Impact of Combined Anti-Retroviral Therapy on HIV-Associated Non-Hodgkin-Lymphoma - a Prospective European Multi-Cohort Study on Behalf of the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) Study Group
Authors: Bohlius Julia 
Published: October 2019

Abstract
Background: Following its introduction in 1996, combination antiretroviral therapy (cART) has led to a substantial reduction in HIV-associated morbidity and mortality. The decline has, however, been less pronounced for non-Hodgkin lymphoma (NHL) than for other HIV-related complications, and NHL has become the most common cancer associated with HIV. Within the framework of a large prospective European multi-cohort project, the Collaboration of Observational HIV Epidemiological Research Europe (COHERE), we studied the incidence and risk factors for the development and survival of NHL in HIV-infected patients in the cART era.
Methods: We analyzed the data of HIV- infected adult patients (aged >16 years) who were cART naïve at inclusion and started cART after 01.01.1998, at a time when cART had become well established and widely used in Europe. cART was defined as a regimen of at least 3 antiretroviral drugs. Patients had to have CD4 count measurements available before the start of cART and the diagnosis of NHL. Patients developing NHL before receiving cART (“not on cART”) and patients developing NHL while receiving cART (“on cART”) were analyzed separately. Both patients with Primary Brain Lymphoma (PBL) and systemic NHL were included in the analysis. Incidence rates were calculated based on the Poisson distribution; risk factors were estimated using crude and adjusted Weibull models, with random effects to account for heterogeneity between cohorts. Models with time varying covariates were used to explore the effects of CD4 cell counts and plasma HIV-RNA loads over time. Survival was estimated using Kaplan-Meier life table probabilities, with 95% confidence intervals (95% CI).
Results: For the incidence analysis 56,305 patients from 22 cohort studies across Europe with 212,042 person-years at risk were evaluated. The incidence for NHL (both systemic NHL and PBL) in patients not on cART was 519 (95% CI 448 to 602) per 100,000 personyears compared to 229 (95% CI 208 to 252) per 100,000 person-years in those on cART. The corresponding rates for PBL were 57 (95% CI 36 to 89) per 100,000 person-years and 24 (95% CI 18 to 33) per 100,000 person years. In cART naïve patients risk factors for NHL were older age and low CD4 cell count nadirs. When included as time up-dated variables, high plasma HIV-1 RNA loads and low CD4 cell counts emerged as important risk factors. In patients receiving cART risk factors included low CD4 cell count nadirs, older age, and groups associated with HHV-8 infection, i.e. men having sex with men and patients with a previous diagnosis of Kaposi Sarcoma. Time up-dated HIV-1 RNA plasma concentration and CD4 cell count were also associated with developing NHL while on cART. For the survival analysis 847 NHL patients were eligible. Of those, 364 (43%) were cART naïve at diagnosis of NHL. After one year 66% (95% CI 63%–70%) of patients with systemic NHL and 54% (95% CI 43%–65%) of patients with PBL were alive. Risk factors for death were diagnosis of PBL, low CD4 cell count nadir and history of injection drug use.
Conclusions: Combined anti-retroviral therapy reduces the risk of developing NHL. In the era of cART more advanced immunodeficiency is the dominant risk factors for developing NHL both in patients receiving and not receiving cART. Two thirds of patients diagnosed with HIV-related NHL other than PBL survive for longer than one year after diagnosis. Survival is poorer in patients diagnosed with PBL.