Clinical Guidelines5 June 2012

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
    Author, Article, and Disclosure Information

    Abstract

    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 (1, 2). 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 (3–6). 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 (9, 10) 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.

    Guidelines Focus and Target Population

    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.

    Guidelines Development Process

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

    Table 1.

    Guidelines

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

    Appendix Table 1. Summary of Recommendations With Scores for Quality of the Body of Evidence and Strength of Recommendation

    Appendix Table 1.

    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 (13–19). 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 (27, 28). 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 (30, 31), 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 (34–36). Results are inconsistent (37, 38) 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 (39, 40) 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 (43–47). Adherence measured electronically is consistently more closely associated with HIV-1 RNA than are other methods (48, 49). In research, EDMs have been the measurement method of choice (50, 51). 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 (53, 54). 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 (55–59). 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 (60, 61). 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 (64, 65). 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 (66–68) 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 [72, 73], or EDM [74–76]) 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, 75, 76). Three studies from the Netherlands and China that used EDMs with counseling about missed doses showed improvement in adherence (74–76), and 2 showed improvement in biological markers (75, 76). 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).

    Appendix Table 2. Evidence Base for Education and Counseling Recommendations

    Appendix Table 2.

    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 (78–81). 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 (82–95), 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, 87–90, 92), and 7 showed no biomarker benefit (83–86, 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, 88–90, 93–103), 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, 106, 107). Of the 17 that included biological outcomes, 12 demonstrated no benefit (83–86, 93, 95, 102, 103, 105–108) 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 (112–114) and 1 study demonstrated effects in specific subsets of participants (115), other studies showed no significant improvements in adherence (116, 117). 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 (119–127). 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 (121–123, 127) and peers to provide social support (119, 124–126), 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 (132, 133). 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 (120–123, 127, 136–139) 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 (141–143). 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 (147–150), ART uptake (149, 150), and biomarkers (147, 151, 152). 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 (154–157) and 3 prospective cohort studies (158–160) 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 (162, 163) 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 (115, 116, 166, 167). 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, 166, 167). 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 (168–170).

    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 (173–175), 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 (177–180) and maintaining persistent ART use during transitions from correctional facilities to the community (181–183).

    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 (193, 194).

    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 (198, 199), whereas others demonstrated promising trends but had significant methodological limitations or did not achieve statistical significance (200, 201).

    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 (203–205). In the 2 studies where DAART was discontinued, however, this improvement was not sustained at follow-up (203, 204). 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.

    Recommendations for Future Research

    Cross-cutting and broadly relevant recommendations for future research are presented here, and topic-specific recommendations are included in Table 2(206–234). 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 2. Recommendations for Future Research

    Table 2.

    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 (236, 237). Although stopping ART increases this risk (238), certain HIV treatments are also associated with higher risk (239–241). Persons with HIV infection have high rates of type 2 diabetes, dyslipidemia, and hypertension (242, 243). 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 [245–247], microbicides [248]) have been tempered by problematic adherence, and comparative research of adherence strategies in these settings will be essential to maximize their benefit.

    Conclusions

    Antiretroviral therapy decreases morbidity and mortality, and early therapy is increasingly recommended for its effect on individual health (249–252), 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.

