The Body Covers: The First International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV
Immune-Based Therapies (IBT)-2 Community Forum
December 14, 1999
The various approaches to immune-based therapy can be summarized in the following way. If untreated, HIV generally leads to immune exhaustion. Our understanding of why this happens is that a key part of our immune system, called cellular immunity, has the potential to control HIV infection. However, HIV usually destroys these key cells within weeks to months. The major approach to the successful treatment of HIV has been to use antiviral medications, which in numerous combinations act to interrupt the ability of HIV to grow. This then allows the immune system to recover, and studies continue to note the increasing success that this approach has in restoring immunity to many infections. However, this restoration occurs while HIV is itself suppressed and barely "seen" by the immune system. Immune function directed against HIV rarely if ever recovers and the body relies on the assistance of HIV medications to control HIV.
However, in those who are long-term nonprogressors, there is evidence that our immune system can sometimes control HIV growth without the need for antivirals. It is estimated that about 3-5% of those with HIV infection do not show any damage to the immune system, even over years of observation. Recently, research has demonstrated that what differentiates this group from the majority is that cellular immunity against HIV itself remains intact. It remains unclear why only as few as 5% emerge with this part of the immune system intact. However, what is clear is that when it happens, both CD4 and CD8 cells -- the two components of cellular immunity -- are collaborators in the control of HIV infection. (CD4 cells can be compared to the "commanding officer" in the immune-control army, directing the CD8 cell soldiers to attack HIV-infected cells and destroy them before more HIV can emerge from them.) Sadly, these cells are among the first to be targeted for destruction by HIV itself, and these cells are effectively eliminated. Since these cells are effective when they are survive this initial battle, it is important to establish whether attempts to recreate these cells could be successful in controlling HIV itself.
This understanding has provided a framework to consider ways to attempt the restoration of HIV-specific immunity. There are a few distinct approaches being tried so far in the attempt to recreate HIV-specific immunity. The first is the theory of using "structured treatment interruptions". The concept here is that a person's own HIV can be used as a vaccination. The first step is to identify people who have the best chance of having cells that can be effective at controlling HIV infection -- therefore, the initial studies are designed for people who are still in the first few weeks after HIV infection first happened. In this case, it is hoped that the cells that could control HIV are still present, and haven't been destroyed yet. Then, antiviral treatment is used to suppress HIV and allow the immune system to normalize again, since even a few weeks exposure to HIV can cause some degree of destruction. Then, after some period of time, the antivirals are stopped, allowing the immune system to be re-exposed to the HIV that is lying dormant. This is done so that, like any vaccination, it might expand the population of cells comprising their cellular immunity. If these cells are sufficiently expanded, they might have the ability to control HIV itself. Since these cells are among the first to be lost, the initial research has focused mainly on those who are identified very soon after the initial exposure to itself; who are still in the process of seroconverting.
A group of 25 were identified and treated during seroconversion with standard triple combination antivirals at Massachusetts General Hospital to test this theory. The viral load when they started treatment was an average of 13 million, a reminder that the viral load can be extremely high during seroconversion. Their initial CD4 count was around 400 cells/mm, with a range from 42 to around 1000, again a reminder of the initial changes observed during seroconversion. After two months on antivirals, there was measurable evidence of intact cellular immunity to HIV (using special research techniques), and this increased over the first year of treatment. It is important to understand that this type of cellular immunity is not restored when treating people months after seroconversion, since those cells are initially destroyed and not normally recovered after that time. However, starting treatment very soon after seroconversion interrupts the initial destruction by HIV and preserves these cells. In the follow up of these studies, while these cells are present, they are only measured at fairly low levels. Therefore, it is not surprising that interruption of antivirals, in those who have this low level of cellular immunity present, results in the rapid return of HIV growth. So, can these cells be expanded in order to do what is seen in the long-term nonprogressors?
