In this population-based assessment of causes of death among people with AIDS, we demonstrated dramatic declines in overall mortality, which reflected falling mortality attributable to AIDS, cancer, and other causes. Across calendar periods of AIDS onset, the declines in mortality due to ADC (specifically KS and NHL) and other AIDS-related conditions (opportunistic infections) can likely be attributed to immune restoration associated with widespread HAART use, and have been demonstrated in other studies in the U.S. and elsewhere [7
]. Prior studies have not specifically evaluated mortality due to individual ADCs and NADCs as reported by death certificates or have not provided rates for these causes of death.
Despite declines in ADC mortality, NHL remained the most common cancer-related cause of death. While NHL incidence among people with AIDS has declined and survival following NHL diagnosis has improved in the HAART era, a large fraction of people with AIDS-associated NHL still die from their malignancy [5
]. For example, in a recent European analysis of patients with AIDS-related NHL, 34% had died by one year after diagnosis and 45% by five years after diagnosis [22
]. Major adverse prognostic factors included a diagnosis of central nervous system NHL, advanced immunodeficiency, and prior receipt of HAART (presumably reflecting incomplete adherence or development of drug resistant HIV) [22
Treatment options for AIDS NHL are complicated by late presentation [23
]. For patients with AIDS-related NHL, a recent phase 2 trial demonstrated the safe addition of rituximab (a chimeric monoclonal B-cell antibody) to concurrent infusional chemotherapy, resulting in complete remission for 73% of patients evaluated [24
]. Another recent study found that NHL tumor subtype was an independent predictor of outcome, emphasizing the heterogeneity of AIDS NHLs and the need for additional clinical studies which evaluate treatments for individual histologic subtypes of NHL [25
]. Finally, improved HAART regimens could also have a major impact on NHL mortality, both by decreasing NHL incidence and increasing survival among people with AIDS who develop NHL.
We also demonstrated notable declines in mortality due to NADCs. Because the incidence of these malignancies has not fallen over time in a corresponding manner [5
], the decline in mortality may reflect improvements in cancer prognosis, perhaps due to earlier detection, better access to cancer care, or more effective use of cancer therapy in conjunction with HAART. Among people with AIDS who died in the HAART era, lung cancer was the most frequent NADC cause of death, underscoring the importance of this malignancy. HIV-infected people have an elevated risk for lung cancer owing to an excess of smoking [27
]. In addition, other factors such as frequent pulmonary infections or inflammation may also contribute in synergy with tobacco [29
]. While we observed declining mortality rates due to lung cancer, survival among HIV-infected lung cancer patients remains poor [9
], emphasizing a need to encourage smoking cessation in people with AIDS. Data from lung cancer treatment trials limited to the HIV population are lacking. For those with early stage cancer, surgical resection is an option, but optimum radiation and chemotherapy protocols are unknown.
Liver cancer mortality rates declined significantly across calendar periods in our study, but with declines in other causes, the fraction of deaths due to liver cancer increased in the HAART era. The overall burden of liver cancer deaths may continue to rise in people with AIDS as the combined effects of alcohol use and coinfection with hepatitis B or C viruses manifests as liver disease [31
The decline in mortality from other causes led to an increase in the fraction of all deaths due to cancer (both ADC and NADC). We note the importance of considering both mortality rates and the fraction of all deaths attributable to a specific cause, since they yield complementary information. In an additional analysis of NHL and lung cancer deaths (which were the most common cancer-related causes of death in our study), we found that most had had that cancer reported to the cancer registry. However, the lack of perfect concordance between information on the cause of death in the HIV/AIDS and cancer diagnoses in the cancer registries suggests that some death certificate diagnoses could have been inaccurate.
A strength of this study is our use of data from population-based HIV/AIDS registries to capture and classify all deaths among people with AIDS. Although information on cause of death was available from only 5 of our study sites, the demographic characteristics of our cohort of people with AIDS were generally similar to the overall U.S. AIDS population. Cause of death was specified for the majority of included subjects, but a limitation is that this information was missing for some (between 7%-15%, depending on the calendar period). We note that it takes multiple years for cause of death information to be verified, and completeness increases over time. Further, as people’s understanding of HIV disease and deaths in this population evolved over time, the attribution of death to a given cause likely changed in parallel (e.g., HIV disease is now considered less limiting, so attribution to other causes may have increased over time). Nonetheless, the overall declines we note in mortality rates are consistent with what has been reported by other studies. It should also be noted that we lacked individual data on HAART use. However, our results accurately reflect overall the population-level effects of HAART use on mortality. Our goal was to evaluate cancer causes of death, so we did not separately evaluate other causes of death. Other studies suggest that cardiovascular disease and substance abuse contribute substantially to this category and should be a focus of prevention programs [7
]. Finally, we evaluated only people with AIDS and did not consider people with less advanced HIV infection. Although we did include data on this group, one would expect lower mortality rates among HIV-infected people without AIDS.
In summary, our findings demonstrate that cancer mortality among people with AIDS has declined in the HAART era, but with concomitant declines in other causes of death, cancers now account for a growing fraction of deaths. As HIV-infected people continue to live longer following an AIDS diagnosis and as they age, cancer may increase as a cause of mortality. In particular, improved prevention and treatment of NHL and lung cancer, the two most common cancer-related causes of death, would be expected to favorably impact survival among HIV-infected people.