    References

    • 1. 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. Google Scholar
    • 2. 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. Google Scholar
    • 3. Bangsberg DRPerry SCharlebois EDClark RARoberston MZolopa ARet alNon-adherence to highly active antiretroviral therapy predicts progression to AIDS. AIDS2001;15:1181-3. [PMID: 11416722] CrossrefMedlineGoogle Scholar
    • 4. Hogg RSHeath KBangsberg DYip BPress NO'Shaughnessy MVet alIntermittent use of triple-combination therapy is predictive of mortality at baseline and after 1 year of follow-up. AIDS2002;16:1051-8. [PMID: 11953472] CrossrefMedlineGoogle Scholar
    • 5. Nachega JBHislop MDowdy DWChaisson RERegensberg LMaartens GAdherence to nonnucleoside reverse transcriptase inhibitor-based HIV therapy and virologic outcomes. Ann Intern Med2007;146:564-73. [PMID: 17438315] LinkGoogle Scholar
    • 6. Paterson DLSwindells SMohr JBrester MVergis ENSquier Cet alAdherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med2000;133:21-30. [PMID: 10877736] LinkGoogle Scholar
    • 7. Centers for Disease Control and Prevention (CDC)Vital signs: HIV prevention through care and treatment—United States. MMWR Morb Mortal Wkly Rep2011;60:1618-23. [PMID: 22129997] MedlineGoogle Scholar
    • 8. Marks GGardner LICraw JCrepaz NEntry and retention in medical care among HIV-diagnosed persons: a meta-analysis. AIDS2010;24:2665-78. [PMID: 20841990] CrossrefMedlineGoogle Scholar
    • 9. Rosen SFox MPGill CJPatient retention in antiretroviral therapy programs in sub-Saharan Africa: a systematic review. PLoS Med2007;4:298. [PMID: 17941716] CrossrefMedlineGoogle Scholar
    • 10. Rosen SFox MPRetention in HIV care between testing and treatment in sub-Saharan Africa: a systematic review. PLoS Med2011;8:1001056. [PMID: 21811403] CrossrefMedlineGoogle Scholar
    • 11. Harrigan PRHogg RSDong WWYip BWynhoven BWoodward Jet alPredictors of HIV drug-resistance mutations in a large antiretroviral-naive cohort initiating triple antiretroviral therapy. J Infect Dis2005;191:339-47. [PMID: 15633092] CrossrefMedlineGoogle Scholar
    • 12. Ortego CHuedo-Medina TBLlorca JSevilla LSantos PRodríguez Eet alAdherence to highly active antiretroviral therapy (HAART): a meta-analysis. AIDS Behav2011;15:1381-96. [PMID: 21468660] CrossrefMedlineGoogle Scholar
    • 13. Giordano TPGifford ALWhite ACSuarez-Almazor MERabeneck LHartman Cet alRetention in care: a challenge to survival with HIV infection. Clin Infect Dis2007;44:1493-9. [PMID: 17479948] CrossrefMedlineGoogle Scholar
    • 14. Cohen MSChen YQMcCauley MGamble THosseinipour MCKumarasamy Net alHPTN 052 Study TeamPrevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med2011;365:493-505. [PMID: 21767103] CrossrefMedlineGoogle Scholar
    • 15. Giordano TPWhite ACSajja PGraviss EAArduino RCAdu-Oppong Aet alFactors associated with the use of highly active antiretroviral therapy in patients newly entering care in an urban clinic. J Acquir Immune Defic Syndr2003;32:399-405. [PMID: 12640198] CrossrefMedlineGoogle Scholar
    • 16. Lucas GMChaisson REMoore RDHighly active antiretroviral therapy in a large urban clinic: risk factors for virologic failure and adverse drug reactions. Ann Intern Med1999;131:81-7. [PMID: 10419445] LinkGoogle Scholar
    • 17. Metsch LRPereyra MMessinger SDel Rio CStrathdee SAAnderson-Mahoney Pet alAntiretroviral Treatment and Access Study (ARTAS) Study GroupHIV transmission risk behaviors among HIV-infected persons who are successfully linked to care. Clin Infect Dis2008;47:577-84. [PMID: 18624629] CrossrefMedlineGoogle Scholar
    • 18. Montaner JSLima VDBarrios RYip BWood EKerr Tet alAssociation of highly active antiretroviral therapy coverage, population viral load, and yearly new HIV diagnoses in British Columbia, Canada: a population-based study. Lancet2010;376:532-9. [PMID: 20638713] CrossrefMedlineGoogle Scholar
    • 19. Walensky RPPaltiel ADLosina EMorris BLScott CARhode ERet alCEPAC InvestigatorsTest and treat DC: forecasting the impact of a comprehensive HIV strategy in Washington DC. Clin Infect Dis2010;51:392-400. [PMID: 20617921] CrossrefMedlineGoogle Scholar
    • 20. Tripathi AYoumans EGibson JJDuffus WAThe impact of retention in early HIV medical care on viro-immunological parameters and survival: a statewide study. AIDS Res Hum Retroviruses2011;27:751-8. [PMID: 21142607] CrossrefMedlineGoogle Scholar
    • 21. Zetola NMBernstein KAhrens KMarcus JLPhilip SNieri Get alUsing surveillance data to monitor entry into care of newly diagnosed HIV-infected persons: San Francisco, 2006-2007. BMC Public Health2009;9:17. [PMID: 19144168] CrossrefMedlineGoogle Scholar
    • 22. Mugavero MJLin HYWillig JHWestfall AOUlett KBRoutman JSet alMissed visits and mortality among patients establishing initial outpatient HIV treatment. Clin Infect Dis2009;48:248-56. [PMID: 19072715] CrossrefMedlineGoogle Scholar
    • 23. Mugavero MJDavila JANevin CRGiordano TPFrom access to engagement: measuring retention in outpatient HIV clinical care. AIDS Patient Care STDS2010;24:607-13. [PMID: 20858055] CrossrefMedlineGoogle Scholar
    • 24. Gardner LIMetsch LRAnderson-Mahoney PLoughlin AMdel Rio CStrathdee Set alAntiretroviral Treatment and Access Study Study GroupEfficacy of a brief case management intervention to link recently diagnosed HIV-infected persons to care. AIDS2005;19:423-31. [PMID: 15750396] CrossrefMedlineGoogle Scholar
    • 25. Naar-King SBradford JColeman SGreen-Jones MCabral HTobias CRetention in care of persons newly diagnosed with HIV: outcomes of the Outreach Initiative. AIDS Patient Care STDS2007;21 Suppl 1 S40-8. [PMID: 17563289] CrossrefMedlineGoogle Scholar
    • 26. Bradford JBColeman SCunningham WHIV System Navigation: an emerging model to improve HIV care access. AIDS Patient Care STDS2007;21 Suppl 1 S49-58. [PMID: 17563290] CrossrefMedlineGoogle Scholar
    • 27. Deschamps AEDe Geest SVandamme AMBobbaers HPeetermans WEVan Wijngaerden EDiagnostic value of different adherence measures using electronic monitoring and virologic failure as reference standards. AIDS Patient Care STDS2008;22:735-43. [PMID: 18754705] CrossrefMedlineGoogle Scholar
    • 28. Miller LGHays RDMeasuring adherence to antiretroviral medications in clinical trials. HIV Clin Trials2000;1:36-46. [PMID: 11590488] CrossrefMedlineGoogle Scholar
    • 29. Gross RYip BLo Re VWood EAlexander CSHarrigan PRet alA simple, dynamic measure of antiretroviral therapy adherence predicts failure to maintain HIV-1 suppression. J Infect Dis2006;194:1108-14. [PMID: 16991085] CrossrefMedlineGoogle Scholar
    • 30. Grossberg RZhang YGross RA time-to-prescription-refill measure of antiretroviral adherence predicted changes in viral load in HIV. J Clin Epidemiol2004;57:1107-10. [PMID: 15528063] CrossrefMedlineGoogle Scholar
    • 31. Bisson GPRowh AWeinstein RGaolathe TFrank IGross RAntiretroviral failure despite high levels of adherence: discordant adherence-response relationship in Botswana. J Acquir Immune Defic Syndr2008;49:107-10. [PMID: 18667926] CrossrefMedlineGoogle Scholar
    • 32. Nachega JBHislop MDowdy DWLo MOmer SBRegensberg Let alAdherence to highly active antiretroviral therapy assessed by pharmacy claims predicts survival in HIV-infected South African adults. J Acquir Immune Defic Syndr2006;43:78-84. [PMID: 16878045] CrossrefMedlineGoogle Scholar
    • 33. Graham JBennett IMHolmes WCGross RMedication beliefs as mediators of the health literacy-antiretroviral adherence relationship in HIV-infected individuals. AIDS Behav2007;11:385-92. [PMID: 17053858] CrossrefMedlineGoogle Scholar
    • 34. Duran SPeytavin GCarrieri PRaffi FEcobichon JLPereira Eet alAntiprotease Cohort (APROCO) study groupThe detection of non-adherence by self-administered questionnaires can be optimized by protease inhibitor plasma concentration determination. AIDS2003;17:1096-9. [PMID: 12700466] CrossrefMedlineGoogle Scholar
    • 35. Duong MPiroth LPeytavin GForte FKohli EGrappin Met alValue of patient self-report and plasma human immunodeficiency virus protease inhibitor level as markers of adherence to antiretroviral therapy: relationship to virologic response. Clin Infect Dis2001;33:386-92. [PMID: 11438909] CrossrefMedlineGoogle Scholar
    • 36. Yasuda JMMiller CCurrier JSForthal DNKemper CABeall GNet alCalifornia Collaborative Treatment GroupThe correlation between plasma concentrations of protease inhibitors, medication adherence and virological outcome in HIV-infected patients. Antivir Ther2004;9:753-61. [PMID: 15535413] MedlineGoogle Scholar
    • 37. Cuevas Gonzalez MJValin LOPerez-Simon MDMostaza Fernandez JLAlcoba Leza MSanchez VMA prospective study of adherence and virologic failure in HIV-infected patients: role of a single determination of plasma levels of antiretroviral medications. J Int Assoc Physicians AIDS Care (Chic)2007;6:245-50. [PMID: 17873246] CrossrefMedlineGoogle Scholar
    • 38. Fletcher CVTesta MABrundage RCChesney MAHaubrich RAcosta EPet alFour measures of antiretroviral medication adherence and virologic response in AIDS clinical trials group study 359. J Acquir Immune Defic Syndr2005;40:301-6. [PMID: 16249704] CrossrefMedlineGoogle Scholar
    • 39. Bangsberg DRHecht FMCharlebois EDZolopa ARHolodniy MSheiner Let alAdherence to protease inhibitors, HIV-1 viral load, and development of drug resistance in an indigent population. AIDS2000;14:357-66. [PMID: 10770537] CrossrefMedlineGoogle Scholar
    • 40. Descamps DFlandre PCalvez VPeytavin GMeiffredy VCollin Get alMechanisms of virologic failure in previously untreated HIV-infected patients from a trial of induction-maintenance therapy. Trilège (Agence Nationale de Recherches sur le SIDA 072) Study Team). JAMA2000;283:205-11. [PMID: 10634336] CrossrefMedlineGoogle Scholar
    • 41. Ferradini LJeannin APinoges LIzopet JOdhiambo DMankhambo Let alScaling up of highly active antiretroviral therapy in a rural district of Malawi: an effectiveness assessment. Lancet2006;367:1335-42. [PMID: 16631912] CrossrefMedlineGoogle Scholar
    • 42. Bangsberg DRCharlebois EDGrant RMHolodniy MDeeks SGPerry Set alHigh levels of adherence do not prevent accumulation of HIV drug resistance mutations. AIDS2003;17:1925-32. [PMID: 12960825] CrossrefMedlineGoogle Scholar
    • 43. Arnsten JHDemas PAFarzadegan HGrant RWGourevitch MNChang CJet alAntiretroviral therapy adherence and viral suppression in HIV-infected drug users: comparison of self-report and electronic monitoring. Clin Infect Dis2001;33:1417-23. [PMID: 11550118] CrossrefMedlineGoogle Scholar
    • 44. Bangsberg DRLess than 95% adherence to nonnucleoside reverse-transcriptase inhibitor therapy can lead to viral suppression. Clin Infect Dis2006;43:939-41. [PMID: 16941380] CrossrefMedlineGoogle Scholar
    • 45. Gross RBilker WBFriedman HMStrom BLEffect of adherence to newly initiated antiretroviral therapy on plasma viral load. AIDS2001;15:2109-17. [PMID: 11684930] CrossrefMedlineGoogle Scholar
    • 46. Oyugi JHByakika-Tusiime JCharlebois EDKityo CMugerwa RMugyenyi Pet alMultiple validated measures of adherence indicate high levels of adherence to generic HIV antiretroviral therapy in a resource-limited setting. J Acquir Immune Defic Syndr2004;36:1100-2. [PMID: 15247564] CrossrefMedlineGoogle Scholar
    • 47. Parienti JJDas-Douglas MMassari VGuzman DDeeks SGVerdon Ret alNot all missed doses are the same: sustained NNRTI treatment interruptions predict HIV rebound at low-to-moderate adherence levels. PLoS One2008;3:2783. [PMID: 18665246] CrossrefMedlineGoogle Scholar
    • 48. Farley JHines SMusk AFerrus STepper VAssessment of adherence to antiviral therapy in HIV-infected children using the Medication Event Monitoring System, pharmacy refill, provider assessment, caregiver self-report, and appointment keeping. J Acquir Immune Defic Syndr2003;33:211-8. [PMID: 12794557] CrossrefMedlineGoogle Scholar
    • 49. Muller ADBode SMyer LRoux Pvon Steinbuechel NElectronic measurement of adherence to pediatric antiretroviral therapy in South Africa. Pediatr Infect Dis2008;27:257-62. [PMID: 18277933] CrossrefMedlineGoogle Scholar
    • 50. Hugen PWLangebeek NBurger DMZomer Bvan Leusen RSchuurman Ret alAssessment of adherence to HIV protease inhibitors: comparison and combination of various methods, including MEMS (electronic monitoring), patient and nurse report, and therapeutic drug monitoring. J Acquir Immune Defic Syndr2002;30:324-34. [PMID: 12131570] CrossrefMedlineGoogle Scholar
    • 51. Walsh JCMandalia SGazzard BGResponses to a 1 month self-report on adherence to antiretroviral therapy are consistent with electronic data and virological treatment outcome. AIDS2002;16:269-77. [PMID: 11807312] CrossrefMedlineGoogle Scholar
    • 52. Bae JWGuyer WGrimm KAltice FLMedication persistence in the treatment of HIV infection: a review of the literature and implications for future clinical care and research [Editorial]. AIDS2011;25:279-90. [PMID: 21239892] CrossrefMedlineGoogle Scholar
    • 53. Flexner CTierney CGross RAndrade ALalama CEshleman SHet alACTG A5073 Study TeamComparison of once-daily versus twice-daily combination antiretroviral therapy in treatment-naive patients: results of AIDS clinical trials group (ACTG) A5073, a 48-week randomized controlled trial. Clin Infect Dis2010;50:1041-52. [PMID: 20192725] CrossrefMedlineGoogle Scholar
    • 54. Molina JMPodsadecki TJJohnson MAWilkin ADomingo PMyers Ret alA lopinavir/ritonavir-based once-daily regimen results in better compliance and is non-inferior to a twice-daily regimen through 96 weeks. AIDS Res Hum Retroviruses2007;23:1505-14. [PMID: 18160008] CrossrefMedlineGoogle Scholar
