Contents
When HAART Is Not Enough
by Dave Gilden
Despite all the publicity about "viral eradication" at this
summer's International Conference on AIDS and at the ICAAC
conference covered in this Treatment Issues, many people
continue to fail on their current HIV medications, even if
they are receiving one of the new triple combinations. (Such
therapy is sometimes called HAART, for "highly active
antiretroviral therapy.") Here are a few of the disappointing
experiences that we at Treatment Issues have heard lately:
- George was in an indinavir monotherapy trial and initially
had great success reversing a sudden crash in CD4 count (it
went from 250 to 70 and eventually to over 600). His viral
load became undetectable (under 200 copies/ml) and stayed
that way for 18 months. Now, even though he also has been
taking d4T/3TC for nearly a year, HIV is again at 20,000.Advertisement
- Darryl, conversely, had been stable on d4T/3TC when he
added indinavir. His viral load went from 50,000 to below
1,000 for six months, while his CD4 count leaped from 250 to
450. Then suddenly, his viral load went up to 180,000, close
to the figure in the days before d4T/3TC.
- Michael was diagnosed with AIDS in 1989 but had been a
long-term AZT success story. In the last few years, though,
he has not done so well: He has had PCP, two cases of MAC and
finally cryptococcal meningitis. Michael switched nucleoside
analogs several times along the way with at most marginal
improvement. Last winter he tried adding saquinavir -- it
provided no evident benefit while causing frequent vomiting.
He went on indinavir more recently, but too late to do much
good given how ravaged his body had become. Michael died in
August of bacterial pneumonia.
"I'm seeing treatment failures most commonly in patients with
very high baseline viral loads -- over 100,000 -- and low CD4
counts. Those with low viral load and high CD4 counts in
general are not crashing or failing" said Gabriel Torres,
M.D., Treatment Issues' medical consultant, reporting on what
he has encountered so far with the new antiviral
combinations.
Aside from their tendency to have more advanced HIV
infections, the people not responding to the new, improved
anti-HIV regimens do not all fall into any particular
pattern. Many doctors blame patient compliance for a
treatment's lack of success -- after all, the HAART regimens
require complicated schedules for taking the different drugs,
and some medications need to be taken with food while others
require an empty stomach. The number of side effects
encountered might also discourage people from taking full and
regular doses of particular drugs. But the experiences
described above all involve very conscientious and
knowledgeable people who swear they faithfully followed their
prescriptions' instructions.
One does not need to blame the patient to find reasons for
treatment failure: Some people may have gastrointestinal
problems that prevent absorption of enough drug (this
absorption problem arises for the great majority of people on
the present version of saquinavir regardless of their
digestive status). Others may have developed HIV resistant to
most nucleoside analogs due to prior sequential therapy with
these agents. Now protease inhibitor-resistant HIV is
emerging in their bodies during ostensible combination
therapy that is basically protease inhibitor monotherapy.
Still others cannot tolerate the currently available agents
-- they suffer from vomiting on ritonavir and saquinavir and
kidney stones on indinavir. Finally, there are the odder
cases, such as people with impaired livers that cannot
process the current protease inhibitors without added hepatic
dysfunction.
At this point, there are no reliable figures about the
frequency with which the widely heralded HAART regimens are
meeting defeat. But it seems to be a common, if not the
predominant, experience. One estimate of its incidence comes
from Agouron Pharmaceuticals, which interviewed several dozen
doctors with large AIDS practices in an effort to determine
the demand for an expanded access program offering the
company's experimental protease inhibitor nelfinavir. (That
program is now in operation -- see below.) Based on the
doctors' responses, the company estimates that about 2,500
Americans with HIV and CD4 counts less than 50 already have
failed or could not take all three protease inhibitors on the
market. Agouron further estimated that 10,000 U.S. patients
with CD4 counts under 200 have failed on or are otherwise
unable to take at least two of the three protease inhibitors.
By comparison, over 50,000 Americans are now taking Merck's
protease inhibitor indinavir.
Ramon Seva, the marketing research official at Agouron who
supervised the survey cautions, "These numbers are very
rough. This was not the most controlled study because we
needed answers within a week and a half. If I had had the
time, I would have made the doctors look at their records for
specific reasons people went off the protease inhibitors and
for people who would go off drug if they had a replacement.
I'd have asked 50 to 100 docs, and it would have taken a
month."
The Limits of Antiviral Therapy
The eventual extent of treatment failure lay behind a
persistent debate at the International Conference about the
need for therapy that strengthens the body's natural immune
defenses against HIV and the opportunistic infections that
interfere with recovery during administration of HAART
regimens. Current therapeutic strategies focus on essentially
poisoning actively replicating HIV without trying to
manipulate overall conditions in the body to make them more
inhospitable to the virus. Several observations reported at
the conference underscored the limits of anti-HIV treatment
as currently conceived.
In particular, although CD4 cell counts rise sharply after
the introduction of potent anti-HIV therapy (combination
therapies that durably reduce viral load by 100-fold -- 2
logs -- or more), there usually is a general ceiling at 100
to 150 above the pretreatment CD4 count. This phenomenon was
observed, among other places, in the striking pilot trial of
triple combination therapy (AZT/3TC/nelfinavir) presented at
the International Conference by Martin Markowitz, M.D.,1 of
the Aaron Diamond AIDS Research Center in New York. In eleven
volunteers who continued on the regimen (there was one drop-
out), HIV levels were reduced to below the limits of
detection with the most sensitive available assay (which
detects down to 25 HIV RNA copies/ml of plasma). CD4 counts,
which initially ranged from 37 to 557, exhibited a mean
increase of 109 at week 16. (In this small study, there was
no measurable correlation between the amount of CD4 increase
and pretreatment CD4 count.)
It appears that as the pressure of the HIV infection is
relieved, existing CD4 T-cells expand to their maximum
capability, but the desperately needed new "naive" CD4 cells
that would trickle out of the bone marrow via the thymus have
yet to be observed in any quantity. This lack may occur
because people's thymus glands are too damaged by HIV
infection to allow the CD4 T-cells to mature, or it may be
that our experience with potent antiviral therapy is as yet
too limited, both in time and numbers of patients, to observe
immune healing. It could take a while for the surviving
thymus tissue as well as small surviving naive CD4 cell
population in the blood and lymph to produce noticeable
numbers of new cells.
