0
Clinical Guidelines |

Guidelines for Improving Entry Into and Retention in Care and Antiretroviral Adherence for Persons With HIV: Evidence-Based Recommendations From an International Association of Physicians in AIDS Care Panel FREE

Melanie A. Thompson, MD; Michael J. Mugavero, MD, MHSc; K. Rivet Amico, PhD; Victoria A. Cargill, MD, MSCE; Larry W. Chang, MD, MPH; Robert Gross, MD, MSCE; Catherine Orrell, MBChB, MSc, MMed; Frederick L. Altice, MD; David R. Bangsberg, MD, MPH; John G. Bartlett, MD; Curt G. Beckwith, MD; Nadia Dowshen, MD; Christopher M. Gordon, PhD; Tim Horn, MS; Princy Kumar, MD; James D. Scott, PharmD, MEd; Michael J. Stirratt, PhD; Robert H. Remien, PhD; Jane M. Simoni, PhD; and Jean B. Nachega, MD, PhD, MPH
[+] Article and Author Information

From the AIDS Research Consortium of Atlanta, Atlanta, Georgia; University of Alabama, Birmingham, Alabama; University of Connecticut, Storrs, Connecticut; Office of AIDS Research, National Institutes of Health, and National Institute of Mental Health, Bethesda, Maryland; Johns Hopkins University and Johns Hopkins University/Stellenbosch University, Baltimore, Maryland; University of Pennsylvania and The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; University of Cape Town, Cape Town, South Africa; Yale University, New Haven, Connecticut; Harvard Medical School, Cambridge, Massachusetts; The Warren Alpert Medical School of Brown University and The Miriam Hospital, Providence, Rhode Island; AIDSmeds.com and Columbia University, New York, New York; Georgetown University, Washington, DC; Western University of Health Sciences, Pomona, California; and University of Washington, Seattle, Washington.

Acknowledgment: The authors thank the following individuals, who were instrumental to the development of these guidelines: José M. Zuniga, PhD, MPH, and Angela Knudson (IAPAC; guideline conception, administrative support); Laura Bernard, MPH, and Kathryn Muessig, PhD (systematic review and evidence grading); Jennifer Johnsen, MD (systematic review); Anne McDonough, MPH (editing); and Adele Webb, PhD, RN (Chamberlain College of Nursing, Cleveland, Ohio; contribution to discussions of children and adolescents), and Morgan Dirlam (Georgetown University; contribution to future recommendations, concomitant medical conditions). The authors also thank the external reviewers, including Jane Anderson, PhD, and John Walsh, MBBS (British HIV Association); Carl Stein, MHS, PA-C, (Physician Assistant AIDS Network); Donna E. Sweet, MD (American Academy of HIV Medicine); Ann Deschamps, RN, MSN (European HIV Nurses Network); Robert T. Carroll, MN, RN (Association of Nurses in AIDS Care); and Donna Futterman, MD, and Brian Gazzard, MD, MA (individual reviewers). The HIV Medicine Association also provided input into these guidelines.

Grant Support: Development of the guidelines was jointly sponsored by IAPAC and the U.S. National Institutes of Health's Office of AIDS Research.

Potential Conflicts of Interest: Disclosures from authors and panel members can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0061.

Requests for Single Reprints: International Association of Physicians in AIDS Care, 1640 Rhode Island Avenue NW, Suite 200, Washington, DC 20036; e-mail, iapac@iapac.org.

Current Author Addresses: Dr. Thompson: AIDS Research Consortium of Atlanta, 131 Ponce de Leon Avenue, Suite 130, Atlanta, GA 30308.

Dr. Mugavero: 1530 3rd Avenue South, Community Care Building 142, Birmingham, AL 35294-2050.

Dr. Amico: 5598 Mounting Road, Brighton, MI 48116.

Dr. Cargill: Office of AIDS Research, National Institutes of Health, 5635 Fishers Lane, Bethesda, MD 20892.

Dr. Chang: Johns Hopkins Center for Global Health, 1503 East Jefferson Street, Room 116, Baltimore, MD 21205.

Dr. Gross: Perelman School of Medicine, University of Pennsylvania, 804 Blockley Hall, 423 Guardian Drive, Pennsylvania, PA 19104-6021.

Dr. Orrell: University of Cape Town, Anzio Road, Observatory 7705, Cape Town, South Africa.

Dr. Altice: Yale University AIDS Program, 135 College Street, Suite 323, New Haven, CT 06510.

Dr. Bangsberg: MGH Center for Global Health, 104 Mt. Auburn Street, 3rd Floor, Cambridge, MA 02138.

Dr. Bartlett: Johns Hopkins School of Medicine, 615 North Wolfe Street, 1830 Building Room 437, Baltimore, MD 21205.

Dr. Beckwith: The Warren Alpert Medical School of Brown University, The Miriam Hospital, 164 Summit Avenue, Providence, RI 02906.

Dr. Dowshen: The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, 11 NW, Suite 10, Room 24, Philadelphia, PA 19104.

Dr. Gordon: National Institute of Mental Health, 6001 Executive Boulevard, Room 6212, Bethesda, MD 20892-9619.

Mr. Horn: AIDSmeds.com, 462 Seventh Avenue, 19th Floor, New York, NY 10018-7424.

Dr. Kumar: Georgetown University School of Medicine, 5PHC Building, 3800 Reservoir Road NW, Washington, DC 20007.

Dr. Scott: Western University of Health Sciences, College of Pharmacy, 309 East 2nd Street, Pomona, CA 91766.

Dr. Stirratt: National Institute of Mental Health, 6001 Executive Boulevard, MSC-9619, Room 6199, Bethesda, MD 20892.

Dr. Remien: Columbia University, 1051 Riverside Drive, Unit 15, New York, NY 10032.

