HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression

Abstract

Identifying the immunologic and virologic consequences of discontinuing antiretroviral therapy in HIV-infected patients is of major importance in developing long-term treatment strategies for patients with HIV-1 infection. We designed a trial to characterize these parameters after interruption of highly active antiretroviral therapy (HAART) in patients who had maintained prolonged viral suppression on antiretroviral drugs. Eighteen patients with CD4(+) T cell counts >/= 350 cells/microliter and viral load below the limits of detection for >/=1 year while on HAART were enrolled prospectively in a trial in which HAART was discontinued. Twelve of these patients had received prior IL-2 therapy and had low frequencies of resting, latently infected CD4 cells. Viral load relapse to >50 copies/ml occurred in all 18 patients independent of prior IL-2 treatment, beginning most commonly during weeks 2-3 after cessation of HAART. The mean relapse rate constant was 0.45 (0.20 log(10) copies) day(-1), which was very similar to the mean viral clearance rate constant after drug resumption of 0.35 (0.15 log(10) copies) day(-1) (P = 0.28). One patient experienced a relapse delay to week 7. All patients except one experienced a relapse burden to >5,000 RNA copies/ml. Ex vivo labeling with BrdUrd showed that CD4 and CD8 cell turnover increased after withdrawal of HAART and correlated with viral load whereas lymphocyte turnover decreased after reinitiation of drug treatment. Virologic relapse occurs rapidly in patients who discontinue suppressive drug therapy, even in patients with a markedly diminished pool of resting, latently infected CD4(+) T cells.

Figure 1

Three representative graphs of viral relapse after discontinuation of HAART, with linear regression lines (red) depicting back extrapolation of viral load to time zero (HAART withdrawal). bDNA results of <50 copies/ml were assigned values of 49 copies/ml before log₁₀ transformation. Vertical black lines indicate when HAART was restarted.

Figure 2

The viral relapse patterns observed in 18 patients in whom HAART was discontinued, color-coded as indicated.

Figure 3

The mean viral load results (± SE) for the 18 patients (black line), separated into the 12 previous IL-2-recipients (red line) and the 6 non-IL-2 recipients (blue line).

Figure 4

The individual patterns of viral load suppression in patients after resumption of HAART, normalized to time zero (the day HAART was restarted in each patient), color-coded as in Fig. 2.

Figure 5

Changes in absolute CD4 cell counts experienced by patients in whom HAART was discontinued. (Upper) CD4 cell changes in three representative patients over time after discontinuation and then resumption of HAART. Vertical black arrows indicate when HAART was restarted in each patient. (Lower) The mean CD4 cell counts (± SE) for the 18 patients (black line) after discontinuation of HAART, separated into the 12 previous IL-2-recipients (red line) and the 6 non-IL-2 recipients (blue line).

Figure 6

Changes in lymphocyte turnover, as measured by percent incorporation of BrdUrd, in relationship to plasma viral load before and after interruption of HAART. (Upper) Mean percent BrdUrd incorporation (±SE) into CD4⁺ (solid blue line) and CD8⁺ (solid red line) T cells at baseline and then after stopping HAART in comparison to plasma viral load (green dashed line). The mean viral relapse rate constant k is indicated. (Lower) Similar mean changes in CD4⁺ (solid blue line) and CD8⁺ (solid red line) T cells after reinitiating HAART therapy, normalized to time zero (the day HAART was restarted in each patient) and shown in comparison to the plasma viral load (green dashed line). The mean viral clearance rate constant c is indicated.

Figure 7

The correlation between log₁₀ plasma RNA HIV-1 RNA levels and logarithmic percent BrdUrd incorporation into both CD4⁺ and CD8⁺ T cells (P < 0.0001). Only time points at which plasma viral RNA was in the detectable range after withdrawal of therapy are plotted.