David Ho, M.D., director of the Aaron Diamond Center,
reported to the International Conference2 that his colleagues
have in fact noted a gradual secondary increase in CD4 counts
after the initial burst, although it remains too early to
determine this secondary rise's frequency or significance in
terms of immune recovery. Emilio Emini, who directs antiviral
research at Merck Research Laboratories, has some of the most
extended data on patients' response to protease inhibitors
from the trials of his company's indinavir. Once again he can
only give his impression, which is that the second phase
immune system improvement mentioned by Dr. Ho is mostly seen
in people with less advanced disease: "Some patients with
late stage disease show no CD4 increase," Dr. Emini notes.
"Some go up 100 and are stable, and some go further down."
Aside from limits to the CD4 response, there is the question
of the durability of the viral load response to a therapy
that consists solely of antiviral compounds to which HIV can
develop resistance. Dr. Emini notes that there have been
"some" breakthrough HIV infections -- a return to measurable
HIV levels (in this case above 500 copies/ml) -- among people
whose viral loads dropped to undetectable levels during the
early indinavir monotherapy trials. These people, most of
whom have added other antiretrovirals to their regimen some
time ago, are precisely some of the people who have been on
indinavir the longest, up to two years. Sequentially adding
antiviral agents, starting with nucleoside analogs and then
adding on one of the new protease inhibitors, is a more
common experience than giving three new drugs to people
without prior exposure to any anti-HIV therapy as in the
Aaron Diamond trial. It is possible that many people have
used up their benefit from the available nucleoside analogs
one by one and now will be going through the protease
inhibitors in similar fashion.
The Merck-sponsored study of AZT/3TC/indinavir in a group
with a median 31 months prior AZT did show that adding two
new drugs (3TC and indinavir) can produce a major response:
Plasma HIV levels were still down by a median of 99 percent
and CD4 counts were up by 130 at 36 weeks.3The trial's
principal investigator, Roy Gulick, M.D., notes that it will
be of great interest to see what happens to the trial
participants in the AZT/3TC control arm when they start
receiving indinavir at the end of the trial. Dr. Gulick
noted, "This is more like a common real world situation,
where people first took AZT, then got 3TC, and are now
receiving indinavir too."
Another limitation in current therapy is that usually when
drugs are used to treat a disease, therapy is reinforced by
the immune system which is able to destroy at least whatever
residual microbes survive the administered medications.
People with progressive HIV infection clearly do not have any
intrinsic effective way to cope with treatment-resistant
mutant HIV as it arises. The further along in the course of
the disease they are, the more likely it is that their
population of CD4 cells that respond specifically to HIV
infection have been killed off by the virus, which preys
preferentially on the CD4 cells activated to defend against
infection. Their immune response, which was not entirely
effective in the first place, can only get weaker and weaker.
There is considerable hope that the new antiviral therapies
will do better than just reestablish the old equilibrium. By
controlling viral load better than the body ever could do on
its own, aggressive anti-HIV treatment might make everyone
have the viral loads of long-term nonprogressors with the
life expectancy to match. Although the analysis of several
clinical trials indicate that treatment-induced reductions of
viral load do improve patients' prognosis (see the newly
published report on ACTG trial 175, for example4), it is not
clear that they create conditions mimicking strong
immunological control.
Robert Coombs, M.D., of the University of Washington, asks,
"Does a person with a viral load of 100,000 that is
subsequently suppressed by drugs down to 10,000 have the same
outlook as a person who naturally has only 10,000? Probably
not, because immunologically, these latter people are totally
different. This is a fundamental flaw in the current
argument."
Such considerations led Anthony Fauci, director of the
National Institute of Allergy and Infectious Diseases to
declare during his address in the opening session of ICAAC
that, "We need to use our knowledge to create effective
treatment by attacking host factors as well as the virus."
Environmental Warfare
Establishing an immune environment hostile to HIV may not
necessarily require creating an active HIV immune response.
Some of the most exciting and quickest-paced research in the
past year concerns the so-called second receptor on cell
walls to which HIV virus particles bind along with the CD4
receptor as they fuse to and enter uninfected cells. The
hubbub started with an article last winter by a team from the
National Cancer Institute led by Robert Gallo, M.D5 This
article reported that three members of a class of immune
regulatory substances known as CC-chemokines (specifically
RANTES, MIP-1a and MIP-1ß) prevent HIV from infecting new
cells. (See Treatment Issues, January 1996.) The
discovery was surprising in that the chemokines previously
had been known as compounds that attracted white blood cells
to the sites of infection. Acting on this lead, several
groups of researchers soon found that CCR-5, a cellular
receptor that interacts with all three of these CC-
chemokines, was necessary for cell entry by the macrophage-
tropic or NSI ("non-syncytia inducing") strains of HIV
prevalent in early infection. (See Treatment Issues,
June/July 1996) Shortly before this, another cell
receptor, known as fusin (more recently designated CXCR-4),
was revealed as the co-receptor necessary for cellular entry
with the highly pathogenic T-cell tropic or SI ("syncytia
inducing") strains of HIV sometimes found in late-stage
disease. Just recently it was discovered that fusin binds to
a chemoattractant called SDF-1.6Other chemokine receptors
may also be used by HIV on some occasions.
Why is all this plethora of initials important? Just before
the International Conference on AIDS, researchers reported on
two individuals who had apparently been exposed to HIV many
times through unprotected sex yet remained uninfected.7
Immediately after the conference, the same research group
reported that these two individuals were missing a segment in
their genes for CCR-5 so that the receptors did not appear on
their white blood cells at all.8In spite of this defect,
these two persons were absolutely healthy. Other cell
receptors seem to be able to take over the work of the
missing CCR-5. Almost simultaneous to this report, a Belgian
team seconded these findings in other exposed but uninfected
persons. A genetic survey of this group conducted of the
prevalence of this CCR-5 genetic defect found it in 1% of 704
HIV-negative persons and in none of 723 HIV-positive persons.
These are the figures for people who received the defective
CCR-5 gene from both parents (homozygotes). Those who possess
one normal gene and one defective one (heterozygotes) were
less frequently represented in the HIV-positive group
compared to the HIV-negative one (16% vs. 11%), indicating
that those with a discordant gene pair have some difference
in numbers or structure of this cell surface receptor than
those whose pair of CCR-5 genes is completely normal.