The idea of brief interruptions is based on the concepts of why vaccinations are generally used in medicine. The general principle is that the immune system expands when it sees foreign proteins that it recognizes. Since treatment with antivirals very early on protects the cells that can recognize HIV, the immune system can still fight HIV. However, starting antivirals leaves us with a level of cellular immunity that appears to be too low to be very active in controlling HIV replication if antivirals are discontinued. If antivirals were permanently discontinued, the cells that were initially preserved would then be destroyed by uncontrolled HIV growth, similar to what happens in those who don't start treatment at all during seroconversion. However, if this cellular population were expanded, it might become strong enough to control HIV itself. Vaccinations are commonly used to expand immunity, and boosters are often used when one dose in not enough to complete the job. For example, a vaccination against either hepatitis A or B requires more than one dose, since the first dosage in not enough to create protective immunity. A repeat dose expands the cells that were created in the first dose and this booster is able to create protective immunity. One experimental approach then is the use of treatment interruption, repeated a few times, in the attempt to increase the cellular immune response directed against HIV.
The results of two patients treated in this way were presented at a recent scientific meeting, and those results were presented at this forum as well. The first patient was treated with a standard triple combination approach shortly after seroconversion was recognized. He was treated for 17 months, during which time his viral load remained below 50 copies, and he had evidence for strong T cell responses against HIV proteins. After the first antiviral interruption, the viral load went up to 17,000, at which time the antivirals were restarted. About four months later he underwent a second treatment interruption. Again the viral load rebounded, this time up to 40,000 copies. However, without treatment, the viral load spontaneously dropped to about 6000 copies, and then further declined to about 400 copies. This drop is considered evidence that cellular immunity was activated in this person, since it is rare to have such spontaneous reductions otherwise. It was noted that after the viral load hit 400, there was a slow increase, and this person did restart antivirals a third time in order to protect the cells that appear to be active in controlling HIV. Test tube studies of this person's immune function show important evidence of T helper cell activity against HIV, and it was much stronger after the second interruption, consistent with this "booster" concept. After the third treatment interruption, the viral load rebounded to about 5000 copies, and stayed there for about 20 weeks off therapy, at which time treatment was restarted. A second person also underwent this similar strategy. Again, the person was diagnosed during seroconversion and given antiviral therapy. After the first interruption, the viral load did rebound to a high of 120,000 and he did restart treatment. This first interruption was associated with an increase in cellular immunity active against HIV proteins. The second interruption did show control of HIV viral load for a short period of time as well, and this person has restarted antivirals. Results of future interruptions in these and other patients will be presented at upcoming meetings.
It is again critical to point out that these interruptions are being done only in those who are treated during seroconversion. If there is any chance that preserving HIV-specific immunity can be effective, it is first going to be demonstrated in those whose immune system has the best chance at controlling HIV. Therefore, these interruptions can be seen as the beginning of a chapter in our knowledge about expanding cellular immunity. These descriptions, along with others from other sources, lead to enthusiasm for recognizing HIV seroconversion. If we can treat with antivirals at that point, we have hope that preserving cellular immunity will allow someone a better chance at becoming a long-term nonprogressor in the absence of antiviral treatments. However, there are as yet only hints that these cells will be sufficient to control HIV in the absence of antivirals, and it is far from clear what the best way will be to create these cells. Thus, it is urged that those who are starting treatment during seroconversion only consider the interruptions while under the care of someone who is expert in monitoring the outcomes. Otherwise, it is possible that interruptions will lead to the destruction of the very cells that we are trying to expand.
Studies of antiviral treatment interruption have two major concerns that are frequently raised. One is the concern that there might be risks to antiviral interruptions, either due to a possibility of creating resistance to the medications, or from the recurrence of symptoms associated with seroconversion. The second concern is that it is exclusively being done for those who are recognized during seroconversion. These studies are difficult to do since the vast majority of people with untreated HIV infection are diagnosed well after that period of time. It remains unclear if treatment interruption could be successful in this group, and studies are far from answering this key question.
