How Much Does It
Really Matter If You Take Your Pills on Time?
by Bruce Mirken
As 3- and even 4-drug combinations have become the standard of care in
the treatment of HIV infection, the new regimens have brought both increased
hope for effective control of the virus and a new and sometimes confusing
set of issues. These regimens are complex, often involving 20 or more
pills a day, with differing requirements regarding timing of doses and
whether or not the drugs should be taken with food. For many taking these
combinations, the need to organize one’s life around a pill-taking
schedule is a chore, and sticking to the regimen is a constant challenge.
But adherence to a treatment regimen is more than just a matter of convenience.
Study data strongly suggest that failure to take antiretroviral medications
on schedule can lead to treatment failure and the development of resistant
strains of HIV. Unfortunately, the existing data are not nearly precise
enough to tell a given person how much latitude he or she has. Nearly
every person with HIV wonders: will I be in trouble if I take my pills
an hour late? Two hours? If I miss one dose? Two? Three? Unfortunately,
scientists lack definitive answers. In addition, individual variations
in drug absorption, metabolism and body chemistry probably make it impossible
to give precise answers that will apply to everyone.
Still, useful lessons can be drawn both from study data and from the
real-world experiences of doctors and people with HIV using these combination
treatments. Much can be learned from experience with other diseases as
well. This article will examine not only the data and the conclusions
that doctors and researchers have reached thus far, but also some of the
methods that physicians and people with HIV are using to make it easier
to adhere to these difficult regimens and reduce the chances of treatment
failure.
A Short Course in Viral Resistance
Doctors have long known that many people do not take prescription drugs
the way they are directed. In an article published in 1984, Stephen A.
Eraker, MD, and colleagues noted, “noncompliance may be the most
significant problem in clinical practice today.” Reviewing hundreds
of studies done over the years, they found that treatment noncompliance
is common among people with chronic conditions. For example, half of high
blood pressure patients in one study discontinued care within a year,
and of those who continued treatment, only about two-thirds took enough
of their medication to control their blood pressure.
Poor adherence can be a problem with any serious illness. Drug-dosing
schedules are designed to maintain adequate blood levels of medication.
When failure to take medicines on time leads to concentrations that are
too low, much or all of the benefit can be lost. In the case of high blood
pressure, this might increase the risk of cardiovascular problems. Ample
evidence shows that among those who use trimethoprim-sulfamethoxazole
(TMP-SMX; brand name Bactrim or Septra) for Pneumocystis carinii pneumonia
(PCP) prophylaxis, “breakthrough” cases of PCP occur most often
among those who fail to take their medication as prescribed. In treatment
of HIV disease, failure to maintain adequate drug levels in the blood
can lead to viral resistance that can render a once-potent drug useless,
and perhaps eliminate other treatment options as well. To understand how
this works, it is necessary to know the basics of how resistance develops.
The HIV in an infected person is constantly replicating or making copies
of itself—hundreds of millions of times per day. When the virus replicates
it sometimes makes mistakes called mutations. Mutations only occur when
HIV replicates; they do not occur when the virus is inactive.
Some mutations do not make any meaningful difference and some may weaken
the virus. But sometimes mutations occur in the specific enzymes (reverse
transcriptase and protease) that are targeted by anti-HIV drugs, and some
of these mutations allow the virus to resist the effect of a given drug.
With certain drugs, a single mutation can create high-level resistance;
with other drugs, several mutations must accumulate before the virus becomes
highly resistant.
When no anti-HIV drugs are being used, viruses with these resistance
mutations have no special advantage and rarely become an established part
of an individual’s virus population. At the other extreme, if anti-HIV
drugs manage to stop viral replication completely, there is little chance
for mutations to occur and thus little chance for resistance to develop.
The possibility of the development of resistance arises when HIV manages
to replicate despite the presence of antiretroviral drugs. The drugs exert
what scientists call “selection pressure” that gives resistant
mutants an advantage. One way to think of this is to picture a partly
effective anti-HIV regimen as a filter that screens out the most drug-susceptible
strains, while viruses with resistance mutations are more likely to get
through. The result is that, over time, normal wild-type virus dies out
and only resistant strains remain, rendering those particular anti-HIV
drugs ineffective. Complicating the situation further is what is known
as cross-resistance. Mutations that cause resistance to one drug can sometimes
cause resistance to other, similar drugs as well, limiting the patient’s
future treatment options.
