Over half the deaths observed in a large cohort of HIV-positive individuals in the combination antiretroviral therapy era, who were followed from seroconversion, were due to non-AIDS-related illnesses, investigators from the CASCADE cohort study report in the online edition of AIDS. The researchers found that deaths due to liver disease, infections, respiratory diseases and non-AIDS-defining cancers were all related to immune deficiency. Although deaths because of cardiovascular disease were not related to CD4 cell count, they were associated with a high viral load.
HIV treatment guidelines have been changed in many countries to recommend earlier initiation of HIV therapy to reduce the risk of death from non-HIV-related causes. The investigators believe that their findings strongly support such guidance and write: “The consistent finding of a raised risk of non-AIDS-defining death and cumulative time spent with a CD4 cell count less than 350 cells/mm3 reveals clinically important information and provides a strong argument that HIV-infected patients may benefit from early initiation of antiretroviral treatment to reduce the risk of AIDS and non-AIDS-related causes of death.”
There has been a marked decrease in deaths amongst people with HIV in countries like the UK since the introduction of effective HIV treatment in 1996. The majority of deaths that still occur are due to non-AIDS-defining illnesses, including some cancers, liver disease, infections, and cardiovascular disease.
Immune suppression and the inflammation caused by ongoing HIV replication have been offered as possible explanations for these non-AIDS-defining deaths.
To gain a better understanding of the contribution of these factors to non-AIDS-defining mortality, investigators studied 9858 individuals with a known time of seroconversion. The period of the study was 1996, the year effective combination HIV treatment first became available, to 2006.
During a total of 71,230 person years of follow-up, 597 individuals died. This provided a five-year mortality incidence of 1.5% and a ten-year incidence of 5.7%.
The majority of deaths (56%) were due to non-AIDS-defining causes. Infections were the cause of 53% of the non-AIDS-defining deaths, with liver disease, non-AIDS-defining cancers and cardiovascular disease also being important causes of death.
Combination HIV therapy was initiated by 66% of patients. Their median CD4 cell count at the time antiretroviral treatment was started was 324 cells/mm3 with median viral load being 40,000 copies/ml. After six months of treatment with anti-HIV drugs, median CD4 cell count had increased to 451 cells/mm3 and median viral load had fallen to 400 copies/ml. Median viral load was still at this level after a year of HIV treatment, and median CD4 cell count had increased to 480 cells/mm3.
The investigators examined the relationship between CD4 cell count and the risk of death. This showed that each 100 cell/mm3 increased reduced the risk of death from any cause by 32%.
Each increase in CD4 cell count of this level reduced the risk of death due to AIDS-defining causes by two-thirds, and also reduced the risk of death from liver disease, non-AIDS-defining cancers, and infections by a third.
Next the investigators looked at the relationship between CD4 cell count and viral load and death from non-AIDS-related causes.
Lowest-ever CD4 cell count (p < 0.001), a latest CD4 cell count below 350 cells/mm3 (p < 0.001) and a longer amount of time spent with a CD4 cell count below 350 cells/mm3 (p < 0.007) were all correlated with death from both non-AIDS-defining infections and respiratory diseases.
In addition, a lowest-ever CD4 cell count (p < 0.001), a lower current CD4 cell count (p < 0.001), and amount of time with a CD4 cell count below 350 cells/mm3 (p = 0.02) were also related to death from liver disease. Both a nadir CD4 cell count (p = 0.015) and latest CD4 cell count (p < 0.001) were also correlated with death from a non-AIDS-defining cancer.
Deaths from cardiovascular disease were not related to immune suppression. However, the investigators did find that a ongoing HIV replication significantly increased the risk of these illnesses (hazard ratio = 3.86; 95% CI: 1.57 to 9.51). They suggest that this is because high viral load causes endothelial dysfunction.
“Our results add to the growing body of evidence of the association of immunodepletion and important non-AIDS-related morbidity,” conclude the investigators.
Marin B et al. Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy. AIDS 23 (online edition), 2009.