The Bay Area Reporter - November 23, 2000
Jeff Gustavson, Survive AIDS Writers Pool

What we need

Dr. Larry Fox, in full United States Public Health Service uniform from the Division of AIDS at the National Institutes of Health, reviewed the limitations of antiretroviral therapy throughout the world. The well-established problems of toxicity, adherence, cost, and incomplete virologic suppression for some people all point to the inadequacy of combination therapy today. The need for less toxic, more effective, cheaper, and easier to take regimens is very apparent. Nevertheless, since eradication only seems likely for patients treated in acute infection, other means of controlling the virus are necessary. Fox showed the worldwide prevalence of HIV, 90 percent of which is in developing nations, with India on the verge of a major catastrophe. The need for more inexpensive therapies couldn't be greater.

What we know

Dr. Dan Kuritzkes, from University of Colorado Health Sciences Center, spoke on what we've learned from antiretroviral therapy. Within the context of clinical trials with naive (have never before used antiretrovirals) persons of long duration and a large number of participants, the virologic failure rates are low. That is, most people have suppressed viral replication to beneath the limits of detection. Kuritzkes said that the half-life (how long the presence of something takes to go from 100 percent to 50 percent) of infectious virus is one to two hours, and the half life of infected activated T-cells is one and a half days.

Kuritzkes went on to discuss the virologic methods beyond viral load by which a given therapy could be tested, both direct and indirectly. The frequency of viral DNA could be assayed -- the number of T-cells which had integrated viral DNA but were not actively producing virus. A slow turnover, however, in this population would have uncertain relevance. One could also quantitatively culture latently infected cells -- see how much virus would be produced -- but this procedure requires a large amount of blood, is labor intensive, and has a lot of interassay variability, rendering any results obtained unclear. Another test that could be run is to look at the number of cells containing two long terminal repeat (LTR) circles, as evidence of recent viral replication in a given cell. One could also use in situ (in place) hybridization (sticking of introduced material) of spliced/unspliced RNA. RNA, which is copied from a cell's DNA has what are called introns, superfluous pieces that like a film which is edited are cut out of it before it is read on the ribosomes and proteins made by reading this blueprint. This method, however, has large inter-patient variability. Indirect methods include rate of viral rebound off therapy (how fast your virus comes back), the magnitude of viral rebound, and control of viremia off therapy.

What we might know

Dr. Michael Lederman, from Case Western Reserve University in Cleveland, spoke of the only in vivo (in people rather than test tubes) measure of adaptive immunity (as distinct from innate -- that is, specific for a given pathogen), delayed-type hypersensitivity (DTH) skin tests. A delayed-type hypersensitivity (hypersensitivity type IV) reaction is the same as what results from poison oak or poison ivy. The loss of adaptive immunity is the hallmark of what constitutes AIDS.

A DTH test is where a small amount of antigen (a small piece of a pathogen) is injected beneath the surface of your skin. If your immune system has seen this antigen before, and your CD4/T-helper cells have proliferated as a result, you will mount a reaction to it visible to the naked eye in the form of swelling. Of course, since HIV disease involves the progressive loss of CD4 cells, and the cells that are there may be anergic (don't respond appropriately), an HIV-positive person may not respond to an antigen that they've seen before. This is the reason that shingles, which is merely a recurrence of chicken pox that most people had in their youth, is common among people with suppressed immune systems including the elderly. DTH tests are commonly used to screen for tuberculosis.

Lederman proposed immunizing with neoantigens (things never before seen by people) after a given therapy and seeing if a response could be generated via antibody levels, DTH and other in vitro (laboratory-based) assays, showing that the immune system had been enhanced by the therapy. He was also candid that DTH tests had their limitations in that their reading was not standardized, somewhat not reproducible and they did not test the efferent limb of the lymphatic system. The lymphatic system (that involving white blood cells) is divided into the afferent and efferent limbs. The afferent limb is when white cells are coming from the tissues to the lymph nodes and the efferent limb is after they leave the lymph nodes and return to the tissues. In other words, if you get a swelling, so what? What happens after the swelling? Would a challenge with a pathogen be successfully controlled?

