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Immune-Based Therapy
Will Immune-Based Therapies Ever Be Approved?

By Brenda Lein

Summer 2002

The development and approval of immune-based therapy (IBT) for the treatment of HIV infection and related conditions is complicated by many factors, not the least of which is a poor understanding of immune responses that promote health and prolong life in people living with HIV. Defining the goal of and how best to use an IBT is an arduous task in itself. Figuring out a way to design studies quickly and efficiently to assess the value of IBTs is even more daunting. Interleukin-2 (IL-2, also known as Proleukin) is an IBT furthest along in study in the context of HIV disease. Using IL-2 as an example, this article will explore the obstacles and challenges to developing IBTs for the treatment of HIV infection.


The currently available anti-HIV drugs work by blocking HIV replication -- interfering with the ability of HIV to reproduce. Initially, anti-HIV drugs were approved for wide-scale use based on their ability to prolong life. Those who received anti-HIV drugs lived longer than those who received a placebo in studies.

In the early 1990s, activist pressure led to reforms at the FDA that allowed for the accelerated approval of therapies for life-threatening conditions if 1) there were few effective options to treat that condition and 2) if there were surrogate markers (see definition in this issue) for the disease in question. Results from large studies showed that CD4 T-cell count correlated with risk of HIV disease progression -- the lower the count, the more likely someone was to develop a severe life-threatening disease or die. Thus, CD4 T-cell count was deemed a good surrogate for determining risk of disease progression.

The FDA mandated that confirmatory studies be conducted to look at whether or not the drugs also prolonged life, but these studies took place after the drugs had been made more widely available (i.e., post-marketing). Several studies confirmed that if an anti-HIV drug was able to increase CD4 T-cell counts, this increase correlated with longer life. In the mid-1990s, new technology to monitor viral levels (HIV RNA levels) was developed and further research found that HIV levels correlated somewhat with risk of disease progression. The ability of a drug to lower HIV levels was determined to be a marker of that drug's activity. Now anti-HIV drugs are largely approved on their ability to lower HIV levels after about 6 months of use.

A Confounder

Currently approved anti-HIV drugs all work by blocking the ability of HIV to reproduce, but IBTs work in vastly different ways. So, unlike the situation with anti-HIV drugs, the FDA is not able to issue clear guidelines to companies and investigators about the kinds of studies required to prove that IBT works. To the contrary, the first question that the FDA will ask is, "What is this particular IBT supposed to do and how does it do it?" The phrase immune-based therapy itself is vague and includes a broad range of approaches and technologies that do very different things. For example, an IBT that enhances immune responses against cytomegalovirus (CMV), which is the leading cause of blindness among people with HIV, might be assessed for its ability to prevent or treat CMV disease. In contrast, an IBT that aims to enhance the immune system's ability to control HIV might be assessed by its ability to lower HIV RNA levels. To assume that there will be one neat path to develop and evaluate IBTs for treating HIV and related complications assumes that all IBTs work in exactly the same way -- but they do not.

Companies, activists, and investigators alike complain that there are not clear guidelines from the FDA about how to develop IBTs. While it's certainly true that the FDA could play a more significant role in developing some parameters and guidelines, it is not as easy and straightforward a task as it might seem. Guidelines are going to depend on what the therapy is touted to do. The guidelines for an IBT to treat CMV are going to be different than the guidelines for an IBT that specifically augments anti-HIV responses or one that claims to enhance immunity in general.

A Case Study: IL-2

IL-2 was discovered in the late 1970s and is a naturally occurring chemical (called a cytokine) produced by cells. One thing that IL-2 does is cause CD4 T cells to reproduce. Because CD4 T-cell counts decrease over the course of HIV disease progression, IL-2 was an obvious therapy to study. In the early and mid-1980s several IL-2 studies were conducted with very mixed results. When IL-2 was delivered intravenously, continuously, and daily, it appeared to have very little impact on CD4 T-cell counts and proved to have many side effects. Researchers played around with ways to administer the therapy and found that when delivered intermittently, every 2 months, it had a pronounced and notable impact on CD4 T-cell counts. Many studies were conducted to define a regimen and route of administering IL-2 that positively affected CD4 T-cell counts in a lasting way. These studies were small and most did not include a placebo or control arm. So despite nearly a decade of study, investigators merely arrived at a place where they figured out how to deliver the drug (by injection, intermittently) in a way that increased CD4 T-cell counts and minimized side effects. They had no idea if the therapy actually improved or prolonged life. Still, with an IBT, simply figuring out how to use a given therapy to realize a desired effect is a big part of the process.

By the early 1990s, it was clear that IL-2, when used intermittently and in conjunction with anti-HIV therapy, had the most pronounced impact on increasing CD4 T-cell counts of any therapy ever studied for the treatment of HIV disease. This is when the first quandary about how to develop and approve IL-2 reared its head. If CD4 T-cell count is an adequate surrogate marker for HIV disease progression, and IL-2 therapy significantly increases CD4 T-cell count, then why not approve the therapy immediately?

A number of scientific questions were raised at this point. When CD4 T-cell count is raised with IL-2 therapy, will those cells function? Will they actually aid the body in controlling HIV or other infections? Does this increase in CD4 T-cell count mean the same thing as the increases seen with anti-HIV drugs, where confirmatory studies show such increases (brought about by controlling HIV replication and immune destruction) delay HIV disease progression and prolong life? The answer to all of these questions was and largely remains, "We don't really know." To know if the boost in CD4 T-cell count from IL-2 therapy actually prolongs life requires a very large and long clinical endpoint study, in which one group gets IL-2 and another group does not and researchers see who lives longer. A clinical endpoint is a major health event, like disease progression or death. Two such studies are currently ongoing.