A final paper published in Septembe9did not find that the
heterozygotes were less likely to be HIV-positive, only that
HIV infection progresses more slowly in such individuals.
Based on data from samples collected from some long-standing
cohorts of U.S. males (either homosexual or hemophiliac),
about half the people with HIV and two normal CCR-5 genes
have an AIDS diagnosis ten years after contracting HIV. For
those with a discordant gene pair, only about 30% have AIDS.
(This gap narrows in the second decade after infection, but
does not close completely.) As for the homozygotes with
absent CCR-5 receptors, once again none could be found among
the HIV-positive men (1,343 individuals), although 17 of 512
HIV-negative men were homozygous.
At the International Conference itself, presenters confirmed
that the CC-chemokines act as suspected, by blocking their
CCR-5 receptor so that HIV cannot enter the cell.10 Hints for
possible nontoxic therapies are emerging here. Ian Clark-
Lewis of the University of British Columbia, who is an expert
on chemokines, not HIV, told Treatment Issues, "This is a
very encouraging field. Chemokines seem to be hangovers from
the past and seem to be predominately involved in unwanted
effects, when the body attacks its own tissues. Though there
are some positive effects, there are so many chemokines that
they can compensate for each other if you disrupt the
functioning of some of them."
In looking at the chemokine/second receptor/HIV interaction,
scientists have happened upon a situation where nature has
done many of the needed experiments for them. People with no
CCR-5 receptors are healthy but apparently protected against
HIV. Those with fewer or altered CCR-5s also seem somewhat
protected. It should be possible therefore to safely block
CCR-5 in people with normal receptors and protect them
against HIV. The problem is to find molecules that bind to
CCR-5 without stimulating the cell. Whether people with
normal, intact receptors will be able to compensate for the
virtual disconnecting of CCR-5 from the intercellular
signaling pathway remains to be seen. One caution has already
appeared in the form of a brief report that natural
chemokines appear to stimulate HIV replication in test tube
cultures of pure macrophages.11 It may yet turn out to be
safest to try to use molecules that bind to the part of the
gp120 molecular unit of HIV's envelope that connects to CCR-
5. But exactly what region on gp120 is involved in this
process has not been determined, so the feasibility of
targeting HIV rather than the cells is unknown.
Then there is the question of how HIV would evolve in the
face of such treatment. The virus might merely mutate into a
more pathogenic T-cell tropic variant that uses fusin as its
second receptor if CCR-5 suddenly became unavailable. While
this does not seem to be what happens in people with
heterozygous genes for CCR-5, who are slow progressors, the
effect of anti-CCR-5 treatment in someone with a firmly
established, high viral load HIV infection might be
different. At the least, any anti-binding therapy along these
lines would have to include compounds that block binding to
fusin and other possible HIV co-receptors as well as CCR-5.
Treatments that take advantage of the newly gained knowledge
of the HIV interaction with cell walls may appear fairly
soon. According to David Ho, M.D., who directs the Aaron
Diamond AIDS Research Center at which many of the experiments
on CCR-5 were conducted, "Many companies have looked at
compounds that bind to seven transmembrane receptors [the
family of receptors that includes CCR-5 and fusin] to treat
neurological and cardiac problems. Many companies already
have compounds but no one is talking about it."
One team that is talking about it just published a letter in
Nature.12This French/Swiss/Canadian group had already been
experimenting with truncated chemokines that would block CCR-
5 and similar receptors without activating the cells.
Researchers were initially looking for allergy and arthritis
therapies, but after the Gallo and other papers appeared,
they found that one of their products, a version of RANTES
missing one end, inhibits HIV very well in the test tube. The
effective concentrations are ten-fold greater than natural
RANTES, though. As to be expected, the truncated RANTES was
ineffective against a T-cell tropic HIV strain utilizing the
fusin receptor. According Ian Clark-Lewis, who was one of
these researchers, "I'd like to make this molecule ten times
more powerful. The next step is to try it out in animal
models to see if it does anything. Also, we should try to
develop a small non-protein molecule that does the same thing
as the truncated RANTES since that would be cheaper and more
stable."
Another potential therapy is already entering human trials.
British Biotech will try out BB 10010, a MIP-1a analog, on 15
HIV-positive volunteers for one week at a London hospital.
Allowable CD4 counts range from 50 to 500. This analog, which
only differs from MIP-1a by having one less amino acid, was
originally developed for use in cancer therapy and bone
marrow transplantation.
Chilling Out the Immune System
These attempts to block chemokine receptors comes on the
heels of a long line of proposals to benignly obstruct
aspects of immune function that supposedly help HIV more than
the body. It is apparent that this overall concept can have
considerable power from comments Anthony Fauci made
concerning interleukin-10 (IL-10) during his lectures at
ICAAC and the International Conference. Single injections of
small amounts of this anti-inflammatory intercellular
messenger (cytokine) can have dramatic effects on a patient's
plasma HIV levels. In the eight volunteers tested so far,
using amounts ranging from one to 25 micrograms per kilogram
of body weight, one quick infusion sent viral loads crashing
down toward or below undetectable levels (200 copies of HIV
RNA per milliliter of plasma in this case) for a short period
of time. Pretreatment viral load values were not regained for
one to three days, depending on the dose. It almost looked as
if HIV replication had switched off momentarily.
Phase II trials with multiple IL-10 infusions are now under
consideration. Dr. Fauci seems almost diffident about IL-10's
therapeutic potential, though. "Am I excited? I've been in
this business too long to be excited!" he said in an
interview. "IL-10 proves that tweaking the cytokine balance
can influence the virus, but we have to proceed very
cautiously in studying its therapeutic value. IL-10 is very
immunosuppressive. It could possibly increase viral load over
the long run -- but let's do the trials and not speculate."
