PI Perspective #24
April 1998 View PDF
Report from the Great Chicago Plateau
The 5th Conference on Retroviruses and Opportunistic Infections,
held in Chicago in the first week of February, heralded few breakthroughs
or surprises. Instead, it painted a picture of slow but steady progress
following the advances seen with the advent of protease inhibitors
and triple combination therapy beginning in 1996. This pattern of
evolutionary change is likely to continue for the next few years,
as the conference reports held out little hope for another major
advance any time in the near future.
Despite these limitations, the collective weight of new information
about existing drugs, how to use and combine them, and changes to
simplify their use will almost certainly add up to improved quality
of life for many people living with HIV, particularly those just
beginning therapy or with only a modest history of antiviral use.
There is little sense, however, that any of the soon-to-be-available
new agents will offer any major advantages for people with the most
advanced disease, for whom truly new approaches to therapy still
remain out of grasp.
This issue of PI Perspective is dedicated primarily to the coverage
of the recent conference and will highlight a number of the more
significant findings in several areas, including: an overview of
major trends and concerns in the use of therapy, new information
about existing therapies, new drugs in the development pipeline
and advances against opportunistic infections.
The Big Picture – Outcomes
The conference included presentations on the impact recent advances
have had on the death rate and the incidence of opportunistic infections.
In a word, all such studies could be described as positive. Reports
from hospitals, medical groups and cohort studies report major reductions
in the death rate compared to recent years. A typical example was
a study entitled “Accelerating Decline in New York City AIDS
Mortality,” prepared by the New York Department of Public
Health. The study reported a 29% reduction in AIDS mortality between
1995 and 1996, and an additional 33% decline from the second half
of 1996 to the first half of 1997. More importantly, the most recent
figures show that groups which did not initially benefit in 1996
are now reporting major gains in 1997. The gap in response initially
seen between white males and minorities closed considerably in the
first half of 1997, reflecting wider access to new therapies across
all populations in the study area. Unfortunately, this pattern of
improved access in places like New York is not always repeated in
other regions for disenfranchised and impoverished populations.
Some people have questioned whether reductions in the death toll
from AIDS can be attributed solely to new therapies. They have argued
that the declining death totals simply mirror an earlier change
in the epidemic, some ten years ago, when the total number of new
infections began to decline. Epidemiologists, however, disputed
such claims, arguing that the changes in the infection rate earlier
were insufficient to account for the mortality reduction seen today.
A clearer way to look at the issue is to examine what has happened
to the incidence of opportunistic infections in recent years. Such
infections, after all, are the final cause of most AIDS deaths.
One particularly revealing study was presented by the Tulane School
of Medicine in New Orleans. Because of its design, it eliminates
any influence from changes in the infection rate a decade ago. This
study simply looked at two large cohorts of HIV positive people
with CD4+ cell counts under 200, one group of 1,181 people in the
18 months before the availability of protease inhibitors and a second
matched group of 1284 people in the first 18 months after protease
inhibitors became available. The groups were compared for the incidence
of opportunistic infections over the equivalent 18 month periods.
The first period represented the era of two-drug combinations, such
as AZT + 3TC, the second represented the initial availability of
three-drug protease inhibitor-based combinations. Incidence of PCP
fell from 18% to 11.7%; wasting from 9.5% to 4.8%; KS from 4.3%
to 2.5%; MAC from 8.5% to 6.1% and CMV from 4.6% to 3%. All changes
favored the period in which protease inhibitors were available.
It should be noted that this study by no means represents the “best”
possible picture of the new therapies, since there was no requirement
that the people in the later group actually be on triple combinations.
The only assumption that can be made is that some of them were,
as compared to none in the earlier group. Additionally, many people
who started protease inhibitors when they first became available
in early 1996 merely added them to their existing regimen, potentially
using them as just monotherapy, and almost certainly not getting
the optimal response. We now know that to get optimal response,
people should start at least two new therapies when they switch
treatment regimens. Nonetheless, there were statistically significant
reductions in the rates of all the most common HIV-related infections.
Side Effects
Other “big picture” news included clarification about
two significant new side effects sometimes attributed to protease
inhibitors, namely diabetes and body fat redistribution. Two studies
which examined the diabetes question concluded that if protease
inhibitors are responsible for new cases of diabetes, it is at best
a rare side effect with no evidence of wide-scale incidence. Researchers
will continue to study individual incidences. The outcome is the
opposite concerning fat redistribution (now being labeled as lipodystrophy),
as several studies documented growing incidences of this problem.
This side effect takes one of three common forms: (1) “buffalo
hump” or an accumulation of fat at the back of the neck at
top of the spinal cord; (2) “truncal obesity” or the
accumulation of hard fat deposits in the abdominal area; or (3)
wasting of the face, arms and legs. Incidence of these effects ranged
from a low of 11% in one study to as high as 64% in another. Differences
in the incidence rate may be attributed to differences in definition
of the problem and differing levels of physical examination by physicians.
The largest study concluded that these problems are not associated
with any particular protease inhibitor but rather with all of them,
perhaps in a potency-related fashion. For now, this problem does
not yet appear to have any immediate clinical significance, but
it does have a major cosmetic and body image impact for those suffering
from it. No clear explanation yet exists of the mechanism. So far,
the only known solution is to stop the use of a protease inhibitor.
Some physicians anecdotally report success from changing the protease
inhibitor regimen. Patients are encouraged to request careful physical
exams by their physicians to look for the onset of this problem
and keep watching for any new information about how to treat the
condition. Some people are seeking help from endocrinologists, but
so far, no one has claimed to have a solution.
