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HIV
Treatment Series part four of four
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sponsored in part by
an unrestricted grant from
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Decisions, Decisions—Starting
or switching
anti-HIV therapy
by Steve McGuire
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Although 18 approved medications
are now available to treat HIV infection, the process of deciding
how best to use them has become complex. Making decisions
about whether or when to start HIV treatment—and which drug
combinations will work best for you—presents complex challenges
for both a person living with HIV and health care providers.
Because there is now so much information to absorb and interpret,
communication and an open mind will be the keys to a successful
treatment regimen. A critical first step is to learn all that
you can about the antiretroviral (ARV) drugs that are available
today, and even about the ones that are likely to gain FDA
approval in the near future.
Another important lesson
to learn early on is that there is no cookie-cutter approach
to selecting an ARV regimen. In other words, there is no right
or wrong approach; you and your physician together need to
select the treatment that will work best for you as an individual.
Two key factors will help determine when to start therapy
and which medications to use:
- Your physical health—meaning
your viral load (VL), T-cell count, how you feel, and any
conditions besides HIV
- Your willingness and ability
to take all of your HIV medications according to the instructions
provided by your doctor and pharmacist
Routine blood tests for your
viral load and T-cell count can help determine how healthy
your immune system is and when you should start or switch
therapy. The T-cell count may be the most critical factor
to consider in deciding when to start treatment, because it
provides a strong indication of how much damage HIV has caused
to the immune system.
Viral load plays a less critical
role in deciding when to start treatment, but it can still
provide vital information for some people who have not yet
started treatment. For example, if your T-cell count is 250
and your viral load is over 100,000, your T-cell count could
fall below 200 before it is measured again three to six months
later. This is because the higher a person’s viral load is,
the faster the T-cell count is likely to decline. A high viral
load could mean that the T-cell count will continue downward
and should be playing a role in deciding whether to start
treatment.
Official guidelines
Two major medical organizations
regularly issue treatment guidelines that make general recommendations
about when people living with HIV should start or switch anti-HIV
therapy. One is the federal agency that is responsible for
setting U.S. health-related policies, National Institutes
of Health (www.aidsinfo.nih.gov/guidelines/).
The other is an association of leading professionals specializing
in HIV research and treatment, the International AIDS Society–USA
(IAS-USA, www.iasusa.org/pub/index.html).
The two sets of guidelines
make somewhat different recommendations about when to start
ARV therapy. However, both guidelines strongly urge therapy
for people who have AIDS-related symptoms or a T-cell count
between 200 and 350. Reseach indicates that individuals who
begin ARV treatment after their T-cell counts have fallen
below 200 may experience a less successful treatment course
than those who begin when their T-cell counts are higher than
200.
A matter that is still controversial
is whether to start ARV therapy “early,” which currently is
considered to be having a T-cell count higher than 350. Some
experts prefer to start therapy early, before the T-cell count
shows that the immune system has been seriously compromised.
Others believe that starting therapy early will not produce
better results and that therapy should wait until the T-cell
count has fallen below 350, though not below 200.
Getting started
Once you and your doctor
have decided that it is time to start therapy, you’ll need
to make equally difficult decisions about what combination
of medications will work best for you. Both the IAS-USA and
the federal guidelines agree that, whatever initial ARV regimen
you decide on, therapy should aim to decrease viral load to
the lowest level possible—that is, undetectable as determined
by viral load testing—for as long as possible. This means
that you should select the strongest ARV drug combination
that suits your clinical condition and lifestyle needs.
Besides T-cell count and
VL, certain non-HIV issues play important roles in determining
an ARV regimen that will be effective and that you can adhere
to over the long haul. Be sure to discuss with your health
care provider:
- Any dietary restrictions
- Limitations related to your daily
routine (work, school, children, and so on)
- Your support system of family
and friends
- Other medications you need to
take
- Financial barriers
An ARV drug regimen should
consist of at least three drugs, usually from at least two
of the four different classes of ARV drugs:
- Protease inhibitors (PIs)
- Nucleoside/nucleotide reverse
transcriptase inhibitors (NRTIs)
- Non-nucleoside reverse transcriptase
inhibitors (NNRTIs)
- Fusion inhibitors
Above all, it is important
that you understand exactly how and when you should take the
combination of drugs you select. Here are some key questions
that you should clarify with your physician:
- Should you take your pills with
food or on an empty stomach?
