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Adherence to HIV Antiretroviral Therapy
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Introduction
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Rates of Antiretroviral Adherence
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Implications of Adherence
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transparent imageVirologic Implications of Adherence
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transparent imageClinical Implications of Adherence
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transparent imageAdherence and Antiretroviral Drug Resistance
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transparent imageResistance in ART Containing Single and Boosted PIs
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transparent imageResistance to NRTI and NNRTI Therapy
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transparent imageAdherence and Antiretroviral Resistance: Summary
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transparent imagePublic Health Implications of Nonadherence
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Predictors of Adherence
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Measuring Adherence
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transparent imageMeasuring Adherence in Research Studies
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transparent imageMonitoring Adherence in Clinical Practice
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transparent imageSelf-Reported Adherence Assessment Tool--One Example
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transparent imageImproving the Sensitivity of Adherence Reports
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Interventions to Promote Adherence
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transparent imagePatient Education and Collaborative Planning
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transparent imageAdherence Case Management
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transparent imageDirectly Observed Therapy
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transparent imageSimplified Treatment Regimens
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transparent imageAdherence Devices
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transparent imageMedication Organizers
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transparent imageReminder Devices
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transparent imageVisual Medication Schedules
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transparent imageCost-Effectiveness of Adherence Interventions
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transparent imageAdherence Interventions: Summary
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Adherence in Resource-Poor Countries
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Adherence in Children and Adolescents
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Conclusions
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References
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Figures
Figure 1.Regimen-Specific Risk of Resistance by Level of Adherence
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Figure 2.Visual Analogue Scale Used in a Research Study
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Related Resources
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transparent imageGuidelines and Best Practices
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transparent imagePresentations, Interviews, and Roundtable Discussions
transparent imageResearch Summaries
transparent imageOnline Books and Chapters
transparent imageProvider Education and Training
transparent imageClinician Support Tools
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transparent imagePatient and Community Education
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Introduction
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In countries with broad access to effective antiretroviral therapy (ART), the clinical benefits have been dramatic. Far fewer people are progressing to AIDS, hospital AIDS wards have practically emptied, and the age-adjusted death rate from HIV/AIDS has declined by more than 70%.(1-3) Adherence to ART has emerged as both the major determinant and the Achilles' heel of this success.

Antiretroviral adherence is the second strongest predictor of progression to AIDS and death, after CD4 count.(4-6) Incomplete adherence to ART, however, is common in all groups of treated individuals. The average rate of adherence to ART is approximately 70%, despite the fact that long-term viral suppression requires near-perfect adherence.(6-9) The resulting virologic failure diminishes the potential for long-term clinical success. Drug-resistant strains of HIV selected through ongoing replication in the presence of ART also can be transmitted to uninfected or drug-naive patients, leaving them with fewer treatment options.(10) Nonadherence may eventually undermine the dramatic improvements in HIV-related health parameters seen in resource-rich countries and expected in developing countries as ART becomes more widely available.

Adherence is not the only determinant of ART failure or success. Other factors include genetic differences in drug metabolism, severe baseline immune suppression, prior drug resistance, and concurrent opportunistic infections. Adherence to ART, however, is one of few potentially alterable factors determining outcomes for patients with HIV. Nonetheless, it is well known that health care providers, in general, are unskilled at assessing and improving medication adherence.(8,11,12) The final crucial step toward ameliorating the impact of HIV--the actual taking of the medications--is often neglected.

This chapter reviews the current understanding of antiretroviral adherence, with a focus on describing the clinical implications of nonadherence and practical strategies for assessing and improving adherence.

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Rates of Antiretroviral Adherence
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Although there is no universally accepted definition, medication adherence may be defined as the extent to which a patient takes a medication in the way intended by a health care provider. The terms adherence and nonadherence are meant to be nonjudgmental, statements of fact rather than expressions of blame toward the patient or provider. Nonadherence to medication, in general, is very common. Typical adherence rates for medications prescribed over long periods of time are approximately 50-75%.(13,14)

Nonadherence to ART, likewise, is common in all groups of treated individuals. The average rate of adherence varies by the method used to assess it and the group studied, but appears to be approximately 70%. For example, in a prospective study, 140 individuals in a public hospital HIV clinic were followed for 1 year after initiation of ART. The investigators assessed adherence using 3 methods: a computer chip embedded in a specially designed pill-bottle cap to record the time and duration of each bottle opening (microelectronic monitoring system [MEMS], or MEMS caps), pill count, and self-report.(7) They calculated a composite adherence rate including all 3 measures that demonstrated a mean adherence rate of 71%. Only 6% of the patients took >=95% of their medications, the optimal level for durable virologic and clinical success.

Studies of different groups of HIV-positive individuals in the United States generally show similar, suboptimal rates of adherence. Adherence measurements can be grouped into measures based on a patient's self-report of pill-taking behavior and measures that are objective surrogates of pill-taking behavior, such as pill count or MEMS caps. While it is difficult to compare studies using different measures of adherence, mean adherence was suboptimal in the following disparate groups of HIV-positive individuals: in a large multicenter clinical trial (85% adherence by self-report),(15) among patients from a veterans and university hospital (75% by MEMS),(8) among the marginally housed (89% by self-report, 73% by pill count, 67% by MEMS),(16) among those with serious mental illness (66% by MEMS),(17) among predominately minority women (64% by MEMS),(18) and among 2 different groups of inner-city residents with a history of injection drug use (80% by pill count, 53.5% by MEMS in one group,(19) and 78% by self-report, 53% by MEMS in the other group (20).

Studies from Canada and developed countries in Latin America and Europe demonstrate similar rates of suboptimal adherence.(5,21-26) In general, 10% of patients report missing at least 1 antiretroviral dose on any given day and 33% report missing at least 1 dose within the past month.(27) Rates of adherence also are known to decline over time.(15,18) It can be concluded that most patients taking ART, regardless of their background or life situation, will encounter difficulties with adherence.

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Implications of Adherence
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Virologic Implications of Adherence
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While the ultimate goal of ART is to reduce HIV-related morbidity and mortality, the initial goal is full and durable viral suppression. Full viral suppression allows for maximal reconstitution or maintenance of immune function and minimizes the emergence of drug-resistant virus selected by ongoing replication in the presence of antiretroviral drugs.

For most patients, near-perfect (>95%) adherence is necessary to achieve full and durable viral suppression.(8,15,16,18,19,28-32) In practice, this degree of adherence requires a patient on a twice-daily regimen not to miss or substantially delay more than 3 doses of antiretroviral medications per month. This degree of adherence is far greater than that commonly associated with other chronic diseases (13) and is quite difficult for most patients to maintain over the course of a lifelong illness.(13,15,18)

The high level of adherence required for successful long-term virologic suppression has been elucidated by a number of recent studies.(8,9,15,16,18,19,28-32) For example, in a study of 81 patients recruited from clinics at a Veterans Affairs (VA) medical center and a university hospital who were already receiving or just beginning an ART regimen that included a protease inhibitor (PI), adherence to the PIs over a median of 6 months was assessed using MEMS caps.(8) Virologic failure was defined as a detectable HIV viral load (>400 copies/mL) at the last study visit. Only 5 of 23 patients (22%) with adherence of >=95% had virologic failure. In comparison, for those patients with adherence rates between 90-94.9%, 55% had virologic failure, and for those with adherence rates between 80-89.9%, 67% had virologic failure. Among patients with baseline undetectable viral loads, no patient (0 of 7) with adherence >=95% had virologic failure compared with 41% (7 of 17) of those with <95% adherence.

Adherence was estimated using pharmacy refill data in 886 treatment-naive individuals in British Columbia followed prospectively for a median of 19 months after starting ART.(9) Of the 502 individuals at the 95-100% adherence rate, 84% achieved plasma viral loads <500 copies/mL, whereas only 64% of the 64 people at the 90% to <95% adherence rate achieved this level of suppression (p = 0.001). Thus, while adherence measurement with MEMS caps and pharmacy refill data may not be strictly comparable, this study also found that near-perfect levels of adherence are required for reliable viral suppression.