    • 55. Boyle BAJayaweera DWitt MDGrimm KMaa JFSeekins DWRandomization to once-daily stavudine extended release/lamivudine/efavirenz versus a more frequent regimen improves adherence while maintaining viral suppression. HIV Clin Trials2008;9:164-76. [PMID: 18547903] CrossrefMedlineGoogle Scholar
    • 56. Dejesus EYoung BMorales-Ramirez JOSloan LWard DJFlaherty JFet alAI266073 Study GroupSimplification of antiretroviral therapy to a single-tablet regimen consisting of efavirenz, emtricitabine, and tenofovir disoproxil fumarate versus unmodified antiretroviral therapy in virologically suppressed HIV-1-infected patients. J Acquir Immune Defic Syndr2009;51:163-74. [PMID: 19357529] CrossrefMedlineGoogle Scholar
    • 57. Maitland DJackson AOsorio JMandalia SGazzard BGMoyle GJEpivir-Ziagen (EZ) Switch Study TeamSwitching from twice-daily abacavir and lamivudine to the once-daily fixed-dose combination tablet of abacavir and lamivudine improves patient adherence and satisfaction with therapy. HIV Med2008;9:667-72. [PMID: 18631255] CrossrefMedlineGoogle Scholar
    • 58. Portsmouth SDOsorio JMcCormick KGazzard BGMoyle GJBetter maintained adherence on switching from twice-daily to once-daily therapy for HIV: a 24-week randomized trial of treatment simplification using stavudine prolonged-release capsules. HIV Med2005;6:185-90. [PMID: 15876285] CrossrefMedlineGoogle Scholar
    • 59. Parienti JJMassari VReliquet VChaillot FLe Moal GArvieux Cet alPOSOVIR Study GroupEffect of twice-daily nevirapine on adherence in HIV-1-infected patients: a randomized controlled study. AIDS2007;21:2217-22. [PMID: 18090049] CrossrefMedlineGoogle Scholar
    • 60. Eron JJYetzer ESRuane PJBecker SSawyer GAFisher RLet alEfficacy, safety, and adherence with a twice-daily combination lamivudine/zidovudine tablet formulation, plus a protease inhibitor, in HIV infection. AIDS2000;14:671-81. [PMID: 10807190] CrossrefMedlineGoogle Scholar
    • 61. Bangsberg DRRagland KMonk ADeeks SGA single tablet regimen is associated with higher adherence and viral suppression than multiple tablet regimens in HIV+ homeless and marginally housed people. AIDS2010;24:2835-40. [PMID: 21045636] CrossrefMedlineGoogle Scholar
    • 62. Gardner EMSharma SPeng GHullsiek KHBurman WJMacarthur RDet alDifferential adherence to combination antiretroviral therapy is associated with virological failure with resistance. AIDS2008;22:75-82. [PMID: 18090394] CrossrefMedlineGoogle Scholar
    • 63. Petersen MLWang Yvan der Laan MJGuzman DRiley EBangsberg DRPillbox organizers are associated with improved adherence to HIV antiretroviral therapy and viral suppression: a marginal structural model analysis. Clin Infect Dis2007;45:908-15. [PMID: 17806060] CrossrefMedlineGoogle Scholar
    • 64. Levy RWRayner CRFairley CKKong DCMijch ACostello Ket alMelbourne Adherence GroupMultidisciplinary HIV adherence intervention: a randomized study. AIDS Patient Care STDS2004;18:728-35. [PMID: 15659884] CrossrefMedlineGoogle Scholar
    • 65. Safren SAHendriksen ESDesousa NBoswell SLMayer KHUse of an on-line pager system to increase adherence to antiretroviral medications. AIDS Care2003;15:787-93. [PMID: 14617500] CrossrefMedlineGoogle Scholar
    • 66. Hardy H, Farmer E, Kumar V, Myung D, Rybin D, Drainoni ML, et al. Assess and Remind (ARemind): a personalized cell phone reminder system is superior to a beeper to enhance adherence to antiretroviral therapy. Presented at the 4th International Conference on HIV Treatment Adherence, Miami, Florida, 5–7 April 2009. Abstract 289. Google Scholar
    • 67. Pop-Eleches CThirumurthy HHabyarimana JPZivin JGGoldstein MPde Walque Det alMobile phone technologies improve adherence to antiretroviral treatment in a resource-limited setting: a randomized controlled trial of text message reminders. AIDS2011;25:825-34. [PMID: 21252632] CrossrefMedlineGoogle Scholar
    • 68. Uzma Q, Emmanuel F, Athar U, Zaman S. An assessment of efficacy of interventions for improving adherence to antiretroviral therapy for HIV/AIDS cases in Islamabad, Pakistan. Presented at the 4th International Conference on HIV Treatment Adherence, Miami, Florida, 5–7 April 2009, Miami. Oral Abstract 172. Google Scholar
    • 69. Lester RTRitvo PMills EJKariri AKaranja SChung MHet alEffects of a mobile phone short message service on antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial. Lancet2010;376:1838-45. [PMID: 21071074] CrossrefMedlineGoogle Scholar
    • 70. McPherson-Baker SMalow RMPenedo FJones DLSchneiderman NKlimas NGEnhancing adherence to combination antiretroviral therapy in non-adherent HIV-positive men. AIDS Care2000;12:399-404. [PMID: 11091772] CrossrefMedlineGoogle Scholar
    • 71. Milam JRichardson JLMcCutchan AStoyanoff SWeiss JKemper Cet alEffect of a brief antiretroviral adherence intervention delivered by HIV care providers. J Acquir Immune Defic Syndr2005;40:356-63. [PMID: 16249712] CrossrefMedlineGoogle Scholar
    • 72. Mannheimer SBMorse EMatts JPAndrews LChild CSchmetter Bet alTerry Beirn Community Programs for Clinical Research on AIDSSustained benefit from a long-term antiretroviral adherence intervention. Results of a large randomized clinical trial. J Acquir Immune Defic Syndr2006;43 Suppl 1 S41-7. [PMID: 17091022] CrossrefMedlineGoogle Scholar
    • 73. Simoni JMChen WTHuh DFredriksen-Goldsen KIPearson CZhao Het alA preliminary randomized controlled trial of a nurse-delivered medication adherence intervention among HIV-positive outpatients initiating antiretroviral therapy in Beijing, China. AIDS Behav2011;15:919-29. [PMID: 20957423] CrossrefMedlineGoogle Scholar
    • 74. de Bruin MHospers HJvan den Borne HWKok GPrins JMTheory- and evidence-based intervention to improve adherence to antiretroviral therapy among HIV-infected patients in the Netherlands: a pilot study. AIDS Patient Care STDS2005;19:384-94. [PMID: 15989434] CrossrefMedlineGoogle Scholar
    • 75. de Bruin MHospers HJvan Breukelen GJKok GKoevoets WMPrins JMElectronic monitoring-based counseling to enhance adherence among HIV-infected patients: a randomized controlled trial. Health Psychol2010;29:421-8. [PMID: 20658830] CrossrefMedlineGoogle Scholar
    • 76. Sabin LLDeSilva MBHamer DHXu KZhang JLi Tet alUsing electronic drug monitor feedback to improve adherence to antiretroviral therapy among HIV-positive patients in China. AIDS Behav2010;14:580-9. [PMID: 19771504] CrossrefMedlineGoogle Scholar
    • 77. Chung M, Benki-Nugent S, Richardson B, Nguti R, Simoni J, Overbaugh J, et al. Randomized controlled trial comparing educational counseling and alarm device on adherence to antiretroviral medications in Nairobi, Kenya, over 18 months follow-up. Presented at the 4th International Conference on HIV Treatment Adherence, Miami, Florida, 5–7 April 2009. Oral Abstract 270. Google Scholar
    • 78. HIV/AIDS Prevention Research Synthesis Project Database. Atlanta, GA: Centers for Disease Control and Prevention; 2011. Updated 15 May 2011. Accessed 15 May 2011. Google Scholar
    • 79. Amico KRHarman JJJohnson BTEfficacy of antiretroviral therapy adherence interventions: a research synthesis of trials, 1996 to 2004. J Acquir Immune Defic Syndr2006;41:285-97. [PMID: 16540929] CrossrefMedlineGoogle Scholar
    • 80. de Bruin MViechtbauer WSchaalma HPKok GAbraham CHospers HJStandard care impact on effects of highly active antiretroviral therapy adherence interventions: A meta-analysis of randomized controlled trials. Arch Intern Med2010;170:240-50. [PMID: 20142568] CrossrefMedlineGoogle Scholar
    • 81. Simoni JMPearson CRPantalone DWMarks GCrepaz NEfficacy of interventions in improving highly active antiretroviral therapy adherence and HIV-1 RNA viral load. A meta-analytic review of randomized controlled trials. J Acquir Immune Defic Syndr2006;43 Suppl 1 S23-35. [PMID: 17133201] CrossrefMedlineGoogle Scholar
    • 82. Brock TPSmith SRUsing digital videos displayed on personal digital assistants (PDAs) to enhance patient education in clinical settings. Int J Med Inform2007;76:829-35. [PMID: 17113345] CrossrefMedlineGoogle Scholar
    • 83. Collier ACRibaudo HMukherjee ALFeinberg JFischl MAChesney MAdult AIDS Clinical Trials Group 746 Substudy TeamA randomized study of serial telephone call support to increase adherence and thereby improve virologic outcome in persons initiating antiretroviral therapy. J Infect Dis2005;192:1398-406. [PMID: 16170757] CrossrefMedlineGoogle Scholar
    • 84. Fairley CKLevy RRayner CRAllardice KCostello KThomas Cet alMelbourne Adherence GroupRandomized trial of an adherence programme for clients with HIV. Int J STD AIDS2003;14:805-9. [PMID: 14678587] CrossrefMedlineGoogle Scholar
    • 85. Golin CEEarp JTien HCStewart PPorter CHowie LA 2-arm, randomized, controlled trial of a motivational interviewing-based intervention to improve adherence to antiretroviral therapy (ART) among patients failing or initiating ART. J Acquir Immune Defic Syndr2006;42:42-51. [PMID: 16763491] CrossrefMedlineGoogle Scholar
    • 86. Goujard CBernard NSohier NPeyramond DLançon FChwalow Jet alImpact of a patient education program on adherence to HIV medication: a randomized clinical trial. J Acquir Immune Defic Syndr2003;34:191-4. [PMID: 14526208] CrossrefMedlineGoogle Scholar
    • 87. Holzemer WLBakken SPortillo CJGrimes RWelch JWantland Det alTesting a nurse-tailored HIV medication adherence intervention. Nurs Res2006;55:189-97. [PMID: 16708043] CrossrefMedlineGoogle Scholar
    • 88. Johnson MOCharlebois EMorin SFRemien RHChesney MANational Institute of Mental Health Healthy Living Project TeamEffects of a behavioral intervention on antiretroviral medication adherence among people living with HIV: the healthy living project randomized controlled study. J Acquir Immune Defic Syndr2007;46:574-80. [PMID: 18193499] CrossrefMedlineGoogle Scholar
    • 89. Kalichman SCCherry JCain DNurse-delivered antiretroviral treatment adherence intervention for people with low literacy skills and living with HIV/AIDS. J Assoc Nurses AIDS Care2005;16:3-15. [PMID: 16433105] CrossrefMedlineGoogle Scholar
    • 90. Murphy DAMarelich WDRappaport NBHoffman DFarthing Results of an antiretroviral adherence intervention: STAR (Staying Healthy: Taking Antiretrovirals Regularly). J Int Assoc Physicians AIDS Care2007;6:113-24. [PMID: 17538003] CrossrefMedlineGoogle Scholar
    • 91. Rawlings MKThompson MAFarthing CFBrown LSRacine JScott RCet alNZTA4006 Helping to Enhance Adherence to Antiretroviral Therapy (HEART) Study TeamImpact of an educational program on efficacy and adherence with a twice-daily lamivudine/zidovudine/abacavir regimen in underrepresented HIV-infected patients. J Acquir Immune Defic Syndr2003;34:174-83. [PMID: 14526206] CrossrefMedlineGoogle Scholar
    • 92. Safren SAOtto MWWorth JLSalomon EJohnson WMayer Ket alTwo strategies to increase adherence to HIV antiretroviral medication: life-steps and medication monitoring. Behav Res Ther2001;39:1151-62. [PMID: 11579986] CrossrefMedlineGoogle Scholar
    • 93. Smith SRRublein JCMarcus CBrock TPChesney MAA medication self-management program to improve adherence to HIV therapy regimens. Patient Educ Couns2003;50:187-99. [PMID: 12781934] CrossrefMedlineGoogle Scholar
    • 94. Tuldrà AFumaz CRFerrer MJBayés RArnó ABalagué Met alProspective randomized two-Arm controlled study to determine the efficacy of a specific intervention to improve long-term adherence to highly active antiretroviral therapy. J Acquir Immune Defic Syndr2000;25:221-8. [PMID: 11115952] CrossrefMedlineGoogle Scholar
    • 95. Williams ABFennie KPBova CABurgess JDDanvers KADieckhaus KDHome visits to improve adherence to highly active antiretroviral therapy: a randomized controlled trial. J Acquir Immune Defic Syndr2006;42:314-21. [PMID: 16770291] CrossrefMedlineGoogle Scholar
    • 96. DiIorio CResnicow KMcDonnell MSoet JMcCarty FYeager KUsing motivational interviewing to promote adherence to antiretroviral medications: a pilot study. J Assoc Nurses AIDS Care2003;14:52-62. [PMID: 12698766] CrossrefMedlineGoogle Scholar
    • 97. DiIorio CMcCarty FResnicow KMcDonnell Holstad MSoet JYeager Ket alUsing motivational interviewing to promote adherence to antiretroviral medications: a randomized controlled study. AIDS Care2008;20:273-83. [PMID: 18351473] CrossrefMedlineGoogle Scholar
    • 98. Johnson MODilworth SETaylor JMNeilands TBImproving coping skills for self-management of treatment side effects can reduce antiretroviral medication nonadherence among people living with HIV. Ann Behav Med2011;41:83-91. [PMID: 20922510] CrossrefMedlineGoogle Scholar
    • 99. Knobel HCarmona ALópez JLGimeno JLSaballs PGonzález Aet al[Adherence to very active antiretroviral treatment: impact of individualized assessment]. Enferm Infecc Microbiol Clin1999;17:78-81. [PMID: 10193067] MedlineGoogle Scholar
    • 100. Parsons JTRosof EPunzalan JCDi Maria LIntegration of motivational interviewing and cognitive behavioral therapy to improve HIV medication adherence and reduce substance use among HIV-positive men and women: results of a pilot project. AIDS Patient Care STDS2005;19:31-9. [PMID: 15665633] CrossrefMedlineGoogle Scholar
    • 101. Pradier CBentz LSpire BTourette-Turgis CMorin MSouville Met alEfficacy of an educational and counseling intervention on adherence to highly active antiretroviral therapy: French prospective controlled study. HIV Clin Trials2003;4:121-31. [PMID: 12671780] CrossrefMedlineGoogle Scholar
    • 102. Reynolds NRTesta MASu MChesney MANeidig JLFrank Iet alAIDS Clinical Trials Group 731 and 384 TeamsTelephone support to improve antiretroviral medication adherence: a multisite, randomized controlled trial. J Acquir Immune Defic Syndr2008;47:62-8. [PMID: 17891043] CrossrefMedlineGoogle Scholar
