Pre-existing immune deficiency main cause of AIDS-defining cancers in patients starting HIV therapy

New research has underlined the importance of the timely initiation of antiretroviral therapy. In a paper published in the online edition of AIDS, investigators from the European CASCADE collaboration showed that the risk of AIDS-defining cancers in patients starting HIV therapy was associated with severe immune deficiency in the preceding year.

“An initially low and decreasing CD4 cell count during the year prior to cancer diagnosis is predictive of both Kaposi sarcoma and NHL [non-Hodgkin lymphoma],” comment the authors.

However, their results also showed that the incidence of both these cancers was increased in the three months following the initiation of antiretroviral therapy.

The investigators emphasise, “most of this increased cancer risk is explained by the immunodeficiency characteristic of the period before cART [combination antiretroviral therapy] initiation.”

But they add, “there may be some additional risk resulting from immune reconstitution during the first few months after cART initiation.”

Immune reconstitution inflammatory syndrome (IRIS) in patients with HIV involves a worsening of health soon after antiretroviral therapy is started. It can involve either a deterioration of an existing condition, or the “unmasking” of sub-clinical disease.

Most of the research into antiretroviral-related IRIS has focused on opportunistic infections such as tuberculosis (TB). However, studies have also identified Kaposi’s sarcoma IRIS.

Investigators from the Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) collaboration wanted to establish a clearer understanding of the risks associated with the development of the AIDS-defining cancers Kaposi’s sarcoma and non-Hodgkin’s lymphoma in the period after the initiation of HIV therapy. The investigators especially wanted to see if the risk of these cancers was associated with immune deficiency in the period before treatment was started, or if any of the risk to be attributed to IRIS.

They therefore designed a case-controlled study. Cases were patients who developed a cancer, and each case patient was matched with up to ten controls.

All the cases had a minimum of two CD4 cell count measurements in the year before their cancer diagnosis. The cases also had similar CD4 data for a reference year.

A total of 689 cases were eligible for inclusion in the study, and they were matched with 4588 controls.

During the year before diagnosis (or the reference year), 31% of cases but only 6% of controls had a CD4 cell count below 100 cells/mm³.

In the year before the diagnosis of Kaposi’s sarcoma or non-Hodgkin’s lymphoma (or the reference year), CD4 cell counts in the case patients fell by an average of 16% compared to a fall of just 2% in the controls.

Analysis showed that patients with a low or falling CD4 count in the year preceding had an increased risk of developing an AIDS-defining cancer. The risk of these malignancies increased as patients’ immune function deteriorated. The association between a poorer and deteriorating immune system was significant even when analysis was restricted to the period after 2000.

However, the investigators also found some evidence that the risk of cancer was increased in the period shortly after HIV therapy was started.

They explain, “there was a significant trend toward an increasing [risk] of cancer as the interval between cART initiation and the reference date decreased.”

An increased risk of an AIDS-defining cancer was seen in patients who started HIV therapy within the previous three months (OR = 2.31; 95% CI, 1.33-4.00).

“Given the known associations of Kaposi sarcoma and NHL with underlying viral infections…it would not be surprising to observe these cancers occurring or worsening in the context of IRIS,” write the authors.

However, they add, “most of the excess cancer risk in patients initiating cART reflects the immunodeficiency that most likely led to the use of cART.”

The authors conclude, “the main risk factor for the appearance of these malignancies is immunodeficiency; and, therefore, the timely initiation of cART remains the best strategy to avoid the development of these malignancies.