There are some solid grounds for caution because like the
many other cytokines that immune system cells exchange, IL-10
has complicated, even contradictory effects. The broad-
ranging activity of interleukin-10 causes cells to go from an
active to quiescent state, which does not support HIV
replication. Dr. Fauci's lab has found that in particular,
IL-10 suppresses cellular production of IL-1, IL-6 and tumor
necrosis factor-alpha.13 These three are immune stimulating
cytokines are present at unusually high levels during HIV
infection. and they also specifically activate HIV
replication. But IL-10 itself is present at increasingly
elevated concentrations as HIV infection progresses. The
Fauci lab further found in test tube experiments that if IL-6
or TNF-a are present in conjunction with IL-10, then IL-10
acts with either of the two stimulators to further increase
HIV's activity.14 In the body, a parallel situation could
arise if IL-10's suppression of production of stimulatory
cytokines turns out to be incomplete at tolerable doses. Such
situations probably are avoidable by using IL-10 in
conjunction with aggressive HAART drug combinations and
perhaps not administering it to people whose HIV infections
are far advanced.
Then there is the worry that it could turn out that "the
operation was a success, but the patient died." Long-term IL-
10 therapy might result in merely trading one type of immune
deficiency for another. But then, a French study with the
anti-inflammatory corticosteroid prednisolone has been
following its 43 HIV-positive participants for up to three
years at last report15 without finding anything particularly
disturbing.
Rather, an overall long-term stability in CD4 count was noted
in people with baseline viral loads below 100,000 after
initial CD4 jumps of 250. People with higher viral loads
deteriorated after the initial CD4 increase. Due to its
small, informal design the exact study results should not be
taken with complete confidence. Also, prednisolone's
mechanism of action differs from that of IL-10. Nonetheless,
there is an indication that lengthy, generalized immune
suppression is endurable by people with HIV and could be
beneficial, at least in people with lower viral loads.
One Nonresponder Has the Last Laugh
Finally, here is an example of "the operation failed, but the
patient thrived." Jeff Getty was having no success on his
AZT/3TC/indinavir regimen (as judged by a series of
opportunistic infections including PCP and bacterial
pneumonia plus and an unbudging CD4 count of 30) when he
received a widely criticized (and publicized) baboon bone
marrow transplant last January. The transplant was an effort
to create a reservoir of functioning immune cells in his body
that were unaffected by HIV. Many of the skeptics did not
expect him to survive the experiment for a variety of
reasons, including the possibility that the baboon cells
would attack the human cells in his body (graft versus host
disease is a common problem even in human-to-human bone
marrow transplants).
Instead, Mr. Getty's CD4 count increased to 70 before
stabilizing around 50, the highest in four years. At the same
time, his viral load slipped from 22,000 to undetectable
levels before stabilizing at under 1,000 by the second month.
He also gained 12 pounds and his chronic sinusitis and asthma
disappeared. "I haven't felt this good in a long, long
time - I'm now off antibiotics, which I used to eat like
candy," commented Mr. Getty, who continued his
AZT/3TC/indinavir regimen during and after the transplant
experiment. (He also has been receiving growth hormone
therapy except in the period around the transplant
procedure.)
But there is no evidence that the baboon cells took root in
Mr. Getty's body. An alternative explanation for his
improvement lies in the mild cyclosporine and radiation
therapy he received to eliminate more of his own immune
system, and hence a great deal of HIV and its target CD4
cells, so as give the transplanted cells a chance to engraft.
At least one similar response to such immune system
"ablation" plus continued antiviral therapy during bone
marrow transplantation has been reported.16 In that case, the
patient died after 47 days, due to a relapse of his lymphoma,
and long-term results were not available.
The cyclosporine and radiation may have "set the clock back"
on Mr. Getty's HIV infection as well as reduced
counterproductive immune over-stimulation. But it would be
miraculous to expect permanent HIV inhibition from one immune
suppressive treatment, especially in people with very
advanced HIV infections. Indeed, Mr. Getty's viral load is
now creeping upwards (it was 20,000 in September), although
he still free of physical illness or weakness.
He also landed in the hospital at the end of August due to
severe kidney stones from the indinavir he has been taking.
He switched to a ritonavir/saquinavir combination, but severe
nausea and diarrhea, probably from the ritonavir, made that
regimen intolerable. He also was not seeing any improvement
in his viral load. The latest word is that he is switching to
nelfinavir through the expanded access program and looking
for some new nucleoside analogs.
Mr. Getty also hopes to get another course of ablative
therapy through a new pilot study in San Francisco that will
look at chemotherapy plus radiation in people with advanced
HIV. This study will provide some confirmation of the
putative benefits of this immune suppressive approach.
Meanwhile, the chief lesson in Mr. Getty's story is that
something can be done for people failing the new combination
therapies -- there is life after HAART failure.
Coming next month: IL-2, therapeutic vaccines and cells that
inhibit virus infection -- rather than turning off various
aspects of the immune system to subvert HIV, can we train the
immune response to be more effective?
Reference
- Markowitz M et al. XI International Conference on AIDS.
July 7-12, 1996; abstract LB.B.6031.
- Ho D. XI International Conference on AIDS. July 7-12, 1996;
presentation We.A.502.
- Gulick R et al. XI International Conference on AIDS. July
7-12, 1996; abstract Th.B. 931.
- Katzenstein D et al. New England Journal of Medicine. Oct.
10, 1995; 335(10):1091-98.
- Cocchi F et al. Science. Dec. 15, 1995; 270(5243):1811-15.
- Bleul C et al. Nature. Aug. 29, 1996; 382(6594):829-33.
Oberlin E et al. Nature. Aug. 29, 1996; 382(6594):833-35.
- Dragic T et al. Nature. June 20, 1996; 381(6584):667-73
- Liu R et al. Cell. Aug. 9, 1996; 86(1).
- Dean M et al. Science. Sept. 27, 1996; 273(5282):1856-61
- Dragic T et al. XI International Conference on AIDS. July
7-12, 1996; abstract Mo.A.275.
- Schmidtmayerova H et al. Nature Aug. 29, 1996;
382(6594):767.
- Arenzana-Selsdedos F et al. Nature. Oct. 3, 1996;
383(6599):400.
- Weissman D et al. AIDS Research and Human Retroviruses.
Oct., 1994; 10(10):1199-1205.
- Weissman D et al. Journal of Acquired immune Defiicency
Syndromes and Human Retrovirology. Aug. 15, 1995; 9(5):442-9.
- Andrieu, JM. HIV Immune-based Therapies Workshop. Clinical
Immunology Society. Jan. 26-28, 1996.
- Holland HK et al. Annals of Internal Medicine. Dec. 15,
1989; 111(12):973-81.
