Highly active antiretroviral therapy (HAART) is usually able to reduce levels of HIV in the blood and increase CD4+ cell counts in people with HIV infection. HAART is also associated with a decreased appearance of AIDS-related illnesses and death. But one of the problems associated with HAART is that it does not usually enable the immune system to develop strong, effective anti-HIV defences. Evidence of this shortcoming was seen most recently in an American study, which showed that viral load rose significantly when people who had been treated for at least two years stop taking therapy.
One research team in Boston has published results on a small number of subjects. These results suggest that taking HAART shortly after HIV infection can help the immune system develop better anti-HIV defences than taking therapy later in the course of infection. They also appear be confirmed by another study, raising the issue of the timing of therapy for PHAs.
Researchers recruited 41 subjects (1 female, 40 males) who were recently infected with HIV. Subjects were divided into two groups:
Researchers monitored both groups for about one year. Standard doses of AZT with 3TC and indinavir were used.
After six months of HAART, viral load fell by 50 to 53 copies in half the subjects. In the other half, it fell by 53 to 2,000 copies. By the12th month, all subjects taking HAART had a viral load of fewer than 50 copies.
Among the subjects who received no treatment, viral load remained relatively high. By the 12th month of the study, viral load in this group ranged from 4,000 to 332,000 copies; the mid-point was 36,000 copies.
After 12 months of HAART, CD4+ count ranged from 526 to 1,035 cells; the mid-point was 763 cells.
Among subjects who received no treatment, by the 12th month, CD4+ count ranged from 134 to 950 cells by the 12th month; 459 cells was the mid-point.
This difference in CD4+ cell counts between subjects taking HAART and those not taking HAART was statistically significant.
At first, T-cells taken from subjects at the start of the study could barely produce a response against bacteria and tetanus proteins in lab experiments. When technicians later tested T-cells of subjects taking HAART, they found that the cells were able to respond to these proteins at a level seen in non-HIV-infected people. This type of response was not detected in subjects who were not given HAART.
At the start of the study, fewer than 11 per cent of subjects had T-cells capable of attacking HIV. Those subjects who received HAART developed a significantly increased level of anti-HIV activity compared with subjects not receiving HAART. This response by subjects receiving HAART was associated with production of the immune-boosting chemical interferon-gamma.
It's interesting to note that it was only when viral load fell below the 50-copy mark that T-cells began to display significant anti-HIV activity. At no time during the study did a strong anti-HIV response develop in those subjects not taking HAART.
The results of this study suggest that early treatment of HIV infection may enhance the anti-HIV responses of T-cells. Ideally, these responses will be maintained over many years and eventually allow some people to stop taking therapy. It remains to be seen whether people who have been infected with HIV for longer periods of time develop effective anti-HIV responses to HAART. Perhaps this issue will become clearer with results from other studies.
1. Davey RT, Bhat N, Yoder C, et al. HIV-1 and T-cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proceedings of the National Academy of Sciences USA 1999;96(26):15109-15114.
2. Rosenberg E, Billingsley J, Caliendo A, et al. Vigorous HIV-1-specific CD4+ T-cell responses associated with control of viremia. Science 1997;287:1447-1450.
3. Connick E, Lederman MM, Kotzin BL, et al. Immune reconstitution in the first year of potent antiretroviral therapy and its relationship to virologic response. Journal of Infectious Diseases 2000;181:358-363.
4. Malhotra U, Berrey MM, Huang Y, et al. Effect of combination antiretroviral therapy on T-cell immunity in acute human immunodeficiency virus type 1 infection. Journal of Infectious Diseases 2000;181:121-131.
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