Malignancies in HIV/AIDS: from epidemiology to therapeutic challenges

Abstract

The incidence of AIDS-defining cancers (ADCs) - Kaposi sarcoma, primary central nervous system lymphoma, non-Hodgkin lymphoma, and cervical cancer - although on the decline since shortly after the introduction of HAART, has continued to be greater even in treated HIV-infected persons than in the general population. Although the survival of newly infected people living with HIV/AIDS now rivals that of the general population, morbidity and mortality associated with non-AIDS-defining cancers (NADCs) such as lung, liver, anal, and melanoma are significant and also continue to rise. Increasing age (i.e. longevity) is the greatest risk factor for NADCs, but longevity alone is not sufficient to fully explain these trends in cancer epidemiology. In this review, we briefly review the epidemiology and etiology of cancers seen in HIV/AIDS, and in this context, discuss preclinical research and broad treatment considerations. Investigation of these considerations provides insight into why malignancies continue to be a major problem in the current era of HIV/AIDS care.

Figure 1. Summary of AIDS-defining cancers (ADC) and non-AIDS-defining cancer (NADC) etiology in the context of HIV and HAART

Colored panels comprise concepts that are closely related: lower blue panel includes concepts related most closely to HIV infection (HIV), upper yellow panel indicates concepts related most closely to HAART treatment in HIV (HIV + HAART), and middle green panel indicates concepts related to both HIV and HIV + HAART. ADCs: AIDS-defining cancers; BL: Burkitt's lymphoma; IV: intravenous; NADCs: Non-AIDS-defining cancers; NPs: non-progressors.

1. HIV infection results in the depletion of CD4 cells leading to ineffective CD4-unhelped CD8+ T effector and B cells, which results in decreased anti-tumor responses and a resultant increase in ADCs.

2. Lack of CD4 help leads to a lack of responses against oncogenic infections, leading to cellular and molecular dysregulation and a resultant increase in ADCs and NADCs.

3. HIV infection results in a state of chronic inflammation leading to a subsequent increase in ADCs and NADCs through mechanisms that are not sufficiently understood.

4. Behaviors increased in HIV/AIDS (e.g., smoking and alcohol overconsumption) lead to an increase in ADCs and NADCs.

5. Despite normal CD4 counts in non-progressors (NPs; i.e., HIV patients not requiring treatment while maintaining low/undetectable HIV viral loads for extended periods of time), NADCs continue to be increased above the level found in the non-HIV infected population.

6. CD4 counts recover in HIV patients treated with HAART, and a resultant decrease in ADCs is observed, but ADCs remain increased above the level found in the non-HIV infected population.

7. Despite recovery of total CD4 counts, the CD4+ T cell subset distribution (Th1, Th2, Th9, Th17, Th35, Treg cells, etc.) may not return to normal proportions, and increased numbers of CD4+ T cells allow for outgrowth of CD4-involved/dependent cancers.

8. Increased survival with HAART results in extended longevity in the context of infection leading to increased age (i.e., time for NADC outgrowth).

9. Increased survival with HAART results in extended time involving behaviors associated HIV/AIDS (e.g., smoking, alcohol overconsumption, IV drug use, and unsafe sex leading to oncogenic infections) and resulting in a subsequent increase in ADCs and NADCs.