Researchers with the D:A:D cohort have uncovered another benefit of keeping the immune system strong in people with HIV: a lowered risk of dying from any type of cancer, including both AIDS-related cancers and non-AIDS malignancies. Their report, published in the October 18th issue of AIDS, also found that non-AIDS cancers are accounting for the majority of cancer deaths among people with HIV and are the more common types of cancer among all people with HIV apart those with the weakest immune systems.
Thanks to antiretroviral therapy, fewer people with HIV who receive the drugs are dying of AIDS-related causes. Instead, a growing number of deaths are due to non-AIDS conditions, such as cardiovascular disease and cancer. As these non-AIDS conditions become more common, investigators are questioning the impact of HIV, and antiretroviral therapy, on these other conditions. (For an overview, see aidsmap.com’s summary of the 2008 CROI plenary session Morbidity and mortality in the HAART era.
Non-AIDS cancers are one class of conditions that have become an important cause of death among people with HIV since the introduction of antiretroviral therapy. There is some evidence that HIV may increase the incidence of some of these cancers, but little is known of factors, including HIV treatment, that influence the risk of cancer death.
In this report, investigators turned to the extensive database of the D:A:D cohort to describe the rates of death due to cancer among people with HIV. The D:A:D cohort is an observational study comprising eleven cohorts of patients receiving antiretroviral therapy from three continents and including 23,437 participants. While the primary aim of the cohort is to evaluate the impact of antiretroviral therapy on risk of cardiovascular disease, the cohort collects data on all causes of death, including cancer.
From the cohort, the investigators identified 305 patients who died from cancer: 112 died of an AIDS cancer, while 193 died of a non-AIDS cancer. Of the 112 AIDS cancers, 82 were non-Hodgkin's lymphoma, 28, Kaposi’s sarcoma, and two, cervical cancer. The 193 non-AIDS cancer cases included 62 lung cancers, 25 gastrointestinal cancers, 22 haematological cancers, 20 anal cancers, 18 urogenital cancers and 16 liver cancers.
The overall death rate for AIDS cancers was 1.1/1000 per years of follow up (95% CI, 0.9 – 1.2) and for non-AIDS cancers, 1.8 (1.5 – 2.1). When investigators assessed death rates at different CD4 cell counts, they found that only when the latest CD4 cell count prior to death were below 50 cells/mm3 were death rates due to AIDS-defining cancers higher than rates due to non-AIDS cancers (20.1 for AIDS cancers versus 6.0 for non-AIDS cancers). Among those with intact immune systems (last CD4 cell count prior to death above 500 cells/mm3), the death rate for AIDS cancers was 0.1 and for non-AIDS cancers, 0.6.
Latest CD4 cell count was strongly associated with risk for AIDS cancer death and non-AIDS cancer death. A doubling of CD4 cell count was associated with a halving of AIDS cancer deaths (adjusted rate ratio 0.53 (0.48 – 0.59) and an almost 40% reduction of non-AIDS cancer deaths (0.61, 0.57 – 0.66). Latest viral load measures were not strongly linked to death by either AIDS or non-AIDS cancer.
Factors associated with risk of AIDS cancer death were being homosexual, being older, having a previous AIDS diagnosis and being from early in the study cohort. Among the people who received HIV treatment, the investigators noted that those with a low current CD4 cell count but a high nadir count were particularly susceptible to AIDS cancer death, “suggesting that those at highest risk were those whose CD4 cell count had remained low on [antiretroviral therapy], or whose count had risen but subsequently fallen.”
When investigators turned their attention to non-AIDS cancer deaths, they found that being older was associated with higher risk, while having joined the cohort more recently was associated with lower risk. Unsurprisingly, non-AIDS cancer deaths due to lung cancer and liver cancer were linked to smoking and active hepatitis B virus infection, respectively. There was not an association between liver cancer and hepatitis C virus infection, though the investigators note that in the cohort, people co-infected with HIV and hepatitis C virus more often die of liver failure than liver cancer.
Unexpectedly, AIDS cancer deaths were not associated with HIV treatment use in adjusted analyses, while non-AIDS cancer deaths were. Compared with people who had taken antiretroviral therapy for less than four years, the rate of death due to non-AIDS cancers was 62% lower among people who had never taken HIV treatment and 76% higher among people who had taken antiretroviral therapy for more than four years. One interpretation is that people on HIV treatment are less likely to die of AIDS cancers and thus may be more likely to die from non-AIDS cancers. However, the investigators argue that “A more likely explanation is that after diagnosis of a [non-AIDS cancer], [antiretroviral therapy] may be started quickly to enhance the immune system in preparation for the detrimental effects of antineoplastic drugs. In contrast, patients dying from [an AIDS-related cancer] may be more likely to have stopped or never received [antiretroviral therapy].”
The investigators also highlighted the finding that for a similar CD4 cell count, being older was a risk factor for dying from either an AIDS cancer or a non-AIDS cancer. Though this may simply be due to the fact that cancer occurs more frequently in older people, the investigators hypothesise that with age the immune system degrades in ways not captured by CD4 cell counts.
While the study did not investigate the impact of antiretroviral therapy directly on risk of cancer death, the investigators conclude that “improvements to patients’ immune systems following the use of [antiretroviral therapy] may be expected to have a positive impact on the risk of death from [non-AIDS cancer], underlining the importance of HIV treatment strategies that aim to prevent immunodeficiency.”
The D:A:D Study Group. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS 22:2143 – 2153.