Download coping with hiv and antiretroviral therapy

REVIEW
COPING WITH HIV AND ANTIRETROVIRAL THERAPY
—
Jean C. Lee, PharmD, BCPS*
ABSTRACT
Highly active antiretroviral therapy (HAART) is
a polypharmic regimen that has been shown to
significantly reduce morbidity and mortality associated with HIV infection. However, HAART is also
complicated and requires strict adherence (nearly
100% for optimal viral suppression) and is associated with significant adverse events and metabolic complications, which diminish quality of life
and are detrimental to adherence. The community pharmacist is the “front-line” professional in
identifying adherence barriers. This article
reviews the metabolic abnormalities associated
with HAART, in addition to the more common
adverse effects that patients should expect and will
need to address. Also reviewed are the common
adherence barriers and the many ways in which
the community pharmacist can identify and manage them. For adherence and management of
side effects, patient education is critical.
Improving adherence and preventing further
infection among those patients who are HIV positive are now part of the national public health priorities with regard to HIV/AIDS. Community
pharmacists often have the most frequent interactions with HIV-infected patients, and thus have the
greatest number of teachable moments.
Increasing the body of knowledge for HIV-infected HAART recipients will offer significant clinical
benefit, not only in terms of adherence but also in
managing side effects and metabolic complications from the medications.
(Adv Stud Pharm. 2006;3(2):65-77)
*Clinical Pharmacist–HIV/AIDS, McAuley Health Center,
Saint Mary’s Health Care, Grand Rapids, Michigan.
Address correspondence to: Jean C. Lee, PharmD, BCPS,
Clinical Pharmacist–HIV/AIDS, McAuley Health Center,
Saint Mary’s Health Care, 245 Cherry Street, Suite 306,
Grand Rapids, MI 49503. E-mail: [email protected].
University of Tennessee Advanced Studies in Pharmacy
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H
ighly active antiretroviral therapy
(HAART) is a polypharmic regimen that
has been shown to significantly reduce
morbidity and mortality associated with
HIV infection. With HAART, HIV infection has now
become a chronic rather than imminently terminal illness. However, HAART is also complicated, requiring
strict adherence, and is associated with significant
adverse events (especially in the initial weeks) and
metabolic complications.
Although eligibility and treatment goals for
HAART are defined by CD4+ cell counts and viral
load, these 2 parameters do not completely define successful treatment. The adverse side effects and metabolic complications with many of the HAART
components can severely attenuate the clinical benefits. Not only do these adverse effects diminish quality
of life but they are also detrimental to adherence.
Suboptimal adherence can place the patient at
increased risk for the progression of HIV infection, in
addition to the development and transmission of
drug-resistant virus, which may reduce future treatment options.1
METABOLIC COMPLICATIONS
Beyond the discomforts of adverse effects, such as
diarrhea, nausea, vomiting, and rash, there can be metabolic complications of HAART that affect not only the
health of the patient but also quality of life and selfesteem. These complications can include fat redistribution, altered glucose metabolism, dyslipidemia,
cardiovascular disease, bone disorders, and mitochondrial disorders. Some of these complications are visibly
obvious, which can thus potentially compromise confidentiality of the patient’s HIV status and thus probably
adherence to HAART. In addition, the patient has to
deal with not only the metabolic disorders but also their
sequelae, and every treatment for a metabolic adverse
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effect increases the already significant pill burden. The
etiology of many of these metabolic complications
remains undefined (ie, related to the viral infection,
HAART, both, or neither), and it is unclear whether they
are distinct phenomenon or part of a syndrome(s).2,3
Table 1 summarizes the adverse effects of HAART components on these metabolic abnormalities.4,5
LIPODYSTROPHY
Lipodystrophy is a generalized term relating to
abnormal fat redistribution in an HIV-infected person. It may be seen as lipoatrophy and lipohypertrophy occurring with HAART. Lipoatrophy with HIV is
a loss of peripheral subcutaneous fat and is most often
seen as facial thinning, in addition to thinning in the
arms, legs, and buttocks. Lipohypertrophy occurs in
the upper back (resulting in a “buffalo hump”), the
abdominal area (central obesity), and in the breasts.
Lipodystrophy occurs in approximately 40% to 50%
of patients on long-term HAART.3
Currently, there is a lack of a standard definition
for lipodystrophy, thus complicating monitoring and
management of this condition. Although the etiology
Table 1. Adverse Effects of Different Classes of
Antiretroviral Drugs
NRTIs
NNRTIs
PIs
+
-
-
• Elevated triglycerides
-
(+)
++
• Elevated LDL-C
-
(+)
+
(+)
-
++
• Fat atrophy
+
-
+
• Fat accumulation
-
-
++
Lactic acidosis
Lipid changes
Insulin resistance
Fat redistribution
+ = sometimes causes adverse reactions; (+) = possibly causes adverse
reactions; ++ = frequently causes adverse reaction; - = not observed to
cause adverse reaction; LDL-C = low-density lipoprotein cholesterol;
NRTI = nucleoside reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; PI = protease inhibitor.
