Poor CD4 response to HIV treatment increases risk of death from non-AIDS-related illnesses, even for those with higher baseline counts

A poor increase in CD4 cell count after starting antiretroviral therapy is associated with an increased risk of death due to non-AIDS-related causes, Danish investigators report in the online edition of AIDS.

All the participants in the study had a suppressed viral load. “Poor CD4 cell count response was associated with increased mortality,” write the authors. “Individuals with low pre-HAART [highly active antiretroviral therapy] CD4 count but adequate CD4 increase had lower mortality than those with a relatively high pre-HAART CD4 count but poor CD4 increase.”

There was also intriguing evidence that a poor immune response to HIV therapy is linked to genetic factors. The parents of people who had a CD4 cell increase of less than 25 cells after two years of HAART were significantly less likely to be alive than either the parents of people who experienced a CD4 cell gain of at least 100 or the parents of people in a general population control group.

Thanks to antiretroviral therapy, the prognosis of many people with HIV is now normal. AIDS-defining illness are now very rare in people who have an undetectable viral load when taking HIV therapy, even if their CD4 cell count is low.

However, a low increase in CD4 cell count after starting HIV treatment has been associated with an increased risk of illness and death due to non-AIDS-related causes. The reasons for this are currently unclear.

Investigators from the Danish HIV Cohort Study therefore looked at the relationship between CD4 cell increase and mortality rates during the first two years of antiretroviral treatment. HIV-positive people who started antiretroviral therapy for the first time between 1996 and 2008 were eligible for inclusion in the study. They were required to have had a baseline CD4 cell count below 500 cells/mm³ and to have achieved a viral load below 400 copies/ml one year after starting treatment.

Each participant was matched with 13 age- and sex-matched controls identified from national registries. The investigators also identified all parents of the participants and controls, alive on the date of HIV diagnosis of the participant to whom they were matched. Parents were included so the investigators could test their theory that genetic factors were related to CD4 cell increases after starting HIV treatment and mortality risk.

The study outcomes were death, date of first admission to hospital or outpatient visit.

Deaths in the HIV-positive participants were categorised as AIDS-related if they occurred within twelve months of an AIDS diagnosis or if they were attributed to an AIDS-related cancer.

The study population comprised 1758 HIV-positive participants, 1603 parents of participants, 22,854 controls and 31,527 parents of controls.

CD4 cell increases after initiating therapy were divided into three categories:

• Below 25 cells/mm³ (4% of participants).

• 25 to 100 cells/mm³ (10% of participants).

• Above 100 cells/mm³ (86% of participants).

Overall, 117 participants died in the two years after starting HIV therapy, and 86% of these deaths were attributed to non-AIDS-related causes. The risk of death because of a non-AIDS-related cause was over three-fold higher for participants whose CD4 cell count increased by less than 25 cells/mm³ after starting HIV therapy compared to those whose CD4 cell count increased by over 100 cells/mm³ after initiating antiretrovirals (MRR = 3.5; 95% CI, 1.8-6.8). 

The association between a poor immunologic response to antiretroviral therapy and an increased risk of non-HIV-related mortality was significant even for participants who had a CD4 cell count above 250 cells/mm³ at the time they started antiretroviral treatment (CD4 cell increase below 25 cells/mm³ vs over 100 cells/mm³: MMR = 3.2; 95% CI, 1.3-7.8).

Parents of patients with poor CD4 cell recovery also had an increased mortality risk (MMR = 1.5; 95% CI, 1.1-2.1).

“Mortality among parents of patients with poor CD4 response was also increased,” comment the investigators. “It is thus possible that the ability to recover CD4 cells reflects genetic traits associated with cell renewal mechanisms and survival.”

There was modest evidence that a poor response to therapy was associated with an increased risk of illness related to cardiovascular disease. However, unlike some previous research, there was no association with either liver disease or cancer.

“Poor CD4 response is associated with adverse prognosis even in individuals without severe immunosuppression at HAART initiation,” conclude the authors. “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.”