Chapter 7
Adherence To HIV Therapies

Laura W. Cheever, MD, ScM

Overview  TOP

What is meant by medication adherence?

Medication adherence means a patient takes the prescribed dose of prescribed medications on the prescribed schedule, following prescribed dietary instructions. Patient adherence to medical appointments and to behaviors that minimize the risk of transmission of HIV to others correlates strongly with adherence to medications and is an important part of primary care of HIV-infected patients but will not be addressed in this chapter.

Why is medication adherence so important in HIV therapy?

Nonadherence to prescribed therapy is a ubiquitous problem in medicine. In chronic diseases, including asthma, diabetes, and hypertension, only 50% of patients take their medication as prescribed more than 80% of the time. The same is true of patients with HIV infection. However, because of the rapid multiplication and mutation rate of HIV and the relatively low potency and short half-life of most antiretrovirals, very high levels of adherence to antiretroviral schedules are necessary to avoid viral resistance. In comparison with patients who are adherent to antiretroviral therapy (ART), nonadherent patients have: 1) Higher mortality (2.5 adjusted relative hazard) (Wood, et al, 2003), 2) Lower increase in CD4 cell count (6 cells/mm³ increase for nonadherent patients versus 83 cells/mm³ increase for adherent patients) (Paterson 2000), and 3) Increased hospital days (12.9 days/1000 days of followup for nonadherent patients versus 2.5 hospital days/1000 days for adherent patients) (Paterson, et al, 2000).

How adherent do patients need to be to avoid viral resistance?

Results of a study of adherence and response to therapy among primarily antiretroviral-experienced patients taking protease inhibitors (PIs) showed that a >95% adherence rate was necessary for 78% of patients to achieve an undetectable viral load (Paterson, 2000); however, some patients with significantly less adherence also had success (see Figure 7-1). Exactly how adherent individual patients need to be is not known and probably depends on several factors, including preexisting antiretroviral resistance, viral load, viral genetic barriers to the development of drug resistance, and drug half-life. Patients should be counseled that the risk of viral resistance increases with nonadherence and that nearly perfect adherence is the goal. Of note, patients with very low levels of adherence may be at decreased risk of developing viral resistance because there is not enough selective pressure (Bangsberg, et al, 2003).

Figure 7-1: Adherence Rates Predict
Viral Load Response

Source: Adapted from Paterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med. 2000;133:21-30. Copyright American College of Physicians. modified with permission.

Assessment   TOP

What factors impact adherence?

Many factors contribute to a patient's ability to adhere to medication schedules (Table 7-1). Note that race, education level, and income are generally not predictive of adherence. Providers must remember that factors predicting adherence or nonadherence are only associations and are not absolutely predictive. For example, although patients who use addictive substances are more likely to be nonadherent, some patients with heavy alcohol or drug use are adherent to ART.

One of the primary predictors of adherence is "self-efficacy" or patient readiness. Patients who have confidence in their ability to take their medications as instructed (ie, they have good self-efficacy) are much more likely to be compliant than patients who lack this confidence. Among HIV-infected patients, the common comorbidities of substance abuse and untreated mental illness contribute significantly to nonadherence. Because side effects of the medications also are a significant barrier to patient adherence, providers need to vigorously address complaints of side effects.

What is the best way to assess a patient's adherence?

There is no gold standard for measuring adherence. A provider's "impression" of a patients' adherence, without specific assessments, is very unreliable. Mechanisms to measure adherence include assessment of serum drug levels, electronic monitoring of pill bottle openings, pill counts made at clinic visits or at surprise home visits, pharmacy record reviews, and patient responses to questioning. In general these different measures have good correlations to adherence levels, although asking the patient will be more likely to overestimate adherence than objective measures. Computer-assisted questioning of patients will improve self-reporting reliability. Serum drug level assessment provides only information about the most recent dose and is quite costly and not practical in clinical practice.

How should providers ask patients about adherence to get the most reliable information?

With appropriate education at the start of ART, a patient should know the importance of adherence. It is important to approach the discussion of adherence at follow-up visits in a nonjudgmental way and "give permission" for missing doses. Also, asking specific questions will yield specific information. An example of an inquiry might be: "Everyone misses doses of their medication some of the time. How many times in the last 3 days/week/month have you missed taking doses of your medicine?" From there, a discussion of the specific events that led to missing doses can lead to problem-solving with the patient to overcome these barriers.

The provider should ask patients to recount exactly when and how they are taking their medications in order to identify any lack of understanding of the regimen itself or of special dietary instructions.

Interventions   TOP

What can be done to improve adherence?

The most important intervention is making sure patients start medication only when they are "ready." Providers need to discuss with patients the risks associated with nonadherence that can result from starting medications before they are ready versus waiting while they "prepare." Preparing can mean entering into substance abuse treatment, finding stable housing, or attending a support group to overcome fears of medication side effects and concerns about confidentiality. Pregnant women and patients with serious complications of HIV infection and very low CD4 counts may not have the luxury of postponing therapy, but for others, being ready to adhere may be critical to the outcome of ART.

Interventions to improve adherence in chronic diseases tend to have, at best, modest effects on adherence. They are most effective if they are multifaceted, ie, they target several aspects of the adherence behavior and are repeated over time. Barriers to adherence differ among patients. Thus, interventions should be tailored to the patient's specific needs. In addition, barriers to adherence vary over time, so interventions need to vary as well. Interventions can occur at the level of the provider, care team, clinic, and/or pharmacy. Ideally, interventions are occurring throughout the patient's medical visit and beyond.