How quickly resistance develops is partly a function of how much selective
pressure drugs exert. A weak regimen, such as AZT monotherapy, exerts
relatively little selection pressure, and may be compared to a filter
full of holes that lets a lot of wild-type virus through. While a patient
on AZT monotherapy is likely to develop resistance eventually, it can
take a year or even longer. Conversely, stronger regimens, if they don’t
stop HIV replication completely, act as more effective filters, and resistance
can develop more quickly.
As knowledge of resistance has increased, more and more HIV/AIDS researchers
and clinicians have come to regard the complete elimination of viral replication
as the goal of therapy. Yet even a completely effective regimen can fail
if not taken properly. If the gap between doses is too long, or if a drug
that must be taken on an empty stomach to be properly absorbed is mistakenly
taken with food, the result can be drug levels that are not high enough
to completely stop HIV from replicating. Because some drug will still
be present, the “filter effect” of selection pressure kicks
in, giving resistant mutants an advantage. If enough of those mutants
get through, a population of resistant virus can take hold. Obviously,
the more erratic the drug-taking schedule, the greater the likelihood
of drug levels dropping into the danger zone of partial viral suppression.
Old Drugs and New
A few years ago, when the standard of care was limited to weaker regimens
such as monotherapy or 2-drug regimens involving AZT, ddI or ddC, there
was less worry that noncompliance with treatment regimens might provoke
resistance. The treatments never stopped replication completely, and they
generally exerted relatively weak selection pressure. Missing a dose or
two made some difference, but not a dramatic one. Now that regimens exist
which can keep viral load to below detectable levels for extended periods,
any break in that line of defense is seen as a cause for concern.
Another new factor is the different chemical behavior of the newer classes
of antiretroviral drugs. The drugs that give these new combinations their
punch, protease inhibitors and non-nucleoside reverse transcriptase inhibitors
(NNRTI), behave somewhat differently in the body than the nucleoside analogs
(e.g., AZT, ddI).
When nucleoside analog drugs enter a cell, they undergo a chemical change
known as phosphorylation. This has the effect of keeping the drug inside
the cell for a considerable length of time. But the protease inhibitors
do not undergo such a change, according to John Leonard, MD, who, as head
of the antiviral program at Abbott Laboratories, spearheaded the development
of the protease inhibitor ritonavir (Norvir). “They’re not trapped
inside these cells by being metabolized” like the nucleoside analogs
are, he explains. “From a metabolic point of view, they behave differently.”
This is important because it is inside cells—where the virus is
hijacking the cell’s machinery to make copies of itself—that
antiretroviral drugs do their work. Once a nucleoside analog drug gets
into a cell, it tends to stay there, even if a missed dose causes the
level of drug in the surrounding blood to drop. Because protease inhibitors
are not chemically locked into cells, a protease inhibitor will flow back
out of the cell when the drug level in the surrounding blood drops, until
the levels inside and outside the cell are the same. The likely result
is that there will not be enough drug left in the infected cell to do
the job. Thus, protease inhibitors are far more sensitive than nucleoside
analogs to varying levels of drug in the bloodstream, and missed doses
are more likely to impact the drugs’ efficacy.
The situation with the NNRTI is similar, notes Maureen Myers, MD, who
directs clinical research in virology for Boehringer Ingelheim, maker
of nevirapine (Viramune). Nevirapine, she notes, “is a small molecule,
smaller than the protease inhibitors, so it penetrates the cell very easily.”
That can be an advantage in that the drug quickly gets to where it must
go to be effective. However, it too can flow out of the cell easily if
the drug level in the surrounding blood drops.
There are important differences between the protease inhibitors and the
NNRTI. On the positive side, some NNRTI tend to stay in the blood longer
before being processed out by the liver. This means that nevirapine, for
example, can be taken twice a day without drastic changes in blood drug
levels, while all of the approved protease inhibitors except ritonavir
must be taken 3 times a day. It also means that NNRTI tend to have a somewhat
greater margin of error, with a late dose less likely to send blood levels
down into the danger zone. In another sense, NNRTI have a smaller margin
of error, since a single mutation alone may produce high-level resistance,
whereas several mutations are required to produce high-level resistance
to the protease inhibitors.