    • 103. Weber RChristen LChristen STschopp SZnoj HSchneider Cet alSwiss HIV Cohort StudyEffect of individual cognitive behaviour intervention on adherence to antiretroviral therapy: prospective randomized trial. Antivir Ther2004;9:85-95. [PMID: 15040540] MedlineGoogle Scholar
    • 104. Mann TEffects of future writing and optimism on health behaviors in HIV-infected women. Ann Behav Med2001;23:26-33. [PMID: 11302353] CrossrefMedlineGoogle Scholar
    • 105. Wagner GJKanouse DEGolinelli DMiller LGDaar ESWitt MDet alCognitive-behavioral intervention to enhance adherence to antiretroviral therapy: a randomized controlled trial (CCTG 578). AIDS2006;20:1295-302. [PMID: 16816559] CrossrefMedlineGoogle Scholar
    • 106. Webel ARTesting a peer-based symptom management intervention for women living with HIV/AIDS. AIDS Care2010;22:1029-40. [PMID: 20146111] CrossrefMedlineGoogle Scholar
    • 107. Wilson IBLaws MBSafren SALee YLu MCoady Wet alProvider-focused intervention increases adherence-related dialogue but does not improve antiretroviral therapy adherence in persons with HIV. J Acquir Immune Defic Syndr2010;53:338-47. [PMID: 20048680] CrossrefMedlineGoogle Scholar
    • 108. Garcia RPondé MLima MSouza ARStolze SMBadaró RLack of effect of motivation on the adherence of HIV-positive/AIDS patients to antiretroviral treatment. Braz J Infect Dis2005;9:494-9. [PMID: 16410944] CrossrefMedlineGoogle Scholar
    • 109. Javanbakht MProsser PGrimes TWeinstein MFarthing CEfficacy of an individualized adherence support program with contingent reinforcement among nonadherent HIV-positive patients: results from a randomized trial. J Int Assoc Physicians AIDS Care2006;5:143-50. [PMID: 17101806] CrossrefMedlineGoogle Scholar
    • 110. Remien RHStirratt MJDolezal CDognin JSWagner GJCarballo-Dieguez Aet alCouple-focused support to improve HIV medication adherence: a randomized controlled trial. AIDS2005;19:807-14. [PMID: 15867495] CrossrefMedlineGoogle Scholar
    • 111. Koenig LJPals SLBush TPratt Palmore MStratford DEllerbrock TVRandomized controlled trial of an intervention to prevent adherence failure among HIV-infected patients initiating antiretroviral therapy. Health Psychol2008;27:159-69. [PMID: 18377134] CrossrefMedlineGoogle Scholar
    • 112. Chiou PYKuo BILee MBChen YMChuang PLin LCA programme of symptom management for improving quality of life and drug adherence in AIDS/HIV patients. J Adv Nurs2006;55:169-79. [PMID: 16866809] CrossrefMedlineGoogle Scholar
    • 113. Kalichman SCCherry CKalichman MOAmaral CMWhite DPope Het alIntegrated behavioral intervention to improve HIV/AIDS treatment adherence and reduce HIV transmission. Am J Public Health2011;101:531-8. [PMID: 21233431] CrossrefMedlineGoogle Scholar
    • 114. van Servellen GNyamathi ACarpio FPearce DGarcia-Teague LHerrera Get alEffects of a treatment adherence enhancement program on health literacy, patient-provider relationships, and adherence to HAART among low-income HIV-positive Spanish-speaking Latinos. AIDS Patient Care STDS2005;19:745-59. [PMID: 16283835] CrossrefMedlineGoogle Scholar
    • 115. Antoni MHCarrico AWDurán RESpitzer SPenedo FIronson Get alRandomized clinical trial of cognitive behavioral stress management on human immunodeficiency virus viral load in gay men treated with highly active antiretroviral therapy. Psychosom Med2006;68:143-51. [PMID: 16449425] CrossrefMedlineGoogle Scholar
    • 116. Berger SSchad Tvon Wyl VEhlert UZellweger CFurrer Het alEffects of cognitive behavioral stress management on HIV-1 RNA, CD4 cell counts and psychosocial parameters of HIV-infected persons. AIDS2008;22:767-75. [PMID: 18356607] CrossrefMedlineGoogle Scholar
    • 117. Sampaio-Sa MPage-Shafer KBangsberg DREvans JDourado Mde LTeixeira Cet al100% adherence study: educational workshops vs. video sessions to improve adherence among ART-naïve patients in Salvador, Brazil. AIDS Behav2008;12:S54-62. [PMID: 18512141] CrossrefMedlineGoogle Scholar
    • 118. Frick PTapia KGrant PNovotny MKerzee JThe effect of a multidisciplinary program on HAART adherence. AIDS Patient Care STDS2006;20:511-24. [PMID: 16839250] CrossrefMedlineGoogle Scholar
    • 119. Chang LWKagaayi JNakigozi GSsempijja VPacker AHSerwadda Det alEffect of peer health workers on AIDS care in Rakai, Uganda: a cluster-randomized trial. PLoS One2010;5:10923. [PMID: 20532194] CrossrefMedlineGoogle Scholar
    • 120. Mugusi FMugusi SBakari MHejdemann BJosiah RJanabi Met alEnhancing adherence to antiretroviral therapy at the HIV clinic in resource constrained countries; the Tanzanian experience. Trop Med Int Health2009;14:1226-32. [PMID: 19732408] CrossrefMedlineGoogle Scholar
    • 121. Muñoz MFinnegan KZeladita JCaldas ASanchez ECallacna Met alCommunity-based DOT-HAART accompaniment in an urban resource-poor setting. AIDS Behav2010;14:721-30. [PMID: 19370409] CrossrefMedlineGoogle Scholar
    • 122. Nachega JBChaisson REGoliath REfron AChaudhary MARam Met alRandomized controlled trial of trained patient-nominated treatment supporters providing partial directly observed antiretroviral therapy. AIDS2010;24:1273-80. [PMID: 20453627] CrossrefMedlineGoogle Scholar
    • 123. Pearson CRMicek MASimoni JMHoff PDMatediana EMartin DPet alRandomized control trial of peer-delivered, modified directly observed therapy for HAART in Mozambique. J Acquir Immune Defic Syndr2007;46:238-44. [PMID: 17693890] CrossrefMedlineGoogle Scholar
    • 124. Ruiz IOlry ALópez MAPrada JLCausse MProspective, randomized, two-arm controlled study to evaluate two interventions to improve adherence to antiretroviral therapy in Spain. Enferm Infecc Microbiol Clin2010;28:409-15. [PMID: 20381924] CrossrefMedlineGoogle Scholar
    • 125. Simoni JMPantalone DWPlummer MDHuang BA randomized controlled trial of a peer support intervention targeting antiretroviral medication adherence and depressive symptomatology in HIV-positive men and women. Health Psychol2007;26:488-95. [PMID: 17605569] CrossrefMedlineGoogle Scholar
    • 126. Simoni JMHuh DFrick PAPearson CRAndrasik MPDunbar PJet alPeer support and pager messaging to promote antiretroviral modifying therapy in Seattle: a randomized controlled trial. J Acquir Immune Defic Syndr2009;52:465-473. [PMID: 19911481] CrossrefMedlineGoogle Scholar
    • 127. Taiwo BOIdoko JAWelty LJOtoh IJob GIyaji PGet alAssessing the viorologic and adherence benefits of patient-selected HIV treatment partners in a resource-limited setting. J Acquir Immune Defic Syndr2010;54:85-92. [PMID: 20418724] CrossrefMedlineGoogle Scholar
    • 128. Matovu F, Wabwire D, Nakibuuka J, Mubiru M, Bagenda D, Musoke P, et al. Efficacy of using peer counselors and nurses to support adherence to HAART among HIV-1-infected patients at the prevention of MTCT program, Mulago Hospital, Kampala, Uganda: a randomized non-inferiority interventional trial. Presented at the 18th Conference on Retroviruses and Opportunistic Infections, Boston, Massachusetts, 27 February–2 March 2011. Paper 1016. Google Scholar
    • 129. Sanne IOrrell CFox MPConradie FIve PZeinecker Jet alCIPRA-SA Study TeamNurse versus doctor management of HIV-infected patients receiving antiretroviral therapy (CIPRA-SA): a randomised non-inferiority trial. Lancet2010;376:33-40. [PMID: 20557927] CrossrefMedlineGoogle Scholar
    • 130. Kipp WKonde-Lule JSaunders LDAlibhai AHouston SRubaale Tet alResults of a community-based antiretroviral treatment program for HIV-1 infection in Western Uganda. Curr HIV Res2010;8:179-85. [PMID: 20163349] CrossrefMedlineGoogle Scholar
    • 131. Wolitski RJKidder DPPals SLRoyal SAidala AStall Ret alHousing and Health Study TeamRandomized trial of the effects of housing assistance on the health and risk behaviors of homeless and unstably housed people living with HIV. AIDS Behav2010;14:493-503. [PMID: 19949848] CrossrefMedlineGoogle Scholar
    • 132. Cantrell RASinkala MMegazinni KLawson-Marriott SWashington SChi BHet alA pilot study of food supplementation to improve adherence to antiretroviral therapy among food-insecure adults in Lusaka, Zambia. J Acquir Immune Defic Syndr2008;49:190-5. [PMID: 18769349] CrossrefMedlineGoogle Scholar
    • 133. Serrano CLaporte RIde MNouhou Yde Truchis PRouveix Eet alFamily nutritional support improves survival, immune restoration and adherence in HIV patients receiving ART in developing country. Asia Pac J Clin Nutr2010;19:68-75. [PMID: 20199989] MedlineGoogle Scholar
    • 134. Andersen MHockman ESmereck GTinsley JMilfort DWilcox Ret alRetaining women in HIV medical care. J Assoc Nurses AIDS Care2007;18:33-41. [PMID: 17570298] CrossrefMedlineGoogle Scholar
    • 135. Hirsch JDRosenquist ABest BMMiller TAGilmer TPEvaluation of the first year of a pilot program in community pharmacy: HIV/AIDS medication therapy management for Medi-Cal beneficiaries. J Manag Care Pharm2009;15:32-41. [PMID: 19125548] CrossrefMedlineGoogle Scholar
    • 136. Gross RTierney CAndrade ALalama CRosenkranz SEshleman SHet alAIDS Clinical Trials Group A5073 Study TeamModified directly observed antiretroviral therapy compared with self-administered therapy in treatment-naive HIV-1-infected patients: a randomized trial. Arch Intern Med2009;169:1224-32. [PMID: 19597072] CrossrefMedlineGoogle Scholar
    • 137. Wohl ARGarland WHValencia RSquires KWitt MDKovacs Aet alA randomized trial of directly administered antiretroviral therapy and adherence case management intervention. Clin Infect Dis2006;42:1619-27. [PMID: 16652320] CrossrefMedlineGoogle Scholar
    • 138. Sarna ALuchters SGeibel SChersich MFMunyao PKaai Set alShort- and long-term efficacy of modified directly observed antiretroviral treatment in Mombasa, Kenya: a randomized trial. J Acquir Immune Defic Syndr2008;48:611-9. [PMID: 18645509] CrossrefMedlineGoogle Scholar
    • 139. Idoko JAAgbaji OAgaba PAkolo CInuwa BHassan Zet alDirect observation therapy-highly active antiretroviral therapy in a resource-limited setting: the use of community treatment support can be effective. Int J STD AIDS2007;18:760-3. [PMID: 18005510] CrossrefMedlineGoogle Scholar
    • 140. World Heath OrganizationAntiretroviral drugs for treating pregnant women and preventing HIV infections in infants: recommendations for a public health approach (2010 version). Geneva, Switzerland: World Health Organization; 2010. Google Scholar
    • 141. Laine CNewschaffer CJZhang DCosler LHauck WWTurner BJAdherence to antiretroviral therapy by pregnant women infected with human immunodeficiency virus: a pharmacy claims-based analysis. Obstet Gynecol2000;95:167-73. [PMID: 10674574] MedlineGoogle Scholar
    • 142. Leisegang R, Nachega JB, Hislop M, Maartens G. The impact of pregnancy on adherence to and default from ART. Presented at the 18th Conference on Retroviruses and Opportunistic Infections, Boston, Massachusetts, 27 February–March 2 2011. Abstract 1021. Google Scholar
    • 143. Mellins CAChu CMalee KAllison SSmith RHarris Let alAdherence to antiretroviral treatment among pregnant and postpartum HIV-infected women. AIDS Care2008;20:958-68. [PMID: 18608073] CrossrefMedlineGoogle Scholar
    • 144. Stringer JSSinkala MStout JPGoldenberg RLAcosta EPChapman Vet alComparison of two strategies for administering nevirapine to prevent perinatal HIV transmission in high-prevalence, resource-poor settings. J Acquir Immune Defic Syndr2003;32:506-13. [PMID: 12679702] CrossrefMedlineGoogle Scholar
    • 145. Megazzini KMSinkala MVermund SHRedden DTKrebs DWAcosta EPet alA cluster-randomized trial of enhanced labor ward-based PMTCT services to increase nevirapine coverage in Lusaka, Zambia. AIDS2010;24:447-55. [PMID: 19926959] CrossrefMedlineGoogle Scholar
    • 146. Altice FLKamarulzaman ASoriano VVSchechter MFriedland GHTreatment of medical, psychiatric, and substance-use comorbidities in people infected with HIV who use drugs. Lancet2010;376:367-87. [PMID: 20650518] CrossrefMedlineGoogle Scholar
    • 147. Altice FLBruce RDLucas GMLum PJKorthuis PTFlanigan TPet alBHIVES CollaborativeHIV treatment outcomes among HIV-infected, opioid-dependent patients receiving buprenorphine/naloxone treatment within HIV clinical care settings: results from a multisite study. J Acquir Immune Defic Syndr2011;56 Suppl 1 S22-32. [PMID: 21317590] CrossrefMedlineGoogle Scholar
    • 148. Margolin AAvants SKWarburton LAHawkins KAShi JA randomized clinical trial of a manual-guided risk reduction intervention for HIV-positive injection drug users. Health Psychol2003;22:223-8. [PMID: 12683743] CrossrefMedlineGoogle Scholar
    • 149. Palepu ATyndall MWJoy RKerr TWood EPress Net alAntiretroviral adherence and HIV treatment outcomes among HIV/HCV co-infected injection drug users: the role of methadone maintenance therapy. Drug Alcohol Depend2006;84:188-94. [PMID: 16542797] CrossrefMedlineGoogle Scholar
    • 150. Uhlmann SMilloy MJKerr TZhang RGuillemi SMarsh Det alMethadone maintenance therapy promotes initiation of antiretroviral therapy among injection drug users. Addiction2010;105:907-13. [PMID: 20331553] CrossrefMedlineGoogle Scholar
    • 151. Roux PCarrieri MPVilles VDellamonica PPoizot-Martin IRavaux Iet alMANIF2000 cohort study groupThe impact of methadone or buprenorphine treatment and ongoing injection on highly active antiretroviral therapy (HAART) adherence: evidence from the MANIF2000 cohort study. Addiction2008;103:1828-36. [PMID: 18778390] CrossrefMedlineGoogle Scholar
    • 152. Springer SAChen SAltice FLImproved HIV and substance abuse treatment outcomes for released HIV-infected prisoners: the impact of buprenorphine treatment. J Urban Health2010;87:592-602. [PMID: 20177974] CrossrefMedlineGoogle Scholar
    • 153. Lucas GMChaudhry AHsu JWoodson TLau BOlsen Yet alClinic-based treatment of opioid-dependent HIV-infected patients versus referral to an opioid treatment program: A randomized trial. Ann Intern Med2010;152:704-11. [PMID: 20513828] LinkGoogle Scholar
