An unexpected increase in immune activation has been seen in a cohort of 20 AZT (zidovudine, Retrovir)-experienced individuals who have remained on continuous highly-active antiretroviral therapy (HAART) for between four-and-a-half and six years. This coincides with a surprising drop in CD4 cell counts in 55% of the cohort between year 5 and year 6. The data are presented as a research letter in the latest issue of the journal AIDS, now available online.
The findings come from up to six years of follow-up of AIDS Clinical Trial Group (ACTG) 315 – which evaluated AZT, 3TC (lamivudine, Epivir) and full-dose ritonavir (Norvir) in AZT-experienced individuals with a baseline CD4 count of 100 - 300 cells/mm3 – and the roll-over study, ACTG 375, which allowed changes in therapy if viral load reached 100 copies/ml, and required changes if viral load was repeatedly over 3000 copies/ml. Twenty individuals on continuous HAART for between 4.5 and 6.2 years, and with viral loads repeatedly under 1000 copies/ml, were included in this analysis.
Remarkably, 17 of the 20 (85%) remained on their original HAART regimen of AZT, 3TC and ritonavir throughout the follow-up period. Of the three who changed their therapy, one was now taking AZT, 3TC and indinavir (Crixivan), another AZT, 3TC and boosted saquinavir, and the third, d4T (stavudine, Zerit), nevirapine (Viramune) and boosted saquinavir. None of the cohort took interleukin-2 or any other immune-modulating therapies.
In the cohort as a whole, the median increase in CD4 cells from year 3 to year 6 was 126 cells/mm3, or 42 cells/mm3 a year (p 3.
When the researchers looked at the quality and type of CD4 cells in these individuals they found a significant increase (p 3) to year 3 (241 cells/mm3) to year 6 (321 cells/mm3).
In addition, the number of naïve CD4 (54 cells/mm3) and CD8 (113 cells/mm3) cells also increased significantly between year 3 and year 6. Unexpectedly, however, the percentages of activated CD4 and CD8 cells increased from year 3 to year 6 in most of the cohort; 75% experienced an increase in activated CD4 cells and 85% experienced an increase in activated CD8 cells.
Thymus size a year after initiating HAART had been previously measured in 16 of the 20 members of this cohort. When the researchers compared naïve CD4 increases from baseline to year 6 in the seven individuals with a thymus size that had been thicker than the median (5mm) with the nine whose thymus size was at or below the median, a marginally significant difference was noted (204 vs. 97 cells/mm3; p = 0.071). However, no differences were seen in the total CD4 increases (319 vs. 306 cells/mm3) between these two groups.
The authors argue that these results suggest that although initial CD4 increases are sustained in moderately immune-suppressed individuals after six years on HAART, and “despite improvements in absolute, naïve and memory CD4 cell counts and percentages,” only seven of the 20 achieved a sustained absolute CD4 count of 700 cells/mm3 or higher during this period, which is "lower than seen among HIV-negative" individuals. They do not say what clinical difference these additional cells make, however.
In addition, despite successful viral suppression for up to six years, the cohort had “persistently elevated markers of immune activation.” Although it is unclear why this occurs, they suggest that it is possible that the CD4 increases seen on HAART provide new targets for viral replication, and that low-level increases in viral replication could be driving this heightened immune activation. However, a more sensitive viral load assay would be needed to detect this low-level replication.
These, and other questions, will be addressed in the follow-up study to ACTG 375, ACTG 5136, which will examine the effect of HAART intensification in these 20 individuals.
Smith K et al. Long-term changes in circulated CD4 T lymphocytes in virologically suppressed patients after 6 years of high active antiretrovrial therapy. AIDS 18: 1953-1956, 2004.