Interruption of antiretroviral therapy in HIV-positive patients leads to a larger fall in CD4 cell count in patients whose lowest-ever, or 'nadir' CD4 cell count is lower, according to a study presented in the 3rd January edition of AIDS.
This leads the investigators to suggest that the CD4 nadir can be used to predict the effect of treatment interruption on CD4 T-cell levels, and the length of time a patient can remain off therapy.
The study also found that high CD4 cell counts and low viral loads were associated with more rapid falls in CD4 T-cell numbers during the first month of a treatment interruption, as was a high level of dendritic cells, which are involved in the control of viral replication. However, the benefit of using dendritic cell counts to predict the outcome of drug holidays remains unclear, the study’s authors warn.
Investigators from Bordeaux, France wished to investigate the changes in various immune system markers during treatment interruptions in a cohort of chronically infected HIV-positive patients.
They recruited 57 patients for their prospective study, measuring CD4 and CD8 cell counts, viral loads and the numbers of dendritic cells in the blood at months 1, 3, 6, 9 and 12 after the beginning of the treatment break. All of the patients started their drug holiday with CD4 cell counts above 400 cells/mm3, after a median of six years on treatment.
“Treatment interruption in patients with a CD4+ T-lymphocyte count greater than 400 × 106 cells/l is followed by a substantial increase in HIV RNA load and a decline in CD4+ T-lymphocyte count within the first month,” they write. “Thereafter, there is a nearly [sic] steady-state situation in those patients who do not resume their therapy during the twelve-month follow-up.
“The nadir of the CD4+ T-lymphocyte count before treatment interruption exerted a major influence on the level of CD4+ T-lymphocyte count reached after one month and therefore on the probability of resuming therapy. This information should become one of the criteria taken into consideration when deciding on treatment interruption.”
The researchers found that the rapid decrease in CD4 cell counts (mean 142 cells/mm3 per month) in the first month off treatment was followed by a slower decline (17 cells/mm3 per month). For each patient, the rate of decline in the two phases was unrelated.
Conversely, viral load increased by 1.92 log10 per month (95% confidence interval [CI]: 1.7 – 3.3) in the first month of interruption, but remained stable thereafter (0.015 log10 per month; 95% CI: -0.0065 – 0.036).
In the first month, the drop in CD4 cell counts was greater in patients with higher baseline CD4 cell counts (p = 0.04) and lower viral loads (p
In addition, the first month’s fall in CD4 cell counts was greater in patients with a lowest-ever CD4 cell count below 350 cells/mm3 than those with higher nadirs (200 vs. 65 cells/mm3 per month, p 3; month 12: 366 vs. 539 cells/mm3). This effect was maintained when the investigators adjusted the analysis for baseline viral load.
“The CD4+ level at the end of the twelve-month follow-up was mainly determined by the baseline level and CD4+ modification during the first month,” the authors write. “This finding implies that the management of supervised treatment interruption in chronically infected patients should be re-evaluated at one month.”
The investigators also found that higher numbers of dendritic cells were associated with higher baseline CD4 cell counts (p
“Myeloid dendritic cell counts were stable whereas lymphoid dendritic cell counts tended to decrease in association with CD4+ T lymphocytes and in negative correlation with the HIV RNA load slope,” they state.
“The decrease in the number of circulating lymphoid dendritic cells with disease progression, which is presumably associated with a decrease in interferon alfa production, should contribute to the lack of HIV virus control. Taken together, these data suggest that lymphoid dendritic cells are directly involved in the antiviral response probably through secretion of interferon alfa and through the specific CD8 T-cell response.
“Although dendritic cells seem to be associated with the CD4+ dynamic, the benefit of monitoring them has still to be defined.”
Analysis of the effect of baseline CD8 T-cell levels on CD4 count declines revealed further significant effects. “The higher the CD8+ T-lymphocyte percentage was, the lower was the initial CD4+ T-lymphocyte level (p = 0.002), and the blunter was the CD4+ T-lymphocyte count decline at month 1 (p = 0.03),” the investigators explain.
However, CD8 cell counts tended to increase in opposition to CD4 cell count declines during the first month of treatment interruption (p
“A higher percentage of the CD8+ T-lymphocyte count, as a surrogate marker for the cytotoxic T-lymphocyte antiviral response, was associated with a slower decline in CD4+ T-lymphocyte count… This result is in agreement with those reported in treated patients where the partial antigenic stimulation due to intermittent viraemia or persistent low levels of HIV RNA leads to an effective HIV-specific T-cell response.”
Thiébaut R et al. Immunological markers after long-term treatment interruption in chronically HIV-1 infected patients with CD4 cell count above 400 × 106 cells/l. AIDS 19: 53-61, 2005.