Updated June 2005

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I. INTRODUCTION

Recommendation:

Clinicians should consider substance users candidates for ARV therapy if they meet the medical eligibility criteria for ARV therapy and demonstrate readiness to begin therapy by attending the majority of their appointments and expressing interest in ARV treatment.

A significant portion of people with HIV use drugs. Injection drug users (IDUs) accounted for 13.63% of people living with HIV in New York State in 2006, and 26.7% of people living with AIDS. In New York City, more than half of all reported AIDS cases are directly or indirectly due to injection drug use. HIV-infected substance users have benefited less than other patients from advances in HIV treatment because of the challenges involved in navigating and sustaining engagement with the often complex system of medical care delivery. However, numerous studies have shown that current and former substance users can adhere to complex ARV regimens.

Potent ARV combinations have provided opportunities for effectively treating HIV-infected persons and have led to a dramatic decline in HIV morbidity and mortality. ARV therapy can inhibit viral replication and markedly delay disease progression; however, achieving this potential often requires careful adherence to regimens that may be complex and/or cause unpleasant side effects. Non-adherence to ARV therapy may result not only in reduced treatment efficacy but also in the selection of drug-resistant HIV strains.^1,2 Because the exact level of adherence that is necessary to prevent the emergence of drug-resistant virus or to delay disease progression and death is unknown, near-perfect adherence (>90-95%) remains the goal for all HIV-infected patients, regardless of whether the patient is a past or current substance user.^3,4

This chapter discusses the general importance of adherence for all HIV-infected persons and presents specific issues that are unique to substance users or that may affect their treatment.

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II. PREDICTORS OF ADHERENCE

Studies of adherence to ARV therapy have identified few stable predictors of adherence. Lack of adherence to treatment recommendations in general is so widespread that no grouping of sociodemographic or psychosocial characteristics can reliably predict it.⁵ Nonetheless, particular emphasis has been given to defining correlates of poor adherence among substance users for the following reasons:

1. Substance users account for a large proportion of prevalent AIDS cases in many US cities.⁶
2. Substance users are traditionally thought to be less capable of adhering to medical treatments.⁷
3. Concern that poor adherence among persons engaged in high-risk behaviors will foster development and transmission of resistant virus.⁸

Active substance or alcohol use is one of the few relatively consistent predictors of poor adherence but past history of drug or alcohol abuse is not.^9,10 Studies have shown that past users who do not currently use drugs, as well as some active users, are able to adhere to ARV treatments with success comparable to that of non-substance users.^11,12

Active mental illness, in particular depression, is consistently associated with poor adherence.¹³ Other common reasons for non-adherence include difficulty remembering to take medications, inconvenient dosing, and medication side effects.^14,15

Predictors of adherence that have been consistently identified among both substance-using and non-substance-using persons with HIV infection include the following:

• Social stability and support
• Beliefs and knowledge about medications
• Confidence in the ability to take HIV medications, including both self-efficacy and how well the regimen works (“fits”) with daily activities^16-18
• A strong and trusting patient-provider relationship

In addition to patient-related factors, several provider- and system-level characteristics have been associated with ARV adherence. These factors may be particularly important for substance users, who often lack access to reliable primary care. Participation in substance use treatment has been associated with adherence to preventive healthcare services in substance users, although the effect of engagement in substance use treatment on ARV adherence has not been formally studied. A strong patient-provider relationship, including trust and engagement with the provider, has been associated with improved ARV adherence.¹⁹ To build trust, clinicians should be aware of their own personal perspectives and explore and respect the patient’s perspective.

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III. ADDRESSING POTENTIAL BARRIERS TO ADHERENCE BEFORE INITIATING ARV THERAPY

Recommendations:

Clinicians should identify and address potential barriers to adherence before initiating ARV therapy in HIV-infected substance users (see Table 1) . If clinicians elect to defer prescribing ARV therapy while addressing potentially modifiable barriers to adherence, they should discuss this decision with the patient.

Clinicians should reassess potential barriers to adherence at least every 3 to 4 months and whenever adherence problems are identified.

Clinicians should discuss with patients the known interactions between prescribed medications and illicit substances.