Dr. Simoni: Department of Psychology, University of Washington, 3909 Stevens Way NE, Campus Box 351525, Seattle, WA 98195-1525.

Dr. Nachega: Johns Hopkins Bloomberg School of Public of Health, 615 North Wolfe Street, Room E5527, Baltimore, MD 21205.

Author Contributions: Conception and design: M.A. Thompson, M.J. Mugavero, K.R. Amico, V.A. Cargill, L.W. Chang, R. Gross, C. Orrell, F.L. Altice, D.R. Bangsberg, J.G. Bartlett, C.G. Beckwith, N. Dowshen, C.M. Gordon, T. Horn, P. Kumar, J.D. Scott, M.J. Stirratt, R.H. Remien, J.M. Simoni, J.B. Nachega.

Analysis and interpretation of the data: M.A. Thompson, M.J. Mugavero, K.R. Amico, V.A. Cargill, L.W. Chang, R. Gross, C. Orrell, F.L. Altice, D.R. Bangsberg, J.G. Bartlett, C.G. Beckwith, N. Dowshen, C.M. Gordon, T. Horn, P. Kumar, J.D. Scott, M.J. Stirratt, R.H. Remien, J.M. Simoni, J.B. Nachega.

Drafting of the article: M.A. Thompson, M.J. Mugavero, K.R. Amico, V.A. Cargill, L.W. Chang, R. Gross, C. Orrell, F.A. Altice, D.R. Bangsberg, J.G. Bartlett, C.G. Beckwith, N. Dowshen, C.M. Gordon, T. Horn, P. Kumar, J.D. Scott, M.J. Stirratt, R.H. Remien, J.M. Simoni, J.B. Nachega.

Critical revision of the article for important intellectual content: M.A. Thompson, M.J. Mugavero, K.R. Amico, V.A. Cargill, L.W. Chang, R. Gross, C. Orrell, F.L. Altice, D.R. Bangsberg, J.G. Bartlett, C.G. Beckwith, N. Dowshen, C.M. Gordon, T. Horn, P. Kumar, J.D. Scott, M.J. Stirratt, R.H. Remien, J.M. Simoni, J.B. Nachega.

Final approval of the article: M.A. Thompson, M.J. Mugavero, K.R. Amico, V.A. Cargill, L.W. Chang, R. Gross, C. Orrell, F.L. Altice, D.R. Bangsberg, J.G. Bartlett, C.G. Beckwith, N. Dowshen, C.M. Gordon, T. Horn, P. Kumar, J.D. Scott, M.J. Stirratt, R.H. Remien, J.M. Simoni, J.B. Nachega.

Statistical expertise: L.W. Chang, F.L. Altice.

Obtaining of funding: V.A. Cargill.

Administrative, technical, or logistic support: M.A. Thompson, M.J. Mugavero, V.A. Cargill.

Collection and assembly of data: M.A. Thompson, M.J. Mugavero, K.R. Amico, V.A. Cargill, L.W. Chang, R. Gross, C. Orrell, F.A. Altice, D.R. Bangsberg, J.G. Bartlett, C.G. Beckwith, N. Dowshen, C.M. Gordon, T. Horn, P. Kumar, J.D. Scott, M.J. Stirratt, R.H. Remien, J.M. Simoni, J.B. Nachega.


Ann Intern Med. 2012;156(11):817-833. doi:10.7326/0003-4819-156-11-201206050-00419
Text Size: A A A

Description: After HIV diagnosis, timely entry into HIV medical care and retention in that care are essential to the provision of effective antiretroviral therapy (ART). Adherence to ART is among the key determinants of successful HIV treatment outcome and is essential to minimize the emergence of drug resistance. The International Association of Physicians in AIDS Care convened a panel to develop evidence-based recommendations to optimize entry into and retention in care and ART adherence for people with HIV.

Methods: A systematic literature search was conducted to produce an evidence base restricted to randomized, controlled trials and observational studies with comparators that had at least 1 measured biological or behavioral end point. A total of 325 studies met the criteria. Two reviewers independently extracted and coded data from each study using a standardized data extraction form. Panel members drafted recommendations based on the body of evidence for each method or intervention and then graded the overall quality of the body of evidence and the strength for each recommendation.

Recommendations: Recommendations are provided for monitoring entry into and retention in care, interventions to improve entry and retention, and monitoring of and interventions to improve ART adherence. Recommendations cover ART strategies, adherence tools, education and counseling, and health system and service delivery interventions. In addition, they cover specific issues pertaining to pregnant women, incarcerated individuals, homeless and marginally housed individuals, and children and adolescents, as well as substance use and mental health disorders. Recommendations for future research in all areas are also provided.


The availability of potent antiretroviral therapy (ART) has resulted in remarkable decreases in HIV-related morbidity and mortality in the past 15 years (12). Entry into and retention in HIV medical care is critical to the provision of ART, and adherence to ART is among the key determinants of HIV treatment success (36). More than 2 decades of targeted research in these areas has produced a varied and complex evidence base that, to date, has not been fully evaluated or distilled into concrete recommendations for how to best monitor or support HIV care and ART adherence.

Recent data from the U.S. Centers for Disease Control and Prevention reveal that only 28% of persons with HIV in the United States have achieved viral suppression (7). Of those who knew they had HIV, only 69% were linked to care, and only 59% were retained in care (8). These figures and comparable global data (910) challenge us to explore best practices for improving entry into and retention in care on a global scale. Only with successful care linkage and retention can ART be accessed. Once patients are in care and are receiving treatment, high levels of adherence are required to prevent the selection of resistance mutations and subsequent virologic failure (11). In a global pooled sample of 33 199 adults taking ART in over 84 observational studies, only 62% of persons achieved adherence of at least 90% of doses (12). These data underscore the need for concise and clear evidence-based recommendations to help care providers monitor and support ART adherence.

