Delaying the start of HAART until the immune system is severely damaged by HIV can mean that the body never fully regains functional immune responses, even if anti-HIV therapy causes a large rise in CD4 cell count and a sustained fall in viral load, according to research published in the September 26th edition of AIDS.
Although it is well established that treatment with HAART can lead to CD4 cell gains which are protective against AIDS-defining opportunistic infections, full immune recovery is often incomplete. Delaying the start of HAART until the CD4 cell count has fallen to between 250 - 200 cells/mm3 may reduce a patient’s exposure to anti-HIV drugs (reducing the risk of side-effects), but the impact of sustained HIV replication on the immune system is little understood.
Accordingly, investigators in Ohio recruited 29 HIV-positive patients who had received anti-HIV therapy resulting in an increase in CD4 cell count to at least 450 cells/mm3 and a fall in HIV viral load to below 400 copies/mL for at least twelve months. Nine of these patients had a nadir CD4 cell count below 250 cells/mm3 prior to starting HAART. The investigators wished to see if the degree of immune damage experienced prior to the initiation of HAART reduced subsequent immune competence even if large gains in CD4 cell count had been made. Nine HIV-negative individuals were also included in the study as controls.
The patients and controls’ immune response were tested by the use of vaccinations. After receiving immunisations against diphtheria, typhoid and keyhole limpet haemocyanin patients’ lymphocyte and serological responses were analysed.
As expected, HIV-positive individuals had fewer naive CD4 cells, fewer CD28 cells, and more CD8 cells than the HIV-negative controls.
The response to immunisations was worse in the HIV-positive patients than the controls. On the last day of follow-up following immunisation, the HIV-positive individuals had significantly lower concentrations against diphtheria and typhoid (p
The investigators also established that nadir CD4 cell count prior to the initiation of HAART was significantly correlated with and predicted the magnitude of responses to immunisation. The number of CD4 cells that co-expressed CD28 at the time of immunisation was also correlated to the immune response of HIV-positive patients.
In multivariate analysis, the nadir CD4 cell count (p
The investigators observe, “our results suggest that even when CD4 T-cell counts have ‘normalized’ prior immune decline determines current immune competence. Changes in the immune phenotype persist in HIV-1 infected patients even after years of suppressive antiviral therapy.”
They add, “although this study was not designed primarily to evaluate the optimal timing of treatment initiation in chronic HIV-1 infection, our data suggest that delaying treatment significantly increases the risk of persistent functional immune defect...even in those patients who normalise CD4 T-cell numbers and are largely protected from opportunistic infection, immune deficits persist.”
Delaying the initiation of HAART, the investigators conclude, results in impaired functional immune restoration. The long-term significance of this warrants, they suggest, further study.
Further information on this website
When to start anti-HIV therapy - menu of information
The immune system and HIV - menu of information
HIV therapy - booklet in the information for HIV-positive people series (pdf)
Viral load and CD4 - booklet in the information for HIV-positive people series (pdf)
Lange CG et al. Nadir CD4+ T-cell count and numbers of CD28+ and CD+ T-cells predict functional responses to immunizations in chronic HIV-1 infection. AIDS 17: 2015 - 2023, 2003.