From: matthew@ooc.uva.nl (Matthew Lewis)
Subject: Conference newspaper - Tuesday, 21 July - part 2
Note: non-commercial reproduction.
Archive-Number: 5749
Organization: Center for Innovation and Cooperative Technology, University of Amsterdam
Date: 21 Jul 92 20:08:56 GMT

CONFERENCE NEWSPAPER - Tuesday, 21 July - part 2 of 4

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Growth factors help antiviral therapy
by Wim Zeijlemaker

Recombinant haemopoietic growth factors can help in the 
treatment of AIDS, the latest studies show. 
The results obtained so far in AIDS patients being treated with AZT 
and/or ganciclovir are promising. 
These antiviral drugs frequently cause anaemia, which means 
therapy must be interrupted until the patient's blood count 
recovers. But treatment with the growth factors appears to reduce 
the need to interrupt therapy, as well as improving the patients' 
quality of life. Recombinant human haemopoietic growth factors 
have only recently become available for therapeutic use in humans. 
They include recombinant granulocyte-macrophage colony-
stimulating factor, recombinant granulocyte colony stimulating 
factor and recombinant erythropoietin (rGM-CSF, rG-CSF and 
rEPO, respectively).

Skeletal pain
Data presented in yesterday's session on haemopoietic growth 
factors dealt with the use of these recombinant factors to alleviate 
neutropenias and anaemias during treatment of HIV patients. 
Scientists from the US and Sweden studied 51, 6 and 17 patients, 
respectively, who were taking ganciclovir or zidovudine. The 
patients received doses of 5 to 10 ug/kg/day of GM-CSF and G-CSF 
for a period of up to seven months. The growth factors increased 
the counts of neutrophil leukocytes sufficiently to avoid the need to 
stop therapy temporarily. The only adverse effect was skeletal pain 
in a minority of patients. 
John Phair from North West University Medical in Chicago 
presented data on the effect of rerythropoietin in 1,943 AIDS 
patients during treatment with AZT. Of them, 40 % required at 
least one blood transfusion during the six weeks before they 
entered the study. After 12 and 24 weeks of treatment with r-EPO, 
this percentage dropped to 22 and 18%, respectively.  

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The rise of the therapeutic vaccine

Is a vaccine to delay or prevent the onset of AIDS in HIV-infected 
people waiting to make its debut? Or is it just wishful thinking? 
Sharon Kingman reports.

Ever since it was first postulated that AIDS develops when the 
immune response against HIV proves inadequate, researchers and 
HIV-positive people have hoped that it may one day be possible to 
make a vaccine that would manipulate the immune system, delaying 
or preventing the onset of AIDS.
Studies being presented at this conference provide some of the 
first indications that such a vaccine - a "therapeutic"vaccine - may 
be feasible. With the exception of the rabies vaccine, all vaccines to 
date have been given to prevent infection. But the results from the 
latest tests on vaccines for HIV show that they can induce new 
immune responses in people already infected with HIV.
No one yet knows what such responses mean for infected people. It 
will be several frustrating years before researchers will be able to 
find out whether therapeutic vaccines can increase the life-span of 
infected people and allow them to remain healthier for longer. 

