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A
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Chapter
7
Adherence To HIV Therapies
Laura W.
Cheever, MD, ScM
Overview
TOP
What is
meant by medication adherence?
Medication
adherence means a patient takes the prescribed dose of prescribed
medications on the prescribed schedule, following prescribed dietary
instructions. Patient adherence to medical appointments and to behaviors
that minimize the risk of transmission of HIV to others correlates
strongly with adherence to medications and is an important part
of primary care of HIV-infected patients but will not be addressed
in this chapter.
Why is medication
adherence so important in HIV therapy?
Nonadherence
to prescribed therapy is a ubiquitous problem in medicine. In chronic
diseases, including asthma, diabetes, and hypertension, only 50%
of patients take their medication as prescribed more than 80% of
the time. The same is true of patients with HIV infection. However,
because of the rapid multiplication and mutation rate of HIV and
the relatively low potency and short half-life of most antiretrovirals,
very high levels of adherence to antiretroviral schedules are necessary
to avoid viral resistance. In comparison with patients who are adherent
to antiretroviral therapy (ART), nonadherent patients have: 1) Higher
mortality (2.5 adjusted relative hazard) (Wood, et al, 2003), 2)
Lower increase in CD4 cell count (6 cells/mm3 increase for nonadherent
patients versus 83 cells/mm3 increase for adherent patients) (Paterson
2000), and 3) Increased hospital days (12.9 days/1000 days of followup
for nonadherent patients versus 2.5 hospital days/1000 days for
adherent patients) (Paterson, et al, 2000).
How adherent
do patients need to be to avoid viral resistance?
Results of
a study of adherence and response to therapy among primarily antiretroviral-experienced
patients taking protease inhibitors (PIs) showed that a >95%
adherence rate was necessary for 78% of patients to achieve an undetectable
viral load (Paterson, 2000); however, some patients with significantly
less adherence also had success (see Figure 7-1). Exactly how adherent
individual patients need to be is not known and probably depends
on several factors, including preexisting antiretroviral resistance,
viral load, viral genetic barriers to the development of drug resistance,
and drug half-life. Patients should be counseled that the risk of
viral resistance increases with nonadherence and that nearly perfect
adherence is the goal. Of note, patients with very low levels of
adherence may be at decreased risk of developing viral resistance
because there is not enough selective pressure (Bangsberg, et al,
2003).
Figure
7-1: Adherence Rates Predict
Viral Load Response
Source: Adapted
from Paterson DL, Swindells S, Mohr J, et al. Adherence to protease
inhibitor therapy and outcomes in patients with HIV infection. Ann
Intern Med. 2000;133:21-30. Copyright American College of Physicians.
modified with permission.
Assessment
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What factors
impact adherence?
Many factors
contribute to a patient's ability to adhere to medication schedules
(Table 7-1). Note that race, education level, and income are generally
not predictive of adherence. Providers must remember that factors
predicting adherence or nonadherence are only associations and are
not absolutely predictive. For example, although patients who use
addictive substances are more likely to be nonadherent, some patients
with heavy alcohol or drug use are adherent to ART.
One of the
primary predictors of adherence is "self-efficacy" or
patient readiness. Patients who have confidence in their ability
to take their medications as instructed (ie, they have good self-efficacy)
are much more likely to be compliant than patients who lack this
confidence. Among HIV-infected patients, the common comorbidities
of substance abuse and untreated mental illness contribute significantly
to nonadherence. Because side effects of the medications also are
a significant barrier to patient adherence, providers need to vigorously
address complaints of side effects.
Table
7-1. Factors that Promote Patients' Adherence to Medication Regimens
Patient-related
factors
Absence
of mental illness/depression
Absence of substance abuse (alcohol and other drugs of abuse)
Perceived ability to take medication as instructed (self-efficacy)
Older age
Higher literacy
Strong social support network
Adherence with medical appointments
Stable housing
Adherence with previous therapies
Positive attitude toward efficacy of medication
Medication-related
factors
Fewer
medications
Fewer doses
Fewer pills
Fewer side effects
Lack of dietary restrictions
Shorter time on therapy
Good "fit" of regimen into patient's daily routine
Health
system-related factors
Trusting
relationship with health care provider
Patient education:
- Patients
understand their regimen, including food restrictions
- Patients
understand the association of adherence and resistance
Convenient
access to medications and refills
|
What is
the best way to assess a patient's adherence?