In this context, the International Association of Physicians in AIDS Care (IAPAC) convened an expert panel to develop evidence-based recommendations to optimize entry into and retention in care and ART adherence and to monitor these processes. Members of the panel are listed in Appendix 1. These guidelines aim to define best practices that can be used by practitioners and health systems to improve adherence and, in turn, health outcomes. Our recommendations are based on the best published science; however, the evidence base remains insufficient in many areas. For that reason, we also highlight areas in which additional research is needed to inform future recommendations. We realize that implementation of these recommendations may, in some cases, require that new resources be identified to bring the benefit of best practices to our clinic populations. We believe that presenting recommendations based on rigorous science is the best avenue to achieve that end.

These guidelines focus on interventions to improve entry into and retention in care and ART adherence for people living with HIV, as well as methods to monitor these critical processes. The target audience includes care providers, patients, policymakers, and organizations and health systems involved with implementing HIV care and treatment.

For these guidelines, a systematic literature search was conducted to produce an evidence base restricted to randomized, controlled trials (RCTs) and observational studies with comparators that had at least 1 measured biological or behavioral end point. For monitoring, correlation between a method and an outcome was required. A total of 325 studies met our criteria. Two reviewers independently extracted and coded data from each study using a standardized data extraction form. Panel members drafted recommendations based on the body of evidence for each method or intervention and then graded the overall quality of the body of evidence and the strength for each recommendation. Table 1 summarizes the quality and strength scales used. Details on the methods used are available in Appendix 2.

Table Jump PlaceholderTable 1.  

Grading Scales for Quality of the Body of Evidence and Strength of Recommendations

Appendix Table 1 summarizes all recommendations and associated quality and strength scores.

Table Jump PlaceholderAppendix Table 1.  

Summary of Recommendations With Scores for Quality of the Body of Evidence and Strength of Recommendation

Entry Into and Retention in HIV Medical Care

The associations between entry into and retention in HIV medical care and both individual health outcomes and HIV transmission dynamics mediated by ART have been well-established in retrospective, prospective, and mathematical modeling studies (1319). Accordingly, individual-level monitoring of entry and retention is essential to the development and evaluation of cost-effective interventions required to improve these critical components of clinical care.

Recommendation 1: Systematic monitoring of successful entry into HIV care is recommended for all individuals diagnosed with HIV (II A).

Entry into care after HIV diagnosis, defined as a visit with an HIV care provider authorized to prescribe ART, has been associated with improved survival (20). Within a given jurisdiction or service area, providers of testing services, local public health institutions, and medical clinics have a shared responsibility to monitor entry into HIV care. Roles and accountability should be clearly established on a local level. Integration of multiple data sources, including surveillance data, administrative databases, and medical clinic records, may enhance monitoring of initial entry into HIV care (21).

Recommendation 2: Systematic monitoring of retention in HIV care is recommended for all patients (II A).

Retention in care is associated with improved individual health outcomes, including HIV biomarker and clinical variables, and may reduce community-level viral burden, with implications for secondary prevention (13, 22). Although monitoring retention is routinely recommended, specific details, such as retention measures to be used and desired visit frequency, vary among jurisdictions and programs and should be in harmony with national and international guidelines. Many retention measures (for example, visit adherence, gaps in care, and visits per interval of time) and data sources (for example, surveillance, medical records, and administrative databases) have been used (23) and may be applied in accordance with local resources and standards of care. As with monitoring of linkage, integration of data sources may enhance monitoring of retention.

Recommendation 3: Brief, strengths-based case management for individuals with a new HIV diagnosis is recommended (II B).

The Antiretroviral Treatment and Access Study evaluated entry into and retention in care as part of a multisite RCT in several U.S. care sites comparing strengths-based case management sessions (up to 5 in a 90-day period) with passive referrals for local care among patients with recently diagnosed HIV infection (24). Trained social workers helped clients to identify their internal strengths and assets to facilitate successful linkage to HIV medical care. A significantly higher proportion of the case-managed participants visited an HIV clinician at least once within 6 months (78% vs. 60%) and at least twice within 12 months (64% vs. 49%). However, availability of resources may impede implementation in a given jurisdiction or service area.

Recommendation 4: Intensive outreach for individuals not engaged in medical care within 6 months of a new HIV diagnosis may be considered (III C).

In a sample of 104 individuals in whom HIV was diagnosed within 6 months before enrolling in the U.S. Special Projects of National Significance Outreach Initiative, 92% attended medical appointments within 6 months of enrollment (25). At study baseline, 14% of individuals had undetectable HIV-1 RNA, which increased to 45% after 12 months of follow-up. This observational demonstration project used a variety of approaches, focusing on individuals considered underserved by the health care system (such as women, youth, and people with a history of substance use or mental illness).

Recommendation 5: Use of peer or paraprofessional patient navigators may be considered (III C).

Patient navigation has been described as a model of care coordination and is largely based on peer-based programs established for patients with cancer. Patient navigators are trained to help HIV-infected patients facilitate interactions with health care. In an analysis of 4 patient-navigation interventions from the U.S. Special Projects of National Significance Outreach Initiative, involving more than 1100 patients who were inconsistently engaged in care, the proportion with at least 2 visits in the previous 6 months increased from 64% at baseline to 87% at 6 months and 79% at 12 months in the intervention group (26). In addition, the proportion of patients with undetectable HIV-1 RNA was 50% greater at 12 months than at baseline.