Rabies vaccine
If such a vaccine can be shown to work in this way, it will be a first 
in immunology. Gordon Ada, emeritus professor in the division of 
cell biology at the John Curtin School of Medical Research in 
Canberra, Australia, points out that the only other vaccine that is 
given to people who are already infected is the rabies vaccine. 
"People know they have been bitten by a rabid dog and therefore 
when they may have been infected. It may take one or two weeks 
before the virus reaches the nerve endings and if you can vaccinate 
before that, you can often effect a cure."
Encouraging signs
But most people do not know exactly when they became infected 
with HIV. "If you knew when someone was infected and immunised 
them right away, you might achieve something before the virus got 
around the body and into lots of different types of cells."
But once infection has taken place, it is too late for a traditional 
vaccine. "It's a case of can we give a vaccine that will mitigate or 
delay the course of the disease? It is too early to say how successful 
that is going to be, but there are some encouraging signs,"Ada says.
The encouraging signs are coming from groups such as those led by 
Robert Redfield of the Walter Reed Army Institute of Research in 
Rockville, Maryland, and Fred Valentine of New York University 
Medical School, who are reporting this week that candidate 
vaccines made of recombinant gp160, the envelope protein of HIV, 
can stimulate the immune systems of people infected with HIV who 
have CD4 counts of 400 or higher. 
Redfield's group has been using the polymerase chain reaction test 
to monitor viral load in HIV-infected volunteers given the vaccine, 
looking at both total amount of genomic viral RNA (which reflects 
the amount of free virus) and the ratio of viral-associated messenger 
RNA to viral-derived DNA in infected cells. The higher this ratio, 
the more active the infection. 
The results, due to be announced today, show a decrease in viral 
load, a lower ratio of RNA to DNA and an increase in neutralising 
antibodies produced by cells of recipients of the vaccine. One of 
Redfield's studies has also shown that the rate of decline of CD4 
cells slowed in vaccinated subjects. 
Valentine says the hypothetical rationale for giving a vaccine to 
infected people is that "If one were able to induce a new immune 
response in an infected individual, that infection had not already 
provoked, then this might be of benefit."But, he warns, "we have no 
evidence for that".
The trial by Valentine's group was placebo-controlled because, he 
says, "We wanted to see if the immune changes were related to 
receiving HIV as opposed to the stimulation caused by just any 
antigen. So subjects had to be antibody-positive for both HIV and 
hepatitis B."
Normally, when a person's lymphocytes are put in contact with an 
antigen they have encountered before, they will respond by dividing 
or proliferating - the "lymphocyte proliferative response". Those 
who took part in Valentine's trial had normal lymphocyte 
proliferative responses to common microbes. But their responses 
to HIV antigens were negligible.
However, after immunisation with rgp160 - but not after 
immunisation with hepatitis B vaccine - these people had a good 
lymphocyte proliferative response to HIV antigens. Valentine's 
group reports that their lymphocytes also made interleukin-2 when 
stimulated with rgp120 in the laboratory and, when shown cells 
with gp160 displayed on their surfaces, the lymphocytes showed 
increased cytotoxic ability.
The fact that these changes occurred only after the gp160, but not 
after the hepatitis B vaccine, shows, Valentine says, that they were 
indeed the specific consequence of the vaccine, and not the result 
of nonspecific perturbations of the immune system, which could be 
caused by any antigen.
The next step for Valentine's team will be to find out how ill 
someone can be with HIV infection and still respond to the vaccine. 
Trials will begin in the autumn in people with lower and lower CD4 
counts, Valentine says. After that will come a very large trial to find 
out if the vaccine can influence the clinical outcome: does it delay 
the onset of AIDS? Will vaccinated patients live longer?

Pressure
Some scientists believe that there is a danger that, if such vaccines 
are shown to halt the decline of CD4 cells in HIV-infected people - 
a so-called "surrogate"or "laboratory endpoint"- there will be 
enormous pressure to make such preparations available without 
waiting for the results of large trials such as that planned by 
Valentine. This would measure "clinical endpoints", in other 
words, the effect on the patients' state of health. 
Geoffrey Schild, head of the British Medical Research Council's 
AIDS Directed Programme in London, says: "There is a danger of 
people coming to hasty conclusions. Let's not confuse surrogate 
markers of benefit like virus load with people surviving longer with 
good quality of life. We need well-controlled long-term studies with 
good clinical endpoints."
Phillip Berman, of Genentech, the Californian biotechnology 
company which is also testing therapeutic vaccines, sums up the 
dilemma: "If you go for clinical endpoints you will have to wait for 
years for the results, particularly if the trial subjects get the kind of 
health care that you get in the US. If the therapeutic vaccine works 
but you have to wait for the results, there's going to be a lot of 
people who could have been helped by such preparations who will 
not get them. But if you go for surrogate endpoints, you take the 
risk of potentially approving something that may not be effective."
One reason why the emphasis on therapeutic vaccines is growing is 
that they are much easier to test. There is no shortage of volunteers 
to take part in efficacy trials. By contrast, efficacy trials for vaccines 
designed to prevent infection are fraught with practical and ethical 
problems.
Berman believes that much work still needs to be done on 
characterising suitable populations to test prophylactic vaccines 
before trials can begin, as well as on many ethical problems. 
Participants must be counselled thoroughly on ways to change their 
behaviour to avoid the risk of HIV infection and discouraged from 
reverting to high-risk behaviour in the belief that taking part in a 
trial means they will be protected. 