Reprinted with permission from Grinspoon. Am J Med. 2005;118(suppl
2):23S-28S.4
Adapted from Health Resources and Services Administration HIV/AIDS
Bureau Web site. Available at: www.hab.hrs.gov/tools/primarycareguide/
PCGchap6.htm. Accessed January 15, 2006.5
66
is unclear, the cause may be multifaceted: type and
duration of HAART, older age, baseline body mass
index, duration of HIV infection, baseline degree of
immunodeficiency, white race, and mitochondrial
toxicity. Gender analyses have showed that women are
more likely to develop lipohypertrophy and men
lipoatrophy. At this time, the management of lipohypertrophy includes diet and exercise, switching of
antiretroviral (ARV) drugs, anabolic steroids, testosterone, recombinant growth hormone, insulin sensitizers (metformin/thiazolidinediones), lipid-lowering
agents, and plastic surgery. Lipoatrophy may be managed with stopping the offending agent (ie, switching
from stavudine or zidovudine to abacavir or tenofovir) or corrective plastic surgery for facial filling.3,610
As shown in Table 2, some of the potential
approaches to addressing lipodystrophy and body
shape changes are drastic and/or expensive.11
ALTERATIONS IN GLUCOSE METABOLISM
Insulin resistance is defined as the diminished
effectiveness of insulin in lowering glucose levels in
the body. Insulin resistance may occur in varying
degrees with decreased functioning of β cells and then
finally to overt type 2 diabetes mellitus.12 Insulin resistance is seen more frequently in those receiving protease inhibitors (PIs), as compared to the other drug
classes of HAART, but the cause is unclear.3 However,
a very recent study that compared the effect of
atazanavir to lopinavir/ritonavir on glucose disposal
rate showed that atazanavir does not affect glucose
metabolism.13 Importantly, hyperinsulinemia appears
to be associated with a “buffalo hump,” thus those
patients exhibiting this feature of lipodystrophy may
need to have closer monitoring for abnormalities in
glucose metabolism.14
Abnormal glucose metabolism and diabetes are
detrimental for reasons beyond the expected complications of diabetes (ie, neuropathy, nephropathy, and
retinopathy). A recent study suggests that diabetes may
significantly increase the risk of HIV-associated dementia. In this study, the odds ratio of diabetes with HIVassociated dementia was 5.43 (1.66–17.70, confidence
interval) after adjustment for covariates, including age,
education, ethnicity, CD4+ cell count, duration of
HIV infection, and PI-based ARV therapy.15
As the rates of PI-associated glucose intolerance/
insulin resistance (16%–46%) and diabetes (1%–13%)
are greater than the incidence of diabetes in the gener-
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al population (7%), it is possible that patients with
HIV receiving PIs are at an increased risk for developing cardiovascular disease, especially in conjunction
with the metabolic abnormalities related to PIs.16-18
Because of the potential for developing abnormal glucose metabolism and other risk factors of cardiovascular disease, the patient’s medical and family history
should also be considered when choosing ARVs.
Diet and exercise have been shown to prevent and
treat complications of diabetes and may be appropriate
for ARV-associated insulin resistance and diabetes.6
Insulin-sensitizing agents, such as metformin and thiazolidinediones, have been shown to improve insulin
resistance resulting from PI therapy.19,20 Another
method to consider includes avoiding the use of PIs,
especially in those patients who have risk factors predisposing them to diabetes or cardiovascular disease.
Switching to alternate ARVs that tend not to aggravate
plasma glucose has also been successful. Studies have
shown improvement in glucose metabolism by switching from a PI to nevirapine, efavirenz, or abacavir.21-23
Switching to atazanavir may also benefit these
patients; however, there are currently no data to support this switch.
DYSLIPIDEMIA
Dyslipidemia is defined as increased levels of
triglycerides, low-density lipoprotein cholesterol
(LDL-C), and total cholesterol, and decreased levels
of high-density lipoprotein cholesterol. These changes
are seen in treatment-naïve patients, but HAART
contributes to these effects, particularly with PI
use.4,24,25 However, in one study, atazanavir (plus ritonavir or saquinavir) had smaller effects on lipids compared to lopinavir/ritonavir, with comparable efficacy
and tolerability.26 Given the changes in abdominal fat
and glucose metabolism, it is not surprising that dyslipidemia is another potential metabolic complication
of HAART.
