I don't think the scientific community lacks faith in Remune. Maybe Fauci does, but that is conjecture at this point. There certainly are "big names" like Bruce Walker, Jay Levy, Jules Levin, Fred Valentine; Autran, Mike Saag and others who seem to be excited about Remune. Some say that Fauci used to be a non-believer in Remune, and spoke out against it, maybe to the FDA, and the FDA has been exceedingly slow to respond to Remune in the past. Apparently the FDA told people to forget about vaccines and to wait for protease inhibitors in the early 90's. That was then. Now it is evident to all that more is required than just HAART and everyone is jumping on the bandwagon; either with new ways to stimulate the immune system or trying to show that their antiviral drugs help reconstitute the immune system better than others. Even the FDA has recently allowed Agouron/IRC to change from using the clinical endpoints of death or the development of opportunistic infections to viral load surrogate markers for studies on Remune.
Bruce Walker, from Harvard, is pretty positive about Remune in the latest issue of the Physicians Research Network. He is also investigating treatment interruption. An earlier study by Walker reported that when he took patients off HAART, who had been treated early with effective HAART, the viral loads rebounded quickly. But I guess he's still trying. Everyone is tring to emulate the "Berlin patient." There is a new article by Walker in the latest Physician Research Network. "Effects of antiviral Therapy on Immune Responses in HIV Infection". September 1999. prn.org
<Dr. Walker also pointed out that HAART might actually lead to declines in HIV-specific immunity in many patients, because the antigenic stimulation is reduced drastically when HAART is successful. ." But the immune system requires antigenic stimulation if it is to successfully respond to HIV. As we are seeing in patients treated intermittently, we may be able to use HAART to regulate antigenic stimulation and, in turn, strengthen the immune response to ultimately control viral replication. Clearly, we need more data to determine whether or not repeated interruptions in therapy truly work to achieve this.>
"Of particular interest to Dr. Walker has been the potential of HIV-immunogen (Remune) as a therapeutic candidate. As discussed in Volume III, Number 4 of The PRN Notebook, HIV-immunogen is an inactivated, gp120-deleted, Zairean clade A/clade E natural recombinant virus."
"In clinical trials, HIV-immunogen has been shown to induce p24- and Gag-specific CD4+ cell proliferative responses which, according to a report by Dr. Fred Valentine at CROI, were surprisingly robust in some patients. Indicative of increased non-cytolytic CTL activity, Dr. Valentine also reported in vitro production of the beta chemokine mip-1b in response to whole HIV antigen in PBMCs from immunogen-treated patients." <Ending his lecture on an optimistic note, Dr. Walker reminded the clinicians and researchers ....that the human immune system should never be underestimated. "It's important for us all to understand that eradication of HIV is not a necessity," he said. "There is absolutely no reason why HIV can not be immunologically contained." Walker continues to recommend potent early antiviral therapy. The immune system appears to require the presence of the antigen, i.e. the presence of HIV antigens to produce anti-HIC|V specific responses, and it won't get that just by adding IL-2, GM-CSF or proleukin etc.
Fauci has been advocating the use of IL-2 to rid the reservoirs of latent HIV virus, to activate the virus which should then be destroyed by HAART. Now he has admitted that IL-2 does not do that. Not only that, when patients with no detectable virus anywhere were taken off HAART and IL-2, the virus that returned (within a week or two) did not come from the reservoirs. Not everyone is in agreement with Fauci's views on IL-2 as a solution. Siliciano has said that the resting cell population does not express IL-2 receptor.
I posted to SI almost a year ago, about IL-2: siliconinvestor.com
<But (IL-2) has to given for months or a year and has many serious side effects. And no one thinks that this will be a cure. There will be remaining HIV virus in certain compartments or sanctuaries that IL-2 will not reach: macrophages, brain, CD4+ T cells in the gut and other places etc. So IL-2 may be reduce or eliminate the virus only in certain areas but something is still needed, like Remune -a substance to stimulate the immune system to control whatever virus remains and to stimulate the CTL's, an anti-HIV specific proliferative response. >
Now it seems that Fauci's next step is trying "Treatment Interruption therapy" as a means of boosting the immune system.. (Maybe someone will patent it.) There is a lot of interest in trying to get the immune system to respond by stopping and starting therapy, where the viral load rebound is used to prime or boost the immune system. It sounds kind of risky to me, bwdik. Even if it is done in a controlled clinical setting, no one really knows yet all the pre-immune response parameters necessary to chose candidates who might be successful at controlling their viral loads off therapy. Stop and go, trial and error.
Here's a study that shows the typical large increase in CD4s following HAART and IL2-, but it does not produce the desirable immune responses that would lead to immune control. Only one nuke was used, no HAART. aegis.com "High-dose IL-2 without HAART Treatmen tUpdate 96 - 1999 March, Volume 11 Issue 2 Hosein SR
Researchers in Australia recruited 115 HIV-positive subjects; baseline CD$ just over 300 CD4+ cells; viral load of 17,000 copies. It was a one year study; subjects received at least one of: AZT, ddC, ddI, 3TC). Some subjects received infusions of the immune booster IL-2, while others did not. The CD4+ cell count of those subjects who received intravenous IL-2 climbed by an extra 360 cells, while the counts of those who did not receive this drug fell. Subjects with the lowest viral load had the greatest CD4+ cell increase. IL-2 boosted immunity to bacteria, fungi and viruses to which subjects already were immune. The drug did not, however, restore immunity to HIV or any other microbes. In this short study, IL-2 had no apparent effect in terms of extending survival. As well, the drug was associated with side effects."