There is no
gold standard for measuring adherence. A provider's "impression"
of a patients' adherence, without specific assessments, is very
unreliable. Mechanisms to measure adherence include assessment of
serum drug levels, electronic monitoring of pill bottle openings,
pill counts made at clinic visits or at surprise home visits, pharmacy
record reviews, and patient responses to questioning. In general
these different measures have good correlations to adherence levels,
although asking the patient will be more likely to overestimate
adherence than objective measures. Computer-assisted questioning
of patients will improve self-reporting reliability. Serum drug
level assessment provides only information about the most recent
dose and is quite costly and not practical in clinical practice.
How should
providers ask patients about adherence to get the most reliable
information?
With appropriate
education at the start of ART, a patient should know the importance
of adherence. It is important to approach the discussion of adherence
at follow-up visits in a nonjudgmental way and "give permission"
for missing doses. Also, asking specific questions will yield specific
information. An example of an inquiry might be: "Everyone misses
doses of their medication some of the time. How many times in the
last 3 days/week/month have you missed taking doses of your medicine?"
From there, a discussion of the specific events that led to missing
doses can lead to problem-solving with the patient to overcome these
barriers.
The provider
should ask patients to recount exactly when and how they are taking
their medications in order to identify any lack of understanding
of the regimen itself or of special dietary instructions.
Interventions
TOP
What can
be done to improve adherence?
The most important
intervention is making sure patients start medication only when
they are "ready." Providers need to discuss with patients
the risks associated with nonadherence that can result from starting
medications before they are ready versus waiting while they "prepare."
Preparing can mean entering into substance abuse treatment, finding
stable housing, or attending a support group to overcome fears of
medication side effects and concerns about confidentiality. Pregnant
women and patients with serious complications of HIV infection and
very low CD4 counts may not have the luxury of postponing therapy,
but for others, being ready to adhere may be critical to the outcome
of ART.
Interventions
to improve adherence in chronic diseases tend to have, at best,
modest effects on adherence. They are most effective if they are
multifaceted, ie, they target several aspects of the adherence behavior
and are repeated over time. Barriers to adherence differ among patients.
Thus, interventions should be tailored to the patient's specific
needs. In addition, barriers to adherence vary over time, so interventions
need to vary as well. Interventions can occur at the level of the
provider, care team, clinic, and/or pharmacy. Ideally, interventions
are occurring throughout the patient's medical visit and beyond.
The most commonly
used interventions address patient readiness using both one-on-one
education and support groups. Peer counseling and support are key
for many patients to work through concerns related to medication-taking.
Making patients partners in the decisionmaking process about when
to start and which regimen to use is also important. The regimen
should be as simple as possible and should be the one least likely
to cause the side effects that the patient fears the most. Substance
abuse and mental illness should be treated before starting medication
whenever possible.
After the patient begins the regimen, close followup and monitoring
of adherence is critical, often through frequent clinic visits during
the first weeks of therapy even if other medical interventions are
not necessary. Providers should ask patients about adherence and
address barriers to adherence at each followup visit. Providers
should be open to changing the regimen if a patient has significant
problems with it, whether related to side effects or to scheduling.
Patients should be encouraged to use pill boxes and incorporate
reminder systems as needed. Various kinds of interventions have
been used in HIV and other chronic diseases (see
Table 7-2).
Table
7-2: Interventions That Have Been Used to Support Adherence
in HIV and Other Chronic Diseases
The
Patient |
Start
when patients are ready |
For
patients with complications of HIV infection, low CD4 cell counts,
or pregnancy, the cost-benefit analysis of treatment is different. |
Treat
substance abuse and depression before initiating ART |
If
there is no antiretroviral emergency, patients with active substance
abuse and depression should have these comorbidities addressed
before starting an antiretroviral regimen. |
Engage
patients in medication tailoring |
Discuss
with patients in detail how the medications will fit into their
daily routine ie, when (and if) meals are eaten, what patients
do on a daily basis that can be linked to dosing times. |
Educate
(group/individual) regarding:
- the
regimen
- side
effects management
- consequences
of nonadherence
|
- Patient
education is essential both group and one-on-one.
