Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV
The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.
Limitations to Treatment Safety and Efficacy
Adherence to the Continuum of Care
Last Updated: October 17, 2017; Last Reviewed: October 17, 2017
|Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion
Treatment adherence includes initiating care with an HIV provider (linkage to care), regularly attending appointments (retention in care), and adherence to antiretroviral therapy (ART). The concept of a “continuum of care” has been used to describe the process of HIV testing, linkage to HIV care, initiation of ART, adherence to treatment, retention in care, and virologic suppression.1-3 The U.S. Centers for Disease Control and Prevention (CDC) estimates that HIV has not yet been diagnosed in about 13% of the people living with HIV in the United States. After receiving an HIV diagnosis, about 75% of individuals are linked to care within 30 days. However, only 57% of persons who receive an HIV diagnosis are retained in HIV care. It is estimated that only approximately 55% of persons with diagnosed HIV are virally suppressed because of poor linkage to care and retention in care.4 The data for adolescents and young adults are even more sobering: only 51% of youth living with HIV receive a diagnosis, 68% are linked to care within 1 month, and 55% are retained in care. As a result, adolescents and young adults had the lowest rate of viral suppression among all age groups, at only 44%.5 Outcomes along the continuum also vary by geographic region and other population characteristics, such as sex, race/ethnicity, and HIV risk factors.4 To achieve optimal clinical outcomes and to realize the potential public health benefit of treatment as prevention, adherence to each step in the continuum of care is critical.6 It is also important to realize that retention and adherence are not static states. Life events, changes in insurance status, comorbid conditions and health system changes can cause people to shift back and forth on the continuum. Knowledgeable providers and high-quality system processes are vital in promoting rapid linkage and sustained retention in care and adherence to ART.
This section provides guidance on linking patients to care, assessing and improving retention in care, and assessing and improving adherence to ART. The CDC maintains a compendium of evidence-based and evidence-informed interventions to improve linkage, retention, and adherence (https://www.cdc.gov/hiv/research/interventionresearch/compendium/index.html). In addition, a number of other groups and organizations have provided guidance for improving adherence to the steps in the care continuum.6,7
Linkage to Care
Receiving a diagnosis of HIV infection can be traumatic and linkage to care efforts must be delivered with sensitivity and persistence. The time from diagnosis to linkage to care can be affected by many factors, including insufficient socioeconomic resources, active substance use, mental health problems, stigma, and disease severity (symptomatic HIV is associated with more successful linkage).8-12 In the United States, youth, people who use injection drugs, and black/African American persons have lower rates of linkage to care.4 Some health system-associated factors have also been associated with linkage success or failure. Co-location of testing and treatment services11 and active linkage services (e.g., assisting the patient in setting up appointments, maintaining an active relationship with the patient until linkage is completed, and providing linkage case management services)13-15 bolster linkage to care. Conversely, passive linkage (e.g., only providing names and contact information for treatment centers) is associated with lower linkage to care.
Monitoring Linkage to Care
Linking to HIV care after a new diagnosis of HIV infection is defined as completing an outpatient appointment with a clinical provider who has the skills and ability to treat HIV infection, including prescribing ART. Patients should be linked to care as soon as possible after diagnosis with HIV, preferably within 30 days. Monitoring linkage is a critical responsibility so that interventions can effectively reach persons who are not linked to care. If the facilities that diagnose and treat an individual are the same or share the same electronic medical record system, it is relatively straightforward to monitor linkage to care. Monitoring linkage for persons whose HIV is diagnosed outside the treatment provider’s healthcare system is difficult and generally is the responsibility of the diagnosing provider/entity and the public health authority. However, once a patient makes contact with the treating clinical system, he or she should be engaged in linkage efforts and monitored for successful linkage to and retention in HIV care.
