For HIV-infected patients receiving antiretroviral therapy (ART), adherence to ART is the major factor in ensuring the virologic success of an initial regimen and 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 ART adherence in the United States is approximately 70%. Individualized assessment of and support for adherence are essential for patients to be successful with ART.

Patients with suboptimal adherence are at risk not only of HIV progression, but also of the development of drug resistance (see chapter Resistance Testing ) and consequent narrowing of options for future treatment. In one cohort study it was estimated that drug-resistant mutations will occur in 25% of patients who report very high but not perfect (92-100%) adherence to ART. It is important to note, though, that the relationship between suboptimal adherence and resistance to antiretroviral (ARV) medications is very complex and is not thoroughly understood.

Characteristics of the ARV regimen and individual patient pharmacokinetic variables also influence the likelihood of both virologic suppression and the development of resistance mutations. For example, in patients on initial ART regimens it appears that more drug resistance occurs in regimens that are based on an unboosted protease inhibitor or a nonnucleoside reverse transcriptase inhibitor, where the genetic barrier to resistance is relatively low, than in regimens that include a ritonavir-boosted protease inhibitor. In patients with suboptimal adherence, these factors can more strongly influence outcomes of therapy.

S: Subjective

Studies indicate that health care providers' assessments of their patients' adherence often are inaccurate, so a calm and open approach to this topic is very important.

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 ARV regimen. Within a trusting relationship, a provider may learn what is actually happening with the patient's adherence rather than what the patient thinks the provider wants to hear. See Table 1 for examples of questions to assess adherence in patients who are receiving ART. For patients who are considering initiation of ART, it is important to lay the groundwork for optimal adherence in advance, and anticipate barriers to adherence; see Table 2 for exploratory questions.

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 simple, nonjudgmental, structured format and listen carefully to the patient to invite honesty about issues that may affect adherence. Asking about adherence over the last 3 to 7 days gives an accurate reflection of longer-term adherence.

Table 1. Important Questions to Ask Patients Taking ART

Do you manage your own medications? If not, who manages them for you?
What HIV medications do you take, and what are the dosages? 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 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?

Table 2. Important Questions to Ask Patients Considering Initiation of ART

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?

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 taken seriously and considered a strong indicator of nonadherence.

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 support from a partner
More advanced HIV infection
Young age
Lack of belief in treatment efficacy
Unstable housing
Competing priorities (e.g., 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 his or her HIV status. Supportive family members 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 ).

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.

Before prescribing ARVs, some clinicians have their patients conduct adherence trials using placebo tablets or jelly beans to measure the patients' readiness to start therapy and their ability to adhere to a regimen. Such a trial allows patients to experience what a regimen will entail in real life, how therapy will affect their daily lifestyles, 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 an actual regimen.

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 (and lowest total expense to the patient), while maintaining efficacy and minimizing adverse effects, is important for maximizing adherence and avoiding pill fatigue. Starting ART is rarely an emergency situation, 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 for Improving Adherence to ART

Use a multidisciplinary team approach
Establish a trusting relationship with the patient
Establish readiness to start ART
Involve the patient in ARV regimen selection
Identify potential barriers to adherence prior to starting ART
Provide mental health and substance abuse resources for the patient if needed
Anticipate and treat adverse effects
Assess adherence at every clinic visit
Use educational aids including pictures, pillboxes, and calendars
Identify the type of nonadherence and the reasons for nonadherence
Simplify regimens if possible

Source: U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents . Table 11. December 1, 2009.

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 regimens. 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, and 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 featuring photos or images of the patient's medications to remind the patient which drugs to take and at what dosages.

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, but 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

Research has shown that the level of adherence in resource-limited countries is at least as good as 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

Educate patients about the importance of adherence and the need to take their ARV medications exactly as prescribed and to take every dose, every day.
Advise patients that if they miss or skip doses of their ARV medications, the regimen may be ineffective, and the virus may develop resistance to ARVs.
Tell patients to notify the clinic if they miss doses of their ARV medications.
Work with patients to devise ways to improve their adherence, and reinforce good adherence behavior.
Advise patients in advance 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

Bangsberg DR, Moss AR, Deeks SG. Paradoxes of adherence and drug resistance to HIV antiretroviral therapy . J Antimicro Chemother 2004: 53: 696-99.

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.

Protopopescu C, Raffi F, Roux P, et al.; ANRS CO8 APROCO-COPILOTE Study Group. Factors associated with non-adherence to long-term highly active antiretroviral therapy: a 10 year follow-up analysis with correction for the bias induced by missing data . J Antimicrob Chemother. 2009 Sep;64(3):599-606.

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 . December 1, 2009.

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 Patients about Adherence

Adapted from Machtinger EL, Bangsberg DR. Adherence to HIV Antiretroviral Therapy . HIV InSite, May 2005.

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:

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

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.
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?

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

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.
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?

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