- Involve
caretakers and patient support network in educational efforts.
- Patients
need to know exactly how to take their medication. A daily
calendar with pills on it will help a patient visualize
the regimen.
- Prior
to initiating therapy, patients should know which side effects
to expect, what they can to do to manage them, and when
to call the provider.
- Patients
need to understand the serious consequences of nonadherence
and what to do in the event of a late or missed dose.
|
Increase
support |
Patients
should enlist the aid of family and friends to promote their
adherence. The HIV health care team can provide support through
office visits, home visits, and telephone calls, especially
in the early days and weeks of ART. |
Use
skill building exercises |
Patients
who are concerned about their ability to adhere should use a
trial of jellybeans in a pill box to accustom themselves to
their pill taking schedule prior to initiating therapy. This
may not increase adherence, but it may give patients insight
into their adherence and affect their decision to start medications.
|
Address
barriers to adherence |
- Have
patients consider when medications are likely to be missed
and make plans to decrease these events.
- Some
patients store a few doses in places where they spend a
lot of time, such as at the houses of friends and relatives.
|
Use
reminders |
- Alarm
clocks, in the form of watch alarms, pagers, or pill boxes
can decrease missed doses due to simply forgetting.
- Patients
can place medications in locations where they will notice
them at dosing times, such on the breakfast table.
|
The
Regimen |
Simplify
as much as possible |
- Once
or twice-a-day regimens are easiest for patients.
- Use
as few pills and medications as possible.
- Try
to use regimens than can be followed without regard to food
intake.
|
Tailor
the regimen to the patient's lifestyle (and not the patient's
lifestyle to the regimen) |
- Ask
patients about their daily routine and comfort in taking
medications in front of others and at work.
- Construct
a regimen that works for the patient.
|
Use
pill boxes |
- Use
of pill boxes allows patients a mechanism for carrying their
daily medication.
- Pill
boxes allow patients to easily recognize when they have
missed taking a dose.
|
Make
refills accessible |
Develop
policies to allow patients ready access to refills. |
The
Clinician-Patient Relationship |
Develop
a trusting relationship |
Rarely
is initiation of antiretroviral regimens required at the first
visit. Invest in the doctor-patient relationship prior to initiating
therapy. |
Ask
about adherence |
- Providers
cannot predict adherence; they must ask patients.
- Ask
in a nonjudgmental way, with a specific time frame, to get
good information.
- Give
permission for missed doses prior to asking.
- Ask
repetitively over time.
|
Use
positive reinforcement |
Share
viral load and CD4 results and reinforce the relationship to
adherence. |
Listen
to the patient |
- Individualize
therapy based on patient preferences regarding fear of specific
side effects or specific medication.
- Negotiate
the regimen with patients.
|
System
of Care |
Maintain
close followup at initiation of regimen |
Have
telephone, office, or home contact with patients within first
few days of therapy to assess for side effects and accurate
understanding of regimen. |
Develop
patient education program |
- Consider
using nurses, case managers, pharmacists, and peers in patient
education.
- Have
written materials accessible.
|
Incorporate
the adherence message throughout the medical practice |
- All
staff members need to understand and promote the importance
of adherence.
- Have
pill boxes, alarms, and other adherence aids available to
patients.
|
What is
the role of Directly Observed Therapy (DOT) for medication adherence?
Directly observed
therapy (DOT) refers to medical staff supervising patients taking
each dose of medication. DOT has increased treatment completion
and decreased the resistance rates of tuberculosis therapy. Whether
it is feasible in HIV therapy is currently under investigation.
A majority of ongoing studies are using modified DOT, with only
1 daily dose of medication observed over the first several months
of therapy or during the administration of methadone maintenance
therapy. The results of these studies will provide valuable information
about the long-term patient acceptability, cost, and efficacy of
this approach to improve adherence over the long term.
- Medication
adherence is a significant challenge in all chronic diseases,
but is particularly important in ART because of the high levels
of adherence that must be maintained to prevent viral resistance.
- Patients
should not start taking antiretroviral medications until they
are ready.