Improving Linkage to Care
Strategies to improve linkage to care are summarized in Table 14. Linkage efforts should include immediate referral to care at diagnosis, appointment reminders, and outreach efforts if needed.13 The only intervention shown to increase linkage to care in a randomized trial conducted in the United States is the Anti-Retroviral Treatment and Access to Services (ARTAS) intervention.14 ARTAS is a strength-based intervention which aims to facilitate linkage to and retention in care for persons with recently diagnosed HIV. The ARTAS intervention was tested in four cities and enrolled a diverse group of persons. The participants in the ARTAS intervention trial were randomized to either an intervention arm or a control arm. Participants randomized to the control arm received information about HIV and care resources and a referral to a local HIV medical provider. Each participant in the intervention arm worked with an ARTAS interventionist for five sessions, 90 days, or until linkage—whichever came first. The interventionist helped the participant to identify and use his or her strengths, abilities, and skills to link to HIV care, and linked the participant to community resources. Linkage to care, defined as completing at least one visit with an HIV clinician within the first 6 months, was greater among the ARTAS participants than the control participants (78% vs. 60%, adjusted RR = 1.36, P < 0.001). Furthermore, a greater percentage of ARTAS participants were retained in care, defined as visiting an HIV clinician at least once in each of the first two 6-month blocks after enrollment (64% vs. 49% for ARTAS and control participants, respectively; adjusted RR = 1.41, P = 0.006). ARTAS has been replicated in a community-based study.15 CDC supports free training in the ARTAS intervention (https://effectiveinterventions.cdc.gov/en/HighImpactPrevention/PublicHealthStrategies/ARTAS.aspx). Other studies support the importance of post-test counseling to educate, motivate, and present positive messages about living with HIV,16 peer support,17 and engaging with the patient at the clinic in advance of the visit with the provider.18 Financial incentives did not increase linkage to care within 90 days in a large randomized trial.19
Retention in Care
Poor retention in HIV care is associated with greater risk of death.20,21 Poor retention is more common in persons who are substance users, have serious mental health problems, have unmet socioeconomic needs (e.g., housing, food, or transportation), lack financial resources or health insurance, have schedules that complicate adherence, have been recently incarcerated, or face stigma.22-25 At the provider and health system level, low trust in providers and a poor patient-provider relationship have been associated with lower retention, as has lower satisfaction with the clinic experience.26-28 Availability of appointments and timeliness of appointments (i.e., long delay from the request for an appointment to the appointment’s date) and scheduling convenience are also factors.
Monitoring Retention in Care
Retention in care should be routinely monitored.6 There are various ways to measure retention, including measures based on attended visits over a defined period of time (constancy measures), and measures based on missed visits.29 Both approaches are valid and independently predict survival.30 Missed visits and a prolonged time since last visit are relatively easy to measure and should trigger efforts to retain or re-engage a person in care. Constancy measures (e.g., at least two visits that are at least 90 days apart over 1 year, or at least one visit every 6 months over the last 2 years), can be used as clinic quality assurance measures.
Improving Retention in Care
Strategies to improve retention in care are summarized in Table 14. The Retention through Enhanced Personal Contact (REPC) intervention was tested in a randomized trial in six clinics in the United States. The intervention relied on personal contact by an interventionist with at-risk patients. It included a brief face-to-face meeting upon returning to care and at each clinic visit and three types of phone calls: to check on patients between visits, as appointment reminders just before visits, and to attempt to reschedule missed visits. REPC resulted in small but significant improvements in retention in care, including in racial/ethnic minority populations and persons with detectable plasma HIV RNA.31 In-clinic opioid replacement therapy helps opioid users remain in care.32 An intervention using the electronic medical record to alert providers when patients had suboptimal follow-up or high viral loads also improved retention in care.33 On the other hand, in two randomized trials involving out-of-care, hospitalized patients with HIV, peer counselors and patient navigators did not improve relinkage to care after hospital discharge.34,35 Data from nonrandomized studies support:
- Clinic-wide marketing (e.g., posters, brochures, and customer service training of patient-facing staff) to promote attending scheduled visits and provide patients a welcoming and courteous experience,36
- Stepped case management and social and outreach services,37 and
- “Data to Care” approaches which use clinic and public health data to reach out-of-care persons and re-engage them into care (see https://effectiveinterventions.cdc.gov/en/highimpactprevention/publichealthstrategies/DatatoCare.aspx).38-40 However, the effectiveness of “data to care” interventions is variable and privacy concerns must be adequately addressed.
