Passive Hyperimmune Therapy (Passive Immunotherapy): New Data Released, California Approval PossiblE
At a press conference on March 23, HemaCare Corporation, asmall blood-products company in Southern California, released
preliminary six-month results from its one-year clinical trial of
passive hyperimmune therapy (also called passive immunotherapy)
in persons with AIDS. Because the company had to be conservative
in its interpretation, and because it did not release supporting
details at this time, the importance of the report has not been
widely understood. The HemaCare results, which are consistent
with those of other studies, confirm once again that this
treatment is highly beneficial for some patients, and almost
certainly should be available as a treatment option.
This article examines the new report in the context of
previous published studies of passive hyperimmune therapy, and
also examines related treatments to see where this therapeutic
approach may lead in the future.
Background: What Is Passive Hyperimmune Therapy
In passive hyperimmune therapy (PHT, also called passive
immunotherapy, or PATH), blood plasma is taken from donors who
are HIV-positive but unusually healthy, and whose plasma has been
found to have high levels of neutralizing antibodies (those which
prevent the growth of HIV in laboratory tests). The plasma is
usually pooled from several such donors, so that it is likely to
contain antibodies effective against many strains of the virus.
The pooled plasma is sterilized chemically to kill HIV and any
other disease-causing organisms. The treated plasma is then
infused into persons with AIDS who have lost their own ability to
produce protective antibodies. In the recipient, these
antibodies can last for several weeks; the current HemaCare study
gives the infusion treatment once per month.
Donating the plasma is not believed to cause any harm, as
the effective antibodies are quickly replaced; donation, in fact,
often appears to be beneficial, as the body is stimulated to
produce more antibodies and the levels rise to be higher than
they were originally. Only blood plasma is donated; the blood
cells are separated by a process called plasmapheresis and
returned immediately to the donor, allowing the plasma collection
to be done more frequently than regular blood donations.
The most challenging steps in passive hyperimmune therapy
are:
(1) Identifying the best plasma donors. This step is partly
an art as well as a science, since at this time there are still
many unknowns about which antibodies are most important in
controlling HIV infection.
(2) Sterilizing the plasma. It is important to be sure that
HIV in the donor's plasma is killed, to avoid re-infection with a
different strain of the virus. But this must be done in a way
that does not destroy the useful antibodies. As a safety check,
every lot should be cultured to confirm that the virus has been
killed; and the plasma should be processed in facilities meeting
the standards of good manufacturing practices for
pharmaceuticals.
(3) Setting up and administering the process. Regulations
require that dedicated equipment and facilities be used to
process HIV-positive blood, to avoid any chance of accidental
contamination of other blood. If the treatment comes into wider
use, community support will be needed to help find donors. And
the treatment is inherently expensive, because it is labor-
intensive and requires skilled medical specialists.
Background: Other Related Therapies
* This treatment is called passive hyperimmune therapy in
contrast to vaccines, which stimulate the body to actively
develop its own immunity. In PHT, the antibodies are provided;
the body does not need to make its own.
* Passive immunization with antibodies derived from human
blood is widely used in medicine to prevent or treat infections
other than HIV. Usually the whole plasma is not given; instead,
the antibodies are extracted, and given as a product called
intravenous immune globulin (IVIG). Several brands of IVIG are
approved in the United States for prescription use; they may be
useful in some cases to help persons with AIDS, especially
children, resist various infections. IVIG appears to be
underused in AIDS treatment, primarily because it is expensive.
IVIG contains no antibodies against HIV, since for safety
purposes the blood used to prepare it is carefully selected to be
HIV-negative; therefore IVIG may help to fight opportunistic
infections, but not HIV itself. Sometimes the supplier of IVIG
can select from a lot which happens to have a higher than average
activity against a certain infection, such as CMV, which the
physician wants to treat.
* A form of IVIG especially made to have high anti-CMV
antibodies, called CMV-IVIG, was approved by the FDA on April 17,
1990 for certain kidney transplant patients. This drug was
developed as an orphan product by the state of Massachusetts, and
distributed by the American Red Cross, Northeast Region. Because
of supply problems, the drug was restricted to the patients
considered most likely to benefitQ those without CMV who received
kidneys from CMV-positive donors. As of two years ago, the
supply problems were expected to last about nine months. We have
not heard of this treatment being tried for persons with AIDS-
related CMV.