Monitoring ART Adherence

Monitoring adherence is necessary to assess the effect of interventions and also to inform providers of the need to implement interventions. Measurement methods include self-reports, pharmacy refill data, pill counts, electronic drug monitors (EDMs), and drug concentrations from biological samples; each has unique strengths and weaknesses (2728). Many of the studies reviewed combined measures to improve sensitivity and specificity, but because of the large variability in these approaches, we will not address these potential combinations here. Regardless of measurement method, adherence is a factor that varies with time and therefore must be repeatedly assessed (29).

Recommendation 6: Self-reported adherence should be obtained routinely in all patients (II A).

Self-reported ART adherence has consistently been associated with HIV-1 RNA levels. Although it commonly overestimates adherence (30), self-reported nonadherence has a high predictive value (27). Self-report is less strongly associated with treatment response than are EDM- or pharmacy-based measures, but relative ease of implementation further supports its use in clinical care. Careful attention must be paid to collecting self-report data in a manner that makes reasonable demands on memory. Therefore, questionnaires should inquire only about specific doses taken over a short time interval (for example, in the previous week or less) and about global measures of adherence over a somewhat longer time (for example, in the previous month).

Recommendation 7: Pharmacy refill data are recommended for adherence monitoring when medication refills are not automatically sent to patients (II B).

Many observational studies across the globe have demonstrated the validity of pharmacy refill data as an ART adherence measure, including medical records (3031), claims data (32), and ad hoc pharmacy contact (33). Pharmacy measures are useful for as long a period as the refill records are maintained. The interval over which refill records can be used depends on the days' supply (that is, the length of time the medication dispensed is intended to last).

Recommendation 8: Drug concentrations in biological samples are not routinely recommended (III C).

The concentration of HIV medications in various biological samples has been assessed as an adherence measure in many settings; relatively few analyses have been associated with clinical outcomes (3436). Results are inconsistent (3738) and are limited by assay issues and the relatively short half-life of most antiretroviral medications.

Recommendation 9: Pill counts performed by staff or patients are not routinely recommended (III C).

An association between pills counts and biological outcomes has been seen in some studies (3940) but not in all (41). Several studies have assessed various operational methods for conducting pill counts, such as making unannounced home visits for marginally housed individuals (3, 39, 42). Clinic-based pill counts are susceptible to pill dumping. The personnel required for pill counts and the burden of bringing medication to visits are further barriers to routine use.

Recommendation 10: EDMs are not routinely recommended for clinical use (I C).

Electronic drug monitors have been used to assess adherence in many studies (4347). Adherence measured electronically is consistently more closely associated with HIV-1 RNA than are other methods (4849). In research, EDMs have been the measurement method of choice (5051). Unfortunately, these technologies are currently impractical outside of studies because they may be burdensome to patients and incompatible with adherence-promoting strategies, such as pill cases.

Interventions to Improve ART Adherence

Interventions to promote ART adherence are broadly defined as strategies that aim to enhance this critical determinant of successful HIV treatment outcomes.

ART Strategies

Important determinants of ART adherence and the related construct of ART persistence (52), or uninterrupted receipt of treatment, include dosing schedule, pill count, tolerability, and toxicity profiles of ART. Advances in ART now allow simplification of dosing schedules and reduction of pill burden for a majority of patients while maintaining excellent viral suppression. Additional factors to be considered in initiating or changing ART include transmitted or emergent viral resistance, individual ART treatment history, medical and psychosocial comorbid conditions, concomitant medications, and patient preference.

Recommendation 11: Among regimens of similar efficacy and tolerability, once-daily regimens are recommended for treatment-naive patients beginning ART (II B).

Many RCTs in treatment-naive patients have compared once-daily with multiply-dosed regimens containing different drugs. As such, it is impossible to ascertain whether adherence and biological benefits derive from the dosing schedule or the regimen components. Some studies, however, have used identical ART components given once or twice daily and have demonstrated improved adherence and noninferior viral suppression with once-daily dosing (5354). Efficacy for once-daily dosing must be confirmed by RCTs before adoption into clinical care.

Recommendation 12: Switching treatment-experienced patients receiving complex or poorly tolerated regimens to once-daily regimens is recommended, given regimens with equivalent efficacy (III B).

Several studies have demonstrated successful switching to once-daily dosing for patients with suppressed virus on a multiply-dosed regimen (5559). Often, studies are limited by small sample size, short follow-up, or changes in ART regimens accompanying the switch to a once-daily regimen, so factors including toxicity, tolerability, and related considerations may contribute to observed findings. Treatment history and prior ART resistance are particularly important considerations when switching regimens for treatment-experienced patients.

Recommendation 13: Among regimens of equal efficacy and safety, fixed-dose combinations are recommended to decrease pill burden (III B).

Because fixed-dose combinations (FDCs) are often approved on the basis of safety and bioequivalence rather than noninferiority to the component regimens, few data comparing adherence outcomes between FDCs and individual components are available. Therefore, many of the data in this area come from surveys of patient satisfaction or extrapolation from diseases other than HIV that are, by definition, not included in our evidence base. The evidence base contains 1 RCT and 1 comparative observational study that demonstrated an adherence benefit with FDCs (6061). It is important to note that when components of different half-lives are combined, there is potential for a monotherapy “tail” and subsequent resistance when doses are missed or a drug is discontinued. On the other hand, the use of FDCs eliminates the possibility of taking an incomplete regimen, as may occur when one drug is not refilled on time or is simply not taken, leading to viral rebound and resistance (62).

Adherence Tools for Patients

Many commonly used self-management adherence tools, including pillboxes and medication planners or calendars, have been associated with improved adherence and HIV-1 RNA suppression (63). It is common for adherence tools to be combined with behavioral and structural interventions. Given their simplicity and observational data supporting their use, they are considered the standard of care despite limited comparative research to establish efficacy. Recommendations regarding use of these tools are limited because of this lack of evidence.