What we don't know

Thomas Fleming, Ph.D., spoke on the limitations of surrogacy. In defining a surrogate marker, one that substitutes for disease progression, he said the marker must be sensitive to effect and have proven clinical relevance. Screening evaluations such as viral load, immunophenotype (the numbers of na ve/memory cells), as well as immunofunctional assays can be contrasted with definitive evaluations such as survival, symptomatic events and functional status. Fleming said the risk in choosing a surrogate is that it may only lie on one pathway of the illness and may miss what is really going on. He stressed that a surrogate must correlate with clinical outcome and it must fully capture the net effect of treatment upon clinical outcome. This is why there has been a mood shift to consider the composite marker of viral load with CD4 count since viral load does not tell the whole picture.

Talk amongst yourselves

The most interesting part of the day was when it was time for the panel to discuss IBTs. Dr. Robert "Chip" Schooley, also from the University of Colorado Health Services Center and chair of the AIDS Clinical Trials Group (ACTG), said "We don't need to reinvent the wheel. A decrease in viral replication" is an acceptable means by which to approve an IBT. He also said that toxicity must be considered and a proposed mechanism of action must be proven. Schooley continued, "No parameter should be considered in isolation. What else besides CD4? Well, the magnitude of the decrease in viral load and the durability of an effect must be taken into account."

Dr. Matthews said, "Focusing on a laboratory measure that has a single integrated overall benefit and has gone through a series of rigorous trials" would be an acceptable measure by which to judge an IBT.

Dr. Michael Saag, from the University of Alabama at Birmingham, said "biologic plausibility" must be shown. He commented that in an early trial of protease inhibitors in combination therapy, of those that were virologic responders but had no concurrent rise in CD4 cell count, at four years out had a death rate of 40 percent. "This became apparent do to the obligation of Phase IV [post-marketing studies] inherent in accelerated approval," Saag said.

The community representative on the panel, Brenda Lein from Project Inform, said that therapies for HIV needed a "reality check. Changes in viral load are perhaps least useful for people with advanced stage illness [low CD4 counts]."

NIH's Fox, speaking from the floor, said, "What is needed are composite endpoints -- viral load, CD4, and toxicity. I think what we will soon be seeing is a shift from a model of continuous antiviral therapy to a cancer model of intermittent therapy, where toxicity is reduced. If we don't act now to capture people going off therapy [who may wish to enroll in trials of IBTs], we run the risk of being left behind by our patients." This last remark was cheered by the audience.

Saag expressed "not all AIDS defining illnesses are created equal. Clearly PML [progressive multifocal leukoencephalopathy -- a neurologic complication of AIDS] is not the same as esophogeal candidiasis [thrush in your throat].

How to proceed

Schooley said a complete immune restoration may not be necessary since there is redundancy in the immune system. Lederman said that DTH and other laboratory based assays need to validated. Lein called on collaboration and sharing of samples from industry and government run trials to coordinate validation of surrogates.

Schooley pretty much summed up the state of affairs by saying, "The agency [FDA] is in unique position to foster collaborations. The field is on the verge of gaining critical insight into markers of relevance. The ALLRT [ACTG Longitudinal Linked Randomized Trial] will link markers to clinical events."

So sue me

The day could be considered frustrating if one had hoped definitive guidance as to how IBTs will be approved. However, the important thing is that dialogue was started around the issue, however late in coming it was. It has been said that the FDA's acceptance of viral load came from a big push from industry as well as the community. A similar push now must be made for IBTs, not lawsuits for publishing data that shows an IBT to have no effect. Dr. Jim Kahn at the University of California, San Francisco, is to be congratulated for doing the right thing and publishing his results on Remune in the Journal of the American Medical Association showing Remune had no positive effect on participants. The Forum for Collaborative HIV research will be holding a two-day meeting on developing IBTs in early December. The FDA meeting was just the first step in the process of hopefully bringing effective IBTs to the public.

001123
BR001118

Always watch for outdated information. This article first appeared in 2000. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 2000. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .