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Project Inform - September, 1998
Researchers presented four IL-2 studies at the conference. Three included people with generally higher starting CD4+ cell counts (~above 350) and one included people with low CD4+ cell counts and advanced disease. All confirmed the ability of IL-2 to induce dramatic CD4+ cell increases without triggering increases in viral load levels. Moreover, these increases were observed in people who administered IL-2 through injections under the skin (subcutaneous injections), a simplification of the methods used in previous studies. Most previous IL-2 studies administered the drug by continuous infusion into a vein (intravenous infusion). Side effects associated with IL-2, when administered by injection under the skin, proved less severe than those observed with intravenous IL-2.
Perhaps the most important of the four studies, a European trial called ANRS 048, compared the impact of IL-2, delivered through different routes of administration, on CD4+ cell count, HIV RNA levels and a number of measures of immune function. ANRS 048 included 94 people with CD4+ cell counts ranging from 250 to 550. The mean, or average, CD4+ cell count at baseline was about 380 in all four study groups. Protease inhibitor therapy was not available at the outset of the study. Volunteers received one of four regimens for one year (a total of 7 cycles of IL-2 therapy):
Of the groups receiving IL-2, those who received PEG IL-2 had the least favorable responses in CD4+ cell count increases. After one year, the group receiving anti-HIV therapy alone demonstrated a CD4+ cell count increase of 55. Those receiving PEG IL-2 showed a mean CD4+ cell increase of 105. The group receiving IL-2 by subcutaneous injection experienced a CD4+ cell increase of 564 and those receiving IL-2 by continuous infusion experienced an increase of 707.
Those receiving either the injections or continuous infusion of IL-2 had the most significant and pronounced CD4+ cell increases. Those receiving IL-2 by continuous infusion, however, were also most likely to experience side effects with nearly 60% experiencing fever and a sizeable number (~14%) experiencing nausea and/or diarrhea. These side effects were also seen among those who received IL-2 by injection, but less frequently. Fever was noted in about 40% of those receiving IL-2 by injection and only about 4% of this group experienced nausea and/or diarrhea. These side effects were primarily limited to the 5 day IL-2 therapy period and did not persist through the 8-week intervals between treatment. The most common laboratory abnormality among IL-2 users was a change in liver function tests, with about 25% of injection IL-2 and 9% of continuous infusion IL-2 recipients experiencing changes in liver function tests. Viral load changes were similar among all groups, but slightly more favorable among those receiving only anti-HIV therapy. Those receiving only anti-HIV therapy demonstrated a mean drop in viral levels of about 1.5 logs, those receiving PEG or injection IL-2 demonstrated a viral load decrease of 1.2 logs and those receiving continuous infusion of IL-2 experienced only a 0.9 log reduction in viral load. These differences were not considered significant.
Virtually all measures of immune function were more favorable among both the injection and continuous infusion IL-2 recipients, compared to those who received either anti-HIV therapy alone or anti-HIV therapy in combination with PEG IL-2. This study is important as it represents the most comprehensive comparative study of the immune effects of IL-2 and suggests that the profound CD4+ cell increases observed with IL-2 therapy are accompanied by improvements in immune function. Only a large study, however, will be able to confirm this definitively.
Long-term follow up on a National Institutes of Health study of IL-2 administered by injection under the skin was also reported. In this study, volunteers receiving anti-HIV therapy with an average CD4+ cell count of 600 received either 1.5 (total daily dose of 3) or 7.5 (total daily dose of 15) MIU of IL-2, twice daily for 5 days, every 4 or 8 weeks. The frequency of the cycles did not impact the magnitude of CD4+ increases observed in either dose group. Study results at 6 months of IL-2 therapy, those receiving the lower dose had experienced an average CD4+ cell increase from 600 to 780. Those receiving the higher dose had experienced a doubling of their CD4+ cell counts, from 600 to 1200. After 6 months of therapy, all volunteers were allowed to modify their IL-2 dose. Many receiving the lower dose increased their IL-2 dose in order to achieve more pronounced CD4+ cell count increases and many receiving the higher dose reduced their dose to lessen the severity of side effects. After 18 months of therapy, the average dose used was 5.8 MIU, twice daily (total daily dose of 11.6 MIU). The average interval between IL-2 therapy cycles, necessary to maintain CD4+ cell increases, was 1 year. At 18 months, the average CD4+ cell count was 1,200, regardless of which dose was originally used.
