Clinical Manual for Management of the HIV-Infected Adult
2006 Edition

Section 3: Antiretroviral Therapy

Adherence

Background

For HIV-infected patients treated with antiretroviral therapy (ART), adherence to ART is a significant determinant of survival. Adherence is second only to the CD4 cell count as a predictor of progression to AIDS and death. Adherence rates approaching 100% are needed for optimal viral suppression, yet the average adherence rate to ART in the United States is approximately 70%. Patients with suboptimal adherence are at risk not only for HIV progression, but also for the development of drug resistance (see chapter Resistance Testing). Studies indicate that health care providers' assessments of their patients' adherence often are inaccurate and limited, so individualized assessment and planning for adherence are essential for patients to be successful with ART.

S: Subjective

Adherence assessment is most successful when conducted in a positive, nonjudgmental atmosphere. Patients need to know that their provider understands the difficulties associated with taking an antiretroviral (ARV) regimen. Within a trusting relationship, a provider may learn what is actually happening with the patient's ARV medication regimen rather than what the patient thinks the provider wants to hear. Important questions to ask a patient who is considering ART may be found in Table 1. Table 2 suggests important questions for patients who are receiving ART.

Common reasons for nonadherence include the following: experiencing adverse effects, finding the regimen too complex, having difficulty with the dosing schedule (not fitting into the daily routine), forgetting to take the medications, being too busy with other things, oversleeping and missing a dose, being away from home, not understanding the importance of adherence, and being embarrassed to take medications in front of family, friends, or coworkers. It is important to look for these and other potential barriers to adherence. (See chapter Initial History.)

O: Objective

Evaluate the following:

• CD4 cell count
• HIV viral load (indicating the effectiveness of ART in suppressing viremia; an indirect indicator of adherence)
• Current drug list (including over-the-counter medications, vitamins, and herbal remedies); check for adverse drug interactions with ARV medications
• Pharmacy refill records

A: Assessment

Assess adherence at each visit using questions such as those in Tables 1 and 2, and assessment scales such as those found in Tables 4, 5, and 6 (Appendix 1). Ask these questions in a nonjudgmental way and listen carefully to the patient to invite honesty about issues that may affect adherence.

Table 1. Important Questions to Ask Patients Considering Antiretroviral Therapy

What is your attitude toward antiretroviral therapy? Do you believe that antiretroviral therapy is effective? What do you hope these medications will do for you? Are you ready to take the medication every day, around the same time each day? Are you committed and motivated to take the medication every day for the rest of your life? Who knows about your HIV status? What other medications are you taking: prescription, over-the-counter, herbals? Are you a morning or afternoon person? What is your daily routine, including waking and bed times? How many meals and snacks do you eat per day, and at what times? Do you use alcohol, marijuana, cocaine, or injectable drugs? If so, how much do you use and how long have you used them?

Table 2. Important Questions to Ask Patients Taking Antiretroviral Therapy

Do you manage your own medications? If not, who manages them for you? What HIV medications do you take and what is their dosage? When do you take these? How do you remember to take your medications? How many doses of your HIV medication have you missed in the last 72 hours, last week, last 2 weeks, and last month? On a scale of 1 to 10, where would you say you are? A score of 1 indicates that you do not take your medicines right at all; for example, not every day or not at the same time every day; 10 indicates that you take your medications perfectly every day, at the same time every day. (Visual analog scales are also used to assess adherence; see Appendix 1.) If not a 10, what causes you not to be a 10? When are you most likely to miss doses? Do you have any adverse effects to from your HIV medications? If so, what are they? Are you comfortable taking medications in front of others? What is most difficult about taking your medications? How do you like working with your pharmacy?

The patient's self-report has been shown to be the most effective measure of adherence. Although, according to some studies, self-report of good adherence has limited value as a predictor of good adherence, self-report of suboptimal adherence should be regarded as a true predictor of poor adherence.