Recommendation 14: Reminder devices and use of communication technologies with an interactive component are recommended (I B).

An adherence benefit of dose-time reminder alarms has been reported (6465). Strategies using cellular technology (short message service communication) have demonstrated improvement in adherence and HIV-1 RNA. Methods ranged from texting dosing reminders with or without requesting a response (6668) to texting weekly check-ins from the clinic with telephone follow-up for those requesting it (69). One study found better ART adherence was achieved with use of texting with expected reply (interactive) than simple 1-way reminders (66).

Recommendation 15: Education and counseling using specific adherence-related tools is recommended (I A).

The available literature suggests that some tools may be more beneficial to patient adherence when combined with education or counseling. Seven studies (Appendix Table 2) evaluated a particular adherence tool (pill organizer [70], dose planner [71], reminder alarm device [7273], or EDM [7476]) as distinguished from general one-on-one education and counseling. All but 1 demonstrated an effect on adherence, and 3 of the 6 that investigated effects on biological markers found significant positive effects (72, 7576). Three studies from the Netherlands and China that used EDMs with counseling about missed doses showed improvement in adherence (7476), and 2 showed improvement in biological markers (7576). A factorial-design RCT and an RCT from Kenya showed the inferiority of using a reminder device without counseling and suggested that tools may be most successful when offered as part of a comprehensive support package (72, 77).

Table Jump PlaceholderAppendix Table 2.  

Evidence Base for Education and Counseling Recommendations

Education and Counseling Interventions

Several systematic syntheses of behavioral interventions targeting ART adherence are available and report generally positive modest effect sizes, but the effect on HIV-1 RNA is less consistent (7881). Recommendations are limited to those appropriate for general clinic populations; interventions targeting behavioral determinants of adherence in specific subgroups are included in other sections. Because of the volume and breadth of data supporting these recommendations, individual study results are not reviewed in detail, but Appendix Table 2 describes studies and outcomes. Across recommendations, pertinent issues exist with regard to best structure, deliverer, training, duration, timing, frequency, and targets of educational and counseling interventions, as well as optimal modalities for dissemination and implementation.

Recommendation 16: Individual one-on-one ART education is recommended (II A).

Of the 14 interventions with ART education components (8295), 10 had favorable effects on adherence outcomes, 2 had initial effects that deteriorated over time (86, 92), and 2 showed no benefit on adherence (87, 91); only 1 study demonstrated clear benefit on biological markers (94), 6 did not evaluate biomarkers (82, 8790, 92), and 7 showed no biomarker benefit (8386, 91, 93, 95). Among effective interventions, education was not the only component; most interventions also included counseling or skills-building, along with activities to promote adult learning. Group-delivered education is addressed in recommendation 18.

Recommendation 17: Providing one-on-one adherence support to patients through one or more adherence counseling approaches is recommended (II A).

Strategies to support adherence that involve one-on-one discussions targeting enhancement of facilitators and easing of barriers are recommended. Twenty-seven interventions in the evidence base used individual adherence counseling; of the 25 evaluating adherence, 16 established positive effects (82, 84, 8890, 93103), 3 demonstrated as-treated or post hoc effects (83, 85, 104), 3 demonstrated early effects that deteriorated over time (86, 92, 105), and 3 demonstrated no benefit (87, 106107). Of the 17 that included biological outcomes, 12 demonstrated no benefit (8386, 93, 95, 102103, 105108) and 5 demonstrated positive effects (94, 97, 99, 101, 109). Although most interventions are delivered in person, there are also successful examples of telephone-based counseling or mixed in-person and telephone-based models (72, 83, 102) and home visits (95). Further, expanding one-on-one counseling to include serodiscordant partners has demonstrated some benefit on adherence, although not on HIV-1 RNA (110), whereas inclusion of “caregivers” with ART-naive patients had mixed results (no benefit in 1 study [91] and support for effects on adherence and HIV-1 RNA overall but not over time in another [111]). The evidence base suggests the utility of providing some form of discussion-based support to individuals receiving ART and provides a wide array of potentially effective specific interventions that should be carefully matched to clinic population needs and resources.

Recommendation 18: Group education and group counseling are recommended; however, the type of group format, content, and implementation cannot be specified on the basis of the currently available evidence (II C).

The evidence base included 7 studies of group-based education and counseling programs targeting general clinic populations (Appendix Table 2). Although some studies have demonstrated significant improvements in ART adherence, HIV-1 RNA, or CD4 cell counts (112114) and 1 study demonstrated effects in specific subsets of participants (115), other studies showed no significant improvements in adherence (116117). Notably, studies targeted diverse patient groups and used a wide range of interventions, so the evidence does not clearly converge to support one particular approach to offering group education and counseling. Characterizing these interventions as “group” interventions designates their main modality, but several interventions also used an individual component or support for group members.

Recommendation 19: Multidisciplinary education and counseling intervention approaches are recommended (III B).

Use of multidisciplinary teams is distinct from multiple team members duplicating efforts or content addressing adherence; multidisciplinary team members have clearly delineated roles and cover content specific to their particular area of expertise. A health-team approach in which 109 ART-naive patients met with a pharmacist, dietitian, and social worker for targeted education and counseling before ART initiation did not produce significant effects on pharmacy refill–based adherence at 12 months but did significantly affect HIV-1 RNA outcomes (118). Another intervention using nurses and pharmacists targeted multiple factors (such as diet, work, social support, tools, and skills-building); significant effects on adherence were reported, but HIV-1 RNA and CD4 cell count did not change significantly (64).

Recommendation 20: Offering peer support may be considered (III C).