This study is important for many reasons. First, initiating IL-2 therapy at the higher dose of 7.5 MIU, twice daily, for five days, every 8 weeks is preferable to 1.5 MIU for inducing pronounced increases in CD4+ cell counts. Unfortunately, a middle dose of 4.5 MIU, twice daily, was not examined in this study. Given the median dose used at 18 months was about 5.8 MIU, twice daily, it's possible that starting at a lower dose might be more tolerable and still induce dramatic CD4+ cell count rises. Second, once a CD4+ cell count increase has been realized, the length of time between IL-2 cycles can be extended to maintain CD4+ cell count increases. Once CD4+ cell counts have risen to the upper limit of normal ranges, it is probably unwise to induce CD4+ increases to above normal limits. Side effects associated with IL-2, predominantly flu-like symptoms, are associated with the time that IL-2 is being administered (the 5 day cycle of therapy). It's encouraging to note that the median interval between cycles, at 18 months, had extended dramatically, obviously lessening the number of times volunteers experienced IL-2 associated side effects.
The third study, from Argentina, examined three different IL-2 doses. Volunteers with CD4+ cell counts greater than 350 received either potent anti-HIV therapy (HAART), or potent anti-HIV therapy in combination with injections of 1.5, 4.5 or 7.5 MIU, twice daily for 5 days, every 8 weeks (total daily doses of 3, 9 or 15 MIU of IL-2). After 6 months, 55% of those receiving only anti-HIV therapy and 75% of those receiving anti-HIV therapy in combination with IL-2 had viral load measures below the limit of detection of the tests. CD4+ cell count changes at 6 months are reported in Table 1 below. This study demonstrates that both of the higher IL-2 doses, 4.5 and 7.5 MIU, twice daily for five days, every 8 weeks, in combination with anti-HIV therapy is superior to both the low IL-2 dose and anti-HIV therapy alone in inducing pronounced CD4+ cell increases.
Table 1 : Argentinean Study Results
| Group | Proportion with greater than 25% CD4+ cell count increase |
Proportion with greater than 200 CD4+ cell count increase |
| AVT* alone | 20% | 10% |
| AVT + 1.5 MIU, twice daily | 40% | 10% |
| AVT + 4.5 MIU, twice daily | 65% | 45% |
| AVT + 7.5 MIU, twice daily | 80% | 60% |
AVT = antiviral therapy. MIU = million international units.
Finally, preliminary data were presented by community physicians in Chicago on an observational study of 15 people with low CD4+ cell counts and more advanced stage disease. Early observations of IL-2 therapy in people with CD4+ cell counts <200 were not encouraging. These studies were conducted prior to widespread availability of protease inhibitors and sophisticated measures of viral load (HIV RNA). This study included people with CD4+ cell counts <200 who had previously had an opportunistic infection, or people with CD4+ cell counts below 50. The mean CD4+ cell count of volunteers, prior to starting IL-2 therapy, was 100 and viral load levels were relatively high, about 50,000 copies HIV RNA. All were on stable 3-drug regimens prior to initiating IL-2 therapy. At time of the presentation, volunteers had received varying numbers of IL-2 cycles and the mean CD4+ cell count was 470. One volunteer discontinued IL-2 because of related side effects. While these data are very preliminary, they are encouraging as no one in the study has yet to experience a new opportunistic infection, been hospitalized or died. The study was largely a retrospective report on the IL-2 use in a treatment setting, so its findings cannot be directly compared to more structured studies. They do provide a bit of comfort in designing future studies of IL-2 for people with lower CD4+ cell counts and measurable viral load.
For more information on IL-2, other studies reported to date and information on side effects, call the Project Inform Hotline.
The HIV-1 Immunogen has been studied for many years. Known as a therapeutic vaccine, it uses the same strategy employed in traditional vaccine development, but rather than prevent or moderate infection it is hoped that it will trigger the immune defenses to better control HIV disease in people who are already infected. The HIV-1 Immunogen is an inactivated form of HIV that cannot reproduce and cause disease, but because it has features similar to the virus it is hoped that the immune system will mount a response that will prove useful in controlling HIV. A possible flaw in this logic is that there is plenty of the real HIV floating around the body and clearly the immune system, despite being chronically stimulated by real virus, is still not able to control infection. Thus, many researchers question why the addition of some modified, impotent version of HIV would stimulate a stronger immune response. Even so, this concept has experienced renewed interest in the era of HAART.
