Persistent COVID-19 cleared after switch to ensitrelvir in three lymphoma patients on anti-CD20 therapy
Three men with follicular lymphoma whose immune systems had been depleted by anti-CD20 antibody therapy recovered from persistent COVID-19 only after doctors switched them from remdesivir to ensitrelvir, an oral antiviral that attacks the virus through a different mechanism, according to a case series published in Respirology Case Reports, bioengineer.org reported.
Each patient had developed prolonged COVID-19 — marked by weeks of viral detection and repeated fever, low oxygen and pneumonia — after B-cell-depleting treatment with rituximab or obinutuzumab. Remdesivir brought temporary relief in all three cases, but symptoms relapsed each time the drug was stopped. When ensitrelvir was given during later relapses, symptoms resolved without further recurrence.
Remdesivir failed repeatedly before ensitrelvir worked
The first patient, a 65-year-old man whose last rituximab dose came one month before infection in March 2024, was hospitalized on Day 22 with fever and hypoxemia. Remdesivir plus prednisolone improved his symptoms, but relapse followed discontinuation. On Day 63, during his third relapse, ensitrelvir produced complete resolution.
The second patient, an 81-year-old man last treated with obinutuzumab 20 months before infection in October 2023, developed respiratory failure on Day 31. Remdesivir, steroid pulse therapy and azithromycin helped only transiently. Ensitrelvir on Day 83 prevented further recurrences.
The third patient, a 59-year-old man whose fifth obinutuzumab dose came one month before infection in March 2025, was admitted on Day 6 with persistent fever. Remdesivir, dexamethasone and levofloxacin produced temporary improvement, but fever and pneumonia recurred twice. Ensitrelvir, started at the second relapse on Day 49, led to improvement with no further relapse.
Different viral target may explain the switch
The mechanistic rationale rests on divergent drug targets. Remdesivir inhibits the SARS-CoV-2 RNA-dependent RNA polymerase, while ensitrelvir blocks the 3-chymotrypsin-like protease, which cleaves viral polyproteins during replication. The study authors note the protease has also been reported to antagonize innate immunity and drive excessive inflammatory responses, and that reduced cytokine production correlates with ensitrelvir’s antiviral effect — suggesting the drug may also dampen inflammation.
Because anti-CD20 therapy strips away the B-cell immunity needed for viral clearance, these patients often cannot eliminate the virus on their own, making the choice of antiviral mechanism critical when the first agent fails.
Small sample and missing resistance data limit conclusions
The authors caution that the series is small, genomic and resistance analyses were absent, and limited follow-up PCR testing means clinical improvement cannot be equated with proven elimination of replicating virus. They also did not systematically compare these patients with others treated with remdesivir at their institution. The authors conclude ensitrelvir may represent a salvage option for remdesivir-refractory persistent COVID-19 in patients on anti-CD20 therapy, but larger studies are required.
How ensitrelvir performs in high-risk patients
What is ensitrelvir? It is an oral inhibitor of the SARS-CoV-2 3-chymotrypsin-like protease, shown in trials to shorten symptom duration and reduce viral load in mild-to-moderate COVID-19.
The case series describes patients with B-cell-depleted immune systems — here, follicular lymphoma patients on rituximab or obinutuzumab — whose persistent COVID-19 relapsed despite remdesivir.
Is ensitrelvir proven for this use? No. The report is a three-patient case series without resistance testing or a control group, so the authors call for larger studies before drawing firm conclusions.
Persistent COVID-19 in B-cell-depleted patients has long posed a therapeutic challenge, and this report adds to a small but growing set of cases in which switching antiviral mechanisms appeared to break the relapse cycle.