Prophylactic vaccine
Many researchers are worried that all the effort being ploughed 
into developing therapeutic vaccines could detract from the search 
for a prophylactic vaccine (see sidebar). Others believe that 
progress towards one will help progress towards the other. 
Valentine, for example, says he thinks the search for a therapeutic 
vaccine would strengthen work on a prophylactic vaccine. "If you 
could get a biological effect in individuals who are infected, it would 
spur on efforts to get a prophylactic vaccine."
But can we assume that something that works therapeutically will 
also work prophylactically? Alan Schultz, acting chief of vaccine 
research and development at the National Institute of Allergy and 
Infectious Diseases in Bethesda, Maryland, says: "Just because a 
vaccine product may show therapeutic benefit, I am not sure that, 
on its own, makes it a lead candidate for a prophylactic vaccine. If 
you are infected, you already have a vigorous response to HIV. So a 
50 microgram dose could be efficacious as a therapeutic vaccine, 
but it could take perhaps 50 times more to achieve a prophylactic 
vaccine."

'Chalk and cheese'
Jonathan Weber, professor of communicable disease at St Mary's 
Hospital Medical School in London, says classical immunology 
suggests that the mechanisms by which a viral infection is 
prevented are quite different from the ones that control it. 
Neutralising antibodies are crucial for protection. Prophylactic 
vaccines, mostly derived from viral envelope subunits, aim to 
stimulate such antibodies, but, Weber says, it is hard to see a role 
for neutralising antibodies once someone is infected. By contrast, 
cellular immunity is needed to control infection once it has taken 
place. "You are comparing chalk and cheese."
He says he has seen no data at all so far that suggests that 
therapeutic immunisation is effective. "For me, it remains wishful 
thinking - wishful thinking that I nevertheless strongly support."

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Sidebar: Vaccine research: 
is there a cuckoo in the nest?

Is there a risk that the desire to develop therapeutic vaccines could 
drain energy and resources from programmes aimed at developing 
prophylactic vaccines? Steven Basta, director of investor relations 
and market development at the Immune Response Corporation, 
which is testing the Salk whole killed virus prepration in 103 HIV-
infected individuals, illustrates how that pressure is operating.
He says: "There are 10 million infected people out there. That is 
the critical human need which is driving the scientific community 
to develop a treatment for this life-threatening epidemic."The same 
urgency does not exist for the development of a prophylactic 
vaccine: "Someone who is not infected does not have a terminal 
illness."
Plenty of researchers fear that the result could be to detract from 
the efforts to develop a prophylactic vaccine.
Gordon Ada of the John Curtin School in Canberra says: "It would 
not be good if that were to happen. You have to look to what is the 
future of a country and the future of the country is people who are 
not yet infected. You should do what you can for infected people, 
but it would be a retrograde step if it did significantly interfere with 
attempts to developt a prophylactic vaccine ."
Jonathan Weber, professor of communicable disease at St Mary's 
Hospital Medical School in London, agrees. "I think it's a tragedy. 
Every vaccine company is quite preoccupied with therapeutic 
immunisation when they should be totally preoccupied with the 
prophylactic work. The priorities are wrong at the moment."
Weber points out that the market for a therapeutic vaccine is 
immediate and First World - the kind of market that a 
pharmaceutical company could expect for a new drug. By contrast, 
the market for a prophylactic vaccine for HIV in the developed 
world is about as large as that for the hepatitis B vaccine: health 
care workers, anyone who is at risk sexually. 
As in the case of the hepatitis B vaccine, while the market in 
developing countries would be much larger, these countries would 
not be able to pay the vast sums that pharmaceutical companies 
would argue they need in order to reimburse them for their 
development costs.
Alan Schultz, of the National Institute of Allergy and Infectious 
Diseases, asks, "Even if we had the data that there was an AIDS 
vaccine as successful as measles and mumps, who would take it? 
Most straight people would say, I'm not at risk and I certainly 
would not give it to my children."
There is a risk, he agrees, that so much money may be sunk into 
developing a therapeutic vaccine that there will be less left over for 
work on a prophylactic vaccine. But at least the "carrot"of the 
market for a therapeutic vaccine may keep some biotechnology 
companies in the field for longer than if they were only looking at 
the market for a prophylactic vaccine, he says.

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Drug legalization: A matter of public health and human rights
Legalise illicit drugs? The idea seems crazy at first; with the all 
violence and corruption already associated with drugs, the suffering 
of many users and their families and, most recently, the clear link 
of AIDS to addiction. Why would you want to make it easier to get 
drugs?

(article continues in part 3)
-- 
Matthew Lewis, University of Amsterdam		Grote Bickersstraat 72
+31-20-52 51 220				1013 KS  Amsterdam
Internet: matthew@ooc.uva.nl			The Netherlands
Newsgroups: sci.med.aids