Frederick L. Altice

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

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.

Trust and the acceptance of and adherence to antiretroviral therapy.

Background: Antiretroviral therapy (ART) has resulted in reduced AIDS incidence and mortality. Socially marginalized individuals with HIV infection, particularly injection drug users (IDUs), have received less ART and derived less benefit than others. Little is known about the therapeutic process necessary to promote acceptance of and adherence to ART among marginalized HIV‐infected populations. We report on the correlates of both acceptance of and adherence to ART among HIV infected prisoners, most of whom are IDUs. Design: Using a cross‐sectional survey design within four ambulatory prison HIV clinics, 205 HIV‐infected prisoners eligible for ART were recruited between March and October 1996. Measurements: Detailed interviews were conducted that included personal characteristics, health status and beliefs, and validated standardized scales measuring depression, health locus of control, social desirability and trust in physician, medical institutions and society. Acceptance and adherence were documented by self‐report and validated for a subset by pharmacy review. Clinical information was obtained from standardized chart review. Adherence was defined as having taken ≥80% of ART. Results: The acceptance of (80%) and adherence to (84%) ART among this group of prisoners was high. Multiple regression models demonstrated that correlates of acceptance of and adherence to ART differed. Acceptance was associated with trust in physician (8% increase for each unit increase with trust in physician scale) and trust in HIV medications (threefold reduction for those mistrustful of medication). Side effects (OR = 0.09), social isolation (OR = 0.08), and complexity of the antiretroviral regimen (OR = 0.33) were associated with decreased adherence. The prevalence of health beliefs suggesting an adverse relationship between ART and drugs of abuse was high (range 59 to 77%). Adherence did not differ among those receiving directly observed therapy (82%) or self‐administration (85%). Conclusions: ART can be successfully administered within a correctional setting. Trust and the therapeutic relationship between patient and physician remain central in the ART initiation process. Characteristics of the therapeutic agents and the degree of social isolation predict adherence. These results may inform the design of interventions to improve both acceptance of and adherence to ART particularly among marginalized populations who have not derived full benefit from these potent new therapies.

Treatment of medical, psychiatric, and substance-use comorbidities in people infected with HIV who use drugs

HIV-infected drug users have increased age-matched morbidity and mortality compared with HIV-infected people who do not use drugs. Substance-use disorders negatively affect the health of HIV-infected drug users, who also have frequent medical and psychiatric comorbidities that complicate HIV treatment and prevention. Evidence-based treatments are available for the management of substance-use disorders, mental illness, HIV and other infectious complications such as viral hepatitis and tuberculosis, and many non-HIV-associated comorbidities. Tuberculosis co-infection in HIV-infected drug users, including disease caused by drug-resistant strains, is acquired and transmitted as a consequence of inadequate prescription of antiretroviral therapy, poor adherence, and repeated interfaces with congregate settings such as prisons. Medication-assisted therapies provide the strongest evidence for HIV treatment and prevention efforts, yet are often not available where they are needed most. Antiretroviral therapy, when prescribed and adherence is at an optimum, improves health-related outcomes for HIV infection and many of its comorbidities, including tuberculosis, viral hepatitis, and renal and cardiovascular disease. Simultaneous clinical management of multiple comorbidities in HIV-infected drug users might result in complex pharmacokinetic drug interactions that must be adequately addressed. Moreover, interventions to improve adherence to treatment, including integration of health services delivery, are needed. Multifaceted, interdisciplinary approaches are urgently needed to achieve parity in health outcomes in HIV-infected drug users.

