AIDS Malignancies in the Era of Highly Active Antiretroviral Therapy

The article by Drs. Gates and Kaplan provides anexcellent review of malignancies associated with human immunodeficiency virus(HIV)-1 disease and chronicles the epidemiologic changes seen during the past 5years. The literature review is very thorough and well balanced.

Since 1981, when acquired immunodeficiency syndrome (AIDS) was firstdescribed, we have observed remarkable changes in the epidemiology ofmalignancies in this country. Previously very rare, Kaposi’s sarcoma (KS)became quite common in HIV-infected patients. In fact, during the early years ofthe AIDS epidemic, the appearance of KS lesions became a hallmark of theinfection and was feared by at-risk populations, especially men who have sexwith men. Non-Hodgkin’s lymphoma (NHL) has also increased in incidence, andsome experts are concerned that the increase may continue despite recentadvances in treatment of HIV disease.

Impact of Potent Antiretroviral Therapy

Widespread use of potent antiretroviral therapy including protease inhibitors(commonly known as HAART) for the treatment of HIV-1 disease has dramaticallydecreased the incidence of opportunistic infections and death.[1] Unfortunately,as the authors point out, the impact on the risk of developing HIV-associatedmalignancies is less clear. Kaposi’s sarcoma, arguably the most sensitive toimmunosuppression, is certainly much less common now and there have been manyreports of regression of lesions.[2] However, NHL has only decreased slightly inincidence during the same period (since 1995). Autopsy studies of HIV-infectedcases have shown a marked decrease in opportunistic infections over time, butNHL has not decreased and even shows an upward trend in some studies.[3-5]Apparently, the reconstituted immune system generated by potent antiretroviraltherapy may not protect patients against AIDS-related malignancies as well as itdoes against infections.

The epidemiologic impact on other cancers is less pronounced. As the authorsnote, lack of relationship to immune deficiency is largely responsible for thisin most cases. For example, anal and cervical cancers are common with HIVbecause of similar risk factors and routes of transmission rather thanimmunosuppression. Drs. Gates and Kaplan provide a careful review of theavailable epidemiologic data, including several helpful tables.

Unanswered Questions

While the recent changes in morbidity and mortality from HIV-1 disease indeveloped countries are gratifying, several unanswered questions remain. Recentdevelopments in pathogenesis research in AIDS malignancies are extremely wellreviewed in the article, and the complex issues are clearly described. As theauthors frequently point out, the interwoven relationships between HIV-1, otherinfectious agents, associated malignancies, and the immune system are onlybeginning to be unraveled. The preexisting immune dysregulation caused by HIVcomplicates these efforts. Research on host factors in HIV-1 infection to datehas focused on control of viral replication, opportunistic infections, and deathas end points. The immune system determinants necessary to protect againstopportunistic infections are becoming clearer, but the same cannot be said atthis time for malignancies.[6]

For the practicing clinician, other unresolved issues surround the managementof HIV-infected patients with malignancies. As discussed by the authors, theeffect of HAART on the natural history of NHL is unclear, although KS lesionsoften regress. Prescribing combination chemotherapy and antiretroviral therapyto the same patient may be challenging. Working with scant pharmacokinetic andtoxicity data, most clinicians resort to commonsense principles, for example,avoiding drugs with overlapping toxicities.

Monitoring HIV disease is also difficult during chemotherapy because ofsecondary lymphopenia, which causes the CD4-positive T-cell count to fall. Theimpact of chemotherapeutic agents on viral replication is largely unknown.Conversely, little is known about the impact of viral load on the risk ofdeveloping AIDS-related malignancies. Unfortunately, the authors do not drawmuch on their extensive experience in treating patients at the University ofCalifornia at San Francisco, as practical suggestions may have been helpful toclinicians in the field.

Conclusions

Overall, this is an excellent summary outlining the state of our knowledgeabout HIV-associated malignancies in the era of HAART. Although great progresshas been made in anti-HIV therapy, the most dramatic declines have been seen inthe incidence of opportunistic infections rather than cancers. Malignanciesstill loom on the horizon, and some experts fear that their incidence may evenincrease as time goes on. Future investigation should focus on optimizingprevention and treatment strategies, especially as HIV-infected patients livelonger.

References:

1. Palella FJ, Delaney KM, Moorman AC, et al: Declining morbidity andmortality among patients with advanced human immunodeficiency virus infection. NEngl J Med 338:853-860, 1998.

2. Goedert HH: The epidemiology of acquired immunodeficiency syndromemalignancies. Semin Oncol 27:390-401, 2000.

3. Masliah E, DeTeresa RM, Mallory ME, et al: Changes in pathologicalfindings at autopsy in AIDS cases for the last 15 years. AIDS 14:69-74, 2000.

4. Semela D, Glatz M, Hunziker D, et al: Cause of death and autopsy findingsin patients of the Swiss HIV Cohort Study (SHCS). Schweiz Med Wochenschr130:1726-1733, 2000.

5. Sansone GR, Frengley JD: Impact of HAART on causes of death of personswith late-stage AIDS. J Urban Health 77:166-175, 2000.

6. Hogan CM, Hammer SM: Host determinants in HIV infection and disease. AnnIntern Med 134:761-776, 2001.