From Persistent to Undetectable: Cerebrospinal Fluid CMV DNA Clearance During PD-1 Blockade treatment With Sintilimab in a HIV-Associated Lymphoma Patient

Technical Summary: Cerebrospinal Fluid CMV DNA Clearance During PD-1 Blockade in an HIV-Associated Lymphoma Patient

Problem Statement
Cytomegalovirus (CMV) neurologic disease is a severe, life-threatening complication of advanced HIV infection, particularly when co-occurring with hematologic malignancies and profound cellular immunodeficiency (CD4⁺ T-cell counts <100 cells/µL). Management is complicated by limited evidence regarding the safety and virologic outcomes of using Programmed cell death protein 1 (PD-1) blockade in patients with active or residual central nervous system (CNS) opportunistic infections. Specifically, the implications of administering PD-1 inhibitors (such as sintilimab) when low-level CMV DNA remains detectable in the cerebrospinal fluid (CSF) are unknown. Existing literature offers only indirect evidence and lacks data on the virologic course or safety of such interventions in this specific clinical context.

Methodology
This study presents a detailed case report of a 57-year-old male patient with HIV-associated, Epstein-Barr virus (EBV)-encoded RNA-positive diffuse large B-cell lymphoma (DLBCL). The patient exhibited persistent severe cellular immunodeficiency (CD4⁺ T-cell counts consistently below 100 cells/µL) despite antiretroviral therapy (ART) and chemotherapy.

The clinical course involved:

1. Diagnosis: The patient developed fever, dizziness, and somnolence. Diagnostic workup revealed a massive disparity in CMV viral loads: CSF CMV DNA was 1.53 × 10⁷ IU/mL, while paired plasma was 96,000 IU/mL. Major alternative CNS opportunistic infections and CNS lymphoma were excluded, leading to a diagnosis of probable CNS CMV disease.
2. Antiviral Therapy: The patient received prolonged, sequential anti-CMV therapy, including oral ganciclovir, oral valganciclovir, intravenous ganciclovir, and intravenous foscarnet.
3. Intervention: After CSF CMV DNA was reduced to 150 IU/mL (still detectable) one day prior to the intervention, the patient received sintilimab (100 mg intravenously) on three occasions (February 25, March 27, and April 24, 2025) as consolidation therapy for lymphoma.
4. Monitoring: The study employed longitudinal monitoring of:
   • Virologic markers: Serial quantitative PCR for CMV DNA in both plasma and CSF.
   • Immunologic markers: Peripheral blood absolute T-cell counts, phenotypic subsets (effector, effector-memory, PD-1⁺ fractions), and CSF cytokine concentrations (IFN-γ, IL-8, IL-6, TNF-α).
   • Clinical status: Neurologic symptoms, CMV end-organ disease, and signs of inflammatory worsening.

Key Results

• Virologic Clearance: While antiviral therapy successfully reduced CSF CMV DNA from 1.53 × 10⁷ IU/mL to 150 IU/mL prior to sintilimab administration, the virus remained detectable. The CSF CMV DNA was first documented as undetectable 27 days after the first sintilimab dose (March 24, 2025) and remained undetectable through October 2025. Plasma CMV DNA had become undetectable earlier (March 4, 2025).
• Immunologic Dynamics:
  • CD8⁺ T-cells: The absolute peripheral CD8⁺ T-cell count increased from a pre-sintilimab nadir. There was an early enrichment of the effector CD8⁺ T-cell compartment (increasing from Day +1 to Day +27) followed by a modest partial recovery of the effector-memory compartment by Day +58.
  • PD-1⁺ Subsets: PD-1⁺ T-cell subsets exhibited non-monotonic, subset-specific changes. CD3⁺PD-1⁺ and CD8⁺PD-1⁺ fractions decreased markedly by Day +7 and remained low at Day +27, while CD4⁺PD-1⁺ declined later. All subsets showed partial recovery by Day +58.
  • CSF Cytokines: CSF IFN-γ and IL-8 increased over time; IL-6 rose and then partially declined; TNF-α remained low.
• Safety: Despite these immunologic shifts and the administration of PD-1 blockade while low-level CSF CMV DNA was detectable, the patient experienced no clinical worsening of CMV disease, no neurologic deterioration, and no clinically significant inflammatory syndrome.

Key Contributions

• Clinical Observation: This report documents the first known case of a patient with HIV-associated lymphoma and probable CNS CMV disease receiving PD-1 blockade (sintilimab) while low-level CSF CMV DNA (150 IU/mL) remained detectable.
• Temporal Association: The study highlights a temporal sequence where the transition of residual CSF CMV DNA to undetectability occurred 27 days after the initiation of sintilimab, coinciding with specific peripheral T-cell phenotypic remodeling (effector enrichment) and dynamic CSF cytokine activation.
• Safety Data: It provides limited tolerability information suggesting that PD-1 blockade may be administered under continued antiviral coverage with a low residual CSF viral burden without precipitating inflammatory worsening or clinical relapse of CMV disease in this specific context.

Significance and Claims
The authors explicitly state that the overall virologic decline is primarily attributable to the prolonged anti-CMV therapy (ganciclovir and foscarnet), which achieved a ~5.0-log10 reduction before sintilimab was introduced. Consequently, the paper does not claim that sintilimab definitively caused the clearance of the virus.

Instead, the paper posits a hypothesis: The temporal association among PD-1 blockade, transient T-cell immunophenotypic remodeling, and the first documented undetectable CSF CMV DNA result suggests that sintilimab-associated immune modulation may have contributed to the final conversion of residual low-level CSF CMV DNA to undetectability.

The authors emphasize that causality cannot be established due to substantial confounders, including ongoing antiviral therapy, ART-related immune recovery, and the completion of chemotherapy. The report serves as a hypothesis-generating case study, noting that while the observed pattern is biologically plausible (based on the restoration of T-cell function via PD-1 blockade), it requires validation in controlled studies with standardized baselines and CMV-specific immune endpoints. The findings are not extrapolated to patients with uncontrolled or high-viral-load CNS CMV disease.