    • 154. Altice FLMaru DSBruce RDSpringer SAFriedland GHSuperiority of directly administered antiretroviral therapy over self-administered therapy among HIV-infected drug users: a prospective, randomized, controlled trial. Clin Infect Dis2007;45:770-8. [PMID: 17712763] CrossrefMedlineGoogle Scholar
    • 155. Altice FL, Tehrani AS, Qiu JJ, Herme M, Springer SA. Directly administered antiretroviral therapy (DAART) is superior to self-administered therapy (SAT) among released HIV+ prisoners: results from a randomized controlled trial (RCT). Presented at the 18th Conference on Retroviruses and Opportunistic Infections, Boston, Massachusetts, 27 February–2 March 2011. Abstract 543. Google Scholar
    • 156. Macalino GEHogan JWMitty JABazerman LBDelong AKLoewenthal Het alA randomized clinical trial of community-based directly observed therapy as an adherence intervention for HAART among substance users. AIDS2007;21:1473-7. [PMID: 17589194] CrossrefMedlineGoogle Scholar
    • 157. Maru DSBruce RDWalton MSpringer SAAltice FLPersistence of virological benefits following directly administered antiretroviral therapy among drug users: results from a randomized controlled trial. J Acquir Immune Defic Syndr2009;50:176-81. [PMID: 19131891] CrossrefMedlineGoogle Scholar
    • 158. Babudieri SAceti AD'Offizi GPCarbonara SStarnini GDirectly observed therapy to treat HIV infection in prisoners [Letter]. JAMA2000;284:179-80. [PMID: 10889588] CrossrefMedlineGoogle Scholar
    • 159. Lucas GMWeidle PJHader SMoore RDDirectly administered antiretroviral therapy in an urban methadone maintenance clinic: a nonrandomized comparative study. Clin Infect Dis2004;38 Suppl 5 S409-13. [PMID: 15156431] CrossrefMedlineGoogle Scholar
    • 160. Mitty JAMacalino GEBazerman LBLoewenthal HGHogan JWMacLeod CJet alThe use of community-based modified directly observed therapy for the treatment of HIV-infected persons. J Acquir Immune Defic Syndr2005;39:545-50. [PMID: 16044005] MedlineGoogle Scholar
    • 161. Berg KMLitwin ALi XHeo MArnsten JHDirectly observed antiretroviral therapy improves adherence and viral load in drug users attending methadone maintenance clinics: a randomized controlled trial. Drug Alcohol Depend2011;113:192-9. [PMID: 20832196] CrossrefMedlineGoogle Scholar
    • 162. Clarke SKeenan ERyan MBarry MMulcahy FDirectly observed antiretroviral therapy for injection drug users with HIV infection. AIDS Read2002;12:305-7, 312-6. [PMID: 12161852] MedlineGoogle Scholar
    • 163. Lucas GMMullen BAWeidle PJHader SMcCaul MEMoore RDDirectly administered antiretroviral therapy in methadone clinics is associated with improved HIV treatment outcomes, compared with outcomes among concurrent comparison groups. Clin Infect Dis2006;42:1628-35. [PMID: 16652321] CrossrefMedlineGoogle Scholar
    • 164. Conway BPrasad JReynolds RFarley JJones MJutha Set alDirectly observed therapy for the management of HIV-infected patients in a methadone program. Clin Infect Dis2004;38 Suppl 5 S402-8. [PMID: 15156430] CrossrefMedlineGoogle Scholar
    • 165. Gonzalez JSBatchelder AWPsaros CSafren SADepression and HIV/AIDS treatment nonadherence: a review and meta-analysis. J Acquir Immune Defic Syndr2011;58:181-7. [PMID: 21857529] CrossrefMedlineGoogle Scholar
    • 166. Safren SAO'Cleirigh CTan JYRaminani SRReilly LCOtto MWet alA randomized controlled trial of cognitive behavioral therapy for adherence and depression (CBT-AD) in HIV-infected individuals. Health Psychol2009;28:1-10. [PMID: 19210012] CrossrefMedlineGoogle Scholar
    • 167. Weiss SMTobin JNAntoni MIronson GIshii MVaughn Aet alSMART/EST Women's Project TeamEnhancing the health of women living with HIV: the SMART/EST Women's Project. Int J Womens Health2011;3:63-77. [PMID: 21445376] CrossrefMedlineGoogle Scholar
    • 168. Horberg MASilverberg MJHurley LBTowner WJKlein DBBersoff-Matcha Set alEffects of depression and selective serotonin reuptake inhibitor use on adherence to highly active antiretroviral therapy and on clinical outcomes in HIV-infected patients. J Acquir Immune Defic Syndr2008;47:384-90. [PMID: 18091609] CrossrefMedlineGoogle Scholar
    • 169. Tsai ACWeiser SDPetersen MLRagland KKushel MBBangsberg DRA marginal structural model to estimate the causal effect of antidepressant medication treatment on viral suppression among homeless and marginally housed persons with HIV. Arch Gen Psychiatry2010;67:1282-90. [PMID: 21135328] CrossrefMedlineGoogle Scholar
    • 170. Yun LWMaravi MKobayashi JSBarton PLDavidson AJAntidepressant treatment improves adherence to antiretroviral therapy among depressed HIV-infected patients. J Acquir Immune Defic Syndr2005;38:432-8. [PMID: 15764960] CrossrefMedlineGoogle Scholar
    • 171. Jürgens RNowak MDay MHIV and incarceration: prisons and detention. J Int AIDS Soc2011;14:26. [PMID: 21595957] CrossrefMedlineGoogle Scholar
    • 172. Seal DWHIV-related issues and concerns for imprisoned persons throughout the world. Curr Opin Psychiatry2005;18:530-5. [PMID: 16639113] CrossrefMedlineGoogle Scholar
    • 173. Chen RYAccortt Westfall AOMugavero MJRaper JLCloud GAet alDistribution of health care expenditures for HIV-infected patients. Clin Infect Dis2006;42:1003-10. [PMID: 16511767] CrossrefMedlineGoogle Scholar
    • 174. Hammett T, Kennedy S, Kuck S. National Survey of Infectious Diseases in Correctional Facilities: HIV and Sexually Transmitted Diseases: U.S. Department of Justice. March 2007. Report no. NCJ 217736. Accessed at www.ncjrs.gov/pdffiles1/nij/grants/217736.pdf on 14 May 2010. Google Scholar
    • 175. Zaller NThurmond PRich JDLimited spending: an analysis of correctional expenditures on antiretrovirals for HIV-infected prisoners. Public Health Rep2007;122:49-54. [PMID: 17236608] CrossrefMedlineGoogle Scholar
    • 176. Baillargeon JGiordano TPRich JDWu ZHWells KPollock BHet alAccessing antiretroviral therapy following release from prison. JAMA2009;301:848-57. [PMID: 19244192] CrossrefMedlineGoogle Scholar
    • 177. Inés SMMoralejo LMarcos MFuertes ALuna GAdherence to highly active antiretroviral therapy in HIV-infected inmates. Curr HIV Res2008;6:164-70. [PMID: 18336264] CrossrefMedlineGoogle Scholar
    • 178. Pontali EAntiretroviral treatment in correctional facilities. HIV Clin Trials2005;6:25-37. [PMID: 15765308] CrossrefMedlineGoogle Scholar
    • 179. Rosen DLGolin CESchoenbach VJStephenson BLWohl DAGurkin Bet alAvailability of and access to medical services among HIV-infected inmates incarcerated in North Carolina county jails. J Health Care Poor Underserved2004;15:413-25. [PMID: 15453178] CrossrefMedlineGoogle Scholar
    • 180. Small WWood EBetteridge GMontaner JKerr TThe impact of incarceration upon adherence to HIV treatment among HIV-positive injection drug users: a qualitative study. AIDS Care2009;21:708-14. [PMID: 19806487] CrossrefMedlineGoogle Scholar
    • 181. Milloy MJKerr TBuxton JRhodes TGuillemi SHogg Ret alDose-response effect of incarceration events on nonadherence to HIV antiretroviral therapy among injection drug users. J Infect Dis2011;203:1215-21. [PMID: 21459814] CrossrefMedlineGoogle Scholar
    • 182. Springer SAPesanti EHodges JMacura TDoros GAltice FLEffectiveness of antiretroviral therapy among HIV-infected prisoners: reincarceration and the lack of sustained benefit after release to the community. Clin Infect Dis2004;38:1754-60. [PMID: 15227623] CrossrefMedlineGoogle Scholar
    • 183. Stephenson BLWohl DAGolin CETien HCStewart PKaplan AHEffect of release from prison and re-incarceration on the viral loads of HIV-infected individuals. Public Health Rep2005;120:84-8. [PMID: 15736336] CrossrefMedlineGoogle Scholar
    • 184. Grodensky GC, Golin C, Sunil A, White B, Cole S, Wohl D, et al. Effect on antiretroviral adherence of directly observed therapy (DOT) versus keep-on-my-person medication (KOM) among HIV-infected prisoners: the DOT-KOM Study. Presented at the 4th International Conference on HIV Treatment Adherence, Miami, Florida, 5–7 April 2011. Oral Abstract 280. Google Scholar
    • 185. Robertson MJClark RACharlebois EDTulsky JLong HLBangsberg DRet alHIV seroprevalence among homeless and marginally housed adults in San Francisco. Am J Public Health2004;94:1207-17. [PMID: 15226145] CrossrefMedlineGoogle Scholar
    • 186. Mostashari FRiley ESelwyn PAAltice FLAcceptance and adherence with antiretroviral therapy among HIV-infected women in a correctional facility. J Acquir Immune Defic Syndr Hum Retrovirol1998;18:341-8. [PMID: 9704939] CrossrefMedlineGoogle Scholar
    • 187. Weiser SDFrongillo EARagland KHogg RSRiley EDBangsberg DRFood insecurity is associated with incomplete HIV RNA suppression among homeless and marginally housed HIV-infected individuals in San Francisco. J Gen Intern Med2009;24:14-20. [PMID: 18953617] CrossrefMedlineGoogle Scholar
    • 188. Moss ARHahn JAPerry SCharlebois EDGuzman DClark RAet alAdherence to highly active antiretroviral therapy in the homeless population in San Francisco: a prospective study. Clin Infect Dis2004;39:1190-8. [PMID: 15486844] CrossrefMedlineGoogle Scholar
    • 189. Kushel MBColfax GRagland KHeineman APalacio HBangsberg DRCase management is associated with improved antiretroviral adherence and CD4+ cell counts in homeless and marginally housed individuals with HIV infection. Clin Infect Dis2006;43:234-42. [PMID: 16779752] CrossrefMedlineGoogle Scholar
    • 190. Martin SElliott-DeSorbo DKWolters PLToledo-Tamula MARoby GZeichner Set alPatient, caregiver and regimen characteristics associated with adherence to highly active antiretroviral therapy among HIV-infected children and adolescents. Pediatr Infect Dis J2007;26:61-7. [PMID: 17195708] CrossrefMedlineGoogle Scholar
    • 191. Reddington CCohen JBaldillo AToye MSmith DKneut Cet alAdherence to medication regimens among children with human immunodeficiency virus infection. Pediatr Infect Dis J2000;19:1148-53. [PMID: 11144374] CrossrefMedlineGoogle Scholar
    • 192. Dowshen ND'Angelo LHealth care transition for youth living with HIV/AIDS. Pediatrics2011;128:762-71. [PMID: 21930548] CrossrefMedlineGoogle Scholar
    • 193. Agwu ALFleishman JAKorthuis PTSiberry GKEllen JMGaur AHet alHIV Research NetworkDisparities in antiretroviral treatment: a comparison of behaviorally HIV-infected youth and adults in the HIV Research Network. J Acquir Immune Defic Syndr2011;58:100-7. [PMID: 21637114] CrossrefMedlineGoogle Scholar
    • 194. Ryscavage PAnderson EJSutton SHReddy STaiwo BClinical outcomes of adolescents and young adults in adult HIV care. J Acquir Immune Defic Syndr2011;58:193-7. [PMID: 21826014] CrossrefMedlineGoogle Scholar
    • 195. Davila J, Miertschin N, Sansgiry S, Mitts B, Parkinson-Windross D, Henley C, et al. Centralization of HIV services in HIV+ African-American and Hispanic youth improves retention in care. Presented at the 5th International Conference on HIV Treatment Adherence, Miami, Florida, 23–25 May 2010. Oral Abstract 62911. Google Scholar
    • 196. Wohl ARGarland WHWu JAu CWBoger ADierst-Davies Ret alA youth-focused case management intervention to engage and retain young gay men of color in HIV care. AIDS Care2011;23:988-97. [PMID: 21390879] CrossrefMedlineGoogle Scholar
    • 197. Ellis DANaar-King SCunningham PBSecord EUse of multisystemic therapy to improve antiretroviral adherence and health outcomes in HIV-infected pediatric patients: evaluation of a pilot program. AIDS Patient Care STDS2006;20:112-21. [PMID: 16475892] CrossrefMedlineGoogle Scholar
    • 198. Naar-King SParsons JTMurphy DAChen XHarris DRBelzer MEImproving health outcomes for youth living with the human immunodeficiency virus: a multisite randomized trial of a motivational intervention targeting multiple risk behaviors. Arch Pediatr Adolesc Med2009;163:1092-8. [PMID: 19996045] CrossrefMedlineGoogle Scholar
    • 199. Berrien VMSalazar JCReynolds EMcKay KHIV Medication Adherence Intervention GroupAdherence to antiretroviral therapy in HIV-infected pediatric patients improves with home-based intensive nursing intervention. AIDS Patient Care STDS2004;18:355-63. [PMID: 15294086] CrossrefMedlineGoogle Scholar
    • 200. Lyon METrexler CAkpan-Townsend CPao MSelden KFletcher Jet alA family group approach to increasing adherence to therapy in HIV-infected youths: results of a pilot project. AIDS Patient Care STDS2003;17:299-308. [PMID: 12880493] CrossrefMedlineGoogle Scholar
    • 201. Rotheram-Borus MJSwendeman DComulada WSWeiss RELee MLightfoot MPrevention for substance-using HIV-positive young people: telephone and in-person delivery. J Acquir Immune Defic Syndr2004;37 Suppl 2 S68-77. [PMID: 15385902] CrossrefMedlineGoogle Scholar
    • 202. Garvie PALensing SRai SNEfficacy of a pill-swallowing training intervention to improve antiretroviral medication adherence in pediatric patients with HIV/AIDS. Pediatrics2007;119:893-9. [PMID: 17353298] CrossrefMedlineGoogle Scholar
    • 203. Glikman DWalsh LValkenburg JMangat PDMarcinak JFHospital-based directly observed therapy for HIV-infected children and adolescents to assess adherence to antiretroviral medications. Pediatrics2007;119:1142-8. [PMID: 17452493] CrossrefMedlineGoogle Scholar
    • 204. McKeegan K, Ramsden D, Prebus O, Rutstein RM. A pilot program of health worker- or nurse-provided directly observed therapy for nonadherent youth with perinatally acquired HIV. Presented at the 6th International Conference on HIV Treatment Adherence, Miami, Florida, 22–24 May 2011. Poster Abstract 70043. Google Scholar
    • 205. Myung PPugatch DBrady MFMany PHarwell JILurie Met alDirectly observed highly active antiretroviral therapy for HIV-infected children in Cambodia. Am J Public Health2007;97:974-7. [PMID: 17463375] CrossrefMedlineGoogle Scholar