Overall, these data support the concept that all clinic personnel, from the facilities staff to nurses to providers, play important roles in supporting retention in care by providing the optimal patient care experience, constructively affirming attendance rather than criticizing non-attendance, and collaboratively problem solving with patients to overcome barriers to care.27,31,36 Flexible appointment schedules, expanded clinic hours, and copay and other financial or insurance assistance such as that provided by the Ryan White program will also provide patients with uninterrupted access to clinical care. Guidelines regarding linkage and retention have been published.6,7 CDC maintains a compendium of evidence-based and evidence-informed interventions (https://www.cdc.gov/hiv/research/interventionresearch/compendium/index.html).
The use of financial incentives or rewards to promote retention in care has been studied. A large study randomized clinic sites to financial incentives or standard-of-care. At baseline, 45% of the patients were retained in care in these clinics. The relative increase in the proportion of participants retained in care was 9% higher in clinics offering incentives than in standard-of-care clinics. Viral suppression also improved 4% at financial incentive clinics, from a baseline of 62%.19 In another large, randomized study of persons out-of-care and hospitalized, financial incentives plus patient navigation did not lead to sustained improvement in retention or viral load suppression over that achieved with standard care.34 The use of financial incentives therefore remains experimental and cannot be recommended for routine care at this time.
Adherence to Antiretroviral Therapy
Adherence to ART can be influenced by a number of factors, including the patient’s social situation and clinical condition, the prescribed regimen, and the patient-provider relationship.41 Poor adherence is often a consequence of one or more behavioral, structural, and psychosocial barriers (e.g., depression and other mental illnesses, neurocognitive impairment, low health literacy, low levels of social support, stressful life events, busy or unstructured daily routines, active substance use, homelessness, poverty, nondisclosure of HIV serostatus, denial, stigma, and inconsistent access to medications due to financial and insurance status).42-44
Characteristics of one or more components of the prescribed regimen can affect adherence. Once-daily regimens,45 including those with low pill burden (even if not one pill once daily), without a food requirement, and few side effects or toxicities, are associated with higher levels of adherence.46,47 Single-tablet regimens (STR) that include all antiretrovirals in one pill taken once daily are easier for people to use. However, data to support or refute the superiority of a STR versus a once-daily multi-tablet regimen (MTR), as might be required for the use of some soon-to-be-available generic-based antiretroviral (ARV) regimens, are limited. There are demonstrated beneficial effects on virologic suppression in switch studies, in which persons on MTR are randomized to stay on MTR or switch to STR.48 Whether an STR is beneficial in treatment-naive patients is not known, with at least one large observational cohort study showing benefit of once-daily STR versus once-daily MTR, but only when switches for simplification of MTR were considered failures.47,49 Comparisons of these regimens are hampered since not all drugs and classes are available as STR.
Characteristics of the clinical setting can also have important structural influences on the success or failure of medication adherence. Settings that provide comprehensive multidisciplinary care (e.g., by case managers, pharmacists, social workers, and mental health and substance abuse providers) support patients’ complex needs, including their medication adherence-related needs. Drug abuse treatment programs are often best suited to address substance use and may offer services that promote adherence, such as directly observed therapy (DOT).
