Being Alive 1995 Mar 5: 1
The Second National Human Retroviral Conference, sponsored by
the American Society of Microbiology in collaboration with
the National Institutes of Health and the Centers for Disease
Control, was held in Washington, DC, late in January. The
importance of this conference for HIV/AIDS researchers has
grown, now that the International Conference on AIDS is being
held every other year (the next is scheduled for the summer
of 1996 in Vancouver). The National Conference provides an
annual forum for a clinically oriented review of the latest
in HIV/AIDS research, and over two thousand participants were
on hand in Washington.
As at past conferences, the epidemiological data presented
provide little reason for optimism. Contrary to popular
belief, the AIDS epidemic is not leveling off. Today, in the
US, AIDS is the leading killer of men and women between the
ages of 25 and 44. And even as the epidemic grows, it appears
that recent political changes may result in a curtailment of
funding for fighting the epidemic. People at the conference
were concerned about cutbacks in research funding, as well as
reductions to the Ryan White Care Act funds. Many did not
consider AIDS to be a partisan issue, but the current
political climate in Washington seems to be making it one.
Along with the pessimism about the extent of the epidemic and
about the current political situation in the US, there was
also optimism about where we now stand in fighting HIV
disease. Indeed, some participants reported that such
optimism had not been seen since the approval of AZT in 1987.
This optimism is based on breakthrough thinking about how HIV
works in the human body, the importance and increasing
availability of viral load tests, and the reasonably good
news about the effectiveness of the protease inhibitors as
monotherapy and 3TC in combination therapy.
The conference began with a presentation by Dr. David Ho on
his recently published research on how HIV works in the human
body (see Walt Senterfitt's report on page 3 for more
complete information). HIV works fast in the human body,
creating some 110 million viral particles each day. In
response, the body's immune system also works fast, producing
some two billion CD4 cells every day. This dynamic continues
throughout infection. Thus, there is a war going on between
the immune system and HIV from day one of infection. And the
body might be called the "best antiviral," because for a
number of years it does a good job of controlling the virus.
At some point, however, HIV gets the upper hand and the
response of the immune system becomes inadequate.
The Leukemia Model
This new understanding of HIV dynamics has implications for
treatment of HIV disease. Some researchers point to how
leukemia is treated as a possible model. When a person is
diagnosed with leukemia, he or she is immediately and
aggressively treated with chemotherapy. A medical provider
would not tell a leukemia patient to wait until symptoms
appear before treating the disease.
Now that we understand that there is no "latency" period for
HIV, researchers are questioning the wisdom of waiting until
T-cells drop or symptoms appear to begin antiviral therapy.
They look to the leukemia model of "hitting hard and hitting
early" as the way to effectively treat HIV disease. The
theory is that such early and aggressive treatment might
suppress viral activity for a long time. When viral load
again goes up, as measured by the new viral load test, other
drugs could be tried to again suppress viral activity.
The problem with this theory is the reality of current drug
availability. We don't yet have the drugs to do the long term
job effectively. Yes, we should start early, but the effects
of the current generation of antivirals don't last long. And
would this leave the patient resistant to antivirals in late
stage disease? At the moment, early antiviral intervention
remains practically if not theoretically problematic.
Viral Load Tests
We now have tests that measure the amount of virus in the
blood. These tests do this by measuring the amount of HIV
genetic material or viral RNA. The two currently available
viral load tests are Q-PCR, developed by Roche, and b-DNA,
developed by Chiron. These tests are not yet FDA-approved and
are not yet widely available. Nonetheless, their development
is very important in research, as well as in treatment.
Up to this time, we have used changes in CD4 count as a
measure of a drug's effectiveness in slowing viral activity.
CD4 count, however, is a surrogate marker. It does not
directly measure viral activity, but rather tells us the
effect of that activity on the immune system. If the CD4
count stays level or rises, we assume that less virus is
being produced. Viral load tests, however, measure virus
directly. They tell us how much virus is in the blood stream
at a given time.
The widespread commercial use of these tests will allow
physicians and patients to make better informed decisions
about when to start antivirals, when to change antivirals,
and when to start prophylaxis for opportunistic infections.
T-cell counts, to some degree, are useful for determining
when OI prophylaxis is called for, but they don't tell us
enough for decisions about antivirals. For that, we need to
know what the virus is doing. For people with over 200
T-cells, it is often difficult to determine if antiviral
therapy is called for; viral load tests will give these
people a much clearer picture of the state of their HIV
disease. And changes in viral load can tell us quickly
whether an antiviral (or a combination of antivirals) is
working for the individual. This means not only quicker drug
development, but also more individualized antiviral regimens.