The association between adherence and virologic control was investigated in San Francisco using continuous measures for adherence and virologic suppression. In a cross-sectional analysis of 34 HIV-positive, homeless individuals taking ART including a PI over 3 months, adherence was assessed using patient report, unannounced pill counts, and MEMS caps.(16) In a multivariate analysis, controlling for drug resistance, duration of therapy, and CD4 count, each 10% decrease in adherence was found to result in a doubling of the viral load. Adherence alone explained between 40-60% of the variation in viral load. The study suggests that small differences in adherence can result in major differences in virologic control and that adherence may be the predominant factor determining virologic outcomes.

These results, suggesting that very high levels of adherence are required for full and durable virologic suppression, have been confirmed in other locations and with other patient populations.(15,20,28-30) The degree of adherence required in these studies for optimal virologic control varied from 80-100%, likely because most of the studies were not designed to differentiate among high levels of adherence. Furthermore, most data were derived from patients using single PIs. More potent regimens, specifically ritonavir-boosted PI-based or nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens, have not been thoroughly studied and may lead to better viral suppression at lower levels of adherence.(33-35) The studies are further limited by their relatively short follow-up periods, ranging from 1 month to 1 year. Consequently, the relationship of adherence to long-term virologic control has not yet been established.

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Clinical Implications of Adherence
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The primary goal of treatment with ART is to prevent HIV-related morbidity and mortality. Many studies have shown a strong correlation between adherence and clinical outcomes and/or laboratory markers (notably CD4 count). Nonadherence has been found to diminish the immunological benefit of ART and increase AIDS-related morbidity, mortality, and hospitalizations.

Adherence clearly has been associated with CD4 count in a number of settings.(8,15,29) In a prospective cohort study of 1,095 patients enrolled in 2 randomized multicenter trials of initial and salvage ART, participants who reported adherence levels of 100%, 80-99%, and 0-79% had CD4 increases of 179, 159, and 53 cells/µL, respectively, from baseline to month 12 (p < 0.001).(15) In the VA/university cohort study cited above,(8) those with >=95% adherence had a mean increase in CD4 count of 83 cells/µL while those with adherence of <95% had a mean increase of 6 cells/µL.(8) A prospective study of 173 HIV-positive patients for 2 to 6 months grouped participants by self-reported adherence rates.(29) Patients reporting 95-99% adherence at 6 months had an increase in CD4 count from baseline of 59 cells/µL while those with adherence <80% showed a net loss from baseline of 8 cells/µL.

Several studies have demonstrated that medication adherence is second only to CD4 count in accurately predicting progression to AIDS and death.(4-6) For example, in a study of 76 HIV-infected patients that measured adherence by unannounced pill count every 3-6 weeks, no patient with >90% adherence progressed to AIDS over the 13-month follow-up period, compared with 8% of those with 51-90% adherence and 41% with <=50% adherence. In bivariate analysis, each 10% difference in mean adherence was associated with a 28% reduction in risk of progression to AIDS (relative risk [RR] = 0.72; 95% confidence interval [CI]: 0.59-0.87).(6)

The relationship between adherence and mortality was further defined in a population-based analysis of 1,282 ART-naive HIV-positive individuals in British Columbia who started triple-combination therapy between August 1996 and December 1999.(5) Adherence was estimated by dividing the number of months of medications dispensed by the number of months of follow-up. In a multivariate model, 2 factors--each 100-cell decrement in baseline CD4 count and <75% adherence to ART--were each associated with increased mortality with a risk ratio of 1.31 (95% CI: 1.16-1.49; p < 0.001) and 2.90 (95% CI: 1.93-4.36; p < 0.001), respectively. After adjusting for all other factors, those participants who obtained <75% of their antiretroviral medication were 2.97 times more likely to die (95% CI: 1.33-6.62; p = 0.008).

In a cohort study of 1,219 HIV-infected patients who began ART during the period 1990 to 1999 at a single hospital in Barcelona, Spain, adherence was assessed by self-report and pharmacy refill data.(4) Patients were considered nonadherent if they took <90% of prescribed ART. The initial regimen consisted of monotherapy in 23.7% of cases, 2 drugs in 30.5%, and 3 drugs in 45.8%. In multivariate analysis, the only modifiable variables that significantly affected mortality were treatment type (monotherapy: relative hazard [RH] = 9.76; 95% CI: 4.56-20.90; 2-drug therapy: RH = 9.12; 95% CI: 4.23-19.64) and adherence (nonadherence: RH = 3.87; 95% CI: 1.77-8.46).

Nonadherence has also been associated with increased rate of hospitalization (8,36) and longer hospital stays.(8)

The association between adherence and clinical progression, however, may not be entirely explained by the full suppression of viral load. On one hand, full and durable viral suppression requires nearly perfect adherence. On the other, despite the average rate of adherence being 70%, few patients on combination ART are actually progressing to AIDS and death.(37,38) Several factors may contribute to this apparent "disconnect" between adherence and clinical outcomes. These factors can be divided into 3 categories. First, antiretroviral resistance, often caused by nonadherence and virologic failure, is rarely complete. Most antiviral drugs exert some degree of anti-HIV activity against drug-resistant virus. Those patients who remain on ART despite the presence of drug resistance are likely to derive some treatment benefit. Secondly, the mutations associated with drug resistance often result in a virus that replicates less efficiently and is less pathogenic than wild-type virus. Selective drug pressure in the setting of high but imperfect adherence suppresses wild-type HIV such that the less fit drug-resistant variant persists. Finally, reduction in the degree of viral replication and pathogenicity may shift the delicate balance between the host and the virus, resulting in an immune system that is better able to control viral replication immunologically.(39)

The phenomenon of persistent clinical benefit despite virologic failure has been documented in a number of recent studies. In a study of 291 patients experiencing virologic failure on ART regimens including a PI,(40) patients who remained on their therapy had a median delay of 3 years before the CD4 count returned to pretherapy levels. The ongoing benefit of a "failing" regimen was primarily due to the persistent, albeit not full, suppression of the viral load below pretreatment levels.

Thus, in the short term, there appears to be a close relationship between adherence and HIV-related morbidity and mortality. Better adherence leads to better outcomes, but even suboptimal adherence can have a significant clinical benefit. Although less-than-ideal adherence may not be without benefit, the goal when taking ART always should be to maximize adherence. Achieving >=90% to 95% adherence significantly reduces the likelihood of virologic failure and drug resistance, which provides, by far, the best chance for long-term clinical success.(41)

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Adherence and Antiretroviral Drug Resistance
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Nonadherence to ART has been clearly implicated in the development of antiretroviral-resistant virus. Initial views, based upon experience with tuberculosis, suggested that patients with low levels of adherence might be at greatest risk for developing drug-resistant infection. Recent data suggests that the relationship between adherence and resistance is more complicated and likely varies by antiretroviral class (see Figure 1).(42)

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Resistance in ART Containing Single and Boosted PIs
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Multiple studies of ART containing a single PI found that resistance is most common in patients with high levels of adherence in the setting of incomplete viral suppression. In 1 study, genotypic analysis was performed in 57 patients with a persistently detectable viral load despite stable ART. The patients were then followed prospectively for 6 months, whereupon genotype analysis was repeated. Adherence was measured by unannounced pill counts at the participant's residence. Mean adherence during the study was 63.5%. The results indicated that during 12 months of observation at the population level, 23% of all drug resistance mutations would occur in the 92-100% adherence stratum, and that >50% of resistance would develop in the top 2 quintiles of adherence (79-100%).

A cross-sectional study compared 32 patients experiencing virologic failure on their initial regimen of single PI-containing ART with 36 similar patients whose viral loads remained fully suppressed.(42) Adherence was measured at baseline by self-report and MEMS caps. In the viremic group, there was a significant positive linear relationship between adherence and PI resistance. For example, viremic patients on nelfinavir with the D30N resistance mutation had significantly higher mean MEMS adherence (90.5%) than did those without this mutation (61.6%) (p = 0.010). Viremic patients with a sensitive phenotype had significantly lower mean MEMS adherence (63.3%) than did those with either intermediate phenotypic resistance (85.1%) or complete phenotypic resistance (90.8%) (p = 0.016). The authors postulated that higher adherence in viremic patients predisposes to PI resistance because it produces greater selective pressure for such resistant viruses.