Another complicating factor is the natural person-to person variation
in drug metabolism. Many of the new drugs are primarily metabolized in
the liver through what is known as the CP450 system. The rates at which
one component of this system, the CYP3A enzyme, clears a drug from the
blood can vary dramatically from one individual to another. Leonard estimates
that this person-to-person variation is about 30% for ritonavir. Laurent
Fischer, MD, Hoffmann-La Roche’s Medical Director for HIV-Related
Products, estimates that patient-to-patient variation in clearance of
saquinavir (Invirase) is in the range of 40%. Dean Winslow, MD, Director
of Medical Affairs for Agouron Pharmaceuticals, says variation in clearance
of his company’s drug nelfinavir (Viracept) is also in the 30% range.
This variation impacts how much margin of error a person has in taking
pills. For most people taking ritonavir, Leonard says, “I’d
guess there’s a couple of hours of play. But there’s always
one guy who needs to be more precise because of how he metabolizes.”
There is no readily available test to measure CYP3A metabolism, but tests
do exist to measure the levels of drug in a person’s blood. Some
doctors are starting to look at using such tests as part of their normal
clinical practice.
What the Data Show
A few studies of anti-HIV treatments have looked at the relationship
between adherence and the efficacy of the regimens being studied. But
researchers hasten to point out that all of this data has limitations,
since there is no perfect method of measuring how study volunteers take
their medications. Much research relies on people’s own reports of
what they took and when, with the obvious problems of misreporting due
to imperfect memories or embarrassment. Other studies have asked participants
to bring their pill bottles with them on follow-up visits so investigators
can count what remains in order to determine how much they have taken.
This seems more precise, but Myers notes that “just because people
return a bottle with 1 pill in it doesn’t mean they consumed the
other 49.”
A few studies have used pill bottles fitted with electronic meters that
record each time the bottle is opened. But again, the fact that a person
opened the bottle does not prove that he or she actually took the required
dose at that moment. The meter tells researchers nothing about whether
the person remembered whether he or she was supposed to take the pills
with or without food.
The first warnings about adherence to protease inhibitor regimens came
from studies that did not specifically examine adherence at all. In early
dose-ranging studies of ritonavir and indinavir (Crixivan) monotherapy,
investigators noted a disturbing pattern in participants who were taking
doses that proved to be too low. People on the lower doses, Leonard explains,
“tended to have declines in virus, but the time they stayed suppressed
was lower.” Worse, when the virus bounced back, resistant strains
emerged.
These studies provided clear evidence that suboptimal dosing can lead
to quick rebound of viral load and the development of resistance, but
they did not directly show what would happen in a real-world situation
involving combination therapy at an appropriate dosage with occasional
missed or late doses. Still, most clinicians and treatment advocates took
the results as a signal that taking these drugs haphazardly would be risky.
More recently, several studies have shown a correlation between adherence
to antiretroviral regimens and their effectiveness. For example, both
Fischer and Leonard point to an ongoing ritonavir/saquinavir combination
trial, in which researchers are doing pill counts as well as asking participants
about their pill-taking. “Noncompliant” patients were defined
as those in the low-dose arm who had taken 85% or less of their medication
and those in the high-dose arm who had taken 60% or less. Final results
have not been compiled, but at week 24 there was a clear difference between
the compliant and noncompliant groups. Of compliant patients, 90% had
a viral load of 200 copies/mL or below. Among noncompliant patients, only
66% reached a level of 200 copies/mL or lower.
The INCAS (Italy-Netherlands-Canada-Australia-States) trial, which compared
AZT/ddI to AZT/nevirapine to AZT/ddI/nevirapine, produced similar findings.
Overall the 3-drug combination produced greater and more prolonged reduction
of viral load than either 2-drug regimen. Using what Myers acknowledges
is an “arbitrary definition” of noncompliance—having missed
1 month’s worth of at least 1 study drug during 28 weeks of follow-up—the
adherent patients in the 3-drug group did strikingly better in terms of
viral load suppression than those classed as noncompliant. When the results
for individual participants were graphed, she adds, the results were “incredible,
because you’d see an interruption [in treatment] and the viral load
would go up.”