There have been laboratory studies looking at a number of measurements of immune function that suggest CD4 T cells increased as a result of IL-2 appear to function just as well (if not better) than CD4 T cells increased as a result of anti-HIV therapy alone. The problem with relying on these immune function tests, however, is that they have never been validated. This means these particular lab tests have never been studied to see if they also correlate with prolonged life in people with HIV. So in a test tube the immune function looks good, but what this means in a person's body remains unclear. At most, the positive laboratory results are encouraging, but they do not lead to any conclusion that these proposed indicators of improved immune function will prolong someone's life.

In addition, several scenarios indicate that raising CD4 T-cell counts might not benefit a person. If the cells reproduced but could not function, a person would clearly receive no benefit from an increased CD4 T-cell count. One way to assess whether this is the case would be to ask if people using IL-2 experience severe and life-threatening conditions, despite having elevated CD4 T-cell counts. This has not been observed in people with IL-2 thus far. Another scenario is simple cell redistribution. At any given time only about 10% of CD4 T cells are circulating in peripheral blood (the source for measuring CD4 T-cell counts). The rest of the cells are in deeper immune compartments, like the lymph nodes. If a therapy simply pushed cells from these deeper compartments into the periphery, the count would look increased when measuring from the blood, but really there would be no change in the number of cells in a person's body. However, studies suggest that IL-2 does not simply result in cell redistribution.

All of these questions about the competency of CD4 T cells increased with IL-2 therapy could just as well be asked of CD4 T-cell count increases realized with anti-HIV therapy. All of the same problems exist with answering the questions about immune function in both cases. The fundamental difference here, however, is that anti-HIV therapies have been shown to prolong life and delay HIV disease progression. The first anti-HIV drugs were approved based on improved clinical outcomes (i.e., patients experienced prolonged life and delayed disease progression) and this increased comfort levels about using CD4 T-cell count as a surrogate marker for approval of future anti-HIV drugs. Because there simply is not another IBT that has been approved for HIV infection, and certainly not one that works by the same mechanism this far along in development as IL-2, there is no information to increase the comfort level by comparison. Even if the CD4 T-cell count increases realized with IL-2 therapy do one day prove beneficial and the therapy is approved, how applicable or useful such information will be to the evaluation of another IBT (that might raise CD4 T-cell counts by a completely different mechanism) is wholly unclear. If the next IBT raised CD4 T-cell counts merely as a result of cell redistribution, the FDA would likely require that a large clinical endpoint study be conducted to affirm the relevance of those increases.

Fundamentally, the obstacles and challenges of IBT development can be described in a nutshell as the following points:

In the case of IL-2, the developer (Cetus Corporation and later, Chiron Corporation) spent relatively little money on researching the therapy for HIV infection during the 1980s. Truly one of the biggest activist challenges during the '80s and early '90s was simply convincing the company to seriously evaluate IL-2 in the context of HIV. The cost of long-term, clinical endpoint studies is enormous and the endeavor quite difficult. Now into the AIDS epidemic's third decade, the challenge remains to maintain corporate investment in this research effort.

To some, the debate about the value of CD4 T-cell counts increased as a result of IL-2 therapy sounds arbitrary and academic, and they believe the therapy should be made immediately available to all those who want it -- despite the unknowns. Others contend that it is unethical to ask people to pay for a therapy, particularly one with the side effects of IL-2, which has not been definitively proven to offer benefit. Some counter that risks were taken to make anti-HIV therapies available before all of the risks and benefits were known about those drugs and that people benefited overall from being allowed to take personal risks with therapies that were not fully proven to be effective.

There are risks involved no matter what. If the therapy is one day proven to delay HIV disease progression and prolong life, the thousands of people denied access while the debate raged will have perhaps paid the price with their lives. If the therapy is one day shown not to result in benefit, the thousands of people spared the expense and side effects will immeasurably benefit from delayed approval. As we wait for the large studies to reach their conclusion, perhaps the debate needs to take a subtle turn. Making IL-2 available to everyone, based on its ability to increase CD4 T-cell count, might not be a good idea because so much is unknown. But perhaps there are some groups of people (for example, those with low CD4 T-cell counts despite the use of anti-HIV therapy) for whom the potential benefits of early access might outweigh the known and unknown risks. This discussion must be kept alive and at a forefront in the activist community -- doing nothing carries with it the potential for harm. Defining what is and is not an acceptable risk is the legacy of AIDS treatment activism. The field of IBT research is still in its infancy and we will face this issue time and again. Undoubtedly, when the history is written we will have made mistakes.

Unfortunately what happens with IL-2 will likely have little impact on the field of IBT research overall. Certainly the prospect of early licensure might lure companies back into the arena of such research, but the results of the study will likely contribute very little toward establishing a regulatory path for future IBTs. For example, IBTs such as HIV therapeutic vaccines will likely be evaluated for their ability to control HIV replication, and not on their ability to affect CD4 T-cell counts per se. An IBT that aims to improve immune function by decreasing immune activation certainly might not be expected to increase CD4 T-cell counts at all, but rather improve the function of existing cells. Regardless of the IBT under consideration, the issues around its development and evaluation are challenging. Perhaps the one advance that would truly help this field is the identification, evaluation, and validation of markers of immune function. That effort, in and of itself, would likely bring many advances to the field of IBT discovery and development.

Brenda Lein is the Director of the Information and Advocacy Department at Project Inform, a national HIV/AIDS treatment information organization ( She also directs Project Immune Restoration, an advocacy program working to facilitate the development of immune-based therapies for HIV with special emphasis on concerns of people with advanced-stage HIV disease.

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