ADDRESSING THE CHALLENGES OF ADHERENCE

Adherence to antiretroviral therapy is a crucial determinant of treatment success. Studies have unequivocally demonstrated the close association between adherence and plasma HIV RNA levels, CD4 cell counts, and mortality in patients with HIV infection and disease. Adherence levels of > 95% are required to maintain virologic suppression. However, actual adherence rates are often far lower; most studies show that 40% to 60% of patients are less than 90% adherent. Adherence also tends to decrease over time.

Although the need to develop effective antiretroviral regimens has largely been met, the need to find a way to promote the near-perfect adherence required for optimal outcomes is a challenge that has yet to be surmounted. Adhering to many antiretroviral regimens is far from easy. The pill burden in some regimens is in the double digit range when all necessary drugs are taken into account. Furthermore, each drug in a regimen may have different administration and storage requirements; for instance, some drugs are prescribed twice or thrice daily; some drugs must be taken with food and others without; and some drugs need refrigeration, while others must be stored at room temperature. Keeping track of and staying adherent to such complex regimens can be daunting tasks for patients. Nevertheless, the challenge must be met, because non adherence is one of two chief causes of treatment failure. The other chief cause, which is intimately linked to non-adherence, is viral resistance.

Presently, clinical and virologic failure is most likely to occur in two types of patients. The first type is those who adhere poorly to their antiretroviral regimens. The second type is those who have received multiple antiretroviral regimens over a protracted period and who may as a consequence, harbour viral strains that are resistant to multiple drugs. The same patient might meet criteria for the two types, because drug-resistant viral strains are likely to emerge in patients with incomplete adherence. Once drug-resistant viral strains are present, therapeutic options become fewer until, eventually, they are exhausted.

Thus, improving adherence is arguably the single most important means of optimizing overall therapeutic outcomes. To meet the challenge, it is necessary to understand the relationship between adherence and optimal therapeutic response, the real-world level of antiretroviral adherence, the barriers that may prevent patients from adhering, and the strategies that can be employed to improve adherence.

1. The connection between therapeutic response and adherence

Former US Surgeon General C. Everett Koop said, "Drugs don't work in patients who don't take them." Although adherence is vital to the success of any medical therapy, there are relatively few conditions in which the consequences of nonadherence are as severe and as certain as they are in the case of HIV infection and disease. Several studies have confirmed the direct association between adherence and plasma HIV RNA levels, CD4 cell counts and mortality.

The relationship between non-adherence and plasma HIV RNA levels is not proportionate - i.e. small amounts of nonadherence yield large losses of viral control. In an analysis of 34 patients with a median of 12 months of protease inhibitor therapy, Bangsberg et al (AIDS 2000; 14: 357-66) found a strong linear relationship between adherence and plasma HIV RNA levels. Importantly, a mere 10% decrease in adherence was associated with a doubling of the HIV RNA level.

Similar trends were noted by Paterson et al (Ann Intern Med 2000; 133: 21-30) who conducted a prospective, observational study of 81 patients to determine the impact of various levels of adherence on virologic outcomes. They found that antiretroviral adherence was significantly associated with successful virologic suppression and immune reconstitution. Only 5 (22%) of 23 patients with an adherence rate of > 95% had virologic failure (HIV RNA level > 400 copies/ml) (Figure 1).

The consequences of non adherence are not limited to plasma HIV RNA levels; CD4 cell counts and mortality rates are also adversely affected. In a prospective, observational study, Singh et al (Clin Infect Dis 1999; 29: 824-30) found that patients who were less than 90% adherent had a mean decrease in CD4 cell counts of 5/ l. In contrast, mean CD4 counts increased by 78/ l for patients whose adherence rates were > 90%. Finally, in the prospective, observational study of 950 HIV-infected patients by Hogg et al (7th Conference Retroviruses Op. Inf 2000, Abstract 73), every 10% decrease in antiretroviral adherence was found to be associated with a 16% increase in mortality.

Taken together, these findings set for clinicians and patients the goal of achieving at least 95% adherence to antiretroviral therapy.

2. Levels of adherence: The 'ideal' versus the 'real'

Although adherence rates of > 95% are necessary for optimal outcomes, actual adherence rates are often, unfortunately, far lower. Researchers who have examined this issue have used several adherence measures and have reported a range of adherence rates. For example, in the previously cited study by Bangsberg et al (AIDS 2000; 14: 357-66), 62% of patients were less than 90% adherent, and the median rate of antiretroviral drug adherence was 89% by patient self-report, 73% by pill count, and 67% by electronic monitoring.

Most studies define nonadherence as missing doses. However, taking antiretroviral drugs inappropriately - not adhering to dietary restrictions or taking doses at the wrong times - is also a form of nonadherence and can facilitate the development of drug resistance.

Moreover, although adherence tends to be thought of as compliance with a medication regimen at a specific time, several studies have demonstrated that adherence changes over time, showing a distinct tendency toward decline (13th International AIDS Conference 2000, abstract TuOrB421; Ann Intern Med 2001; 134: 968-77). Mannerheimer et al (13th International AIDS Conference 2000, abstract TuOrB421) reported that in two ongoing randomized clinical trials in which 96 patients completed 8 months of follow-up, 70% of patients reported 100% adherence to their antiretroviral regimens at one month into treatment. By the 8-month time point, however, only 58% of patients were reporting 100% adherence (Figure 2) (p<0.01 for differences between months 1 and 4 and months 1 and 8).