Adherence was measured using MEMS caps in 62 HIV-positive patients on ART for a mean of 6 months.(43) If the viral load was >1,000 copies/mL at baseline or at follow-up, phenotypic resistance was also measured. Controlling for baseline resistance, adherence levels correlated positively with the degree of antiretroviral resistance at follow-up (r = .35; p = 0.04). Notably, those patients with particularly low adherence (<30%) sustained over the study period were significantly less likely than those with better adherence (>30%) to develop further phenotypic resistance (7% vs 33%; p = 0.01). The authors postulated that very low levels of adherence do not produce adequate selective pressure for resistance to develop.

In a cross-sectional analysis of 87 patients experiencing virologic failure following suppression on their initial regimen of indinavir-containing ART, adherence was measured by self-report, and genotypic analysis was performed at the time of first viral rebound.(44) In those with >90% adherence, 51% had primary nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations and 27% had primary PI resistance mutations. In those with <90% adherence, no resistance mutations were observed.

In a mathematical model, single PI-based therapy maximally selects for resistance at the population level at 87% adherence.(45) This degree of adherence is sufficiently impotent to allow for virologic failure while high enough to exert selective pressure for resistant virus. With regimens containing a single PI, even perfect adherence does not guarantee viral suppression sufficient to prevent the evolution of drug resistance.

The term "boosting" refers to the practice of administering a PI with another drug, usually ritonavir, in an effort to increase PI blood concentrations through a pharmacokinetic interaction. Lopinavir/ritonavir and indinavir/ritonavir are common boosted combinations. The increased potency of such regimens appears to change their adherence-resistance relationship. More potent vial suppression reduces the emergence of resistant virus. Even in the setting of viral breakthrough, resistance to PIs usually requires multiple mutations, each of which significantly reduces enzymatic efficiency and viral fitness in the absence of drug. Therefore, high-level drug resistance requires both ongoing viral replication and sufficient drug exposure to create a selective advantage for drug-resistant virus. Also, since the half-life of a PI is increased by boosting, PI concentrations likely remain in a suboptimal therapeutic range for only a brief time during periods of nonadherence.(46) Given these factors, it is perhaps not surprising that PI resistance is rarely observed during early virologic failure of ritonavir-boosted regimens.(46,47) Even if resistance does emerge during PI therapy, there are theoretical arguments and some empiric data suggesting that these variants will be less fit and therefore less virulent than NNRTI-resistant variants.(48,49)

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Resistance to NRTI and NNRTI Therapy
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The adherence-resistance relationship seen with NRTIs is thought to be similar to that of single PI-based therapy.(16,50) High levels of adherence in the setting of a detectable viral load maximally predispose to NRTI mutations.

The adherence-resistance relationship seen with NNRTIs, however, is markedly different. NNRTI resistance is associated with interruptions of therapy (51) and develops at lower levels of adherence than those associated with development of PI resistance.(52) In a prospective study of 71 patients who had recently started an NNRTI-based regimen and who had reached viral suppression at the time of enrollment, 28% experienced virologic failure during the median follow-up of 29 months.(51) Virologic failure was independently associated with reporting repeated drug holidays (48 hours of unplanned drug cessation). Moreover, repeated drug holidays reported at baseline was the only risk factor for developing a major mutation conferring cross-resistance to the NNRTI class (hazard ratio = 22.5; 95% CI: 2.8-180.3; p < 0.0001). In another cohort of 195 patients with an undetectable viral load on ART, adherence was assessed by self-report at each visit, and plasma samples were obtained and stored for resistance testing.(52) Over the 1-year course of the study, 28 patients (14%) experienced virologic failure associated with clinically significant resistance. Most of these patients (79%) had developed NNRTI mutations. A cumulative adherence of 70-89% (measured by self-report) was independently associated with an increased hazard of viral rebound accompanied by clinically significant NNRTI resistance. This level of adherence, which in actuality is likely to reflect overestimation by self-report when compared with more objective measures of adherence, is a lower level than that associated with resistance to single PI-based regimens.

A different adherence-resistance relationship for NNRTIs also is consistent with reports of resistance to these medications occurring after a single dose or short course of therapy given during perinatal HIV trials.(53) Because single-dose therapy is analogous to the lowest level of adherence possible, it appears that NNRTIs have an adherence-resistance relationship wherein almost any exposure in the absence of full viral suppression is sufficient to cause resistance.

Why would the relationship between adherence and resistance differ substantially among drug classes? Although the answer to this question remains unknown, substantial in vivo data and theoretical considerations suggest that NNRTIs have several characteristics that might result in an unfavorable adherence-resistance relationship. First, resistance to NNRTIs requires only a single genetic point mutation, whereas resistance to all other antiretroviral medications, except lamivudine, requires the accumulation of multiple point mutations. Second, NNRTIs are very potent and therefore exert a strong selective pressure. Third, NNRTIs act at a site distant from the active site of their target enzyme. Mutations that confer drug resistance therefore do not dramatically impact enzymatic efficiency and, by extension, viral replicative capacity (or viral "fitness"). Fourth, NNRTIs have long half-lives and remain in plasma for extended periods after several missed doses; this allows the virus an opportunity to replicate in the presence of suboptimal drug exposure. Fifth, resistance to 1 NNRTI almost universally confers cross-resistance to all other NNRTIs. And finally, NNRTI resistance persists in most cases after the drug is discontinued.(54) Thus, several factors appear to favor the virus over NNRTIs in terms of resistance. The clinical implications of NNRTI resistance are considerable because significant phenotypic resistance develops after a single genetic mutation. NNRTIs should be considered a relatively fragile drug class in patients whose adherence may be marginal.(33)

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Adherence and Antiretroviral Resistance: Summary
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The relationship between adherence and resistance to ART is more complex than the basic assertion that "nonadherence increases the risk of drug resistance." For nonboosted PI-based regimens and NRTIs, there is likely a bell-shaped relationship between adherence and resistance, with the peak of the curve shifted to the high end (80%) of adherence. This degree of adherence is sufficiently impotent to allow for virologic failure while high enough to exert selective pressure for resistant virus. For NNRTIs, resistance mutations likely will be very common in patients with any level of adherence insufficient for full viral suppression but uncommon in highly adherent patients. For ritonavir-boosted PI regimens, resistance is rare in early virologic failure at any degree of adherence because high rates of viral suppression limit resistance at high adherence, and the fitness cost of resistance mutations limits resistance at low adherence.

Therefore, considering only resistance arguments, it would appear that the widespread use of NNRTIs could have greater public health costs than the widespread use of ritonavir-boosted PIs. However, it remains difficult to ignore the facts that NNRTIs are far less expensive than PIs and that NNRTIs generally are easy to store and easy to administer. In our opinion, regimen choice both on an individual level and on a population-based level should take into account many factors, including fiscal constraints, clinical effectiveness, and tolerability, as well as risk of drug resistance.

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Public Health Implications of Nonadherence
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Many have viewed nonadherence as a significant public health concern based on the expectation that nonadherence would speed the development and transmission of drug-resistant virus. However, the usual focus of these concerns, namely, populations thought to have the lowest rates of adherence, are actually not the groups in which resistance is most likely to develop.(55) For single PI-based therapy and NRTIs commonly used in the late 1990s, it is the familiar scenario of high but imperfect adherence that appears to account for the majority of adherence-related resistance. Although, as discussed above, the adherence-resistance relationship may be different for NNRTIs, the perceived public health concern regarding the treatment of populations vulnerable to poor adherence, such as the homeless, mentally ill, and substance addicted, is not supported by the data, which in fact reflect relatively low rates of antiretroviral resistance in these populations relative to general HIV-infected populations in industrialized settings.(56,57)

The importance of efforts to minimize resistance is emphasized by recent studies indicating that transmission of drug-resistant virus is common.(48,49,58) In a retrospective analysis in 10 North American cities, antiretroviral resistance was analyzed in 377 people with acute HIV infection who had not yet received treatment. The overall prevalence of high-level phenotypic resistance to 1 or more drugs increased from 3.4% during the 1995-98 period to 12.4% during the 1999-2000 period (p = 0.002).(49) Significant increases were seen within each class of antiretroviral medication: NRTIs (from 2.3% to 6.2%; p = 0.07), NNRTIs (1.7% to 7.1%; p = 0.03), and PIs (0.4% to 8.0%; p = 0.001). The prevalence of resistance to drugs from 2 or more classes also increased from the earlier period to the later period, from 1.1% to 6.2% (p = 0.01). Furthermore, the percentage of subjects with 1 or more major genotypic resistance mutation increased from 8% to 22%. Overall, among newly HIV-infected patients in North America, approximately 1 in 8 had phenotypic resistance and 1 in 5 had genotypic resistance to 1 or more antiretroviral drug.