However, research has also focused on ways to use more traditional vaccination approaches to recreate or expand cellular immunity. The most studied approach to attempt this has been the use of the product called Remune. Remune, formerly known as the "Salk" vaccine or immunogen, is similar to other vaccines -- it is an intramuscular vaccine made of a strain of HIV that is completely killed and has had the outer envelope removed. This product has had nearly a decade of research documenting its potential in expanding cellular immunity. It is hoped that if someone is on effective antivirals, the addition of Remune might recreate HIV specific cellular immunity, which could allow better control of HIV by both creating and expanding enough of the critical cells that are lost after seroconversion.
Why is this product still considered experimental? One reason is that the largest studies completed to date were done in the era in which HIV itself was not fully controlled. Thus, in these studies, the immune system was significantly hampered in its ability to better learn how to control HIV, since it was under constant attack by uncontrolled HIV replication. This likely accounts for the disappointing results of the largest study done to explore the potential for this vaccine approach to work, which was completed earlier this year. The results showed that in those not on effective antivirals, there is little if any evidence that boosting immunity with this vaccine can work. In a study of about 2,500 people who participated in this pivotal placebo-controlled study, there were similar rates of opportunistic infections and deaths in the groups who did and did not receive the vaccine. There were also similar rates of HIV RNA declines, consistent with the increased use of effective antiviral combinations that became available during the study period. However, there was a small but significant increase in the T4 cell count in the Remune-treated group over the placebo group, although the clinical significance of this T4 cell increase remains unclear.
However, other more promising studies have been done recently, including in those just starting triple combination therapy. One small study suggested that starting antivirals in combination with Remune led to a more rapid decline in viral load, and a higher likelihood of achieving viral suppression. These results have led to a much larger confirmatory study now enrolling in many sites in which those who have never taken antivirals before are randomized to a standard antiviral combination (with Combivir and Viracept) either with or without Remune vaccination. This study is specifically looking at those who are not seroconverting. From this and other studies underway we hope to learn if the addition of a vaccine approach can recreate and/or sufficiently expand cellular immunity in those on an effective antiviral combination. One small recently completed study did illustrate some evidence of cellular immunity directed toward HIV proteins when Remune was administered in conjunction with a standard, triple combination therapy. Future studies could show if this or other vaccine approaches added to standard antivirals would make the use of antivirals more successful. It could also lead to clues that might lead to more complete restoration of HIV-specific immunity, even in those in whom these cells have been essentially eliminated by untreated HIV infection.
One key observation made about the nature of illness due to HIV infection remains true today -- HIV leads to illness mainly after significant immune damage has occurred. The presence of HIV itself, even with elevated viral loads, rarely produces any symptoms. The damage done by uncontrolled HIV growth leads to immune destruction, and that leads to the entire cascade of illnesses grouped together as a diagnosis of AIDS, and its related illnesses. Therefore, if despite HIV infection the CD4 count could be maintained at a high enough level, it is possible that there would be little if any illness associated with HIV infection. Unfortunately, uncontrolled HIV replication comes at the expense of a steady decline in the CD4 count. In addition to the work on antivirals, over a decade of research has gone into understanding the potential role of T4 cell growth factor, known as IL-2. As research also expands into recognition that cellular immunity might be effective in assisting with the control of HIV itself, research into approaches to further expand cellular immunity are also of heightened interest.
Initial studies of IL-2 have defined several issues involved in its use. The initial studies were done using the drug as a continuous intravenous preparation. Fortunately, several studies have been done with comparable results when it is taken as a self-administered subcutaneous injection twice a day (similar to how insulin is used). Thus, current research is using IL-2 in this preferable twice-daily schedule. The standard schedule that has been studied most extensively is when the medication is taken for five days in a row, followed by an eight-week rest period in between the 5-day cycles. Studies have also been done over a range of CD4 counts. Some results are available from the time period before effective antivirals were in use, while others have been done more recently and these results are summarized below. A range of doses has also been studied, although based on tolerability and effectiveness, most studies at this point now initiate the drug at a dose of 4.5 million units twice a day. There also are studies of much lower doses and these are discussed below.