- How many times a day should you
take each drug?
- What should you do if you miss
a dose?
- What should you do if you don’t
feel well when starting therapy?
Make sure you know the answers
to these questions before starting your regimen. Fortunately,
ARV regimens do not have to be difficult to take. For example,
some HIV drugs need to be taken only once a day, and at least
one combination involves taking just three pills, once a day
(Viread, Videx-EC, and Sustiva).
What to expect after starting
treatment
After a person begins anti-HIV
therapy, his or her viral load (VL) should drop dramatically.
After two weeks of treatment, VL typically drops at least
90%. For example, a starting VL of 100,000 should drop to
10,000 or less within two weeks. (By the eighth week, the
viral load should have dropped even more, with the goal being
to go below the level of the viral load test’s ability to
detect any viral particles. That is, the VL should become
undetectable.) For someone with a very high viral load, up
to 16 weeks may pass before the VL becomes undetectable. Many
physicians still use the VL test in which undetectable means
fewer than 400 copies of HIV. However, more and more doctors
prefer to use the ultrasensitive tests that can detect as
few as 50, or even 20, copies. In many, if not most, cases,
the T-cell count will likely increase by 100–200 cells during
the first 12 to 18 months of treatment.
To make sure your VL remains
undetectable, you will need to visit your doctor’s office
every three to six months to have it checked. An increase
in VL during ARV treatment could mean that drug resistance
has developed. You should also be sure that your doctor’s
lab always uses the same type of VL test. This is because
there are two different types of test, and test results from
the different types should not be compared directly. Even
when the same type of test is used regularly, you and your
doctor need to interpret any changes in VL. The VL needs to
change by at least a factor of three (3 times) before the
change is considered meaningful. For example, an increase
from 10,000 to 25,000 copies may be due only to the sensitivity
of the test and may not reflect an actual change in viral
load. A T-cell count should also be performed at the same
time as the VL test.
Even if you are not due to
have another set of lab tests done, do not hesitate to discuss
with your provider any problems that you are having with your
ARV regimen. If you find that you have trouble taking every
dose on time or are experiencing side effects, you and your
doctor may be able to find a different combination that is
easier to take or has fewer side effects. Doing this sooner
rather than later is crucial. Having a regimen that you can
adhere to for the long run will help the treatment work best.
Strict adherence to your treatment regimen will mean that
resistance will take a longer time to develop and you won’t
have to consider new treatment regimens so soon.
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When a regimen fails
In spite of best efforts
to adhere to an HIV treatment regimen, nearly everyone with
HIV will at some point need to switch to a different regimen.
This can happen for several reasons:
- Viral load begins to climb
- The T-cell count consistently declines
- HIV-related illness occurs
- Side effects worsen
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Occurrence of any of these
developments is called “treatment failure,” which is a more
harsh-sounding term that it really is. Treatment failure basically
means that the anti-HIV drugs you are currently taking are
no longer doing what they should. The key tool for determining
whether treatment failure has occurred is a VL test to check
for the amount of virus in your blood. If your viral load
does not decrease significantly and stay down while you are
using highly active antiretroviral therapy (HAART), your T-cell
count could decrease and you could be at risk for symptoms
of HIV disease progression.
If any of the following occurs,
your ARV treatment may not be working the way it should:
- If your viral load does not decrease
by 90% within eight weeks after starting therapy.
- If your viral load does not become
undetectable within 16 weeks after starting HAART.
- If a VL that had been undetectable
becomes detectable, the test should be done again. This
is to be sure that the increase was not due to an error
or is not just a temporary blip. If the second test confirms
the results of the first, you should discuss with your doctor
whether you need to consider switching therapies.