If you compare that study to the pediatric study on Remune reported recently in the Journal Of Infections Disease: children received Remune and only one or two nukes for 18 months. Four out of four children who received the higher dose of Remune (10U) showed strong anti-Gag responses and increased production of the chemokine Rantes, a cell mediated response, and they were able to keep their viral loads undetectable for the 18 months of that phase of the study.And they were only receiving one or two nukes. Only one out of four children at the weaker dose of Remune, also on AR, kept their viral load suppressed. Message 11352115
A study presented at ICAAC, showed that while baseline height and weight correlated with viral load, even children on effective HAART did not achieve height or weight appropriate for their age at 48 weeks. They showed declining weight and height remained the same through week 24, and then declined. The only ones who showed improvement were those who started with viral loads >100,000. The authors concluded: Although further longitudinal studies of growth need to be done, use of adjuvants to HAART therapy may need to be evaluated in this population. From: Lack of Improvement in Growth in HIV-Infected Children on HAART. asm.ctt-inc.com
In the pediatric study of Remune, described several posts above: Message 11352115 <Nine of the ten children on Remune showed normal patterns of weight and height gain, according to age-appropriate growth charts. The one child whose weight gain slowed also showed increasing viral load and decreasing CD4 counts. >
One study (Ortiz et al;) examined six patients who showed poor adherence to HAART and had their HAART stopped completely. When HAART was stopped, 3/6 kept their viral loads lows for 4-24 months and the other three rebounded quickly. Those who kept it low had strong virus-specific immune responses. They found that viral load was inversely correlated with a strong anti HIV specific immune responses.
There were two patterns observed:1. There is no viral rebound upon therapy discontinuation and there are very high anti-HIv CTL's and moderate neutralizing antibody titers. 2. Viral rebound occurred, but at low levels. Neutralizing antibody titers were boosted to high levels, as were HIV-1 specific CTL responses.
The maintenance of the of the HIV-1 IR appears to depend on the presence of the HIV antigen and HAART reduces the HIV virus to levels that may not be sufficient to stimulate CTL's or antibodies. HAART. In the threee subjects here, intermittent adherence provided the antigen stimulus. In one successful subject, viral rebound occurred but was kept low. There was a very strong neutralizing antibody titers, as well as CTL's. In the other two patients, who were able to keep their viral load down for 4 and 12 months respectfully, their were strong CTL's responses, as well as moderate neutralizing antibodies.
HIV vaccines. Review. Frey SE: Division of Infectious Diseases and Immunology, Saint Louis University Health Sciences Center, Missouri, USA. Infectious Disease Clinics of North America. 13(1):95-112, 1999 Mar.
In summary, the development of HIV vaccines has progressed from simple first-generation env subunit vaccines to second-generation vaccines containing multiple subunits. Vaccines with epitopes for CMI and Ab responses have broadened the immune response and the potential efficacy of these vaccines. It is hoped that newer technologies including the development of adjuvants, new types of vaccines, such as naked DNA, and new delivery systems, such as liposomes, will evoke stronger immune responses with longer duration. Improved schedules for dosing and combinations of HIV vaccines may result in longer lasting immune responses. After a temporary lull, the outlook for HIV vaccine development is being met once again with strong enthusiasm and encouragement for the future. >
Jonas Salk is still regarded as a great humanitarian. He is mentioned in the latest issue of the Economist: "Gone are the days when Jonas Salk refused to patent polio vaccine, saying that to do so would be "like patenting the sun". When a drug company spends millions to develop a vaccine, it wants an economic return." (editorial), "Balms for the Poor/Helping the Poorest" (14 Aug 1999):
economist.com
A really interesting older article (1995) about the history of IMNR's struggle with the FDA and others. critpath.org
<Since the company is paying for these large-scale trials, there are few if any non-bureaucratic obstacles to Immune Response Corporation's implementation of these large-scale trials which many persons in the community have been patiently waiting for as their health declined. Unfortunately, a growing number of those who signed up with ACT UP/Philadelphia in 1992 as being interested in enrolling in Salk Immunogen trials have died waiting. >
"In the first fourteen years of the AIDS epidemic, researchers have sought to discover a drug that targets and destroys the invading micro-organism. Such a drug thus far has eluded all our efforts. During those years, our research has determined that HIV is a highly complex, systemic moving target that sequesters itself in every part of the human body--a "metadisease."
"This increasingly obvious disparity between effort and results may be telling us that we have been barking up the wrong tree. And, with that realization, we are on the brink of a paradigm shift of unprecedented proportions in our approach to AIDS research and treatment. "
"The federal drug development process, often driven by ego and the high stakes of finding a salable "product," has virtually ignored immune-based and immune restorative regimes; such treatments would try to "jog the memory" of a failing immune system, and bolster or restore a [weak] immune response to infection. "
"In 1986, Jonas Salk, the maverick scientist who developed the first polio vaccine in the l950s, pondered this question and, counter to the beliefs of all others in the field, began working on a therapeutic vaccine. All previous vaccines were to prevent initial infection. Salk's novel approach was to help the immune system respond over the long term, warding off disease progression through inoculation. As had happened to Salk before, his scientific peers scoffed. "
Well, that's my opinion, I could be wrong, but then so are a lot who are now working to accomplish what they said was not possible just a few years ago. And I don't mind anyone asking me for my opinion. If i have time.
As far as other trials, I was planning on reviewing some of the different trials going on, but it takes too much time. I haven't seen anything very impressive that is in human trials. Lots of monkey trials. No one expects much from VaxGen's vaccine. There have already been 11 people infected with HIV in the trial, although that was in the Phase I, not designed to look at that.
That is probably why all these researchers like Gallo and others are now saying that even " a partially effective vaccine would still be valuable in significantly reducing the rate at which HIV is spread" or in improving control, once infected. But unspoken yet implied is: Accept my way, of course.
|
