IL-2 for HIV: The Long March Toward FDA Approval
Interleukin-2 (IL-2), a candidate immune-based therapy for HIV disease, is now at a pivotal stage in its development. (See Treatment Issues, November 1996, for IL-2's history as an experimental treatment for HIV/AIDS.) Researchers are finally starting up a massive phase III trial to determine once and for all whether IL-2 therapy offers any clinical benefit for people with HIV in terms of retarding or preventing the advent of opportunistic infections. At the same time, years before any such clinical data will be available, the Chiron Corporation, which produces the Proleukin brand of recombinant human IL-2, is preparing to apply for FDA approval of IL-2 for HIV infection on the basis of surrogate data -- i.e., CD4 cell-count rises. (Proleukin is already approved in the U.S. for renal cell carcinoma.)
IL-2, formerly known as T-cell growth factor, is an immune regulatory protein called a cytokine, that is normally produced by T-cells to help them divide, multiply, and combat invading pathogens (viruses, bacteria, etc.) and cancers. In the test tube, IL-2 causes T-cells to proliferate, and can essentially turn one T-cell into thousands of T-cells. If achieved in the bodies of persons with HIV/AIDS, the theory goes, declining T-cell levels, especially in the CD4 "T-helper cell" subset, could be reversed.
Researchers have been able to accomplish this with high doses of IL-2 administered either by continuous (24-hour) infusion or multiple daily injections for five days every eight weeks. In trials of "intermittent continuous" IL-2, all participants experience debilitating toxic effects and transient increases in HIV. (A rival low-dose approach employs much less toxic amounts of IL-2 and seeks more to improve immune cell functioning than increase CD4 cell count.)
Intermittent continuous IL-2 therapy, has, however, been associated with dramatic (greater than 50%) and sustained CD4 cell increases in some people with CD4 counts of 200 or greater. Conversely, the majority of patients who have begun high-dose IL-2 therapy with a CD4 count less than 200 do not experience increases in their CD4 cells, but do experience dangerous, sustained rises in HIV levels. Treatment-related toxicity also appears to be more pronounced in patients with advanced HIV disease. But the simultaneous use of potent antiretroviral therapy has been associated with improved responses to IL-2 in a handful of patients with low CD4 cell counts.
A study by the AIDS Clinical Trials Group (ACTG 328) is currently seeking to enroll 150 volunteers who have CD4 counts between 50 and 300 and have never taken a protease inhibitor. This 72-week phase II study will compare the effects of triple anti-HIV therapy (two nucleoside analogs and indinavir) alone, triple therapy plus intermittent subcutaneous IL-2, and triple therapy plus intermittent IL-2 infusions. The investigators will monitor changes in immunologic parameters, viral load and the development of antiretroviral drug resistance. Only patients whose viral loads drop to below 5,000 copies (by bDNA assay) after ten initial weeks on antiviral therapy alone will continue in the study.
ACTG 328 is exploring an innovative use of IL-2. Formerly, IL-2 was administered in an attempt to spark rises in CD4 cell proliferation that would outrun the CD4 cell death triggered by HIV. ACTG 328 for the first time uses IL-2 in conjunction with the new highly active antiretroviral therapy (HAART). The objective is to see whether IL-2 aids in immune system recovery once virus production has been suppressed. There is some fear that IL-2 will speed the development of drug resistance by enhancing HIV reproduction in opposition to antiviral therapy, but if successful, ACTG 328 may expand the population able to make use of IL-2. The information yielded by the trial will be limited in scope, though. The results will only be pertinent to advanced patients who have never taken protease inhibitors before. And there will be no information on the clinical benefit from adding IL-2 even if the agent proves to give CD4 counts an extra boost.
Obtaining Clinical Validation
At it now stands, it is entirely uncertain whether IL-2-induced CD4 cell increases will translate into a clinical benefit to patients (i.e., delay disease progression or improve survival). Researchers at Community Programs for Clinical Research on AIDS (CPCRA), the National Institute of Allergy and Infectious Diseases (NIAID), and elsewhere (to be decided) are proposing to remove this uncertainty by implementing an international, multicenter, phase III trial of high-dose IL-2. The study will seek to enroll 3,700 persons with CD4 cell counts above 350, half of whom will receive twice-daily injections of IL-2 for five days every eight weeks, and half of whom (the control group) will receive no IL-2. The proposed trial will take a minimum of six years to complete and will cost around $30 million. (Note that NIAID, and not Chiron, is sponsoring the trial. This circumstance is consistent with Chiron's "passive development" of IL-2 for HIV infection to date. It remains to be seen how much Chiron will contribute to the trial budget.)
In order for IL-2 to be clinically validated by this study, a relatively large number of control patients will need to progress to AIDS, while people in the IL-2 arm do not. Unfortunately, because this is an early intervention trial (CD4 count above 350), and because of the effects of HAART upon patients' prognosis, a significant difference in progression may not appear in a timely manner. Even with five years of follow-up, it is possible that too few people may progress to AIDS to show whether IL-2 has a clinical benefit or not.
