Success with any pharmacologic intervention depends not only on the intrinsic properties of the medications being prescribed but on the individual's ability to take them reliably. Although there are many reasons for failure of highly active antiretroviral therapy (HAART), including medication intolerance and acquisition or prior selection of resistant virus, nonadherence to HAART is the most common reason for failure to achieve or sustain expected treatment benefits. The consequences of failing to achieve maximal virologic suppression durably are a rebound in viral replication and a loss of the immunologic and clinical benefits of the intervention. In many cases (when viral replication is occurring in the presence of suboptimal drug concentrations), an additional consequence is the development of drug resistance and a limitation of future treatment options.1,2 The relation between adherence and therapeutic success has been demonstrated across a range of HAART regimens, including protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs).3-5 In studies of directly observed therapy (DOT) and directly administered antiretroviral therapy (DAART), in which high levels of adherence are maintained through ongoing active (and often expensive) interventions, therapeutic benefit is often greater than that achieved with conventional self-administration of medications.6,7
Nevertheless, significant concerns have been expressed regarding the considerable amount of health care resources and patient engagement that are required for the successful operation of DOT/DAART programs. Although such programs may be practical and cost-effective for managing patients in time-limited settings, such as may be the case with tuberculosis or even hepatitis C virus infection, their long-term use by most HIV-infected patients may not be feasible.8
Another approach to improving adherence may be to address it indirectly by dealing with the factors that seem to influence it, an approach known in sales and marketing as “objection handling.” Solidifying an individual's belief systems regarding medication9 and improving literacy and education around HIV disease and its management10,11 are 2 good examples of this approach. Additional considerations such as strategic selection of the regimen are essential because they allow us to address issues of importance to the individual (eg, specific side effects, pill burden, and frequency of administration). More active interventions short of full-blown DOT/DAART may also include addressing the social, emotional, and financial status of the individual9,12 and more individual considerations such as cognitive status and substance misuse. Finally, concerns about confidentiality and stigmatization that would surround the discovery of pills by family, friends, or coworkers may be of importance to some patients and may be best approached in a preemptive manner before they have any effect on adherence and therapeutic success.13
However one considers it, the development of a plan to address the issue of adherence is essential to the short- and long-term success of HAART.
ADDRESSING BARRIERS TO ADHERENCE
The social and psychologic barriers to adherence and issues related to mental health and substance abuse14 are best addressed through targeted interventions before initiating HAART.12 Education about HIV disease, the individual antiretroviral agents, and the consequences of poor adherence may empower patients to overcome barriers raised by their belief systems. One example is a telephone-based education and support group for persons 50 years of age or older with HIV infection that addressed a range of issues, including health status maintenance, understanding diagnostic tests and the management of HIV, and methods to improve the quality of interactions with health care providers. Program participants reported improvements in patient-physician relationships, were more informed about how diagnostic tests reflect their health status, and received information on how to manage adverse events and avoid drug interactions with other medications and over-the-counter products.15
Maintaining an honest, open, nonpaternalistic care provider-patient relationship is critical to addressing adherence and its barriers. In some circumstances, well-intentioned physician interventions may paradoxically lead to patient disengagement if there is a belief that an admission of poor adherence may lead to physician disapproval.16 Motivational interviewing (which, by its design, is meant to mitigate this concern) has shown modest favorable impacts on subsequent adherence.17 Some other well-meaning interventions (eg, medication alarms) may actually have a negative impact on adherence.18 This is particularly instructive and reinforces the need to evaluate any intervention in a formal manner before making assumptions about its efficacy.
Input from social and financial workers may help individuals to sort out their finances, welfare, and housing, and mental health professionals may address issues around substance use and other psychosocial issues. For example, within a population of predominantly (86.7%) African-American women in New Orleans, the provision of a range of ancillary services, including case management, was associated not only with improved adherence to required primary care visits but with greater overall retention in care and improved health status.19 Frequent contact with health care and other social services within a case management-based system may further facilitate good adherence in particular patient populations.20 Thus, a multidisciplinary individualized approach that proactively addresses potential adherence issues with regular reinforcement may be the most practical way to support adherence in persons with HIV infection.21 For patients with recreational drug use, a combined approach that includes addiction care (particularly if this includes methadone substitution therapy for heroin addiction)22 can be particularly beneficial not only to the efficacy of HAART but to the overall health status of the affected patient.