- If your viral load increases
significantly, most specialists would recommend a change
in treatment. This is because a VL that is increasing while
you stick with the same regimen can mean that your HIV is
becoming increasingly resistant.
- If your T-cell count drops significantly
or if it drops continuously, your ARV therapy may not be
working well enough.
HIV can stop responding to
HAART for a number of reasons, but the good news is that you
and your health care provider can control some of these:
- For some people with high viral
loads before starting therapy—for example, more than 1 million
copies—VL may not become undetectable using a three-drug
combination. Some specialists prescribe four or more drugs
to control very high viral loads.
- Poor drug absorption can also
lead to treatment failure. Absorption refers to the amount
of drug that is absorbed into the bloodstream after being
swallowed or injected. Regular vomiting or diarrhea due
to ARV medications or other reasons may affect the amount
of drug that remains in the system to get absorbed. Not
following dietary requirements carefully can also affect
the amount of drug that is absorbed by the body. Some drugs
must be taken either on an empty stomach or with food. Be
sure to ask your doctor to explain any food or liquid restrictions
required for each drug in your regimen—and discuss any nausea,
vomiting, or diarrhea you are experiencing.
- Drug-drug interactions can affect
the levels of drug in the body. This can prevent the drug
from working well enough or can cause adverse reaction.
Drug interactions can occur from ARV drugs in combination
with other medications you may be taking—such as, painkillers,
antifungal drugs, birth-control pills, or antibiotics. Tell
your doctor about all medications you are taking—both prescription
and over-the-counter—before starting ARV therapy, and from
then on.
- Not adhering exactly to the directions
for taking each drug in your regimen can be a major cause
of the ineffectiveness of ARV drugs. However, this is one
problem over which you can have a lot of control. If you
are missing doses of your anti-HIV drugs or do not clearly
understand how you need to take them, discuss this with
your doctor immediately.
- Drug resistance—which refers
to the tiny changes, or mutations, in HIV’s genetic structure
that can make the virus less sensitive to ARV drugs—is one
of the most common and serious reasons for treatment failure.
Some of the things that can contribute to the development
of drug resistance include the factors listed above, so
understanding what resistance is and how it can be avoided
is important.
Dealing with side effects
If you started HAART recently
and are experiencing a major side effect, like serious or
persistent diarrhea, feel free to talk with your doctor about
switching the drug that is causing the problem for one that
offers the same strength but with fewer or more tolerable
side effects. Your health care provider may also suggest things
you can do to help control problems like diarrhea, without
having to switch to a different HIV medication.
Of course, people who have
been taking HAART for some time and have an undetectable viral
load can also experience serious side effects. Perhaps the
best-known example of this is lipodystrophy, which many researchers
believe is due at least in part to ARV therapy. Lipodystrophy
refers to body-shape changes and increased levels of fats
(triglycerides and cholesterol) and sugar in the blood.
Furthermore, high cholesterol
or triglycerides in an HIV-positive person can be treated
according to the guidelines for the general population published
by the National Cholesterol Education Project (www.nhlbi.nih.gov/about/ncep/index.htm).
Be sure to discuss with your doctor any changes in body shape
that you feel you are experiencing—and make sure to have a
regular blood lipid screening performed.
Dealing with resistance
problems
The primary reason that HIV
becomes resistant is the mistakes that the virus makes as
it replicates. Because HIV replicates very rapidly, it makes
many mistakes, leading to mutations in the virus’s genetic
code. These mutations then cause anti-HIV medications to work
less and less well. Therefore, holding down replication is
the key to limiting the development of resistance.
A number of HIV mutations
caused by treatment with one drug can cause your HIV to become
resistant to other drugs in the same class as the one that
led to that particular mutation. This is called cross-resistance,
and it poses one of the biggest hurdles in switching ARV regimens.
Cross-resistance is most difficult among PIs and NNRTIs. For
example, if your HIV has become resistant to Sustiva (efavirenz),
it is likely also fairly resistant to Viramune (nevirapine).
