The National Cancer Institute’s Dr. Robert Biggar has probably studied the impact of the acquired immunodeficiency syndrome (AIDS) epidemic on cancer trends at least as thoroughly as anyone in the field. His long-term experience is reflected in this comprehensive and well-written overview, which summarizes the evidence concerning highly active antiretroviral therapy (HAART). Indeed, patients are developing fewer opportunistic infections and living significantly longer than they did before the advent of these potent anti-human immunodeficiency virus (HIV) drugs. However, the question remains as to what extent this treatment might also change the incidence of cancers?
Loss of Immunologic Control
In light of the connection between HIV infection and loss of immunologic control, many researchers expected the incidence of more cancers to be increased in HIV-positive individuals than 20 years’ experience with HIV and AIDS has actually shown. Greatly increased relative risk estimates have been documented only for Kaposi’s sarcoma and non-Hodgkin’s lymphoma, whereas other cancers with a potential infectious etiology, such as Hodgkin’s disease, anogenital cancers, hepatomas, gastric cancer, and testicular cancer have shown much more moderate risk associations.
Some of these surprising findings are likely explained by the influence of other factors present in groups at high risk for HIV infection. Nevertheless, a long-held argument for the lack of more cancers being convincingly increased by the advent of HIV-induced immunodeficiency is that infected persons do not live long enough for some of the more solid cancers to manifest and become clinically apparent.
With the introduction of HAART and related therapies, this condition for a longer life expectancy has been met. However, as Dr. Biggar points out, cancer trends in recent years (ie, the HAART era) are essentially unchanged, and, if anything, show a slight decrease primarily as a result of a decrease in the incidence of Kaposi’s sarcoma and perhaps also non-Hodgkin’s lymphoma. There is no indication that new cancers are becoming more frequent. We are, however, still in the early phase of a new era, and it is too early to draw any conclusions about what cancers might be part of the clinical picture of long-term survivors of HIV infection.
Incidence of the Human Herpesvirus
Although the incidence of Kaposi’s sarcoma is still relatively high, the time of its being by far the leading cancer among HIV-infected individuals is long over. Dr. Biggar offers several explanations for this development, some of which have to do with issues relating to the reporting of the disease, others to changes in the demographics of the HIV-infected population, and still others directly influencing the pathogenicity of Kaposi’s sarcoma. It seems reasonable to argue that the decline in the true incidence of Kaposi’s sarcoma is caused by the last of these explanations.
Here, primarily two phenomena appear important, one of which is the dwindling of the human herpesvirus 8 (HHV-8) epidemic and exhaustion of the population susceptible to Kaposi’s sarcoma. At least two reports have shown a significant drop in HHV-8 incidence from very high levels at the beginning of the 1980s (when the incidence of HIV was at its highest), to significantly lower levels after 1984-1985.[1,2] These changes most likely occurred as a direct result 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’s sarcoma, it follows directly that a drop in the incidence of HHV-8 might lead to a subsequent drop in the incidence of that disease.
Drug Therapies That Improve Immune Competence
The other important phenomenon seems to be the introduction of drug therapies that, throughout the 1990s, have improved the immune competence of HIV-infected individuals with increasing success. As discussed by Dr. Biggar, Kaposi’s sarcoma is influenced by changes in immune status, albeit in a still poorly understood manner. Indeed, prior to the advent of the AIDS epidemic, case reports described how Kaposi’s sarcoma might disappear after restoration of immune competence. It is biologically plausible that the well-described effect of HAART in causing severe immunosuppression to revert to a less severe stage may not only reduce the development of new Kaposi’s sarcoma lesions, but may also reverse a subclinical Kaposi’s sarcoma lesion to normal.
Although evidence supporting the effect of HAART therapy on the lowered incidence of Kaposi’s sarcoma continues to increase, it is difficult, at present, to estimate its precise effect. Such studies would, among other things, need to take into consideration the influence of HHV-8. Furthermore, therapeutic regimens for HIV-infected individuals undergo continuous changes and modifications, and it may well be difficult to get precise estimates of the impact of specific HIV treatments on cancer development.
Immunologic Changes and Non-Hodgkin’s Lymphoma
Although the general immunosurveillance hypothesis, which argues that all cancers are sensitive to immunologic changes, has been dead for decades, it seems appropriate in the context of non-Hodgkin’s lymphoma. The incidence of that disease is influenced by even moderate changes in immune competence, independent of the underlying cause. Some reports suggest that there may be a dose-response relationship with increasing immunosuppression, giving rise to an increase in the incidence of non-Hodgkin’s lymphoma.
Based on experience from studies among non-HIV-infected individuals who have undergone transplantation or who received immunosuppressive therapy for other reasons, the latency period between immunosuppression and non-Hodgkin’s lymphoma development is only a few years. Therefore, any improvement in immunosuppression as a result of HAART or equivalent therapies would a priori be expected to decrease the incidence of non-Hodgkin’s lymphoma, perhaps even shortly after the introduction of therapy.
There is some evidence that a decline in the incidence of non-Hodgkin’s lymphoma began after HAART was introduced, but the evidence is inconclusive at present. It may still be too early to see the full effect of HAART on the incidence of non-Hodgkin’s lymphoma, but the lack of a clear association could argue, as discussed by Dr. Biggar, for a more complex association between the pathogenesis of non-Hodgkin’s lymphoma and immune dysregulation.
Finally, it should be noted that significant increases in immune competence as a result of new therapies such as HAART may not only reduce the incidence of AIDS-related cancers, but may also help improve the tolerance of certain cancer regimens, and thus help improve the survival of HIV-infected patients with cancer.