Providers will be better able to tell what works for an
individual and what does not. Viral load has predictive
value; it correlates with the stage of HIV infection. The
less virus measured in an individual, the less chance that
individual has of getting sick. Conversely, the higher the
viral load the shorter will be the time to clinical symptoms.
Both the Q-PCR and b-DNA express their results in terms of
how many genetic copies of HIV are found in a milliliter of
blood. A "low" value would be less than 10,000 copies per ml;
a "high" value would be more than 100,000 copies per ml. As
with CD4 counts, one test is not the full story; one needs to
look at the trend over time.
The AIDS Research Consortium of Atlanta (ARCA) reported on a
study of over 5000 people treated in Atlanta over the past
few years. The group was broken down into those who only took
one antiviral (monotherapy), those who took one drug and then
switched to another (sequential monotherapy), and those who
took two or more antivirals at the same time (combination
therapy). The researchers found that the sequential
monotherapy group had a 21% survival advantage over the
monotherapy group; the combination therapy group had a 43%
survival advantage over the monotherapy group. The
researchers conclude that adding a second drug has a clear
advantage over switching from one drug to another.
In some research circles, combination therapy is now looked
upon as the optimal approach to treating HIV. These
researchers believe that one should start out with a
combination of antivirals; they see no point in the
Update on AZT Plus 3TC
Two US studies of AZT plus 3TC confirm the antiviral efficacy
reported by a French study and by a German study last fall
(and covered at length in last month's Newsletter). One
multicenter study compared AZT alone to 3TC alone to a
combination of the two drugs. Everyone in this study started
with a CD4 count between 200 and 500. All participants had no
prior AZT therapy. At 24 weeks, those on the combination had
greater drops in viral load than those usingmonotherapy, as
well as higher increases in CD4 count. In comparing the two
monotherapies, 3TC alone appeared to have some benefit over
AZT alone in terms of reduced viral load and increased CD4
count. Researchers report that CD4 and viral load differences
are holding steady after 52 weeks of treatment.
The second US study compared two different doses of AZT plus
3TC to AZT plus ddC. All participants were on combination
therapy. The starting CD4 counts for this study were between
100 and 300, and everyone had been taking AZT for at least
two years prior to the study. The results were less clear
than those seen in the French, German and other American
studies. The high dose combination of AZT/3TC was somewhat
more effective in reducing viral load than the low dose
combination. The AZT/ddC combination was equally effective as
the low dose AZT/3TC combination in lowering viral load.
After 24 weeks, both the AZT/3TC groups showed a mean CD4
cell increase (32 for low dose and 15 for high dose), while
the AZT/ddC group had a mean CD4 cell decrease of 15.
What continues to impress researchers is the durability of
the antiviral effect offered by the AZT/3TC combination. The
response at 48 weeks is greater, both in terms of decreased
viral load and increased CD4 count, than has been seen with
any other antiviral therapy. And 3TC does not appear to have
significant side effects associated with its use.
Protease Inhibitor Update
Protease inhibitors continue to show more promise than
fulfillment. The promise is that we will at long last have an
antiviral that works at a point in the HIV life cycle that is
different from AZT, ddI, ddC and the like. The currently
available antivirals are all reverse transcriptase inhibitors
and only work in "virgin" cells, i.e. cells that have not yet
been infected with HIV. Protease inhibitors, on the other
hand, work in chronically infected cells, cells already
infected by the virus. The long range hope is that protease
and reverse transcriptase inhibitors in combination will
truly be able to fight off HIV by stopping viral replication
in both acutely and chronically infected cells. Some refer to
this as "stomping out fires" wherever they are found.
Today we are still at the point of small dose-ranging studies
of a number of protease inhibitors. Merck's L-735,524 and
Hoffman-LaRoche's saquinavir both appear to work best at the
higher doses studied. Both show promise of being potent
antivirals. Some believe that Abbott's ABT-538 may be the
most potent of all. In a twelve week dose-ranging study, CD4
counts more than doubled at all doses tested; researchers
also noted equally impressive reductions in viral loads. The
optimal dose of ABT-538 has been set at 600 mg/day for future
To date, the protease inhibitors appear to be well tolerated.
Relative few side effects were reported in the early studies
of L-735 and saquinivir. Some diarrhea, headaches and nausea
were reported in the ABT-538 studies. The problem with the
protease inhibitors, as we have seen with other antivirals,
is the rapid development of viral resistance to the drug.
This is why higher doses of the drug were needed in the
dose-ranging studies. At the lower doses, rapid resistance
rendered the drug ineffective.