    • 206. Craw JAGardner LIMarks GRapp RCBosshart JDuffus WAet alBrief strengths-based case management promotes entry into HIV medical care: results of the antiretroviral treatment access study-II. J Acquir Immune Defic Syndr2008;47:597-606. [PMID: 18285714] CrossrefMedlineGoogle Scholar
    • 207. Horstmann EBrown JIslam FBuck JAgins BDRetaining HIV-infected patients in care: Where are we? Where do we go from here? Clin Infect Dis2010;50:752-61. [PMID: 20121413] MedlineGoogle Scholar
    • 208. Rajabiun SCabral HTobias CRelf MProgram design and evaluation strategies for the Special Projects of National Significance Outreach Initiative. AIDS Patient Care STDS2007;21 Suppl 1 S9-19. [PMID: 17563295] CrossrefMedlineGoogle Scholar
    • 209. Rigsby MORosen MIBeauvais JECramer JARainey PMO'Malley SSet alCue-dose training with monetary reinforcement: pilot study of an antiretroviral adherence intervention. J Gen Intern Med2000;15:841-7. [PMID: 11119180] CrossrefMedlineGoogle Scholar
    • 210. Rosen MIDieckhaus KMcMahon TJValdes BPetry NMCramer Jet alImproved adherence with contingency management. AIDS Patient Care STDS2007;21:30-40. [PMID: 17263651] CrossrefMedlineGoogle Scholar
    • 211. Llibre JMArribas JRDomingo PGatell JMLozano FSantos JRet alSpanish Group for FDAC EvaluationClinical implications of fixed-dose coformulations of antiretrovirals on the outcome of HIV-1 therapy. AIDS2011;25:1683-90. [PMID: 21673556] CrossrefMedlineGoogle Scholar
    • 212. Petry NMWeinstock JAlessi SMLewis MWDieckhaus KGroup-based randomized trial of contingencies for health and abstinence in HIV patients. J Consult Clin Psychol2010;78:89-97. [PMID: 20099954] CrossrefMedlineGoogle Scholar
    • 213. Cunningham COSohler NLCooperman Berg KMLitwin AHArnsten JHStrategies to improve access to and utilization of health care services and adherence to antiretroviral therapy among HIV-infected drug users. Subst Use Misuse2011;46:218-32. [PMID: 21303242] CrossrefMedlineGoogle Scholar
    • 214. Sullivan LEBarry DMoore BAChawarski MCTetrault JMPantalon MVet alA trial of integrated buprenorphine/naloxone and HIV clinical care. Clin Infect Dis2006;43 Suppl 4 S184-90. [PMID: 17109305] CrossrefMedlineGoogle Scholar
    • 215. Broadhead RSHeckathorn DDAltice FLvan Hulst YCarbone MFriedland GHet alIncreasing drug users' adherence to HIV treatment: results of a peer-driven intervention feasibility study. Soc Sci Med2002;55:235-46. [PMID: 12144138] CrossrefMedlineGoogle Scholar
    • 216. Deering KNShannon KSinclair HParsad DGilbert ETyndall MWPiloting a peer-driven intervention model to increase access and adherence to antiretroviral therapy and HIV care among street-entrenched HIV-positive women in Vancouver. AIDS Patient Care STDS2009;23:603-9. [PMID: 19591602] CrossrefMedlineGoogle Scholar
    • 217. Feaster DJMitrani VBBurns MJMcCabe BEBrincks AMRodriguez AEet alA randomized controlled trial of Structural Ecosystems Therapy for HIV medication adherence and substance abuse relapse prevention. Drug Alcohol Depend2010;111:227-34. [PMID: 20538417] CrossrefMedlineGoogle Scholar
    • 218. Purcell DWLatka MHMetsch LRLatkin CAGómez CAMizuno Yet alfor the INSPIRE Study TeamResults from a randomized controlled trial of a peer-mentoring intervention to reduce HIV transmission and increase access to care and adherence to HIV medications among HIV-seropositive injection drug users. J Acquir Immune Defic Syndr2007;46 Suppl 2 S35-47. [PMID: 18089983] CrossrefMedlineGoogle Scholar
    • 219. Samet JHHorton NJMeli SDukes KTripps TSullivan Let alA randomized controlled trial to enhance antiretroviral therapy adherence in patients with a history of alcohol problems. Antivir Ther2005;10:83-93. [PMID: 15751766] MedlineGoogle Scholar
    • 220. Williams ABFennie KPBova CABurgess JDDanvers KADieckhaus KDHome visits to improve adherence to highly active antiretroviral therapy: a randomized controlled trial. J Acquir Immune Defic Syndr2006;42:314-21. [PMID: 16770291] CrossrefMedlineGoogle Scholar
    • 221. Copenhaver MChowdhury SAltice FLAdaptation of an evidence-based intervention targeting HIV-infected prisoners transitioning to the community: the process and outcome of formative research for the Positive Living Using Safety (PLUS) intervention. AIDS Patient Care STDS2009;23:277-87. [PMID: 19260773] CrossrefMedlineGoogle Scholar
    • 222. Klein SJO'Connell DADevore BSWright LNBirkhead GSBuilding an HIV continuum for inmates: New York State's criminal justice initiative. AIDS Educ Prev2002;14:114-23. [PMID: 12413199] CrossrefMedlineGoogle Scholar
    • 223. Rich JDHolmes LSalas CMacalino GDavis DRyczek Jet alSuccessful linkage of medical care and community services for HIV-positive offenders being released from prison. J Urban Health2001;78:279-89. [PMID: 11419581] CrossrefMedlineGoogle Scholar
    • 224. Wohl DAScheyett AGolin CEWhite BMatuszewski JBowling Met alIntensive case management before and after prison release is no more effective than comprehensive pre-release discharge planning in linking HIV-infected prisoners to care: a randomized trial. AIDS Behav2011;15:356-64. [PMID: 21042930] CrossrefMedlineGoogle Scholar
    • 225. Belzer MEFuchs DNLuftman GSTucker DJAntiretroviral adherence issues among HIV-positive adolescents and young adults. J Adolesc Health1999;25:316-9. [PMID: 10551660] CrossrefMedlineGoogle Scholar
    • 226. Macdonell KENaar-King SMurphy DAParsons JTHuszti HSituational temptation for HIV medication adherence in high-risk youth. AIDS Patient Care STDS2011;25:47-52. [PMID: 21162691] CrossrefMedlineGoogle Scholar
    • 227. Murphy DASarr MDurako SJMoscicki ABWilson CMMuenz LRAdolescent Medicine HIV/AIDS Research NetworkBarriers to HAART adherence among human immunodeficiency virus-infected adolescents. Arch Pediatr Adolesc Med2003;157:249-55. [PMID: 12622674] CrossrefMedlineGoogle Scholar
    • 228. Naar-King STemplin TWright KFrey MParsons JTLam PPsychosocial factors and medication adherence in HIV-positive youth. AIDS Patient Care STDS2006;20:44-7. [PMID: 16426155] CrossrefMedlineGoogle Scholar
    • 229. Rao DKekwaletswe TCHosek SMartinez JRodriguez FStigma and social barriers to medication adherence with urban youth living with HIV. AIDS Care2007;19:28-33. [PMID: 17129855] CrossrefMedlineGoogle Scholar
    • 230. Brackis-Cott EMellins CAAbrams EReval TDolezal CPediatric HIV medication adherence: the views of medical providers from two primary care programs. J Pediatr Health Care2003;17:252-60. [PMID: 14576630] CrossrefMedlineGoogle Scholar
    • 231. Marhefka SLTepper VJBrown JLFarley JJCaregiver psychosocial characteristics and children's adherence to antiretroviral therapy. AIDS Patient Care STDS2006;20:429-37. [PMID: 16789856] CrossrefMedlineGoogle Scholar
    • 232. Mellins CABrackis-Cott EDolezal CAbrams EJThe role of psychosocial and family factors in adherence to antiretroviral treatment in human immunodeficiency virus-infected children. Pediatr Infect Dis J2004;23:1035-41. [PMID: 15545859] CrossrefMedlineGoogle Scholar
    • 233. Hightow-Weidman LBJones KWohl ARFutterman DOutlaw APhillips Get alYMSM of Color SPNS Initiative Study GroupEarly linkage and retention in care: findings from the outreach, linkage, and retention in care initiative among young men of color who have sex with men. AIDS Patient Care STDS2011;25 Suppl 1 S31-8. [PMID: 21711141] CrossrefMedlineGoogle Scholar
    • 234. Martinez JBell DDodds SShaw KSiciliano CWalker LEet alTransitioning youths into care: linking identified HIV-infected youth at outreach sites in the community to hospital-based clinics and or community-based health centers. J Adolesc Health2003;33:23-30. [PMID: 12888284] CrossrefMedlineGoogle Scholar
    • 235. Antiretroviral Therapy Cohort CollaborationCauses of death in HIV-1-infected patients treated with antiretroviral therapy, 1996-2006: collaborative analysis of 13 HIV cohort studies. Clin Infect Dis2010;50:1387-96. [PMID: 20380565] CrossrefMedlineGoogle Scholar
    • 236. Grunfeld CDelaney JAWanke CCurrier JSScherzer RBiggs MLet alPreclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study. AIDS2009;23:1841-9. [PMID: 19455012] CrossrefMedlineGoogle Scholar
    • 237. Mocroft AReiss PGasiorowski JLedergerber BKowalska JChiesi Aet alEuroSIDA Study GroupSerious fatal and nonfatal non-AIDS-defining illnesses in Europe. J Acquir Immune Defic Syndr2010;55:262-70. [PMID: 20700060] CrossrefMedlineGoogle Scholar
    • 238. El-Sadr WMLundgren JDNeaton JDGordin FAbrams DArduino RCet alStrategies for Management of Antiretroviral Therapy (SMART) Study GroupCD4+ count-guided interruption of antiretroviral treatment. N Engl J Med2006;355:2283-96. [PMID: 17135583] CrossrefMedlineGoogle Scholar
    • 239. Currier JSLundgren JDCarr AKlein DSabin CASax PEet alWorking Group 2Epidemiological evidence for cardiovascular disease in HIV-infected patients and relationship to highly active antiretroviral therapy. Circulation2008;118:29-35. [PMID: 18566319] CrossrefMedlineGoogle Scholar
    • 240. Friis-Møller NReiss PSabin CAWeber RMonforte AEl-Sadr Wet alDAD Study GroupClass of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med2007;356:1723-35. [PMID: 17460226] CrossrefMedlineGoogle Scholar
    • 241. Dubé MPSattler FRInflammation and complications of HIV disease [Editorial]. J Infect Dis2010;201:1783-5. [PMID: 20446849] CrossrefMedlineGoogle Scholar
    • 242. Barbaro GCardiovascular manifestations of HIV infection. Circulation2002;106:1420-5. [PMID: 12221062] CrossrefMedlineGoogle Scholar
    • 243. Kalra SKalra BAgrawal NUnnikrishnan AUnderstanding diabetes in patients with HIV/AIDS. Diabetol Metab Syndr2011;3:2. [PMID: 21232158] CrossrefMedlineGoogle Scholar
    • 244. Friedland GInfectious disease comorbidities adversely affecting substance users with HIV: hepatitis C and tuberculosis. J Acquir Immune Defic Syndr2010;55 Suppl 1 S37-42. [PMID: 21045598] CrossrefMedlineGoogle Scholar
    • 245. Baeten J, Celum C, for the Partners PrEP Study Team. Antiretroviral pre-exposure prophylaxis for HIV-1 prevention among heterosexual African men and women: the Partners PrEP Study. Presented at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Rome, Italy, 17–20 July 2011. Abstract MOAX0106. Google Scholar
    • 246. Grant RMLama JRAnderson PLMcMahan VLiu AYVargas Let aliPrEx Study TeamPreexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med2010;363:2587-99. [PMID: 21091279] CrossrefMedlineGoogle Scholar
    • 247. Thigpen MC, Kebaabetswa PM, Smith DK, Segolodi TM, Soud FA, Chillag K, et al. Daily oral antiretroviral use for the prevention of HIV infection in heterosexually active young adults in Botswana: results from the TDF2 study. Presented at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Rome, Italy, 17–20 July 2011 Abstract WELBC01. Google Scholar
    • 248. Abdool Karim QAbdool Karim SSFrohlich JAGrobler ACBaxter CMansoor LEet alCAPRISA 004 Trial GroupEffectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science2010;329:1168-74. [PMID: 20643915] CrossrefMedlineGoogle Scholar
    • 249. U.S. Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. HHS Panel on Antiretroviral Guidelines for Adults and Adolescents—A Working Group of the Office of AIDS Research Advisory Council (OARAC). Washington, DC: U.S. Department of Health and Human Services; 2011. Accessed at aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/0/ on 19 December 2011. Google Scholar
    • 250. European AIDS Clinical Society (EACS). Guidelines. Version 6.0. October 2011. Accessed at www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/eacsguidelines-v6_english.pdf. Google Scholar
    • 251. Thompson MAAberg JACahn PMontaner JSRizzardini GTelenti Aet alInternational AIDS SocietyAntiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society- panel. JAMA2010;304:321-33. [PMID: 20639566] CrossrefMedlineGoogle Scholar
    • 252. World Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach, 2010 revision. Geneva: World Health Organization; 2010. Accessed at whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf. Google Scholar
    • 253. Brouwers MCKho MEBrowman GPBurgers JSCluzeau FFeder Get alAGREE Next Steps ConsortiumAGREE II: advancing guideline development, reporting, and evaluation in health care. Prev Med2010;51:421-4. [PMID: 20728466] CrossrefMedlineGoogle Scholar
    • 254. Laine CTaichman DBMulrow CTrustworthy clinical guidelines [Editorial]. Ann Intern Med2011;154:774-5. [PMID: 21646561] LinkGoogle Scholar
    • 255. Whiting PRutjes AWReitsma JBBossuyt PMKleijnen JThe development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol2003;3:25. [PMID: 14606960] CrossrefMedlineGoogle Scholar
    • 256. Guyatt GHOxman ADVist GEKunz RFalck-Ytter YAlonso-Coello Pet alGRADE Working GroupGRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ2008;336:924-6. [PMID: 18436948] CrossrefMedlineGoogle Scholar
    • 257. Qaseem ASnow VOwens DKShekelle PClinical Guidelines Committee of the American College of PhysiciansThe development of clinical practice guidelines and guidance statements of the American College of Physicians: summary of methods. Ann Intern Med2010;153:194-9. [PMID: 20679562] LinkGoogle Scholar
    • 258. Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy. 2009. Accessed at srdta.cochrane.org/handbook-dta-reviews on 19 December 2011. Google Scholar
    • 259. Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 [updated March 2011]. 2011. Accessed at www.cochrane.org/training/cochrane-handbook on 19 December 2011. Google Scholar
    • 260. Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Accessed at www.ohri.ca/programs/clinical_epidemiology/oxford.asp on 19 December 2011. Google Scholar