The management of dyslipidemia should follow
the National Cholesterol Education Panel (NCEP)
guidelines. All efforts should be made to modify or
alter risk factors for coronary heart disease through
therapeutic lifestyle changes (diet and exercise). When
LDL-C and total cholesterol lowering is needed,
HMG-CoA (hydroxymethylglutaryl-coenzyme A)
reductase inhibitors, such as pravastatin and atorvastatin, may be used. Lovastatin and simvastatin are
contraindicated with the use of PIs because of similar
Table 2. Potential Therapeutic Approaches for HIV Therapy-Associated Body Shape Changes
Body Shape Change
Comments
Fat wasting
• Switch from stavudine or zidovudine to abacavir or tenofovir
Virologically safe; adverse effects of new agent must be considered
• Polylactic acid
Expensive; multiple series of injections are typically required; surgical
infection, expense, and risk of fat hypertrophy of the transplanted tissue
limit use of this procedure; requires surgical expertise
• Rosiglitazone
Data are mixed but tend to indicate limited benefit, especially in
absence of hyperinsulinemia
Fat accumulation
• Metformin
Best data are from studies of hyperinsulinemic patients; may worsen
lipoatrophy
• Growth hormone
Accumulation of data support use for central fat hypertrophy and buffalo hump; can worsen insulin resistance, increase fluid retention, produce
arthralgias; expensive
• Liposuction
Reaccumulation of fat not uncommon; requires surgical expertise;
expensive
Reprinted with permission from Wohl. Curr HIV/AIDS Rep. 2005;2:74-82.11
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metabolism via cytochrome P450 enzyme system.
Rosuvastatin is another potential statin that may also
be used; however, no clinical studies have been performed in patients with HIV. To lower triglycerides,
fibrates (fenofibrate and gemfibrozil) may also be
used.27,28 Recently, omega-3 fatty acids have also been
used to treat hypertriglyceridemia.29,30 Modification of
ARVs may also be an option. Studies have shown
reductions in lipids after switching to atazanavir,
boosted atazanavir, or nevirapine.31-33
CARDIOVASCULAR DISEASE
In healthy individuals, obesity, insulin resistance,
and dyslipidemia are strongly linked. In fact, these
abnormalities constitute a metabolic syndrome and are
thought to increase the risk of cardiovascular disease in
HIV-infected patients, as metabolic syndromes do in
the general population. In fact, HIV-infected patients
are at increased risk for cardiovascular disease. The
Data Collection on Adverse Events of Anti-HIV
Drugs study showed that patients exposed to HAART
had a 26% increase in relative risk of myocardial
infarction per year of HAART exposure, with risk
increasing each year (Figure 1).34 Thus, cardiovascular
risk factors need to be managed aggressively and management should follow the guidelines set forth by the
NCEP: namely, low-fat diet, increased exercise, smoking cessation, and, when necessary, lipid-lowering
agents. However, as discussed earlier in this article,
lipid-lowering agents are associated with drug interactions and liver toxicity, particularly in patients coinfected with hepatitis B or C.3
BONE ABNORMALITIES
Osteopenia, osteoporosis, and osteonecrosis are the
most significant bone disorders affecting patients with
HIV infection. Osteoporosis is a bone disorder in
which reduced bone mass (osteopenia) reduces bone
strength, resulting in an increased risk of fractures after
minimal trauma. HIV infection appears to increase the
risk of osteopenia and osteoporosis, but the cause is
unclear. Some of the typical causes of osteopenia and
osteoporosis, such as corticosteroid use and nutritional deficits, are also common among HIV-infected individuals, and other risk factors from the general
population (eg, Caucasian and Asian ethnicity and
female gender) also apply to those infected with HIV.
HIV-infected women have lower bone mineral density
(BMD) than HIV-negative women and thus may be at
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increased risk of developing osteopenia and osteoporosis.35,36 One study indicated that ARVs were not associated with lower BMD.35 Medroxyprogesterone acetate
injection suspension is commonly used to prevent
pregnancy. This hormone may decrease BMD in
women receiving this medication (“Dear Doctor” letter from Pfizer, Inc, November 2004). HIV-infected
women who are using this form of birth control may
need to be monitored more closely for osteopenia and
osteoporosis. Although some reports suggest that certain HAART components can increase the risk of
osteopenia and osteoporosis, the relationship (if any) is
Figure 1. Incidence of MI According to Duration of
Exposure to HAART
The incidence of primary events was assessed beginning at baseline according to the cumulative duration of HAART since the initiation of therapy.
