Impact of antiretroviral dosing frequency and pill burden on adherence among newly diagnosed, antiretroviral-naive HIV patients

There are few data on the impact of antiretroviral therapy (ART) regimen factors on adherence in ART-na?ve HIV patients on contemporary once- or twice-daily regimens. Ninety-nine newly diagnosed patients in a prospective observational cohort study completed a visual analogue scale to assess their ART adherence. Adherence by type of ART and dosing frequency were compared by Brown-Mood median tests. Participants taking once-daily regimens had higher adherence (n = 70, 99.5%) compared with participants taking twice-daily regimens (n = 29, 94%; P = 0.01). Adherence of participants taking the fixed dose combination efavirenz-emtricitabine-tenofovir (n = 34, 100%) compared with those taking once-daily regimens of two or more pills was no different (n = 36, 99.3%; P = 0.34). Among a cohort of newly diagnosed ART-na?ve patients, once-daily dosing of ART resulted in higher adherence than twice-daily dosing. Pill burden among once-daily regimens did not predict adherence, suggesting that factors other than pill burden should drive regimen selection.     

Relationship between adherence level, type of the antiretroviral regimen, and plasma HIV type 1 RNA viral load: a prospective cohort study

The relationship between adherence, antiretroviral regimen, and viral load (VL) suppression was assessed through a 1 year prospective follow-up study among 1142 HIV-infected patient. Patients on antiretroviral therapy who attended to the pharmacy during a 6-month period were considered eligible. Those included in the final analysis were patients who had been taking the same antiretroviral therapy for > or =6 months since their inclusion. The cohort included patients taking first line therapy (n = 243) and antiretroviral-experienced patients (n = 899). Naive patients who were included had to have reached undetectable VL at enrollment. Antiretroviral-experienced patients with detectable VL determinations in the previous 6 months were excluded. Adherence was measured by means of announced pill counts and dispensation pharmacy records. Of patients, 58% were taking NNRTI, 31.4% boosted PI, and 10.6% unboosted PI-based regimens. Overall, the relative risk of virologic failure was 9.0 (95% CI 4.0-20.1) in patients with adherence 80-89.9%, 45.6 (95% CI 19.9-104.5) with adherence 70-79.9%, and 77.3 (95% CI 34.2-174.9) with adherence <70%, compared with adherence of > or =90%. The risk of virologic failure in patients with adherence <90% taking unboosted PI was 2.5 times higher than the group taking boosted PI (95% CI 1.2-5.3). There were no statistical differences in patients taking boosted PI and those who were taking NNRTI. Less than 95% of adherence is associated with high virologic success. For patients taking NNRTI- or boosted PI-based regimens with adherence rates of 80%, the failure rate is <10%. These data do not affect the goal of achieving the highest level of adherence possible.     

The impact of monitoring on adherence and persistence with antiresorptive treatment for postmenopausal osteoporosis: a randomized controlled trial

Long-term adherence and persistence with any therapy are very poor ( approximately 50%). Adherence to therapy is defined as the percentage of prescribed medication taken, and persistence is defined as continuing to take prescribed medication. We examined whether monitoring by nursing staff could enhance adherence and persistence with antiresorptive therapy and whether presenting information on response to therapy provided additional benefit. In addition we evaluated the impact of monitoring on treatment efficacy. Seventy-five postmenopausal women with osteopenia were randomized to 1) no monitoring, 2) nurse-monitoring, or 3) marker-monitoring. All subjects were prescribed raloxifene. At 12, 24, and 36 wk, the nursing staff reviewed subjects in the monitored (nurse-monitoring or marker-monitoring) groups using a predefined protocol. The marker-monitored group were also presented a graph of response to therapy using percentage change in urinary N-telopeptide of type I collagen (uNTX), a bone resorption marker, at each visit. Biological response to therapy at 1 yr was determined using the percent change in bone mineral density (BMD) and uNTX. Treatment adherence and persistence were assessed using electronic monitoring devices. Survival analysis showed that the monitored group increased cumulative adherence to therapy by 57% compared with no monitoring (P = 0.04). There was a trend for the monitored group to persist with therapy for 25% longer compared with no monitoring (P = 0.07). Marker measurements did not improve adherence or persistence to therapy compared with nurse-monitoring alone. Adherence at 1 yr was correlated with percent change in hip (BMD) (r = 0.28; P = 0.01) and percent change in uNTX (r = -0.36; P = 0.002). In conclusion, monitoring of patients increased adherence to therapy by 57% at 1 yr. Increased adherence to therapy increased the effectiveness of raloxifene therapy determined using surrogate end points.     

Effect of adherence to newly initiated antiretroviral therapy on plasma viral load.

OBJECTIVE: To determine whether differences in adherence to newly initiated antiretroviral therapy exist between subjects who do and do not achieve undetectable plasma viral loads. DESIGN: Observational cohort study monitoring adherence and virological and immunological parameters over the initial 4 months of therapy with nelfinavir. Adherence was measured using the microelectronic monitoring system (MEMS; APREX Corporation, Menlo Park, California, USA). SETTING: General Clinical Research Center at a tertiary care center. PARTICIPANTS: Forty-one protease inhibitor-naive subjects with viral loads > 10 000 copies/ml newly starting a regimen including nelfinavir, referred from HIV clinics in Philadelphia. MAIN OUTCOME MEASURES: The primary outcome was undetectable viral load (< 50 copies/ml) after 4 months. Secondary measures included changes in viral load and CD4 cell counts. We hypothesized that adherence would be greater in subjects who achieved undetectable viral loads. RESULTS: Adherence was greater in undetectable subjects, who took a median of 93% of prescribed doses [interquartile range (IQR) 84-96%], whereas detectable subjects took a median of 70% (IQR 46-93%). Adherence correlated with viral load decrease (Spearman's rho = 0.38, P < 0.01) and CD4 cell count increase (Spearman's rho = 0.25, P = 0.06). Despite differences between the groups over 4 months of therapy, there were no adherence differences over the first month [undetectables, 95% (IQR 88-98%) versus detectables, 94% (IQR 87-98%), P > 0.50]. CONCLUSIONS: Adherence is important in determining whether or not individuals achieve suppression with a newly initiated antiretroviral regimen. Adherence begins to wane after the first month of therapy. Therefore, closer assessment of adherence particularly after this first month is important.     

