Stop the Drugs—
“Hit Hard, Hit Early” Takes a Beating
by Enid Vázquez
True or false: Newly
infected people with HIV are being put on powerful drug therapy
long before they need it.
Answer: Depends on
who you talk to.
In 1996, “hit hard, hit
early” became popular in HIV therapy. Go in with as strong
a drug combination as you can, as early in the disease as
you can. Now, four years later, treatment advocate Carlton
Hogan says, “It’s so out of fashion these days.”
Another longtime treatment advocate, Theo Smart, calls this
the era of “retrenchment.”
No one disputes that strong
drug combinations benefit people with advanced disease. Problem
is, the assumption became that what’s good for people
with AIDS must be good for people with HIV. What looked like
a simple solution—pop some pills—covered up the
difficult realities of side effects and other problems with
HIV treatment—such as, maybe it’s not such a good
idea to rush onto a drug regimen.
“Giving a complex three-drug regimen to
someone who’s not ready to take it is a recipe for
resistance and failure. We’re also plagued by a number
of poorly understood long-term toxicities.”
—Dr. Joel E. Gallant,
Positively Aware Annual HIV Drug Guide, January/February
2000
Wait, wait, wait
Mark Harrington, a leading
HIV treatment advocate, has been saying for years that waiting
a long time to go on drugs can be a good thing. He calls the
reasons to “hit hard and hit early” theoretical.
In a talk last year at the 11th Annual AIDS Update Conference
in San Francisco, Harrington pointed out that there are no
data from randomized controlled trials (which generate the
most scientifically reliable information) showing any clinical
benefit from antiviral therapy in people with T-cell counts
above 350. Of course, the way science operates, such evidence
would take time and trouble to gather. It would be great to
know what happens to one group of people on drugs and one
group of people not on medication, but that study has not
been done, and is not in the works. Such a trial would take
a long time and require large numbers of participants to obtain
scientifically valid answers. The question of viral load (amount
of HIV in the blood) is less clear. Harrington says that at
this time, a reasonable goal is to prevent AIDS from developing
within three years, which might be indicated by having two
consecutive viral loads over 100,000. But he notes that this
concept is based on only one study. At a follow-up talk at
this year’s conference in March, Harrington gave his
audience a new slogan to think about: Hit hard, but only when
you need to.
Harrington had stunned doctors
two years earlier at the World AIDS Conference in Geneva when
in a speech there he announced that he was glad he waited
until he had only 200 T-cells before going on therapy. With
powerful drugs drastically cutting the death rate due to AIDS,
shouldn’t everyone with HIV be put on medicine?
The problem is that the survival
and health benefits were seen in people with advanced disease.
Harrington notes that one of the most frequently cited studies
supporting strong combination therapy showed survival benefits,
but in people who had less than 200 T-cells. More recently,
five observational studies did not find a benefit for groups
starting therapy above 200 T-cells compared to groups starting
below that. AIDS deaths have gone down, but newly infected
people aren’t at risk of dying. Nor have they ever spent
time in a hospital. It’s the medicine that’s making
them sick. Yet, the public perception of the “cocktail”
has developed to the point that even today many newly infected
people are automatically put on medication.
Harrington, who tested positive
in 1990, benefited from all the HIV knowledge gained by the
time his T-cells went down to 200 in 1996. He benefited from
all the mistakes of the past, and that is part of his message.
As he told his audience in Geneva, he bypassed AZT monotherapy,
which was later found to be inferior. Nor did he take AZT
with Videx (ddI), the next therapy down the pike, also later
found to be inferior. On he went, until the best therapy to
that date, triple combination with a protease inhibitor, came
along just when he needed it most.
“There may be no advantage to starting
therapy at a CD4 count above 200, according to a review
of several large cohort studies presented at the British
HIV Association Autumn meeting in London last week.”
“Cohort Evidence
Challenges Conventional Wisdom” by Keith Alcorn, aidsmap.com,
October 20, 1999
In theory…
There are, of course, reasons
behind “hit hard, hit early.” People with HIV hope
to protect their immune system and never progress to AIDS.
There are difficulties with that premise, and the arguments
for hitting early remain theoretical. Harrington lists some
of the main arguments for early therapy and then refutes them.
“Hitting early preserves
immune function.” He says that in general, immune function
is fine until T-cell counts go below 350. There might be some
damage going on, but it’s not threatening to your health,
and it’s not permanent. He also notes that according
to various treatment guidelines, symptoms of disease are also
an important indicator for starting therapy, not just a magic
lab number.
“Hitting early delays
resistance.” Drug resistance usually doesn’t develop
until drug is in the body. Therapy that doesn’t “work”
well according to the goal of achieving undetectable viral
load may actually speed up resistance.
“Hitting early may speed
time to eradication.” Very few people bought into the
idea of eradication. Besides, it was first estimated that
getting rid of HIV in the body would take three to five years
and eradication is now estimated to take 60 to 70 or more
years with current approaches.
“Hitting early preserves
anti-HIV immune function, or anti-HIV CD4 cells.” This
may be true, if someone’s been infected within the past
six months. But even then, the evidence comes from only a
small group of people. Moreover, more recent evidence indicates
that HIV-specific T-cells are found throughout chronic infection,
but decline when using HAART.
What if you wait? Harrington
notes that “impressive” immune restoration has been
seen in people who started therapy quite late in their disease.
Waiting until you reach 350 T-cells, he suggests, does not
cause irreversible immune system damage or disease. The recently
updated (February 2000) treatment guidelines from the International
AIDS Society (IAS-USA), along with the British, French and
Brazilian guidelines, all suggest 350 T-cells for starting
therapy.