* An IVIG preparation specifically made with anti-HIV
antibodies, called HIVIG, may be tested as an HIV treatment, at
least in infants, or tested to see if it can prevent mother-
infant transmission of HIV during pregnancy. This treatment
appears to be essentially equivalent to passive hyperimmune
therapy. HIVIG is only made by Abbott Laboratories, however, and
that company seems less than enthusiastic about developing it.
* The ultimate future direction of passive immunotherapy for
HIV and other diseases is likely to be in monoclonal antibodies.
These are not extracted from human blood, but are produced by
cells which are created in the laboratory by genetic engineering
and other techniques. An anti-CMV monoclonal antibody is
currently in clinical trials.
The development of anti-HIV monoclonal antibodies may be
more difficult because of uncertainty about which antibodies are
beneficial and clinically important. In the laboratory the wrong
antibodies can actually increase viral infection; this has not
been a problem in passive hyperimmune therapy trials, however.
There is intense research interest in learning which antibodies
are effective, since this information is important not only for
developing antibodies for treatment, but also for developing
vaccines, and for preventing HIV transmission during pregnancy.
The AIDS community must pay more attention to developments in
monoclonal antibodies around the world, to make sure that
research and development move forward as fast as technically
feasible.
Passive Hyperimmune Therapy: The HemaCare Study
HemaCare Corporation had not previously run clinical trials,
but it did have experience well suited for a study of passive
hyperimmune therapy. The company specializes in therapeutic
hemapheresis, a process of "separating the blood into its
components, removing unwanted substances, and returning the other
components to the patient." This therapy is used in at least 30
different diseases; HemaCare provides mobile units which travel
to hospitals and administer the treatment at the patient's
bedside. The company also sells platelet concentrates and other
blood products from healthy donorsQas well as plasma which
contains rare antibodies. It had this experience before becoming
involved in AIDS.
The current placebo-controlled study has 219 volunteers with
ARC or AIDS. They are randomized to three groups: full-dose
(500 cc of plasma once a month), half dose, and placebo. Although
six-month interim data was reported, the trial is still
continuing.
The most important result so far is that there were only a
third of the deaths in the full-dose group as in the placebo
group. However, there have not been enough deaths in the study
for this result to reach the level of statistical proof; it only
reached the statistical significance level of p=0.1276 (meaning
that if the treatment were useless, the odds would be one in
eight that a result this good or better could have occurred by
chance alone). In most medical research, the statistical
significance must be p<.05 (meaning that the odds are less than
one in 20 that the result could occur by chance alone) for a
finding to be taken seriously. As a result, the company could not
emphasize this survival difference, and its significance has been
underreported and underrated.
What is widely overlooked is that the value of p<.05 is an
arbitrary level which has become customary, not a gold standard
of truth. A result which fails to reach that level because there
were too few volunteers (or too few deaths) in a trial should not
be ignored as if it did not exist. Instead, it should be
considered together with other information which is available
from the same or other trials. And when the available information
on passive hyperimmune therapy is considered togetherQnot broken
up into pieces which are each thrown away because no piece by
itself is conclusiveQit provides considerable confidence that
this treatment can provide substantial benefit to persons with
AIDS, including survival benefit.
The six-month data did show statistically significant
changes in T-helper counts, and in levels of beta-2
microglobulin, in those receiving full dose compared to placebo.
There were also fewer opportunistic infections with full dose
than with placebo, although this change was not statistically
significant at this time. The treatment may have worked best in
patients who started with T-helper counts over 50. The trial is
continuing, so more results should be available in about six
months.
Side effects were minor. Over 1300 infusions have been
given (counting treatment and placebo groups together); and none
of the more than 200 volunteers has had to discontinue treatment
due to toxicity.
There was also a large drop in p24 antigen in the full-dose
group. But this measurement may be hard to interpret in studies
of passive hyperimmune therapy, since the infused antibodies may
simply combine with the p24 antigen, directly affecting what is
being measured without necessarily helping the patient.
Other Studies
* The most recently published study of passive hyperimmune
therapy was conducted by researchers at the Hospital Necker in
Paris; it was reported in French in May 1991 (1) and in English
in February 1992 (2). This study randomized 18 patients to
either an experimental group, to receive plasma with high levels
of antibodies against HIV, or to a control group given plasma
from HIV-negative donors, which would not have any antibodies
against HIV; the treatment was given every two weeks. Both
groups also received AZT, and conventional opportunistic
infection (OI) prophylaxis. The experimental group had a greatly
reduced number of opportunistic infections compared to the
control groupQtwo vs eight OIs, a difference which is
statistically significant.