Monitoring Adherence to Antiretroviral Therapy
Adherence to ART should be assessed and addressed in a constructive and nonjudgmental manner at every visit. Given the potency of contemporary ART, a detectable viral load identified during chronic care for a patient with stable access to ART is most likely the result of poor adherence. Patient self-report, the most frequently used method for evaluating medication adherence, remains a useful tool. Carefully assessed patient self-report of high-level adherence to ART has been associated with favorable viral load responses.50,51 Patient admission of suboptimal adherence is highly correlated with poor therapeutic response. The reliability of self-report often depends on how the clinician elicits the information. It is most reliable when ascertained in a simple, nonjudgmental, routine, and structured format that normalizes less-than-perfect adherence and minimizes socially desirable responses. To allow patients to disclose lapses in adherence, some experts suggest inquiring about the number of missed doses during a defined time period. For example, for a patient with a detectable viral load, a provider might state, “I know it is difficult to take medicine every day. Most people miss doses at least sometimes. Thinking about the last 2 weeks, how many times have you missed doses? Please give me a rough estimate so I can help you take the best care of yourself.” Other research supports simply asking patients to rate their adherence during the last 4 weeks on a 5- or 6-point Likert scale.52,53
Other measures of adherence include pharmacy records and pill counts. Pharmacy records can be valuable when medications are obtained exclusively from a single source. Because pill counts can be altered by patients, are labor intensive, and can be perceived as confrontational, they are generally not used in routine care. Other methods of assessing adherence include the use of therapeutic drug monitoring and electronic measurement devices (e.g., Medication Event Monitoring System [MEMS] bottle caps and dispensing systems). However, these methods are costly and are generally reserved for research settings.
Improving Adherence to Antiretroviral Therapy
Strategies to improve adherence to ART are summarized in Table 14. Just as they support retention in care, all health care team members play integral roles in successful ART adherence programs.51,54-56 An increasing number of interventions have proven effective in improving adherence to ART (for descriptions of the interventions, see https://www.cdc.gov/hiv/research/interventionresearch/compendium/ma/index.html). The many options can be customized to suit a range of needs and settings.
It is important that each new patient receives and understands basic information about HIV infection, including the goals of therapy (achieving and maintaining viral suppression, which will decrease HIV-associated complications and prevent transmission), the prescribed regimen (including dosing schedule and potential side effects), the importance of adherence to ART, and the potential for the development of drug resistance as a consequence of suboptimal adherence. Patients must also be positively motivated to initiate therapy, which can be assessed by simply asking patients if they want to start treatment for HIV infection. Clinicians should assist patients in identifying facilitating factors and potential barriers to adherence, and develop multidisciplinary plans to attempt to overcome those barriers. Processes for obtaining medications and refills should be clearly described. Transportation to pharmacy and to clinic visits should be assessed with linkage to appropriate services as needed. Plans to ensure uninterrupted access to ART via insurance, copay assistance, pharmaceutical company assistance programs, or AIDS Drug Assistance Programs (ADAP), for example, should be made and reviewed with the patient. Much of this effort to inform, motivate, and reduce barriers can be achieved by support staff, and can be accomplished concomitant with, or even after, starting therapy.57-60 While delaying the initiation of ART is rarely indicated, some patients may not be comfortable starting treatment. Patients expressing reluctance to initiate ART should be engaged in counseling to understand and overcome barriers to ART initiation. Although homelessness, substance use, and mental health problems are associated with poorer adherence, they are not predictive enough at the individual level to warrant withholding or delaying therapy given the simplicity, potency, and tolerability of contemporary ART. Rapid ART initiation at the time of HIV diagnosis has been pursued as a strategy to increase viral load suppression and retention in care, but safety data, data on intermediate or long-term outcomes, and data from randomized controlled trials conducted in high-resource settings are currently lacking.57-60 For more details, see Initiation of Antiretroviral Therapy.
