HIV-Associated Lymphoma

AIDS-defining and non-AIDS-defining lymphomas in people living with HIV — improved outcomes with ART, full-dose chemoimmunotherapy, and unique CNS and infectious considerations

Key Points

• People living with HIV (PLWH) have a 50–150-fold increased risk of non-Hodgkin lymphoma compared to the general population; lymphoma is now the leading cause of cancer-related death in PLWH in the ART era.
• The most common HIV-associated lymphomas are DLBCL (~30%), Burkitt lymphoma (~30%), and primary CNS lymphoma (~20%); Hodgkin lymphoma is also significantly elevated (~10–15× background risk) though it is not AIDS-defining.
• Highly active antiretroviral therapy (ART) has dramatically improved outcomes for HIV-associated lymphoma — modern PLWH with controlled viremia and adequate CD4 counts tolerate and respond to standard-dose R-CHOP similarly to HIV-negative patients.
• Full-dose rituximab plus anthracycline-based chemotherapy (R-CHOP, DA-EPOCH-R) is the standard of care for most HIV-associated B-cell NHL; older concerns about excessive infectious toxicity with rituximab in PLWH are not supported by contemporary data when CD4 counts are ≥50/µL.
• Concurrent ART is maintained throughout chemotherapy, with attention to drug-drug interactions (particularly between PIs/NNRTIs and chemotherapy agents metabolized by CYP3A4); integrase strand transfer inhibitors (INSTIs) have fewer interactions and are preferred.
• Primary CNS lymphoma in PLWH occurs at much lower CD4 counts (median ~30/µL) than systemic NHL and is nearly universally EBV-driven; HD-MTX–based therapy and CNS-directed consolidation are the cornerstones of treatment.

Epidemiology and Pathogenesis

The association between HIV and lymphoma reflects the dual role of HIV-driven immunosuppression in impairing tumor immunosurveillance and the oncogenic activity of co-infecting viruses (EBV, HHV-8/KSHV) in driving B-cell transformation. **Pre-ART era:** NHL incidence in HIV was 50–150× the general population; CD4 counts were low, EBV reactivation uncontrolled, and median survival after lymphoma diagnosis was 200/µL: DLBCL, HL, Burkitt lymphoma (systemic), plasmablastic lymphoma - CD4 50–200/µL: All of the above + increased incidence of all subtypes - CD4 90%; similar to sporadic BL but with…

Major HIV-Associated Lymphoma Subtypes

**HIV-Associated DLBCL (~30% of HIV-NHL):** Presentation mirrors HIV-negative DLBCL but with more extranodal disease (CNS, GI, bone marrow), more frequent B symptoms, and higher IPI scores at diagnosis. Two pathogenic subtypes: centroblastic (GC-like) with CD4 >100 and immunoblastic (non-GC) with lower CD4. Treat with R-CHOP × 6 cycles (or DA-EPOCH-R for double-hit features). ART concurrent. Outcomes in ART era approach HIV-negative patients: 2-year OS ~55–70% with contemporary therapy. **HIV-Associated Burkitt Lymphoma (~30% of HIV-NHL):** Paradoxically occurs at higher CD4 counts than…

Diagnosis and Staging

Diagnosis follows the same principles as the corresponding lymphoma subtype in immunocompetent hosts, with additional HIV-specific considerations: **Mandatory baseline assessments:** - HIV viral load and CD4+ T-cell count - ART history, current regimen, and drug-resistance genotype if viremia is unsuppressed - EBV DNA (plasma), HHV-8 serology (if PEL or MCD suspected), HBV surface antigen/core antibody (HBsAg, anti-HBc — rituximab may cause HBV reactivation), HCV antibody - CMV DNA (risk of reactivation with immunosuppression) - Cryptococcal antigen (if CD4 1 extranodal site should undergo…

Treatment Principles and ART Interactions

**Principle 1: Full-dose chemotherapy is the standard.** Early studies showing excess toxicity with rituximab in HIV-NHL (ACTG 5142 — CD4 1 extranodal site DLBCL should receive IT MTX prophylaxis. IV HD-MTX for double-hit and very high-risk DLBCL.

Prognosis and Long-term Considerations

The ART era has transformed outcomes for HIV-associated lymphoma: - **HIV-DLBCL:** 2-year OS ~55–70% with R-CHOP + ART; approaching HIV-negative DLBCL outcomes in patients with CD4 >100/µL and controlled viremia - **HIV-Burkitt lymphoma:** 3-year OS ~60–70% with intensive regimens + ART; curative in a significant proportion - **HIV-HL:** 5-year OS ~70–80% with ABVD or BV-AVD + ART, similar to HIV-negative HL - **PCNSL in HIV:** 1-year OS ~30–50% with HD-MTX + ART; substantially worse than immunocompetent PCNSL - **PEL and PBL:** Median OS <6–12 months; emerging targeted therapies under…