Data are stratified as follows: in 1-year intervals from the initiation of therapy to 4 years, more than 4 years of exposure, and no exposure. The rate
of myocardial infarction (MI) was generally lower among the patients not
exposed to HAART than in any of the treated groups. As compared with
the rate of MI among the patients treated for less than 1 year, the univariable relative rate was:
Exposure
No exposure to therapy
1 to <2 years of exposure
2 to <3 years of exposure
3 to 4 years of exposure
>4 years of exposure
Relative Rate (95% confidence interval)
0.24 (0.07–0.89)
1.34 (0.58–3.10)
1.73 (0.80–3.76)
1.98 (0.94–4.15)
2.55 (1.25–5.20)
P <.001 for trend.
The vertical bars represent the 95% confidence intervals.
HAART = highly active antiretroviral therapy.
Reprinted with permission from Friis-Moller et al. N Engl J Med.
2003;349:1993-2003.34
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not yet clear.37 There have not been many studies investigating the treatment of osteopenia/osteoporosis in
HIV-infected patients. However, one study did show
that alendronate, vitamin D, and calcium were safe and
potentially useful in treating osteopenia/osteoporosis
associated with HIV infection.38
Osteonecrosis, also termed avascular necrosis,
refers to skeletal pain from death of cellular elements
of bone and is thought to be caused by the interruption of blood supply to bone. As with
osteopenia/osteoporosis, the link between HAART
and this disorder is debatable.37 Available data suggest
that corticosteroids and other risk factors may predispose HIV-infected patients in developing osteonecrosis.39 A recent study showed that ritonavir significantly
increased systemic exposure to prednisolone in healthy
subjects after receiving prednisone (20 mg) and ritonavir (200 mg twice daily) at 4 and 14 days.40 Clinicians
should be aware of the potential for bone disorders,
but screening is not recommended at this time.
MITOCHONDRIAL DISORDERS
Some of the older nucleoside reverse transcriptase
inhibitors (NRTIs) are implicated in mitochondrial
toxicity, which may contribute to many of the metabolic abnormalities associated with these agents (eg,
polyneuropathy, myopathy, cardiomyopathy, pancreatitis, pancytopenias, steatosis, peripheral fat wasting,
and hyperlactatemia and lactic acidosis).3 The role of
HIV infection itself in mitochondrial toxicity is
unclear; however, NRTIs have been associated with
reduction in mitochondrial DNA content and changes
in mitochondrial morphology and function, which in
some cases lead to clinical events.41
Lactic acidosis may occur approximately 4 months
after treatment initiation and is defined as arterial pH
less than 7.25 and venous lactate level greater than 5
mmol/L. The symptoms are vague and include weight
loss, fatigue, abdominal pain, nausea, cardiac dysrhythmias, dyspnea, and possible evidence of hepatic
dysfunction (hepatomegaly and modest increase in
liver enzyme levels).6,37 Treatment requires supportive
care mostly consisting of bicarbonate and respiratory
support and the discontinuation of the causative medications, which is likely the NRTI class. Normalization
of serum lactate can take several months.37,42 Patients
may be restarted on combinations of non-nucleoside
reverse transcriptase inhibitors and PIs, as they lack
affinity for mitochondrial DNA. There are also some
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NRTIs that may not have as potent affinity for mitochondrial DNA production (ie, abacavir, emtricitabine, lamivudine, and tenofovir).42
EMPHASIZING THE IMPORTANCE OF
CAREFUL COMPLIANCE
Although the efficacy of HAART in clinical trials
has been impressive, the effectiveness has been disappointing, with viral suppression falling to a reported
40% to 50%.43-46 The most likely explanation is
reduced adherence to the treatment regimen. Thus,
the healthcare team needs to focus on overcoming or
minimizing the numerous obstacles to optimal implementation of HAART. The community pharmacist is
the “front-line” professional in identifying adherence
barriers. They are the first to notice late refills, thus
they can question the patient regarding possible
missed doses. They can also talk to the patient about
side effects or other problems they may be having that
are affecting adherence. By contrast, in an HIV clinic,
the provider only sees the patient for follow-up. If the
patient is having side effects, the provider is unaware
of these issues unless the patient contacts the HIV
clinic directly. However, the community pharmacist
can ask about side effects with each monthly pickup
and refer the patient to the clinic if needed.
Some of the many challenges for community pharmacists to addressing these adherence barriers include
lack of privacy for counseling patients, service
demands that are unscheduled, physical separation
from other healthcare providers, and time pressure.
Smith et al surveyed 440 pharmacy managers in
ambulatory care settings.1 Fifty-nine percent of
respondents said they did not have enough time to
provide adherence counseling to patients receiving
ARV therapy and only 35% felt they were adequately
skilled to provide adherence counseling. There were
also significant differences in counseling behaviors
when dispensing ARV therapy between time-stressed
and non–time-stressed respondents (Table 3).1 Perhaps
an increase in communication between the community pharmacist and the HIV clinic may help address
these obstacles.