Salvage Therapy
Salvage therapy remains one of the most important but understudied
aspects of AIDS research. Most new drug studies focus on people
who are just beginning therapy or who have limited prior use of
anti-HIV drugs. If there is any clear message emanating from the
Chicago conference, it is that people in these categories have a
wide range of increasingly well proven options. In contrast, people
who have experienced high level clinical and virological failure
with existing drugs have few if any places to turn. A number of
small studies labeled as “salvage therapy” were presented
in Chicago, but they could all be summed up as a strategy of “try
whatever’s left” or “take everything at once.”
Small uncontrolled studies reported varying degrees of short-term
success from four-, five-, and six-drug combinations. Nothing, however,
even hinted at an effective long-term strategy. Even if a five-
or six-drug regimen works in the short-term, it seems unlikely that
people could sustain such intensive therapy for long periods. Many
people already have difficulty working with three-drug combinations,
so the challenges of adherence and toxicity in a five- or six-drug
regimen may be overwhelming. Some of the small salvage studies reported
in Chicago are described in Antiviral Update of this issue of PI
Perspective.
Immune Restoration
Several key studies at the Chicago conference characterized the
state of the immune system in people successfully treated for long
periods with highly active antiviral therapy (HAART). In short,
the studies show a surprising but still imperfect level of immune
restoration. Progress or reversal seems to be occurring in nearly
every documented defect of immunity associated with AIDS. The level
of resulting immune response is still not comparable to uninfected
controls, but this perhaps is too much to ask. Instead, the question
might be “is the restored level of immunity sufficient to
lead a normal life?” The answer to this question increasingly
seems to be yes, with growing evidence that some people are able
to successfully withdraw from the use of maintenance and preventive
therapies against opportunistic infections. Even if the immune response
remains imperfect, it may be adequate.
Some remaining important but unanswered questions about immune
response include:
- Why do some people experience immune restoration but not everyone?
- What are the characteristics of the level of immune restoration
needed to warrant withdrawal of maintenance or preventive therapies?
- Why doesn’t the immune response return to a normal state,
even in the presence of near-complete viral suppression?
- What can be done to augment the natural return of immunity?
These and related issues will be addressed extensively in the
March 1998 meeting of the Project Inform Immune Restoration Think
Tank (San Francisco, March 20–21).
Ease of Use – Adherence
The challenge of adherence to difficult therapy regimens remains
a major roadblock to more wide-scale success with treatment. Several
papers presented in Chicago demonstrated how truly difficult this
challenge is, noting high levels of nonadherence even under the
best of circumstances. While many behavioral programs are under
development to assist people with adherence, the most fertile ground
for attacking this problem is the development of better drugs that
are less toxic and easier to use. Along these lines, reports at
the conference noted the first therapy designed for “once
a day” dosing (efavirenz), new ways to use existing drugs
more easily (twice daily dosing for nelfinavir and indinavir; once
daily dosing for nevirapine and ddI), as well as new drugs designed
with ease of use in mind. Within a year or less, it will be common
to see twice daily dosing regimens, and perhaps some complete combinations
which require only a single dose period daily. Information on many
of these simpler dosing regimens can be found in Lower Dose Maintenance
Therapy for HIV?, while a wider discussion of the issues, challenges
and strategies of adherence can be found in the “Adherence
to HAART” presentation module on the Project Inform website.
And lest people despair about their own inability to achieve perfect
adherence, we should remember that all the good news about reduced
death and opportunistic infection rates has come from a patient
population which is imperfect in its adherence to therapy.
New Drugs in Development
New data were presented on a number of drugs expected to become
widely available in the next 1–2 years. These are covered
in detail in New Drugs on the Horizon. One important characteristic
of most of the drugs expected in the near future is that they are
unlikely to offer the necessary breakthrough needed by people with
advanced disease and high level failure with current drugs. The
immediate crop of new agents is composed largely of new and improved
drugs of the same types as those previously offered. Thus, nearly
all will suffer problems of cross-resistance with one or more existing
agents. They may well be better choices for people just beginning
therapy or those with only a modest history of therapy use, but
will offer no panacea for the highly experienced patients. Drugs
which fall into this category include abacavir, adefovir, amprenavir,
FTC and efavirenz. A few additional new protease inhibitors are
in early development which claim to overcome problems of resistance,
but such claims should be viewed very cautiously until there are
real data to support them. Though such claims have often been made
before, it’s hard to cite a single example in which they proved
true.
What the advanced patient population needs are new types of drugs
which react with entirely new targets on the virus. This includes
such agents as zinc finger inhibitors (now in phase 1), fusion inhibitors
(also in phase 1), and integrase inhibitors (struggling to get out
of the laboratory). Unfortunately, there will be a considerable
time gap before such compounds become routinely available.
In Summary
The Chicago conference stands largely as a model for where we stand
in the course of the AIDS epidemic: resting on slowly rising new
plateau. Advances of the size and quality seen in 1996 can’t
be expected every year, perhaps even every few years. Slow gradual
improvement is taking place which will indeed make a difference,
but it falls far short of a revolution or major step forward. For
most people, this is more than sufficient, however, it remains sadly
lacking for those people with the most advanced disease and those
who have experienced high level failure on existing therapies. For
them, the near future remains clouded with uncertainty. For their
sake, we must all forsake the temptation of complacency and renew
the demand for better therapy.
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