There’s nothing wrong
with these theories, until people suffer for them. In HIV,
the problems of side effects and adherence were underestimated.
Sick people got better, but healthy people got sick. For them,
the effects of the drugs on the body and mind were a big price
to pay. Side effects (including disfigurements) deteriorate
quality of life, a problem that many healthcare providers
didn’t care anything about. In addition, people sickened
and sometimes died as a result of the side effects, not the
disease itself. Doctors’ answering services were often
unhelpful, and many times doctors didn’t respond to desperate
calls from patients, or responded weakly. Then, too, taking
pills every day for a serious disease creates a severe psychological
burden, sometimes leading to the inability to take the drugs.
Moreover, the many drug combinations themselves often had
rigid requirements that were hard to adhere to.
For example, for a while the
gold standard of care was a three-drug regimen that included
a protease inhibitor, Crixivan (indinavir), which had to be
taken every eight hours sharp. That was just too easy to forget.
Plus it had to be taken without food and with lots and lots
of water throughout the day. Few people could comply, and
excruciatingly painful kidney stones were common.
Yet adherence rates, for all
the combinations, need to be higher than adherence for any
other disease. Last year, researchers reported that if HIV
drugs are not taken correctly 95% of the time, drug resistance
(and treatment failure) usually results. In other diseases,
80% adherence is usually all right.
Research also continues to
show that healthcare providers accidentally exposed to HIV
are unable to take an HIV drug combination correctly for one
month (the amount of time thought to prevent infection). The
majority fail to do so. These findings give a clue to what
people with HIV must put up with. Other researchers found
that adherence in HIV goes down more and more with each passing
year.
When drugs start to fail people
(according to the treatment standard of having undetectable
virus in the blood), a switch is needed to another drug regimen
and options soon begin running out. Estimates of treatment
“failure” range from 20 to 60% of all people on
the therapies. (Viral load is one measure of treatment effect,
and people with detectable viral load could still benefit
from therapy when looking at other measures.)
“There is a trend to
more doctors treating to preserve CD4 at this point, rather
than to keep viral load undetectable at all costs, says Harrington.
“The pendulum is swinging.”
“If you go to a doctor, you’re probably
going to be put on drugs. And if you’re not ready,
maybe you shouldn’t be on them. People come in here
all the time and they’ll say, ‘Oh, I stopped taking
all of that.’ The doctors didn’t explain the medicines
and the side effects.”
—Joe McCue, support
group facilitator,
Test Positive Aware Network
(publisher of Positively Aware), Chicago
Disgruntled genius
Ironically, Harrington is
part of the group of advocates who persuaded the Food and
Drug Administration (FDA) to speed up the drug approval process
so that people with HIV could get medicines faster. Part of
the recognition he received for his role in that struggle
came in a “genius” award from the MacArthur Foundation,
with a $240,000 check attached.
“We wanted drugs available,”
he says of the struggle for accelerated approval. “It
doesn’t mean we wanted everyone to take them. It just
means they should be taken by people who need them.”
Accelerated approval essentially puts drugs that are still
experimental out on the market. They have been found to be
safe and effective, but have not completed the full approval
process of the FDA.
It’s also ironic that
he criticizes the HIV treatment guidelines of the U.S. Department
of Health and Human Services (HHS), since he’s a member
of the panel of experts that puts those guidelines together
(they’re not unanimous opinions). But, he points out
that even though the thick document states many times that
the decision to start therapy is a highly individual choice,
doctors instead simply focus on the chart listing the best
drug combinations to take. The guidelines are just that, guidelines,
created to help doctors and people with HIV understand the
latest knowledge around treatment, since there is no standard
of care for the disease.
“While the guidelines represent the current
state of knowledge regarding the use of antiretroviral agents,
this is a rapidly evolving field of science, and the availability
of new agents or new clinical data regarding the use of
existing [drugs] will result in changes in therapeutic options
and preferences… Although there is theoretical benefit
to treatment for patients with CD4+ T-cells greater than
500, no long term clinical benefit of treatment has yet
been demonstrated.”
HHS Guidelines for the
Use of Antiretroviral Agents in HIV-Infected Adults and
Adolescents,
January 28, 2000 (latest update)
In a perfect world
If HIV medications were perfect,
there would be no problem. Doctors, who used to watch hopelessly
as their HIV patients got sick and died, were happy to see
all that change with potent drugs. Today treatment advocates
continue to press for early access to experimental drugs.
Many of them are themselves waiting for a new drug, a new
hope. But the severe problems with current treatments are
clear. Many prominent HIV specialists have expressed frustration
with the regimens. Even the ones who advocate hitting hard
and early have trouble getting around the side effects issue,
when the long-term results of treatment are still unknown.
Understanding of HIV and the
immune system is continuously growing. What’s important
today may tomorrow be only a small part of the picture. As
always, waiting to go on medications can preserve future options,
with its promise of new and better therapies. That’s
not a new theory, but maybe it’s one that didn’t
get enough weight. In HIV, people who are newly diagnosed
often have no clue what’s in store for them when they
start therapy. There’s only one thing that’s for
sure for all positive people whether they’re on therapy
or not: see a specialist and monitor closely.
“My take-home message is, There’s
nothing wrong with hitting HIV ‘hard’ when it’s
the right time. But, until we have evidence from randomized
studies, there’s no reason not to let the immune system
control the virus until CD4 drops below 350.”
—Mark Harrington
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