COPING WITH HIV AND ANTIRETROVIRAL THERAPY

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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].

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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

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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.

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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

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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-

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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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