Nine studies were reviewed and showed mixed outcomes (119127). One reported null findings from a peer-based psychoeducational group (120), and 8 studies examining interventions involving treatment partners or peers, or both, demonstrated some success. The evidence base exhibits diverse results for use of peers. Several interventions, including treatment partners to supervise or directly administer ART (121123, 127) and peers to provide social support (119, 124126), showed improvement in adherence or biological markers or both. Combination of use of peers and intervention in these studies limits the ability to draw conclusion on the specific effect of peers versus the interventions they delivered.

Health System and Service Delivery Interventions

We focused on interventions targeting factors believed to be related to adherence and ones that are also associated with systems of care or service delivery (for example, transportation to clinic and food supplements, staffing and service modifications, co-location of services) or influence social determinants, such as HIV-associated stigma.

Recommendation 21: Using nurse- or community counselor–based care has adherence and biological outcomes similar to those of doctor- or clinic counselor–based care and is recommended in underresourced settings (II B).

Two RCTs showed noninferiority of nursing ART care to physician-based care. A trial from Uganda found a nurse-peer model was not inferior to the traditional doctor-counselor model in adherence, HIV-1 RNA, and CD4 outcomes (128). Another RCT from South Africa also demonstrated noninferiority of CD4 and HIV-1 RNA outcomes with nurses rather than physicians caring for people receiving ART (129). A cohort analysis, also from Uganda, with a notable limitation (the exposed cohort differed from control cohort) showed that a system of providing ART through volunteers (trained and supervised by a clinical officer) in a rural community was not inferior, in the short term, to a clinic-based standard of care (130).

Recommendation 22: Interventions providing case management services and resources to address food insecurity, housing, and transportation needs are recommended (III B).

Research with U.S. homeless populations have shown mixed results, but HIV-1 RNA levels improved in an as-treated analysis of a housing provision intervention (131). Case management is discussed in Recommendation 32. Cohort studies from Nigeria and Zambia with comparator groups evaluated outcomes of interventions for food-insecure patients and showed that ART adherence, retention in care, and clinical outcomes can be enhanced with food supplementation programs (132133). Addressing transportation issues in the context of case management and a home visit also may decrease missed appointments, especially among women with mental health or substance use disorders (134).

Recommendation 23: Integration of medication management services into pharmacy systems may be considered (III C).

Pilot pharmacies in California offered services to manage adverse drug effects, evaluate patient adherence in consultation with physicians and case managers, and tailor drug regimens to accommodate specific patient needs. Analysis of claims data for pilot pharmacies found that a larger percentage of pilot pharmacy patients were classified as adherent to ART on the basis of pharmacy refill data, used fewer contraindicated regimens, and had fewer excess medication fills than those with standard pharmacy care (135).

Recommendation 24: Directly administered ART is not recommended for routine clinical care settings (I A).

Although directly administered ART (DAART) has demonstrated benefit for some vulnerable populations (see Recommendations 28, 29, 31, and 37), well-controlled RCTs from well-resourced as well as resource-limited settings (including South Africa, Mozambique, Tanzania, Kenya, and Peru) have shown no benefit for various forms of DAART (clinic- or home-based; once-daily, twice-weekly, or once-weekly) among general populations (120123, 127, 136139) on adherence or biological markers. Thus, strong evidence supports not recommending DAART for routine HIV clinical care settings.

Special Populations

Treatment of a stigmatized and complex medical disorder with associated poor health outcomes is challenging in the best of circumstances for individuals with adequate social support, health literacy, stable housing, and economic resources. The additional challenges of incarceration, poverty, food and housing instability, and substance use and mental health disorders can further complicate adherence and require specialized interventions.

Pregnant Women

More than 50% of the 37.2 million adults with HIV in the world are women, and most are of childbearing age (140). Optimal ART adherence during pregnancy and the postpartum period remains a challenge globally (141143). The evidence regarding ART adherence interventions during pregnancy comes predominantly from resource-limited settings and is focused only on short-term prevention of mother-to-child transmission (PMTCT) rather than on ART adherence throughout pregnancy and afterward.

Recommendation 25: Targeted PMTCT treatment (including HIV testing and serostatus awareness) improves adherence to ART for PMTCT and is recommended compared with an untargeted approach (treatment without HIV testing) in high HIV prevalence settings (III B).

A Zambian RCT designed to test universal (without HIV testing) versus targeted (for those testing positive for HIV) single-dose nevirapine for PMTCT found that although nevirapine uptake was somewhat higher in the universal-treatment group, adherence was lower in women who were illiterate and unaware of their HIV status (144). Health literacy education is recommended in these settings.

Recommendation 26: Labor ward–based PMTCT adherence services are recommended for women who are not receiving ART before labor (II B).

A cluster RCT in 12 public-sector delivery centers in Zambia found that offering HIV counseling and testing and ART adherence training in the labor ward was feasible and significantly improved nevirapine coverage and adherence (145).

Substance Use Disorders

Individuals with alcohol and other substance use disorders are at increased risk for poor retention in care, poor adherence, and virologic failure (146). Several adherence strategies not recommended for general clinic populations are effective among those with substance use disorders.

Recommendation 27: Offering buprenorphine or methadone to opioid-dependent patients is recommended (II A).

Among patients with opioid dependence, both methadone and buprenorphine maintenance treatments improve medication adherence (147150), ART uptake (149150), and biomarkers (147, 151152). Integration of buprenorphine into HIV clinical care settings increased retention in care and ART prescription in 1 RCT, but ART adherence was unchanged because most patients were already adherent to ART at baseline (153).

Recommendation 28: DAART is recommended for individuals with substance use disorders (I B).

Four RCTs (154157) and 3 prospective cohort studies (158160) of DAART showed significant HIV-1 RNA or CD4 cell count improvements compared with self-administered therapy. Follow-up data from 1 trial, however, failed to demonstrate persistent effects on biological outcomes after DAART was discontinued (157).

