HIV-associated B cell lymphoma

HIV-associated aggressive B-cell lymphomas (HIV-NHL) are AIDS-defining and the second most common HIV-associated neoplasm after Kaposi's sarcoma. In contrast, Hodgkin's lymphoma is among the most common non-AIDS-defining malignancies (Morlat P et al. 2000).

The staging of HIV-NHL is done according to the Ann Arbor classification.

The WHO classification distinguishes lymphomas that also occur in immunocompetent patients from those that are predominantly diagnosed in patients with HIV.

The most common representatives are:

• Diffuse large B-cell lymphoma (DLBCL)
• Burkitt's lymphoma. In HIV-associated BL, disseminated (secondary) skin involvement has also been described (de Masson A et al. (2016) See primary cutaneous Burkitt's lymphoma. Granulomatous lymph node reactions in Burkitt's lymphoma are interpreted as prognostically benign signs (Li JN et al. (2014).
• Effusion lymphoma (PEL) with evidence of malignant, usually CD20-negative immunoblastic or anaplastic cells (Guillet S et al (2016).
• Precursor lymphomas such asplasmoblastic lymphomas (PBL).

• Hodgkin's lymphomas.

The incidence of aggressive NHL compared with the HIV-negative population is increased 4- to 16-fold even under optimal treatment conditions (Franceschi S et al. 2010; Park LS et al. 2016). The risk for developing HIV NHL increases with CD4 cell nadir or falling CD4 cell counts and is reduced by sustained viral suppression. The risk of developing HL is increased 7- to 28-fold in HIV-infected individuals (HIV-HL).

In addition to chronic antigen stimulation and cytokine dysregulation, coinfections with oncogenic viruses play an important etiologic role in the development of HIV-associated lymphomas. These include:

• Epstein-Barr virus(HHV-4: detection of EBV genome in 40 - 50 %)
• Human herpes virus 8(HHV-8: detection in 100% of primary effusion lymphomas and Castleman's lymphoma)

The diagnostic steps correspond to those in HIV-negative patients with malignant lymphomas. Approximately 70% of patients are diagnosed in advanced stages. B-symptoms and extranodal involvement are frequently found. According to a retrospective study, 6% of all patients with HIV-DLBCL have CNS involvement (Barta SK et al. 2016).

The therapeutic goal is curative. The treatment depends on the lymphoma entity, the disease stage as well as the general condition and the comorbidity caused by the HIV infection.

Antiretroviral therapy

CART should be continued simultaneously with chemotherapy or initiated with the start of chemotherapy according to the current guidelines on cART (Barta SK 2015; Schommers P 2015; German-Austrian Guidelines on Antiretroviral Therapy of HIV-1 Infection 2017) .

Interactions between chemotherapeutic and antiretroviral substances must be taken into account (potential increase in chemotherapy-associated toxicity). This is especially true for antiretroviral combinations with potent enzyme inducers such as ritonavir-boosted protease inhibitors or cobicistat.

Therefore, if therapy history and resistance situation allow, an integrase inhibitor-based therapy regimen is recommended during chemotherapy, preferably raltegravir in combination with two nucleoside reverse transcriptase inhibitors.

Tenofovir disoproxil fumarate (TDF) should be avoided during platinum-containing chemotherapies (DHAP, ICE) due to the risk of cumulative nephrotoxicity.

PCP prophylaxis preferably with cotrimoxazole is indicated for CD4 cell counts < 200/µl. In contrast, general antibacterial prophylaxis cannot be recommended. The administration of antibacterial, antifungal and antiviral prophylaxis should be based on appropriate guidelines, taking into account the stage of HIV infection or previous opportunistic diseases.

The prognosis of patients with HIV-NHL has improved considerably since the introduction of cART [17, 18, 19, 20]. It is largely determined by the CD4 cell count and the international prognostic index (IPI), which includes the factors age, lymphoma stage, LDH level, extranodal infestation and performance status (PS) (Hoffmann C et al. 2003; Bower M et al. 2005). With a good CD4 cell count and low IPI, HIV infection no longer appears to be prognostic. A high IPI and the presence of CD20-negative NHL are to be regarded as prognostically unfavourable.

Follow-up should follow the recommendations developed for HIV-negative lymphoma patients.

1. Barta SK et al (2016) Central nervous system involvement in AIDS-related lymphomas. Br J Haematol 173: 857-866.
2. Barta S et al (2013) Treatment factors affecting outcomes in HIV-associated non-Hodgkin lymphomas: a pooled analysis of 1546 patients. Blood 122:3251-3262
3. Bower M et al (2005) A prognostic index for systemic AIDS-related non-Hodgkin lymphoma treated in the era of highly active antiretroviral therapy. Ann Intern Med 143: 265-273.
4. German-Austrian guidelines on antiretroviral therapy for HIV-1 infection (2017) . www.awmf.org/leitlinien/detail/ll/055-001.html (version 7 of 29.11.2017).
5. de Masson A et al. (2016) Disseminated skin involvement in HIV-associated Burkitt lymphoma: a rare clinical feature with poor prognosis. Br J Dermatol174:184-186.
6. Franceschi S et al. (2010) Changing patterns of cancer incidence in the early- and late-HAART periods: the Swiss HIV Cohort Study. Br J Cancer 103: 416-422.
7. Guillet S et al (2016) Classic and extracavitary primary effusion lymphoma in 51 HIV-infected patients from a single institution. Am J Hematol 91: 233-237.
8. Hoffmann C et al (2003) Response to highly active antiretroviral therapy strongly predicts outcome in patients with AIDS-related lymphoma. AIDS 17:1521-1529.
9. Li JN et al (2014) HIV-related Burkitt lymphoma with florid granulomatous reaction: an unusual case with good outcome. Int J Clin Exp Pathol 7:7049-7053.
10. Morlat P et al: Causes of death among HIV-infected patients in France in 2010 (national survey): trends since 2000. AIDS 28: 1181-1191.
11. Park LS et al. (2016) Time trends in cancer incidence in persons living with HIV/AIDS in the antiretroviral therapy era: 1997-2012. AIDS 30: 1795-806.
12. Schommers P, Hentrich M, Hoffmann C, et al: Survival of AIDS-related diffuse large B-cell lymphoma, Burkitt lymphoma, and plasmablastic lymphoma in the German HIV Lymphoma Cohort. Br J Haematol 168: 806-810, 2015. DOI:10.1111/bjh.13221.