Adherence can be one of the biggest challenges to
the healthcare team managing an HIV-infected
patient, not only because of the very high adherence
levels required for viral suppression but also because it
can be very difficult to accurately measure.47,48
However, it is a challenge that must be aggressively
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Table 3. Counseling Behaviors When Dispensing Antiretroviral Prescriptions in Ambulatory Care Settings:
The Effect of Time Stress
Respondents Performing Behavior, %
Time Stressed*
Not Time Stressed
P†
Ask if patient has questions or concerns about his or her treatment
39§
42
.5131
Explain the administration schedule for each prescribed medication
31||
52
.0001
In addition to the label, provide written administration instructions
35§
32
.5774
Explain the oral intake requirements of the regimen
28
48
.0001
Explain potential drug interactions
13||
31
<.0001
Discuss storage requirements for antiretroviral medications
14||
28
.0009
Discuss potential adverse effects of antiretroviral medications
13
24¶
.0089
Explain what to do if a dose is missed
8
23
<.0001
Discuss resistance or other consequences of nonadherence
5
15¶
.0010
Advise patients about ways to manage ARV adverse effects
4
11
.0132
Tell patient when he or she is due back for a refill
3
5¶
.3881#
Help patient plan administration times to fit his or her daily routine
2
8¶
.0059#
Suggest strategies for remembering when to take ARVs
1
4
.0251#
Provide a pill box or pill organizer with compartments for doses
1
3
.4256#
Ask patient to repeat or rehearse administration instructions
1
3
.3648#
<1
0
1.0000
14
19
.1503
10††
18
.0359
Review administration instructions for the regimen with the patient
6
15
.0042
Asked whether ARVs were being taken on time
8
11
.3496
Ask about barriers that make it hard to take ARVs
4
7
.1573
Warn patient you would call his or her physician if ARVs were not taken as prescribed
5
6
.6203
Practice
Always Performed with New Prescriptions‡
Telephone patient to follow up on ARV use or adverse effects
Usually or Always Performed with Refills**
Ask whether the patient experienced adverse effects
Praise patient if he or she was highly adherent
Gray shading indicates statistical significance.
*Pharmacists were classified as time stressed if more time was needed than what was allocated to provide high-quality care to patients with HIV infection presenting
new or refill prescriptions. Sample size varies because of missing data.
†Pearson’s chi-square statistic.
‡272 respondents were time stressed and 113 were not.
§n = 270.
||
n = 271.
¶n = 112.
#Fisher’s exact test.
**193 respondents were time stressed and 190 were not.
††n = 192.
ARV = antiretroviral.
Adapted with permission from Smith et al. Am J Health Syst Pharm. 2004;61:1120-1129.1
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Figure 2A. Virologic and Immunologic Outcomes
According to Self-Reported Adherence Level
of Participants
n = 1074, 922, 699, and 525 for months 1, 4, 8, and 12, respectively.
n denotes the number of study participants who provided self-reported
adherence data at follow-up visits made during the months indicated.
*P <.001 for 3-way comparison outcomes, by adherence level.
HIV = human immunodeficiency virus.
Data from Mannheimer et al.49
Figure 2B. Virologic and Immunologic Outcomes
According to Self-Reported Adherence Level of
Participants
n = 1074, 922, 699, and 525 for months 1, 4, 8, and 12, respectively.
n denotes the number of study participants who provided self-reported
adherence data at follow-up visits made during the months indicated.
*P <.001 for 3-way comparison outcomes, by adherence level.
HIV = human immunodeficiency virus.
Data from Mannheimer et al.49
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managed, as numerous studies have shown that higher
adherence levels result in greater decreases in HIVRNA levels, greater CD4+ cell counts, and more
patients with nondetectable HIV-RNA levels at 12
months. An example of these study results is shown in
Figures 2A-C.49
Several factors that negatively affect adherence in
HIV-infected patients have been identified and many
are not surprising (Table 4), such as active substance
abuse, active depression, pill burden, food requirement, and side effects.48,50 The recently updated
guidelines on HIV treatment from the Department
of Health and Human Services (DHHS) cite other
predictors of inadequate adherence to HIV medications, of which the pharmacist should be aware, such
as a lack of trust between clinician and patient, lack
of reliable access to primary medical care or medication, and low literacy.48,51 Notably, in her review,
Chesney showed that side effects were the third most
frequent cause for nonadherence (following “forgot
or busy” and “away from home”).50 Thus, even with
the side-effect profiles of the HAART components,
poor adherence is multifactorial. Predictors of optimal adherence to HIV medications, and hence optimal viral suppression, include availability of
emotional and practical life supports, a patient’s abil-
Figure 2C. Virologic and Immunologic Outcomes
According to Self-Reported Adherence Level of
Participants
n = 1074, 940, 709, and 531 for months 1, 4, 8, and 12, respectively.
n denotes the number of study participants who provided self-reported
adherence data at follow-up visits made during the months indicated.