Recommendation 29: Integration of DAART into methadone maintenance treatment for opioid-dependent patients is recommended (II B).

One RCT and several longitudinal cohort studies report improved HIV-1 RNA and adherence outcomes when DAART is integrated into methadone maintenance. Among 77 stable patients receiving methadone maintenance treatment, DAART compared with self-administered therapy significantly improved ART adherence and viral suppression over 24 weeks (161). Similarly, 3 prospective observational studies of DAART confirm improved CD4 counts and viral suppression over 12 (162163) and 24 (164) months compared with contemporaneous controls. Long-term durability of benefit has not been confirmed.

Mental Health

Mental health disorders may predispose individuals to acquiring HIV, are common among individuals living with HIV, and present serious challenges for HIV treatment adherence. A meta-analysis of 95 studies found a significant relationship between depression and ART nonadherence that was consistent across patients in resource-rich and resource-limited settings (165). Research has linked depressive symptoms to poor HIV care engagement and health outcomes, including impaired immunologic response and mortality.

Recommendation 30: Screening, management, and treatment for depression and other mental illnesses in combination with adherence counseling are recommended (II A).

Randomized, controlled trials indicate that cognitive–behavioral therapy for depression and psychosocial stress improves ART adherence when conducted in tandem with ART adherence counseling (115116, 166167). Combined mental health and ART adherence counseling interventions have shown significant reductions in depressive symptoms, improved ART adherence, and improved treatment outcomes in RCTs (115, 166167). In contrast, an RCT of a stress management intervention with no ART adherence counseling reduced psychological distress but did not improve ART adherence or treatment outcomes (116). Evidence further indicates that pharmacologic treatment of depression is beneficial for ART adherence and treatment outcomes (168170).

Incarceration

Prevalence of HIV and AIDS is higher among incarcerated populations in low-, middle-, and high-income countries (171). Globally, incarceration negatively affects continuity of care; development of trust; and, ultimately, optimal adherence (172). Incarceration provides a public health opportunity to provide ART to HIV-infected persons; however, barriers to ART delivery and adherence exist (173175), and unintended ART interruptions sometimes occur after release (176). Key challenges to ART adherence among criminal justice populations include identifying successful strategies for medication distribution that preserve confidentiality and avoid stigma (177180) and maintaining persistent ART use during transitions from correctional facilities to the community (181183).

Recommendation 31: DAART is recommended during incarceration (III B) and may be considered upon release to the community (II C).

In a small, comparative observational study of 84 Italian prisoners, DAART in prison was associated with a higher proportion of patients with viral suppression to levels less than 400 copies/mL than was self-administered treatment (158). A small RCT compared ART adherence for DAART with that for self-administered treatment in 43 prisoners (184). Overall adherence was high at 92%, with a higher adherence rate in the DAART group than in the self-administered treatment group. Another RCT compared DAART given daily by community outreach workers versus self-administered treatment among 154 postrelease patients (155). Six months after release, DAART was superior to self-administered treatment in achieving viral suppression to levels less than 400 copies/mL and less than 50 copies/mL.

Homeless and Marginally Housed Individuals

In communities where stable housing is a societal norm, homeless persons represent a special population with respect to ART adherence because of the multiple and often interrelated adherence challenges in this population (such as unstable housing, mental illness, substance use disorders, food insecurity, mistrust of the health care system, incarceration, and inconsistent provider–patient relationships). Homelessness itself often disrupts daily routines, including medication taking, and can make medication storage difficult. In highly resourced countries, many homeless people have concomitant mental illness or substance use disorders that are associated with incomplete adherence (185). Mistrust of the health system and inconsistent provider–patient relationships can contribute to delayed entry into care (186). The homeless have competing survival needs, including food access, which have been associated with incomplete adherence and poor viral suppression (187). Excellent adherence and reliable viral suppression can, however, be achieved despite these multiple barriers (61, 188).

Recommendation 32: Case management is recommended to mitigate multiple adherence barriers in the homeless (III B).

Case management includes referral to mental health and substance use treatment and housing (or housing vouchers), as appropriate, and can facilitate continuity when individuals are transitioning into and out of incarceration. However, referrals require the availability of infrastructure and resources, which differ dramatically among communities. One observational study in the United States showed that case management was associated with improved adherence and CD4 cell counts in a marginally housed population (189).

Recommendation 33: Pillbox organizers are recommended for persons who are homeless (II A).

Pillbox organizers offer a simple visual reminder of missed doses. In an observational study, their use was associated with improved adherence and higher probability of achieving an HIV RNA level less than 400 copies/mL in homeless people with multiple adherence barriers (63).

Children and Adolescents

HIV-infected young people between birth and 24 years of age are a developmentally diverse group, including those perinatally and behaviorally infected. For perinatally infected children, adherence to medications is determined largely by their caregivers, who often have many challenges, including HIV infection (190). Unique medication-related factors associated with nonadherence for children include difficulty swallowing pills, bad taste of medications, and difficulty timing medication administration around meals (191). Perinatally infected teens often experience deterioration in medication adherence during adolescence, as do their peers with other chronic diseases. Transition from pediatric to adult care settings may create additional adherence barriers because of disruptions in comprehensive services and insurance issues (192). Adolescents and young adults are less likely than their older counterparts to be retained in care and receive prescriptions for ART, and they have worse clinical outcomes (193194).

Recommendation 34: Intensive youth-focused case management is recommended for adolescents and young adults living with HIV to improve entry into and retention in care (IV B).

Among 174 HIV-infected youth, appointment attendance improved significantly after introduction of individualized case management focusing on increasing self-efficacy and developing group activities to improve support networks (195). In a cohort study of 61 young gay men who were newly diagnosed or in intermittent care, intensive case management, including initially weekly and then monthly meetings, also improved attendance to medical visits, and more intervention visits were associated with increased likelihood of ART prescription (196).