But when the treatment was stopped at the end of the study,
the p24 antigen, which had become undetectable, rose to higher
than its original value, and was correlated with severe clinical
deterioration. This rebound effect suggested that it may be
dangerous for persons with severe immune deficiency to stop
passive hyperimmune therapy unless a similarly effective
treatment can be substituted, "as virologic relapse may be
explosive and poorly tolerated."
* The most important work on passive hyperimmune therapy has
been published by the group headed by Abraham Karpas, M. D., of
Cambridge University, who is generally credited with developing
this technique as an AIDS therapy. Karpas and others published a
series of papers starting in December 1988 (3-8).
* Another group of researchers, including G. Jackson, M. D.,
at The London Medical College, and colleagues at the University
of Illinois College of Medicine and at Abbott Laboratories,
published early studies of this treatment in several patients
(9-11).
* A larger trial has been conducted at the Bronx Veterans
Administration Hospital in New York. Results have not been
published, however.
Passive Hyperimmune Therapy: A Brief History
PHT for AIDS is not new. It was first tested in patients
over five years ago. Three years ago there was a large, active,
and enthusiastic patient-activist movement, especially in San
Francisco, to support testing and availability of this treatment.
AIDS TREATMENT NEWS listed PHT as one of the most important new
AIDS treatments to watch during 1989 (issue #72, January 13,
1989).
A brief chronology of early public interest:
* January 23, 1987: THE TIMES (London) reported that
Karpas' method was being tested on four patients, who had been
treated for just over a month. This trial followed published
research by Karpas which showed that antibodies were effective
against HIV in laboratory tests. The idea of administering
antibodies this way as a treatment was not new, having long been
used successfully with other diseases.
* August 21, 1987: THE WALL STREET JOURNAL reported that
Medicorp, a Montreal company which now holds patent rights to
passive hyperimmune therapy and licensed the method to HemaCare
for its current study, was planning to begin a trial at two
hospitals in London, and at a Veterans Administration hospital in
New York. A spokesperson for the U. S. National Institutes of
Health expressed the usual skepticism, saying that the treatment
had "not much rationality for AIDS, because we don't know the
function of antibodies, especially since many infected people
with antibodies in their blood often go on to develop the disease
anyway."
* June 15, 1988: Dr. Jackson's group reported evidence of
clinical improvement with this treatment, in a talk at the IV
International Conference on AIDS in Stockholm.
* August 1988: The AIDS / HIV EXPERIMENTAL TREATMENT
DIRECTORY of the American Foundation for AIDS Research (AmFAR)
published a section on passive immunotherapy, briefly reviewing
the results to that time.
* December 1988: THE NEW YORK TIMES reported encouraging
indications from studies by Jackson's group (10) and by Karpas'
group(8).
* February 6, 1989: An article by Tim Campbell in the
Minneapolis, Minnesota GLC VOICE reported that the U. S. Food and
Drug Administration (FDA) had approved HIVIG for human trials, on
January 27 of that year. The article discussed the history of
the development of this drug, and suggested that it might eclipse
AZT as the treatment of choice.
* February 1989: The first issue of PATH PROJECT NEWS, a
newsletter of the Passive Immunotherapy Foundation (often called
the PATH Foundation), reported that California physicians hoped
to obtain approval to begin a study of passive hyperimmune
therapy "within two to four weeks, and to begin screening donors
soon afterward."
* March 10,1989: AmFAR and the Pharmaceutical Manufacturers
Association sponsored a discussion by invited experts on passive
hyperimmune therapy; a report appeared in the AIDS / HIV
EXPERIMENTAL TREATMENT DIRECTORY. The meeting focused on
producing a more standard product for future research and
possible use, and it suggested designs for future studies.
* December 1989: The fourth issue of PATH PROJECT NEWS
reported that HemaCare was recruiting both donors and recipients
for what was then expected to be a 100-patient study.
In the last two years there has been little public interest
in passive hyperimmune therapy. The reason is simply that there
is no way people could get the treatment. The plasma cannot be
obtained by buyers' clubs or guerilla clinics; preparation of the
plasma is too complex and exacting to be done safely in the
average physician's office. Regulatory and commercial obstacles
continually impeded the development of this therapy.
