In this large and nationally representative cohort of people with AIDS, significant declines in mortality over time were observed along with similar declines in the cumulative incidence of ADCs, which reflect the effects of increasingly widespread access to improved HIV therapies, including HAART (widely available since 1996). In striking contrast, however, a rise in the cumulative incidence of NADC was noted, including malignancies that occur with heightened frequency among HIV-infected people.
Major declines in mortality attributable to improved antiretroviral therapies are well documented.(1
) HAART is effective in controlling HIV replication, leading to improved immune function and prolonged survival.(3
) Declines in mortality among HIV-infected people were also observed in the U.S. prior to 1996, presumably due to increasing use of less potent antiretroviral regimens and better prophylaxis against opportunistic infections.(17
) These strong trends in mortality required the application of a competing risk framework to assess the cumulative incidence of cancer. The cumulative incidence estimates in the present study correspond to the probability of observing cancer while a person with AIDS was still alive, are useful in assessing cancer risk for patients and clinicians, and can inform public health practice as a measure of cancer burden in the AIDS population.
Risk of the 2 major ADCs (KS and NHL) is elevated in the presence of immune suppression, and dramatic declines in the cumulative incidence of KS and NHL over time were demonstrated, consistent with partial immune restoration associated with HAART.(18
) The steep rise in the cumulative incidence of KS and NHL, in the few months immediately after AIDS onset reflects that some of these cases were likely initial AIDS-defining events. Indeed, the decline across calendar periods in KS and NHL in the earliest months after AIDS can partly be attributed to the 1993 revision of the AIDS surveillance case definition, which allowed asymptomatic HIV-infected individuals with <200 CD4 cells/μL to be classified as AIDS cases.(4
) Over time, the fraction of AIDS cases meeting the case definition via immunologic criteria increased due to laboratory reporting of these individuals. However, these changes in AIDS surveillance would not readily explain declines in cumulative incidence later after AIDS onset (), and in an additional analysis excluding the earliest follow-up period after AIDS onset (months 0–3), similar declines in cumulative incidence were noted relative to widespread HAART use (data not shown).
The five-year cumulative incidence of KS and NHL declined 87% and 44%, respectively, among people diagnosed with AIDS during diagnosed during 1996–2006 (HAART era) compared with those diagnosed in the 1980s. However, NHL was the most common cancer during the most recent calendar period of AIDS. The continued occurrence of both KS and NHL suggests the need for increases in access and adherence to HAART.(21
) Among women, the cumulative incidence of cervical cancer changed little with the widespread availability of HAART.
Overall, cumulative incidence of NADCs was low, but increased over time. This trend largely reflects the decline in mortality, which has allowed people with AIDS to live long enough to develop cancer. In particular, cumulative incidence of anal and liver cancers increased among people diagnosed with AIDS in the HAART era compared with earlier periods. It is possible that HAART-associated immune restoration, particularly late after an AIDS diagnosis, does not influence the natural history of infections with human papillomavirus (anal cancer) or hepatitis C and B viruses (liver cancer).(23
) In addition, an increase in the cumulative incidence of Hodgkin lymphoma in the HAART era was noted. Some studies,(9
) although not all,(27
) have reported an increase in Hodgkin lymphoma incidence in the HAART period, which may reflect the complex relationship between immunosuppression and development of this malignancy.(28
) We also noted a rise over time in the cumulative incidence of lung cancer; however, the burden of lung cancer was unchanged between the 2 most recent calendar periods. The excess risk of lung cancer is partly due to a high prevalence of smoking,(29
) but chronic pulmonary inflammation or repeated lung infections in HIV-infected people may also be involved.(30
Strengths of this study include its large size and inclusion of major U.S. areas affected by the HIV/AIDS epidemic. The present estimates of cumulative incidence were derived using a non-parametric competing risk framework and indicate the probability of actually observing cancer in people with AIDS. We are not aware of similar previous estimates in the field of HIV/AIDS research. A limitation is that individual-level data were lacking on important cancer co-factors such as HAART use, infection with oncogenic viruses, and smoking, which influence cancer risk. Nonetheless, we believe our estimates accurately reflect the overall cumulative incidence of cancers among people with AIDS and the impact of widespread HAART use on cancer burden over time.
While our findings can likely be generalized to the entire U.S. AIDS population, an additional limitation is that we evaluated only people with AIDS, who comprise a subset of the overall HIV-infected population. The cumulative incidence of most NADCs would be expected to be higher in HIV-infected people without AIDS, because the competing risk of death is lower in this group than among people with AIDS. Finally, our cumulative incidence estimates for people more than five years after AIDS onset should be interpreted cautiously. In particular, some people with AIDS would have migrated away from the cancer registry area, which would have led to underreporting of observed cancers.
Patterns of cancer incidence among people with AIDS in the United States are changing in the HAART era. Dramatic declines in the cumulative incidence of ADCs were noted along with an increase in the cumulative incidence of some NADCs, including those for which incidence is higher than in the general population (cancers of the anus, liver, and lung, and Hodgkin lymphoma). As HIV infection is increasingly considered with chronic disease management paradigms, greater attention should be focused on cancer screening and prevention strategies.