A largely promotional satellite symposium sponsored by the company developing the HIV-1 Immunogen garnered much attention. It appears that individuals who are believed to have received the HIV-1 Immunogen in studies were more likely to have HIV-specific CD4+ responses than those who are believed to have received placebo. The study is still "blinded" so researchers don't actually know who received the drug and who received the placebo. Because of the blinded nature of the study, all the researchers can say for sure is that there appears to be a group of people in the study who are having improved HIV-specific CD4+ cell responses. If the HIV-1 Immunogen is truly capable of enhancing or preserving HIV-specific CD4+ responses, this could be quite important because it may help the body control HIV with less reliance on antiviral drugs. Unfortunately the test to measure HIV-specific CD4+ responses has not yet been validated and thus far it remains unclear what exactly the test is measuring and whether its results have any bearing on disease progression.
While some people have gotten quite excited about the HIV-1 Immunogen information, Project Inform finds it impossible to draw any conclusions with regard to the HIV-1 Immunogen or the value of the HIV-specific CD4+ test. Early studies in people with HIV showed that the HIV-1 Immunogen was safe, but volunteers receiving the drug had no appreciable increases in CD4+ cell counts or decreases in viral levels (HIV RNA). One would hope that if a drug was able to "boost" immune responses against HIV there would be some kind of noticeable impact on these validated measures of disease progression. If changes in HIV-specific CD4+ response fail to correspond to decreased viral load, increased CD4+ cell counts, decreased disease progression or improved survival, then it would be hard to say the product has value. The current study of the HIV-1 Immunogen is following a large enough number of people to determine whether there is a difference in disease progression or survival between those receiving the HIV-1 Immunogen and those receiving a placebo so a clear answer can be expected. Until then, the current enthusiasm over the company sponsored presentation is probably a little more hype than hope, and at best merely an interesting observation.
Perhaps the best news out of the study is that HIV-1 Immunogen continues to appear safe and associated with very few side effects, primarily pain at the site of injection as would be expected with any type of vaccination.
The thymus is an important organ for new T cell development (both CD4+ and CD8+ cells). Previously, Project Inform has reported on data from Dr. McCune and his colleagues at the Gladstone Institute in San Francisco which suggest that adults with HIV infection are more likely to have detectable thymus mass compared to their HIV-negative counterparts. Moreover, thymus mass was more likely to be present in people with higher CD4+ cell counts (above 300) compared to people with lower CD4+ cell counts. The presence of thymus mass was associated with higher CD4+ cell counts and higher percentages of naïve cells, suggesting evidence of thymic function. Questions remain regarding the ability of the thymus to regenerate in people with low CD4+ cell counts in the context of suppression of HIV replication.
A small study of thymus scans in children before and after therapy with potent anti-HIV regimens provides encouraging preliminary results suggesting that the thymus can regenerate if viral replication is brought under control. The study was very small, including children at different stages of HIV disease. The researcher highlighted the case of a 7-year-old child with advanced (CDC stage III) stage AIDS. Prior to therapy the child had virtually no detectable thymus (0.07 cm3). After one year of successful anti-HIV therapy, the child had an over 100 fold increase in detectable thymus mass (19.4 cm3). Observed increases in thymus mass were associated with decreases in viral load and increases in both CD4+ cell counts and percent naïve cells. It is not as clear, however, whether these results can be expected to be the same in adults as in children. The thymus is generally larger and believed to contribute more to new T cell development in children compared to adults. This study is certainly encouraging with regard to the impact of anti-HIV therapy on the thymus in children. In the highlighted report referenced above, however, the child was 8-years-old at the time of the second thymus scan and in many regards the immune system of an 8 year old is more similar to the immune system of an adult than it is to a newborn. Thus, there is at least this one hint that the results might also apply to adults with advanced-stage AIDS. However, the study certainly needs to be duplicated in the adult population.
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