Before initiating (or changing) ART, it is important to assess the patient's readiness for ART. Patient factors that have been associated with poor adherence in the United States and western Europe include:

• Depression
• Active alcohol or drug use
• Low literacy
• Lack of social support
• Lack of belief in treatment efficacy
• Unstable housing
• Competing priorities (eg, housing, childcare, food, work)

Most of these factors are modifiable. Before starting ART, appropriate interventions should be made, and sources of adherence support should be identified to help patients overcome potential barriers to adherence.

It is important to note that sociodemographic variables such as sex, HIV risk factors, and education level generally are not associated with adherence. In addition, a history of substance or alcohol abuse is not a barrier to adherence.

Assess the patient's support system, and ask who knows about the patient's HIV status. Supportive family or friends can help remind patients to take their medications and assist with management of adverse effects. For patients who have accepted their HIV infection as an important priority in their lives, taking medications can become routine despite other potential adherence barriers such as alcohol or drug use.

Assess patients' willingness to accept and tolerate common adverse effects of ART. Patients may identify some adverse effects that they wish to avoid completely and others that they are willing to accept and manage; this may help in tailoring the selection of ARV medications to the individual patient. Describe strategies for the management of adverse effects before starting a regimen (see chapters Patient Education and Adverse Reactions to HIV Medications).

Before prescribing ARVs, some clinicians have their patients do adherence trials using placebo tablets or jelly beans to measure the patients' readiness to start therapy and their ability to adhere to a regimen. This trial allows patients to experience what a regimen will entail in real life, how therapy will affect their daily lifestyle, and what changes will be needed to accommodate the regimen. The shortcoming of placebo trials is that patients are not challenged with adverse effects as they might be with a true regimen.

For patients taking ART, it is important to assess adherence at every clinic visit. Tools such as those in Appendix 1 may be useful in predicting adherence. Adverse effects are a common cause of suboptimal adherence to ART. Continue to ask whether the patient has adverse effects from the ARV medications and assess his or her ability to accept and tolerate these. Work closely with the patient to treat adverse effects, and consider changes in ART if adverse effects are not tolerated. Continue to offer support to improve or maintain optimal adherence.

P: Plan

Start the ARV regimen only when the patient is ready. Starting it too early may result in poor adherence, failure of the regimen, and increased risk of ARV resistance. Comorbid conditions that interfere with adherence, such as mental health issues or depression, must be treated initially. It is important to consider the patient's preferences in selecting the drug regimen. The regimen must fit into the patient's daily routine, and the patient must believe in the potential success of ART. Simplifying the ARV regimen to the extent possible with once-daily regimens and the lowest number of pills, while maintaining efficacy and minimizing adverse effects, is important for maximizing adherence and avoiding pill fatigue. Starting ART is rarely an emergency, so taking time to identify the patient's wishes for care, make a thorough readiness assessment, select the ARV regimen, and plan for adherence support is important in maximizing the likelihood of treatment success. (See Table 3 for additional suggestions.)

Table 3. Strategies to Improve Adherence to Antiretroviral Therapy

Establish readiness to start therapy Provide education on medication dosing Review potential adverse effects Anticipate and treat adverse effects Utilize educational aids including pictures, pillboxes, and calendars Engage family, friends Simplify regimens, dosing, and food requirements Utilize team approach with nurses, pharmacists, and peer counselors Provide accessible, trusting health care team

Source: U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Table 15. May 4, 2006.

Patients who can identify their medications (in their own words) and describe the proper dosing and administration have higher adherence rates. Providing patient education before writing a prescription helps ensure adherence to ARV medications. Education can be provided in oral, written, or graphic form to assist the patient's understanding of the medications and their dosing. Basic information, including number of pills, dosages, frequency of administration, dietary restrictions, possible adverse effects, tips for managing adverse effects, and duration of therapy will help patients to understand their ARV regimens. Patients should understand that the success of ART depends upon taking the medications every day and that adherence levels of >95% are important in preventing virologic failure.