*P <.001 for 3-way comparison outcomes, by adherence level.
Data from Mannheimer et al.49
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ity to fit medications into his or her daily routine,
understanding that suboptimal adherence leads to
resistance, recognizing the factors that lead to suboptimal adherence (ie, missed/delayed doses, drug
interactions, and incomplete absorption), recognizing that taking all medication doses is critical, feeling
comfortable taking medications in front of others,
and keeping clinic appointments.44,48,52
Mindful of these predictors of optimal and suboptimal adherence, there are several actions the community pharmacist can take to increase adherence in their
HIV-infected population, some of which have shown
success in published studies. These are described in the
DHHS guidelines and in a publication from the 2000
International Conference on Adherence to
Antiretroviral Therapy.43,53 In fact, the DHHS guidelines state that optimal adherence requires full participation by the healthcare team, with goal reinforcement
by more than 2 team members.53 First, patient education on treatment goals and drug mechanisms clearly
improves adherence. Pharmacists can serve as a
reminder to patients about the importance of adherence and how the HAART components work in
reducing
HIV
morbidity
and
mortality.
Recommendations for the “body of knowledge” that
HAART recipients should have prior to starting therapy are outlined in Table 5.43 Second, pharmacists can
focus on new patients who are most susceptible to
experiencing drug interactions, or patients who are
switching ARV therapy because of failure with another drug, perhaps because of poor adherence. These
Table 4. Factors Reported to Negatively Affect
Adherence in HIV-Infected Patients
Patient factors
• Active substance abuse (drugs and/or alcohol)
Table 5. Suggested Body of Knowledge that
Patients Should Be Taught Before Starting HAART
• Male sex
• Youth
• Active depression
• Lower level of education
• Lack of self-efficacy
• Extreme anxiety
• How HIV is transmitted
• How HIV replicates and weakens the immune system
• How immunosuppression is gauged by the degree of CD4+ cell
depletion
• How the rate of disease progression can be gauged by the viral
load and CD4+ cell count
• No change in health status
• The effect of antiretroviral therapy on viral load, CD4+ cells, and
thus disease progression and survival
• Non-white
• The common laboratory tests and their meanings
• Extreme pain
Medication factors
• The need to have laboratory tests done on time, and the time
necessary for the tests to be processed by the laboratory
• Dose frequency of more than twice a day
• The need for 100% medication adherence
• Pill burden
• The fact that minor lapses in adherence can lead to the emergence of drug-resistant mutations that may cause the current
regimen to fail, and limit future treatment options
• Type of drug
• Inability to take medication when away from home
• Food requirement
• Side effects
• Poor doctor-healthcare provider relationship
System of care
• Dissatisfaction with past experience of healthcare system,
leading to avoidance
Reprinted with permission from Chesney. Clin Infect Dis. 2000;30(suppl
2):S171-S176.50
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• That many medication adverse effects are time limited and
manageable
• What to do if a patient misses a dose of medication or cannot
access medication
• How to obtain medications if the pharmacy or the healthcare
professional on call will not provide a refill
HIV = human immunodeficiency virus.
Reprinted with permission from Reiter GS, Stewart KE, Wojtusik L, et al.
Elements of success in HIV clinical care: multiple interventions that promote adherence. Available at: http://hivinsite.ucsf.edu. Accessed
December 15, 2005.43
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patients are more prone to adherence problems.
Pharmacists in conjunction with the treating physician can ensure that the regimen fits the patient’s
lifestyle in terms of pill burden and food requirements. In this monograph, Dr Romanelli discusses
the pill burden with each recommended HAART
regimen. The DHHS guidelines also recommend
ensuring that the patient understands the regimen
and commits to it.48 Pharmacists can encourage
patients to use a pillbox, timer, or a CADEX watch.
In fact, the pharmacist can ask the patient to fill a 7day pill box with his/her medications to ensure that
the patient understands the regimen. Charts with
pictures of the pills are also helpful.43 Some patients
may not understand the concept of “refills,” thus a
brief explanation of how to obtain a refill and what
to do when the number of refills expires may be
needed. Patients may be instructed to obtain a refill
approximately 1 week before running out of medications, leading to continuous supply of ARVs and
thus preventing any interruption in dosing.