- Providers
should take the time to assess their readiness, conduct interventions
to prepare them to begin therapy, and follow them closely once
they start.
- Interventions
to support adherence should be multifaceted and repeated over
time. However, interventions have a modest effect on adherence.
Suggested
Resources
TOP
Antinori A,
Ammassari A, Wu AW. "Proceedings of the 1st workshop on HAART
adherence: state of the art." JAIDS. 2002;31:S95-169.
Bangsberg DR,
Hecht, FM, Charlebois ED, et al. "Adherence to protease inhibitors,
HIV-1 viral load, and development of drug resistance in an indigent
population." AIDS. 2000 14:357-366.
Roter DL, Hall
JA, Merisca R, Nordstrom B, Cretin D, Svarstad B. "Effectiveness
of interventions to improve patient compliance: a meta-analysis."
Medical Care. 1998;36:1138-1161.
Sackett DL,
Haynes RB, Gibson ES, et al: "Randomized clinical trial of
strategies for improving medication compliance in primary hypertension."
Lancet. 1975;1:1265-1268.
Stone, VE:
"Strategies for optimizing adherence to highly active antiretroviral
therapy: lessons from research and clinical practice." Clin
Infect Dis. 2001; 33:865-872.
References
TOP
Bangsberg DR,
Charlebois ED, Grant RM, et al. "High levels of adherence do
not prevent accumulation of HIV drug resistance mutations."
AIDS. 2003;17:1925-1932.
Paterson DL,
Swindells S, Mohr J, et al. "Adherence to protease inhibitor
therapy and outcomes in patients with HIV infection." Ann
Intern Med. 2000;133:21-30.
Shingadia D,
Viani Rm, Yogev R, et al: "Gastrostomy tube insertion for improvement
of adherence to highly active antiretroviral therapy in pediatric
patients with human immunodeficiency virus." Pediatrics.
2000;105:E80.
Wood E, Hogg
RS, Yip B, et al. "Effect of medication adherence on survival
of HIV-infected adults who start highly active antiretroviral therapy
when the CD4+ cell count is 0.200 to 0.350x109 cells/mL." Ann
Intern Med. 2003;39:810-816.
Cases
TOP
1.
AR is a 37-year-old woman who uses heroin and cocaine
daily and has a CD4 count of 300 cells/mm3 and an HIV viral load
of 150,000 copies/mL. Since she was diagnosed with HIV infection
10 years ago she has primarily sought care when acutely ill. She
comes to clinic for the first time in 6 months because she has decided
to start "the cocktail."
Question:
How do you manage this patient?
Answer:
This patient is not engaged in primary care and is using heroin
daily. Although she might be able to adhere to therapy, she probably
won't. Beginning ART is reasonable given her CD4 cell count and
viral load; however nothing makes it critical to start therapy immediately.
The patient
did not agree with her physician's assessment that her substance
abuse was a barrier to medical care or medication adherence. She
agreed to contract with her physician to start ART after she made
5 consecutive clinic visits. After several attempts at consecutive
visits, the patient enrolled in a methadone-based substance abuse
treatment program. She began to come regularly to clinic, engaged
in in-depth medication education, and eventually started ART. She
had good adherence, maintaining an undetectable viral load for 18
months before a drug abuse relapse. When she began to miss doses,
she stopped all her medications as instructed and did not develop
significant resistance.
2. DP
is a 4-year-old with perinatally-acquired HIV infection. He is taken
care of by his maternal great- grandmother, who is also caring for
3 other great-grandchildren. He resists taking ART because of the
taste, so that it takes his great-grandmother 30-60 minutes to administer
each dose when she can get him to take it. Although she has worked
closely with the behavior modification team at the pediatric clinic,
the situation has not improved. His viral load and CD4 cell count
have not changed significantly on therapy.
Question:
What do you do to treat this patient?
Answer:
Given the patient's refusal to take medication, the decision was
made to place a g-tube for ease of administration. Within 1 month
the viral load was undetectable, and the time to administer medications
had decreased to less than 10 minutes per dose. The great-grandmother
reported a significant improvement in their relationship and in
DP's behavior in a number of domains. Although this may seem extreme,
this is an example of individualizing the intervention to the barriers
that exist for the patient (Shingadia, et al 2000).
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