Resistance tests
Both the federal and IAS-USA
guidelines support the use of drug-resistance testing in these
situations:
- When viral load becomes detectable
(to more than 1,000 copies) while on ARV therapy
- When VL fails to become undetectable
within about 16 weeks of starting a new ARV regimen
Not all insurance companies,
Medicaid programs, and other third-party payers cover the
high costs of resistance tests. This may eventually change,
because both guidelines now officially recommend using them.
If your viral load is increasing while on therapy, ask your
doctor about having an HIV drug-resistance test. If your doctor
can prove that it is medically necessary, your third-party
payer may agree to cover the cost.
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Deciding what to switch
to
Like figuring out when to
start therapy and what drugs to start with, deciding when
to switch therapies and what drugs to switch to is a complex
process. The choices of ARV regimens available to you will
depend on which drugs you are now taking and those you have
used in the past. This is because of the resistance patterns
that your HIV might have developed to either specific drugs
or whole classes of drugs.
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You and your physician should
consider the following federal guidelines when selecting a
different treatment regimen:
- If your viral load becomes detectable
while taking your current ARV drug regimen, you should have
a second VL test to confirm the results. A VL can show a
one-time blip that will disappear with a second test.
- In most cases, just switching
one drug or just adding one drug to a failing regimen is
not advisable. The best approach is to use at least two
new drugs or, preferably, an entirely new combination. If
a drug-resistance test shows that your HIV is resistant
to only one drug in your regimen, it may be possible to
replace only that drug.
- Among the PIs, avoid switching
from Norvir (ritonavir) to Crixivan (indinavir) or vice
versa, as high-level cross-resistance is likely.
- Among the NNRTIs, switching from
one NNRTI (like Sustiva) to another (like Viramune) to control
viral load is not likely to work because of cross-resistance
between the two.
Salvage treatment
People who have extensive
treatment experience—meaning they have used most of the approved
HIV medications—have special problems in switching ARV regimens.
Treatment strategies for such individuals are often referred
to as salvage therapy.
One possible approach is
to “recycle” drugs that you have used in previous ARV regimens.
Drugs that you stopped using for reasons other than development
of resistance (due, for example, to side effects) may be the
best candidates for recycling. Recycling drugs to which you
are resistant is much less likely to help. Before doing so,
discuss with your doctor the possibility of performing an
appropriate resistance test to see if you may be able to recycle
any of the drugs you have used before. If you and your doctor
agree on a combination of drugs to which your HIV has only
low-level resistance, this type of salvage treatment may be
able to reduce your VL to a low level again.
Another option is “mega-HAART,”
a strategy that uses a combination of up to nine anti-HIV
drugs. The idea behind this approach is that, no matter how
many drugs and drug combinations a person has taken, the virus
in his or her body is not likely to be resistant to all of
the drugs in such a complex regimen. Of course, adherence
and side effects will pose serious difficulties with this
strategy.
Treatment intensification
Treatment intensification
is another form of salvage therapy. Intensification means
adding one or two additional drugs to an existing regimen.
It does not mean increasing the dose of any of the drugs in
your regimen. This might be an option for people who are unable
to achieve an undetectable viral load within four to six months
after starting therapy. Intensification may also work for
someone who has been on HAART with an undetectable VL, but
whose VL has recently become detectable again.
To intensify a regimen, your
doctor can prescribe a fourth anti-HIV drug, often the protease
inhibitor Norvir (ritonavir). Although ritonavir can have
undesirable interactions with a number of other medications,
it can also raise the blood levels of other PIs and some NNRTIs.
These increased levels can help put additional pressure on
the virus, with the goal of reducing it to an undetectable
level.
Continuing with a “failing”
regimen
Sometimes people on HAART
may experience a VL that becomes detectable, while their T-cell
counts remain relatively high or even increase. If you are
in this situation, your provider may recommend continuing
on your current regimen, particularly if you have already
used most of the available anti-HIV drugs. This strategy may
be most appropriate for those with a high T-cell count and
no symptoms of HIV progression. Other specialists feel that
continuing on a failing regimen, with an increasing viral
load, could cause your HIV to become even more resistant to
other drugs, even ones that have not yet been approved.
