Cancer: further evidence that long-term immune suppression will boost risk for people with HIV

A comprehensive meta-analysis of studies looking at cancer incidence in people with HIV and people who received long-term immunosuppressive therapy after organ transplants shows a similar and elevated risk of a wide range of cancers, especially those caused by infectious agents, suggesting that cancer is likely to become an increasingly common complication as people with HIV live longer.

The findings, published this week in The Lancet, come from a meta-analysis carried out by Professor Andrew Grulich and colleagues at the National Centre in HIV Epidemiology and Clinical Research, Sydney, Australia.

The study identified seven incidence studies of cancer in people with HIV from the United States, United Kingdom, Australia, Switzerland and Italy, and five studies of cancer incidence in people immunosuppressed after organ transplants from Scandinavia, Canada and Australia. The data were derived from cohort studies in which cancer incidence was confirmed by reference to national cancer registries, ensuring the reliability of the data captured. All studies have been published in peer-reviewed medical journals.

The cohorts comprised 444,172 people with HIV and 31,977 transplant recipients, with 42,000 cancers in the HIV-positive group and 3,000 in the transplant group.

The researchers wanted to compare cancer rates in people with HIV and in immunosuppressed people in order to see if there were any differences with expected rates of cancer in the general population, and also to see whether any common patterns emerged that might be linked to long-term immunosuppression.

The researchers calculated standardised incidence ratios (SIR) for each type of cancer but say that the numerical SIRs are less important than the overall trend identified.

The meta-analysis found a higher incidence of all cancers related to infectious causes in HIV-positive people than in the general population, and most of these cancers occurred more frequently in people with HIV than in transplant recipients. These infectious causes included human papillomavirus (cervix, vulva, vagina, penis, anus, oral cavity, pharynx), Epstein-Barr virus (Hodgkin’s lymphoma and non-Hodgkin’s lymphoma), HHV-8 (Kaposi’s sarcoma), hepatitis C (liver) and helicobacter pylori (stomach).

However, common epithelial cancers of the breast, prostate, colon, rectum and ovary did not occur at a higher rate in HIV-positive people when compared with the general population. One site of epithelial cancer did appear to be over-represented among HIV-positive people: the trachea, bronchus and lung, where the incidence was 2.7-fold higher than in the general population, with a similarly elevated risk seen in transplant recipients. An elevated risk of colorectal cancer was seen in transplant recipients but not in people with HIV, while men with HIV appeared to have a lower risk of prostate cancer than the general population.

Four types of cancer occurred more frequently in both groups when compared with the general population: kidney (much greater elevation in risk in transplant recipients), multiple myeloma, leukaemia and melanoma. Bladder and thyroid cancer were seen more frequently in the transplant group but not in people with HIV, while brain and testicular cancer rates were elevated only in people with HIV.

“Our data indicate that an extensive range of cancers occurs at increased incidence both in people with HIV/AIDS and in transplant recipients. Our meta-analysis suggests that the range of infection-related cancers associated with immune deficiency is much wider than previously appreciated and that a range of infectious organisms seems to be implicated.”

The authors dismiss lifestyle factors as an explanation for the elevated risk in each group, pointing out that despite the substantial difference in smoking rates between the two groups, the incidence of tobacco-related cancers was similar in the two groups.

They admit that immune deficiency has not been shown to be linked with a higher risk of cancer in all studies in people with HIV. "For example the largest study of cancer risk in people with HIV/AIDS found no relation between immune deficiency - as measured by CD4 count at AIDS diagnosis - and risk of most of types of cancer.”

“We believe that CD4 count at AIDS diagnosis could be an insensitive indicator of association with immune deficiency,” say the authors.

“First, the relation between cancer risk and degree of immune deficiency might not always be linear, and could be different for different types of cancer. For example, the striking increase in risk of HPV-related cancers seen in long-term transplant recipients suggests that even modest immune suppression, if present for long enough, could increase the risk of these cancers. Second, CD4 count at AIDS diagnosis might not be an accurate or unbiased measure of immune function at cancer onset.”

In an accompanying editorial Gary Clifford and Silvia Franceschi of the International Agency for Research on Cancer agree. “Unfortunately, perfect markers of immune deficiency do not exist. CD4+ count has served well for people with HIV, but we are far from sure that this measure explains all the effects of HIV on immunological surveillance.“

“The excess risk for lung cancer found by Grulich and colleagues in both patients with HIV and transplant recipients is difficult to reconcile with a mere confounding effect of tobacco smoking, while the relative risk for colorectal cancer, for which no infectious cause is known, is of similar magnitude in transplant recipients as the one seen for Helicobacter-related stomach cancer in both groups.”

The findings also contain little comfort for people taking antiretroviral therapy.

“The only study that compared non-AIDS-defining cancer rates before and after HAART found that rates of most non-AIDS-defining cancers did not change,” Professor Grulich and colleagues comment.

In conclusion, Professor Grulich and colleagues discuss the theory put forward in 1970 by Frank Burnet, which postulated that the immune system was responsible for the recognition and destruction of cancerous cells.

“The theory predicted that immune deficient populations should experience high rates of cancer of all types. Clearly, this is not the case, and until now, it has been concluded that only a few viral-associated cancers are related to immune deficiency.”

But they go on, “the increased rates of cancers we have found at a very large range of sites suggests a broader than previously appreciated role for the immune system in the prevention of cancers related to infection. If immune deficiency is associated with such a broad range of cancer types, then cancer is likely to become an increasingly important cause of morbidity in people with HIV/AIDS.”