Karina M. Berg

Practical and Conceptual Challenges in Measuring Antiretroviral Adherence

Summary:Accurate measurement of antiretroviral adherence is essential for targeting and rigorously evaluating interventions to improve adherence and prevent viral resistance. Across diseases, medication adherence is an individual, complex, and dynamic human behavior that presents unique measurement challenges. Measurement of medication adherence is further complicated by the diversity of available measures, which have different utility in clinical and research settings. Limited understanding of how to optimize existing adherence measures has hindered progress in adherence research in HIV and other diseases. Although self-report is the most widely used adherence measure and the most promising for use in clinical care and resource-limited settings, adherence researchers have yet to develop evidence-based standards for self-reported adherence. In addition, the use of objective measures, such as electronic drug monitoring or pill counts, is limited by poor understanding of the source and magnitude of error biasing these measures. To address these limitations, research is needed to evaluate methods of combining information from different measures. The goals of this review are to describe the state of the science of adherence measurement, to discuss the advantages and disadvantages of common adherence measurement methods, and to recommend directions for improving antiretroviral adherence measurement in research and clinical care.

Association Between Alcohol Consumption and Both Osteoporotic Fracture and Bone Density

OBJECTIVE Alcoholism is a risk factor for osteoporotic fractures and low bone density, but the effects of moderate alcohol consumption on bone are unknown. We performed a systematic review and meta-analysis to assess the associations between alcohol consumption and osteoporotic fractures, bone density and bone density loss over time, bone response to estrogen replacement, and bone remodeling. METHODS MEDLINE, Current Contents, PsychINFO, and Cochrane Libraries were searched for studies published before May 14, 2007. We assessed quality using the internal validity criteria of the US Preventive Services Task Force. RESULTS We pooled effect sizes for 2 specific outcomes (hip fracture and bone density) and synthesized data qualitatively for 4 outcomes (non-hip fracture, bone density loss over time, bone response to estrogen replacement, and bone remodeling). Compared with abstainers, persons consuming from more than 0.5 to 1.0 drinks per day had lower hip fracture risk (relative risk=0.80 [95% confidence interval, 0.71-0.91]), and persons consuming more than 2 drinks per day had higher risk (relative risk=1.39 [95% confidence interval, 1.08-1.79]). A linear relationship existed between femoral neck bone density and alcohol consumption. Because studies often combined moderate and heavier drinkers in a single category, we could not assess relative associations between alcohol consumption and bone density in moderate compared with heavy drinkers. CONCLUSION Compared with abstainers and heavier drinkers, persons who consume 0.5 to 1.0 drink per day have a lower risk of hip fracture. Although available evidence suggests a favorable effect of alcohol consumption on bone density, a precise range of beneficial alcohol consumption cannot be determined.

Gender differences in factors associated with adherence to antiretroviral therapy

OBJECTIVE: To identify gender differences in social and behavioral factors associated with antiretroviral adherence.DESIGN: Prospective cohort study.SETTING: Methadone maintenance program.PARTICIPANTS: One hundred thirteen HIV-seropositive current or former opioid users.MEASUREMENTS AND MAIN RESULTS: Participants were surveyed at baseline about social and behavioral characteristics and at monthly research visits about drug and alcohol use and medication side effects. Electronic monitors (MEMS) were used to measure antiretroviral adherence. Median adherence among women was 27% lower than among men (46% vs. 73%; P<.05). In gender-stratified multivariate models, factors associated with worse adherence in men included not belonging to an HIV support group (P<.0001), crack/cocaine use (P<.005), and medication side effects (P=.01). Among women, alcohol use (P=.005), heroin use (P<.05), and significant medication side effects (P<.005) were independently associated with worse adherence. In a model including both men and women, worse adherence was associated with lack of long-term housing (P<.005), not belonging to any HIV support groups (P<.0005), crack or cocaine use (P<.01), and medication side effects (P<.0005). In addition, worse adherence was associated with the interaction between female gender and alcohol use (P ≤ .05).CONCLUSIONS: In this cohort of current and former opioid users, gender-stratified analysis demonstrated that different social and behavioral factors are associated with adherence in men and women. Among both men and women, worse adherence was associated with lack of long-term housing, not belonging to an HIV support group, crack/cocaine use, and medication side effects. Among women only, alcohol use was associated with worse adherence.