A somewhat similar finding emerged from a small group of participants
in a high-dose saquinavir monotherapy study conducted at Stanford University.
After an initial cohort showed wide variation in response to the drug,
investigators decided to follow a group of 7 patients closely in an attempt
to correlate pill-taking (measured by metered pill bottles) with changes
in viral load (measured monthly) and the emergence of resistant mutants.
Their results were published in the December 25, 1996 issue of The
Journal of the American Medical Association.
Two patients who took clear “drug holidays” (defined as 3 or
more days off treatment) showed a dramatic spike in viral load shortly
thereafter. Their viral load dropped again when they resumed treatment,
but resistant mutants soon appeared. In 2 other patients, an increase
in viral load late in the study seemed to correlate with more haphazard
pill-taking.
But the pattern did not always hold. The most adherent patient, who hardly
missed any doses, still developed resistance and saw his viral load eventually
rebound. One patient who took a drug holiday showed no increase in viral
load and no emergence of resistance.
Overall, the researchers wrote, the results “suggest a relationship
between brief periods of low compliance and increases in plasma RNA levels.”
Still, other factors were clearly at work. For example, it may have been
that the adherent patient whose viral load rebounded simply was not absorbing
the drug well. Like the ritonavir dose-ranging trials discussed above,
this was a monotherapy study not reflective of currently accepted combination
treatments.
Several other studies are underway in which patient adherence is being
monitored, but for now, existing research paints only a fairly crude picture—what
San Francisco AIDS specialist Virginia Cafaro, MD, refers to as “wisps
of data.” Clearly, missing a large number of doses or several doses
in a row is undesirable, but just how many lapses a person can have without
getting into trouble—and how much this varies from individual to
individual—remains an open question.
Is Testing the Answer?
The key to any drug’s efficacy is reaching and maintaining an adequate
level of drug in the body. Given the natural variations in absorption
and metabolism of anti-HIV drugs, some believe a solution may lie in testing
patients’ blood levels of the drugs they are taking. In the May issue
of the Los Angeles-based newsletter Being Alive, Bernard Bihari, MD, describes
a combination trial using indinavir and nevirapine in addition to nucleoside
analog therapy. “The 3 patients who did not show dramatic drops in
viral load all described no indinavir side effects, and 2 still have none
on 1,600 mg every 8 hours,” he notes. That dose is 60% higher than
what Boehringer Ingelheim has recommended be used to compensate for nevirapine-induced
reduction in indinavir blood levels. Interestingly, Bihari noted a spike
in the viral load of one person who briefly failed to follow the requirement
that indinavir be taken on an empty stomach, an issue that researchers
have thus far barely examined.
Bihari speculates that these individuals are not reaching therapeutic
levels at this higher dose because of variations in absorption and/or
metabolism, and compares the situation with “drugs used to treat
such diseases as epilepsy, congestive heart failure, bipolar disorder
and cardiac arrhythmias.” Doses of drugs for these conditions, he
writes, need to be adjusted by as much as 300% in normal clinical practice,
adjustments that are done with the aid of tests for blood levels of drugs.
Similar adjustments may be needed with some antiretrovirals. As a result,
“I am arranging for the availability of indinavir and nevirapine
blood level testing, and expect to incorporate these as routine clinical
tools in my practice.”
So far there has not been a headlong rush in the direction of blood level
testing among AIDS physicians, although many are intrigued by the idea.
Meg Newman, MD, a clinician at the San Francisco General Hospital (SFGH)
AIDS ward and director of SFGH’s AIDS education program, says, “I
think it’s interesting. And I think it needs to be tested and clinically
validated.”
However, Abbott’s Leonard is skeptical about the usefulness of blood
level testing, at least with the current level of knowledge. “There
are plusses and minuses to it,” he observes. While it would “be
nice for a patient and physician to know, whatever drug he’s taking,
that he’s in the ballpark” in terms of maintaining adequate
levels, such testing could be “potentially misleading.” He explains,
“I can give you a [blood level] number for ritonavir based on populations
infected with a virus that’s never been exposed to a protease inhibitor
before,” but with increasing use of these drugs more and more people
will have virus that has at least some exposure to them. Resistance to
protease inhibitors is “a gradient,” with many intermediate
steps between zero resistance and high-level resistance, “and we
don’t know the [therapeutically effective blood level] number for
each of those intermediate steps.” For testing of blood levels of
drugs to be truly meaningful, Leonard argues, “you have to have the
genotypic [relating to the virus’ genetic structure] and phenotypic
[relating to the virus’ actual characteristics] information to put
alongside it.” Such testing is not impossible, he continues, “that’s
what we do all the time in people we give antibiotics to.” Whether
it will become the standard of care in treatment of HIV disease remains
to be seen.
