AIDS-Related Cancers in the Era of Highly Active Antiretroviral Therapy

The National Cancer Institute’s Dr.Robert Biggar has probably studied the impact of the acquired immunodeficiencysyndrome (AIDS) epidemic on cancer trends at least as thoroughly as anyone inthe field. His long-term experience is reflected in this comprehensive andwell-written overview, which summarizes the evidence concerning highly activeantiretroviral therapy (HAART). Indeed, patients are developing feweropportunistic infections and living significantly longer than they did beforethe advent of these potent anti-human immunodeficiency virus (HIV) drugs.However, the question remains as to what extent this treatment might also changethe incidence of cancers?

Loss of Immunologic Control

In light of the connection between HIV infection and loss ofimmunologic control, many researchers expected the incidence of more cancers tobe increased in HIV-positive individuals than 20 years’ experience with HIVand AIDS has actually shown. Greatly increased relative risk estimates have beendocumented only for Kaposi’s sarcoma and non-Hodgkin’s lymphoma, whereasother cancers with a potential infectious etiology, such as Hodgkin’s disease,anogenital cancers, hepatomas, gastric cancer, and testicular cancer have shownmuch more moderate risk associations.

Some of these surprising findings are likely explained by theinfluence of other factors present in groups at high risk for HIV infection.Nevertheless, a long-held argument for the lack of more cancers beingconvincingly increased by the advent of HIV-induced immunodeficiency is thatinfected persons do not live long enough for some of the more solid cancers tomanifest and become clinically apparent.

HAART Therapy

With the introduction of HAART and related therapies, thiscondition for a longer life expectancy has been met. However, as Dr. Biggarpoints out, cancer trends in recent years (ie, the HAART era) are essentiallyunchanged, and, if anything, show a slight decrease primarily as a result of adecrease in the incidence of Kaposi’s sarcoma and perhaps also non-Hodgkin’slymphoma. There is no indication that new cancers are becoming more frequent. Weare, however, still in the early phase of a new era, and it is too early to drawany conclusions about what cancers might be part of the clinical picture oflong-term survivors of HIV infection.

Incidence of the Human Herpesvirus

Although the incidence of Kaposi’s sarcoma is still relativelyhigh, the time of its being by far the leading cancer among HIV-infectedindividuals is long over. Dr. Biggar offers several explanations for thisdevelopment, some of which have to do with issues relating to the reporting ofthe disease, others to changes in the demographics of the HIV-infectedpopulation, and still others directly influencing the pathogenicity of Kaposi’ssarcoma. It seems reasonable to argue that the decline in the true incidence ofKaposi’s sarcoma is caused by the last of these explanations.

Here, primarily two phenomena appear important, one of which isthe dwindling of the human herpesvirus 8 (HHV-8) epidemic and exhaustion of thepopulation susceptible to Kaposi’s sarcoma. At least two reports have shown asignificant drop in HHV-8 incidence from very high levels at the beginning ofthe 1980s (when the incidence of HIV was at its highest), to significantly lowerlevels after 1984-1985.[1,2] These changes most likely occurred as a directresult of behavioral changes in the populations at high risk for HIV infection.If we consider HHV-8 a necessary component of the development of Kaposi’ssarcoma, it follows directly that a drop in the incidence of HHV-8 might lead toa subsequent drop in the incidence of that disease.

Drug Therapies That Improve Immune Competence

The other important phenomenon seems to be the introduction ofdrug therapies that, throughout the 1990s, have improved the immune competenceof HIV-infected individuals with increasing success. As discussed by Dr. Biggar,Kaposi’s sarcoma is influenced by changes in immune status, albeit in a stillpoorly understood manner. Indeed, prior to the advent of the AIDS epidemic, casereports described how Kaposi’s sarcoma might disappear after restoration ofimmune competence. It is biologically plausible that the well-described effectof HAART in causing severe immunosuppression to revert to a less severe stagemay not only reduce the development of new Kaposi’s sarcoma lesions, but mayalso reverse a subclinical Kaposi’s sarcoma lesion to normal.

Although evidence supporting the effect of HAART therapy on thelowered incidence of Kaposi’s sarcoma continues to increase, it is difficult,at present, to estimate its precise effect. Such studies would, among otherthings, need to take into consideration the influence of HHV-8. Furthermore,therapeutic regimens for HIV-infected individuals undergo continuous changes andmodifications, and it may well be difficult to get precise estimates of theimpact of specific HIV treatments on cancer development.

Immunologic Changes and Non-Hodgkin’s Lymphoma

Although the general immunosurveillance hypothesis, which arguesthat all cancers are sensitive to immunologic changes, has been dead fordecades, it seems appropriate in the context of non-Hodgkin’s lymphoma. Theincidence of that disease is influenced by even moderate changes in immunecompetence, independent of the underlying cause. Some reports suggest that theremay be a dose-response relationship with increasing immunosuppression, givingrise to an increase in the incidence of non-Hodgkin’s lymphoma.[3]

Based on experience from studies among non-HIV-infectedindividuals who have undergone transplantation or who received immunosuppressivetherapy for other reasons, the latency period between immunosuppression andnon-Hodgkin’s lymphoma development is only a few years. Therefore, anyimprovement in immunosuppression as a result of HAART or equivalent therapieswould a priori be expected to decrease the incidence of non-Hodgkin’slymphoma, perhaps even shortly after the introduction of therapy.

Conclusions

There is some evidence that a decline in the incidence ofnon-Hodgkin’s lymphoma began after HAART was introduced, but the evidence isinconclusive at present. It may still be too early to see the full effect ofHAART on the incidence of non-Hodgkin’s lymphoma, but the lack of a clearassociation could argue, as discussed by Dr. Biggar, for a more complexassociation between the pathogenesis of non-Hodgkin’s lymphoma and immunedysregulation.

Finally, it should be noted that significant increases in immunecompetence as a result of new therapies such as HAART may not only reduce theincidence of AIDS-related cancers, but may also help improve the tolerance ofcertain cancer regimens, and thus help improve the survival of HIV-infectedpatients with cancer.

References:

1. Melbye M, Cook OM, Hjalgrim H, et al: Risk factors for Kaposi’s-sarcoma-associatedherpesvirus (KSHV/HHV-8) seropositivity in a cohort of homosexual men,1981-1996. Int J Cancer 77:543-548, 1998.

2. O’Brien TR, Kedes D, Ganem D, et al: Evidence forconcurrent epidemics of human herpesvirus 8 and human immunodeficiency virustype 1 in US homosexual men: Rates, risk factors, and relationship to Kaposi’ssarcoma. J Infect Dis 180:1010-1017, 1999.

3. Opelz G, Henderson R: Incidence of non-Hodgkin’s lymphomain kidney and heart transplant recipients. Lancet 342:1514-1516, 1993.