Directly observed antiretroviral therapy improves adherence and viral load in drug users attending methadone maintenance clinics: A randomized controlled trial

OBJECTIVE To determine if directly observed antiretroviral therapy (DOT) is more efficacious than self-administered therapy for improving adherence and reducing HIV viral load (VL) among methadone-maintained opioid users. DESIGN Two-group randomized trial. SETTING Twelve methadone maintenance clinics with on-site HIV care in the Bronx, New York. PARTICIPANTS HIV-infected adults prescribed combination antiretroviral therapy. MAIN OUTCOMES MEASURES Between group differences at four assessment points from baseline to week 24 in: (1) antiretroviral adherence measured by pill count, (2) VL, and (3) proportion with undetectable VL (< 75 copies/ml). RESULTS Between June 2004 and August 2007, we enrolled 77 participants. Adherence in the DOT group was higher than in the control group at all post-baseline assessment points; by week 24 mean DOT adherence was 86% compared to 56% in the control group (p < 0.0001). Group differences in mean adherence remained significant after stratifying by baseline VL (detectable versus undetectable). In addition, during the 24-week intervention, the proportion of DOT participants with undetectable VL increased from 51% to 71%. CONCLUSIONS Among HIV-infected opioid users, antiretroviral DOT administered in methadone clinics was efficacious for improving adherence and decreasing VL, and these improvements were maintained over a 24-week period. DOT should be more widely available to methadone patients.

Providers' experiences treating chronic pain among opioid-dependent drug users.

BACKGROUNDSuccessful management of chronic pain with opioid medications requires balancing opioid dependence and addiction with pain relief and restoration of function. Evaluating these risks and benefits is difficult among patients with chronic pain and pre-existing addiction, and the ambiguity is increased for patients on methadone maintenance therapy for opioid dependence. Providers treating both chronic pain and addiction routinely make diagnostic and therapeutic decisions, but decision-making strategies in this context have not been well described.OBJECTIVEOur objective was twofold. We sought first to explore providers’ perceptions of ambiguity, and then to examine their strategies for making diagnostic and treatment decisions to manage chronic pain among patients on methadone maintenance therapy.DESIGNQualitative semi-structured interviews.SETTING AND PARTICIPANTSWe interviewed health-care providers delivering integrated medical care and substance abuse treatment to patients in a methadone maintenance program.RESULTSProviders treating pain and co-morbid addiction described ambiguity in all diagnostic and therapeutic decisions. To cope with this inherent ambiguity, most providers adopted one of two decision-making frameworks, which determined clinical behavior. One framework prioritized addiction treatment by emphasizing the destructive consequences of abusing illicit drugs or prescription medications; the other prioritized pain management by focusing on the destructive consequences of untreated pain. Identification with a decision-making framework shaped providers’ experiences, including their treatment goals, perceptions of treatment risks, pain management strategies, and tolerance of ambiguity. Adherence to one of these two frameworks led to wide variation in pain management practices, which created tension among providers.CONCLUSIONSProviders delivering integrated medical care and substance abuse treatment to patients in a methadone maintenance program found tremendous ambiguity in the management of chronic pain. Most providers adopted one of the two divergent heuristic frameworks we identified, which resulted in significant variations in pain management. To reduce variation and determine best practices, studies should examine clinically relevant endpoints, including pain, illicit drug use, prescription drug abuse, and functional status. Until then, providers managing chronic pain in patients with co-morbid addiction should attempt to reduce tension by acknowledging ambiguity and engaging in open discourse.

Comparison of antiretroviral adherence questions.

Our objective was to compare antiretroviral adherence questions to better understand concordance between measures. Among 53 methadone maintained HIV-infected drug users, we compared five measures, including two single item measures using qualitative Likert-type responses, one measure of percent adherence, one visual analog scale, and one multi-item measure that averaged responses across antiretrovirals. Responses were termed inconsistent if respondents endorsed the highest adherence level on at least one measure but middle levels on others. We examined ceiling effects, concordance, and correlations with VL. Response distributions differed markedly between measures. A ceiling effect was less pronounced for the single-item measures than for the measure that averaged responses for each antiretroviral: the proportion with 100% adherence varied from 22% (single item measure) to 58% (multi-item measure). Overall agreement between measures ranged from fair to good; 49% of participants had inconsistent responses. Though responses correlated with VL, single-item measures had higher correlations. Future studies should compare single-item questions to objective measures.

Lack of sustained improvement in adherence or viral load following a directly observed antiretroviral therapy intervention.

