AIDS TREATMENT NEWS #220, April 7, 1995
With the development of protease inhibitors and other new
approaches for treating HIV disease, there are more potential
treatments, and many more combinations, which are worth trying.
At the same time, the resources available for research, both
public and private, may be shrinking. Efforts toward small,
rapid trials must be encouraged; still, it has always been
difficult to get even small trials of leading- edge ideas off
the ground. Usually they do not happen at all, or take place
only after months or years of delay.
The main task is to address the apathy and lack of commitment
that makes it so difficult to get studies done -- not to learn
to live with the problem. But also, there is always a place for
learning how to accomplish the most with limited resources.
We propose a program for careful, consistent monitoring of
experimental treatments which are already being used by
patients and physicians. The goal is to greatly reduce the time
and cost of getting the first widely credible information about
the effects of new treatments, combinations, and treatment
strategies in people.
The new therapies of interest are already being tried by
individual patients and physicians. Reports of results often
circulate anecdotally. But for many reasons it is difficult to
rely on these reports. For example:
(1) Our interview with Dr. Feigal (AIDS TREATMENT NEWS #219,
March 24, 1995) noted that even in the most research-
intensive settings, sponsored by the largest pharmaceutical
companies, there is concern that results of individual
cases may be reported selectively.
(2) Most experiences with new treatments are in a clinical, not
research, setting. Often there is no advance planning to
assure that the data will be credible to third parties.
(3) There is little standardization among clinical physicians
regarding which tests and laboratories to use, exactly when
to give the tests, how to keep compatible records, etc.
(4) Even if the data is completely in order for research
purposes, there is still the credibility problem of
convincing others of this. It is much more difficult for
each physicians' practice to establish research credibility
independently, than for one research organization to build
its credibility over time.
New therapies of interest are also tried in pharmaceutical
company development programs. Here there are different
(1) Leading-edge approaches are seldom considered, since the
needs of corporate drug development are different from
those of patient care. Usually the best to hope for is
monotherapy with one experimental agent, combined with
approved drugs; for example, see the current ICC protocol
[Inter-Company Collaboration for AIDS Drug Development],
which at most combines one experimental drug with two
(2) Even unimaginative trials take excruciatingly long to
actually begin; again consider the ICC trials, starting
only now despite the high-level attention and support long
put into them.
(3) Early trials of new agents or new approaches often do not
measure viral load or any other indication of activity; or
they start by testing doses known to be ineffective. These
trials, by design, can only be pieces in a long, expensive
development process; no possible outcome could establish a
rationale for human use of any treatment.
When considering options in trial design, we should be aware
that certain limitations of randomized clinical trials have
long been known and analyzed in the medical literature, but
ignored in AIDS research.
Arvin R. Feinstein, from the Yale University School of
Medicine, examined these limitations in a paper published in
1983 ("An Additional Basic Science for Clinical Medicine: II.
The Limitations of Randomized Trials," ANNALS OF INTERNAL
MEDICINE, volume 99, pages 544-550); Robert J. Levine, in
ETHICS AND REGULATION OF CLINICAL RESEARCH, Yale University
Press, 1986, recommends that this article "should be required
reading for all persons who conduct or review plans to conduct
randomized clinical trials."
Feinstein noted that randomized trials have been successful
when studying treatments to remedy an existing condition, but
have "sometimes created rather than clarified controversy" when
used in studies of either primary or secondary prevention of
conditions which the patients do not have yet. And there has
long been a seemingly irreconcilable conflict between
"pragmatic" investigators (usually clinicians), who want the
trial to provide useful clinical information, and "fastidious"
investigators, usually biostatisticians, who want a clean
Feinstein also considered many ethical and logistical
limitations of randomized trials. He concluded, "The scientific
resolution of most future problems in clinical management will
have to come from analyses of events and observations that
occur in non-experimental circumstances, during the interaction
of nature, people, technologic artifacts, and clinical
practitioners. By recognizing the informal "experiments" that
are done whenever a clinician treats a patient, and by
developing better observational methods for acquiring and
analyzing the data, clinical investigators can be liberated
from their previous intellectual restrictions and can take the
fundamental steps needed to develop an additional basic science
for clinical practice."
Proposal: Monitoring Project
A research organization could implement a monitoring program
for systematic data collection, analysis, and reporting about
treatments of interest which are already being tried.