Close follow-up by telephone, clinic visits, or other contact with the patient during the first few days of therapy is useful in identifying adverse effects, assessing the patient's understanding of the regimen, and addressing any concerns before they become significant adherence barriers. Individualized interventions should be designed to optimize outcomes for each patient. Pharmacists, peer counselors, support groups, adherence counselors, behavioral interventions, and community-based case managers are useful in supporting adherence for the HIV-infected patient. Multidisciplinary teams that include nurses, case managers, nutritionists, and pharmacists, in which each care provider focuses on adherence at each contact with the patient, are extremely effective in supporting adherence.

Many physical devices can be used to support adherence. The following are simple, inexpensive, and easy to incorporate into the routine of the HIV patient:

• Medication organizers include pillboxes and medisets. These are available in several shapes and sizes to fit the needs of the individual patient. They can be filled weekly so that the patient can easily determine whether a dose of medication was missed.
• Reminder devices include alarm watches, beepers, or cell phone alarms. They are effective in reminding the patient when to take medications. Medication diaries may be used for the patient to record doses that were taken.
• Visual medication schedules: are calendars with pictures of the patient's medications on them to remind the patient to take the doses.

Interventions for successful adherence are an ongoing effort, not one-time events. Studies have suggested that adherence rates decline when patient-focused interventions are discontinued. Therefore, positive reinforcement at each clinic visit or contact is extremely important. Reinforce what the patient has done well and assist the patient in identifying and problem-solving areas for improvement. Whenever possible, share positive information about the patient's health, such as improvements in quality of life, CD4 cell count, and viral load, to encourage a high level of adherence.

Special Populations and Issues

Mental Illness

Patients with mental health issues may have difficulty with adherence. In this population, it is particularly important to incorporate ARV medications into structured daily routines. Medication cassettes, reminder signs, and calendars have been very effective for these patients. Nursing care providers and family members may be instrumental in filling medication boxes or ordering prescription refills.

Pediatrics

Adherence can be a challenge for young children who rely on parents and caregivers to provide their medications. Adolescents are more likely than younger children to have poor adherence. To improve adherence in this population, it is important to support the family. The Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection review some of the adherence issues and considerations for this patient population.

Low Literacy

Health literacy is an important predictor of treatment adherence, particularly in low-income populations. Adherence interventions are necessary in this population to accommodate individuals who have difficulty reading and understanding medical instructions. Providers often fail to recognize this disability. In addition, adherence support is needed for patients who have difficulty navigating the health care system.

Resource-Limited Settings

Early research has shown that the level of adherence in resource-limited countries is at least as good as that in resource-rich settings and that rates of virologic suppression are equivalent or better. Lack of access to a consistent supply of ARV medications, including financial barriers that may cause interruptions in treatment, appears to be the primary obstacle to adherence in resource-limited settings.

Patient Education

• Providers must urge patients to take their ARV medications exactly as prescribed and to take every dose, every day.
• Patients must know that if they miss or skip doses of their ARV medications, they may not work well to fight HIV, and the virus may develop resistance to them.
• Tell patients to notify the clinic if they miss doses of their ARV medications.
• Discuss with patients how to improve their adherence, and support good adherence.
• Warn patients that some people have adverse effects from the medications, and tell them to notify the clinic if they develop adverse effects. Discuss ways to reduce these effects.

References

• Brummet L. AIDS care: adhering to antiretroviral therapy. Nurs BC. 2002 Oct;34(4):24-5.
• Gaithe J Jr. Adherence and potency with antiretroviral therapy: a combination for success. J Acquir Immune Defic Syndr. 2003 Oct 1;34 Suppl 2:S118-22.
• Golin CE, Smith SR, Reif S. Adherence counseling practices of generalist and specialist physicians caring for people living with HIV/AIDS in North Carolina. J Gen Intern Med. 2004 Jan;19(1):16-27.
• Machtinger EL, Bangsberg DR. Adherence to HIV Antiretroviral Therapy. In: Peiperl L, Coffey S, Volberding PA, eds. HIV InSite Knowledge Base [textbook online]; San Francisco: UCSF Center for HIV Information; May 2005. Accessed February 7, 2006.
• Malcolm SE, Ng JJ, Rosen RK, et al. An examination of HIV/AIDS patients who have excellent adherence to HAART. AIDS Care. 2003 Apr;15(2):251-61.
• Stone VE, Smith KY. Improving adherence to HAART. J Natl Med Assoc. 2004 Feb;96(2 Suppl):27S-29S.
• U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. May 4, 2006. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=7.
• U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. November 3, 2005.