Identifying and addressing potential barriers to adherence before initiating ARV therapy in HIV-infected substance users is critical (see Table 1). Clinicians may choose to defer ARV therapy while addressing potentially modifiable barriers to adherence. In patients with advanced AIDS, it may be appropriate to initiate ARV therapy even if barriers to adherence are present. In these cases, referrals should be made for intensified adherence support (see Appendix IX).

Additional Barriers to Address With Patients Receiving Concurrent Opioid Pharmacotherapy

Recommendations:

Clinicians should educate patients who receive concurrent opioid pharmacotherapy and ARV therapy about the safety and efficacy of methadone and buprenorphine because these patients may have misconceptions regarding the safety of concurrent opioid pharmacotherapy and ARV therapy.

Clinicians should assess potential interactions between ARV therapy and methadone before and  during therapy by inquiring about oversedation and opioid withdrawal symptoms. If withdrawal symptoms are present, the primary care clinician should conduct a detailed history and facilitate a dose increase by educatingthe patient and communicating with the methadone provider.

A unique barrier to ARV therapy adherence among many substance users in substance use treatment is the interaction between ARV medications and methadone.²⁰ Clinicians should educate patients about drug interactions, especially when initiating a new drug. It is critical that such interactions are identified in clinical practice because  precipitation of narcotic withdrawal by an ARV agent that induces methadone metabolism may result in resumption of heroin use or in non-adherence to ARV medications. Most significantly, the non-nucleoside reverse transcriptase  inhibitors (NNRTIs) efavirenz and nevirapine substantially induce methadone metabolism and may precipitate  significant narcotic withdrawal symptoms and reduce methadone blood levels.^21,22

More specific information about medication interactions can be found in Drug-Drug Interactions Between ARV Agents, Medications Used in Substance Use Treatment, and Recreational Drugs.

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IV. ADHERENCE AND ANTIRETROVIRAL RESISTANCE

Recommendations:

Clinicians should counsel patients before initiating ARV therapy and at routine monitoring visits during therapy concerning the need for strict adherence and the risk of viral drug resistance when adherence is compromised.

Clinicians should perform a thorough adherence assessment and obtain antiretroviral resistance assays prior to changing regimens in patients who are receiving a failing regimen (failure to demonstrate ≥1.5-log drop in viral load within 3 months of initiating treatment and, more importantly, failure to achieve a viral load <50 copies/mL within 6 months of initiating treatment).

Any discussion of adherence to ARV therapy must take into account the issue of drug resistance. Although the belief that low levels of adherence promote drug resistance is often cited as a reason to withhold ARV therapy from active substance users, there is little empirical evidence to support this decision. Evidence is beginning to accumulate demonstrating that the selection of drug resistance occurs most readily in patients with higher levels of adherence and incomplete viral suppression.²³ Studies have shown that among patients with low adherence (<50-60%), lack of viral suppression is more likely due to inadequate drug exposure than to the presumed development of drug resistance. Sustained low levels of adherence are not automatically or even generally associated with development of high levels of drug-resistant virus.²³ Rather, the documented close relationship between poor adherence and both disease progression and death is most likely associated with inadequate drug exposure and resulting high levels of viral replication.^3,24 Higher levels of adherence are associated with improved clinical outcome, although they may also be associated with an increased risk of developing drug-resistant virus. Therefore, the decision to withhold ARV therapy should not be based solely on the potential of developing drug resistance, but rather efforts should be directed toward a regimen that is pharmacologically and behaviorally appropriate to the individual.

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V. MEASUREMENT OF ADHERENCE

Recommendations:

Clinicians should assess adherence at every routine monitoring visit.

Clinicians should use finite time intervals when inquiring about and quantifying the patient’s self-report. Clinicians should average responses across visits to obtain a more accurate estimate of adherence.

When assessing adherence, clinicians should use precise language that the patient can understand. In addition, clinicians should verify that patients are taking the medications as prescribed, specifically, correct medications, correct number of pills per dose, and correct number of doses per day.

Measurement of adherence is challenging in both clinical and research settings and usually relies on any one of the following methods or a combination:

• Self-report
• Pill counts
• Pharmacy records
• Electronic pill bottle monitors
• Therapeutic drug monitoring
• Directly observed therapy (DOT)
• Modified directly observed therapy (MDOT)
• Computer-assisted self interview (CASI) assessment

The advantages and disadvantages of each method are discussed in Appendix X.

