July 11, 2002
Although we have seen a tremendous reduction in morbidity and mortality among HIV-1 infected individuals on HAART, one of the questions that remains is whether the CD4+ T-cell count improvements really mean that there has been complete restoration of the immune system.
Dr. Lange and colleagues evaluated the immune responses to commonly-used vaccines to ascertain whether delaying antiretroviral therapy will compromise functional immunologic recovery in HIV-1 infection. They studied patients who normalized circulating CD4+ T-cell counts after HAART using responses to immunization as a measure of functional immunologic competence.
A total of 29 HIV-1 infected persons with CD4+ T-cell counts more than 450 cells/µl and HIV-RNA less than 400 copies/µl for more than one year after ART and nine HIV(-) controls were immunized at study entry and four weeks later with tetanus-toxoid, diphtheria-toxoid, and keyhole limpet hemocyanin. An immune-response-score (IRS) was calculated using post-immunization antibody concentration, lymphocyte proliferation, and delayed-type-hypersensitivity responses. The median CD4+ T-cell count nadir was 250 cells/µl. The current median CD4+ count for subjects who had a nadir less than 250 cells/µl was 744 cells/µl and 725 cells/µl for those whose nadir CD4+ count was more than 250 cells/µl. The median IRS was significantly lower in patients who started HAART with CD4+ T-cell counts less than 250 cells/µl when compared to patients who started HAART with CD4+ T-cell counts more than 250 cells/µl (0.4 vs. 0.67; p<0.005) or to HIV(-) controls (0.4 vs. 0.7; p<0.001). Of note, the nadir CD4+ T-cell counts between 150-450 cells/µl correlated linearly with the IRS whereas, the subject's current CD4+ T-cell count showed no relationship to the IRS at the time of vaccine challenge.
Dr. Lange and colleagues concluded that even among persons with "normalization" of CD4+ T-cell counts and well-controlled HIV replication after HAART, the CD4+ T-cell nadir predicts the immune response to vaccination while current CD4+ T-cell count does not. Delaying the initiation of HAART in chronic HIV-1 infection results in progressive impairment of functional immune competence despite normalization of circulating CD4+ T-cell numbers. The long-term clinical consequences of delaying HAART initiation remain to be determined.
I think another question we need to ask is how well do these in-vitro laboratory tests reflect actual clinical relevance. There have been several case reports of atypical manifestations of opportunistic infections where the patients develop localized infections such as Mycobacterium avium complex (MAC) despite immunologic assays revealing adequate immunity to MAC. I think Dr. Lange's findings are intriguing and certainly are of concern if, in fact, recovery of CD4+ counts does not necessarily equate to full immunocompetence. This will have broad implications for therapies such as interleukin-2, which stimulates the production of CD4+ T-cells, in knowing whether such an increase in CD4+ T-cells results in improved immune functional capacity. I agree with the authors that it is too early to conclude that these laboratory assays correlate clinically and will be predictive of whether one will be able to mount adequate immunity against pathogens. This is one of the first steps and their future studies will be of great interest to the community.
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