Pharmacists can work with the patient to identify
the patient’s potential weak spots with adherence
and find ways around them. For example, patients
may also wish to have an extra “stash” of medication
on a key chain, in a purse, or at a friend’s/relative’s
house, as a back-up source when a dose is forgotten
or a prescription cannot be refilled on time. Also,
patients may have transportation difficulties that
preclude timely pickup of their medications. These
patients would then benefit from a pharmacy that
delivers prescriptions.
Other suggested strategies for the pharmacist
include clarifying instructions using a personal treatment plan, showing patients how to keep a medication
diary, which is recommended by the DHHS, and
encouraging planning ahead for changes in daily routine (ie, weekends and holidays).50 The recommended
elements of a patient communication plan are outlined in Table 6.43 Pharmacists should also look into
adolescent-specific training programs and be prepared
to address this population of patients differently.
The community pharmacist has a critical role to
play with all of these strategies, but implementing
them requires a proactive approach by the pharmacist,
particularly for indigent or homeless patients and
those without social support structures. Also, adherence wanes as time progresses, thus it is important to
assess adherence at every clinic encounter. Every inter-
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action is an opportunity to evaluate and reinforce
adherence, and pharmacists often have the most frequent patient encounters of the healthcare team.43
If it is determined that adherence is not optimal,
the community pharmacist should try to determine
the cause(s). For this, message delivery is critical
because the attitudes and behaviors of healthcare professionals can influence patients’ acceptance of therapy
and commitment to long-term adherence.43,54
Pharmacists should ask open-ended questions to elicit
information. For example, instead of asking “Did you
miss any doses in the last week?,” try “How many
doses have you missed or were delayed in the last
week?” This allows the patient to feel comfortable in
admitting to missed doses. Also, the patient needs to
realize and be assured that admitting to a missed dose
is not a prelude to punishment, but often an insight
into a barrier to adherence. Asking these questions
helps to acknowledge that HAART regimens are difficult and thus can also reinforce adherence through a
supportive undertone.
Two recent studies have shown the valuable role of
the pharmacist in improving adherence to HAART.
Rathbun et al describe their randomized, controlled
pilot study to examine the impact of a pharmacistoperated adherence clinic on HAART adherence and
viral suppression over 28 weeks.55 During the study,
patients received an adherence intervention by the
study pharmacist or education provided by the primary care provider (physician or nurse practitioner). The
adherence intervention included education on
Table 6. Elements of a Patient Communication Plan
• General orientation to the care team and program
• Who and when to call for refills
• Who and when to call for problems with medications
• Who and when to call if feeling ill
• Who and when to call for issues related to mental health, substance abuse, housing, social problems, or any perceived emergency that may interfere with adherence
Reprinted with permission from Reiter GS, Stewart KE, Wojtusik L, et al.
Elements of success in HIV clinical care: multiple interventions that promote adherence. Available at: http://hivinsite.ucsf.edu. Accessed
December 15, 2005.43
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HAART administration, food restrictions, and adverse
effect management strategies; monitoring of patient
progress after therapy initiation; use of visual aids
provided by the pharmaceutical industry; and
reminder devices. Patients received a 1- to 1.5-hour
visit for HAART initiation, follow-up at 2 weeks (30
minutes), with additional visits through week 12 as
necessary. The adherence intervention resulted in
slower decline in adherence over 28 weeks (Figure 3).
Also, more patients achieved HIV-RNA levels less
than 400 copies/mL (Figure 4).55 A retrospective
study of 110 patients at a Veteran’s Administration
hospital showed the beneficial effects of more frequent pharmacist interaction with patients. HIVinfected patients obtaining monthly refills at the
pharmacy had lower adherence compared to those
obtaining refills via pill organizers dispensed by pharmacist (every 2 weeks) or mail order (monthly; 80%
vs 99% vs 91%, respectively). In this study, patients
chose their own refill mechanisms and, if the prescription was unfilled, the pharmacist called to
remind the patient about their prescription. Although
the study limitations include possibly selecting for a
more adherent population overall, the results suggest
that frequent pharmacist interaction appears to have
an important impact. If, in clinical practice, patients
with more hectic lifestyles opt for monthly refills or
mail order, perhaps a more targeted intervention by
the pharmacist may improve adherence.56
MANAGING THERAPY SIDE EFFECTS
As mentioned earlier in this article, patient education before initiation of HAART is critical. Patients
need to understand what to expect from this long-term
medication regimen. Side effects are common and can
be especially troubling in the first few weeks of treatment. Also, the patient response to these effects will
vary. Reassurance that the side effects will pass may be
sufficient for some people, whereas others may require
treatments. The DHHS guidelines state that treatment
for side effects should be included with the first prescription of HAART, in addition to instructions on
how to respond to those side effects.48 When dispensing HAART, the pharmacist should remind the
patient that side effects, although expected, should be
reported to the pharmacist and/or prescribing physician. The patient should not simply try to “stick with
it” when adjustments to dosing or other treatments
may be available.
