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Non-AIDS Cancers Linked to Lower CD4 Count in People with HIV


HIV positive people who spent more time with a CD4 cell count < 200 cells/mm3 had a higher risk of developing non-AIDS cancers, in particular those related to infectious causes, according to findings from the Dutch ATHENA cohort published in the June 15, 2011, issue of Clinical Infectious Diseases.

n the era of effective antiretroviral therapy (ART), people with HIV are developing more non-AIDS malignancies such as anal, liver, and lung cancer, give that they are less likely to die of AIDS-related causes and are living longer with risk factors such as smoking. But it has been unclear how immunodeficiency, HIV viral load, and exposure to antiretroviral therapy are related to non-AIDS cancers in people on treatment.

Several non-AIDS cancers are caused by an infectious agent, including human papillomavirus (HPV), which causes cancer of the anus, penis, vulva, and throat; hepatitis B or C virus (HBV and HCV, respectively), which can cause hepatocellular carcinoma (a type of liver cancer); Epstein-Barr virus, the cause of Hodgkin lymphoma; and Heliobacter pylori, which causes gastric cancer.

Anouk Kesselring from the University of Amsterdam and colleagues analyzed 11,459 people with HIV starting antiretroviral treatment in the ATHENA (AIDS Therapy Evaluation in the Netherlands) observational cohort. Since January 1996 cohort investigators have recorded information about participant demographics, CD4 T-cell count and HIV viral load, treatment and adverse events, and AIDS defining and selected non-AIDS clinical events at 23 treatment centers in the Netherlands. Smoking and heavy alcohol use were recorded irregularly, but the researchers determined that about 75% had a history of smoking. About 5% had hepatitis B or C.

The media follow-up period was 4.8 years. Statistical models were used to analyze the time to diagnosis of first non-AIDS-defining malignancies in the cohort (that is, all except AIDS-defining Kaposi sarcoma, non-Hodgkin lymphoma, and invasive cervical cancer). Certain skin cancers such as basal-cell and squamous-cell carcinoma were not counted (A study presented at the recent 6th International AIDS Society Conference in Rome looked specifically at these skin cancers.)


  • A total of 236 non-AIDS malignancies were recorded.
  • 102 malignancies (43%) were related to infectious agents, including:
    • 37 anal cancers;
    • 21 laryngeal cancers;
    • 20 cases of Hodgkin lymphoma;
    • 16 cases of hepatocellular carcinoma;
    • 4 vulvar cancers;
    • 3 esophageal cancers;
    • 1 gastric cancer.
  • The remaining 134 malignancies (57%) not known to be caused by infectious agents included:
    • 44 lung cancers;
    • 8 testicular cancers;
    • 8 cases of melanoma;
    • 6 bladder cancers;
    • 5 pancreatic cancers;
    • 4 renal (kidney) cancers;
    • 3 brain cancers cerebral cancers (not including CNS lymphoma);
    • 1 case of bone cancer.
  • Participants had a median CD4 cell count of 340 cells/mm3 at the time of cancer diagnosis, which occurred a median of 5 years after starting ART.
  • All but 2 cases of anal cancer were seen in men, the majority being men who have sex with men.
  • In a multivariate analysis, longer time spent with a CD4 count below 200 cells/mm3 was significantly associated with development of anal cancer (hazard ratio [HR] 1.52 per additional year with < 200 cells/mm3); having 200-350 cells/mm3 also increased the risk.
  • Other risk factors for anal cancer were older age and having an AIDS diagnosis prior to antiretroviral treatment.
  • All 16 cases of hepatocellular carcinoma were in men.
  • 8 were coinfected with HBV and 3 were coinfected with HCV, but 3 did not have viral hepatitis.
  • HBV coinfection increased the risk of liver cancer by more than 26-fold, but HCV was not found to be a significant risk factor.
  • Other significant risk factors for liver cancer were older age and alcohol abuse.
  • Older age was a significant risk factor for lung cancer, with a trend for smoking.
  • Unlike anal cancer, the length of time with a low CD4 count was not a significant risk factor for either liver or lung cancer.
  • Overall, longer time with a CD4 count below 200 cells/mm3 was a significant risk factor for non-AIDS cancers (HR 1.12 for additional year with < 200 cells/mm3).
  • Longer time with a CD4 count below 350 cells/mm3 was also associated with higher cancer risk, but did not quite reach statistical significance.
  • When stratified by cause, however, low CD4 count remained a significant predictor only for cancers caused by infectious agents.
  • Longer exposure to detectable HIV viral load was not associated with non-AIDS-defining malignancies overall.

The study came to the conclusion that even with effective HIV suppression on ART, past or present immunodeficiency was a significant predictor of non-AIDS-defining cancers. The effect of immunodeficiency was related to cancer-causing infections, and the authors suggested impaired CD4 cell restoration played a role. They concluded that many of the cancers that occur in people with HIV are those with known or suspected infectious causes, and that immunodeficiency is associated with persistence, reactivation, and progression of these infectious agents.

This study strengthens existing data showing that treating HIV earlier, before the immune system sustains serious damage, may help to prevent non-AIDS malignancies. Screening for anal HPV infection and pre-malignant lesions, hepatitis B vaccination, and smoking cessation and alcohol counseling, were also mentioned as important considerations to prevent non-AIDS cancers among people with HIV.

Investigator affiliations: HIV Monitoring Foundation, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Internal Medicine, Medical Center, Alkmaar, Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands; Center for Poverty-Related Communicable Diseases, Amsterdam, Netherlands; Department of Internal Medicine, Subdivision Infectious Diseases Tropical Medicine and AIDS, Amsterdam Medical Center, University of Amsterdam, Amsterdam, Netherlands.



A Kesselring, L Gras, C Smit et al. Immunodeficiency as a Risk Factor for Non-AIDS-Defining Malignancies in HIV-1-Infected Patients Receiving Combination Antiretroviral Therapy. Clinical Infectious Diseases 52(12):1458-1465 (free full text). June 15, 2011.