    Appendix 1: Guideline Panel Members

    In addition to the authors, the following are members of the Guideline Panel and participated in discussions of the content or review of the manuscript: Magda Barini-García, MD (Health Resources and Services Administration, Rockville, Maryland); Vanessa Elharrar, MD, MPH (National Institute of Allergy and Infectious Diseases, Bethesda, Maryland); Tia Morton, RN, MS (National Institute of Allergy and Infectious Diseases, Bethesda, Maryland); Charles Holmes, MD, MPH (Office of the Global AIDS Coordinator, Washington, DC); Shoshana Kahana, PhD (National Institute on Drug Abuse, Bethesda, Maryland); Peter Kilmarx, MD (Centers for Disease Control and Prevention, Harare, Zimbabwe); Cynthia Lyles, PhD (Centers for Disease Control and Prevention, Atlanta, Georgia); Henry Masur, MD (National Institutes of Health, Bethesda, Maryland); Celso Ramos, MD, MSc (Federal University of Rio de Janeiro, Rio de Janeiro, Brazil); Evelyn Tomaszewski, MSW (National Association of Social Workers, Washington, DC); Marco Antônio de Ávila Vitória, MD (World Health Organization, Geneva, Switzerland).

    Appendix 2: Methods for Guidelines Development Process

    Summary

    A systematic search for studies on interventions to improve entry into and retention in care and antiretroviral adherence and monitoring was performed. A total of 325 studies were identified for inclusion in the evidence base for the guidelines. Two reviewers independently extracted and coded data from each study using a standardized data extraction form. Differences were resolved by consensus with a third reviewer. Reviewers assessed bias in RCTs by using the Cochrane Risk of Bias Tool and in observational studies by using the Newcastle-Ottawa Quality Assessment Scale. Studies were then grouped by intervention type. Adherence monitoring articles were abstracted and graded using a modified Quality Assessment for Diagnostic Accuracy Studies (QUADAS) tool. Panel members drafted a recommendation statement based on the body of evidence for each monitoring method or intervention type. They then graded the overall quality of the body of evidence for each recommendation on the basis of its risk for bias, quantity, and consistency using methods adapted from the American College of Physicians guidelines and the Grading of Recommendation Assessment, Development and Evaluation (GRADE) System for Rating Clinical Guidelines processes. Finally, panel members graded the strength of each recommendation on the basis of not only the quality and quantity of the body of evidence but also the magnitude of benefit, risk and burdens, costs, and generalizability, recording scores on standardized forms.

    Guideline Focus and Target Population

    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, organizations, and health systems involved with implementing HIV care and treatment.

    Guideline Development Process

    Development of these guidelines was funded by IAPAC through a grant from the National Institutes of Health Office of AIDS Research, but IAPAC did not have approval authority over specific recommendations or the completed manuscript. The IAPAC convened a panel of 31 members, consisting of experts in clinical care, clinical trials, behavioral science, pharmacy, and guideline methods and patient representatives. From this panel, 20 members volunteered to be on the writing team. Each member completed a written conflict-of-interest disclosure. All potential conflicts of interest were declared, discussed, and resolved by the panel. The panel determined the issues to be covered on the basis of a systematic literature review and developed these guidelines using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument for practice guideline assessment (253). This process was conducted in accordance with Institute of Medicine Standards for Developing Trustworthy Clinical Practice Guidelines (254).

    Literature Search

    Interventions

    The following were the interventions of interest: 1) any intervention for improving entry into and retention in care for people with HIV and 2) any intervention for improving adherence to ART. The objective of the literature search was to identify optimal interventions for improving entry into and retention in care and ART adherence to assist with developing guidelines.

    To be included, the studies had to meet the following criteria: 1) evaluated an intervention intended to improve entry into and retention in care or ART adherence; 2) had an RCT or observational design that included comparators (if sufficient RCT-level evidence for an intervention was available, then observational studies were not considered in the body of evidence); and 3) reported 1 or more relevant outcomes assessed after the intervention was completed (biological or behavioral). The following were exclusion criteria: observational studies without comparators, letters, and editorials.

    The study participants were children, adolescents, and adults with HIV. The included studies had the following biological and behavioral outcomes of interest: mortality, morbidity, virologic failure, immunologic response, development of HIV resistance, adherence behaviors (as measured by self-report, pill count, electronic drug monitor, pharmacy refill, and other methods), entry into and retention in care behaviors (such as clinic attendance and loss to follow-up), and adverse events.

    Identification of Studies

    The search largely consisted of a systematic search performed on the Centers for Disease Control and Prevention (CDC) Prevention Research Synthesis Project Database (78), with some specific adaptations for this project. Since 1996, the CDC Prevention Research Synthesis Project has been conducting ongoing systematic searches of the HIV prevention intervention literature, focusing on HIV risk reduction and medication adherence, to establish a cumulative, comprehensive research database for conducting regular systematic reviews. This database has been developed and updated by annual automated electronic database searches, quarterly hand searches of journals, and daily ad hoc searches of the published literature from 1988 to the present. The database created for these guidelines began with pertinent evidence from 1996 and included the most recent annual electronic search of the CDC database (February 2011), hand searching through March 2011, and additional ad hoc searching through November 2011. The searches were performed with no limits for language, setting, or age. The evidence base for these guidelines was restricted to RCTs and observational studies with comparators that had at least 1 measured biological or behavioral end point.

    The panel searched the following journal databases: MEDLINE, EMBASE, PsycINFO, CINAHL, and AIDSLINE (before retirement in 2000). The following conference databases were searched from July 2009 to June 2011: Conference on Retroviruses and Opportunistic Infections; IAPAC Adherence Conference; International AIDS Conference; and the International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention.

    The clinical trials databases searched were CENTRAL (Cochrane Central Register of Controlled Trials), ClinicalTrials.gov (clinicaltrials.gov), Current Controlled Trials (www.controlled-trials.com), and Pan-African Clinical Trials Registry (www.pactr.org).

    Sixteen journals that typically contribute the most relevant citations were also hand-searched for medication adherence and retention studies. We contacted individual researchers and members of relevant organizations working in the field, including panel members, to identify studies and completed or ongoing trials.

    We checked the reference lists of all studies identified by the preceding methods and examined the bibliographies of any relevant systematic reviews, meta-analyses, or current guidelines we identified during the search process.

    Monitoring

    In addition to producing evidence-based guidelines for entry into care, retention in care, and ART adherence interventions, the panel also targeted the identification of strategies and methods for adherence monitoring or assessment, which required separate methods to search, grade, and synthesize evidence. The resulting list of articles was reviewed to include only studies that compared an adherence measurement method with a biological outcome.

    Study Inclusion Criteria

    The studies must have included one or more methods of adherence measurement and compared clinical or biological outcomes (as listed above).

    Search Strategy

    Keyword searches (monitoring, measure) were performed on the original database to identify articles specific to HIV monitoring. One panel member reviewed citations found from keyword searches to determine whether they met inclusion criteria. In addition, all articles initially identified as potential intervention articles were screened to see whether they were also of relevance to HIV monitoring. Supplementary searching for relevant articles was also performed as described above.

    Data Abstraction and Grading

    Articles identified for inclusion were abstracted (for example, study title, date, measures used, and estimates of association) and graded by using a modified QUADAS tool (255).

    Evidence Synthesis Strategy

    Data on measures from the studies were compiled into summary tables listing ranges of association, quality ratings, and other factors. Quality of the body of evidence and strength of recommendation were then rated according to the methods detailed below.

    Overall Grading Scale for Recommendations

    We used a grading scale based on the GRADE System for rating Clinical Guidelines and the American College of Physicians methods for development of clinical practice guidelines (256, 257). This pragmatic and systematic approach allowed for transparent, intuitive, and efficient production of these guidelines. Each guideline recommendation has a grade for quality of the body of evidence and a grade for strength of recommendation. Table 1 summarizes the quality and strength scales used. The following sections detail how these 2 grades were derived.

    Individual Study Evaluation Methods

    Data Extraction and Management.

    After the initial search and article screening, 2 reviewers independently coded and entered information from the included studies onto a standardized data extraction form; differences were resolved by consensus with a third reviewer. Extracted information included the following: study details (citation, start and end dates, location, study design); participant details (study population, ages, population size); interventions details (duration, nature, and intensity of the intervention); and outcome details (mortality, clinical disease progression [AIDS and non-AIDS events], treatment response [CD4 recovery and viral load response], adherence, retention, loss to follow-up, resistance, and adverse events). These data were then summarized in a table.

    Assessment of Risk for Bias in Included Studies.

    The 2 reviewers then assessed each study for risk for bias; differences were resolved by consensus with a third reviewer. The results were summarized in tables. The Cochrane Risk of Bias Tool was used for RCTs (258, 259). This tool assesses risk for bias in individual studies across 6 domains with 3 potential responses for each domain: yes, no, or unclear.

    Reviewers assessed observational studies for risk for bias by using the Newcastle-Ottawa Quality Assessment Scale (260). This validated scale assesses quality of cohort and case–control studies in 3 main areas by using a “star rating system” ranging from 0 to 9.

    Evaluating the Body of Evidence

    After each individual study was evaluated, panel members proposed draft recommendation statements based on the evidence gathered and concurrently grouped individual studies together to form the body of evidence for each specific recommendation. The body of evidence for each recommendation was then evaluated according to the factors listed in Appendix Table 3.

    Appendix Table 3. Process for Evaluating the Body of Evidence

    Appendix Table 3.

    All of these factors were considered in decreasing or increasing the quality of the body of evidence and were framed around the standards and interpretation listed in Table 1. Panel members then decided on a grade and, using standardized forms, detailed instances if and why they increased or decreased the quality of the body of evidence, specifically referencing the factor(s) involved.

