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Clinical
trials to clinical reality—
"Bridging
the gap" between science and the patient
HIV+ Clinical trial volunteers live longer than HIV+ patients
in routine care. How could careful scientific investigation
fail to accurately predict outcomes in the clinic?
The
media hype surrounding the success of protease inhibitor-containing
regimens as reported at the XI World AIDS Conference in Vancouver
has evolved into somber reports from Geneva on the realities
of drug resistance, compliance managing, and adverse side
effects in the general patient population. This "gap" is highlighted
by a recent report which shows that participants of clinical
trials live longer and progress more slowly to AIDS than the
average patient in routine care (Ferrigno et al., 1997). Since
the objective of clinical trials is to identify strategies
that are effective in routine care, this disparity is cause
for concern. How could carefully-controlled scientific investigation
fail to accurately predict outcomes in the clinic?
At
a satellite symposium of the XII World AIDS Conference sponsored
by F. Hoffmann-La Roche Ltd., Dr. Melanie Thompson of the
AIDS Research Consortium of Atlanta, Georgia, presented an
excellent overview of the reasons why patients in clinical
trials do better. She provided three general arguments. First,
participants in many studies are not representative of the
population in general. Second, trial sites extend services
to patients that can factor into the level of care. Third,
liberal analytical techniques can portray data in ways that
appear to favor the regimen studied.
Selection
criteria for trials are often biased towards patients likely
to respond well to treatment. Inclusion criteria often require
participants to be naive to antiretrovirals. Conditions that
could make adverse effects more likely are frequently grounds
for exclusion. The result is a relatively healthy population
(even taking CD4 counts and initial viral load into account)
that presents minimal drug resistance problems. There is also
a self-selection effect; patients who volunteer tend to be
more proactive with their treatment.
These
selection biases imply that many of those who respond well
in the context of a clinical trial would have responded equally
as well in a routine treatment setting. There are also ways
in which participation in a study actively improves the patient's
care. Clinical trial sites provide diligent attention to volunteers,
including follow-up phone calls, compliance monitoring, and
prompt management of adverse effects as they arise. In general,
sites have a vested interest in aggressively supporting their
patients. This level of attention naturally has an impact
on how participants handle their treatment regimen.
Another significant factor in evaluating an anti-HIV drug
is the limit of detection of the viral load assay used in
the study. The detection limits can vary by more than an order
of magnitude, depending on which assay is used. For example,
Chiron's "branched chain DNA" test can quantify viral load
down to 400 copies per milliliter of plasma, although a new
version of this test just released for investigational use
can go down to 50 copies/mL. OrganonTeknika's NASBA test can
detect down to 80 or to 400 copies/mL, depending on how much
sample is used. Roche's FDA-approved Amplicor test can go
down to 200 copies/mL, although a newer, experimental version
of the test called the Ultra Sensitive Amplicor can quantify
HIV at concentrations as low as 50 copies/mL.
A treatment regimen evaluated with a detection limit of 400
copies/mL might work well enough to be deemed successful,
but the clinical utility of this "successful" regimen might
be minimal. A recent report (Gunthard et al., 1998) has shown
that there is evidence of low-level viral replication in patients
whose viral load was less than 400 copies/mL, but higher than
20 copies/mL (measured with especially sensitive molecular
techniques). However, patients with a viral load under 20
copies/mL showed no evidence of ongoing viral replication.
Since even low-level replication is associated with the eventual
development of drug resistance, one might expect substantial
differences in the durability of patient responses to treatment
when their viral load is below 20, as opposed to 400, copies/mL.
In a clinical trial, if a patient's viral load goes down to
the assay's detection limit, the patient is considered successfully
treated. If the patient began with a viral load only 10-fold
higher than the detection limit, that patient may have experienced
only a one log drop in viral load. As a result, the number
of trial participants for whom a regimen is successful can
depend substantially on the assay used to test viral load.
Certainly, an average patient in routine care can achieve
a degree of viral reduction consistent with that seen in studies
and yet not go below detectable limits.
In addition, clinical trial reports utilize different methods
of data analysis, which materially affects the reported outcome.
"On-treatment" analyses consider only the patients that actually
receive treatment for the full course of the study and tend
to show the possible, not necessarily probable, benefit of
the treatment. This means that this analysis technique ignores
the data from patients who were non-compliant, withdrew due
to side effects, or simply dropped out of the study. On the
other hand, the more conservative "intent-to-treat" analysis
includes all patients assigned to treatment groups, even those
who had to drop out during the study for any reason. Therefore,
clinical trial results which present data utilizing an "intent-to-treat"
analysis will more accurately predict the clinical response
of the general patient population.
After Ziagen (Abacavir), Sustiva (Efavirenz),and Adefovir
(bis-POM PMEA) receive FDA approval later this year (as expected),
it will be possible to prescribe anti-HIV drugs in 1028 possible
triple therapy combinations. When you consider that 4, 5 and
even 6 drug combinations are becoming widely prescribed, the
number of possible drug regimen configurations grows logarithmically.
While some of these combinations will be studied in phase
IV post-marketing trials, it would be impossible to study
them all. Against this backdrop, patients and their physicians
are faced with the challenge of constructing the optimal regimen
to meet the patient's needs. The gap between the published
clinical literature and the usual clinical experience complicates
this task.
There
has been irrefutable progress in the clinical management of
HIV disease in the last several years, and this progress can
be understood in terms of the expanded possibilities for treatments
and our improved comprehension of the biology of AIDS. Between
Geneva and the XIII World AIDS Conference in South Africa,
the challenge will be to complete the picture and translate
that progress into better routine care. In addition to showing
what's possible to achieve in the treatment of HIV in clinical
trials, we look forward to seeing data from these studies
that better predict what is probable in the thousands of patients
who will take these drugs after the trials are completed.
References
Ferrigno L et al. (1997) Survival and progression of disease
in HIV-infected individuals in interventional treatment studies
as compared to an observational cohort. 37th Interscience
Conference on Antimicrobial Agents and Chemotherapy. Abstract
I-179. Gunthard H et al. (1998) Human immunodeficiency virus
replication and genotypic resistance in blood and lymph nodes
after a year of potent antiretroviral therapy. Journal
of Virology, 72:2422-2428.
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