BACKGROUND Methadone clinic-based directly observed antiretroviral therapy (DOT) has been shown to be more efficacious for improving adherence and suppressing human immunodeficiency virus (HIV) load than antiretroviral self-administration. We sought to determine whether the beneficial effects of DOT remain after DOT is discontinued. METHODS We conducted a post-trial cohort study of 65 HIV-infected opioid-dependent adults who had completed a 24-week randomized controlled trial of methadone clinic-based DOT versus treatment as usual (TAU). For 12 months after DOT discontinuation, we assessed antiretroviral adherence using monthly pill counts and electronic monitors. We also assessed viral load at 3, 6, and 12 months after DOT ended. We examined differences between DOT and TAU in (1) adherence, (2) viral load, and (3) proportion of participants with viral load of <75 copies/mL. RESULTS At trial end, adherence was higher among DOT participants than among TAU participants (86% and 54%, respectively; P < .001), and more DOT participants than TAU participants had viral loads of <75 copies/mL (71% and 44%, respectively; P = .03). However, after DOT ended, differences in adherence diminished by 1 month (55% for DOT vs 48% for TAU; P = .33) and extinguished completely by 3 months (49% for DOT vs 50% for TAU; P = .94). Differences in viral load between DOT and TAU disappeared by 3 months after the intervention, and the proportion of DOT participants with undetectable viral load decreased steadily after DOT was stopped until there was no difference (36% for DOT and 34% for TAU; P = .92). CONCLUSIONS Because the benefits of DOT for adherence and viral load among HIV-infected methadone patients cease after DOT is stopped, methadone-based DOT should be considered a long-term intervention.

Rationale, design, and sample characteristics of a randomized controlled trial of directly observed antiretroviral therapy delivered in methadone clinics.

BACKGROUND Directly observed therapy (DOT) programs for HIV treatment have demonstrated feasibility, acceptability, and improved viral suppression, but few have been rigorously tested. We describe a randomized controlled trial testing the efficacy of an antiretroviral DOT program in methadone maintenance clinics. Our objective was to determine if DOT is more efficacious than self-administered antiretroviral therapy for reducing HIV viral load, improving adherence, and reducing drug resistance among opioid dependent drug users receiving methadone treatment. METHODS Participants were randomized to treatment as usual (TAU) or antiretroviral DOT for the 24-week intervention. TAU participants received standard adherence counseling, and DOT participants received standard adherence counseling plus directly observed antiretroviral therapy, which was delivered at the same time as they received daily methadone. Assessments occurred at baseline, weekly for 8 weeks, and then monthly for 4 months. Our primary outcomes were between-group changes from baseline to the end of the intervention in: HIV viral load, antiretroviral adherence, and number of viral mutations. RESULTS Between June 2004 and August 2007, we screened 3231 methadone-maintained patients and enrolled 77; 39 participants were randomized to DOT and 38 to TAU. 65 completed the 24-week intervention. CONCLUSIONS Our trial will allow rigorous evaluation of the efficacy of directly observed antiretroviral therapy delivered in methadone clinics for improving adherence and clinical outcomes. This detailed description of trial methodology can serve as a template for the development of future DOT programs and can guide protocols for studies among HIV-infected drug users receiving methadone for opioid dependence.

Strategies to Improve Access to and Utilization of Health Care Services and Adherence to Antiretroviral Therapy Among HIV-Infected Drug Users

We review five innovative strategies to improve access, utilization, and adherence for HIV-infected drug users and suggest areas that need further attention. In addition, we highlight two innovative programs. The first increases access and utilization through integrated HIV and opioid addiction treatment with buprenorphine in a community health center, and the second incorporates adherence counseling for antiretroviral therapy in methadone programs. Preliminary evaluations demonstrated that these strategies may improve both HIV and opioid addiction outcomes and may be appropriate for wider dissemination. Further refinement and expansion of strategies to improve outcomes of HIV-infected drug users is warranted.

Self-efficacy and depression as mediators of the relationship between pain and antiretroviral adherence

Abstract The goals of this study were to examine the association between pain and antiretroviral adherence and to estimate the mediating effect of adherence self-efficacy and depression symptom severity. Surveys using audio computer-assisted self-interview were conducted among 70 HIV-infected current and former drug users enrolled in a methadone program. We assessed antiretroviral adherence and adherence self-efficacy using questions from the Adult Clinical Trials Group survey. We considered participants adherent if they reported taking at least 95% of prescribed antiretrovirals over the past seven days. We assessed depression symptom severity using the depression subscale of the Brief Symptom Inventory. Participants reported pain of any duration in response to a question from the Brief Pain Inventory. Participants reporting pain were 87% less likely to be classified as adherent compared to those without pain (Unadjusted OR = 0.13, 95%CI: 0.03–0.52). When we examined adherence self-efficacy as a mediator of the relationship between pain and adherence, criteria for partial mediation were met. Adjusting for self-efficacy, the beta coefficient for pain decreased by 23% but the independent relationship between pain and antiretroviral adherence was maintained. Mediation criteria were not met when we examined the mediating effect of depression symptom severity on the relationship between pain and adherence. Adjusting for depression symptom severity, the beta coefficient for pain decreased by 9% and the relationship between pain and antiretroviral adherence remained significant. Our results indicate that neither adherence self-efficacy nor depression symptom severity fully mediated the relationship between pain and adherence. HIV providers should recognize the potential impact of pain on antiretroviral adherence among current and former drug users.