Effectiveness of Antiretroviral Therapy among HIV-Infected Prisoners: Reincarceration and the Lack of Sustained Benefit after Release to the Community

Responses to highly active antiretroviral therapy (HAART) in correctional settings and their sustained benefit in prisoners after release are currently not known. To examine the human immunodeficiency virus type 1 (HIV-1) RNA level (VL) and CD4 lymphocyte response to HAART during incarceration and upon reentry to the correctional system, we conducted a retrospective cohort study of longitudinally linked demographic, pharmacy, and laboratory data from the Connecticut prison system. During incarceration, the mean CD4 lymphocyte count increased by 74 lymphocytes/ mu L, and the mean VL decreased by 0.93 log10 copies/mL (P<.0001). Fifty-nine percent of the subjects achieved a VL of <400 copies/mL at the end of each incarceration period. For the 27% of subjects who were reincarcerated, the mean CD4 lymphocyte count decreased by 80 lymphocytes/ mu L, and the mean VL increased by 1.14 log10 (P<.0001). Although HAART use resulted in impressive VL and CD4 lymphocyte outcomes during the period of incarceration, recidivism to prison was high and was associated with a poor outcome. More effective community-release programs are needed for incarcerated patients with HIV disease.

A systematic review of the impact of alcohol use disorders on HIV treatment outcomes, adherence to antiretroviral therapy and health care utilization.

BACKGROUND Alcohol use disorders (AUDs) are highly prevalent and associated with non-adherence to antiretroviral therapy, decreased health care utilization and poor HIV treatment outcomes among HIV-infected individuals. OBJECTIVES To systematically review studies assessing the impact of AUDs on: (1) medication adherence, (2) health care utilization and (3) biological treatment outcomes among people living with HIV/AIDS (PLWHA). DATA SOURCES Six electronic databases and Google Scholar were queried for articles published in English, French and Spanish from 1988 to 2010. Selected references from primary articles were also examined. REVIEW METHODS Selection criteria included: (1) AUD and adherence (N=20); (2) AUD and health services utilization (N=11); or (3) AUD with CD4 count or HIV-1 RNA treatment outcomes (N=10). Reviews, animal studies, non-peer reviewed documents and ongoing studies with unpublished data were excluded. Studies that did not differentiate HIV+ from HIV- status and those that did not distinguish between drug and alcohol use were also excluded. Data were extracted, appraised and summarized. DATA SYNTHESIS AND CONCLUSIONS Our findings consistently support an association between AUDs and decreased adherence to antiretroviral therapy and poor HIV treatment outcomes among HIV-infected individuals. Their effect on health care utilization, however, was variable.

