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Poor CD4 Cell Recovery on ART Predicts Non-AIDS Death

People with HIV who have poor CD4 T-cell recovery despite viral suppression on antiretroviral therapy (ART) have a higher risk of death due to non-AIDS-related causes, but so do their parents, suggesting a genetic factor may be involved in T-cell regeneration, according to a Danish study described in the November 28, 2012, advance online edition of AIDS.

A growing body of evidence indicates that HIV positive people are more likely to develop non-AIDS conditions such as cardiovascular disease and certain cancers compared with HIV negative people of the same age. But whether this is due to HIV infection itself, resulting inflammatory and metabolic changes, toxicities of antiretroviral drugs, or other factors is not well understood. It is also unclear why some people experience excellent CD4 cell recovery after starting ART while others never regain normal levels.

Marie Helleberg from Copenhagen University Hospital and colleaguesanalyzed the impact of CD4 cell gains and non-AIDS mortality among patients on ART who achieved undetectable viral load. They also looked at deaths among the patients' parents to see if non-HIV-related genetic factors might play a role.

The researchers estimated mortality rates among 1758 participants in the Danish HIV Cohort Study at 2 years after they started combination ART for the first time between 1996 and 2008, as well as 1603 of their parents.

The HIV positive participants had all achieved viral loads < 400 copies/mL with 1 year of starting ART, but at baseline had a CD4 count < 500 cells/mm³. A small proportion experienced CD4 cell gains of fewer than 25 cells (4%) or 25-100 cells (10%) during their first 2 years on therapy, while most (86%) gained more than 100 cells.

The study team then matched each participant with 13 control subjects of the same age and sex from national registries (22,854 controls matched to patients; 31,527 controls matched to parents). The researchers calculated incidence rate ratios (IRRs) for non-AIDS-related illness and mortality rate ratios for non-AIDS death (MRRs), and assessed their correlation with CD4 cell levels and increases.

Results

• A total of 116 HIV positive participants died within 2 years after starting ART, mostly (86%) due to non-AIDS natural causes.
• HIV positive participants who gained fewer than  25 CD4 cells had increased mortality due to non-AIDS causes compared with people who gained more than 100 cells.
• The mortality rate ratio was 3.5, indicating more than a 3-fold higher risk of death.
• Higher risk of death among people with small CD4 cell gains was apparent even for those who started ART with a CD4 count >250 cells/mm³ (MRR 3.2).
• However, among people who gained more than 100 cells, mortality was low regardless of CD4 count prior to starting ART.
• Among participants who had CD4 increases of 25 to 100 cells, mortality was higher among those with lower pre-ART CD4 counts.
• The association between small CD4 cell gains and mortality was not significantly affected after controlling for comorbidities, cancer in particular, smoking, or alcohol or injection drug use.
• Parents of patients with poor CD4 cell recovery also had a higher risk of death, though the difference was not as great (MRR 1.5).
• There was a trend towards an association between poor CD4 cell recovery and increased risk of cardiovascular disease and cancer (both with an IRR of 1.6), but not liver disease.

"Poor CD4 increase after HAART [highly active antiretroviral therapy] is associated with adverse prognosis even in absence of severe immunosuppression," the study authors concluded. "CD4 response in HIV patients is associated with mortality among their parents, thus poor CD4 response may be caused by genetic factors, which might also affect morbidity and mortality in the HIV negative population."

"It is thus possible that the ability to recover CD4 cells reflects genetic traits associated with cell renewal mechanisms and survival," they elaborated in their discussion. "HIV patients with poor CD4 response to HAART have increased activation of CD8 T-cells and elevated markers of inflammation. It is hypothesized that inflammation is both a cause of impaired immunological response and of excess morbidity and mortality among poor immunological responders. Genes involved in immune activation and T-cell apoptosis have been associated with CD4 increase during HAART. It is possible that these genetic traits may also be associated with inflammation and increased mortality in the HIV negative population."

As a limitation to their study, they noted that they could not rule out the influence of socioeconomic, environmental, and lifestyle factors -- such as poverty, smoking, and alcohol use -- that might be shared between children and their parents.

"We conclude that poor CD4 response is associated with adverse prognosis even in individuals without severe immunosuppression at HAART initiation, whereas individuals, with a low pre-HAART CD4 count, who survive the following 2 years with adequate CD4 increase, do not have increased mortality," they wrote. "Genetic factors may influence CD4 response and risk of morbidity and mortality. These factors may also affect morbidity and mortality in the HIV negative population."

12/8/13

Reference

M Helleberg, G Kronborg, CS Larsen, et al. Poor CD4 response despite viral suppression is associated with increased non-AIDS related mortality among HIV patients and their parents. AIDS. November 28, 2012 (Epub ahead of print).