Little if anything would have happened in the United States,
except for the fact that California can approve its own clinical
trials without the approval of the FDA, provided that the drug
being tested is manufactured entirely within California. Since
the plasma used in the HemaCare trial is collected and processed
without ever crossing state lines, the California Food and Drug
Branch (FDB) was able to approve this trial. As a result,
passive hyperimmune therapy may be approved only in California.
(Since the treatment is given only once a month, others could
presumably come to California for it.)
HemaCare plans to apply to the FDB for a "treatment IND" to
allow it to provide passive hyperimmune therapy to up to one
thousand additional patientsQbefore full approval, which would
presumably come at the completion of the trial. The company
could not provide this treatment without charging enough to at
least cover its costs. It does not yet know what its costs will
be when the plasma is collected and processed on a larger scale.
The treatment IND will also require community support to
help in recruiting HIV-positive donors. Only a minority of
persons with HIV have the best antibodies and could qualify as
donors. Therefore several potential volunteers will need to be
tested for each donor who is accepted.
What will be most needed over the next several months is
community vigilance to see that this project stays on track, and
that the detours of the past are not repeated.
References
1. Lefrere JJ, Vittecoq D, Mattlinger B and others. Passive
immunotherapy in AIDS: transfusion of plasma rich in anti-p24
antibody (phase I trial). [English translation of title.] REV.
FR. TRANSFUS. HEMOBIOL. May 1991: volume 34, number 3, pages
199-211.
2. Vittecoq D, Mattlinger B, Barre-Sinoussi F, and others.
Passive immunotherapy in AIDS: A randomized trial of serial
human immunodeficiency virus-positive transfusions of plasma rich
in p24 antibodies versus transfusions of seronegative plasma.
JOURNAL OF INFECTIOUS DISEASES February 1992: volume 165, number
2, pages 364-368.
3. Karpas A, Gray J, Byron N, and others. Passive immunization
in ARC and AIDS. BIOTHERAPY 1990: volume 2, number 2, pages
159-172.
4. Karpas A, Hill F, Youle M, Gray J, and Gazzard B. Long-term
follow-up on the effects of passive immunization in patients with
ARC and AIDS. Sixth International Conference on AIDS, San
Francisco, June 20-23, 1990 [abstract S. B. 499].
5. Hewlett IK, Epstein JS, Lee SF, and Karpas A. Evaluation by
PCR of HIV-1 status of AIDS patients receiving passive
immunotherapy. Sixth International Conference on AIDS, San
Francisco, June 20-23, 1990 [abstract #S. B. 498].
6. Karpas A, Hill F, Youle M, Gray J, Oates JK, and Gazzard B.
Effects of passive immunization in patients with ARC and AIDS.
J. CHEMOTHER. INFECT. DIS. MALIGNANCIES (Supplement 1) 1989
[meeting abstract A295].
7. Karpas A, Hill F, Youle M, Gray J, Oates JK, and Gazzard B.
Effect of passive immunization in patients with ARC and AIDS.
Fifth International Conference on AIDS, Montreal, June 4-9, 1989
[abstract #W. B. P. 314].
8. Karpas A, Hill F, Youle M, Cullen V, Gray J, Byron N, and
others. Effects of passive immunization in patients with the
acquired immunodeficiency syndrome-related complex and acquired
immunodeficiency syndrome. PROCEEDINGS OF THE NATIONAL ACADEMY
OF SCIENCES, USA, December 1988: volume 85, number 23, pages
9234-9237.
9. Hague R, Yap P, Mok JY, Jackson GG, Hargreaves FD, and Coutts
NA. Infusion of anti p24 antibody rich plasma in two children
with persistent HIV antigenaemia -- a pilot study. Fifth
International Conference on AIDS, Montreal, June 4-9, 1989
[abstract # T. B. P. 246].
10. Jackson GG, Perkins JT, Rubens M, and others. Passive
immunoneutralization of human immunodeficiency virus in patients
with advanced AIDS. LANCET, September 17, 1988: pages 647-652.
11. Jackson GG, Perkins JT, Paul DA, and others. Passive
immunoneutralization of HIV p24 antigenemia in patients with
advanced AIDS by infusion of human plasma. Fourth International
Conference on AIDS, Stockholm, June 12-16, 1988 [abstract #3064].
source: AIDS Treatment News