The Era of Adherence to HIV Therapy

The past 2 years have witnessed stunning benefits of antiretroviral therapy. Dramatic delays in HIV progression, improved survival, and decreased hospitalization for HIV-infected patients have created a renewed sense of optimism [1, 2]. For many, HIV disease has been transformed into a manageable chronic disease. However, complete enthusiasm for these recent successes has been dampened by biological, clinical, social, and economic realities that limit both access to and success of antiretroviral therapies. High HIV replication and mutation rates, varying potency of regimens, stage of HIV disease, and previous antiretroviral therapy all influence therapeutic success and failure. In addition, it has become increasingly clear that differing levels of adherence to therapy explain much of the magnitude and durability of the therapeutic response. For example, clinical trials of antiretroviral therapies have shown reductions in HIV-1 RNA copies to levels less than 500 copies/mm3 in up to 80% to 85% of patients [3], but results in clinical sites may be as low as 50% [4]. In both settings, adherence predicts which patients achieve nondetectable viral levels [4-6]. Adherence, often used interchangeably with compliance, is the act, action, or quality of being consistent [7] with administration of prescribed medications. Adherence is preferred because it affirms that patients actively participate in choosing and maintaining a medication regimen. Nonadherence may mean not taking medication at all, taking reduced amounts, not taking doses at prescribed frequencies or intervals, or not matching medication to food requirements. Typical rates of medication adherence for persons with chronic diseases are about 50%, with a range from 0% to 100% [8]. Self-reported adherence to HIV therapy ranges from 46% to 88% [9-12]. Many factors have been associated with adherence, including patient characteristics, clinician-patient relationship, type of disease, treatment regimen, and clinical setting [13]. Patient characteristics include knowledge about and belief in the medication, social support, and stable living circumstances. Altered mental states caused by substance abuse, depression, or psychological stress contribute to non-adherence. Conversely, adherence does not seem to be predicted by age, sex, race, education level, socioeconomic status, or occupation [14]. Trust in and special attributes of the clinician can positively influence adherence. Asymptomatic and chronic diseases are less likely to have high rates of adherence, and complex treatment regimens decrease adherence. The organization of clinical services can affect adherence, including availability of expertise, linkages with drug treatment and mental health services, flexibility in the hours of operation, and the presence of nonjudgmental and supportive staff [15]. In addition to encompassing all of the above features, adherence to HIV therapies presents special issues that result from the biology of HIV, the magnitude of the required therapeutic effort, and the changing demography of HIV infection. Replication of HIV is rapid and highly error-prone, resulting in great species diversity and de novo drug-resistant mutants unless replication is completely suppressed. Under the selective pressure conferred by imperfect adherence, drug-resistant mutants rapidly emerge. Cross-resistance among drugs within a therapeutic class limits future treatment options, emphasizing the importance of maximal suppression and strict adherence during the initial course of antiretroviral therapy. Thus, compared with therapies for other chronic diseases, which are often forgiving of lapses in adherence, HIV therapy is unforgiving. The development and transmission of antiretroviral-resistant species carries potentially disastrous public health consequences, further distinguishing HIV infection from many other chronic diseases [16]. The magnitude of therapeutic effort for patients receiving HIV therapy is daunting. Large numbers of medications, many pills, frequent dosing, the need to match dosage to meals, and frequent side effects characterize most regimens. For example, a commonly prescribed regimen of stavudine, lamivudine, and nelfinavir requires taking 13 pills (3 doses) per day or 4745 pills (1095 doses) per year. The shifting demography of HIV diseases raises additional concerns about adherence. Increasing numbers of ethnic minority patients, injection drug users, and women have developed AIDS. However, these groups may be difficult to engage in care and have not achieved the same decrease in AIDS incidence and survival benefit as white men have [1]. Interventions that promote adherence to anti-HIV therapies are urgently needed. Despite the limited evaluation of interventions promoting adherence for other diseases [17], the urgency of the issue requires that strategies be implemented on the basis of what little is known and what is reasonably likely to be effective. Initiation of antiretroviral therapy is rarely a medical emergency. A careful plan to maximize adherence should precede initiation of therapy. Interventions to improve adherence should target the patient, clinician, treatment regimen, and clinical setting. Patient-targeted interventions include educating patients about therapy, treating substance abuse and mental illness, strengthening support systems, and tailoring medication to daily life activities. Untested technological reminders that use telephone calls, timers, or beepers may promote adherence for some patients; however, these reminders may be irrelevant for socially marginalized populations that lack access to technological cues. Improving adherence is not the sole responsibility of the patient. Clinicians should use the repeated encounters before initiation of therapy to provide information, promote trust, and motivate the patient. Consistency, availability, and competence are essential characteristics for the clinician. Sharing successful changes in viral load and CD4 count links adherence to therapeutic benefit and helps to motivate patients. A team approach to improve adherence by using nonphysician providers, family members, and trusted peers is useful. Simplification of regimens, elimination of unnecessary medications, repeated assessment of adherence and proactive monitoring, and management of side effects should be routine. The complexity of existing medication regimens impairs adherence. Pharmacologic improvements in existing and newer therapies should allow for twice-daily or even once-daily regimens. Clearly, the pharmaceutical industry has a key role and interest in the development of simpler and safer regimens. Special attention to the site and organization of care is needed to reach marginalized populations. With adequate resources, prisons, jails, drug treatment programs, homeless shelters, needle-exchange sites, and other community locations can become important settings in which to implement HIV therapy. In Connecticut, up to 67% of HIV-infected prisoners first received antiretroviral therapy while in prison [10], and 84% continued HIV care through a novel transitional case-management program [18] after returning to the community. In San Francisco, effective outreach has led to successful adherence in homeless populations [19]. For injection drug users, flexibility and convenience are necessary, and for some women, provision of child care at treatment sites may enhance adherence. Directly observed therapy, which has been successful in the treatment of tuberculosis, is impractical with HIV therapeutics because current treatment regimens consist of multiple daily doses. However, modified versions could use case managers, family members, and peers. Directly observed therapy can also be implemented in prisons; at needle-exchange sites; and in drug treatment programs such as therapeutic communities, methadone maintenance programs, or heroin maintenance programs of the type that are available in Switzerland [20]. Improvement in adherence is key to preventing the emergence of drug-resistant viruses that compromise therapeutic benefit and may be transmitted to others. The cost of interventions to enhance adherence is minimal compared with the cost of the therapies themselves and should be weighed against the costs to individual patients and to society that will result if therapeutic benefit is compromised. The introduction of protease inhibitor combinations led to an era of renewed optimism in the HIV and AIDS epidemic. An era of adherence is now necessary to sustain and expand the benefits of these therapies.

