID-19 in March 2025. Laboratory testing revealed a profoundly compromised immune status with an absolute CD19-positive B-cell count of 0.2 cells per microliter. His infection brought recurrent fever and pneumonia that resisted remdesivir, dexamethasone, and levofloxacin. Ensitrelvir was initiated on Day 49 of his second relapse, halting the cycle of clinical deterioration.
| Patient | Lymphoma Type | Prior Anti-CD20 Therapy | Initial Failed Antiviral | Ensitrelvir Administration |
|---|---|---|---|---|
| Patient 1 (65yo) | Grade 2 Follicular Lymphoma | Rituximab maintenance | Remdesivir | Day 63 (Third relapse) |
| Patient 2 (81yo) | Grade 3B Follicular Lymphoma | Bendamustine-obinutuzumab | Remdesivir | Day 83 (Third relapse) |
| Patient 3 (59yo) | Grade 3A Follicular Lymphoma | Obinutuzumab maintenance | Remdesivir | Day 49 (Second relapse) |
Ensitrelvir Inhibits Crucial Viral Protease
The rationale for switching to ensitrelvir rests on the fundamental differences in how these therapeutics disrupt the viral life cycle. While remdesivir and molnupiravir inhibit the RNA-dependent RNA polymerase, ensitrelvir specifically inhibits the SARS-CoV-2 3-chymotrypsin-like protease (3CL protease). This enzyme is essential for cleaving viral polyproteins during replication.
Beyond direct antiviral activity, the 3CL protease is implicated in antagonizing host innate immunity and driving excessive inflammatory responses. Research indicates that reductions in inflammatory cytokine and chemokine production correlate with the antiviral effects of ensitrelvir, suggesting an additional anti-inflammatory mechanism. While systemic corticosteroids were administered to these patients, high doses alone had failed to resolve fevers prior to the introduction of the protease inhibitor.
Despite these promising outcomes, the authors of the report highlight significant limitations. The sample size is restricted to three cases, genomic and resistance analyses were absent, and cost constraints limited follow-up polymerase chain reaction testing to confirm true virological clearance. The absence of a controlled, systematic comparison with other lymphoma patients treated with remdesivir means these observations cannot yet be confirmed as definitive proof of superiority outside of a controlled trial setting.
Ensitrelvir Helps Immunocompromised Patients Recover
Patients receiving B-cell-depleting therapies such as rituximab or obinutuzumab face unique risks from persistent viral pathogens. Patients with follicular lymphoma and depleted immune systems who experience persistent COVID-19 and recurrent symptoms after an initial diagnosis may show improvement after being switched to ensitrelvir, an oral inhibitor of the SARS-CoV-2 3-chymotrypsin-like protease.
References
- Horie, M. et al. (2026). Persistent Coronavirus Disease 2019 (COVID-19) in Patients With Malignant Lymphoma Treated With Anti-CD20 Antibodies Who Responded to Ensitrelvir: A Report of Three Cases. Respirology Case Reports, 14(11), Article e70804.