At a public hospital in San Francisco, very high rates of drug resistance were found in recently infected individuals.(48) In a consecutive case series of 225 untreated patients with recent HIV infection identified between 1996 and 2001, genotypic resistance to 1 or more antiretroviral drug ranged from 25% to 27.4%. Significant increases were seen over the study period in the prevalence of genotypic resistance against NNRTIs (p = 0.01) but not against NRTIs or PIs. Increased prevalence of HIV resistant to 2 or more drugs was also found (p = 0.004).

A large study of patients from Europe and Israel confirmed that the transmission of drug-resistant virus is not unique to North America. The CATCH study evaluated more than 1,600 recently infected individuals and found that 9.6% of them had genotypic resistance to 1 or more antiretroviral medication.(58) The rate was higher in individuals infected over the previous year (10.9% vs 7.5%; p = 0.06), suggesting that the problem is increasing.

A related public health implication of medication nonadherence is the potential for the increased viremia associated with nonadherence to raise the overall transmissibility and incidence of HIV. There is a strong, albeit imperfect, association between viral load in the plasma and that in the seminal and vaginal fluids.(59) Decreasing the serum viral load with antiretrovirals is known to decrease mother-to-child transmission of HIV (60) and is thought to decrease sexual transmission,(10) even after taking into account an increase in high-risk sexual activity by individuals whose health improves with ART.

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Predictors of Adherence
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A number of factors have been associated with nonadherence to ART. Understanding these factors can increase a clinician's attention to adherence when working with particularly susceptible patients and can inform the development of interventions to improve adherence.

Several excellent reviews addressing the predictors of adherence have been published.(27,30,61-63) As described by Reiter and by Ickovics et al in separate publications, the factors associated with medication adherence are commonly divided into 5 intersecting categories.(27,64)

  1. Patient Variables
    Patient variables include sociodemographic factors (age, gender, race/ethnicity, income, education, literacy, housing status, insurance status, HIV risk factors) and psychosocial factors (mental health, substance use, social climate and support, knowledge and attitudes about HIV and its treatment).

    Studies report conflicting evidence about the association between sociodemographic factors and adherence behavior. Nonetheless, when an association is found, the direction is consistent: younger age, nonwhite race/ethnicity, lower income, lower literacy, and unstable housing are associated with nonadherence in resource-rich settings. Gender, educational level, insurance status, and HIV risk factors generally are not associated with adherence behavior.(7,8,15,24,28,29,62,65-71)

    More consistent associations are found between certain psychosocial factors and adherence behavior. Common predictors of nonadherence include depression/psychiatric morbidity, active drug or alcohol use, stressful life events, lack of social support, and the inability to correctly identify the drug regimen or describe the relationship between adherence and drug resistance.(8,11,24,28,29,69,71-76)

  2. Treatment Regimen
    Factors related to the treatment regimen include the number of pills prescribed, the complexity of the regimen (dosing frequency and food instructions), the specific type of antiretroviral drugs, and the short- and long-term medication side effects.

    The complexity of the regimen and side effects caused by it are clearly associated with nonadherence. At least 1 study has found the number of pills per dose to be associated with adherence.(77) The impact of once-daily regimens on adherence behavior, amid great hope for a beneficial effect, has yet to be examined adequately. Other studies report that the "fit" of the regimen into an individual's daily routine is another important determinant of adherence.(28,78) The specific type of pills prescribed generally is not associated with adherence behavior.(7,8,18,30,69,72,73,79-81)

  3. Disease Characteristics
    Disease characteristics include the stage and duration of HIV infection, associated opportunistic infections, and HIV-related symptoms.

    A few studies describe a relationship between HIV-related symptoms and nonadherence.(28,66,69) Other studies describe an association between a lower CD4 count and nonadherence, although this finding is seen less consistently across studies.(8,24,28,65,75) Two studies describe increased adherence in those with a history of opportunistic infections.(82,83) The authors postulate that experience with illness stokes the desire for health and a motivation to adhere.

  4. Patient-Provider Relationship
    Patient-provider relationship characteristics that may affect adherence include the patient's overall satisfaction and trust in the provider and clinic staff, the patient's opinion of the provider's competence, the provider's willingness to include the patient in the decision-making processes, the affective tone of the relationship (warmth, openness, cooperation, etc), the concordance of race/ethnicity between patient and provider, and the adequacy of referrals.

    Clinical studies investigating the effect of the patient-provider relationship on adherence behavior are limited. A patient's trust in the physician has been associated with improved adherence in at least 2 studies of incarcerated women.(67,84) A qualitative study using focus groups of HIV-positive men and women reported improved adherence when a patient has a longstanding and trusting relationship with a single provider.(85)

  5. Clinical Setting
    Aspects of the clinical setting that may influence adherence include access to ongoing primary care, involvement in a dedicated adherence program, availability of transportation and childcare, pleasantness of the clinical environment, convenience in scheduling appointments, perceived confidentiality, and satisfaction with past experiences in the health care system.

    Again, despite an association being intuitive, clinical studies addressing the relationship between the clinical setting and adherence behavior are very limited. Dissatisfaction with prior experience in the health care system has been associated with nonadherence.(78)

In conclusion, many factors have been associated with adherence behavior. Some of these factors are largely immutable by the clinician, such as older age, low income, low literacy, and the patient's social milieu. Immutable factors can nonetheless be used by clinicians to help identify those patients at high risk for nonadherence so they can receive the most intensive adherence support. Other factors associated with nonadherence are potentially alterable, such as depression, substance abuse, homelessness, regimen complexity, medication side effects, and the therapeutic relationship between patient and provider. Alterable factors that impact adherence should be attended to, if possible, prior to starting ART, and in a proactive and ongoing way throughout therapy.

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Measuring Adherence
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Clinicians working with patients on ART need an accurate and relatively simple method of assessing adherence in order to support its vital role in treatment outcomes. It is well known that providers' estimates of adherence are inaccurate and often lead to the incorrect assumption of good adherence.(8,12,29) Adherence measurements used in research studies will be described briefly prior to discussing those commonly used in clinical practice. This section will conclude with an example of an adherence self-report measurement tool and a novel computer-based method of assessing adherence.

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Measuring Adherence in Research Studies
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Clinical studies employ a number of methods, alone or in combination, to measure medication adherence. This reflects the fact that there is no gold standard by which to measure adherence. A number of studies have shown, however, that the objective measures used in research, although impractical for most clinical settings, are more sensitive than patient self-report for detecting medication nonadherence.(7,8,16,19,20,66,86) The following is a brief discussion of common adherence measures used in research studies.

  1. MEMS Caps
    The MEMS caps measure utilizes a computer chip embedded in a specially designed pill-bottle cap to record the time and duration of each bottle opening. MEMS adherence usually is calculated by dividing the number of time-appropriate bottle openings by the number of expected doses over the study period.

    MEMS appears to be the most sensitive method for detecting nonadherence.(7,8,16,19,20,66,86) However, a number of limitations to the accuracy and practicality of the system restrict its use primarily to research settings. For example, the use of commonly utilized pill organizers or blister packs is impeded because the patient must retrieve all doses of the studied medication from the MEMS bottle. Because MEMS usually can assess only 1 prescribed medication, adherence to the other components of a combination therapy generally is not measured. The number of pills withdrawn at each bottle opening is not recorded. If the patient withdraws an additional dose to be taken at a later time, the system may underestimate adherence. Recent studies have attempted to adjust the MEMS adherence calculation to account for extra "pocket doses" removed from the bottle to be taken later.(16)

  2. Pill Counts
    Pill counts can be conducted in clinic or at unannounced home visits. Pill count adherence is usually calculated by counting the remaining doses of medication and assuming that remaining pills in excess of what is expected represent missed doses.(7,16,19,86) Pill counts are more easily performed if the patient uses a pill organizer; remaining medication in compartments from past days indicates missed doses.

