By Liz Highleyman

It is well known that people with HIV are at higher risk for AIDS-defining cancers such as Kaposi's sarcoma, but data has accumulated in recent years indicating that HIV infection also raises the risk of certain non-AIDS-defining malignancies, even at CD4 cell levels above the traditional opportunistic infection "danger zone" of 200 cells/mm3.

ATHENA Cohort

Anouk Kesselring from the HIV Monitoring Foundation in Amsterdam and colleagues investigated the association between immunodeficiency, HIV viremia, and non-AIDS defining malignancies, while adjusting for traditional cancer risk factors.

The investigators looked at 11,459 patients in the observational Netherlands ATHENA cohort who started combination antiretroviral therapy (ART) since January 1, 1996. A majority (77%) were men and the median age was 38 years. Participants could be either treatment-naive or have previously used nucleoside reverse transcriptase inhibitor (NRTI) monotherapy or dual therapy. About one-quarter had a prior AIDS diagnosis, the median nadir (lowest-ever) CD4 cell count was 150 cells/mm3, more than 70% had ever smoked, and 5% each had hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection.

The researchers compared the risk of fatal and non-fatal non-AIDS-defining cancers occurring after the start of combination ART (excluding basal cell and squamous cell skin cancers), and their association with potential risk factors including age, sex, region of origin, smoking, alcohol use, HBV and HCV coinfection, HIV transmission route, prior AIDS diagnosis, nadir CD4 count, CD4 cell count and viral load at the start of treatment, interval between HIV diagnosis and treatment, and duration of ART. CD4 count and viral load were also considered as time-updated variables and as a measure of cumulative time with a CD4 count below 200, 350, or 500 cells/mm³ and with detectable HIV RNA > 400 cps/mL.

Malignancies were classified as being non-infectious or related to infections including human papillomavirus (HPV), which can cause cervical, anal, and oral cancers, and HBV or HCV, which can cause liver cancer.

Results

	During 67,179 person-years (PY) of follow-up, a total of 232 malignancies were reported.
	43% were related to infections and 57% were due to other causes.
	The most common types were lung cancer (44%), anal cancer (37%), and other epithelial cancers (33%).
	Within the 6 months prior to cancer diagnosis, 89% of affected patients were on combination ART, 75% had undetectable HIV viral load, and the median CD4 count was 340 cells/mm3.
	Longer duration with a CD4 count below 350 cells/mm³ was associated with development of non-AIDS-defining malignancies.
	This association was attributable to infection-related cancers.
	Longer duration of detectable viral load, however, was not a significant risk factor.

"In the setting of treated HIV infection, longer exposure to immunodeficiency below 350 CD4 cells/mm3 [is] associated with non-AIDS-defining malignancies," the researchers concluded. "Longer exposure to viremia was not associated with non-AIDS-defining malignancies."

HIV Monitoring Foundation, Amsterdam, Netherlands; Academic Medical Center of the University of Amsterdam, Department of Infectious Diseases, Tropical Medicine and AIDS, Amsterdam, Netherlands.

CD4 Count

In a related study, Nancy Crum-Cianflone from the Naval Medical Center San Diego and colleagues asked what CD4 cell levels are associated with a reduced rate of cancer in people with HIV.

The investigators retrospectively analyzed 4963 participants from 7 sites enrolled in a prospective, multicenter U.S. Military HIV Natural History Study between 1984 and 2008, representing 37,660 person-years. In this study, patients were on average younger (median 28 years) and were more likely to men (92%).

Here too, malignancies were classified as AIDS-defining (Kaposis sarcoma, non-Hodgkins lymphoma, or invasive cervical carcinoma) or non-AIDS-defining.

Results

	A total of 501 patients (10.3%) developed cancer during the study period (including 20 with more than 1 type).
	There were 336 AIDS-defining cancers and 186 non-AIDS-defining cancers.
	The most common non-AIDS-defining cancer were skin cancers (52%), anal cancer (15%), and Hodgkin?s disease (9%).
	Individuals who developed cancer and in particular an AIDS-defining cancer had a lower CD4 nadir before cancer developed and a lower CD4 count nearest the time of cancer diagnosis.
	The median CD4 count nearest the time of AIDS-defining cancer diagnosis was 53 cells/mm3, compared with 454 cells/mm3 for non-AIDS-defining cancer diagnosis.
	Overall, the highest rate of AIDS-defining cancer was 44.7 per 1000 PY, observed in people with CD4 counts < 200 cells/mm3.
	As CD4 counts increased, the incidence of AIDS-defining cancer progressively declined, with the lowest rate of 1.3 per 1000 PYs seen in people with a CD4 count > 700 cells/mm3.
	The incidence of non-AIDS-defining cancers was similar in people with CD4 counts < 200 cells/mm3 and 500-700 cells/mm3 (5.1 and 5.6 per 1000 PY, respectively).
	The rate fell to 3.6 per 1000 PY, however, for those with CD4 counts > 700 cells/mm3.
	Compared with the pre-HAART era, the rate of AIDS-defining cancer was lower in each CD4 cell strata after the advent of HAART.
	Rates of non-AIDS-defining cancers, in contrast, were slightly higher in the HAART era.
	Rates of non-AIDS-defining cancers other than skin cancers were relatively similar across CD4 cell strata, but skin cancers occurred at lower rates in people with > 700 cells/mm3.

"While the risk of AIDS-defining cancers was highest at CD4 counts < 200 cells/mm3, increased risk was also present at counts < 500," the researchers concluded. "There was an association between non-AIDS-defining cancers and CD4 counts < 700 cells/mm3 during follow-up."

This association was mainly seen in the pre-HAART era and for skin cancers: they continued. "During the HAART era, there was no association between non-skin non-AIDS-defining cancers and CD4 strata."

"Maintaining robust CD4 counts is useful in reducing AIDS-defining cancers among HIV patients, but did not have a significant impact on non-AIDS-defining cancers in the HAART era."

Infectious Disease Clinical Research Program, Bethesda, MD; Naval Medical Center San Diego, San Diego, CA; University of Minnesota, Minneapolis, MN.

7/28/09

References

A Kesselring, L Gras, C Smit, and others. Immunodeficiency, not viremia, is a risk factor for non-AIDS-defining malignancies in patients on cART. 5th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2009). July 19-22, 2009. Cape Town, South Africa. Abstract WeAb104.

N Crum-Cianflone, K Huppler Hullsiek, V Marconi, and others. What CD4 cell count levels are associated with a reduced risk of cancer? 5th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2009). July 19-22, 2009. Cape Town, South Africa. Abstract WePeB249.

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