 

3. Understanding nonadherence

Because anti-HIV regimens are life-saving therapy, the reasons for nonadherence can be difficult to fathom. However, if adherence is to be improved, it is important to understand the reasons behind nonadherence.

Several studies have shown that when patients are asked why they fail to adhere, the most frequently given reason is simply forgetting. Among participants in the Adult AIDS Clinical Trials Group (AACTG) Study (AIDS Care 2000; 12: 255-66), 66% of patients cited forgetting as their reason for nonadherence (Table 1). Almost the same percentage (64%) cited forgetting in a study by researchers at Johns Hopkins University (J Acquir Immune Defic Syndr 1998; 18: 117-25). Another reason cited by patients in both of these studies was having too many medications or too many pills to take.

Table 1: Reasons cited by 51 participants in the AACTG trial for missing medications

 

Can a complex regimen compromise adherence?
Many studies over the years attest to the fact that when it comes to promoting adherence, regimen complexity counts. In general, adherence tends to decline as pill burden, dosing frequency, and dietary restrictions increase.

A meta-analysis of 22 clinical trials (AIDS 2001; 15: 1367-77) demonstrated that the detrimental impact of pill burden on adherence translated into a suboptimal virologic outcome. The analysis included 3257 patients, all of whom were antiretroviral-naïve at the outset and were taking triple-drug regimens. All the regimens studied were approximately equally effective in suppressing viral load. However, regimens that required a higher pill burden were associated with a lower antiretroviral response (Figure 3). Simpler regimens consisting of fewer pills resulted in a higher rate of virologic suppression.

 

Do side effects impede adherence?
Side effects are common with antiretroviral therapy, and they have the potential to substantially reduce quality of life. Ironically, as a direct by-product of the survival-enhancing effectiveness of current antiretroviral regimens, side effects are increasingly emerging as an issue that affects adherence. Patients are often willing to tolerate side effects when they perceive their illness as life-threatening. With increasing treatment success, however, more patients are returning to active life styles, at which point side effects may be perceived as main effects. In the AACTG study mentioned above, 24% of patients cited the wish to avoid side effects as a reason for failing to take their medication as prescribed.

Can patient's beliefs boost adherence?
Accurate perceptions about HIV infection and its treatment have been shown to support adherence. Wenger et al (6th Conference Retroviruses Op Inf, 1999; abstract 98) found that adherence was significantly higher among patients who perceived antiretroviral agents as effective and believed that nonadherence would result in viral resistance (strongly agree, 64%; agree, 56%; disagree, 50%; strongly disagree, 43%; p<0.0001).

Do psychiatric disorders decrease adherence?
Depression and other untreated affective disorders have been found in several studies to impede adherence, whereas the absence of such factors improves it (Ann Intern Med 2000; 133: 21-30).

Do sociodemographic factors affect adherence?
Some studies have found associations between adherence and older age, male gender, higher income and white race. By contrast, others have found no such associations.

4. Adherence intervention strategies

Given the crucial importance of antiretroviral adherence to maintaining virologic suppression and preventing resistance, efforts to support and improve adherence are significant. Several strategies can be employed in this effort and are most effective when used in combination and continued over the term of treatment. These include:

i. Educate and motivate:
Patients cannot be expected to adhere to a treatment plan if they do not understand it or its objective. Patients also need to be motivated by a patient-specific goal of treatment eg. to live to see their children reach adulthood.

ii. Simplify the regimen:
The simpler the regimen, the better patients' adherence to it is likely to be. An effort should be made to design an antiretroviral regimen that minimizes pill burden, dosing frequency and dietary restrictions.

iii. Tailor treatment to the patient's lifestyle:
Patients are less likely to adhere to regimens that require them to substantially alter their lifestyles. It is important to problem-solve with patients to help them remember their medications when their routine changes and when they will be away from home.

iv. Prepare for and manage side effects:
Adherence is usually increased by letting patients know at the outset which side effects are possible with a given regimen and by assessing for such effects within the first or second week of treatment, which is likely to be the most troublesome.

v. Gear intervention toward reason for nonadherence:
Patients have a range of reasons for failing to adhere to their antiretroviral regimens. These reasons should be assessed for each patient so that an appropriate adherence-enhancing intervention can be undertaken.

Adherence to therapy for HIV infection and disease is uniquely challenging; few, if any, other medical conditions require regimens that are as complex or as demanding. However, adherence is as essential as it is difficult; the close connection between adherence and viral load, CD4 cell counts, and mortality has been unequivocally demonstrated.

At least 95% adherence is required to maintain the virus at undetectable levels. Unfortunately, real-life adherence rates often fall short of this percentage, and the potential barriers to adherence are numerous. Several adherence-enhancing interventions have been identified and as many as possible should be deployed, beginning at the start of treatment and continuing throughout its course. Few factors are more vital to the success of treatment of HIV infection and disease.