Can rituximab be given to an HIV‑positive patient with a low CD4 count (e.g., <200 cells/µL) for CD20‑positive lymphoma or severe autoimmune disease, and what precautions, prophylaxis, and monitoring are required?

Rituximab in HIV-Positive Patients with Low CD4 Count

Rituximab can be given to HIV-positive patients with CD4 counts ≥50 cells/µL for CD20-positive lymphomas, but should be used with extreme caution—or delayed—when CD4 counts fall below 50 cells/µL due to a significantly elevated risk of fatal opportunistic infections. 1

CD4 Count Thresholds for Rituximab Use

CD4 ≥50 cells/µL: Rituximab Recommended

• Rituximab should be routinely combined with chemotherapy for HIV-associated diffuse large B-cell lymphoma (DLBCL) when CD4 counts are ≥50 cells/µL. 1
• Standard regimens include R-CHOP (six cycles every 3 weeks) or dose-adjusted R-EPOCH (six cycles). 1
• The benefit of rituximab in improving overall survival and progression-free survival outweighs infection risk at this threshold. 2

CD4 <50 cells/µL: High-Risk Zone

• The 2024 EHA-ESMO guidelines explicitly state that rituximab should be used with caution in patients with CD4 <50 cells/µL and may need to be delayed after a few courses of chemotherapy alone (e.g., etoposide). 1
• A landmark phase III trial (AMC-010) demonstrated that rituximab increased treatment-related infectious deaths to 14% (versus 2% with chemotherapy alone), with 60% of these deaths occurring in patients with CD4 <50 cells/µL. 3
• A large retrospective analysis showed no overall survival benefit from rituximab when CD4 counts were <50 cells/µL, and documented increased risk of lethal infections. 1

Special Context: HHV-8-Associated Multicentric Castleman Disease (MCD)

• For HHV-8-MCD, rituximab is first-line therapy and improves outcomes even in severely immunosuppressed patients. 1
• However, rituximab should still be used with caution when CD4 <50 cells/µL and may be delayed after initial etoposide cycles to reduce cytokine storm risk. 1
• Rituximab reduces the risk of subsequent lymphoma development in MCD, which may justify its use despite low CD4 counts in this specific disease. 1

Mandatory Precautions and Prophylaxis

Pre-Treatment Screening (All Patients)

• Screen for hepatitis B virus (HBV) before rituximab initiation, as reactivation can cause fulminant liver failure and death. 4, 5
• Obtain baseline immunoglobulin levels and complete blood count. 4
• Screen for tuberculosis in immunocompromised patients. 4
• Ensure HIV viral load is suppressed on antiretroviral therapy (ART). 1

Infection Prophylaxis During Treatment

• Initiate Pneumocystis jirovecii pneumonia (PCP) prophylaxis with trimethoprim-sulfamethoxazole for all patients receiving rituximab-based chemotherapy, particularly with bendamustine-rituximab regimens. 6, 4
• Consider broad antibacterial and antiviral prophylaxis given the high infection risk with rituximab-chemotherapy combinations. 6
• For patients with CD4 <200 cells/µL, continue PCP prophylaxis until CD4 recovers above 200 cells/µL. 7
• Weekly CMV screening (PCR or antigenemia) is recommended for patients with severe lymphopenia (grade 3-4). 7

Monitoring Requirements

• Obtain complete blood count with differential every 2-4 months during treatment. 4
• Monitor for cytopenias, as rituximab causes B-cell depletion lasting 6-12 months. 4
• Maintain high vigilance for opportunistic infections, including progressive multifocal leukoencephalopathy (PML), a rare but fatal complication. 4, 5

Evidence Reconciliation: Conflicting Data

The evidence shows a clear divergence based on CD4 thresholds:

• Supportive evidence for rituximab use: A German multicenter cohort (n=163) found that rituximab improved overall survival and progression-free survival even in patients with CD4 <100 cells/µL, with no increase in fatal infections. 2 This study contradicts earlier findings.

• Cautionary evidence against rituximab: The AMC-010 randomized trial demonstrated increased infectious deaths with rituximab when CD4 <50 cells/µL, with no improvement in progression-free survival or overall survival. 3 A systematic review and meta-analysis found no overall increase in severe infections across all patients, but acknowledged lack of data in HIV-positive subgroups. 8

The most recent and highest-quality guideline (2024 EHA-ESMO) prioritizes the cautionary approach, recommending rituximab be used with caution or delayed when CD4 <50 cells/µL. 1 This represents the current standard of care.

Clinical Algorithm for Decision-Making

1. Confirm CD20-positive disease by flow cytometry or immunohistochemistry.
2. Check CD4 count:
   • If CD4 ≥50 cells/µL → Proceed with rituximab plus chemotherapy
   • If CD4 <50 cells/µL → Consider delaying rituximab until after initial chemotherapy cycles (e.g., 2-4 cycles of chemotherapy alone), then reassess CD4 count
3. Ensure HIV viral suppression on ART before starting rituximab. 1
4. Screen for HBV and initiate preemptive antiviral therapy if positive. 4, 5
5. Initiate PCP prophylaxis with trimethoprim-sulfamethoxazole. 6, 4
6. Monitor weekly for infections and cytopenias during treatment. 7, 4

Common Pitfalls to Avoid

• Do not withhold rituximab solely based on low CD4 count if the patient has HHV-8-MCD, as the disease itself is life-threatening and rituximab improves outcomes. 1
• Do not assume that rituximab is contraindicated in all HIV-positive patients—the key threshold is CD4 <50 cells/µL, not HIV status alone. 1
• Do not forget HBV screening, as reactivation can be delayed and fatal. 4, 5
• Do not confuse chronic lymphopenia with chronic lymphocytic leukemia (CLL), which presents with lymphocytosis (>5,000 cells/µL), not lymphopenia. 7