    The sensitivity of pill counts for detecting nonadherence is compromised when patients remove pills from their containers without taking them (ie, "pill dumping" or "decanting"). This practice leads to an overestimate of adherence. Unannounced pill counts were developed to account for this practice but are too intrusive and cumbersome for common clinical practice.

  3. Biological Markers
    Biological markers of adherence refer primarily to plasma concentrations of antiretroviral drugs. Plasma concentrations of PIs have been significantly associated with adherence behavior in a limited number of studies, including those in which adherence was measured by self-report,(23) unannounced pill counts,(87) and MEMS caps.(88) Biological markers also have been associated and with virologic outcomes in at least 1 study.(89) For example, a study of 83 individuals found that a single low, untimed antiretroviral drug level was sensitive in identifying those with very poor adherence (<60%), but that therapeutic drug levels were not necessarily indicative of good adherence.(87) However, another study found that plasma concentrations of PIs did not add to the sensitivity of a composite adherence assessment that included self-report and pharmacy data.(90) Plasma concentrations are limited by their ability to detect only recent adherence behavior. Furthermore, low concentrations of antiretrovirals also may be caused by factors other than adherence, such as malabsorption, drug interactions, and individual metabolic differences.

    Other surrogate markers of adherence currently are being evaluated. Serum lactate levels in children on ART were associated in 1 study with virologic success, presumably because the elevated lactate levels were a reflection of better adherence behavior.(91) An increased mean corpuscular volume has long been associated with zidovudine treatment. These markers, however, are coarse measures of adherence and are of limited use in clinical practice. Antiretroviral concentrations in hair samples are being evaluated as a marker for antiretroviral exposure and, less directly, long-term adherence.(92,93)

  4. Pharmacy Refill Data
    Pharmacy refill data can serve as an adherence measure by providing the dates on which antiretroviral medications were dispensed. These dates can be provided by the pharmacy or the insurer. In the event that refills are not obtained in a timely fashion, it is assumed that the patient is not taking medication between refills or is missing doses in a way that allows the medication to last longer than it should.(94,95) This provides a less intrusive means of measuring adherence than most other measures. A number of studies in the treatment of HIV and other diseases have used pharmacy refill records to assess adherence.(95-97) For example, 1 study examined the refill history of 681 Medicaid-enrolled women on ART by investigating their Medicaid claims and found that only 28% were >80% adherent to their medications. Another study demonstrated that patients who are adherent to ART, as measured by consistent pharmacy refills for >4 months, were significantly more likely to achieve virologic control and benefit immunologically than were less-adherent patients.(97) Other studies have demonstrated that, in large populations of people, pharmacy refill measures are associated with viral suppression, resistance, and progression to AIDS and death.(5,9,98)

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Monitoring Adherence in Clinical Practice
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In contrast to the objective measures used primarily in research settings, patient self-report is a relatively simple and efficient method of assessing adherence in clinical practice. When compared with objective measures such as MEMS caps and unannounced pill counts, self-assessment is a less sensitive measure of nonadherence (ie, overestimates adherence). For example, a 6-month observational study of 67 antiretroviral-experienced individuals found that the mean 1-week adherence was 78% by self-report and 53% by MEMS monitoring.(20) In another study, which followed 108 patients on recently prescribed ART for 48 weeks, mean adherence was 93% by self-report, 83% by pill count, and 63% by MEMS caps.(86) Several other studies indicate similar overestimates of adherence by self-report when compared with MEMS caps and pill counts.(99) Nonetheless, these studies and others have shown that self-reported adherence is significantly associated with viral suppression and that self-reported nonadherence is significantly associated with virologic failure.(20,28,29) Thus, although less sensitive than other measures used in research, self-reported adherence is clinically relevant. The main task of the clinician is to elicit the self-report in a manner that maximizes its likelihood of revealing nonadherence.

A commonly used method for measuring self-reported adherence was developed by a multidisciplinary team at the Adult AIDS Clinical Trials Group,(74) has been validated repeatedly, and has been modified in a number of ways to increase its sensitivity and accuracy. For example, recent studies have documented that, prior to assessing adherence, it is imperative to review the patient's understanding of the prescribed antiretroviral regimen.(37,100-103) Otherwise, the clinician may document good adherence to an incorrect regimen. Studies in HIV and other diseases indicate that patients are best able to identify their medical regimens using a visual aid (commonly a pill chart).(37,102,104) Furthermore, the inability to visually identify the prescribed regimen has been associated with poor adherence to antiretrovirals (101) and with poor clinical outcomes in other diseases.(102-104) Thus, establishing and correcting a patient's understanding of the antiretroviral regimen through use of a visual aid is now seen as a crucial component of an adherence self-report.

It also has been recognized that individual adherence behavior can vary during a given period and usually deteriorates over time. A single adherence assessment provides only a snapshot of adherence behavior. It is therefore important to reassess adherence periodically, and if problems have been identified, as frequently as each visit. Adherence assessments now commonly ask about adherence over more recent periods of time (eg, past 3 days and/or past 7 days) and over longer periods (eg, past 1 month).(22) Both time frames have been validated against MEMS caps and both are commonly addressed to maximize the sensitivity of the self-report. An example of a commonly used technique for assessing self-reported adherence can be found at the end of this section.

A simple visual method of assessing adherence recently has been found to be equivalent to the more commonly used verbal self-report. The Visual Analogue Scale (VAS) asks subjects to indicate a point on a line that shows their best guess about how much of each drug they have taken in the past 3 or 4 weeks. For example, 0% means they have taken no drug, 50% means they have taken half their drugs, and 100% means they have taken every single dose (see Figure 2).(105) Adherence assessments using the VAS are highly correlated with MEMS caps (105) and have been shown, in U.S. and international settings, to be equivalent to 3-day verbal self-reports when compared with unannounced pill counts.(106) The primary advantage of the VAS is that it is simpler to administer than a structured 3-day self-report.

Accurately assessing adherence requires clinicians to develop a collaborative and nonjudgmental relationship with patients. The key to asking patients about their adherence is not in the specifics of the tool used but in taking the time to ask about adherence regularly, and doing so in an open and truly inquisitive manner. Otherwise, many patients will simply state what they believe the clinician wants to hear: that they have been perfectly adherent.

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Self-Reported Adherence Assessment Tool--One Example
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(adapted from Chesney et al)(74)

  1. Introductory Statement
    Make a statement acknowledging that difficulties taking antiretrovirals are common and inevitable at some point in treatment. State that one role of the clinician is to help identify these difficulties and try to make it easier for the patient to take the medication. The following is one example among many that can be used:

    Taking pills every day is really hard. Most people have problems taking their pills at some point during treatment. I am going to ask you about problems that you have had taking your pills. Please feel comfortable telling me about pills you may have missed or taken late; I am asking because I want to make it easier for you to take them.

  2. Confirm Understanding of Regimen
    Using a visual aid, such as a chart that shows color images of the available antiretroviral pills, ask the patients which medications they are taking. For each of the indicated pills, ask how many and exactly how often they are taking them. Ask if they have special instructions for any of the pills, such as dietary restrictions or extra fluid requirements. If any answers are incorrect, it is important at this time to focus on clarifying the regimen prior to completing the adherence assessment.

  3. Assess Adherence
    Ask the patients about their adherence over the past 3 days, 1 day at a time. Start with the day prior to the interview (ie, yesterday) and ask them how many of their pills they had missed or taken late that day. Then ask about the 2 days prior to that, addressing each day separately. Next, ask about how many doses they had missed or taken late over the past 7 days and 30 days. If they report no missing doses, ask them how long it has been since a dose was missed. Alternatively, a VAS can be used to assess recent adherence using a more simple visual scale.

