Immunotherapy for Infectious Diseases

Immunopathogenesis of HIV Disease 159
With the development of immune-based therapies given with a background of potent
antiviral therapy, and the ensuing rate of disease progression being as low as 1% per
year or less, surrogate marker end points are essential. At the same time, although interventions
that may result in change in viral load can be tested against that measure, it
is quite conceivable that an intervention could confer significant immunologic benefit
with little impact on viral load. Interventions that reverse immune dysregulation,
increase CD4� T-cell levels, modulate excessive immune activation, or decrease apoptosis
all might fall into this category. Validation of appropriate surrogate markers for
immune-based therapies is the next hurdle in the advancement of this field.
The choice of the population in which to test interventions is also an important consideration
in clinical trial design. Patients with advanced disease, who have failed potent
antiretroviral therapy, are eager to find alternate therapies, and their outcome might be
relatively quickly learned. Unfortunately, many of the interventions being tried are the
least effective and most toxic in subjects with advanced disease. Populations with a
more intact immune response are therefore currently favored for trials of immune-based
therapies. At the same time, if surrogate markers are being relied on for end points, there
must be something to measure in the population chosen. For example, if change in viral
load is chosen, then either the subjects must not have their viral load suppressed below
the level of detection to begin with, or must have a likelihood of sufficient numbers of
participants to experience viral breakthrough to be able to measure benefit from the
intervention. An alternate model being explored is to withdraw therapy at some time and
measure the rate or the magnitude of viral load resurgence as an end point. The possible
risks to participants of this study design are being carefully examined.
Further complicating the design of clinical trials is the rapid evolution of the standard
of care of HIV disease. In trials that may take years to develop, enroll, and then
follow to end points, care must be devoted to considering incorporation of the use of
new antiviral drugs, new measures of efficacy of therapy, and new techniques for determining
suitable antiviral regimens. (Examples are the routine use of potent antiretroviral
cocktails, plasma viral load for assessing efficacy of therapy, and screening for
antiviral resistance.) Otherwise, the outcome of the trial may not be relevant in the context
of the current standard of care at the trial’s conclusion.
Ethical considerations are extremely important in clinical trial design. Consideration must
be given not only to the risk to the individual participant but also to the benefit to the community
from which participants are recruited. In the United States, for instance, consideration
must be given to including women and minorities in the participants in clinical trials
and to not unnecessarily barring participation by pregnant women. The greatest challenge is
in designing trials suitable for developing countries. The data gathered from such trials must
be relevant to the population of that country and the prospect must exist for the therapy being
tested to be available there if found to be effective. An exquisite tension exists between the
dire need for therapies in developing nations and the barriers of cost that may be insurmountable.
The unavailability of potent antiretroviral therapy in developing nations and the
rapid rate of HIV disease progression still seen there makes this setting suitable for therapeutic
trials with clinical end points. However, the lack of therapeutic options outside the
clinical trials mechanism makes this group especially vulnerable to exploitation, and careful
ethical review of clinical trials planned for developing nations is extremely important.