The Role of Lymphomas in Subsequent Primary Cancers in People with HIV/AIDS: An Australian National Population-Based Data Linkage Study
Authors: Di Ciaccio Pietro R , Jin Fengyi , Law Matthew , Van Leeuwen Marina , Grulich Andrew , Amin Janaki , Vajdic Claire , McGregor Skye , Polizzotto Mark N. 
Published: November 2020

Background
Despite combination antiretroviral therapy (cART), the incidence of lymphomas remains elevated in persons with HIV/AIDS (PWHA).
While the risk of subsequent primary cancers (SPCs) in the general population is well understood, these data are lacking for PWHA. Underlying aetiologic factors in PWHA, including oncogenic viruses and immunodeficiency, may have a differential impact on SPCs.
We conducted a nationwide data linkage study in order to examine the role of lymphoma in SPCs in PWHA in two ways. First, we determined the incidence of and risk factors for Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) (including chronic lymphocytic leukaemia) in PWHA previously diagnosed with an initial cancer of any type. Second, we assessed the incidence and features of SPCs of any type in PWHA after a primary HL or NHL.
Methods
Since 1982 Australia has had compulsory disease notification of all new HIV infections and all invasive cancers. We conducted a probabilistic data linkage study between the Australian National HIV Registry, the Australian Cancer Database and National Death Index to identify PWHA diagnosed with an initial cancer, followed by at least one SPC between 1982 and 2012. Follow up commenced from 90 days post the date of first cancer diagnosis at or following HIV diagnosis, and ended on 31 December 2012 or death, whichever came earlier. A SPC was defined as a cancer of diverse site and histology to the first cancer and diagnosed more than 90 days later (in order to mitigate ascertainment bias).
The incidence of SPC was compared using Poisson regression. Risk factors considered included: age, sex, HIV exposure modality (such as male-to-male, intravenous drug, etc.) and CD4+ cell count at HIV diagnosis (&lt;50, 50-199, 200-499, &gt;500 cells/µL). Incidence was also compared across various eras corresponding to HIV treatment advances: 1982-1995 (pre-cART); 1996-1999 (early-cART); 2000-2004 (availability of protease inhibitors for HIV); and, 2005-2012 (availability of fusion inhibitors for HIV and rituximab for CD20-positive lymphomas).
Results
Out of 28,696 PWHA, 3,548 were identified with a first cancer. Among them, 229 SPCs were identified over 27,398 person-years (PY) of follow-up. The crude incidence of SPCs was 8.36 per 1000 PY (95% CI 7.34-9.51). Of 229 SPCs, 88 were lymphomas, comprising 42 diffuse large B cell, 4 Burkitt, 3 T cell, 2 primary effusion, 3 low grade lymphomas and 5 HLs; 29 NHLs were not sub-classified in the Database. The majority of first cancers in the group with SPCs were Kaposi sarcoma (KS) (55%).
The incidence of lymphoma as an SPC decreased from 8.10 to 0.79 per 1000 PY from 1982-1995 to 2005-2012 (p=0.003). Median time from first cancer diagnosis to the diagnosis of a lymphoma SPC was 2.0 years (interquartile range (IQR): 0.8-4.0). Median age at diagnosis of a lymphoma SPC was 39 years (IQR: 34-49). The risk of a lymphoma SPC decreased with older age, from 10.68 per 1000 PY in those under 35 to 1.28 per 1000 PY in those above 55 (p=0.003). CD4 count at HIV diagnosis and HIV exposure modality were not associated with the risk of a lymphoma SPC.
The incidence of a SPC after lymphoma as a first cancer (n=39) was 5.60 per 1000 PY, versus 9.30 per 1000 PY when the first cancer was not lymphoma (n=190, p=0.004). KS was the most common SPC after an initial lymphoma (49% of cases). Only two myeloid SPCs occurred. Median time to diagnosis of SPC after an initial lymphoma was 2.6 years (IQR: 1.1-6.7). Risk of a SPC after a first lymphoma increased significantly from 4.12 per 1000 person-years in those diagnosed with HIV in the 1982-1995 pre-cART era, to 33.15 per 1000 person-years in patients diagnosed with HIV between 2009-2012 (p=0.005).
Conclusion
The incidence and spectrum of SPC in PWHA is increasingly important as overall and cancer-specific survival of these patients continues to improve. The incidence of lymphomas as SPC in PWHA has decreased over time, which may be a function of improved HIV treatment and reduced susceptibility to immunosuppression-related lymphoma. However, PWHA diagnosed with lymphoma as a first cancer are experiencing increasing incidence of SPCs, occurring after relatively short intervals. Longer survival is likely contributing to this effect. Importantly, therapy-related cancers do not appear prominent, suggesting HIV-specific factors may play a role. These findings emphasise the importance of SPC surveillance tailored to this special population.

Disclosures
Di Ciaccio: Janssen: Honoraria.