One way to both greatly decrease the cost of research, and
simultaneously increase its relevance, is to study the
treatments which physicians and patients have decided to use
anyway. Since the actual treatment is already planned or
underway, aside from the research project, the costs and
obstacles involved in making a human trial happen are not a
problem. Financially, the costs will be largely for lab work
and administration. But the real costs of any clinical research
includes not only the money, but also human costs (including
increased risk and lost-opportunity cost) of asking patients
and physicians do to something different from what they would
have chosen to do otherwise. By studying treatments which would
have been used in any case, this larger cost is also greatly
reduced or eliminated.
A protocol for this project would not specify the treatment to
be used, as the physicians and patients would choose that in
each case. The protocol might include formal selection criteria
for the treatments and the patients to be considered. But since
different patients' results will not usually be averaged
together, inclusion/exclusion criteria need not be severe; the
real question is whether there is a clinically interesting
question that might be addressed, and this decision can best be
made case by case by a medical review board.
For example, such a project might study patients who are trying
to lower their viral load (plasma HIV RNA) by using an
experimental treatment or combination. Those entered into the
study would be given specified baseline and after-treatment
viral load tests -- as well as a physical exam, medical history
interview, and immunological and other tests widely used in HIV
trials. These results could be reported quickly; but there
might also be scheduled followup which continues much longer
(for example, through interviews at six months and then
annually, continuing indefinitely whether or not the treatment
To avoid any question of selective reporting, everyone accepted
for study by the review board would immediately be given a
sequence number and be accounted for in the published reports
-- even if they never received the tests, or never used the
intended treatment. This is only a matter of thoroughness of
reporting; it does not affect statistical results, since the
different patients are usually not averaged together.
The particular tests, schedules, and other details will
ultimately be chosen by the researchers. This outline is
intended as a basis for discussion.
Inclusion/Exclusion: Volunteers who are using antiretroviral
therapy must not change that therapy for at least a month
before beginning the treatment to be monitored by this program.
And they must be starting a treatment which might affect the
overall course of HIV disease; it could be an antiviral, or
work by some other mechanism, or have an unknown mechanism. But
treatments for opportunistic conditions will not be studied in
Tests: The primary test to be monitored will be plasma HIV RNA,
by the Hoffmann-La Roche quantitative PCR. Other standard
panels -- immunological, hematological, blood chemistry -- will
also be specified. A physical exam and medical history will be
given when the volunteer enters the program, and a physical
exam and exit interview (including questions on compliance) at
the end of the primary monitoring period.
Visits: Ideally three baseline viral load tests will be given;
on the day treatment begins, half a week (3 or 4 days) before,
and one week before. Other baseline blood tests will be
included as necessary.
Length of Study: The primary monitoring period will be eight
weeks. After treatment begins, blood draws will be at half a
week, one week, two weeks, four weeks, and eight weeks. Test
results will not be batched or blinded, so that the volunteer
can use them in making treatment decisions, including whether
or not to stay in the monitoring program. Volunteers can change
their antiviral regimen and still remain in the program.
Ideally the entire panel of tests would be given at each blood
draw; however, the protocol may specify reduced testing, for
economic or practical reasons.
Followup: After the primary monitoring period, the treatment
being studied may or may not be continued. In either case,
follow-ups will be scheduled at six months after treatment
began, one year after, and annually after that. Ideally each
followup would include the blood tests; but at a minimum,
followup could be by phone interview.
At the end of the primary monitoring period, results would be
published, or otherwise made available to other investigators
An Ethical Concern
When an individual case is reported, the person is easier to
identify than if they are one of many who are summarized
statistically. This problem may be reduced, if the only test
results reported are those done specifically for this research;
the numbers would not be identical with those in the person's
medical record. And some results might be reported in summary
form -- for example, percentage changes might be given instead
of absolute values in some cases. But ultimately the volunteers
will need to understand that this research does not offer the
anonymity of a large trial, and accept or reject participation
with that in mind.
We believe that patients and physicians will find more
interesting treatments to test than we could list by ourselves.
But there is no harm in discussing some questions that might be
addressed by this kind of screening study.
AIDS TREATMENT NEWS occasionally publishes a list of about 30
treatments which have a valid rationale for testing in HIV
disease, are not in a major development project currently, and
are already widely used in people for other purposes (making
research much easier than with a new chemical); this list last
appeared in issue #218, March 3, 1995. In many cases, the
possible mechanism of action is not known, and therefore it is
not known how relevant a viral load test would be for measuring
drug effects. But it may still make sense to include such
treatments in an exploratory study based on viral load; there
is little cost of doing so, and the results might give some
insight into a mechanism of action.