Anti-HIV Agents at ICAAC
by Theo Smart
After satiation at the International Conference in Vancouver,
the usually informative yearly Interscience Conference on
Antimicrobial Agents and Chemotherapies (ICAAC) held in New
Orleans, September 15-18 seemed to offer only Cajun-spiced
bread crumbs to many seeking information on new anti-HIV
treatments. The optimism evidenced at Vancouver, though, had
been a once-in-a-lifetime distillation, brewed from an
improved understanding of the dynamics of viral replication
and resistance, as well as the potency of the new anti-HIV
drugs. During the opening plenary ICAAC, leading virologist
Douglas Richman, M.D., of the University of California, San
Diego, noted that what happened at Vancouver was a " shift in
treatment strategy, from palliation with sequential
monotherapy to complete suppression" with potent combination
therapy.
Dr. Richman reviewed how the development of viral mutations
that confer resistance to antiretroviral drugs has given the
virus an upper hand in the battle against it. He believes
that while single mutations that confer resistance to one
drug generally exist before treatment with that drug is
initiated, multiple mutations are required to defeat protease
inhibitors and combination therapy. This resistance must
evolve over time, which requires that a low level of viral
replication continue in the presence of therapy. To keep the
virus in check indefinitely, there needs to be truly complete
suppression of the virus in all the body compartments in
which the virus finds a home.
The growing number of reports of people who experience a
rebound in viral load while on combinations that include a
protease inhibitor indicate that this complete viral
suppression is not being accomplished in all patients. The
failure of the combinations to contain the virus may be due
to heavy pretreatment with nucleoside analogs. It also should
be remembered that nucleoside analogs often fail to suppress
the virus even in the absence of mutations conferring
resistance. This may be because natural processes in cells
need to alter these nucleoside analogs before they become
active against HIV, and this intracellular activation may
decrease over time. Or perhaps treatment fails because the
adverse effects of drugs such as ddI, AZT, d4T and ddC
understandably lead patients simply to stop taking the pills
over time. Resistance to the combinations also may evolve
because they just do not penetrate every part of the body in
which the virus resides, or because they are not quite
bioavailable or potent enough (see the HAART articlein this issue by Dave
Gilden).
ICAAC did offer a few new leads that may push us a little
closer toward finding a truly optimal combination of drugs,
or at least providing options to switch to after failing
indinavir/AZT/3TC, or whatever cocktail one is currently
ingesting. The new data include a further follow-up report on
the combination of ritonavir and saquinavir, a report on the
antiviral activity of the Glaxo Welcome/Vertex protease
inhibitor 141W94, test-tube data on novel protease inhibitors
from Ciba-Geigy and Gilead, plus the first antiviral data on
the combination of a non-nucleoside reverse transcriptase
inhibitor with a protease inhibitor (in this case DuPont
Merck's DMP 266 plus indinavir).
141W94
The safety and antiviral activity of 141W94, the protease
inhibitor that Glaxo Wellcome licensed from fledgling biotech
Vertex, has been under investigation in a dose-ranging study
that started last November. The time it has taken for the
company to release data on the compound is longer than usual
and rumors of the drug's activity or lack thereof have
flourished. The interest in this drug is particularly intense
because of preclinical reports that, in contrast to the other
protease inhibitors, levels of this drug in the brain tissue
of animals was equal to or greater than levels of the drug in
the blood (170%), suggesting that this drug would reach viral
reservoirs in the brain. Also, Glaxo Wellcome has made claims
that the drug may be active against most, though not all,
viral strains resistant to indinavir or ritonavir, making
this drug an appealing option for anyone who has failed on
those treatments.
The long-awaited data were meager, but did confirm that the
drug has an antiviral effect which increases with the dose
(abstract LB7a). Four-week data were available for the first
four doses studied: 300 mg two or three times a day and 900
or 1,200 mg twice a day. Around ten people were enrolled in
each arm, with a median baseline CD4 count of 282 cells and
viral load of 4.83 logs. The lowest dose only reduced viral
load by 0.58 log at peak, the next two highest doses were
significantly more potent at peak, but the effect for all
three lower doses lessened by week four at around a half a
log below baseline. The highest dose reduced viral load by
almost 99 percent (1.95 log reduction). This drop was
sustained through the fourth week.
It is not clear that the lower doses are failing due to the
development of resistance. The reduced antiviral effect may
be because there are decreased levels of drug in the blood
after the first couple of weeks on therapy, due to the way
141W94 is metabolized by the liver. The same phenomenon has
been observed with ritonavir.
CD4 counts increased by a range of 35 to 110 cells over the
four week study. Side effects were mostly mild, although two
patients discontinued the study due to serious rash and one
person quit because of worsening of colitis. Nine of the
study's total of 42 enrolled patients had loose stools
(similar to what has been reported for nelfinavir).
Three people bravely elected to undergo lumbar punctures so
that the researchers could gauge the level of drug that
reached the CSF, which was found to range between 0.45 to
1.3% of what was seen in the blood. The study's presenter,
Chip Schooley, M.D., said that these were " very preliminary
data that we decided to present in light of the early reports
of very high levels of the drug in [the brains of] animals."
Dr. Schooley says that two of these patients were on lower
doses in the study. Also, in contrast to the animal studies
that measured the drug levels in brain tissue at various
timepoints (with the peak occurring five hours post-dosing),
these were measurements of drug concentrations in the CSF at
one timepoint two hours after dosing. Since protease
inhibitors bind to protein, and cerebrospinal fluid has low
levels of protein in relation to brain tissue, it could be
expected that drug levels would be lower in the CSF.
Nevertheless, Dr. Schooley notes that the level of drug that
reaches the brain is " clearly not 170% of what is seen in the
plasma." Even so, he believes that the levels in the brain
may still be adequate to treat the virus. Such antiviral
concentrations were found in the patient with the highest CSF
drug level. This patient also had very high blood levels of
the drug, though.
In a meeting with activists, Glaxo Wellcome detailed its
ongoing and planned studies for 141W94. The present dose-
ranging study is evaluating four other dosing regimens. The
company also is planning dose-ranging studies of 141W94 in
combination with the other protease inhibitors. Pivotal
clinical endpoint studies are slated to begin in the first
quarter of 1997. Activists have been working to convince
Glaxo Wellcome to commit itself to an expanded access program
at roughly the same time.
