Immune system defects persist in people who start treatment late

People who started treatment with a CD4 count below 350 in a major international clinical trial were left with the immune system profile of people in advanced old age even though they appeared to have good responses to treatment, according to a report in the February 1^st edition of Clinical Infectious Diseases. The findings suggest that additional immunotherapies may eventually be needed to achieve a full restoration of immune health in people taking antiretroviral therapy.

As people age, their immune systems begin to decline, losing the ability to respond to new pathogens, and the CD4:CD8 cell ratio falls, indicating that regardless of the absolute CD4 cell count, the immune system's ability is weakened.

Researchers examined the immunological profiles of a large population of treatment-naïve HIV-positive people who took part in the ACTG 384 study, a three-year randomised comparison of first-line treatment with either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI) in combination with either d4T and ddI or AZT and 3TC. Another group was assigned to take both the protease inhibitor and the NNRTI. Patients switched to another of the study regimens after virological failure.

Initial results from ACTG 384 were reported in 2002, and showed that efavirenz was superior to nelfinavir in first-line treatment. Subsequent analysis showed that greater CD4 cell increases on treatment were strongly associated with a higher baseline CD4 count.

The new analysis published in Clinical Infectious Diseases looks specifically at T-cell subsets to determine the quality of the immune response to treatment.

Comprehensive immunological data were available for 623 of the 978 participants in the study, and there were no significant differences in baseline characteristics between those who underwent full assessments and those who did not.

Participants were assessed in five baseline CD4 cell strata: 500 CD4 cells/mm³.

CD4 cell counts increased by approximately same number of cells in each CD4 cell strata: around 250 cells gained after 96 weeks regardless of baseline CD4 cell count, and around 300 cells after three years. As a consequence the median CD4 cell count in those with a baseline count below 50 still lay below 350 cells after three years, while in those with a CD4 cell count between 50 and 200, the median count reached 400 cells/mm³ after three years.

People with low CD4 counts when starting treatment thus continued to be exposed to a higher risk of serious illness despite a successful response to treatment throughout the follow-up period. In comparison, those who started treatment with a CD4 count above 350 cells/mm³ had a median CD4 count of 739 after three years.

The researchers then looked at the proportion of CD4 cells that were newly generated (so-called naïve cells). The body’s ability to generate naïve T-cells declines with age due to the atrophy of the thymus, the organ in which lymphocytes are assigned their roles as different types of T-cells (such as CD4 cells).

It is this age-related loss of naïve cells that leaves the elderly vulnerable to new pathogens and unable to replace memory cells that are lost. The health of the balance between naïve cells and memory cells is expressed as a ratio, with a ratio of 0.87 recorded in an age-matched HIV-negative control group of 48 individuals in this study.

The researchers found that, regardless of age, people who started antiretroviral therapy with a higher CD4 count (above 350 cells/mm³) had a significantly greater improvement in the ratio of naïve cells to memory CD4 cells after three years, indicating a superior quality of immune reconstitution (p=0.008). These patients exhibited a normal naïve cell to memory cell ratio after three years of treatment.

The study also found that despite three years of viral suppression below 50 copies/ml, individuals with CD4 counts below 500 cells/mm³ still exhibited a higher level of activated CD4 cells than the HIV-negative control group, and all participants continued to exhibit higher levels of CD8 cell activation after three years than the HIV-negative control group.

The persistence of immune activation might be explained either by continued low-level viral replication, or by microbial translocation across a gut wall damaged by HIV. The consequences of persistent immune activation, note the authors, might be cardiovascular disease or cancers, although the mechanisms by which persistent HIV-related immune activation might cause health problems for people with HIV still need to be explored.

The authors conclude: “Relying solely on absolute CD4+ cell counts as a measure of immune reconstitution may be misleading. Understanding differences in immune cell subsets and ratios … may refocus the goal of ART towards normalization of T cell subsets and higher CD4+ thresholds for initiating ART.

“These findings support ART initiation at a threshold of 350 cells/mm³ and further suggest use of an even higher CD4+ cell count, at which time CD4+ naïve cell populations and naïve-memory cell ratios are more likely to still be intact.”

An accompanying editorial by Steven Deeks and Elvin Geng of San Francisco General Hospital notes the significance of these findings for individuals in resource-poor settings, where the median CD4 count at the time of treatment initiation recorded in several large studies was between 108 and 131 cells/mm³.

“Persistent inflammation and immunological defects are likely the norm globally. If anything, the greater prevalence of chronic viral, helminthic and protozoal infections in these regions is likely to exacerbate the persistent T cell subset derangements seen in [ACTG 384], with potentially negative consequences.”

They point out that regardless of how early people are encouraged to start treatment, many people will not start treatment until much later in the course of HIV infection, and may be left with permanent immunological defects, leaving them vulnerable to a greater range of health problems than HIV-negative people or those who started treatment earlier. “Novel immune-based therapeutics aimed at reversing these defects are urgently needed,” they argue.

However, they admit that the causal link between immunological defects, persistent immune activation and poorer health outcomes still needs to be proved, noting “determining the causal association among these factors will be a challenge, given the complexity of the human immune system”.