74
Each component of HAART is associated with
specific adverse events and, in many cases, black box
warnings in the product labeling.53 Certain acute
side effects, such as nausea and vomiting, may be
Figure 3. Impact of a Pharmacist-Run Adherence
Clinic on Adherence in HIV-Infected Patients
Consecutive eligible patients initiating HAART at an indigent-care clinic were
randomized to an adherence clinic or to standard care (information provided
by physician or nurse practitioner) for education and monitoring. Adherence
was assessed by electronic monitoring and patient self-report. Differences in
adherence at week 16 were 21% (90% confidence interval [CI], 1%–42%) and
23% (90% CI, 1%–44%) at week 28. Sixty-nine percent of patients in the adherence clinic group took their medication on schedule versus 42% in the standard
care group (P = .025). Mean decline in adherence from weeks 4 to 28 was 12%
in the adherence clinic group (P = .15) versus 22% in the standard care group
(P = .002).
HIV = human immunodeficiency virus.
Data from Rathbun et al.55
Figure 4. Impact of a Pharmacist-Run Adherence
Clinic on Viral Load in HIV-Infected Patients
HIV = human immunodeficiency virus.
Adapted with permission from Rathbun et al. Clin Ther. 2005;27:199-209.55
Vol. 3, No. 2
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treated with antiemetics and dietary changes. Herbal
remedies and over-the-counter medications need to be
checked for drug interactions. Diarrhea may be managed with an antidiarrheal agent, fluid replenishment,
and dietary changes. All rashes should be evaluated by
the HIV clinic to determine if the rash is a hypersensitivity reaction to the drug. All pharmacists should be
familiar with the hypersensitivity syndrome associated
with abacavir, including the presentation, and should
immediately refer the patient to the HIV clinic or a
provider when the syndrome is observed. (Of note,
abacavir is also a component of Trizivir [abacavir sulfate, lamivudine, and zidovudine; GlaxoSmithKline,
Research Triangle Park, NC] and Epzicom [abacavir
sulfate and lamivudine; GlaxoSmithKline, Research
Triangle Park, NC].) As there is the potential of multiple drug interactions, any recommended treatment of a
side effect should be discussed with the HIV clinic.
LIVING A HEALTHY LIFESTYLE
The responsibility for HIV management lies ultimately with the patient, not only in medication
adherence but also in general health issues, such as
regular appropriate exercise and eating well. Being
infected with HIV requires a higher caloric intake,
especially if medication side effects, including vomiting or diarrhea, occur. Patients should be encouraged to explore various forms of healthy practices
from all members of the healthcare team, including
community pharmacists.
Unfortunately, initiation of HAART therapy can, in
some patients, instill a false sense of security and confidence with regard to viral transmission. These attitudes
can lead to increased risky behaviors, with the belief that
decreased viral load will limit the chance of infecting
someone else or an indifference to being infected by
someone else (ie, “I’m already infected with HIV, so who
cares if I am reinfected”).57-59 In reality, HIV-infected
patients should practice safe sex, even with other HIVinfected people. Superinfection or acquiring a drug-resistant strain can compromise chances of treatment success.
Patients should be educated on the consequences of
transmitting their virus and acquiring different viruses.
The Centers for Disease Control and Prevention has
worked with the HIV Medicine Association to create
“Prevention for Positives: An Online Resource Center”
for healthcare practitioners (www.idsociety.org/Content/
NavigationMenu/Resources/HIVMA/Prevention3/
Prevention_for_Positives.htm) and published guide-
University of Tennessee Advanced Studies in Pharmacy
n
lines.60 This is the result of a significant shift in US public health priorities toward HIV infection: to include
prevention of HIV-infected individuals from transmitting HIV to others and to tap into the HIV treatment
setting as additional opportunities to address this issue
with patients.
CONCLUSIONS
Increasing the body of knowledge for HIV-infected HAART recipients offers significant clinical benefit, not only in terms of adherence but also in
managing side effects and metabolic complications
from the drugs. The healthcare team, when reinforcing
messages and providing patient education, needs to be
open-minded and nonjudgmental. Improving adherence and preventing further infection among those
patients who are HIV infected are now part of the
national public health priorities with regard to HIV.
Community pharmacists often have the most frequent
interactions with HIV-infected patients, thus they
have the opportunity for the greatest number of teachable moments.
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