PI Perspective #33
August 2001 View PDF En
español
Drug Level Monitoring:
The Next Advance in Diagnostics
The past few years have brought major advances in the treatment
and management of people with HIV. In many of the early trials for
HIV-positive people, different blood markers were studied to determine
whether they might be beneficial in monitoring the health of people
with HIV and whether they might be able to predict the risk of disease
progression. Many were deemed not useful including beta-2 microglobulin,
neopterin and p24 antigen. Others have become part of routine standard
of care including CD4+ cell counts, viral load (HIV RNA levels)
monitoring and resistance testing. Many other blood markers are
still being evaluated although the next major advance is likely
to come from the field of pharmacology and specifically, therapeutic
drug monitoring (TDM). Pharmacology is the study of how drugs are
absorbed, broken down (metabolized) and eliminated in the body.
TDM monitors the level of various drugs in the bloodstream.
The goal of TDM is to ensure that there are adequate drug levels
in the body to effectively block HIV from reproducing. TDM involves
drawing a blood sample to measure the amount of a particular drug
in the blood [notably protease inhibitor and/or non-nucleoside reverse
transcriptase inhibitor (NNRTI)]. Most experts believe that measuring
the levels of the nucleoside reverse transcriptase inhibitors (NRTIs),
like AZT, will be of little value as these drugs block HIV replication
inside the cell and the levels found in blood may not necessarily
correlate with those inside the cell.
TDM may be particularly useful for the protease inhibitors as drug
levels can vary greatly between individuals since there are differences
in how people’s body’s break down and use these drugs.
Ensuring that people are within a ‘therapeutic range’—a
range where we know the drug works and which doesn’t cause
excessive side effects—may significantly increase the likelihood
of a durable response and may decrease risks of side effects. TDM
makes it possible to adjust the dose to meet the needs of a particular
person. Weight, sex, stage of HIV disease, hepatitis co-infection
and presence of liver/kidney dysfunction may all affect the need
for a dose adjustment of a drug for an individual. Today, we simply
give a single dose calculated to work in the “average”
person. For some people, this “average” dose may be
excessive, while for others it may be insufficient.
The ‘therapeutic range’ may be different for someone
starting anti-HIV therapies for the first time than for someone
who has previously taken different drugs and may have developed
some degree of resistance to them. It may be necessary for people
with drug-resistant virus to achieve higher drug levels in order
to “overcome” the resistant virus. This might be achieved
by taking higher doses of a given drug or through the use of a boosting
drug like ritonavir (Norvir).
There are a few hurdles that still have to be overcome before TDM
can be used as part of routine care. One area of concern is the
accuracy of the tests themselves.
Perhaps the bigger hurdle is determining the appropriate time to
draw the blood sample to be used in detecting drug levels. Different
people taking the same drug will have a different pattern in how
the drug gets absorbed and eliminated from the body. Soon after
a dose of the drug is taken, the maximum level of the drug, or Cmax
as it is commonly known, can be found in blood. Most researchers
believe that the higher the Cmax level, the more likely someone
will experience side effects. Over time, the drug level gradually
decreases, eventually reaching a minimal level called the Cmin.
When this level is reached, the next dose of the drug must be taken
to raise the blood level. If the Cmin falls below the amount needed
to fully suppress HIV replication, the risk of drug resistance increases.
The lower the Cmin level, the more likely resistance to the drug
will develop.
For anti-HIV drugs, the Cmin level is probably the most important
factor when looking at anti-HIV response, so people would need to
have their blood drawn right before they take their next scheduled
dose. In practice this will be very difficult to do. The more likely
scenario is that people will be coming in for blood draws whenever
they can get a appointment at the laboratory or at their doctor’s
office and this may not be right before their next scheduled dose
of their drug regimen.
Preliminary results from the ATHENA study supports the use of TDM.
This study included 600 people, half of whom had not previously
been on anti-HIV therapies. Half of the participants received TDM
in addition to standard monitoring (CD4+ cell counts, viral load,
etc.) while the other half only received standard monitoring. Results
were reported only for people who had not previously received anti-HIV
therapies and started on either nelfinavir (Viracept) or indinavir
(Crixivan). Results on participants starting on other anti-HIV therapies
and people who had previously been on anti-HIV therapies are forthcoming.
Fifty-five people started indinavir as their first-line regimen,
with about equal numbers taking standard dose indinavir (800mg every
eight hours) and two different doses of indinavir + ritonavir (800mg
indinavir and 100mg ritonavir twice a day or 400mg indinavir and
400mg ritonavir also taken twice a day). After a year of the study,
there was a trend suggesting that fewer people receiving TDM had
to discontinue their therapy, primarily due to side effects. Additionally
significantly more people receiving TDM achieved viral loads below
500 copies/mL after twelve months of the study.
The results for the group taking nelfinavir were slightly different.
Ninety-two people took nelfinavir as first-line therapy in this
study. Significantly fewer people receiving TDM discontinued therapy
compared to the non-TDM group, but this was almost entirely due
to fewer people experiencing virologic failure (rebound in viral
load) rather than due to side effects as seen among people taking
indinavir. As a result significantly more people receiving TDM achieved
viral loads below 500 copies/mL after twelve months of the study
than those not receiving TDM.