Ritonavir/Saquinavir
The data from the ongoing study of ritonavir and saquinavir
presented at ICAAC were similar to what was reported at
Vancouver (see the August Treatment Issues, page 5). The
antiviral effect now seems to be increasing with time, and
there also are newly collected six-week data on the more
recently initiated higher doses (abstract LB7b).
The study has enrolled at least 136 patients split into four
groups receiving either 1) 400 mg ritonavir plus 400 mg
saquinavir each twice a day, 2) 600 mg ritonavir plus 400 mg
saquinavir, again, both twice daily, 3) 400 mg ritonavir plus
400 mg saquinavir each three times a day, or 4) 600 mg
ritonavir plus 600 mg saquinavir both twice daily. The mean
baseline viral loads between the arms ranged from 4.29 to
4.72 logs, and CD4 counts were between 278 to 313 at
baseline.
Each arm had a profound effect on viral activity. By week
twelve, doses one and two reduced viral load by 2.74 and 3.06
logs, respectively. Doses three and four dropped viral load
by 2.09 and 2.19 log respectively by week six, which is very
similar to (actually less than) the 2.43 log reduction after
six weeks for group one reported at Vancouver. CD4 cell count
increases for groups one and two at week 12 were 80 to 100
cells, and at six weeks 60 to 70 cells for groups three and
four. None of these differences are statistically
significant.
Circumoral paresthesia (numbness around the mouth and
tongue), nausea, diarrhea and fatigue continue to be the most
common toxicities. Elevated triglyceride levels have been
observed as well, although this has not been associated with
any physical effects. All doses seem to be equally well
tolerated except for the three times daily dosing regimen.
Although the drug-related adverse events do not seem to be
more common on this arm, they may be more severe since they
have led eight people to discontinue treatment (with only
four discontinuing on the other three arms combined).
Other Protease Inhibitors
At least three other companies presented laboratory findings
on protease inhibitors that may be effective against viral
strains resistant to both indinavir and ritonavir. Pharmacia
& Upjohn's compound was scheduled to be in dose-ranging
studies by now, but these trials have been put off for
several weeks because of a temporary shortage of one of the
drug's primary ingredients (abstract I5).
In several ways, the protease inhibitor development programs
at Gilead and Ciba-Geigy share much in common. Each company
has a very potent protease inhibitor poised to enter human
studies that would be much simpler to manufacture and
therefore, one hopes, less expensive than the currently
marketed drugs. It is too bad that these two protease
inhibitors show dramatically reduced activity against virus
that is resistant to ritonavir and indinavir.
Meanwhile, both companies have other compounds, also very
potent and relatively simple to make, that are active against
ritonavir/indinavir resistant virus (abstracts I3 and I5 for
Gilead's compounds, and I6, I7 and I156 for Ciba-Geigy's).
Ciba-Geigy's drug may be the more interesting, as the company
has demonstrated that its protease inhibitor is also active
against virus resistant to saquinavir and 141W94 as well.
Each company realizes the advantage these compounds would
have since there will soon be a large group of people who
have failed or become resistant on the Merck and Abbott
drugs. Both companies would prefer to quickly move these
agents into human studies. The hitch is that in certain
animal studies their drugs seem to be poorly absorbed by the
digestive tract. So for the time being, each company is
slowly proceeding with their first class of protease
inhibitors while trying to quickly solve the bioavailability
problem that limits the potential of the second generation
drugs.
DMP 266
The first data on the activity of a non-nucleoside reverse
transcriptase inhibitor (NNRTI) combined with a protease
inhibitor were presented at ICAAC (abstract LB8a). DuPont
Merck's DMP 266 is a unique NNRTI in that HIV seems slower to
develop resistance to it than to delavirdine or nevirapine.
The study randomized eleven patients to DMP 266 (200 mg a
day) alone and five patients to placebo for two weeks. All
patients were then given indinavir as well for an additional
12 weeks. Baseline mean viral load was 5.1 log (126,000
thousand copies/ml), and the mean CD4 cell count was 249. At
the end of the second week, DMP 266 lowered viral load by
more than 98% (1.68 log) and boosted CD4 cell counts by 96
cells. After the addition of indinavir to DMP 266, viral load
dropped by a mean of 3.2 logs (more than 99.9% and
surprisingly similar to what is seen with
ritonavir/saquinavir).
These results may appear more dramatic than than for other
antiretroviral combinations, but other trials count 400
copies/ml as the minimum viral load. The DMP 266 study
included the less reliable viral load figures that fell below
400. Such a maneuver can have a dramatic effect when you
consider that a reduction to 4 copies/ml is 2 logs greater
than a reduction to 400 copies/ml.
Still, there was a strong trend for the reduction in viral
load to be superior to the reduction seen with indinavir
alone. Eighty percent of those on combination had
" undetectable" viral loads (below 400 copies/ml) at the
combination's peak effect, but by week twelve only 55% were
below the limit of the assay's detection, which still
compared favorably to the 20% below the limit of detection on
indinavir monotherapy. CD4 cell counts jumped by more than
100 from baseline in all patients treated with indinavir.
The most commonly reported adverse events were rash,
headache, dizziness and diarrhea, but none of these events
was severe enough to lead any participant to quit the study.
One potential "adverse event" of DMP 266 was that it lowered
blood plasma levels of indinavir by 37%. This could mean that
the blood levels of indinavir are too low to suppress HIV
over the long term. The added antiviral effect of DMP 266
could counter the reduction in indinavir levels since
resistance can only occur when there is enough residual
replication to allow for it to evolve. The lower levels of
indinavir may also reduce the potential for kidney stones.
Nevertheless, preferring to err on the side of caution, the
study investigators are expanding this study and
investigating higher doses of both drugs.
A few other clinical trials of DMP 266 are currently
enrolling participants. Two are evaluating different doses of
the NNRTI in combination with AZT/3TC. One study will enroll
people with at least two months of experience on AZT/3TC, and
one is for treatment-naive patients. Another opening this
month will compare DMP 266/indinavir/AZT/3TC to
indinavir/AZT/3TC in 330 patients who are naive to DMP 266,
3TC or protease inhibitor and have CD4 cell counts between 50
and 500, with viral loads of at least 20,000. For information
on sites near you, call 800/877-8899.
