Shortly after entering the body, HIV begins to damage the ability of the immune system to fight microbes in general and HIV in particular. A major focus of AIDS research is to find a way to restore the immune system's ability to fight HIV.
Treating PHAs with highly active antiretroviral therapy (HAART) usually leads to increased CD4+, CD8+ and other cells as viral load falls. These changes persist in people who are able to adhere to and tolerate these drug regimens. As well as increasing the numbers of immune cells, HAART also appears to improve their ability to fight many of the microbes that cause life-threatening complications in PHAs.
Unfortunately, several research teams have found that despite the use of HAART, the immune system does not usually develop the ability to control HIV. Because the immune system does not fully recover despite the use of HAART, some researchers have suggested that immune boosters may also be needed to help with "immune healing." It may be that one reason for the incomplete immune recovery is the long-term impact of anti-HIV treatment on the immune system. Although HAART has potent anti-HIV activity, it may also suppress some of the immune system's subtle functions. In the short term, this may be useful, as parts of the HIV-infected immune system may well be overactive. In the long term, the drugs' interference with the functions of immune cells may not be helpful.
In trying to understand the impact of HAART on the immune system, it may be useful to study the effect of different classes of anti-HIV drugs separately before studying their effects together. For instance, nucleoside analogues, or nukes, such as AZT, may have a different impact on the immune system than do protease inhibitors (PIs). In the report below, researchers in Ottawa conducted a two-year study on PHAs using, in most cases, just two drugs — ritonavir with saquinavir, two protease inhibitors. (Note: Prescribing this combination is a highly unusual practice that is not considered appropriate treatment. However, these people were part of a carefully planned clinical trial. Do not try this at home.) We discuss the implications of their findings.
Researchers enrolled 42 subjects who had no previous exposure to PIs and gave them a minimum of ritonavir 400 mg and saquinavir 400 mg, both twice daily. If after 12 weeks of this dual PI combination their viral load was not below the 200 copy mark, then subjects could include the nukes d4T (Zerit) and 3TC (lamivudine) to their regimens. At the start of the study, the profile of subjects was as follows:
After two years of treatment, 35 subjects remained in the study. By this time, their lab values were as follows:
After two years of treatment, the proportion of subjects taking the following drugs was:
Four subjects had viral loads above the 200 copy mark. In two people, this event occurred because they had temporarily stopped taking their drugs. In the other two, the increased viral loads were only temporary.
It's one thing to have a lot of CD4+ and CD8+ cells, but a big question is: "Do they work?" Researchers conducted many tests on blood cells taken from the subjects. The purpose of these tests was to find out how well immune cells were able to respond to HIV.
According to their results, at the start of the study only about 5% of subjects had T cells that could recognize and attack HIV. By the end of the second year of the study, this figure had increased to 50%. This may not seem like much, but readers should note that it takes many years for HIV to degrade the immune system, and it is likely that it will take many years to rebuild it.
The research team thinks that the improvement in the immune system's ability to function properly happens because viral load is suppressed by HAART. They found that in cases where viral load was temporarily increased, the immune system's ability to respond to and attack microbes (in simulated tests) was weakened. This finding of a link between viral load and a weakened immune response is something to bear in mind when thinking about "drug holidays" or strategic therapy interruptions (STIs).
Researchers looked at several factors that could help them identify which of their subjects would develop strong immunologic responses to HIV while receiving HAART. These factors included the following:
According to their analysis, the researchers could find no link between any of the factors and the development of anti-HIV responses.
In this study, it is interesting that 66% of subjects did not use nukes but relied upon a combination of the two PIs ritonavir and saquinavir for viral suppression. This may be one reason why the immune recovery seen in these subjects was more dramatic than detected in several previous studies. Other researchers have usually included nukes, particularly AZT, in anti-HIV treatment combinations. It may be that the impact of some nukes over the long term weakens the immune response against HIV in some people. Studying this impact of anti-HIV drugs on the immune system is important if safe, effective and long-term therapies are to be developed. There are several studies underway that are comparing regimens containing nukes against regimens containing no nukes. Preliminary results from these studies should be available next year.
We eagerly look forward to further analysis of the Ottawa study data, specifically information on which regimens were associated with an increased risk of developing certain side effects, such as the following:
Preliminary analysis suggests that those subjects who used nukes were more likely to develop fat wasting in the face and buttocks than subjects who did not use nukes (JB Angel, personal communication, 2001).
Drug holidays or STIs have been embraced by some PHAs who welcome relief from HAART side effects or who are simply tired of taking handfuls of pills several times a day for years. But short drug holidays may also be a way for the immune system to become re-exposed to HIV after the virus has been suppressed for long periods of time.
An important message from this study is that rebuilding the immune system takes time and may also depend on the type of therapy used. As well, prolonged suppression of viral load is beneficial. Thus, drug holidays need to be carefully planned, taking into account several factors. More effective and less toxic drugs might be a more useful path to better control of HIV infection.
1. Tovo P-A. Highly active antiretroviral therapy inhibits cytokine production in HIV-uninfected subjects. AIDS 2000;14(6):743-744.
2. Rinaldo CR, Huang X-L, Fan Z, et al. Anti-human immunodeficiency virus type 1 (HIV-1) CD8+ T-lymphocyte reactivity during combination antiretroviral therapy in HIV-1-infected patients with advanced immunodeficiency. Journal of Virology 2000;74(9):4127-4138.
3. Stranford SA, Ong JC, Martinez-Mariño B, et al. Reduction in CD8+ cell noncytotoxic anti-HIV activity in individuals receiving highly active antiretroviral therapy during primary infection. Proceedings of the National Academy of Sciences 2001;98(2):597-602.
4. Angel JB, Parato KG, Kumar A, et al. Progressive human immunodeficiency virus-specific immune recovery with prolonged viral suppression. Journal of Infectious Diseases 2001;183:546-554.
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Copyright © 2001 - TreatmentUpdate. Reproduced with permission. Reproduction of this article (other than one copy for personal reference) must be cleared through the Editor, The Canadian AIDS Treatment Information Exchange, 555 Richmond St. West, Suite 505, Box 1104, Toronto, ON, M5V 3B1 • Phone: 416-203-7122 • Toll Free: 1-800-263-1638 • Fax: 416-203-8284 http://www.catie.ca.
AEGiS is made possible through unrestricted grants from Boehringer Ingelheim, Elton John AIDS Foundation, iMetrikus, Inc., the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2001. This material is designed to support, not replace, the relationship that exists between you and your doctor.
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