Additional information from this study is forthcoming including
results from people who had previously been on anti-HIV therapies
as well as more specific information about who were more likely
to require dose adjustments based on gender, weight or other factors.
Drug Levels Inside Cells (intracellular)
Another possible complicating factor about TDM is the recent finding
of protease inhibitor levels inside cells, similar to what has been
seen with NRTIs. To date, nobody has shown a connection between
protease inhibitor levels inside cells and the anti-HIV effect of
the drugs, but studies are now being done to examine this question.
It is also not known if there’s a connection between protease
inhibitor levels found in blood to those found inside cells.
Human cells have certain genes called P-glycoprotein (P-gp) and
Multi-drug Resistance Proteins (MRPs). They control what substances,
including drugs, can get into cells and how quickly they’re
expelled in order to protect the cells from toxic effects.
It’s still not clear what role these genes play in the overall
effectiveness of anti-HIV therapy, although it is thought they factor
in how well drugs are absorbed and how efficiently they get into
certain parts of the body, like the brain. These genes already play
a major role in the effectiveness of therapies for other diseases.
For instance, a high expression of these genes has been shown to
make cancer cells more resistant to traditional drugs.
Drug Interactions
Many anti-HIV drugs and the therapies used to prevent or treat opportunistic
infections are metabolized by the same enzymes in the body. This
means that there are many possible drug interactions. As a result,
it is very important to talk about this issue with your doctor or
pharmacist, especially when using drugs to prevent opportunistic
infections. Your doctor, as well as your pharmacist, should be aware
of all the meds you’re taking, including over-the-counter
herbs and vitamins. More information on drug interactions is available
through Project Inform’s Hotline.
One of the most discussed issues on drug interactions in the past
few years has been using ritonavir to boost the levels of other
protease inhibitors. This approach can result in less frequent dosing
and a reduced daily dose. This is achieved in one of two ways: A]
ritonavir can greatly increase the Cmax (maximum level) of lopinavir
and saquinavir in the blood without significantly changing the rate
at which the other drug is eliminated from the body, or B] ritonavir
can slow down the rate indinavir and amprenavir are eliminated from
the body without greatly changing the Cmax.
Dark line – lopinavir or saquinavir taken
alone
Gold line – results when taking drug with ritonavir
Dark line – indinavir, nelfinavir or amprenavir
taken alone
Gold line – results when taking drug with ritonavir
Early results suggest that ritonavir is able to boost the levels
of two protease inhibitors at the same time, indicating that this
may possibly be a useful strategy for third line therapy.
Boosting drug levels, however, may make interpreting resistance
results more challenging because the higher drug levels may ‘overpower’
some of the drug-resistant viruses. Currently, most people consider
a four-times decrease in sensitivity to a drug to mean low-level
resistance while anything over a ten-times decrease means high-level
resistance. This is generally considered acceptable because blood
levels of a drug are usually only four to eight times higher than
what is simply needed to block HIV from reproducing.
However, ritonavir boosts the drug levels of some protease inhibitors
upward of fifteen times or higher and so these standard four to
ten times reductions used as indicators on resistance tests may
become irrelevant. In other words, you may “overpower”
some of these resistant viruses by using ritonavir and another protease
inhibitor even though your test results indicate you may be resistant
to one or more of these drugs. As a result, it may be important
for your doctor to factor in drug levels and the levels of reduced
drug sensitivity when evaluating results from your tests.
Protein Binding
It is widely known that anti-HIV drugs get bound to certain proteins
in the body, which results in decreased anti-HIV activity. In some
cases, this has resulted in the drug being pulled from development
because it lost almost all of its activity. The more a drug is bound
to these proteins, the greater the loss in anti-HIV activity.
The amount of these proteins is:
- higher in HIV-positive than HIV-negative individuals,
- lower among people with cirrhosis (a liver disease caused by
the loss of functioning liver cells) as the liver produces these
proteins,
- higher during periods of inflammation, and
- different between genders and among ethnicities.
What makes this even more confusing is that tests measuring drug
levels in the blood do not always reflect the effects of protein
binding. Thus, a therapeutic drug monitoring test may indicate there
is an adequate level of drug in the blood stream, but in fact not
all of the drug is actually available to do it’s job. This
has been an area of intense debate among the pharmaceutical companies
developing drugs because you can get very different results on anti-HIV
activity depending on the amount of protein used in their lab experiments.
As a result, each company claims that its drugs, at least in their
labs, are more active against HIV compared to their competitors.
Commentary
There is a strong likelihood that future advances in the field of
pharmacology can result in significant improvements in the care
of people living with HIV by optimizing the dose of anti-HIV therapies
as well as reducing the risk for certain side effects. TDM is likely
to provide another useful piece of information, along with CD4+
cell counts, viral load and resistance testing, that can help in
assessing the effectiveness of an anti-HIV regimen. However, there
are still several issues that have to be worked out before this
test can be used as part of routine care. Moreover, the level of
benefits provided by TDM must be weighed against the costs and complexity
of additional testing.
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