Non-AIDS-defining malignancies are more common than AIDS-defining cancers in the recent HAART era, and the risk of both types of cancer is higher for individuals with lower CD4 cell counts, according to a study presented Tuesday at the at the Fourteenth Conference on Retroviruses and Opportunistic Infections in Los Angeles.
On behalf of the D:A:D study team, Antonella D’Arminio Monforte of the University of Milan, Italy, presented data on rates of fatal AIDS-defining and non-AIDS-defining cancers, and factors associated with their development. It is well known that immunodeficiency increases the risk of AIDS-defining malignancies, but the extent to which immunodeficiency or HIV infection itself influences the risk of non-AIDS-defining malignancies is less clear.
D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) is an ongoing observational study that was established in 1999 to track the long-term safety of antiretroviral therapy. Involving more than 23,000 HIV-positive people in eleven cohorts on three continents, the study has collected data representing nearly 77,000 person years of prospective follow-up.
Out of a total of 1,246 deaths observed so far, 193 were due to non-AIDS-defining cancers (a rate of 1.05 per 1,000 person years), while 112 deaths were due to AIDS-defining cancers (a rate of 1.79 per 1000 person-years).
The four most frequently reported fatal non-AIDS cancers were lung cancer (20% of cases); cancer of the gastrointestinal tract, such as stomach or liver cancer (13%); cancers of the haematological system, such as Hodgkin’s lymphoma (7%); and anal cancer (7%). Fatal AIDS-defining malignancies were non-Hodgkin’s lymphoma (82 cases), Kaposi’s sarcoma (28 cases), and cervical cancer (two cases); notably, many experts believe that anal cancer should be redefined as an AIDS-defining malignancy, due to its association with human papilloma virus (HPV) infection.
Over 95% of patients who died of either type of cancer had ever been on antiretroviral therapy; about 61% of people with non-AIDS-defining malignancies and 46% of those with AIDS-defining cancers were on treatment at the time of death.
Individuals with non-AIDS-defining cancers had a higher median CD4 cell count at the time of death than those with AIDS-defining cancers (211 vs. 75 cells/mm3). Looking at nadir (lowest-ever) CD4 counts, the corresponding numbers were 87 vs. 30 cells/mm3.
In a multivariate analysis, the relative risk of dying from either AIDS-defining or non-AIDS-defining cancers increased gradually as CD4 cell counts fell. For AIDS-defining cancers, the risk increased from 0.6 per 1,000 person years for patients with CD4 counts above 500 cells/mm3 to 6.0 per 1,000 person years for those with CD4 counts below 50 cells/mm3 to. For non-AIDS-defining cancers, the corresponding figures were 0.1 and 20.1 per 1,000 person years.
These results agree with data presented on Monday from the FIRST study, which also found that lower CD4 cell counts in patients on antiretroviral therapy were associated with an increased risk of developing non-AIDS-defining cancers.
By contrast, the most recent HIV viral load measurement prior to death did not predict the risk of either type of malignancy. The percentages of patients with a viral load below 400 copies/ml at the time were 40% for those with AIDS-defining cancers and 56% for those with non-AIDS-defining malignancies.
As expected, the overall risk of both types of cancer was higher amongst older individuals, but the risk of non-AIDS-defining cancer increased more steeply than that of AIDS-defining malignancies with every additional five years of age.
Current tobacco smokers were found to have a significantly increased risk of cancer death (RR 2.92) – and ex-smokers were also at higher risk - although smoking was not significant once lung cancer was excluded from the analysis.
Individuals with active hepatitis B virus (HBV) infection were also found to be at significantly increased risk of cancer-related death (RR 1.82), an association that was significant only when liver cancer was included in the analysis.
Patients who had previously experienced non-fatal AIDS-related illnesses had a significantly increased risk of death from AIDS-defining cancers. About 80% of patients who died from AIDS-defining cancers had a previous AIDS diagnosis, compared with about 50% of those who died from non-AIDS-defining malignancies.
Interestingly – and in conflict with some past research -- overall rates of both AIDS-defining and non-AIDS-defining cancers decreased over the study period, and were significantly lower in 2004-2005 compared with 1999-2001. Given that patients who died of cancer had similar CD4 counts in both periods, Dr D’Arminio Monforte suggested the decrease might be attributable to earlier diagnosis and more aggressive treatment in recent years.
Nevertheless, the investigators noted that in populations with access to potent antiretroviral therapy, deaths due to non-AIDS-defining cancers are now more common than deaths from AIDS-defining malignancies. They suggested that as the HIV-positive population ages, the incidence of fatal non-AIDS-defining cancers is likely to continue to increase.
They concluded that since lower CD4 counts appear to significantly increase the risk of dying from either AIDS-defining or non-AIDS-defining cancers, there should be a focus on treatment strategies that keep CD4 counts high. They further recommended that smoking cessation, as well as vaccination against and treatment of chronic hepatitis B, should be key cancer prevention strategies for people with HIV.