  4. Ask About Reasons for Missing Doses
    For patients that report missing any dose, ask them if they know the reasons why. Prompt them if they cannot offer an explanation. Common reasons why people miss medications include simply forgetting, being away from home, being too busy with other things, a schedule change, too many side effects, feeling sick or depressed, and running out of pills.

  5. Ask About Medication Side Effects or Other Problems
    Ask the patients about medication side effects or other problems that they may be experiencing. Prompts can be offered, such as asking about nausea, diarrhea, difficulty swallowing the pills, headaches, fatigue, depression, or any other physical or emotional complaints.

  6. Collaborate with the Patient to Facilitate Adherence
    Reassure the patients again that problems with adherence are common. Explain that your concern is based on the fact that missing more than 5-10% of the doses in a month (eg, more than 3-6 doses a month in a twice-daily regimen) can lead to the medications not working well anymore, and that missing less than this would be a good goal. Take seriously all complaints about side effects or other physical or emotional problems and address them concretely. Offer suggestions to overcome specific obstacles the patients may have mentioned, such as the use of a watch alarm, medication organizer, extra packages of pills at work or in the car, or an unmarked bottle for enhanced privacy. Ask the patients if they have any ideas of their own to make it easier to take the medications. Finally, do not worry if the problem cannot be solved immediately; uncovering a problem with adherence is an important accomplishment and solutions to it can evolve in subsequent visits.

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Improving the Sensitivity of Adherence Reports
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Ideas for making self-reported adherence measurement more accurate generally involve creating a more comfortable and trusting situation in which patients can honestly report nonadherence, as discussed above. Other ideas include having the adherence assessment performed by a "neutral" person, such as a clinic aide.

Two recent reports document the development of a computer-assisted structured interview (CASI).(37,100) The CASI is an interactive computer program that allows patients to identify their regimens using pictographs and report their adherence in responses to nonjudgmental questions displayed by a computer. The program produces a report for the provider detailing discrepancies in patients' understanding of their antiretroviral regimens as well as an analysis of their adherence behavior. To minimize literacy requirements, the program can "read" the questions to patients over attached headphones.

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Interventions to Promote Adherence
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Increasing recognition of medication adherence as a crucial factor in treatment outcomes has sparked a number of recent studies investigating methods to support and improve adherence. The following is a synopsis of selected adherence intervention studies, organized into 5 categories: Patient Education and Collaborative Planning, Adherence Case Management, Directly Observed Therapy, Simplified Treatment Regimens, and Adherence Devices. Additional information about antiretroviral adherence interventions can be found in a number of recently published review articles on this topic.(27,62,107,108)

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Patient Education and Collaborative Planning
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The majority of antiretroviral adherence interventions reported in the literature involves dedicated time with patients to plan for and support medication adherence. The nature and frequency of these interventions vary, but those that appear effective are characterized by an initial educational session including individualized collaborative medication planning with follow-up sessions maintained regularly over the course of treatment.

A prototype for such an intervention derives from a randomized controlled trial (RCT) of 116 people initiating their first or second regimen of ART in the Netherlands.(109) The intervention group received an individualized educational counseling session at baseline and at each follow-up visit (0, 4, 24, and 48 weeks) designed to increase knowledge and "self-efficacy" regarding treatment adherence. Specifically, information was provided about HIV and its treatment as well as the relevance of adherence in clinical outcomes and preventing resistance. In addition, a personalized dosing schedule was developed with the patient and plans about how to manage side effects were made. During follow-up visits, strategies for solving any encountered problems were developed. The most common strategies were to design a new drug-dosing schedule, to develop habits that make remembering doses easier, and to provide additional skills to manage mild side effects. The control group received standard-of-care clinical follow-up. At week 48, 94% in the intervention group vs 69% of those in the control group achieved >=95% self-reported adherence (p = 0.008); 89% of the intervention group vs 66% of the control had HIV viral loads <400 copies/mL (p = 0.026). The intervention was found to prevent the decline in adherence commonly seen over time. Both groups started with good adherence, and the intervention helped maintain it, although adherence in the control group progressively worsened.

A randomized controlled trial involving 170 Spanish patients on stable ART found a similar effect.(110) The intervention was a pharmacist-led individualized education and supportive counseling session at baseline with follow-up telephone sessions focusing on adapting medication scheduling to the patient's lifestyle. After 24 weeks, 76% of intervention group vs 52.5% in the control group had >=90% self-reported adherence (RR = 1.45; 95% CI: 1.35-2.62) and there was a small trend in the intervention group towards improved virologic suppression (RR = 1.19; 95% CI: 0.93-1.59).

Other randomized controlled trials in Europe and the United States have confirmed that dedicated time with patients to plan for and support medication adherence leads to improved adherence and virologic suppression.(111-114) The importance of maintaining this support over time is further illustrated by an uncontrolled study that found a significant improvement in adherence over a 4-week study period with an intervention based upon ongoing education and financial rewards for good adherence.(115) However, 4 weeks after the intervention was discontinued, adherence in the intervention group returned to baseline levels.

On the other hand, in a study to assess the impact of 4 weekly educational sessions in 196 HIV-positive patients belonging to minority groups in the United States, at no point during the 24-week follow-up did the intervention and control groups differ in terms of MEMS adherence, viral load, or CD4 count.(116) Therefore, it remains unknown what constitutes an effective educational intervention and for whom it may work. Furthermore, this study and others illustrate the likelihood that effective adherence interventions will need to include an element of ongoing support.

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Adherence Case Management
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Adherence case-management programs consist of intensive adherence education and collaborative planning that is multidisciplinary and designed to be maintained over an extended period of time. In practice, such programs are designed for patients who have demonstrated, or are at great risk for, inadequate adherence and can exist separate from or within the primary clinical site.

In a prospective study of one such program, which included weekly medication organization sessions using pillboxes (medi-sets) and monthly individualized adherence counseling, 21 nonadherent men on ART were compared with 21 matched controls.(117) After 5 months, compared with the control group, those in the program had a significant improvement in their medication adherence as measured by pharmacy refill data and also had fewer hospitalizations.

An adherence case-management program developed by the San Francisco Department of Public Health focuses on homeless or marginally housed individuals on ART.(118) This independent program, called Action Point, has been in existence since 1999 and involves patients cared for at clinical sites throughout the city. The program provides weekly medication organization and dispensing, among other services.

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Directly Observed Therapy
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Directly observed therapy (DOT) has been identified as a possible means of helping patients with difficulties adhering to ART. Enthusiasm for DOT in HIV care is based on its successful use treating nonadherent patients with tuberculosis (TB).(119-124) TB, however, differs from HIV in several relevant respects. TB is curable and the duration of its treatment is limited, whereas treatment of HIV is thought to be lifelong. Treatment of TB can be compelled by law because of the risk of airborne transmission, whereas treatment of HIV is voluntary. Furthermore, some have argued that the successes documented in programs offering DOT for TB result more from the strength of structural elements of the programs, such as a reliable drug supply, than from witnessed dosing.(125,126)

Nonetheless, due to the evident difficulties with medication adherence, DOT in HIV has been evaluated in a number of recent studies in the developed and developing world. One study compared 50 incarcerated participants who received their initial ART through DOT with 50 patients initiating ART at an outpatient clinic who monitored their own medication.(127) Those who received DOT had a significantly higher chance at any point in the study of achieving an undetectable viral load (p < 0.01). For example, after 48 weeks, 100% of the DOT group had viral loads <400 copies/mL compared with only 68% of the self-monitored patients.

The first randomized controlled trial of community-based DOT followed 112 HIV-positive, actively drug-using individuals for 6 months.(128) Those in the intervention group received all of their medication each day in a blister pack from multidisciplinary personnel aboard a roving health van. For those on a once-daily regimen, all doses were directly observed. Those on a twice-daily regimen received modified DOT (m-DOT); 1 dose was observed and the other packet of medication was dispensed to the patient. Those in the control group received standard-of-care follow-up. After 6 months, compared with those in the control group, the patients receiving DOT had significant improvements in 3-day self-reported medication adherence (+32% vs +8%; p < 0.01), 6-month median CD4 count (+151 cells/µL vs +20 cells/µL; p < 0.01), and 6-month median log reduction of viral load (-2.01 copies/mL vs -0.41 copies/mL; p < 0.01).