    Moving From Evidence to Recommendation

    After recommendation statements had been proposed and the corresponding body of evidence for each recommendation graded, the factors listed in Appendix Table 4 were considered to determine the strength of the recommendation.

    Appendix Table 4. Factors Considered in Determining the Strength of the Recommendation

    Appendix Table 4.

    Each of the factors was explicitly considered. Panel members then decided on a strength of recommendation and, using standardized forms, detailed how they came to this decision, specifically referencing each factor as appropriate. Note that quality of the body of evidence was only 1 factor considered in the strength of recommendation.

    Comments and Modification

    An international group of content experts reviewed a draft of these guidelines, and relevant modifications were made to the manuscript. Guideline panel members will review these guidelines periodically and make updates as new evidence becomes available.

    Comments

    0 Comments
    Sign In to Submit A Comment
    Frederick A. Altice, MD, MA (Yale University), Curt G. Beckwith, MD (Brown University), Tim Horn (AIDSmeds.com), Jane M. Simoni, PhD (University of Washington)20 September 2012
    Author's Response

    Letters from Fitzpatrick, et al, and Wood and Montaner illustrate areas that were addressed by the panel but for which insufficient evidence limited the ability to make definitive recommendations. Given the assumptions needed for interpreting uncontrolled studies, we confined our evidence base to studies with either randomized or observational comparative data. We agree with Fitzpatrick, et al that peer-navigation and intensive individual outreach may be helpful in achieving successful entry into and retention in clinical care, particularly among individuals with co-morbid psychiatric and substance use disorders. Currently, the strength of evidence for such strategies is limited by a paucity of high quality published research. Similarly, Fitzpatrick and colleagues’ identification of pharmacist-led interventions as meriting a specific recommendation is constrained by a lack of literature on unique contributions of interventions led by pharmacists versus others. It is important to emphasize that while scientific evaluation requires resources, it remains the cornerstone of evidence-based practice and arguably produces cost-savings in the longer-term. Precisely because of shrinking healthcare resources, recommended approaches should be those that are effective, and determining effectiveness requires scientific investigation. We encourage those who are implementing interventions in practice or research settings to evaluate them with controlled observational studies or randomized trials and disseminate their results in order to inform the next version of these guidelines.We agree with Wood and Montaner that incarceration may lead to antiretroviral (ART) non-adherence, interruptions in care, and virologic failure for HIV-infected people who use drugs (PWUDs). Our guidelines presented evidence-based interventions (EBIs) that addressed barriers to HIV treatment outcomes among PWUDs and within criminal justice settings and did not seek to describe or weight the negative contributors themselves. Consistent with our guidelines methodology, only interventions with robust study designs were included. While the data appear incontrovertible that there are profound negative consequences on longitudinal HIV care associated with incarceration, currently there are no EBIs that reduce the negative health consequences of incarceration on PWUDs. It is provocative to speculate, however, that structural interventions that address increased community-based drug treatment, homelessness, unemployment, healthcare access, and legal reform could lead to alternatives to incarceration, thereby improving ART adherence, treatment and retention in care among HIV-infected PWUDs. We encourage the development and evaluation of methodologically sound, innovative interventions that improve HIV treatment outcomes through enhanced ART adherence and coordination of HIV care among PWUDs in criminal justice settings. Our guidelines further outline many research priorities for this population and we also refer readers to more detailed treatises on these issues that have been recently reviewed (1-3).

    Frederick A. Altice, MD, MA (Yale University)

    Curt G. Beckwith, MD (Brown University)

    Tim Horn (AIDSmeds.com)

    Jane M. Simoni, PhD (University of Washington)

    On behalf of the International Association of Physicians in AIDS Care Panel on Guidelines for Improving Entry into and Retention in Care and Antiretroviral Adherence for Persons with HIV

    References

    1. Altice FL, Kamarulzaman A, Soriano VV, Schechter M, Friedland GH. Treatment of medical, psychiatric, and substance-use comorbidities in people infected with HIV who use drugs. Lancet. 2010;376(9738):59-79.

    2. Wolfe D, Carrieri MP, Shepard D. Treatment and care for injecting drug users with HIV infection: a review of barriers and ways forward. Lancet. 2010;376(9738):355-66.

    3. Binford MC, Kahana SY, Altice FL. A Systematic Review of Antiretroviral Adherence Interventions for HIV-Infected People Who Use Drugs. Curr HIV/AIDS Rep. 2012:In press. Authors

    EvanWood, Professor of Medicine, Julio S. G. Montaner6 June 2012
    Drug Addiction, Incarceration and Entry and Retention in Care for Persons with HIV
    Thompson et al.'s review of strategies to improve entry and retention in HIV care and antiretroviral adherence for HIV infected individuals is timely given the proven role of HIV testing and antiretroviral therapy treatment in preventing the spread of HIV. While we recognize that their review sought to identify strategies to improve entry, retention and adherence, there are known barriers to HIV care that were largely overlooked in their article particularly with respect to challenges delivering timely HIV care to drug addicted individuals. Numerous studies have demonstrated that the frequent incarceration of drug addicted individuals promotes barriers to seeking HIV testing and treatment, and contributes to the interruption of antiretroviral therapy once it has begun. Our group recently demonstrated a dose-response effect of incarceration episodes on HIV treatment non-adherence (1). Similarly, a recent study of HIV-infected patients from Baltimore similarly found that periods of incarceration were associated with a two-fold risk of syringe sharing and a greater than seven-fold risk of virological failure (2). High rates of incarceration among drug users with or at risk of HIV infection are a matter of serious public health concern, given that incarceration has been associated with HIV outbreaks in a range of countries. For instance, incarceration has been identified as a risk factor for acquiring HIV infection in countries of western and southern Europe, Russia, Canada, Brazil, Iran and Thailand, and outbreak investigations using phylogenetic analyses of viral sequences have proven how HIV transmission occurs as a result of syringe sharing among inmates (3). The fact that drug law enforcement measures often disrupt HIV treatment efforts, promoting HIV drug resistance and increasing risk of HIV transmission, has yet to be appropriately addressed in national and international HIV prevention and treatment strategies. In fact, "treatment as prevention" and new prevention strategies such as scaled-up use of pre-exposure prophylaxis with antiretroviral medicines are rarely even considered or discussed by policymakers as responses to HIV among injection drug users (4). Given the proven role of expanded use of HIV antiretroviral therapy in preventing the spread of HIV, greater partnership between public health and HIV medicine is urgently needed to address the above concerns. Research conducted in the United States, where ethnic minorities are many times more likely than whites to be incarcerated for drug-related offenses, has found that disproportionate incarceration rates are one of the key reasons for the markedly elevated rates of HIV infection among African Americans (5).

    References

    1. Milloy MJ, Kerr T, Buxton J, et al. Dose-response effect of incarceration events on nonadherence to HIV antiretroviral therapy among injection drug users. J Infect Dis. May 1 2011;203(9):1215-1221.

    2. Westergaard RP, Kirk GD, Richesson DR, Galai N, Mehta SH. Incarceration Predicts Virologic Failure for HIV-Infected Injection Drug Users Receiving Antiretroviral Therapy. Clinical Infectious Diseases. 2011;53(7):725-731.

    3. Yirrell DL, Robertson P, Goldberg DJ, McMenamin J, Cameron S, Leigh Brown AJ. Molecular investigation into outbreak of HIV in a Scottish prison. BMJ. 1997;314(7092):1446-1450.

    4. Wood E, Milloy MJ, Montaner JSG. HIV treatment as prevention among injection drug users. Current Opinion in HIV and AIDS. 2012.

    5. Johnson R, Raphael S. The effects of male incarceration dynamics on acquired immune deficiency syndrome infection rates among African American women and men. Journal of Law and Economics. 2009;52(2):251-293.

    Conflict of Interest:

    None declared

    Lisa KFitzpatrick, Medical Epidemiologist, Daveda Hudson, Aurnell Dright3 April 2012
    Peer navigation and Individual Patient Outreach for Entry to HIV Care: Reaching beyond the data

    We commend Thompson and colleagues for the development and publication of Guidelines for Improving Entry Into and Retention in Care(1). These guidelines are important for consolidating best practices for the approach to this multi-dimensional and complex issue. However, while we understand the science gaps presented, we disagree with IIIC recommendations for the use of peer-navigators and intensive individual outreach. Based on our experiences in Washington DC, these strategies should be considered vital to engaging clients from impoverished and disadvantaged communities. Both peer navigation and intensive individual outreach have become anchors for successfully engaging and retaining both new and lost clients into HIV care, often in minutes rather than months. Therefore, these guidelines will serve as a minimum effort required to achieve and maintain entry and retention in care. In 2011, of 210 lost-to -care clients targeted by our outreach efforts, over 50% required unorthodox approaches that exceed parameters outlined or not mentioned in these guidelines. For example, successful outreach efforts included: 1. Seventeen phone calls to a single client, 2. An impromptu meeting on a street corner between a physician and client, 3. Twice weekly phone calls and monthly written notes for eleven months.

    In an era of shrinking healthcare resources, we do not believe additional research on entry into care, particularly via randomized trials, should be prioritized over implementation of effective strategies highlighted in federally-funded observational studies2, 3. In addition, a wealth of data exist on barriers to engagement in care4,5. Similarly, among our clients, the most common explanations and barriers to care include: 1. depression and denial associated with a new diagnosis, 2. non- IDU substance use and 3. delays in securing health insurance. Given this, we believe the solutions to improving engagement in HIV care largely involve shifting resources to develop targeted policy and implementing structural interventions such as improving access to integrated mental health and substance use treatment, expanded clinic hours, improving community health literacy and dialogue about HIV and alleviating bureaucratic delays in securing health insurance.

    Finally, the guidelines do not specifically address the integration of pharmacists within healthcare teams. The inclusion of a PharmD for treatment adherence counseling on our team has been invaluable for client retention. If more research is funded, we agree with the recommendation to conduct operational research to demonstrate the impact of interventions like this since doing so will provide evidence to justify funding for this service delivery model.

    REFERENCES

    1. Thompson MA, Mugavero MJ, Amico KR, et al. 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. Annals of Internal Medicine. March 5, 2012 2012:E-419.

    2. Gardner LI, Metsch LR, Anderson-Mahoney P, Loughlin AM, del Rio C, Strathdee S, et al; Antiretroviral Treatment and Access Study Study Group. Efficacy of a brief case management intervention to link recently diagnosed HIV-infected persons to care. AIDS. 2005;19:423-31.

    3. Bradford JB, Coleman S, Cunningham W. HIV System Navigation: an emerging model to improve HIV care access. AIDS Patient Care STDS. 2007;21 Suppl 1:S49-58. [PMID: 17563290

    4. Cavaleri MA, Kalogerogiannis K, McKay MM. Barriers to HIV care: an exploration of the complexities that influence engagement in and utilization of treatment. Soc Work Health Care. 2010;49(10):934-45.

    5. Rumptz MH, Tobias C, Rajabiun S, Bradford J, Cabral H. Factors associated with engaging socially marginalized HIV-positive persons in primary care. AIDS Patient Care STDS. 2007;21 Suppl 1:S30-9.

    Conflict of Interest:

    We do not have competing interests.

    IsabelleArnet, Senior Researcher, Heiner C. Bucher, Kurt E. Hersberger30 March 2012
    Polymedication Electronic Monitoring System (POEMS) in future research

    The expert panel from the IAPAC proposed pioneering guidelines to improve entry into and retention in care, as well as adherence to HIV medications, the three pillars of HIV treatment success. We highly honour their article. We agree that the currently most used electronic drug monitors (a microchip embedded in a pill bottle cap) can not be recommended for routine use outside of studies because they only measure one single drug and not the whole regimen, they impede the use of pillboxes and because patients often remove pocket doses.

    To overcome these shortcomings we developed a self-adhesive polymer film, with conductive wires that can be affixed to commercial multidose blister packs. The new technology allows recording of date, time and location of drug removed from a blister pack. Thus, we can track intake of an entire regimen with all solid oral drugs and the system can easily be combined with time reminder alarms. Furthermore, the visualization of individual intake behaviours with the entire medication, and not only with one drug, would permit to correlate adherence with eg drug-drug interactions, reasons of treatment failure and drug resistance, and guide decision making. We obtained first promising results with this new adherence tool in a study on aspirin resistance (ClinicalTrials.gov Identifier: NCT01039480) and are going to soon start a study with HIV- patients at the University Hospital Basel.

    Therefore we would like to strengthen the recommendation for future research into electronic monitoring ART adherence and to overcome drawbacks of existing EDMs. We suggest as new strategy and as amendment to Table 2, the development of electronic monitoring technology with direct link to supporting drug reminder systems. Such tools should enable both, monitoring and patient support and they should be convenient for patients in daily life.

    Conflict of Interest:

    None declared