We cannot escape the realities of biology. Just as children rescued from leukemia and lymphoma live to grow into adults who must confront the adverse effects of their curative treatment, people rescued from AIDS by HAART (highly active antiretroviral therapy) are showing a substantially increased risk of cancers other than the "AIDS-defining" malignancies designated by the Centers for Disease Control in the 1980s: Kaposi sarcoma, non-Hodgkin lymphoma (NHL), and cervical cancer.
With increasing numbers of people surviving for long periods whose immune systems have been weakened by HIV, we can expect to witness an increased incidence of this spectrum of "non-AIDS defining" cancers, or NADCs. This is the independent conclusion from unrelated studies in the United States and Switzerland, which show nearly identical increases in the risk of Hodgkin lymphoma and anal cancer many years after the initiation of HAART therapy.
The US-based AIDS Malignancy Consortium has referred to a coming "epidemic" of these cancers. "NADCs are here to stay," remarked immunologist Dirk Dittmer PhD of the Center for AIDS Research at the University of North Carolina, Chapel Hill, in an editorial about the US study.
That study, apparently the largest and longest-term comparison to date matching cancer rates among HIV+ people with those of other cancer patients, used records from a national cancer registry and those of more than 260,000 adults and adolescents diagnosed with AIDS or HIV-positive status between 1980 and 2008. Thus it can speak to the experience of people who have lived as long as 10 years after diagnosis.
The new analysis of data from the NCI-sponsored HIV-AIDS Cancer Match Study appears this month in the Archives of Internal Medicine.
The latest results from the analogous but smaller Swiss HIV Cohort Study were published last month in the British Journal of Cancer. The investigators from the International Agency for Research on Cancer (IARC) matched records from 9,429 persons with HIV or AIDS against data from a Swiss cancer registry.
"By and large, we all agree that several cancers (especially those associated with HPV [human papilloma virus] and HBV/HCV [hepatitis B and hepatitis C virus]) are going to increase in people with HIV and AIDS unless effective screening/treatment of cancer-associated infections are found and implemented," said two of the IARC authors, Silvia Franceschi and Gary Clifford, when asked to compare the two studies.
The NCI researchers found a decline in Kaposi sarcoma (KS) and the AIDS-associated varieties of NHL during the study period, presumably due to the effects of HAART treatment. But there was an overall increase of 20% in non-AIDS defining cancers during the HAART era. The incidence of Hodgkin lymphoma doubled (most commonly the mixed-cellularity type associated with the Epstein-Barr virus). The incidence of anal cancer in this population tripled between the non-HAART and the HAART era, with a relative risk about 30 times that of the general population.
The IARC study also showed a decline in KS and NHL, accompanied by an increase in NADCs to a level approximately double that of the general population.
It is important not to attribute to HAART any "unproven responsibility" for these recent upward trends in NADCs, Franceschi and Clifford remarked. The increase in risk of NADCs can likely be attributed to "age as a proxy of duration of exposure to cancer-causing chronic infections … that are much more common in people with HIV and AIDS than in the general population, and are characterized by long latent phases," they added.
In other words, the oncogenic events that trigger these cancers may happen even before HIV infection is discovered (as the NCI authors also observed). A weakened immune system predisposes to the NADC malignancy, and HAART treatment allows it the time to develop.
Environmental factors implicit in HIV infection—specifically sexual practices and intravenous drug use—might equally play a role, the NCI authors observed, given that most of the NADCs involve the anal and genital regions, the mouth, throat, and tongue, and the blood.
After the advent of HAART, anal cancer became as prevalent as KS and NHL among AIDS/HIV patients. It may be time to add anal cancer to the AIDS-defining malignancies, Dittmer speculated in his editorial. It's also important not to minimize their total impact, he added in an email. "Despite their relative decline, AIDS defining cancers (Kaposi sarcoma and NHL) still account for more diagnosis than any one other cancer," Dittmer wrote. "The AIDS-related cancers are here to stay as well, as new people continue to be infected with HIV."
HAART is not to blame, exactly, but it must be accounted for in using chemotherapy to treat NADCs. Look for results from a collaborative study assessing the effects of HAART on the effects of cancer chemotherapy with the tyrosine kinase inhibitor sutinib maleate. Recruitment is scheduled to close next month. According to a report at this year's annual meeting of the American Society for Clinical Oncology, so far the drug has been well tolerated in this scenario and pharmacokinetic information is being analyzed.