Classic helper T cells (left) are equipped with receptors that facilitate communication with other cells, inducing cell activation and providing T-cell help. The cell surface profile of CD4 NK-T cells (right) is dramatically altered, imposing novel functional capabilities on these unconventional T lymphocytes. First, NK-T cells have lost the CD28 molecule, a receptor regulating T-cell reactivity, expansion, and apoptosis. Second, NK-T cells have gained the potential to destroy contacting cells. And third, NK-T cells have acquired a series HLA class I-specific receptors (KIR) and other receptors (CD161) that are typical in the innate immune system.
During the past 16 years, combination antiretroviral (ARV) therapy has transformed the course of HIV disease. Whereas the risk of illness and death remained extremely high for people with HIV before 1996, those risks have diminished considerably since then.
More recently, however, experts have noted an increase in the risk of diseases not typically associated with the immune dysfunction that accompanies an AIDS diagnosis. In particular, non-AIDS-related malignancies (NAMs) appear to be on the rise as people live much longer with HIV. While the beneficial effects of maintaining a high CD4 count through ARV therapy are known when it comes to AIDS-related cancers, the impact of these factors on NAMs is less clear.
To explore this further, Anouk Kesselring, MD, from the University of Amsterdam, and her colleagues, examined the medical records of 11,459 people living with HIV enrolled in the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort study since 1996. Most of the people whose records were reviewed were men who have sex with men (MSM).
Since 1996, there were 239 diagnoses of NAMs in 231 people; a few of them received multiple NAM diagnoses. Of these NAMs, 43 percent were linked to infection from a virus other than HIV—typically hepatitis B or C virus (HBV or HCV), Epstein-Barr virus (EBV) or human papillomavirus (HPV). Of those cancers tied to a viral infection, the most common were anal cancer, cancer of the larynx, liver cancer and Hodgkin’s lymphoma.
Kesselring and her colleagues found that a low past or present CD4 count was strongly correlated with a diagnosis of a NAM. Conversely—and this finding stands in contrast to previous studies—past and present viral load and use of specific ARV regimens were not associated with a NAM diagnosis.
When the research team looked at a variety of factors associated with NAMs, a key finding was that the more time a person spent with a CD4 count under 200, the more likely he or she was to develop a NAM caused by a viral infection. The same was not true, however, for NAMs that are not associated with viral infection.
Current guidelines recommend starting ARV therapy “at CD4 cell counts which are higher than the levels of immunodeﬁciency that we found to be associated with an increased risk of developing malignancies, which might help in preventing malignancies in such patients,” the authors note.
“Screening for anal human papillomavirus infections and premalignant lesions, counseling patients to quit smoking, and vaccinating against HBV could further reduce the incidence of non–AIDS-deﬁning malignancies in the HIV-1–infected population treated with [ARVs],” they conclude.