The first principle of successful treatment is to design a plan to which the patient can commit.61,62 It is important to consider the patient’s daily schedule; tolerance of pill number, size, and frequency; and any issues affecting absorption (e.g., use of acid-reducing therapy and food requirements). With the patient’s input, a medication choice and administration schedule should be tailored to his or her daily activities. Clinicians should explain to patients that their first regimen is usually the best option for a simple regimen that affords long-term treatment success. Establishing a trusting patient-provider relationship and maintaining good communication will help to improve adherence and long-term outcomes. Medication taking can also be enhanced using medication reminder aids. There is strongest evidence for text messaging, but pill box monitors, pill boxes, and alarms may also improve adherence.63-67
Positive reinforcement can greatly help patients maintain high levels of adherence. This technique to foster adherence includes informing patients of their low or suppressed viral load and increases in CD4 T lymphocyte cell counts. Motivational interviewing has also been used with some success.68-70 Other effective interventions include nurse home visits, a five-session group intervention, and couples- or family-based interventions. Interventions involving several approaches are generally more successful than single-strategy interventions, and interventions based on cognitive behavioral therapy and supporter interventions have been shown to improve viral suppression.71 Problem-solving approaches that vary in intensity and culturally tailored approaches also are promising.70,72,73 To maintain high levels of adherence in some patients, it is important to provide substance abuse therapy and to strengthen social support. DOT has been effective in providing ART to active drug users74 but not to patients in a general clinic population75 or in home-based settings with partners responsible for DOT.76 The use of incentives or rewards to promote adherence has been studied, and they have been shown to improve adherence in one study.19 However, the durability and feasibility of financial incentives are not known at this time, hence rewards for adherence are not generally recommended.34,77,78
Even armed with accurate information about a patient’s adherence and barriers to ART and appointment adherence, clinicians often fail to engage patients in a productive conversation and instead simply tell patients to be adherent and offer warnings about what might ensue with continued poor adherence. This approach fails to acknowledge a patient’s barriers to adherence, fails to provide the patient with actionable information, erodes rather than builds the patient-provider relationship, and has been demonstrated to not improve adherence.79,80 At the same time, however, many of the interventions shown to improve adherence are difficult to implement in routine care. Nonetheless, effective lessons from this body of research can be applied to routine care to improve linkage to care, adherence to ART, and adherence to appointments. These lessons include the following:
- Regularly assess adherence to ART and appointments.
- Engage a patient who is struggling with adherence at any step on the care continuum with a constructive, collaborative, nonjudgmental, and problem-solving approach rather than reprimanding them or lecturing them on the importance of adherence.
- Elicit an individual’s barriers to adherence, which may include personal barriers (e.g., substance use, housing instability, stigma, lack of transportation), clinic barriers (e.g., limited clinic hours, processes that make it more difficult to obtain prescriptions or schedule appointments), and system barriers (e.g., copays, prior approvals, processes that complicate maintaining pharmacy benefits or obtaining refills).
- Tailor approaches to improve adherence to an individual’s needs and barriers, for example, by changing ART to simplify dosing or reduce side effects, finding resources to assist with copays or other out-of-pocket costs (see Table 14) to maintain an uninterrupted supply of ART and access to clinicians, or linking patients to counseling to overcome stigma, substance use, or depression.
- Place patients with apparent ART adherence problems on regimens with high genetic barriers to resistance, such as dolutegravir or boosted-darunavir regimens. When selecting the regimen, consider possible side effects, out-of-pocket costs, convenience, and patient preferences since the only regimen that will work is the one the patient can obtain and is willing and able to take.
- Understand that multidisciplinary approaches and time to understand and address barriers are needed in many situations, and that the clinician’s role is to help the patient to understand the importance of adherence to the continuum of care and reveal any barriers to adherence, and link the patient to resources to overcome those barriers.
|Provide an accessible, trustworthy, nonjudgmental multidisciplinary health care team.||
|Strengthen early linkage to care and retention in care.||
|Evaluate patient’s knowledge about HIV infection, prevention, and treatment and, based on this assessment, provide HIV-related information.||
|Identify facilitators, potential barriers to adherence, and necessary medication management skills both before starting ART and on an ongoing basis.||
|Provide needed resources.||
|Involve the patient in ARV regimen selection.||
|Assess adherence at every clinic visit.||
|Use positive reinforcement to foster adherence success.||
|Identify the type of and reasons for poor adherence and target ways to improve adherence.||
|Select from among available effective adherence and retention interventions.||
|Systematically monitor retention in care.||
|Key to Acronyms: ART = antiretroviral therapy; ARTAS = Anti-Retroviral Treatment and Access to Services; ARV = antiretroviral; CD4 = CD4 T lymphocyte; CDC = Centers for Disease Control and Prevention; DOT = directly observed therapy; DTG = dolutegravir; PI/r = ritonavir-boosted protease inhibitor; STR = single tablet regimen|
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