The primary results from many studies shows clearly that IL-2 can expand the T4 cell count. One early study, done in those with a T4 count over 300 using intravenous IL-2, showed an increase of around 400 cells, with over half of participants showing over a 50% increase in their T4 counts from their baseline. Participants were, after a year, allowed to go on a maintenance schedule to maintain CD4 counts over 1000, and were able to decrease the need for IL-2 done to one five-day dosing on average every 9 months. This study, done before antivirals were highly suppressive, showed some increase in the HIV RNA after the dose was given, but over time there was no clear increase in the "set point" even after one year. These results have led to some research exploring how IL-2 might allow interruptions from regular antivirals for those finding that daily use is associated with excessive toxicity.
Studies have shown that while lower doses are more easily tolerated, a five-day schedule of only 1.5 million units every eight weeks had a minimal impact on T4 counts, although this same dose given every four weeks did result in a 37% increase in the T4 count. However, higher doses still -- including the higher dose in one study of 7.5 million units -- results in at least a 50% increase in the T4 counts.
One randomized study, comparing IL2 plus antivirals versus antivirals alone, recently completed did show that there was a larger increase in the T4 count in those receiving IL-2, with a near doubling of the counts in those on IL-2 versus an increase of 18% in the control group. Further, an analysis by CD4 count at baseline showed similar improvements at all levels between 200 and 500 cells. An intriguing finding was also that there were more people whose viral loads were below 50 copies in the IL-2 treated group versus the control arm, although these results may have been influenced by the background antivirals that were used. Studies of IL-2 have also been done on those with lower CD4 counts at baseline. One small study did show that the standard IL-2 dose could result in a 39% increase in CD4 counts, even in those who are treated with counts below 200 cells.
According to Dr. Smith, much lower doses have also been studied with IL-2 treatment, and results of randomized studies testing this approach are expected soon. This lower dose, generally starting at around 1 million units or less per day and gradually increasing over time, is studied based on the premise that lower doses will have different effects on the different types of IL-2 receptors on cells. It will also have fewer side effects, since one of the major challenges in the wider use of IL-2 at the standard doses are the constitutional symptoms that are commonly seen. One early report from the use of lower dose IL-2 was presented at ICAAC in 1999. This study used IL-2 at lower doses in persons undergoing a treatment interruption from effective antiviral therapy given with IL-2. Like other studies, there was a viral load rebound off antivirals which occurred at about week three. However, after a peak of nearly 400,000 copies, the viral load came back down to about 25,000 copies still off antivirals, which was noted to be less that the pretreatment viral load of about 70,000 copies. These early results are being followed up with other research to better understand how low dose IL-2 might play a role in enhancing immune function.
One key question is whether the cells created by IL-2 are functional. So far, by all lab measures, these cells are fully functional. However, the question that has remained unanswered is whether the use of IL-2, in addition to current antivirals, further reduces the rate of opportunistic infections. One study is now underway to definitively answer this question. It is an international study called SILCAAT (1-800-244-7668). It is enrolling those whose CD4 counts are between 50-299 cells, with a viral load below 10,000 copies while on antivirals. In this study, participants are randomly assigned to either stay just on antivirals, or to add IL-2 initially at a dose of 4.5 million units twice a day for 5 days, with an eight-week rest in between these cycles. After one year, participants have the options to go on a maintenance approach, using IL-2 only as needed based on the CD4 count. Over 1,000 participants are needed for this study, which is happening at several countries across the entire world. Since it is focusing on those with lower CD4 counts, and for those whose viral loads are still detectable, it is designed for those in that very important niche of having some benefit from antivirals, but not getting the full expansion of CD4 cells. This group may still be at some risk of opportunistic infections as well as the concern that the antivirals might lose some of the benefits now seen as a result of increased antiviral resistance. Therefore, attempts to increase the CD4 count in that group may be of particular interest as a way to further minimize the risk of OI's while better antivirals are being investigated.
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