Recommendation 35: Pediatric- and adolescent-focused therapeutic support interventions using problem-solving approaches and addressing psychosocial context are recommended (III B).

A cohort study of multisystemic therapy intervention (a form of cognitive–behavioral therapy that considers multiple factors in a youth's environment that contribute to behavior change) in 19 perinatally infected youth with poor adherence showed no significant effect on caregiver-reported adherence but significantly improved virologic outcomes through 3 months after the intervention (197). Two other RCTs showed promising, if mixed, results (198199), whereas others demonstrated promising trends but had significant methodological limitations or did not achieve statistical significance (200201).

Recommendation 36: Pill-swallowing training is recommended and may be particularly helpful for younger patients (IV B).

Pill-swallowing training improved adherence in a small cohort study of 23 patients with identified pill-swallowing difficulties or who needed to switch from other formulations to pills (202).

Recommendation 37: DAART improves short-term treatment outcomes and may be considered in pediatric and adolescent patients (IV C).

Three cohort studies of DAART for perinatally infected children and adolescents living with HIV showed improvement in short-term immunologic outcomes (203205). In the 2 studies where DAART was discontinued, however, this improvement was not sustained at follow-up (203204). In 1 study, it did help to determine the cause of treatment failure in several patients. Another study in Cambodia showed improved immunologic outcomes for orphaned children at a cost of $60 for DAART per child per year (205). In some low-resource settings, DAART may be a practical, cost-effective, long-term strategy to improve adherence for younger patients, but a plan for increasing disease self-management is needed as children transition to adolescence.

Cross-cutting and broadly relevant recommendations for future research are presented here, and topic-specific recommendations are included in Table 2(206234). Long-term studies of intervention and postintervention outcomes on adherence and, especially, HIV biomarkers are needed. Formal cost-effectiveness analyses from a range of perspectives are needed to inform institution, government, and policy-level programmatic decisions. Similarly, rigorous implementation and dissemination studies are needed to guide best practices and procedures for replication and scale-up of effective interventions.

Table Jump PlaceholderTable 2.  

Recommendations for Future Research

Further, there are emerging issues for which insufficient evidence exists to provide recommendations at this time. In settings where ART use has been long-standing and widespread, non-AIDS diseases now account for more deaths among persons with HIV than do AIDS-defining diseases (235). Cardiovascular disease is more common in persons with HIV than in those without it and accounts for a substantial proportion of serious non-AIDS events (236237). Although stopping ART increases this risk (238), certain HIV treatments are also associated with higher risk (239241). Persons with HIV infection have high rates of type 2 diabetes, dyslipidemia, and hypertension (242243). High rates of hepatitis C co-infection are seen in Asia, Eastern Europe, and the United States (244). Patients with comorbid conditions often struggle with multiple medications, increased pill burden, drug interactions and side effects, and complex medication scheduling. Comparative research is needed to evaluate intervention strategies to improve adherence and outcomes in the context of multiple comorbid conditions. Finally, new successes in biomedical HIV prevention (pre-exposure prophylaxis [245247], microbicides [248]) have been tempered by problematic adherence, and comparative research of adherence strategies in these settings will be essential to maximize their benefit.

Antiretroviral therapy decreases morbidity and mortality, and early therapy is increasingly recommended for its effect on individual health (249252), as well as for control of HIV transmission (251). Entry into and retention in medical care is a prerequisite for providing lifesaving treatments to persons with HIV. Few validated strategies exist, however, for improving this aspect of care, and the need for robust research is compelling. More data are available on interventions to improve adherence to ART in both general and special populations; however, much of the existing research lacks comparative rigor and correlation to changes in HIV-1 RNA, CD4 cell count, and clinical outcomes. To assure that implementation is feasible for evidence-based recommendations, it will be necessary to strengthen resources, including multidisciplinary linkages, dedicated to ART and care adherence. As the global economy contracts, the identification and implementation of evidence-based strategies to maximize the individual and societal benefit of HIV treatment will become increasingly important. With proper research and resources, the tools are at hand for substantially decreasing—and perhaps ending—the global HIV epidemic.

Centers for Disease Control and Prevention.  HIV Surveillance Report, 2009; vol. 21. February 2011. Accessed www.cdc.gov/hiv/surveillance/resources/reports/2009report on 21 December 2011.
 
UNAIDS.  UNAIDS Data Table 2011. 2 December 2011. Geneva, Switzerland; Joint United Nations Program on HIV/AIDS. Accessed at UNAIDS at www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2011/JC2225_UNAIDS_datatables_en.pdf on 19 December 2011.
 
Bangsberg DR, Perry S, Charlebois ED, Clark RA, Roberston M, Zolopa AR, et al..  Non-adherence to highly active antiretroviral therapy predicts progression to AIDS. AIDS. 2001; 15:1181-3.
PubMed
CrossRef
 
Hogg RS, Heath K, Bangsberg D, Yip B, Press N, O'Shaughnessy MV, et al..  Intermittent use of triple-combination therapy is predictive of mortality at baseline and after 1 year of follow-up. AIDS. 2002; 16:1051-8.
PubMed
 
Nachega JB, Hislop M, Dowdy DW, Chaisson RE, Regensberg L, Maartens G.  Adherence to nonnucleoside reverse transcriptase inhibitor-based HIV therapy and virologic outcomes. Ann Intern Med. 2007; 146:564-73.
PubMed
 
Paterson DL, Swindells S, Mohr J, Brester M, Vergis EN, Squier C, et al..  Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med. 2000; 133:21-30.
PubMed
 
Centers for Disease Control and Prevention (CDC).  Vital signs: HIV prevention through care and treatment—United States. MMWR Morb Morta