Acceptance and adherence with antiretroviral therapy among HIV-infected women in a correctional facility

We examined attitudinal and demographic correlates of antiretroviral acceptance and adherence among incarcerated HIV-infected women. Structured interviews were conducted with 102 HIV-infected female prisoners eligible for antiretroviral therapy. Three quarters of the women were currently taking antiretroviral agents, of whom 62% were adherent to therapy. Satisfaction was very high with the HIV care offered at the prison; 67% had been first offered antiretroviral agents while in prison. Univariate and multivariate analyses showed acceptance of the first offer of antiretroviral therapy to be associated with trust in medication safety, lower educational level, and non-black race. Current acceptance of therapy was associated with trust in the medications efficacy and safety. Medication adherence was correlated with the patient-physician relationship and presence of emotional supports. Nearly one half of these HIV-seropositive women were willing to take experimental HIV medications in prison. This was correlated with satisfaction with existing health care, the presence of HIV-related social supports, and perceived susceptibility to a worsening condition. Acceptance and adherence with antiretroviral agents appear to be significantly associated with trust in medications, trust in the health care system, and interpersonal relationships with physicians and peers. Development of models of care that encourage and support such relationships is essential for improving adherence to antiretroviral therapy, especially for populations that have historically been marginalized from mainstream medical care systems.

Substance Abuse, Violence, and HIV in Women: A Literature Review of the Syndemic

Women in the United States are increasingly affected by HIV/AIDS. The SAVA syndemic-synergistic epidemics of substance abuse, violence, and HIV/AIDS-is highly prevalent among impoverished urban women and potentially associated with poor HIV outcomes. A review of the existing literature found 45 articles that examine SAVAs impact on (1) HIV-associated risk-taking behaviors, (2) mental health, (3) healthcare utilization and medication adherence, and (4) the bidirectional relationship between violence and HIV status. Overall, results confirm the profound impact of violence and victimization and how it is intertwined with poor decision making, increased risk taking and negative health consequences, particularly in the context of substance abuse. Among current findings, there remain diverse and inconsistent definitions for substance abuse, violence, mental illness, adherence, and healthcare utilization that confound interpretation of data. Future studies require standardization and operationalization of definitions for these terms. Development and adaptation of evidence-based interventions that incorporate prevention of violence and management of victimization to target this vulnerable group of women and thereby promote better health outcomes are urgently needed.

