PI Perspective #16
May 1995 View PDF
Advances, Challenges and Growing Frustration
Last year has brought more advances in the treatment of AIDS than
perhaps any similar period in the history of the epidemic. New treatments,
such as ocular implants for CMV retinitis, oral CMV prevention,
and growth hormone for wasting syndrome offer a major improvement
in the quality of life for people with advanced disease. New understandings
of the rate of viral replication and immune pathogenesis have advanced
our knowledge of HIV, while new drugs and combination (protease
inhibitors, non-nucleoside RT inhibitors, AZT/3TC) have improved
our ability to suppress it. Other work in the field of immune reconstitution
(see Report: Immune Restoration Think Tank in this issue) offers
new hope of restoring immunity for people with advanced disease.
A study proving that it is possible to reduce the rate of mother-to-child
HIV transmission offers hints that it may be possible to completely
block such transmission in the near future. But each of these possible
advances is limited by a lack of urgency about implementing them,
optimizing them, or making them equitably available to the broad
patient community. Similarly, a lack of courage and an unwillingness
to take risks hampers new and more advanced efforts to go beyond
even these admitted steps forward. Overall, the value of these advances
seems diminished by a growing sense of complacency and lack of leadership
in community-based and government-sponsored research. They could
be seen as shining new tools, ready to make their respective contributions
and awaiting optimization in the hands of leaders who are equally
anxious to advance the state-of-the-art in AIDS care and treatment.
Challenge CMV and the Quality of Life
Advances against CMV retinitis, in the form of ocular implants,
new drugs (HPMPC), and oral formulation of existing drugs are described
in Advances in the Treatment of CMV in this issue. The advances
promise a major improvement in the quality of life for those who
have a diagnosis of retinitis and extend the time before recurrence
of disease. Yet these advances are currently available to only a
small portion of the patient community. Wider use is hampered by
several issues:
- The FDA approval process: sponsors of the ocular implants have
applied for FDA approval while sponsors of the new drug, HPMPC,
have not. It will be at least several months before either product
becomes more widely available.
- The physician learning curve: although the advantages of these
forms of treatment are readily apparent in the latest studies,
many physicians are unaware of the latest data or how to get these
products for their patients.
- Inadequate knowledge about the optimal way to use the new advances:
should ocular implants be accompanied by oral ganciclovir to prevent
spread of CMV elsewhere in the body? Can infrequent doses of HPMPC
also function as a preventative medicine? It will be many years
before these questions are answered, if ever.
Challenge: Growth Hormone vs. Profits
The use of growth hormone as a treatment for wasting syndrome poses
another kind of dilemma, one based on costs. There is little doubt
that the product works very well, but it is priced so high as to
create a public health crisis over its use. Despite its medical
value, physicians groups, insurance companies and government health
support (Medicare and state AIDS Drug Assistance Programs) are lining
up to oppose its use. They fear that paying the steep price will
bankrupt the systems or come at the cost of diminishing other forms
of needed care and therapies for the same patients. Surely, no company
should be permitted to enrich itself to the endangerment of patients
it claims to serve. In short, the benefits of growth hormone simply
will not be available to the vast majority of people with AIDS.
Challenge Neo-Natal Transmission vs. Politics
After last year’s study showed that it was possible to make
a 2/3 reduction in the rate of HIV transmission from mother to child
using the oldest AIDS drug (AZT), the focus quickly shifted from
science to politics. The Congress and several state legislatures
are now locked in debate about whether to force pregnant women to
get tested, and once tested, whether to force them to use the now
standard AZT treatment against mother-to-child transmission. Instead,
women should be simply be informed and given their choice, while
scientists should race ahead to improve upon the results achieved
from this study. If simple, short-term monotherapy AZT, with all
its limitations and concerns, can produce a 2/3 reduction in transmission,
today’s much more potent antiviral medications and combinations
will likely produce a superior outcome. While studies with protease
inhibitors and non-nucleoside RT inhibitors (NNRTIs) are being developed,
it’s clear there has been no rush to prioritize or accelerate
this research. Instead, the science is being pushed aside by the
politics and the likely result (other than driving pregnant women
underground to hide their HIV status) is that AZT monotherapy may
inappropriately become the standard for many years to come in neo-natal
prevention, whether or not it is the most effective approach.
