PI Perspective #19
September 1996 View PDF
The XIth International Conference on AIDS …
New Milestones for AIDS Research and Treatment
The XI International Conference on AIDS, held in Vancouver, British
Columbia, will be remembered as a milestone in the history of the
AIDS epidemic. The question of whether treatment is extending life
was answered affirmatively by several studies. In fact, studies
presented at the conference showed that just about any two-drug
combination seems capable of slowing disease progression and extending
survival. For the first time, HIV’s response to therapy is
beginning to look more like other infectious diseases. Exotic theories
are no longer needed to explain its relentless assault on the immune
system. The principal dangers now are the risk of overstatement
and the fear that reports of progress might lessen urgency on a
governmental level or reduce the sense of risk on a personal level.
Dealing with such problems seems to many to be a luxury compared
to the bleakness of past years. Whether or not the scientific advances
so enthusiastically reported in the media hold up to long-term scrutiny,
at the very least Vancouver in 1996 was the city where the misguided
despair of the 1993 conference in Berlin gave way to hope.
Key Treatment Themes from Vancouver
The complete picture of the two years’ worth of studies reported
at Vancouver cannot be covered in a single issue of this or any
other journal. Project Inform will report only on the most relevant
treatment information from the conference in this PI Perspective.
This issue will focus on the broad themes and most widely discussed
topics. The loudest messages from Vancouver regarding treatment
advances can be summarized as:
Confirmatory data and consensus on the use of viral load markers
(HIV RNA PCR and bDNA): These data were not new and were reported
previously in PI Perspective
#18. However, they were now extended and supported by additional
studies. This led the International AIDS Society—USA to present
the first guidelines for the use of viral load testing in managing
HIV disease.
Identification of a clear target for the use of antiretroviral
therapy and indications that viral resistance may be more manageable
than previously thought: Several studies showed that when viral
reproduction is reduced below the limit of detection on the currently
available tests, the dynamics of viral resistance are dramatically
changed. Study of a 3-drug combination with nevirapine demonstrated
that even drugs which are subject to very rapid development of resistance
can become useful for long periods when used properly. The rate
at which a virus can produce resistant mutations is directly tied
to how much it replicates. Slow its replication and its ability
to make resistant mutations decreases proportionally. The same pattern
has been shown in studies of protease inhibitors, as reported in
the antiviral update article. Thus, most scientists agree that the
goal of antiviral therapy is to reduce viral replication to the
lowest possible level (preferably below the limit of detection on
the viral load test) for the longest possible time.
Other data supporting this treatment goal come from the large Multicenter
AIDS Cohort Study (MACS) presented by John Mellors of the University
of Pittsburgh. They showed that even small differences in viral
load, over time, have a large survival impact. The longest survival
was routinely seen in people with the lowest level of viral replication.
Each stepped increase in viral load correlated to measurably worsened
chances of survival over time.
These findings support a shift in HIV disease management. It is
no longer enough to merely reduce viral load or cause modest increases
in CD4+ cell counts, or even to make short-term improvements in
disease progression and survival. Instead, physicians must now learn
to establish long-term disease management strategies to counter
the risk of viral resistance. The key is long-term suppression of
HIV RNA at or below the limit of detection of the test.
Extension of our knowledge about the use of protease inhibitors—both
longer-term data and additional studies: Many studies previously
reported in PI Perspective #18
have been extended and almost all show long-term retention of the
benefits initially seen. These longer-term data, and new studies,
are detailed in the Update on Antivirals.
Impressive new data on a previously overlooked class of drugs—non-nucleoside
reverse transcriptase inhibitors (NNRTIs): A new study of nevirapine,
demonstrates that it is possible to overcome or greatly delay viral
resistance when a drug combination is sufficiently powerful, no
matter how prone the individual drugs are to inducing resistance
when used alone. Triple-drug therapy with nevirapine is far less
expensive than therapy with protease inhibitors and can also shut
down all measurable viral activity in many people. This creates
an option for people to preserve the use of protease inhibitors
for later in the course of disease management. Additionally, the
combination of nevirapine with AZT and ddI was shown to have very
impressive initial results in treating pediatric HIV, signaling
the first time triple-drug therapy has been used in children.
Growing concern over the risk of multi-drug resistant HIV strains
and the critical importance of using antiretroviral therapies exactly
as prescribed: Several studies demonstrate that the development
of resistance to antiviral drugs is linked to failure to adhere
to the prescribed use of therapies. Dose reductions and inconsistent
use of therapies were shown to contribute to the quick development
of resistance against protease inhibitors and the NNRTI drugs (and
probably to earlier generation drugs as well). Conversely, careful
adherence to the prescribed dosing regimen was shown to keep the
viral load unmeasurable and prevent the development of resistance.
The treatment of HIV disease has thus come to mimic the patterns
established for the treatment of tuberculosis. The primary rule
is to treat the disease correctly or you may do more harm than good.
Once multi-drug-resistant strains of virus develop, not only do
they cripple the drugs’ ability to fight the disease, but
they can also be passed to others. Thus, poor adherence to therapy
regimens has public health consequences as well as personal ones.
This has major implications for HIV prevention programs. It also
increases the consequences of re-infection when two HIV-positive
people play without regard for risk of transmission, as they can
transfer drug-resistant HIV from one to the other.
Growing awareness of the difficult choices posed by the current
generation of protease inhibitors: Despite the glowing promise attributed
to protease inhibitors as a class of drug, the fact is that the
currently available therapies (saquinavir, ritonavir, and indinavir)
range widely in potency, risk of side effects, drug interactions
and ease of use. The choices are complex and not well understood
by many patients and physicians and are often complicated by widespread
misinformation. These issues are discussed in the article New Treatment
Strategies.
First public discussion of whether HIV might someday be eradicated
from infected people: Most discussion of this startling topic took
place at a meeting a month prior to the Vancouver conference. Project
Inform was one of the few community groups privileged to attend.
(See the article Eradication of HIV.)
What’s Missing?
Despite the hope generated by these advances, the conference was
something of a letdown in several areas. There were virtually no
major reports on advances in the treatment or prophylaxis of opportunistic
infections, except those reported earlier in the year. Likewise,
little in the way of advance was reported on immune reconstitution
or immune-based therapies. Although much work is underway in this
area, studies are simply not at the point where it is meaningful
to begin reporting results. Finally, as at previous conferences,
little attention was given to alternative therapies, leaving patients
once again to fend for themselves when exploring these approaches
to treatment.
Perhaps the most significant hole in the new data was the complete
lack of therapeutic advances relevant to the developing world. The
much touted theme of the Vancouver conference was “One World,
One Hope.” After a few days of hearing about $12,000 per year
therapy regimens, many activists began to rephrase the theme as
“One World, One Hope - Big Joke.” The cost and complexity
of the new therapeutic advances rule out their use in most of the
world, and certainly in the countries where 90% of the HIV cases
exist today. Many such places haven’t the resources to provide
a safe glass of water each day for HIV-infected people, let alone
protease inhibitors and combination therapy. Even in the U.S., the
cost of these therapies is bankrupting state drug assistance programs
and threatens to bring Medicaid to its knees over time (see the
article on access).
Clearly, while this has been a time of major advances, the solution
to AIDS is not yet upon us. As long as the embers of AIDS are smoldering
in any corner of the globe, or on any impoverished block in our
cities, HIV disease poses a serious threat to all. There will be
no solution until we find one which is available and accessible
to everyone. However grateful we may feel because of the advances
now so dramatically helping some, we cannot rest until there are
safe, simple and inexpensive solutions for everyone. We still have
a long way to go.
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