Treatment Decisions
Fear that haphazard use of combination therapy could speed emergence
of resistant strains that might in turn be transmitted to other people,
leading to an epidemic of multidrug-resistant HIV, has provoked considerable
discussion among physicians and others. Important questions include: should
some people with HIV be refused combination antiretroviral treatment if
a doctor does not think they can adhere to the regimen? How does a physician
decide who can or cannot handle these treatments? Is there a conflict
between a patient’s right to optimal treatment and the public health
needs of society?
Unfortunately, many media accounts seem to be based on stereotypical
assumptions about certain groups of people which suggest, for example,
that homeless individuals or users of illegal drugs are unable to handle
combination anti-HIV regimens. But research suggests that many of these
stereotypes are inaccurate.
In a number of studies, factors such as poverty, homelessness and lack
of education have correlated poorly or not at all with failure to adhere
to treatment regimens. “Sociodemographic characteristics have never
predicted adherence very well,” observes Lois Eldred, MD, of the
Johns Hopkins University School of Medicine. Eldred’s work with a
mostly poor and African American urban clinic population was presented
at the XI International Conference on AIDS in Vancouver, BC, last July.
“Class has never predicted it. Race has never predicted it. We would
like providers to not be biased in who they prescribe drugs to, but to
take a closer look at people’s lifestyles.”
While some studies do seem to show a correlation between injection drug
use and lack of adherence to HIV/AIDS treatments, in other research drug
injectors have done just as well as non-drug users at sticking to their
regimens. Eldred found no correlation between adherence and use of marijuana,
alcohol or smoked or snorted cocaine, but did find that those who injected
drugs at least “several times a week” were less likely than
others to adhere to their treatments. Eldred suspects that more frequent
drug injecting may be associated with what some researchers call a “chaotic
lifestyle”—instability in many of the basics of day-to-day living
such as food and shelter—that makes it harder for such individuals
to take their medicines as directed. But she emphasizes that it is dangerous
to assume that because a person uses drugs their life is chaotic, noting,
“There are people who inject drugs who work full-time jobs.”
David Bangsberg, MD, of SFGH has noted a similar pattern in his ongoing
work with homeless and marginally housed HIV patients in a study headed
by principal investigator Andrew Moss, PhD. In this group of patients,
many of whom have substance abuse and mental health issues in addition
to HIV infection, Bangsberg says that so far the SFGH researchers have
found that “most of the homeless access medical care and adhere to
medication in very reasonable ways, not dissimilar from stably housed
HIV-infected people… But there’s a small portion that have fairly
chaotic lives” and have trouble staying on their treatments, keeping
clinic appointments, etc. The poor and homeless, of course, hardly have
a monopoly on chaotic lives. An educated, affluent, self-employed businessperson
or professional with a frenzied schedule, constantly rushing from one
appointment to another, may have as much trouble adapting to a complex
medication regimen as a homeless person.
Anticipating who will do well and who will not is “a daunting challenge”
for physicians, Bangsberg adds, noting that even doctors in quiet suburban
practices have trouble assessing which patients are correctly taking their
medications for high blood pressure or other chronic conditions. Indeed,
Eraker and colleagues noted, “Few medical schools teach their students
to recognize the conditions under which the patient can be expected to
follow advice (much less the methods for communicating effectively with
patients), or the interview skills needed to assess what the patient knows,
believes or is concerned about.”
Some factors do seem to be consistently significant in predicting adherence.
For example, patients do better on simpler regimens than on complex ones.
The number of times per day that medicines must be taken, rather than
the number of pills taken each time, is the main factor. Eldred, who was
studying 1- and 2-drug regimens, notes, “In my study, compliance
really dropped off when there was more than twice-a-day dosing.”
