Results from a retrospective study, published online in Lancet HIV, showed that both prolonged infection with the human deficiency 1 virus (HIV-1), and recent immunosuppression, as evaluated by CD4+ T-cell (ie, CD4) count, were independently associated with the development of non-Hodgkin lymphoma (NHL).1

Previous research has provided evidence for an inverse relationship between NHL risk and CD4 count, and a direct relationship between NHL risk and HIV viral load (ie, HIV-1 RNA level) that is independent of CD4 count. In addition, earlier evidence also suggested that the importance and mechanism of low CD4 count as an NHL risk factor might vary between different subtypes of NHL (eg, CNS NHL, diffuse large B-cell lymphoma [DLBCL], and Burkitt lymphoma) associated with HIV infection. In this study, different timed assessments of CD4 count and viral load (eg, recent, past, cumulative, nadir, and peak) were evaluated to provide greater insight into the respective roles played by immunosuppression and viremia in the development of different NHL subtypes.

This study examined 21 cohorts of people living with HIV during 1996 to 2014 who were included in the North American AIDS Cohort Collaboration on Research and Design. CD4 count and viral load were estimated at 30-day intervals using laboratory measurements. Recent and later CD4 counts and viral loads were assessed at specific time points. In addition, cumulative CD4 counts and viral loads were also determined during “prespecified moving time windows.” All measures were lagged by at least 6 months to lessen the likelihood of reverse causality. Models were used to stratify data by cohort and adjust for demographic characteristics.

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Of the 102,131 people included in this analysis, 712 developed NHL, with 9%, 50%, and 12%, diagnosed with CNS NHL, DLBCL, and Burkitt, respectively. Using fewer than 50 CD4 cells per µL to represent low CD4 count and 500 CD4 cells per µL or higher to represent high CD4 count, recent low CD4 count (lagged by 6 months) was an independent predictor of overall NHL risk (hazard ratio [HR], 3.2; 95% CI, 2.2-4.7).

In addition, using a maximum of 500 copies per mL or less and 100,000 copies per mL or higher to represent low and high HIV viral load, high average viral load during a 3-year period (lagged by 6 months) also independently predicted for overall risk of NHL (HR, 9.6; 95% CI, 6.5-14.0).

With respect to NHL subtype, both recent low CD4 count (HR, 2.4; 95% CI, 1.4-4.2) and high average viral load during a 3-year time window (HR, 7.5; 95% CI, 4.5-12.7) were also independent predictors of developing DLBCL. However, only recent low CD4 count independently predicted for the development of CNS NHL (HR, 426.3; 95% CI, 58.1-3126.4). In addition, only the proportion of time the viral load was greater than 500 copies per mL during the 3-year window was an independent predictor for development of Burkitt lymphoma (100% vs 0%; HR, 41.1; 95% CI, 9.1-186.6).

“Our finding that the cumulative viral load is a key predictor for NHL reinforces the importance of early diagnosis of HIV infection followed by prompt [active retroviral treatment] ART initiation, before prolonged HIV viremia has exerted its lymphomagenic effects. Full implementation of the current recommendation of immediate ART initiation on diagnosis, only in effect since 2016, is likely to result in further declines in incidence of NHL, as would early diagnosis through widespread adoption of US Preventive Services Task Force screening recommendations,2 followed by prompt linkage to care,” the study authors wrote in conclusion.


  1. Hernández-Ramírez RU, Qin L, Lin H, et al. Association of immunosuppression and HIV viraemia with non-Hodgkin lymphoma risk overall and by subtype in people living with HIV in Canada and the USA: a multicentre cohort study [published online February 27, 2019]. Lancet HIV. doi: 10.1016/S2352-3018(18)30360-6
  2. US Preventive Services Task Force. Final recommendation statement: human immunodeficiency virus (HIV) infection – screening. Dec 2016. Accessed March 25, 2019.