Even when the CD4 cell count is above 350 there is an increased risk of AIDS-related illnesses—provided that viral replication remains unchecked—according to a new analysis from the EuroSIDA study published online ahead of print by the journal AIDS. The authors also suggest a slightly increased rate of non-AIDS-related illnesses when the CD4 cell count is above 500, notably when the viral load is very high, though it was not possible to entirely rule out confounders—health risks not accounted for in the study.
U.S. treatment guidelines recommend antiretroviral (ARV) therapy for all people living with HIV with CD4s below 500 cells. This recommendation, along with the suggestion by some HIV experts that ARV treatment should be started even earlier, is based on preliminary research indicating that uncontrolled viral replication leads to immune activation and inflammation that can drive up the risk of certain AIDS and non-AIDS illnesses.
But is HIV replication, independent of a person’s CD4 count, a risk factor for disease? This was the question raised by Joanne Reekie of the University College of London and her colleagues with EuroSIDA, a cohort study of more than 16,000 adults under care in a network of 103 hospitals in 33 European countries plus Israel and Argentina.
To look for associations between viral load and AIDS-defining illnesses, Reekie’s group conducted an analysis involving nearly 11,500 people living with HIV who were receiving care from 1997 onward. The potential for associations between viral load and non-AIDS-defining illnesses—such as cardiovascular disease, various cancers and liver-related problems—was explored in nearly 11,000 people living with HIV who were active in the cohort from 2001 onward.
To be included in the analysis, patients had to have a recent CD4 count above 350—a cell count below this level, in the past, didn’t disqualify patients. If they qualified, patients were divided into three groups: those with low viral loads (below 500 copies), which accounted for 82 percent of the study volunteers; those with intermediate viral loads (between 500 and 10,000 copies), consisting of 11 percent of the study volunteers; and those with high viral loads (above 100,000 copies), which included 7 percent of the study volunteers.
Of note, 61 percent of those in the intermediate viral load group and 36 percent of those in the high viral load group were receiving ARV treatment.
Overall, 354 AIDS-related illnesses were reported during the follow-up period, with tuberculosis, esophageal candidiasis, cervical cancer and non-Hodgkin’s lymphoma being the most common.
Even in the researchers’ crude analysis—a look at the data without adjustments for potential risk factors like HIV transmission category, geographic region, hepatitis coinfection, smoking and diabetes—there was a clear association between intermediate and high viral loads and a new onset of an AIDS-related illness.
After adjusting the data, those with intermediate viral loads were 44 percent more likely to experience an AIDS-related disease, compared with those with low viral loads. Those with high viral loads faced a greater than 200 percent increase in the risk of an AIDS-related illness, despite having a CD4 count above 350.
Five hundred seventy-two non-AIDS-related illnesses were reported, with cardiovascular disease and various cancers being the most common. In the researchers’ crude analysis, however, there did not appear to be an association between viral load and a new onset of a non-AIDS-related illness.
Only after adjusting the data did researchers document associations with viral load, and only among those with CD4s greater than 500. The risk was increased by 61 percent among those with intermediate viral loads, compared with those with low viral loads, and 66 percent among those with high viral loads.
Looking at the specific non-AIDS illnesses and potential associations with viral load, the researchers found inconsistent results. For example, a higher incidence of cardiovascular disease was observed in individuals with intermediate viral loads, but not with high viral loads. And for non-AIDS-defining cancers, liver-related diseases and pancreatitis, no significant differences in the incidences were seen when comparing those in the low, intermediate and high viral load groups. And because there were only limited numbers of other non-AIDS illnesses, conclusions regarding the association between unchecked viral load and these diseases could not be reached.
“In conclusion,” the authors write, “in HIV-positive individuals with a CD4 count [greater than 350], an increased incidence of AIDS and a slightly increased incidence of non-AIDS was found in those with uncontrolled viral replication. The association with AIDS was clear and consistent. However, the association with non-AIDS was only apparent after adjustment, and no differences were observed between intermediate and high viremia.”
Additional studies, the authors suggest, are needed to better understand potential links between untreated HIV among people with high CD4s and the risk of non-AIDS illnesses.