The Bay Area Reporter - May 11, 2000
Jeff Gustavson, Survive AIDS Writers' Pool

At the same time, there was a perceptible shift in attention from the virology (replication and inhibition of viral replication) to immunology (looking to the infected person's immune system to have a role). One of the splashier stories out of Geneva was the laboratory results Fred Valentine, M.D. from NYU/Bellevue, showed for a relatively small number of people who had received a therapeutic vaccine.

The inability to ascertain whether immune-based therapies are actually beneficial is a quandary that continues to baffle the HIV positive community. Some possess an almost religious-like fervor of belief in their efficacy, while others outright reject any claim of benefit. Most people, though, are somewhere in the middle, hopeful yet wary of the hype, and are unclear as to what to believe. At the same time, industry seems unsure how to proceed, and in some instances have directly sought community advocates to be their champion.

The FDA has recognized this dilemma and is planning on devoting a two-day meeting to address the problem this summer, and will hopefully provide guidance to industry as well as listen to input from the community.

A central problem in evaluating immune-based therapies is trying to determine relevant surrogate markers. Donna Mildvan, M.D., is the Chief of Infectious Diseases at Beth Israel Hospital in New York City. Dr. Mildvan says, "a surrogate marker is in the eye of the beholder. We define it as a biological marker that can be shown through a rigorous validation process to substitute for a clinical event."

Dr. Mildvan continues: "In the more recent era of achieving effective viral control in HIV/AIDS, we as researchers recognize we must move more proximal to laboratory markers, and that in order to advance ideas requires debate around the validity of any given marker. The proportion of treatment effect explained by CD4 count or viral load alone does not fully cover the benefit seen with antiretroviral therapy. A composite marker of the two comes close to this goal."

Some in the community have been frustrated trying to gauge whether using Interleukin 2 (IL-2), a cytokine (chemical messenger) central to many processes in the immune system including mitogenic (causing cell division) for CD4 (T-helper) cells would be wise. Clearly, substantial increases of CD4 cells can be seen, and, so the argument goes, since their (CD4's) declining numbers portend immune decline, how can this not be good?

One answer is that not all CD4s are created equal, that is a given CD4 cell and all its progeny are specific for (can only recognize) a particular antigenic sequence. In other words, each cell will only react to a specific piece of digested pathogen (virus' or bacteria's nine to eleven amino acid piece) shown to it by an antigen presenting cell. Therefore, the range of pathogens would not be expected to increase solely by proliferation. At the same time, it may be that IL-2 induces more stem cells to go through development and become effective in a person's immune system.

Dr. Mildvan continues, "An analogous situation occurred while studying interferon gamma for chronic granuloma disease (CGD). People who have CGD have white blood cells that have a defect in the normal oxidative burst; thus their cells are incapable of killing intracellular organisms. The method by which interferon gamma was thought to have therapeutic effect did not, in fact, bear out in clinical trials. Nevertheless, the drug in terms of clinical benefit, had an enormous impact that you'd have missed, were it not being looked for."

A large international trial, ESPIRIT, was recently awarded $43 million by the National Institutes of Health, to answer the question of whether IL-2 provides clinical benefit. It is not expected, however, that the answer will become known for several years.

There are two interrelated areas of immune deficiency in HIV disease which need to be addressed - general immune competency for everyday pathogens (CMV, PCP, etc.) and HIV-specific immunity. The premise of a therapeutic vaccine is that under the cover of viral control provided by combination therapy, HIV-specific immunity could be enhanced - that is, the number of cells committed to fighting the sequence of the ingested vaccine would be expanded to sufficient numbers to better control the virus. Dr. Mildvan explains "I believe we could extrapolate existing short term safety data and withdraw therapy [go off medicine] under close supervision as an endpoint in a clinical trial. This way we could test a therapeutic vaccine by withdrawing antiretrovirals and see whether the host [a person with HIV] has gained improved control of virus replication." In other words, validate clinically the Lymphocyte Proliferation Assays (LPA), that caused so much stir at Geneva.

Dr Mildvan clarifies "This is a distinct concept from a Structured Treatment Interruption as an intervention [see Act Up/Golden Gate Writer's pool article "STI - a drug holiday by any other name?"], even though some STI trials are using the endpoint concept as well."

There has been a fair amount of controversy over a Remune trial in Thailand where a statistically insignificant difference in CD4 count was shown among those who received Remune with no other anti-HIV medicine versus those who received no therapy at all. The manufacturer of Remune (Immune Response Corporation, funded to a large degree by Aguoron Pharmaceuticals) is claiming evidence of benefit while the results do not support such a claim. It is this kind of manipulation of data that has confused so many in the community, leaving us unsure what to believe.

We hope that the FDA hearing this summer will bring us closer to developing consensus on the interpretability of results from trials of immune based therapies or at least will provide the ground rules for designing trials to evaluate them.
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