Another obstacle -- one that is common to all large and/or long-lasting clinical trials -- is keeping people participating in the study, particularly the control arm. The current draft protocol predicts a mere 2% annual dropout rate. This optimistic figure is predicated on experience from previous controlled trials of IL-2, which were comparatively short, and which enrolled a combined total of less than 160 participants, all of whom were offered open-label IL-2 on completion of the relatively short trial observation period. Other incentives, such as sophisticated blood tests, additional medical expertise, access to free and/or experimental antiretroviral drugs, and cash, further helped to keep participants on-study. The proposed phase III trial, in contrast, will enroll participants at their primary care settings and offer no supplementary services. Nucleoside analog reverse transcriptase inhibitors and viral load tests will be made available for free to a fraction of the trial participants.
Logic dictates that in a long-term trial, participants randomized to IL-2 who experience major CD4 increases will stick with the trial in order to continue receiving therapy. Control patients and participants who experience nothing but side effects on IL-2 are likely to drop out of the study at a greater rate than the projected 2% per year.
In addition, because the majority of people in the treatment arm will probably sustain dramatic CD4 increases, a large number of control patients should be expected to obtain IL-2 surreptitiously. This will weaken the trial's ability to determine whether IL-2 is clinically effective. In the U.S., where IL-2 is accessible, hype surrounding CD4 increases could effectively disband the control arm of the proposed trial. Concomitant marketing of IL-2 by Chiron would contribute to this effect. In other parts of the world, trial participants receiving IL-2 may share the drug with friends in the control arm (drug pooling), or access the drug through international buyers' clubs. The Catch-22 is that the potential CD4 cell increases on IL-2 will need to be hyped in order to enroll the trial in the first place.
The Ethical Hurdles
To circumvent the possibility that the proposed phase III trial might fail by virtue of trial participants being too healthy because of HAART, the protocol team has proposed enrolling large numbers of patients in underdeveloped countries where prognosis is poor and HAART is not available. Accordingly, the draft protocol does not require that patients entering the study be on antiretroviral therapy. Rather, the protocol mandates that all trial participants have "access to antiretroviral therapy." In underdeveloped countries, this "access" would be ensured by giving trial participants free access to nucleoside analogs only (i.e., suboptimal therapy).
This raises several serious ethical questions: (1) Why test a therapy in populations that would never have access to the drug if validated? (2) How can one administer a drug that has the potential to increase HIV levels without the protection of adequate antiretroviral therapy? The current protocol will be handed off to an external panel of bioethicists. One can only hope that they will recognize that all trial participants must have access to therapy equivalent to that obtainable in the sponsoring country (i.e., to HAART). Exploitation of Third World populations in the name of expedient science is widely recognized as unconscionable. (See the "Declaration of Helsinki IV," 41st World Medical Assembly, Hong Kong, September 1989, in: Annas GJ, Grodin MA eds., The Nazi Doctors and the Nuremberg Code: Human Rights in Human Experimentation. New York: Oxford University Press, 1992:339-42.)
Early Approval and Promotion of IL-2 for HIV
Whereas HAART-associated drops in viral load and increases in CD4 counts have been correlated with positive clinical effects, IL-2-associated CD4 increases have not. It is impossible to say that a CD4 count of 1,000 achieved with IL-2 signifies better immunologic health or prognosis than does a naturally occurring CD4 count of 200. For this reason, CD4 cell increases cannot be said to be a surrogate maker for the clinical efficacy of IL-2. Nonetheless, in about two years Chiron plans to apply to the FDA for the accelerated approval of IL-2 on the basis of these cell count boosts.
Activists and physicians have had mixed reactions to Chiron's approval calendar, ranging from skepticism to disbelief. In two years' time, Chiron will only have a patient database of about 300 people. Although a substantial proportion of these patients will have exhibited large IL-2-related CD4 cell increases, some will have suffered significant increases in viral load. Most importantly, serious adverse events are common. In addition, the virologic safety of IL-2 has yet to be determined--particularly with regard to drug resistance. Once again, ACTG 328 would be able to show whether IL-2 hastens the development of antiretroviral drug resistance but will only in patients without prior protease inhibitor experience.
As the "Background and Rationale" of the proposed NIAID phase III study concludes, "There is substantial evidence that IL-2 increases CD4+ cell counts; however, this apparent benefit is offset by serious flu-like symptoms during treatment for most patients. Furthermore, IL-2 is associated with a transitory rise in viral load, for which the clinical significance is uncertain. Whether IL-2 delays progression to AIDS and extends survival is unknown. The clinical benefit of IL-2 can only be established unequivocally in a large, long-term randomized trial."
Meanwhile, a section in the Senate FDA reform bill (S830) would allow companies to promote off-label uses of approved drugs for at least three years before filing a supplemental New Drug Application to the FDA. Companies with approved trial protocols on a new indication would be allowed to disseminate off-label information, including preliminary trial results, if they commit to file within three years. Although it is uncertain whether this proposed legislation will become enacted, it is likely that FDA regulation of off-label information dissemination will become more lax.
Active marketing of IL-2 for HIV would have the potential to undermine the ability of such a trial to yield unequivocal findings, as trial enrollment is disrupted and individuals in the control arm obtain IL-2 on their own. Only time will tell if Chiron's intentions are consistent with those of NIAID, the CPCRA and their international collaborators and whether NIAID's ambitious clinical endpoint trial will be able to achieve its stated goals.
This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.