Challenge: Incorporating New Treatment Advances
The development of new combinations of drugs and new protease inhibitors
offer their own set of advances, challenges and opportunities. Existing
data suggests that several approaches offer clear advances over
all currently approved forms of therapies. The advances include:
- AZT plus 3TC combination (see 3TC: Good News and Bad News):
This combination has shown striking effectiveness, but as a consequence
of positive publicity, it is now plagued by supply problems. Many
people who need and want it simply cannot obtain the combination,
even if they qualify for the current expanded access program.
- Nevirapine and delavirdine in two- and three-drug combinations:
Both of these non-nucleoside RT inhibitors offer potent viral
suppression. Although resistance develops rapidly when they are
used alone, each has shown significant and lasting benefits when
used in combination with other therapies. Overstated fears of
resistance have led to a loss of public interest when, in fact,
these drugs are certainly as important as the AZT/3TC combination
and may play a critical role in future combinations because they
offer a different mechanism of action.
- Protease inhibitors are showing strong activity along with concerns
about resistance: Due to economic and manufacturing concerns,
the ability to deliver these drugs lags far behind the reports
of their prowess, leading to rising frustration and anger. (See
Advances in Protease).
The combined research, regulatory and drug development systems
of this country have apparently not yet figured out how to make
new advances in therapy widely and routinely available to all who
need them. There are only small, limited plans for expanded access
to the Roche and Merck protease inhibitors, and no announced plan
for the Abbott drug. Thus, the most potent drugs yet seen in the
epidemic will not soon be made available through the wide expanded
access programs offered with almost all previous drugs. Perhaps
the only recent example in which the process has worked well is
the case of d4T, in which nearly unlimited access has been provided
to people in need without production or regulatory problems. (See
First Report: Full-term d4T Study Results.)
Challenge: New Models of Pathogenesis
New models of HIV pathogenesis have created new hope as well as
new risks in AIDS research. Recent findings have suggested a simpler
and more aggressive model of how HIV works. The work presented by
researchers David Ho and George Shaw at their respective institutions
describes a furious daily battle between HIV replication and the
immune system response, a battle in which billions of new copies
of virus are made daily, along with massive replication of immune
system cells to fight them. The danger this poses is the risk of
over simplification, leading scientists to ignore other evidence
and other approaches. In presenting the new theory, some scientists
argued against further research into immune-based therapies and
urged concentrating solely on antiviral approaches. Others looking
at the same data drew the exact opposite conclusion. However important
the findings might be, they do not change the strengths and limitations
of current therapies, nor do they open any possible new targets.
Challenge: Immune Restoration
Some stages of HIV disease remain beyond the reach of antiviral
therapies. Project Inform has long recognized and pursued this need
through its Immune Restoration Think Tank. Although progress has
finally been seen in such long-awaited advances as thymic transplantation,
cytokine therapy and gene therapy, the field remains under-funded
and under-appreciated. Some potential areas of advance, such as
xeno-transplantation (using tissue or cells from other animal species)
seem headed for confrontation with newly erected regulatory obstacles.
Perhaps of even greater concern is the likelihood that innovative
new programs currently funding immune restoration, such as the NIAID’s
SPIRATS program, seem headed for defunding by the new regime holding
the purse string in Washington. Despite the efforts of many dedicated
people, the road ahead for innovative immune-restoration research
seems clouded.
Challenge: The Big Picture
An overview of the advances and challenges ahead for AIDS research
cannot help but recall an old theme from many past issues. of PI
Perspective. There are many good and dedicated people working in
AIDS research, both in and outside of government, academia, and
industry. But if there is an overall tone today, it is one of a
return to the complacency seen in earlier years of the epidemic.
Few in the management of government research seem to believe they
can make a difference in the lives of people currently infected.
They only seem able to envision a long-term view, a perspective
that says we will see advances in 15 to 20 years, but not much before.
Missing is any sense of urgency, or a sense that people are suffering
today or that we can do anything about it. There seems little or
no interest in testing innovative approaches which might offer the
hope of “burning out” the disease-only approaches for
long-term management. There is little hint of courage or a sense
that the leadership is willing to look beyond existing models and
try new approaches to either the science or its management—and
not even the smallest sense that it matters to the President or
others in the national leadership.
What AIDS research lacks can be summed up in a few words: Leadership,
Courage, and a Sense of Urgency. We will continue to see a slow
but steady pace of advances without them, as we do today. But the
pity is that we could move so much faster and so much more effectively,
with them.
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