Immune Suppression Predicts Non-AIDS-related as well as AIDS-defining Malignancies in people with HIV

By Liz Highleyman

Cancer Cell

Evidence continues to accumulate suggesting that ongoing HIV replication and declining CD4 counts are linked to various conditions that traditionally have not been considered AIDS-related. For example, in the large SMART trial, patients who interrupted treatment when their CD4 count fell below 350 cells/mm3 not only had a higher risk of opportunistic infections and death, but also had more heart, liver, and kidney disease.

Another recent analysis by researchers studying the large Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) cohort indicates that immune suppression also increases the risk of non-AIDS-defining malignancies.

The 3 traditional opportunistic or AIDS-defining cancers are Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer. Anal cancer is not considered AIDS-defining, although it is caused by the same strains of human papillomavirus (HPV) as cervical cancer, and many experts believe it should be. Other studies have shown that certain other cancers associated with infectious pathogens, including liver cancer related to chronic hepatitis B or C, are also more common in people with HIV.

Cervical Cancer

As described in the October 18, 2008 issue of AIDS, the D:A:D investigators evaluated deaths due to AIDS-defining and non-AIDS-defining malignancies in their multinational cohort, looking at the relationship between these deaths and immunodeficiency as indicated by CD4 cell count. The analysis included 23,437 HIV positive patients from 188 sites in Europe, the United States, and Australia, prospectively followed for 104,921 person-years.

The researchers used Poisson regression analysis to identify factors independently associated with death due to AIDS-defining and non-AIDS-defining malignancies. Analyses of factors associated with mortality due to non-AIDS-defining cancers were repeated after excluding those malignancies known to be associated with a specific risk factor (e.g., lung cancer with smoking).

Results

• A total of 305 patients died due to any type of malignancy during the study period:

• non-Hodgkin lymphoma: 82 deaths;
• Kaposi sarcoma: 28 deaths;
• cervical cancer: 2 deaths;
• lung cancer: 62 deaths;
• gastrointestinal cancer: 25 deaths;
• hematological cancer: 22 deaths;
• anal cancer: 20 deaths;
• urogenital cancer: 18 deaths;
• liver cancer: 16 deaths;
• cancer of the upper airway: 10 deaths;
• miscellaneous other non-AIDS-defining malignancies: 20 deaths.

• 298 of these deaths occurred prior to the cut-off date and were included in further analysis:

• 110 AIDS-defining malignancies;
• 188 non-AIDS-defining malignancies.

• Mortality rates for non-AIDS-defining malignancies were higher than those for AIDS-defining cancers for all but patients with very low CD4 counts (< 50 cells/mm3).

• The mortality rate due to AIDS-defining malignancies decreased from 20.1 per 1000 person-years when the most recent CD4 count was < 50 cells/mm3 to 0.1 per 1000 person-years when the latest CD4 count was > 500 cells/mm3.

• The mortality rate from non-AIDS-defining malignancies decreased from 6.0 per 1000 person-years when the latest CD4 count was < 50 cells/mm3 to 0.6 per 1000 person-years when it was > 500 cells/mm3.

• In multivariate regression analyses, when the latest CD4 count doubled, the risk of AIDS-defining malignancies was cut in half.

• Other predictors of increased risk of death due to AIDS-defining malignancies were:

• homosexual risk group;
• older age;
• previous non-malignancy AIDS diagnosis;
• earlier calendar year.

• Predictors of an increased risk of mortality due to non-AIDS-defining cancers included:

• lower CD4 cell count;
• older age;
• current or past smoking;
• longer cumulative exposure to combination antiretroviral therapy;
• active hepatitis B virus (HBV) infection;
• earlier calendar year.

• The relationship between the latest CD4 cell count and non-AIDS-defining malignancies remained after excluding anal cancer and Hodgkin lymphoma (which may in fact be opportunistic).

• The relationship remained similar whether the non-AIDS-defining cancers did or did not have a underlying viral cause.

• HIV viral load was only weakly associated with mortality due to AIDS-defining malignancies, and was not independently associated with death due to non-AIDS-defining cancers.

Based on these findings, the investigators concluded that, "The severity of immunosuppression is predictive of death from both AIDS-defining malignancies and non-AIDS-defining malignancies in HIV-infected populations."

In their discussion, the authors noted that there was no clear explanation for the link between HAART use and higher risk of non-AIDS-defining malignancies. They offered a few possible reasons, including the fact that individuals on effective HAART are less likely to die from AIDS-defining malignancies and therefore may be more likely to develop non-AIDS-defining cancers, patients dying from AIDS-defining malignancies may be more likely to have stopped or never received HAART, and long-term exposure to some antiretroviral drugs may be carcinogenic.

Since immunosuppression increases the risk of dying from cancer, the authors suggested that, "improvements to patients' immune systems following the use of combination antiretroviral therapy may be expected to have a positive impact on the risk of death from non-AIDS-defining malignancies, underlining the importance of HIV treatment strategies that aim to prevent immunodeficiency."

They also emphasized the importance of other cancer prevention strategies, in particular smoking cessation and hepatitis B vaccination and treatment. Contrary to expectations, however, they did not see an association between hepatitis C coinfection and non-AIDS-defining malignancies, even though HCV is a well established risk factor for liver cancer.

10/10/08

Reference
A Monforte, D Abrams, C Pradier, and others (D:A:D Study Group). HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS 22(16): 2143-2153. October 18, 2008. (Abstract).