Depression and other psychological problems may interfere with adherence
and must be addressed. Numerous studies suggest that communication between
doctor and patient is critical, not just in terms of transmitting knowledge,
but in establishing trust as well. One study found that a patient education
program greatly increased patients’ knowledge of the drugs they were
taking, but did not significantly affect their adherence. The person with
HIV must feel secure about the treatment that has been prescribed, and
the doctor must take the time to understand the attitudes, beliefs and
lifestyle factors that will impact the person’s willingness and ability
to stick to a treatment plan.
Promoting Adherence
What all of this means is that in 1997 it is no longer adequate for a
physician to simply write out a prescription for antiretroviral drugs
and hand it to a patient with a couple of sentences worth of mumbled instructions.
With regimens now so complex that people often have to literal-ly organize
their lives around their pill-taking, physicians are finding that they
need to spend some time getting to understand those lives before recommending
treatment.
“I’d certainly say that your first shot at a protease inhibitor
is likely to be your best shot,” Newman says, “and everything
else may be salvage therapy.” This means that physicians and patients
must choose that first shot carefully, paying attention to a regimen’s
ability to fit an individual’s lifestyle as well as its effectiveness,
and must avoid the temptation to move too fast. “I’ve learned
to take a deep breath and really get to know somebody and work with them,”
Newman comments, “even if it means deferring therapy for 2 to 6 or
8 months until they really understand what the regimens are about and
they really make a personal choice that they’re ready for the type
of focus and commitment that these regimens require.”
Physicians and people with HIV also must take the time to go over the
requirements of a particular drug’s dosing schedule and potential
side effects to make as sure as possible that the treatment chosen will
be one the individual can live with. Indinavir, for example, must be taken
at least 1 hour before and 2 hours after eating, 3 times a day, which
can present a real problem for people with hectic and irregular schedules.
(See the list of new, FDA-approved meals that can
be eaten with indinavir.)
Some possible combinations present such a logistical obstacle that physicians
tend to avoid them. One example many cite is indinavir plus ddI, both
of which require an empty stomach, but which must be taken at least an
hour apart. Cafaro calls this “the nightmare combination if you have
any semblance of a normal life.”
Both Newman and Cafaro say they work closely with their patients to develop
strategies for keeping track of when to take medications. “You try
to simplify as much as possible,” Cafaro says. That involves things
like making sure people know which drugs can be taken together so that
they can, for example, get into a routine of taking a set batch of pills
together with breakfast every day. Cafaro notes, “that way they can
package them in little baggies or pill containers” for easy access
and organization. She adds, “I’ve got people actually going
to the hardware store or sporting goods store and getting big, compartmented
things like fishing tackle boxes,” to organize their drugs. Whatever
method is chosen, the idea is to organize pill-taking into a pattern that
synchronizes reasonably well with the rest of a person’s life.
It’s also important that a doctor establish an atmosphere in which
their patients feel relaxed enough to talk about their concerns and to
acknowledge if a regimen is giving them trouble. “I think it involves
getting to know someone and making sure they feel very comfortable,”
Newman says. “The last thing I want someone to do is feel shame about
[not taking their medicine as directed].”
This process requires more effort than many doctors are accustomed to
putting into their relationships with patients, but Newman has no doubt
that it is necessary, since patients are being asked to do a tremendous
amount as well. “I think the medicines are terribly unforgiving,”
she observes, and living with them is “a full-time job.”
Although many AIDS specialists are now in the habit of working closely
with people with HIV in choosing and monitoring their therapies, some
physicians—especially those who do not do much HIV/AIDS care—are
not accustomed to this approach. When in doubt, specialists agree, people
should ask plenty of questions and make sure they understand what their
doctor is suggesting and what is expected of them. Newman says, “Make
sure before you leave the office that you have a very clear understanding
of how to take your medicines, what to do if you have side effects, how
to reach your provider, what you might anticipate. And if they don’t
tell you [whether to take your medications] with or without food, that
should be a red signal that there’s a huge problem.” As Cafaro
observes, “There is no such thing as a stupid question. There really
isn’t.”
The bottom line, then, is: when in doubt, ask. In HIV therapy, it is
better to slow down the process a bit if that’s what it takes to
make sure the choices a person with HIV and his or her doctor make are
ones the person will be able to live with.
Bruce Mirken is a freelance journalist.
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Page last updated 1 October 1997
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