A prospective study of m-DOT in a methadone clinic provided m-DOT (witnessed morning doses and prepackaged evening doses) for 12 months to 50 HIV-infected drug users (DUs).(129) Their outcomes were compared with those for 2 groups of control patients: 90 matched patients from the same methadone clinic (DU controls), and 146 patients without a history of drug use (non-DU controls). At 6 and 12 months, m-DOT patients (DUs) were significantly more likely to achieve full viral suppression (<50 copies/mL) than were DU controls and were somewhat more likely to achieve full viral suppression than were non-DU controls. Median increases in CD4 counts at 12 months, however, were similar in all groups.

An uncontrolled pilot study in Rhode Island used outreach workers to deliver and observe doses of ART.(130,131) Therapy was initially observed 5 or 7 days per week and observation was then slowly tapered, according to clinical judgment, to once weekly as tolerated. After 6 months, individuals in the program showed a decrease in viral load from 4.6 log10 copies/mL at baseline to 2.6 log10 copies/mL.

DOT also has been studied in pregnant women thought to be at high risk for nonadherence and consequent mother-to-child transmission.(132) Eight HIV-infected pregnant patients who were hospitalized for DOT during their third trimester were identified by chart review. Their outcomes were compared with those of 32 controls. The main outcome measure was success of therapeutic goals, defined as: no perinatal transmission, suppression of viral load to <1,000 copies/mL, delivery by intended route and at planned delivery site, and receipt of appropriate ART during labor. Despite having significantly greater social barriers to care (no family support, nondisclosure, substance abuse, mental illness, and homelessness), DOT patients achieved a level of success similar to that of control patients (63% vs 69%, respectively; p = 0.7).

Antiretrovirals have been provided in the context of an established DOT program for TB in a resource-poor setting in Haiti. In the absence of intensive laboratory monitoring, the 60 patients initially enrolled showed excellent clinical responses to therapy and limited drug toxicity. Again, isolating the impact of observed dosing from that of the support services and stable medication supply provided by the program is not possible.

Taken together, these studies indicate that DOT is feasible and can improve clinical outcomes. However, DOT is expensive, labor intensive, and potentially perceived as intrusive. It remains unclear which populations of patients warrant DOT. It is important to recognize the myriad differences between TB and HIV prior to extrapolating the experience of DOT from one disease to the other. Care should be taken to ensure that DOT programs in HIV care remain optional and voluntary unless an unequivocal public health benefit can be established in the particular population of patients in question.(125)

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Simplified Treatment Regimens
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Treatment regimens as simple as 2 pills once or twice daily are now available and have the potential to reduce the scheduling requirements and pill burden associated with ART. Studies clarifying the potency of these regimens, the patients for whom they are appropriate, and their long-term clinical benefit are emerging.(133) Adherence to simplified regimens, in particular to those taken once daily, is of great interest and concern. On one hand, as discussed above, regimen complexity (dosing frequency plus food instructions) and pill burden have been identified as predictors of nonadherence. Indeed, a metaanalysis of 23 clinical trials involving 3,257 patients to determine predictors of virologic suppression found pill burden to be the most significant predictor of antiretroviral response at 48 weeks (p = 0.0085).(77) On the other hand, missing a once-daily dose of ART may result in long periods of drug exposure that are inadequate to maintain viral suppression. Our understanding of adherence to once-daily regimens is limited at this time to the clinical studies evaluating their virologic and immunological outcomes. In the 2 largest randomized controlled trials to date comparing once-daily with twice-daily regimens (one comparing didanosine + emtricitabine + efavirenz with a twice-daily regimen in 571 treatment-naive patients over 60 weeks, and the other evaluating a switch from a stable PI-based regimen to didanosine + emtricitabine + efavirenz in 355 treatment-experienced but NNRTI-naive patients over 48 weeks), the once-daily regimens resulted in improved attainment of virologic control and improved maintenance of virologic control, respectively.(134-137) It is difficult to determine, however, whether the benefits seen with once-daily ART result from increased potency of the regimens studied, better adherence, or both. Studies to evaluate adherence and clinical outcomes of once-daily regimens in more representative populations are needed. Meanwhile, efforts should be made to reduce the dosing frequency and pill burden of ART when appropriate. Decisions regarding whether or not a patient will benefit from a once-daily regimen should be made collaboratively on a case-by-case basis.

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Adherence Devices
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A variety of devices that may help patients adhere to their treatment regimens are available. Most of them are simple, inexpensive, and easy to integrate into the routine care of patients on ART. Because these devices are often provided free of charge by pharmacies or pharmaceutical companies, it is usually possible for clinicians to provide these devices or for patients to obtain them on their own. The following are examples of commonly used adherence devices.

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Medication Organizers
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Medication organizers (eg, pillboxes, medisets) are readily available and come in many different shapes and sizes appropriate to the needs of individual patients. They allow patients to organize their weekly doses of medication in 1 convenient location instead of carrying multiple pill bottles, and to verify whether they have taken a given dose. Patients taking pillboxes to appointments helps clinicians monitor for recent nonadherence. When a new regimen is prescribed, clinicians commonly supervise patients as they set up their first medication organizer. Some pharmacies also provide medications prefilled into weekly organizers. Medication organizers are a staple of adherence case-management programs for HIV and other diseases.

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Reminder Devices
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Reminder devices are particularly important given that patents cite "simply forgot" as the primary reason for missed doses.(74) Common devices include alarms on watches, beepers, or other electronic items that allow for multiple daily reminders. Calendars, paper or electronic, allow patients to document scheduled doses and note when they have been taken.

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Visual Medication Schedules
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A visual medication schedule (VMS) shows pictures of prescribed medications superimposed upon a weekly calendar. Images of many prescribed medications are available in sticker sets provided by drug makers or in computer programs. It is also possible to create a VMS by affixing actual pills to a paper calendar. A VMS can help ensure that the patient understands the prescribed regimen and can help other caregivers assist in medication adherence. A VMS provided at each clinic visit has been shown to improve outcomes in patients receiving anticoagulation therapy, another situation requiring chronic treatment and exact adherence.(104)

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Cost-Effectiveness of Adherence Interventions
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The cost-effectiveness of antiretroviral adherence interventions is difficult to assess because the cost of such interventions is not well defined, and because the long-term clinical benefit of improved adherence does not lend itself easily to quantification. One study used a model to assess the impact of adherence interventions on patients' costs of care and life expectancy in a developed-world setting, investigating low-cost (eg, electronic reminders, medication organizers) and high-cost (eg, DOT) interventions in hypothetical cohorts of patients at varying stages of the HIV disease progression.(138,139) The authors found that, by the usual standards of cost-effectiveness, the ratio of costs to gains was reasonable for the low-cost interventions at all stages of the disease, even if the impact of the intervention was minimal. More expensive interventions such as DOT, which can cost approximately $500-$1,500 per patient-month, were found to be cost-effective only in the late stages of HIV and only if the intervention produced significant clinical benefits.

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Adherence Interventions: Summary
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Improving adherence requires a combination of methods appropriate to the patient and clinical setting. Alterable factors known to impact adherence, such as depression, substance abuse, homelessness, and the therapeutic relationship between patient and provider should be addressed in a proactive and ongoing manner. Adherence interventions should include dedicated educational and collaborative time with every patient to plan for medication adherence and to maintain necessary support and collaboration throughout the course of treatment. In this way, problems can be addressed, side effects dealt with, medications simplified or changed if necessary, and adherence devices supplied where appropriate. The nature and degree of adherence support, as well as the determination of which member of the clinical team will be responsible for it, will vary from site to site. What is likely required, however, is a commitment to ask about and support medication adherence regularly in an open, nonjudgmental, and collaborative manner.

