Whatever
happened toTDM?
A few years ago, therapeutic drug monitoring looked like our best hope for
reducing the side effects of HIV drugs, so why aren’t all
clinics using it, asks Jeff Williams
Illustration: C(Aitch)
Several
years ago, when providing information and guidance on HIV treatments, one
advance I thought would be particularly useful to people living with HIV was
therapeutic drug level monitoring (TDM).
Clients always asked me: “Why are the side effects of therapy so bad?”
What struck me was this was being asked by those who had evidently suffered
severe body wasting and by people who were very much heavier.
One size doesn’t fit all
Both groups were adults taking the ‘one size fits all’ dosage
of HIV medications.
I understood why someone weighing less than 60kg would suffer more severe
side effects that someone taking the same drugs weighing more than 85kg. A
thin patient and a heavy patient take the same amount of a drug, but in the
case of the lighter patient, the drug is more concentrated in their body.
Any meds designed to kill or control an invading bacteria or virus must be
poisonous to the invading microbe but not to the person taking the medication.
Pharmacology is the science of designing the dosage to make it sufficient
to kill or control the bugs, but not poison the patient. Side effects are
a measure of this balance not being quite right.
A big step forward on side effects
Drug level testing offered the possibility of measuring the HIV drugs in a
patient’s body (in the blood) directly. If drug levels were too high,
which would likely contribute to severe side effects, then they could be reduced.
Similarly, if levels were too low and likely to cause drug resistance, they
could be increased.
Monitoring of drug levels in each patient would maximise the medication’s
therapeutic benefit and allow doctors to minimise side effects. Perfect. Other
HIV patients who could also benefit from TDM included pregnant or those coinfected
with hepatitis B or C.
This seemed a great step forward for the person taking the drugs, maximising
drug efficacy while minimising drug toxicity. Yet with passing years we have
heard less and less about drug level monitoring and I wondered about its current
status.
Why isn’t TDM routine?
One reason TDM seems to have not taken off is that such individualisation
of HIV treatment is enormously expensive, both in the cost of the testing
and the time the clinician spends supporting each patient. Meds also come
in standardised quantities. There is one licensed dosage for each drug, which
has to be taken each day. If this is too much for you, too bad. The drugs
do not come in a variety of sizes.
Another problem with widespread drug level monitoring is the wide variation
in drug levels seen in patients with a standard, ‘one size fits all’
dose. For both protease inhibitors and NNRTIs, the levels of HIV drugs measured
in the blood of adults may vary ten-fold, despite them taking the same dose
at the same time.
Standardised drug level monitoring becomes even more problematic when
considered in the context of paediatrics, pregnancy, kidney disease and complicated
drug regimens.
When TDM is used
Drug level monitoring is usually considered when there is a clear relationship
between drug levels and the drug’s efficacy and toxicity. In fact, it’s
only routinely used in medicine to measure drugs that do not appear to be
as vital or difficult to use, including antibiotics, drugs for seizures, antidepressants
and immuno-suppressants. For HIV, this relationship exists only for PIs and
NNRTIs, which rules out other classes of HIV meds.
Much discussion surrounding the use of TDM for HIV drugs is on how to define
target levels; what the appropriate level of a particular drug should be.
Several complex methods exist to estimate this target level, including the
‘inhibitory quotient’ and the ‘normalised inhibitory quotient’.
These are variations on the idea of dividing the amount of drug in a patient’s
blood by the amount of drug that inhibits the virus. The problem is the virus
that needs destroying is not freely present floating around in people’s
blood, but in their CD4 cells, which are floating around in the blood. While
it’s relatively easy to measure the amount of free drug dissolved in
the blood, it’s extremely difficult to measure the amount of drug present
inside cells where HIV resides.
Getting the measure
There are many ways to calculate ‘inhibitory quotient’ but these
are largely theoretical estimates. And sometimes the debate can take on an
unhealthy commercial orientation, with the discussion turning on which method
makes one drug look better rather than which method works for the patient.
Although of great potential benefit to the patient, drug level monitoring
has inherent limitations. Several involve adherence; could low drug levels
simply mean the patient has missed doses? Where do we draw target levels and
how do we make sure we know when the last pills were taken? Who will interpret
the levels and provide expert advice? And after all that, will the outcome
actually improve?
Another difficulty is the limited availability of prospective trial data.
One study, PharmAdapt, failed to show a benefit from TDM while another, ATHENA,
showed benefit for a limited number of drugs.
Costs and discrepancies
Other issues include cost, the need for us to go for yet more blood tests,
and the quality of the test results. A single blood measurement costs less
than a measurement of CD4 count or viral load, but the bill can increase rapidly.
Most importantly, the companies who manufacture HIV drugs need to take part
in international quality assurance programmes designed to ensure confidence
in lab measurements of drug levels.
This is a problem, as discrepancies can be clearly seen when a number of identical
samples are measured by different labs. With PIs, a wide range in the measured
quantities are observed, so which should the clinician trust when deciding
on a patient’s treatment?
So there are still fundamental questions to be answered before TDM can become
a routine tool in HIV medicine:
• There is no agreement about the acceptable therapeutic range for each
HIV drug. To complicate matters, this range is probably different for patients
who have drug resistance, since higher drug levels may be necessary to control
HIV in these patients.
• TDM for nukes isn’t yet practical because it’s the amount
of the drug inside the cells, not in the blood, that matters and measuring
this is difficult with present standard lab technology.
• Drug levels can even vary within a patient, so it may be necessary
to gauge drug levels multiple times before making treatment decisions.
Many problems are of a technical nature and will eventually be resolved. This
is certainly something to be hoped for as drug level monitoring still seems
to be a valuable tool in HIV medicine.
Effective therapy: TDM measures whether the concentration of meds
in a patient are too high (toxic) or too little (ineffective)
How TDM helped Kojo improve his regimen
“I changed my treatment from Combivir and nevirapine as it hadn’t
worked properly for several years, but my viral load was low and my CD4 count
was still slowly climbing. After discussion with my doctor, I changed to lopinavir-ritonavir
(Kaletra), atazanavir and tenofovir, with one extra capsule of ritonavir to
boost the atazanavir.
“Two weeks into my new regime,
I went along for drug monitoring. Bloods were taken first thing in the morning,
before taking my once-a-day meds. Breakfast at a local café was followed
by my once-a-day tabs and after a couple of hours I went back for a repeat
of the blood test. The results showed my absorption of lopinavir and atazanavir
were both way higher than necessary.
I was pleased to be told to stop taking the extra ritonavir capsule as it
enabled me to switch to taking the meds at night instead of in the morning,
and this had caused so much stomach upset and bloating.
“It was even suggested that the dose of lopinavir-ritonavir could be
reduced too, but we haven’t done that. In fact, I’m now waiting
for my first prescription of the tablet formulation of lopinavir which is
currently only available on a named patient basis, as it’s not yet licensed
in Europe.