(1) For example, it would be interesting to see if viral load
can fall after a patient starts acyclovir (due to an
indirect effect of the drug, which is not believed to have
anti-HIV activity). Apparently no one has tried this yet.
Any effect on viral load might be seen in only some
patients -- those who have another virus which may act as a
cofactor for HIV and which is susceptible to acyclovir.
Therefore, a single negative result obviously does not mean
that this line of research should be abandoned; instead, a
number of patients will need to be tested.
(2) Another area where we do not know the mechanism concerns
micronutrients. Consumption of certain micronutrients
(either in food or in supplements) during asymptomatic
disease has been found to be associated with substantial
delay in disease progression, and increased survival; for
other micronutrients, no such effect was found (see "Some
Vitamins Associated with Decreased Risk of AIDS and Death."
AIDS TREATMENT NEWS # 214, January 6, 1995.) Could a
well-designed supplementation regimen (perhaps given by
injection to avoid absorption problems) have an effect
which could be seen in viral load reduction?
(3) Some physicians have suggested doxycycline as possibly
beneficial in AIDS treatment, for unknown reasons. Possible
mechanisms include controlling possible mycoplasma
infections, or treating other infections which may not be
diagnosed. These rationales are probably too weak to get
this drug into a formal trial, even a small one; but still
it would be interesting to see if there are any consistent
changes in viral load or other tests when patients start
the drug. We should remember that some of the most
important leads in the history of medicine have been
completely unexpected in advance. The proposed monitoring
project brings down the cost of research to the point where
such a study could happen.
(4) Hydroxyurea has had a strong rationale as an antiviral at
least since the Berlin conference over a year and a half
ago, but it has been notoriously difficult to get a formal
trial going, in part because no one has exclusive rights to
the drug. And the drug is dangerous enough that physicians
who are not experienced with it are reluctant to use it
without a good reason. Only recently have a number of
patients started to try it. With the proposed monitoring
study in place, drugs like this could be tested in a
research setting as soon as someone wanted to try them; if
strong antiviral activity is found, it would bring more
attention to a potential treatment. This is a drug that
physicians can learn to use safely, if they first have a
reason for doing so.
(5) Ribavirin, a broad-spectrum antiviral, was rejected
prematurely as an AIDS treatment years ago, after an
intense conflict between the Commissioner of the FDA at
that time, and the president of ICN, the company developing
the drug. Ribavirin might have a role for some patients,
especially in combination with ddI or certain other drugs;
and today, its antiviral activity could be followed with
viral load tests. Despite continuing popular interest,
ribavirin has not been revived as a potential treatment
because of the lack of commercial motivation for organizing
new formal trials. The proposed monitoring project -- based
on viral load testing, which was not available when
ribavirin was studied previously -- could greatly reduce
the cost of getting new credible data about this drug.
(6) The monitoring project could also be used for early
information to guide clinical trials of combinations of
protease inhibitors or other drugs in mainstream
development -- combinations that would not otherwise be
tested. One important question here is the effect of these
drugs and combinations in people who already had much
experience with antiretrovirals, and were unable to lower
their viral load further with conventional treatments. The
mainstream trials are now focusing on antiviral-naive
subjects; but the main use of the new drugs, at least
initially, will be for people who have already failed other
available treatments. We need to know what combinations are
likely to work in these difficult cases, and we may not get
that knowledge from the trials currently planned.
The Next Step
This monitoring project should probably begin at one site (AIDS
Research Alliance [formerly SEARCH Alliance, in Los Angeles]
would be ideal); the tests and treatments could be administered
either there, or in the offices of physicians associated with
the organization. Later, other research institutions or
clinical practices might also use the same protocol.
The first critical step is to refine this proposal and develop
a detailed protocol, incorporating the views of medical and
A working monitoring project will mean that as soon as the
first patient is ready to try a treatment, that treatment can
be tested, with results becoming available almost immediately.
While the results from the first few patients will clearly be
limited, they will be completely consistent, without selection
bias, and collected exactly as specified. If early results are
favorable, more people will try the treatment, strengthening
the confidence in the results of the monitoring, and also
generating early interest in other studies, including larger,