Módulo 2 – Curso pós-graduado – VIH e Envelhecimento

Non-AIDS Defining Cancers Among HIV Infected People

The epidemiology of non-AIDS defining cancers among HIV infected patients

Autor: Prof. Doutor Julian Falutz, MD, FRCP (McGill University Hospital Center, Montreal, Canada)

Pathogenesis of NADCs

Several factors may contribute to the pathogenesis of NADCs in the HIV population, such as the increased prevalence of oncogenic infectious agents, immunosuppression, the increased immune activation and chronic inflammation, which predisposes to accelerated immunosenescence, and the higher exposure to tobacco use and alcohol. There may be possible direct HIV effects, and the role of antiretroviral drugs remains uncertain. There have been a few reports that perhaps non nucleosides may be specifically involved, but there is no consensus17.

NADCs are divided into viral and non-viral related ones. The human papilloma virus (HPV) increases the risk of anal cancers and oral squamous carcinoma. Epstein-Barr virus (EBV) is involved in the pathogenesis of HL and childhood malignancies. The Merkel cell polyomavirus, which was recently identified, may be involved in the pathogenesis of Merkel cell carcinoma. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are well known risk factors for development of primary hepatocellular carcinoma. From an epidemiological perspective, the proportion of cancers attributable to infections was, in 2008, 10 times higher in HIV-infected persons (40%) compared with the general USA population (4%)18. Furthermore, when considering age-specific incidence rates of cancer related to specific infections among USA HIV patients, it was observed an increased rate of cancers unrelated to infections with age and that the rate of cancers attributable to infections increased very little after the age of 30 years. Thus, most of the infectious related malignancies occur in a younger population.

The non-viral related malignancies (lung, prostate colorectal, and breast cancers) are not consistently higher or lower among HIV patients, as described above. In fact, the link between effectively treated HIV patients and the risk of these non-AIDS events, and specifically of the non-AIDS malignancies is still unclear, although probably related to immune activation and inflammation. Effectively treated HIV infection is associated with a state of chronic inflammation, with increased biomarkers of inflammation that, in turn, can predict the development of some non-AIDS events.

Some factors may contribute to the state of chronic inflammation in HIV infection, such as:

  • Ongoing low level HIV replication;
  • HIV associated microbial translocation in the gastrointestinal tract that increases immune activation trough translocation of lipopolysaccharide into the circulation;
  • Co-infection with hepatitis viruses, which can contribute to chronic immune activation;
  • Co-infection with cytomegalovirus (CMV) that is emerging as a very important co-factor for the development of chronic inflammation;
  • Accelerated immune-senescence.

Results from the SMART study confirmed the interaction be- tween inflammation and clinical events. The study compared two groups of HIV patients with CD4+ cell count <350 cells/ mm3, with one group receiving ART to maintain viral load as low as possible throughout follow-up (virologic supression strategy) and the other group stopping or deferring ART until CD4+ count <250 cells/mm3 followed by episodic ART to increase CD4+ counts to >350 cells/mm3 (drug conservation strategy)19, 20. The study was stopped because of the very early evidence that all serious non-AIDS events were increased in the group that was on the drug conservation arm, with the most common non-AIDS event being cardiovascular diseases, although non-AIDS malignancies were not statistically different. However, AIDS defining malignancies occurred more commonly in the drug conservation group21. Hence, the SMART study showed that subjects who discontinued ART went from a state of relatively low systemic inflammation (with fully suppressed viral load) to a state of high inflammation as they cycled off ARV.

Hsue et al. looked at carotid intima-media thickening (IMT), a surrogate marker for cardiovascular disease, in HIV patients, whether they were on therapy, off therapy, and whether or not having undetectable viral load22. Patients with no ART, undetectable HIV, and not immunodeficient in terms of CD4+ cell count, had thicker carotid intima media than a control HIV negative population. Thus, untreated elite controllers showed evidence of a chronic inflammatory process with evidence of an abnormal clinical parameter, the carotid IMT22.

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