Nelfinavir Expanded Access Program
On September 16, Agouron Pharmaceuticals opened a program to
provide expanded access to its experimental protease
inhibitor nelfinavir (brand name: Viracept). The program is
open to anyone with HIV and CD4 cells below 50 who is unable
to use any of the three approved protease inhibitors " because
of intolerance, contraindication or prior failure." These
criteria were established with an eye toward limiting
enrollment in the expanded access program to 500 persons per
month, the maximum Agouron says its nelfinavir supply can
accommodate. The entry restrictions may loosen if fewer than
the expected number of people apply. Doctors, health care
providers or patients interested in the program can call
800/621-7111 for further information.
It is not clear how effective nelfinavir may be in people
that harbor virus resistant to ritonavir and/or indinavir.
Most virus that has become resistant to either of these two
is resistant to nelfinavir as well.
Also, taking nelfinavir in combination with another new drug
(or two) offers the best chance of enjoying a sustained
antiviral effect. It is unfortunate that no company has had
the foresight to conduct a drug interaction study with
nelfinavir in combination with delavirdine or nevirapine.
These two newly available drugs usually can be added with
advantage along with nelfinavir to antiviral regimens since
few people have as yet been exposed to them.-TS
Cidofovir Warning
Following new reports of severe kidney damage, Gilead
Sciences, has inserted a black-bordered warning box into the
package insert for its new anti-CMV retinitis drug cidofovir
(brand name: Vistide). The box declares that it is of utmost
importance that clinicians closely follow new guidelines for
safe usage of this drug. Even when the treatment is
discontinued, the product labeling notes elsewhere that the
kidney damage may be permanent. There have been cases in
which kidney dialysis was required to compensate for the
kidney damage. This damage even proved fatal on one occasion.
The drug's usage guidelines now clearly state that cidofovir
should not be used at the same time as other drugs that are
toxic to the kidneys or in patients with impaired kidney
function (as indicated by serum creatinine levels above 1.5
mg/dl, a creatinine clearance of 55 ml/min. or less, or a
urine protein level above or equal to 100 mg/dl). Laboratory
tests for kidney malfunction must be undertaken both before
and 48 hours after starting cidofovir. If cidofovir causes
serum creatinine to rise by more than 0.3 to 0.4 mg/dl over a
patient's pretreatment reading, or if 2+ proteinuria occurs,
the dosage of cidofovir should be reduced. If serum
creatinine increases by more than 0.5 mg/dl, or 3+
proteinuria develops, the patient should be taken off
cidofovir altogether.
In addition to these warnings, the labeling dictates that
people who have been on other kidney-toxic drugs must
terminate those drugs at least a week before starting
cidofovir. (Among such drugs is foscarnet, a drug many people
with CMV retinitis may have used before switching to the only
recently approved cidofovir.) Also, the guidelines mandate
strict adherence to the schedule for administering probenecid
and intravenous hydration on the day of the cidofovir
infusion. To protect the kidneys, two grams of probenecid
must be taken three hours before the cidofovir infusion, one
gram two hours after the infusion and again eight hours that.
Intravenous hydration with one liter saline solution should
take place over a one-to-two hour period immediately before
the cidofovir infusion. If the patient can tolerate a second
liter, it should be infused over a one-to-three hour period,
either in a period overlapping the 60 minute cidofovir
infusion or immediately afterwards.
Although Gilead has gone to great effort to inform clinicians
of the proper usage of cidofovir, sending out letters to over
35,000 HIV-treating physicians, the clarity of the new
guidelines is perhaps overdue. Studies have shown that the
drug can be safely and effectively used, but the close
monitoring that participants in drug trials receive is rare
in general medical practice. When cidofovir was being
considered for approval by the Food and Drug Administration
last summer, many activists were concerned that " in the real
world, patients would not be followed rigorously enough,
resulting in adverse event rates not seen in the cidofovir
trials" -TS
ICAAC's Future Fungal Fighters
by Theo Smart
Although there have been many changes in the treatment of
certain opportunistic infections such as CMV over the last
year, little has changed in the treatment of fungal
infections since the introduction of fluconazole and
itraconazole. At the same time, the rate of azole resistance
has increased dramatically. The central role that these two
azoles play in the treatment of fungal infections and fear
that resistance will develop to the drugs has led a number of
clinicians to be cautious about over using them as
prophylaxis or for mild cases of candidiasis. When azole-
resistant fungal infections crop up, there are few
alternatives available.
The toxicity and inconvenience of amphotericin B make it the
treatment of last resort. Meanwhile, controlled clinical data
on the easier-to-tolerate liposomal formulations of
amphotericin and nystatin have been long awaited. Liposomal
formulations involve surrounding medically active compounds
with tiny fat globules that allow the drugs to reach their
targets with fewer adverse effects on other tissues.
Information on the use of these drugs is beginning to trickle
in (see below), but even if safer, these liposomal compounds
still must be intravenously administered and this limits
their usage to acute infections. But a note of optimism is
emerging: The large number of presentations at ICAAC on new
agents that attack fungi in new ways suggest that the
treatment of fungal infections will undergo major changes
over the next few years.
AmBisome vs. Amphotericin B for Cryptococcal Meningitis
There have been a number of case reports suggesting that
Fujisawa and Vestar's AmBisome can effectively treat
cryptococcal meningitis, even in patients who have failed on
amphotericin B. At ICAAC, Dutch researchers presented the
first placebo-controlled study comparing the two intravenous
treatments (abstract LM35). Twenty-eight volunteers were
randomized to receive three-week induction therapy with
AmBisome (4 mg per kg a day) or amphotericin B (0.75 mg per
kg per day). The median time to clearance of the infection
from the cerebrospinal fluid was 14 days for AmBisome and
more than 21 days for amphotericin B, which was statistically
significant. The median time to improvement of meningitis
symptoms was not significantly different, though.
Amphotericin B was significantly more toxic to the kidneys,
although those on AmBisome did experience some increase in
levels of serum creatinine (greater than 50%). Two patients
on amphotericin B stopped treatment due to toxicity compared
to no discontinuations on AmBisome. The study's presenter,
Dr. Leeanders of the University Hospital in Rotterdam,
concluded that "in a larger study, AmBisome may lead to a
sooner response. [It] is probably the most effective
available treatment for those with cryptococcal meningitis"
AmBisome has yet to be approved in the U.S. even though it
has been marketed in Europe and Mexico for several years.