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Adherence in Resource-Poor Countries
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There is a common perception that poor adherence to ART in resource-poor countries, once it becomes more available, will accelerate widespread antiretroviral resistance.(140-142) Some believe that treatment should be delayed until programs are established to ensure adequate adherence.(140,141,143) Others describe the potential for "antiretroviral anarchy" (141) and "explosive unintended negative consequences" (140) if treatment is initiated in developing countries without first establishing comprehensive adherence programs.

Contrary to prior concerns, adherence in developing countries has been found to be at least as good as adherence in developed countries. In a 48-week study of 289 poor South Africans attending a public hospital HIV clinic and receiving ART through Phase III studies, mean adherence as measured by clinic-based pill counts and pharmacy refill data was 87.2% (median 93.5%).(144) In a study of 34 self-paying patients at a clinic in Uganda who were followed for 90 days after initiating ART, mean adherence as measured by 3-day self-report, 30-day self-report, unannounced pill counts, and MEMS caps was 92.9%, 91.6%, 91.9%, and 90.35%, respectively.(145) A prospective study in Senegal followed 58 patients on recently prescribed, state-subsidized ART for a mean of 20 months.(146) Overall, 87.9% of these patients self-reported taking >=80% of their doses, a rate comparable to those seen in the developed world. A cross-sectional study assessed self-reported adherence in 109 patients receiving ART in 3 private clinics in Botswana.(147) In this cohort, 54% of the patients had >=95% adherence, a percentage again within the range of that described in the developed world. Although the emerging studies are few and limited to selected patient populations, taken together, they suggest that patients in the developing world are able to adhere to their medications as well as those in the developed world. The observation of equivalent adherence behavior has prompted some to suggest that withholding treatment from those in developing countries based on imperfect adherence is not supported by the available data and may violate basic principles of human rights and equity.(148)

The limited data thus far regarding adherence interventions in the developing world focus primarily upon m-DOT programs. As mentioned previously, antiretrovirals have been provided in the context of an established DOT program for TB in a resource-poor setting in Haiti. In the absence of intensive laboratory monitoring, the 60 patients initially enrolled showed excellent clinical responses to therapy and experienced limited drug toxicity.(149)

A program in rural Uganda led by the U.S. Centers for Disease Control and Prevention (CDC) and The AIDS Support Organization (TASO) has had initial success in the multidisciplinary treatment of hundreds of HIV-infected individuals, largely in their own homes.(150,151) This program, the Home-Based AIDS Care Project (HBAC), includes a weekly home visit by a medical field officer and a basic package of medical services for affected individuals' families. At the weekly visits, the field officer delivers antiretrovirals, performs a pill count, provides adherence support, administers a questionnaire to assess drug failure or toxicity, and collects necessary specimens and measurements. In addition, adherence is supported by a volunteer "medicine companion" and support groups. The program also studies the degree of laboratory services necessary for the safe and effective treatment of HIV by randomizing each participant to 1 of 3 groups, each with a varying degree of laboratory services. To date, the program has initiated ART in 816 individuals and has described, anecdotally, a dramatic improvement in the health of the participants and a significant reduction in AIDS-related deaths in the rural community in which they live.

A prospective observational cohort study of 171 primarily ART-naive, HIV-positive individuals in Senegal also demonstrates successful treatment with ART, with high rates of adherence and viral suppression and low rates of resistance mutations.(152) Patients were followed for a median of 30 months. After 2 and 3 years of treatment, respectively, the median increases in the CD4 count were 193 cells/µL (interquartile range [IQR]: 99-289 cells/µL) and 225 cells/µL (IQR: 157-465 cells/µL), the median decreases in viral load were -2.6 log10 copies/mL (IQR: -1.6 to -3.6 log10 copies/mL) and -2.2 log10 copies/mL (IQR: -0.6 to -3.2 log10 copies/mL), and suppression of detectable viral load was achieved in 65.8% (95% CI: 54.3-76.1%) and 61.8% (95% CI: 43.6-77.8%) of patients. The emergence of drug resistance in those with detectable viremia was relatively infrequent (12.5%). At least 95% adherence was claimed in 1,323 (86.4%) of the 1,532 patient visits in which adherence was recorded. This level of adherence was reported by 79.8% (95% CI: 71.1-86.9%) and 88.1% (95% CI: 74.4-96.0%) of patients at years 2 and 3, respectively.

In summary, even without dedicated adherence programs, recent data suggest that patients in resource-poor settings have levels of adherence and virologic suppression that are equivalent to, or possibly better than, those seen in resource-rich settings. To date, financial barriers to access have been the only consistent predictor of incomplete adherence in resource-limited settings.(153,154) Broader access to therapy, without the selection bias likely to have affected earlier studies, may reveal lower levels of adherence than those currently described, but even lower levels may exceed the average adherence rates seen in resource-rich settings.

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Adherence in Children and Adolescents
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Antiretroviral adherence in young children and adolescents poses unique and formidable challenges. Young children may have particular difficulty taking medication. Adolescents may refuse to take medication as a manifestation of otherwise normal rebellious behavior. Furthermore, the crucial role of family support in pediatric adherence can be compromised by other associated burdens, such as low income, an HIV-infected parent, stigmatization, or unclear familial responsibilities regarding the child's medication adherence. Despite these challenges, ART is successfully administered much of the time and has dramatically changed the prognosis of pediatric HIV disease. A number of articles describe the rates and predictors of pediatric adherence to ART.(155-163)

A review of the pediatric HIV literature describes 13 studies addressing the rates and predictors of adherence.(156) Mean adherence rates described in these studies, as with rates for adults, are suboptimal, typically ranging from <50% to >95%, depending on the method of assessment. When an objective measure of adherence such as MEMS caps or pharmacy refill data was included in the adherence assessment, mean adherence ranged from <50% to 75%. For example, 1 study used pharmacy data and laboratory markers to assess adherence over the first 180 days of treatment and found that only 58% of participants achieved an adherence rate of >75%.(157)

Predictors of adherence were more difficult to ascertain given the small sample size of many of the studies. Predictors specific to pediatric adherence included factors related to both children and their caretakers. Predictors described in the studies included patient/family variables (social instability, unstable housing, lack of disclosure, pediatric depression, and the family's perception of the disease and the value of its treatment) and factors related to the treatment regimen (regimen complexity, pill burden, and tolerability).(155,156)

A study investigating predictors also asked patients to describe methods they used to support adherence.(155) Successful strategies, in general, depended on shared responsibility within the household for remembering and giving each day's doses. The aforementioned predictors of nonadherence all impede a family in this process. To support adherence in pediatric populations, the authors suggest a focus on supporting the family in a collaborative effort at adherence. Specific suggestions include helping achieve disclosure within the family and enrollment of the child in a dedicated adherence case-management program.

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Conclusions
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Adherence to ART is closely tied to virologic, immunologic, and clinical outcomes. Small increases in adherence can result in significant improvements in these outcomes. Near perfect adherence, however, is required to maximize the likelihood of long-term clinical success. People from all groups of treated individuals commonly have difficulty maintaining such a high level of medication adherence.

To help patients benefit fully from ART, clinicians need to take time to ask about and support medication adherence. There are many methods used to assess adherence; in clinical practice, patient self-report is the most simple and economical. Although self-report clearly is associated with virologic and clinical outcomes, efforts must be made to increase its sensitivity for detecting nonadherence. Such efforts include asking about adherence regularly in an open, nonjudgmental, and collaborative manner.

There are many ways available for clinicians to support and improve medication adherence. Alterable factors known to affect adherence, such as depression, substance abuse, homelessness, regimen complexity, medication side effects, and the therapeutic relationship between patient and provider, can be addressed prior to starting therapy and in an ongoing way throughout treatment. During therapy, the detection of nonadherence is itself a valuable accomplishment. Improving adherence requires collaborating with the patient in an effort to understand and ameliorate individual impediments to adherence, generally by establishing dedicated time with every patient to educate, plan for adherence, and maintain support and collaboration throughout the course of treatment. In this way, adherence can be regularly assessed, problems can be addressed, side effects can be dealt with, medications can be simplified or changed if necessary, and adherence devices can be supplied where appropriate.

Acknowledgments
The authors would like to thank Barbara Turner, MD for her thorough review of this chapter and for her very insightful suggestions.

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