E-drug: HIV+ Africans can adhere to ART (cont'd)
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In respect to the question who can/cannot, or will/will not, adhere
to anti-retroviral drug regimens, earlier this year Dr Joel Gallant
(Johns Hopkins) made the following wise statement, which was
carried in a Medscape article on February 22:
"Now that antiretroviral therapy is so effective, adherence has
never been a more important issue. To derive the full benefit
from their therapy, patients must fully understand the benefits
of treatment and the risks associated with nonadherence.
Outpatient care settings must develop a comprehensive and
consistent plan for supporting and evaluating patient
adherence."
A key word is "evaluating", because adherence, when measured by
reliable means, has been found to be widely variable, more or less
irrespective of patients' socio-economic and educational status.
Thus, it would appear that everyone is in 'the same boat', so to
speak, in respect to the odds that nonresponse to a usually
effective drug has its origin in inadequate adherence.
Insofar as predicting who will or won't adhere satisfactorily, the
only reliable predictor of future adherence is a reliable measure of
past adherence. Insofar as socio-economic/educational aspects go,
there is enough anecdotal data about physicians' adherence with
self-prescribed medicines to question assertions that the 'adherence
problem' can be solved either by patient empowerment or advanced
education in pharmacology & therapeutics. Naturally, no one in
his/her right mind would deny the importance of patients' having a
basic understanding of the rationale for treatment and clear
instructions about what to take, when. Having those basics will
avoid a number of problems due to miscommunication, but will not,
per se, insure uniformly good adherence to prescribed drug
regimens.
It is useful, and probably essential, to think of adherence as a
clinical variable that has diagnostic importance, and thus needing
reliable measurement. As with any diagnostic, the questions are
'how to measure?' and 'when to measure?'.
Clinical judgment about adherence was aptly characterized in a
recent editorial in Ann Int Med as being no better than a coin-toss
(1), and counting returned, unused tablets has a decade-long
history of grossly exaggerating adherence, recently characterized by
Brian Haynes as follows: "Counting pills that patients bring to clinic
visits gives rates of 90% to 100%, making a mockery of the
procedure, although it is remarkable how many drug trials blithely
report such figures"(2). Electronic monitoring has emerged in the
research setting as the 'gold standard' method, but is not yet seen
as a practical tool for routine clinical work (1). Nevertheless, some
key findings from the research uses of electronic monitoring provide
useful guidance for practice, where one still has to rely on common
sense and strong inference as the main resources for dealing with
the odds that insufficient adherence is responsible for nonresponse
to treatment that should be effective.
Haynes (1) gives good practical advice in suggesting that one
watch, first, for missed clinic appointments, then for nonresponse,
and then to focus most efforts on nonresponders. While there are
many possible reasons for nonresponse, the odds usually favor
inadequate adherence, particularly in antiretroviral treatment where
studies by Paterson et al (3) and Gross et al.(4) demonstrate the
very unforgiving nature of currently available ARV drugs, which
appear to require strict continuity of drug exposure in order to
maintain viral suppression. The concept of 'forgiveness' has to do
with how much latitude there can be for delays or omissions in
dosing, before therapeutic effectiveness is compromised by
inadequate drug exposure (5). As it happens, the two groups of
important contemporary medicines that appear to be least forgiving
are the low-dose estrogen-progestin oral contraceptives and the
current crop of protease inhibitors -- both allowing very little latitude
for delayed or omitted doses, before effectiveness is lost. It would
be an important advance if new antiretroviral agents had
considerably more forgiveness than that provided by currently
available agents.
A nice addition to the clinical management of adherence comes
from Cramer and Rosenheck (6). They suggest to spend a few
minutes in making a little inventory of the patient's daily routines,
looking for the routines that are most robust, and then showing the
patient how to link the medicine-taking to one or more such
routines. They have validated this approach with electronic
monitoring data.
The subject of patient adherence to prescribed drug regimens
integrates two very different, rather immiscible disciplines: human
behavior and clinical pharmacology. During the past decade, the
research uses of electronic monitoring have made possible
considerable advances in knowledge about the clinical
pharmacologic aspects of variable adherence, giving a much better
idea than ever before, about clinical consequences of lapses in
dosing of various lengths, which are lengths, which are the most
commonly occurring deviations from prescribed drug regimens. A
prime example is the seminal work of van Hove, Merigan, Blaschke,
and others in 1996, which first showed how multiday, sequential
lapses in dosing ('drug holidays') with a protease inhibitor was
associated with an upsurge in viral replication and emergence of
drug resistant virus (7).
Where does this leave us?
We're left with the unfortunate combination of exceptionally
unforgiving drugs and, in routine clinical work, only inferential
means for estimating adherence, with the always looming threat of
emergent drug-resistance. The commonsensical approaches
suggested by Haynes, plus the linkage of dosing to robust routines,
suggested by Cramer & Rosenheck, are tools in hand. These are
presently usable tools, though will be more effective when their use
is informed by reliable, objective data on patients' dosing histories.
That measurement capability will inevitably come, given the
importance of correct dosing, the clinical need for better-assured
outcomes of ARV treatment, and the ultimate versatility and
economics of microelectronics (8). Of key importance is recognition
that patient adherence is ultimately a quantifiable clincial factor of
sometimes key diagnostic import, especially when ordinarily
effective drugs aren't working.
John Urquhart, MD, FRCP(Edin)
Professor of Pharmaco-epidemiology
Maastricht University, Maastricht, NL
Chief Scientist, AARDEX Ltd/APREX Corp, Zug CH & Union City,
CA, USA
Professor of Biopharmaceutical Sciences, UCSF, San Francisco
home office: 975 Hamilton Avenue, Palo Alto, CA 94301 USA
email: urquhart@ix.netcom.com
References:
1. Turner BJ, Hecht FM. Improving on a coin-toss to predict
patient adherence to medications. Ann Int Med 134: 1004-6,
2001.
2. Haynes RB. Improving patient adherence: state of the art, with
a special focus on medication taking for cardiovascular
disorders. pp 3-21. In: Compliance in Healthcare and Research.
Eds Burke LE, Ockene IS. Armonk (NY): Futura Publishing Co.,
2001 (American Heart Association Monograph Series).
3. Paterson DL, Swindells S, Mohr J, Brester M, Vergis EN, Squier
C, Wagener MM, Singh N. Adherence to protease inhibitor
therapy and outcomes in patients with HIV infection. Ann Int
Med 133: 21-30, 2000.
4. Gross R, Friedman HM, Bilker WB, Strom BL. Adherence to
nelfinavir: magnitude and patterns associated with HIV
suppression. Poster, 40th Interscience Conference on
Antimicrobial Agents and Chemotherapy, Toronto, Canada,
2000.
5. Urquhart J. The electronic medication event monitor - lessons
for pharmacotherapy. Clin Pharmacokinet 32: 345-356, 1997.
6. Cramer JA, Rosenheck R. Enhancing medication compliance for
people with serious mental disease. J Nervous Mental Dis 187:
53-4, 1999.
7. Vanhove GF, Schapiro JM, Winters MA, Merigan TC, Blaschke
TF. Patient compliance and drug failure in protease inhibitor
monotherapy. JAMA 276: 1955-6, 1996.
8. Urquhart J. Mis- and non-use of prescription drugs: confusion,
lost revenues, and future commercial opportunities. Pharm
Visions summer issue, pp 9-17, 2001.
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