HIV-associated Non-Hodgkin Lymphoma (NHL) is a well-recognized complication of chronic HIV infection [1] . Historically, NHL was considered an AIDS-defining illness occurring predominantly in patients with CD4 counts <200 cells/μL [2] . However, accumulating evidence suggests that lymphomas may also develop in patients with higher CD4 counts, particularly when other risk factors are present, such as persistent immune activation, chronic inflammation, and co-infection with oncogenic viruses like Epstein-Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV), or human T-cell leukemia virus type 1 (HTLV-1) [3] .

The pathogenesis of lymphoma in HIV-infected individuals with preserved immunity is multifactorial and includes:

1) Chronic Immune Activation and Inflammation

Even in the absence of profound CD4 depletion, untreated HIV leads to persistent immune activation and systemic inflammation. This is driven by continuous viral replication, microbial translocation due to gut mucosal barrier damage, and dysregulated cytokine production [4] . Chronic inflammation creates a permissive environment for malignant transformation by promoting DNA damage, cell proliferation, and resistance to apoptosis [5] .

2) Epstein-Barr Virus (EBV) Co-Infection

EBV is strongly implicated in the pathogenesis of many HIV-associated lymphomas, particularly Burkitt lymphoma and Diffuse Large B-Cell Lymphoma (DLBCL). The virus has potent transforming properties via latent gene expression, including the upregulation of anti-apoptotic proteins such as Bcl-2 and LMP-1, which mimic activated CD40 signaling [6] . In our patient, although EBV, KSHV, and HTLV-1 PCR/serology were not performed due to limited local laboratory capacity, the presence of high-grade B-cell lymphoma raises the possibility of underlying EBV-driven oncogenesis.

3) Impaired Immune Surveillance

HIV causes qualitative defects in both adaptive and innate immunity long before CD4 counts fall below critical thresholds. These include:

These impairments allow for unchecked clonal expansion of transformed B-cells and reduced clearance of EBV-infected cells, contributing to lymphomagenesis even in the setting of relatively normal CD4 counts [7] .

4) Significance of Antiretroviral Therapy (ART) Initiation Timing

Late initiation of ART allows for prolonged periods of uncontrolled viraemia and immune dysfunction, increasing the risk of malignancy. Our patient had no prior diagnosis or treatment for HIV, suggesting a long-standing untreated infection. Early ART initiation has been shown to significantly reduce the incidence of NHL by restoring immune function and reducing systemic inflammation [8] .

5) Persistent Immune Activation and B-Cell Dysregulation in HIV

Even in the era of effective Antiretroviral Therapy (ART), individuals with HIV exhibit persistent immune activation and B-cell dysregulation, which contribute to an elevated risk of non-Hodgkin lymphoma independent of CD4 count. Chronic antigenic stimulation, microbial translocation, and residual viral replication drive a pro-inflammatory milieu that promotes genomic instability and aberrant B-cell proliferation. A recent prospective cohort study by Anastos et al. (2022) demonstrated that elevated levels of soluble CD14, IL-6, and B-cell activating factor (BAFF) were independently associated with increased lymphoma risk among HIV-positive individuals, even those with sustained viral suppression and CD4 counts >500 cells/μL. This supports the notion that qualitative immune dysfunction—not just quantitative CD4 depletion—plays a central role in lymphomagenesis, reinforcing the importance of early diagnosis and comprehensive immune profiling in at-risk patients [9] .

6) Advances in Risk Stratification and Management of HIV-Associated Lymphoma

Recent advances in the management of HIV-associated lymphomas emphasize the importance of early integration of oncology and infectious disease care, as outcomes now closely mirror those of HIV-negative patients when treated with combined ART and risk-adapted chemotherapy. A 2023 review by Patel et al. highlighted that dose-adjusted EPOCH-R and DA-EPOCH regimens have significantly improved survival in aggressive B-cell lymphomas among people living with HIV, particularly when ART is initiated promptly and drug interactions are carefully managed. Furthermore, the authors advocate for routine use of PET-CT and molecular profiling (e.g., MYC/BCL2/BCL6 FISH) to guide risk stratification, although such tools may not be available in resource-limited settings. This underscores the need for equitable access to advanced diagnostics and multidisciplinary care models to improve outcomes globally [10] .

HIV-positive patients are susceptible to multiple Opportunistic Infections (OIs) that mimic lymphoma clinically and radiologically, including:

In this case, the presence of positive Toxoplasma IgG, CMV IgG, and syphilis serology complicated the differential diagnosis. Additionally, the CNS imaging findings were nonspecific, necessitating CSF analysis and bone marrow evaluation for definitive diagnosis.

The empiric initiation of antimicrobials was justified by the high pretest probability of opportunistic infections in a newly diagnosed HIV patient with neurological symptoms and nonspecific CNS lesions. Alternative infections were definitively excluded through negative CSF cultures (bacterial, fungal, TB), lack of response to empiric therapy, and progression of systemic and neurological findings despite antimicrobial coverage, which ultimately shifted the clinical suspicion toward malignancy.

Bone marrow involvement occurs in approximately 20% - 30% of HIV-associated NHL cases [11] . Our patient demonstrated extensive marrow infiltration with hemophagocytosis, leading to pancytopenia and a leucoerythroblastic picture. This finding underscores the aggressive nature of the disease despite preserved immunity.

This case emphasizes the need for: