Risk Factors for HIV Associated Cancer

Executive Summary

Risk factors influence the chance of developing cancer among individuals, but individuals with no risk factors also develop cancer. Various traditional cancer risk factors such as Oncogenic viral infection, smoking, etc., and immunodeficiency have been among the essential key risk factors for HIV associated cancer. The role of proto-oncogenic effects of HIV, and although there appears to be a high prevalence of traditional cancer risk factors (e.g., smoking, oncogenic viral infection), there is evidence of the direct proto-oncogenic effect of HIV. Active inflammatory and coagulation pathways and cART toxicity may also increase cancer risk. Some of the common risk factors that develop the risk of HIV associated cancer include immunodeficiency, HIV viral load and direct oncogenic effects of HIV, enhanced inflammation and coagulation, and cART (combination Antiretroviral Therapy) toxicity.

Risk Factors Associated with HIV or AIDS Related Cancer

Studies pertaining to the various factors that lead to the increased risk for cancer among HIV-infected patients remain ambiguous and are not clearly understood. Various traditional cancer risk factors such as Oncogenic viral infection, smoking etc., as well as immunodeficiency, have been observed to be among the important key risk factors for HIV associated cancer. Various reports also elucidate the role of proto-oncogenic effects of HIV, and although there appears to be a high prevalence of traditional cancer risk factors (e.g., smoking, oncogenic viral infection), there is evidence of the direct proto-oncogenic effect of HIV. Active inflammatory and coagulation pathways, as well as cART toxicity, may also contribute to increasing the risk for cancer. However, it is still difficult to determine whether these factors work independently or synergistically​1​.

  •  Immunodeficiency

There is a strong, well-established association between immunodeficiency (low CD4+ levels) and an increased risk of AIDS associated cancers. There is also growing evidence of an inverse relationship between CD4+ count and non-AIDS-associated cancer risk.

On the other hand, an increased risk for infection-unrelated non-AIDS associated cancer among immunodeficient individuals is consistent among patients with undetected pre-malignant and cancerous cells. Thus, HIV-associated immunodeficiency exerts cancer-predisposing effects through two main mechanisms: (1) eradication and control of oncogenic viral infections and (2) decreased immune surveillance of malignant cells.

  • HIV viral load and direct oncogenic effects of HIV

Studies have consistently reported an association between increased cancer risk and viral replication. Increased HIV RNA levels (> 500 copies/mL) were observed to be associated with an increased risk for AIDS associated cancer. Studies have also reported a direct association between current HIV RNA levels and the risk for KS and NHL. HIV RNA levels of more than 100,000 copies/mL have been observed to be associated with increased anal cancer risk. There is evidence that HIV itself might have a proto-oncogenic effect using TAT and VPR proteins. Possible mechanisms of HIV associated cancer are complex and multifactorial and include synergistic effects with other proto-oncogenic viruses, blockade of tumour suppressor gene function, disruption of cell cycle regulation, increased chromosome instability, telomerase activity inhibition, impaired DNA repair mechanism as well as the effect of exogenous carcinogens.

  • Enhanced inflammation and coagulation

Coagulation and activated inflammatory pathways are associated with cancer risk, as evidenced by high plasma levels of biomarkers. Studies have demonstrated a relationship between hepatic C-reactive protein (CRP) production and plasma levels of the inflammatory cytokine interleukin-6 (IL-6). There is increasing evidence that persistent inflammatory conditions in HIV-infected patients, even with low serum viral loads, are responsible for the development of comorbidities. Although this persistent inflammation is multifactorial, it is thought to be due to blood clotting disorders, immune dysregulation, and latent viral replication. Studies suggest that HIV patients have higher levels of biomarkers of inflammation and coagulation, such as highly sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6), and D-dimer, which are associated with poor health outcomes and cancer onset. Although there is a lack of conclusive evidence of a causal relationship between inflammation/coagulation and an increased risk of cancer among HIV infected patients, findings suggest that interventions for reducing the level of biomarkers of coagulation and inflammation, particularly IL-6, may be warranted​2​.

  • cART (combination Antiretroviral Therapy) toxicity

Considering cART toxicity as a cancer risk factor, several studies have reported a positive association between the use of cART and cancer risk. The potential carcinogenic potential of some forms and classes of cART may increase the risk of cancer. These include older toxic drugs such as zidovudine and antiretroviral drugs, which are currently recommended as first-line treatment for newly diagnosed patients. Studies have reported the association of protease inhibitors used in cART in increasing the risk for Hodgkin’s lymphoma and anal cancer​2​.

References

  1. 1.
    Borges A, Dubrow R, Silverberg M. Factors contributing to risk for cancer among HIV-infected individuals, and evidence that earlier combination antiretroviral therapy will alter this risk. Curr Opin HIV AIDS. 2014;9(1):34-40. doi:10.1097/COH.0000000000000025
  2. 2.
    Mooney S, Tracy R, Osler T, Grace C. Elevated Biomarkers of Inflammation and Coagulation in Patients with HIV Are Associated with Higher Framingham and VACS Risk Index Scores. Apetrei C, ed. PLoS ONE. Published online December 7, 2015:e0144312. doi:10.1371/journal.pone.0144312