New developments
Some newly approved HIV medications
and others that are expected to be approved this year should
offer improved treatment choices for many HIV-positive people,
both those deciding when to start therapy and those needing
to switch ARV regimens:
- Zerit XR:
This once-a-day extended-release formulation of Zerit received
FDA approval early this year.
- Fuzeon:
This first drug in the new class of ARV treatments known
as fusion inhibitors was approved by the FDA in early March.
- Atazanavir:
By the middle of 2003, most observers expect this protease
inhibitor to be approved. One expected advantage is that
atazanavir does not cause adverse effects in blood lipids.
- fos-Amprenavir (908):
A reformulated version of this protease inhibitor will likely
receive approval later this year. (see “A
Different Class”)
Helping to chart your
treatment course
HIV treatment will probably
never become a truly simple matter. However, you can take
a number of measures to help direct the course and success
of your HIV treatment:
- Learn as much as you can about
current and future HIV treatments and how they work.
- Communicate openly and regularly
with all your health care providers and your personal support
network.
- Do all that you can to adhere
strictly to the requirements of your anti-HIV treatment
regimen.
In the foreseeable future,
drugs that are simpler to take and drugs that do not have
the same resistance patterns as the current ones will become
available. Doing all that you can today will leave you in
a stronger position to benefit from these upcoming developments.
Steve
McGuire is a Chicago-based writer and consultant specializing
in medicine, public policy, and nonprofit issues. He can be
reached at: gstevenmcguire@aol.com.
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What about logs?
Log is short for “logarithm,”
which is a mathematical term used to describe a change by
a factor of 10 (that is, “times 10”) in the quantity of whatever
is being measured. Put another way, logs are a shorthand way
to express a very large number. A log is the number of times
10 must be multiplied by itself to equal a certain number.
In relation to HIV, logs
are sometimes used to state a patient’s total viral load.
For example, a viral load of 100,000 is log5 because it equals
to 10 x 10 x 10 x 10 x 10.
Most people with HIV, however,
have read or heard “log” used as the way to state how much
their viral load has gone up or down. For example, if the
baseline viral load is 20,000 copies/ml plasma, then a 1-log
increase equals a 10-fold (10 times) increase, or 200,000
copies/ml. A 2-log increase equals 2,000,000 copies/mL plasma,
or a 100-fold increase. As another example, a reduction in
viral load from 100,000 to 1,000 copies/ml is a 2-log (or
99 percent) reduction. However, a half-log (0.5 log) change
is not a five-fold difference, but a change of 3.16-fold.
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Understanding resistance
tests
Genotype
tests—If highly active antiretroviral therapy
(HAART) is no longer working well for a patient, genotypic
resistance testing helps medical providers make decisions
about switching to a different therapy. It does this by identifying
which drug or drugs in a HAART cocktail the patient’s HIV
has become resistant to. Genotype tests look for specific
changes, called mutations, in the genetic code of an individual’s
HIV that are known to be associated with resistance to particular
antiretroviral drugs. A genotype test will determine the genetic
code of a person’s HIV by examining a sample of the virus
from the patient’s blood to identify any mutations in the
virus. HIV that does not have any mutations is called wild
type virus, which is the most common form of HIV. This usually
means that antiretroviral drugs can still work against the
virus.
Phenotype
tests—Phenotype tests aim to see how an individual
patient’s HIV actually responds when it is exposed to specific
antiretroviral medications. Technicians grow a sample of a
patient’s HIV in the lab and then expose the virus to different
antiretroviral medications. The phenotype test will determine
if the virus grows slower or faster when each drug is present.
If the HIV sample grows faster, the virus is more “resistant”
to that drug. If the sample of virus grows slower, the virus
is considered “susceptible” to the medication. This means
the medicine will still work for that patient.
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