The most commonly used interventions address patient readiness using both one-on-one education and support groups. Peer counseling and support are key for many patients to work through concerns related to medication-taking. Making patients partners in the decisionmaking process about when to start and which regimen to use is also important. The regimen should be as simple as possible and should be the one least likely to cause the side effects that the patient fears the most. Substance abuse and mental illness should be treated before starting medication whenever possible.
After the patient begins the regimen, close followup and monitoring of adherence is critical, often through frequent clinic visits during the first weeks of therapy even if other medical interventions are not necessary. Providers should ask patients about adherence and address barriers to adherence at each followup visit. Providers should be open to changing the regimen if a patient has significant problems with it, whether related to side effects or to scheduling. Patients should be encouraged to use pill boxes and incorporate reminder systems as needed. Various kinds of interventions have been used in HIV and other chronic diseases (see
Table 7-2).

What is the role of Directly Observed Therapy (DOT) for medication adherence?

Directly observed therapy (DOT) refers to medical staff supervising patients taking each dose of medication. DOT has increased treatment completion and decreased the resistance rates of tuberculosis therapy. Whether it is feasible in HIV therapy is currently under investigation. A majority of ongoing studies are using modified DOT, with only 1 daily dose of medication observed over the first several months of therapy or during the administration of methadone maintenance therapy. The results of these studies will provide valuable information about the long-term patient acceptability, cost, and efficacy of this approach to improve adherence over the long term.

• Medication adherence is a significant challenge in all chronic diseases, but is particularly important in ART because of the high levels of adherence that must be maintained to prevent viral resistance.
• Patients should not start taking antiretroviral medications until they are ready.
• Providers should take the time to assess their readiness, conduct interventions to prepare them to begin therapy, and follow them closely once
  they start.
• Interventions to support adherence should be multifaceted and repeated over time. However, interventions have a modest effect on adherence.

Suggested Resources   TOP

Antinori A, Ammassari A, Wu AW. "Proceedings of the 1st workshop on HAART adherence: state of the art." JAIDS. 2002;31:S95-169.

Bangsberg DR, Hecht, FM, Charlebois ED, et al. "Adherence to protease inhibitors, HIV-1 viral load, and development of drug resistance in an indigent population." AIDS. 2000 14:357-366.

Roter DL, Hall JA, Merisca R, Nordstrom B, Cretin D, Svarstad B. "Effectiveness of interventions to improve patient compliance: a meta-analysis." Medical Care. 1998;36:1138-1161.

Sackett DL, Haynes RB, Gibson ES, et al: "Randomized clinical trial of strategies for improving medication compliance in primary hypertension." Lancet. 1975;1:1265-1268.

Stone, VE: "Strategies for optimizing adherence to highly active antiretroviral therapy: lessons from research and clinical practice." Clin Infect Dis. 2001; 33:865-872.

References   TOP

Bangsberg DR, Charlebois ED, Grant RM, et al. "High levels of adherence do not prevent accumulation of HIV drug resistance mutations." AIDS. 2003;17:1925-1932.

Paterson DL, Swindells S, Mohr J, et al. "Adherence to protease inhibitor therapy and outcomes in patients with HIV infection." Ann Intern Med. 2000;133:21-30.

Shingadia D, Viani Rm, Yogev R, et al: "Gastrostomy tube insertion for improvement of adherence to highly active antiretroviral therapy in pediatric patients with human immunodeficiency virus." Pediatrics. 2000;105:E80.

Wood E, Hogg RS, Yip B, et al. "Effect of medication adherence on survival of HIV-infected adults who start highly active antiretroviral therapy when the CD4+ cell count is 0.200 to 0.350x109 cells/mL." Ann Intern Med. 2003;39:810-816.

Cases   TOP

1. AR is a 37-year-old woman who uses heroin and cocaine daily and has a CD4 count of 300 cells/mm³ and an HIV viral load of 150,000 copies/mL. Since she was diagnosed with HIV infection 10 years ago she has primarily sought care when acutely ill. She comes to clinic for the first time in 6 months because she has decided to start "the cocktail."

Question: How do you manage this patient?

Answer:
This patient is not engaged in primary care and is using heroin daily. Although she might be able to adhere to therapy, she probably won't. Beginning ART is reasonable given her CD4 cell count and viral load; however nothing makes it critical to start therapy immediately.

The patient did not agree with her physician's assessment that her substance abuse was a barrier to medical care or medication adherence. She agreed to contract with her physician to start ART after she made 5 consecutive clinic visits. After several attempts at consecutive visits, the patient enrolled in a methadone-based substance abuse treatment program. She began to come regularly to clinic, engaged in in-depth medication education, and eventually started ART. She had good adherence, maintaining an undetectable viral load for 18 months before a drug abuse relapse. When she began to miss doses, she stopped all her medications as instructed and did not develop significant resistance.

2. DP is a 4-year-old with perinatally-acquired HIV infection. He is taken care of by his maternal great- grandmother, who is also caring for 3 other great-grandchildren. He resists taking ART because of the taste, so that it takes his great-grandmother 30-60 minutes to administer each dose when she can get him to take it. Although she has worked closely with the behavior modification team at the pediatric clinic, the situation has not improved. His viral load and CD4 cell count have not changed significantly on therapy.

Question: What do you do to treat this patient?

Answer:
Given the patient's refusal to take medication, the decision was made to place a g-tube for ease of administration. Within 1 month the viral load was undetectable, and the time to administer medications had decreased to less than 10 minutes per dose. The great-grandmother reported a significant improvement in their relationship and in DP's behavior in a number of domains. Although this may seem extreme, this is an example of individualizing the intervention to the barriers that exist for the patient (Shingadia, et al 2000).