Researchers have also noted some cross resistance with
protease inhibitors. If a person is resistant to L-735,
he/she will also be resistant to AB-538. Such cross
resistance has not been seen with the reverse transcriptase
inhibitors. That is why RT inhibitors seem to be more
effective in combination. Current research suggests that this
may not be true for protease inhibitors.
Hoffman-LaRoche is currently planning to study saquinivir in
combination with other, non-protease inhibitor antivirals to
see if resistance can be stopped or delayed. Researchers also
hope that combinations with other antivirals will allow for
lower doses of protease inhibitors. Because of the cross
resistance problems, combination studies must proceed with
great caution so as not to induce even faster resistance.
The other problem with protease inhibitors is that they are
not easily absorbed by the body. Their bioavailability is low
and thus a high dose is required. Agouron has developed a
protease inhibitor, AG1343, that has bioavailability as high
as 80%. The promise of high concentration in the blood could
result in reduced viral resistance. AG1343 has not shown
cross resistance to the other protease inhibitors in the test
tube. Other test tube studies show AZT and AG1343 working
well together and enhancing each other's antiviral activity.
Human studies of AG1343 are currently in the planning stage.
The promise of protease inhibitors is a more effective
antiviral, but significant problems in fulfilling that
promise still remain to be resolved. Researchers expect that
there will be different generations of protease inhibitors.
The first generation may receive FDA approval sometime late
this year or early next year.
New Formulations of Ganciclovir
The oral form of ganciclovir was recently approved by the FDA
as maintenance therapy for CMV disease (see R. Scott Hitt's
article on page 6). This form of ganciclovir also has
potential as prophylaxis for this opportunistic infection. At
the conference, researchers reported on a study that compared
1000 mg of oral ganciclovir a day to a placebo. To be
eligible for this study, a person needed to have less than
100 T-cells and an AIDS-defining OI (other than CMV) or less
than 50 T-cells. As it happened, the average T-cell count of
the study group was less than 25. During the course of the
study, 24% of those on ganciclovir had a CMV event, and the
time to the first event was 270 days. In contrast, during the
same period, 47% of those on placebo had a CMV event, and the
time to first event was 240 days. Researchers did not find a
survival benefit, but did note that the drug was relatively
This study shows, as other early studies have, that
prophylaxis with oral ganciclovir can cut the incidence of
CMV almost in half. There are, however, some problems. About
2% of the study participants became resistant to the drug.
And some researchers are concerned that prophylactic use of
ganciclovir may increase ganciclovir resistant strains of
The other new form of ganciclovir is implants,
peppercorn-size pellets that hold 6 mg of ganciclovir. These
pellets are surgically placed directly into the eye, and the
drug is then released over time to fight CMV retinitis, one
of the terrible scourges of late-stage HIV disease.
Researchers argue that such an approach ensures that the drug
gets where it is needed, and thus offers superior therapy to
the current standard treatment of IV ganciclovir or
In a study of over one hundred patients with CMV retinitis,
the two treatments were compared. Those that received
ganciclovir implants had a median time to disease progression
of 190 days, while those receiving IV ganciclovir had a
median time to progression of only 72 days. However, the
occurrence of CMV in other parts of the body was less common
for those on IV ganciclovir.
Side effects of the implants centered on post-operative
complications; about 10% had a problem with retinal
detachment and some 8% experienced hemorrhaging in the
Clearly, there are serious risk/benefit issues when
considering ganciclovir implants. The studies do show greater
efficacy in fighting off CMV retinitis. On the other hand,
there is greater risk of developing CMV elsewhere in the
body, since the drug is not being taken systemically. High
dose IV ganciclovir does have toxicities and these appear to
be avoided with the use of the implants. Finally, without the
central line required for IV ganciclovir, there is decreased
risk of bacterial infection and increased quality of life.
Treatment for Microsporidiosis
Microsporidiosis is one of the causes of HIV-related
diarrhea, and, to date, there has not been an effective
treatment. At the conference, the CDC reported on a small
(eight patient) study that used Mepron as treatment for
microsporidiosis. Mepron, as you may know, is approved as a
second-line treatment for PCP. In this study, participants
saw reduced diarrhea after two weeks of therapy with Mepron.
Study participants also reported an average weight gain of
(The main source of information for this article was the
February 27 panel discussion, co-sponsored by Being Alive and
LA Shanti. Panel participants were Mark Katz, MD, R. Scott
Hitt, MD, David Hardy, MD, and Peter George. Additional
information was taken from Martin Majchrowicz's report in the
March 1995 issue of Positive Living and Mark Mascolini's
report in the March/April 1995 issue of Positively Aware.)