REGIMEN-RELATED FACTORS
It is important to consider how specific medications and the overall regimen fit into the patient's lifestyle. Typical reasons for missing HAART doses include simply forgetting, being busy, being away from home, concern about being seen taking medication, changes in daily routine (eg, weekends vs. weekdays, vacations), and failure to understand dosing or scheduling instructions.23 Intentional missing or delaying of doses may also occur to avoid side effects24 or to facilitate other social behaviors (including recreational drug use). It is not surprising, therefore, that issues such as pill burden, dosing frequency, meal restrictions, and short-term toxicities may have a significant impact on adherence. In the past several years, there has been a move toward more compact and convenient regimens with few or no food restrictions, fewer pills, less frequent dosing, and even entire regimens in 1 or 2 pills taken once daily.25,26 The availability of a single-pill once-a-day regimen (consisting of tenofovir [TDF] plus emtricitabine [FTC] plus efavirenz [EFV])27 may alter the adherence paradigm, especially in difficult-to-treat populations. The only issue in question is the ability of some of the patients to tolerate the central nervous system (CNS)-related side effects of the EFV component of such a combination. Although CNS-related side effects attributable to EFV frequently resolve within 2 to 4 weeks of initiating therapy, clear provider/patient communication regarding this issue, along with careful prospective monitoring, may help to ensure that no harm is done by the widespread use of this most simple of HAART regimens.
Surveys of HIV-infected patients in the United States and Europe indicate that there is a strong preference for once-daily dosing and compact therapy, albeit not at the cost of additional adverse events.28,29 A meta-analysis of virologic outcomes in relation to pill burden in studies of initial triple-agent HAART regimens indicated a significant correlation between lower pill burden and greater virologic suppression.30 Available data on dosing interval and adherence in other areas of medicine have been examined in a systematic manner.31 This review examined 76 carefully selected studies and indicated that adherence to once-daily regimens was somewhat better, with a particular effect on dose-timing accuracy. Mean adherence to once-daily therapy was 79% as compared with 51% to 69% for regimens administered more frequently. Dose-timing compliance was 74% for once-daily therapy as compared with only 40% to 58% for other regimens. These adherence levels fall short of the 95% adherence levels required during the first months of HAART administration;32 thus, the simple availability of once-daily HAART is not a panacea in terms of the impact of adherence on treatment efficacy.
It may be that, among the once-daily regimens, some agents or combinations are better tolerated and more likely to yield better long-term adherence and virologic suppression. This may be most relevant for the nucleoside reverse transcriptase inhibitor (NRTI) backbone. It is now clear that some agents traditionally administered twice daily can be safely and effectively administered once daily. Studies comparing twice-daily and once-daily lamivudine (3TC) (with twice-daily zidovudine [AZT] plus once-daily EFV)33 and twice-daily and once-daily abacavir (ABC) (with once-daily 3TC/EFV)34 have clearly established this. Once-daily TDF has proved similarly effective to twice-daily stavudine (d4T) when dosed with twice-daily 3TC plus once-daily EFV.35 Once daily-dosed TDF/FTC has recently proven superior to twice daily-dosed AZT/3TC in an open-label initial therapy study in which all participants received EFV as the third agent.36 The greater success of TDF/FTC was evidenced not only by fewer adverse event-related discontinuations but by relatively fewer virologic failures. It thus seems that in most settings in first- and second-line therapy, a once-daily NRTI backbone (with 2 NRTIs from among 3TC, FTC, TDF, and ABC) may be used. In addition, the availability of 3TC/ABC and FTC/TDF coformulations further simplifies therapy by allowing this backbone to be administered as a single tablet.
Data are less conclusive for PIs. A definitive comparison of once-daily atazanavir/ritonavir (ATV/r) versus twice-daily lopinavir/ritonavir (LPV/r), each with TDF/FTC as initial therapy, is currently ongoing. In a recent prospective trial of antiretroviral-naive individuals given a once-daily regimen of LPV/r soft-gel capsules (800/200 mg administered once daily) plus TDF/FTC or a twice-daily regimen of LPV/r soft-gel capsules (400/100 mg administered twice daily) plus TDF/FTC, adherence rates were significantly higher in the patients on once-daily regimens. Unfortunately, once-daily dosing did not lead to improved efficacy, possibly because of the inadequate pharmacokinetics of LPV/r as a once-daily drug and the burden of excess gastrointestinal adverse events with once-daily dosing.37,38 Nonetheless, once-daily PI-based regimens are in widespread use in clinical practice and should be seriously considered as the treatment of choice in populations in which twice-daily regimens are not feasible for reasons of adherence.