Appendix 1. Scales to Assess Adherence to HIV Medication Regimens

Table 4. Visual Analog Scale Used in a Research Study to Assess Adherence to HIV Medication Regimens

Script for Interviewing Patient about Adherence Interviewer Now I'm going to ask some questions about your HIV medications. Most people with HIV have many pills or other medications to take at different times during the day. Many people find it hard to always remember to take their pills or medicines. For example: Some people get busy and forget to carry their pills with them. Some people find it hard to take their pills according to all the instructions, such as "with food" or "on an empty stomach," "every 8 hours," or "with plenty of fluids." Some people decide to skip taking pills to avoid adverse effects or to just not take pills that day. We need to understand what people with HIV are really doing with their pills or medicines. Please tell us what you are actually doing. Don't worry about telling us you don't take all your pills or medicines. We need to know what is really happening, not what you think we "want to hear." Which antiretroviral medications have you been prescribed to take within the last 30 days? INTERVIEWER: LIST CODES FOR ALL ANTIRETROVIRALS THAT SUBJECT WAS PRESCRIBED TO TAKE IN LAST 30 DAYS. IDENTIFY UP TO 4 DRUGS. DRUG A: DRUG C: DRUG B: DRUG D: Interviewer Now, I am going to ask you some questions about these drugs. Please put an "X" on the line below at the point showing your best guess about how much (DRUGS A-D) you have taken in the last 3-4 weeks. We would be surprised if this were 100% for most people. HAND INSTRUMENT AND PEN TO RESPONDENT Interviewer 0% means you have taken no (DRUG A) 50% means you have taken half your (DRUG A) 100% means you have taken every single dose of (DRUG A) Adherence Self Assessment Instrument Instructions for Patient: Put an "X" on the line below at the point showing your best guess about how much of each drug you have taken in the last 3 to 4 weeks. 0% means you have taken none of the drug 50% means you have taken half of the drug 100% means you have taken every single dose of the drug DRUG A: DRUG B: DRUG C: DRUG D:

Adapted from Machtinger EL, Bansberg DR. Adherence to HIV Antiretroviral Therapy. HIV InSite, May 2005. Available online at hivinsite.ucsf.edu. Accessed June 1, 2006.

Table 5. Morisky Scale to Assess Adherence to HIV Medications: Dichotomous Response Options

Subjects were asked: "Thinking about the medications PRESCRIBED to you by your doctor(s), please answer the following questions." NO YES Do you ever forget to take your medications? Are you careless at times about taking your medications? When you feel better, do you sometimes stop taking your medications? Sometimes if you feel worse when you take your medications, do you stop taking them?

Adapted from Morisky DE, Green LW, Levine DM. Concurrent and predictive validity of a self-reported measure of medication adherence. Med Care 1986;24:67-74.

Table 6. Morisky Scale to Assess Adherence to HIV Medications: 5-Point Response Options

Subjects were asked: "Thinking of the medications PRESCRIBED to you by your doctor(s), please answer the following questions." Response options: never = 0; rarely = 1; sometimes = 2; often = 3; always = 4 0 1 2 3 4 Do you ever forget to take your medications? Are you careless at times about taking your medications? When you feel better, do you sometimes stop taking your medications? Sometimes, if you feel worse when you take your medications, do you stop taking them?

Adapted from Morisky DE, Green LW, Levine DM. Concurrent and predictive validity of a self-reported measure of medication adherence. Med Care 1986;24: 67-74.