Despite its tendency to overestimate adherence, self-report remains the most practical measure in most clinical settings and is most likely to facilitate discussion between patients and providers about the reasons for non-adherence. Many studies, including those in substance-using populations, have demonstrated a strong correlation between actual medication intake and viral load.^1,9,26 Self-report is most valid when patients are asked about the number of missed doses within a short time frame (1-7 days), but some studies have found that asking about adherence within the past month is also valid.^27,28 In either case, finite time intervals should be used. For example, the clinician should ask about the number of doses taken and missed in the past day or past week.

Clinicians should acknowledge the difficulty of adhering to ARV medications and ask about missed doses in the immediate past. For example:

• Taking all of these pills must be very hard. How many pills did you miss yesterday?
• How many pills did you miss the day before yesterday? What about 2 days ago?
• Sometimes the weekends can be a hard time to take medications. Did you miss any pills last weekend?

Therapeutic drug monitoring may become a useful adjunct measure in the future, but because plasma drug levels reflect only recent adherence, its usefulness will be limited.

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VI. INTERVENTIONS TO IMPROVE ADHERENCE

Recommendation:

Clinicians should refer patients to substance use treatment programs to optimize patients’ ability to successfully utilize and adhere to ARV therapy and other medical therapies.^29,30

Adherence intervention strategies should include the following elements:

• Education and motivation, including treatment readiness, should be part of every visit
• If medically feasible, simplifying the regimen and tailoring it to the patient’s lifestyle
• Preparation for and management of side effects
• Identification and treatment of depression and other psychiatric conditions
• Substance use treatment
• Involving an adherence team or monitor
• Referring the patient to social services and mental health
  providers for assistance in dealing with (or resolving) issues that are
  barriers to adherence

Clinicians and substance-using patients should work together to develop a plan to decrease or stabilize substance use in preparation for initiating ARV therapy.

Few reliable adherence-enhancing interventions have been described among HIV-infected substance users, and almost none of these interventions have been evaluated using randomized designs.³¹ Many adherence intervention programs have relied on the information-motivation-behavior skills (IMB) model of behavior change. This model asserts that information is necessary but insufficient to alter behavior, and that motivation and behavioral skills are critical determinants in promoting behavior change.³² Several techniques that may improve adherence are shown in Table 2.

One randomized trial demonstrated that a single-session intervention that used cognitive-behavioral, problem-solving, and motivational interviewing techniques resulted in significant improvements in adherence after 12 weeks.¹⁷ Another study demonstrated that a brief medication counseling and behavioral intervention (20 minutes per month for 5 months) for substance-using men improved adherence and decreased subsequent hospitalizations.³³ Other non-controlled studies have suggested that prompt, frequent, and intensive follow-up is essential to adherence to ARV therapy.³⁴ Despite limited published data, it is well-accepted that behavioral counseling coupled with information enhances adherence.³⁵

Strategies to educate patients about adherence include the following:

• Providing information in an organized manner, both orally and in written form, with easy to understand, brief statements that include common examples.
• Using educational tools, such as pamphlets and information cards; however, these should complement and enhance the direct communication and not replace it.
• Providing culturally competent, patient-centered care by tailoring educational efforts to the individual patient through language interpretation, including services for the hearing impaired, translation, health literacy, avoiding cultural categorization, and identifying and addressing areas of cross-cultural sensitivity.

Because twice- and even once-daily dosing of HIV medication regimens have become common, the concept of directly observing pill ingestion has received increased attention. DOT relies on the visual observation of pill taking to ensure adherence. Although shown to be effective in several non-randomized trials,^36,37 published data are limited that compare the efficacy of DOT with other modalities for successful treatment of HIV disease. However, preliminary data from several pilot programs suggest that modified DOT strategies (for example, daily observation of morning doses with self-administration of evening doses, or observation of a once-daily regimen on 4 days of the week with self-administration on the other 3 days) might be appropriate for adoption in substance use treatment settings where patients are seen daily or several times per week.³⁸

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