Fujisawa is now running studies evaluating the drug in
neutropenic patients and in people with HIV and cryptococcal
meningitis.
New Azoles
At least two new azole antifungal drugs similar to
fluconazole and itraconazole have entered into human studies.
Azoles block the spread of the fungi by slowing the synthesis
of sterols needed by the fungus to grow. Voriconizole, made
by Pfizer (abstracts F81-F86) and Schering-Plough's SCH 56592
(abstracts F87-F103) both purportedly are active against
fluconazole-resistant candida, and have dramatically improved
activity against other fungal organisms such as aspergillosis
and histoplasmosis. In light of the history of the azole
drugs, though, it seems likely that with increased use over
time, the new azoles will also demonstrate increased cross-
resistance with fluconazole and itraconazole. For example,
despite early hopes, itraconazole has not proven to be
particularly effective against fluconazole-resistant fungal
infections.
Both voriconazole and SCH 56592 now have been evaluated in
dose-ranging studies. Phase II clinical studies of
voriconazole are complete, although the data are yet to be
released. Three phase III clinical endpoint studies of
voriconazole for invasive aspergillus, serious candida, and
as empiric therapy for invasive fungal infections in
neutropenic patients are anticipated to begin in Europe by
the end of the year, and to expand into the U.S. in the
beginning of 1997.
Meanwhile, Schering-Plough refuses to discuss with Treatment
Issues where or in what population the clinical trials for
SCH 56592 are being conducted, saying only that the oral form
of the drug was in international early phase studies for
" serious systemic infections." The company president and CEO
Richard Kogan, though, has publicly said that the trials
began in April, and that the drug was " orally active" (see
SCRIP June 11, pg. 8).
Pradimicin
Bristol-Myers has a new antifungal, pradimicin, derived from
a bacteria. Some antifungals, such as amphotericin B, kill
fungi by punching holes in the fungal cell wall. Pradimicin
works in a similar way but by binding to sugars in the fungal
cell wall, which disrupts the membrane's integrity. Other
studies previously have reported that this class of compounds
also has both anti-HIV activity and anti-PCP activity.
Unfortunately, these compounds do not appear to be absorbed
orally.
Laboratory and animal studies presented at the conference
documented that pradimicin is active against aspergillosis,
candida and cryptococcus (abstracts F179-F183). Although no
pradimicin-associated toxicity was observed in rabbits or
mice, some possibly drug-related liver enzyme elevations have
been noted in dose-ranging human studies of intravenous
pradimicin. Bristol-Myers currently is reviewing the data
from these early studies before deciding whether to move
ahead with this compound or one of its more than 200 analogs.
The Echinocandins
Two members of a new class of antifungal drugs known as
echinocandins have entered clinical trials. One, L-724,872,
is owned by Merck, and the other, LY303366, by Lilly. As
opposed to the antifungal azoles, which merely block growth
of fungus cultures, echinocandins kill the fungi by
interrupting the synthesis of ß-1,3 glucan, an integral part
of the fungal cell wall. This cell wall component is not
found in mammalian cells, raising the hope that the drug will
prove less toxic than amphotericin B, which can cause
channels to form in the walls of both fungal and mammalian
cells.
In laboratory and animal studies, the echinocandins show
activity against histoplasma, difficult-to-treat
aspergillosis and azole-resistant candida. By themselves, the
echinocandins do not seem to be active against the fungi that
cause cryptococcal meningitis, but one study noted that L-
743,872 was synergistic with amphotericin B and fluconazole
against this disease (abstracts F36, S25).
In one poster at the conference, evaluating the use of L-
743,872 in mice, an echinocandin was shown to have activity
against Pneumocystis carinii during one stage of its life
cycle (abstract F42). It is unclear whether these drugs will
prove useful as a treatment of acute PCP, since they kill
only the cyst form of the parasite (which can be thought of
as the egg) but not the active parasitic form found during
acute infection.
Merck's L-724,872 has been well tolerated in phase I dose-
ranging studies. Unfortunately, the drug is not absorbed
orally and must be given as a once-a-day intravenous
infusion. This requirement will reduce the drug's use in
clinical practice. Currently L-724,872 is in phase II non-
U.S. studies in patients with people with HIV and esophageal
candidiasis.
Lilly's LY303366 is bioavailable when taken orally. A dose-
ranging study reported at the meeting showed that the drug is
very well tolerated, causing mild-to-moderate diarrhea and
abdominal pain only at very high doses (abstract F50). Much
lower doses achieved blood levels of the drug more than
adequate to suppress candida. The drug has a very long half-
life that will allow for once-a-day dosing. Lilly is
currently conducting a dose-ranging study of LY303366 in 160
people with HIV and oral candidiasis.
Other Compounds
The above is just a short list of some of the more advanced
compounds. There were many other compounds in earlier stages
of development. Shaman Pharmaceuticals reported on an
antifungal, Nikkomycin Z, that blocks the synthesis of fungal
chitin, used in making the fungal microorganisms' exoskeletal
structure (abstracts F189 and 190). XOMA Corp. reported on a
synthetic peptide, Mycoprex, that also kills the fungus by
increasing the permeability of the fungal cell wall but that
acts earlier in the fungal lifecycle than amphotericin B
(F185, 186 and 187). Many of these presentations noted
synergy with other available antifungal drugs.
The development of another class of well-tolerated oral
antifungals could ultimately reduce the incidence of azole-
resistance or provide a feasible option for instances when
such resistance arises. There is also the possibility that
antifungal medications could be combined for hard-to-treat
infections. Appropriate drug combinations also could create
less invasive and less toxic induction therapy for conditions
such as cryptococcal meningitis. If a drug also proves active
as a prophylaxis for PCP, it could provide an alternative for
those intolerant to sulfa drugs, or reinforce prophylaxis in
the substantial number of patients with breakthrough
infections on Bactrim/Septra during late-stage disease.
But it is too soon to say whether any of these drugs will be
effective in humans. Further information, no doubt, will be
available at upcoming conferences -- certainly by next year's
ICAAC.
Email
Print-Friendly
Glossary