Hiv Treatment Outcomes Among Hiv-infected, Opioid-dependent Patients Receiving Buprenorphine/naloxone Treatment within Hiv Clinical Care Settings: Results From a Multisite Study

Background:Having opioid dependence and HIV infection are associated with poor HIV-related treatment outcomes. Methods:HIV-infected, opioid-dependent subjects (N = 295) recruited from 10 clinical sites initiated buprenorphine/naloxone (BUP/NX) and were assessed at baseline and quarterly for 12 months. Primary outcomes included receiving antiretroviral therapy (ART), HIV-1 RNA suppression, and mean changes in CD4 lymphocyte count. Analyses were stratified for the 119 subjects not on ART at baseline. Generalized estimating equations were deployed to examine time-dependent correlates for each outcome. Results:At baseline, subjects on ART (N = 176) were more likely than those not on ART (N = 119) to be older, heterosexual, have lower alcohol addiction severity scores, and lower HIV-1 RNA levels; they were less likely to be homeless and report sexual risk behaviors. Subjects initiating BUP/NX (N = 295) were significantly more likely to initiate or remain on ART and improve CD4 counts over time compared with baseline; however, these improvements were not significantly improved by longer retention on BUP/NX. Retention on BUP/NX for three or more quarters was, however, significantly associated with increased likelihood of initiating ART (β = 1.34 [1.18, 1.53]) and achieve viral suppression (β = 1.25 [1.10, 1.42]) for the 64 of 119 (54%) subjects not on ART at baseline compared with the 55 subjects not retained on BUP/NX. In longitudinal analyses, being on ART was positively associated with increasing time of observation from baseline and higher mental health quality of life scores (β = 1.25 [1.06, 1.46]) and negatively associated with being homo- or bisexual (β = 0.55 [0.35, 0.97]), homeless (β = 0.58 [0.34, 0.98]), and increasing levels of alcohol addiction severity (β = 0.17 [0.03, 0.88]). The strongest correlate of achieving viral suppression was being on ART (β = 10.27 [5.79, 18.23]). Female gender (β = 1.91 [1.07, 3.41]), Hispanic ethnicity (β = 2.82 [1.44, 5.49]), and increased general health quality of life (β = 1.02 [1.00,1.04]) were also independently correlated with viral suppression. Improvements in CD4 lymphocyte count were significantly associated with being on ART and increased over time. Conclusions:Initiating BUP/NX in HIV clinical care settings is feasible and correlated with initiation of ART and improved CD4 lymphocyte counts. Longer retention on BPN/NX was not associated with improved prescription of ART, viral suppression, or CD4 lymphocyte counts for the overall sample in which the majority was already prescribed ART at baseline. Among those retained on BUP/NX, HIV treatment outcomes did not worsen and were sustained. Increasing time on BUP/NX, however, was especially important for improving HIV treatment outcomes for those not on ART at baseline, the group at highest risk for clinical deterioration. Retaining subjects on BUP/NX is an important goal for sustaining HIV treatment outcomes for those on ART and improving them for those who are not. Comorbid substance use disorders (especially alcohol), mental health problems, and quality-of-life indicators independently contributed to HIV treatment outcomes among HIV-infected persons with opioid dependence, suggesting the need for multidisciplinary treatment strategies for this population.

Nevirapine induced opiate withdrawal among injection drug users with Hiv infection receiving methadone

BACKGROUND Pharmacokinetic interactions complicate and potentially compromise the use of antiretroviral and other HIV therapeutic agents in patients with HIV disease. This may be particularly so among those receiving treatment for substance abuse. OBJECTIVE We describe seven cases of opiate withdrawal among patients receiving chronic methadone maintenance therapy following initiation of therapy with the non-nucleoside reverse transcriptase inhibitor, nevirapine. DESIGN Retrospective chart review. RESULTS In all seven patients, due to the lack of prior information regarding a significant pharmacokinetic interaction between these agents, the possibility of opiate withdrawal was not anticipated. Three patients, for whom methadone levels were available at the time of development of opiate withdrawal symptoms, had subtherapeutic methadone levels. In each case, a marked escalation in methadone dose was required to counteract the development of withdrawal symptoms and allow continuation of antiretroviral therapy. Three patients continued nevirapine with methadone administered at an increased dose; however, four chose to discontinue nevirapine. CONCLUSION To maximize HIV therapeutic benefit among opiate users, information is needed about pharmacokinetic interactions between antiretrovirals and therapies for substance abuse.