For NNRTIs, EFV is indicated for once-daily therapy39 and can be easily prescribed as part of an overall once-daily regimen, and most easily in the coformulation with TDF/FTC.27 Nevirapine has been evaluated mainly as a twice-daily agent, and there is some concern that its once-daily administration may lead to increased toxicity.40 Some case series of once-daily nevirapine use in recreational drug users do not confirm this concern, however, even in the long term.22
A number of studies have looked at the modification of therapy from twice-daily to once-daily regimens to enhance long-term adherence. In patients receiving a regimen that included 3TC and EFV switching from twice daily-dosed AZT or d4T the extended-release formulation of d4T (d4T XR), establishing a once-daily regimen, improved adherence and dose-timing accuracy as assessed by electronic adherence monitoring were documented.26 When the initial regimen is even more complex, however, treatment simplification to maintain virologic suppression may be more beneficial. Switching from a twice-daily, high-pill-burden, PI-based regimen to a combination didanosine (ddI)/FTC/EFV once-daily regimen seems to maintain virologic efficacy better than the continuation of the PI regimen over the course of 1 year, a finding linked to improved adherence.41 A recent study evaluated 96 persons stable on twice-daily HAART who were randomized to immediate switch versus 4-week-delayed switch from twice-daily ABC and 3TC to the once-daily fixed-dose combination tablet of ABC/3TC, thereby achieving a once-daily regimen. Adherence was assessed electronically using Medication Event Monitoring System (MEMS) caps over 8 weeks. Patient satisfaction was assessed using an HIV treatment satisfaction questionnaire (HIVTSQ). The change of formulation and dosing schedule was well tolerated and virologic suppression was maintained in all patients. All adherence parameters, including compliance (the percentage of prescribed doses taken), correct dosing compliance (the percentage of days with the correct number of doses taken), and timing compliance (the percentage of doses taken within 3 hours of the prescribed dosing interval), were significantly improved (P < 0.05, P < 0.05, and P < 0.01, respectively) by switching to once-daily dosing. The results of the HIVTSQ also improved significantly (P = 0.004) with switching.42 These data underline the potential to revise therapy using compact formulations and once-daily dosing to support adherence and quality of life in our patients.
FORGIVENESS
In addition to minimizing pill burden, selecting HAART regimens based on pharmacokinetic data that allow “forgiveness” if dosing is delayed or missed is critical. Those who argue against the once-daily approach say that if a dose is missed, there is a greater interval between doses (as long as 48 hours), creating greater risk of viral rebound (in the absence of therapeutic drug levels) and the possible development of drug resistance. This may be mitigated by the use of agents originally approved for once-daily use. EFV, TDF, and ddI have long elimination half-lives of more than 24 hours, and perhaps even more than 50 hours. These drugs may thus actually have more flexibility and forgiveness as part of once-daily regimens. For example, a 24-hour delay of an EFV dose may result in a decrease of drug plasma levels of only approximately 25%. Additionally, many individuals remember “missed” doses well before their next dose is due. In fact, health care providers should be counseling patients that if a dose is missed, it is always better to take that dose late rather than not at all. Some data exist to suggest that in patients for whom such missed doses are to be more frequent, the use of a PI-based regimen may lead to lesser frequency of emergence of drug resistance during the frequent treatment interruptions and be more forgiving in terms of treatment efficacy.43
Interestingly, studies of so-called “structured treatment interruptions” have been conducted to determine the efficacy and safety of ARV regimen dosing schedules that allow for brief periods (days) of being off treatment (ie, drug holidays). Results from these trials have shown that in patients on HAART with established viral suppression (<50 copies/mL), HIV RNA may remain undetectable up to 7 days after treatment is stopped.44,45 These data suggest that for individuals with established virologic suppression who miss a dose, detectable viral replication does not resume immediately. This may allow the opportunity to re-establish optimal drug levels before viral replication resumes or ARV-resistant virus has been selected. Accordingly, it is more likely that recurrently missing doses or episodically missing consecutive doses is less detrimental to the long-term efficacy of the HAART regimen than during the period when suppression is being established. Our own data suggest that adherence levels as low as 60% can lead to the maintenance of virologic suppression but are clearly insufficient in the setting of active viral replication.46 This suggests that if intensive interventions to enhance adherence are to be implemented, it may be that their most cost-effective application is in the first few months of HAART. Less intensive measures may then be applied, knowing that they may be associated with some loss of adherence that may not be clinically significant. This long-term degree of forgiveness must be better quantified in prospective studies to inform clinical practice optimally.
CONCLUSIONS
Treatment success with HAART requires a high level of therapeutic adherence. A number of different characteristics of individuals and their environments and of the treatment regimen prescribed are known to influence this important parameter. Dealing with these characteristics in a specific manner is the key to the long-term success of HAART in a given patient. Interventions that address an individual's support systems, provide education around HIV disease, and optimize the individual's personal environment can demonstrably improve adherence and reduce the risk of treatment failure and subsequent disease-related morbidity. Enhancement of adherence through DOT programs may not be practical or cost-effective for the long-term management of this condition on a widespread basis. The choice of simple treatment options involving compact once-daily regimens goes a long way toward addressing many barriers to adherence. The increased availability of once-daily agents from a number of different drug classes provides a wide range of treatment options to fulfill this paradigm. If it turns out that the highest degree of adherence is required only in the months until virologic suppression is achieved, it may be that a combination of regimen- and patient-based interventions (including some form of DOT/DAART) may be implemented in the short term to maximize the likelihood of initial success. Thereafter, a less intensive strategy may be enough to maintain improved treatment outcomes in the long term. A better understanding of adherence and its determinants and how to define specific goals in a given clinical setting are keys for clinicians to become more effective partners with patients in the achievement and maintenance of long-term virologic suppression and more importantly, long-term health.
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