Use of an on-line pager system to increase adherence to antiretroviral medications

Adherence to antiretroviral therapy is critical for treatment success. Antiretroviral therapy typically requires multiple pills at multiple dosing times. To address this, we tested the feasibility, utility, and efficacy of a customizable reminder system using pagers, which were programmed using web-based technology, to increase and maintain proper adherence in patients with pre-existing adherence problems. After a two-week monitoring period with an electronic pill-cap, participants with less than 90% adherence were randomized to continue monitoring or to receive a pager. The group who received the pagers had greater improvements in adherence from baseline to Week 2 and Week 12 than those who monitored their medications only. However, adherence in both groups at the outcome assessments points was still poor. While the provision of a reminder system helped improve adherence, it is likely that more intensive interventions are required for patients with pre-existing problems.     

Randomized controlled trial of a personalized cellular phone reminder system to enhance adherence to antiretroviral therapy

Adherence to antiretroviral therapy (ART) represents one of the strongest predictors of progression to AIDS, yet it is difficult for most patients to sustain high levels of adherence. This study compares the efficacy of a personalized cell phone reminder system (ARemind) in enhancing adherence to ART versus a beeper. Twenty-three HIV-infected subjects on ART with self-reported adherence less than 85% were randomized to a cellular phone (CP) or beeper (BP). CP subjects received personalized text messages daily; in contrast, BP subjects received a reminder beep at the time of dosing. Interviews were scheduled at weeks 3 and 6. Adherence to ART was measured by self-report (SR, 7-day recall), pill count (PC, past 30 days at baseline, then past 3 weeks), Medication Event Monitoring System (MEMS; cumulatively at 3 and 6 weeks), and via a composite adherence score constructed by combining MEMS, pill count, and self report. A mixed effects model adjusting for baseline adherence was used to compare adherence rates between the intervention groups at 3 and 6 weeks. Nineteen subjects completed all visits, 10 men and 9 females. The mean age was 42.7 ± 6.5 years, 37% of subjects were Caucasian and 89% acquired HIV heterosexually. The average adherence to ART was 79% by SR and 65% by PC at baseline in both arms; over 6 weeks adherence increased and remained significantly higher in the ARemind group using multiple measures of adherence. A larger and longer prospective study is needed to confirm these findings and to better understand optimal reminder messages and user fatigue.     

Sustained antiretroviral treatment adherence in survivors of the pre-HAART era: attitudes and beliefs

The objective of this study was to assess adherence of HIV-1-infected patients who started treatment in the pre-HAART era and to determine variables associated with better adherence, including relevant attitudes and beliefs. This is a cross-sectional study enrolling patients who had received antiretroviral therapy for >or=10 years. Adherence was evaluated through self-reporting and plasma drug concentrations. Treatment variables, attitudes and beliefs were collected during structured interviews. The results show that for 87 patients the median (interquartile range) time on therapy was 13 (10-19) years; 80 were on therapy at the time of analysis. Adherence was >or=95% in 54 patients (67.5%), 90-94% in 22 (27.5%) and <90% in 4 (5%). Drug concentrations were below the lower limit of detection in five patients. Younger age (p=0.014), female gender (p=0.005), current substance abuse (p=0.004) and hepatitis C virus co-infection (p<0.001) were related to lower adherence. Adherence did not differ in relation to different drug families or once- or twice-daily regimens. Patients with adherence <95% were more likely to have interrupted treatment without doctor's recommendation (p=0.009). Adherent patients exhibited a higher perception of risk of developing the illness and of benefits of therapy, higher self-efficacy and intention to adhere and were more influenced by events that motivate medication intake. To conclude, adherence was >90% in most patients on antiretroviral therapy for >or=10 years. Adherence was more related to beliefs about health and illness than to the characteristics of medication or level of knowledge about treatment. Care adherence interventions should include assessment of health beliefs.     

Effect of twice-daily nevirapine on adherence in HIV-1-infected patients: a randomized controlled study

OBJECTIVE: For optimal adherence, once-daily dosing is best. Whether this applies to antiretroviral therapy is unknown. We thus aimed to determine the effect of once-daily dosing on adherence to nevirapine. DESIGN: A three-phase (3-month observational, 4-month randomized, 5-month interventional) open-label, clinical trial at four French academic medical centres during 2005-2006 among 62 chronically HIV-1-infected subjects with long-lasting viral suppression under a twice-a-day nevirapine-based antiretroviral combination. METHODS: Adherence was measured using electronic monitoring devices and validated by sequential plasma drug levels. Participants were randomly assigned to switch to nevirapine 400 mg once-daily (n = 31) or continue nevirapine 200 mg twice-a-day (n = 31). After the randomized phase, participants had an opportunity to choose their antiretroviral dosage. Primary outcome was the mean percentage of adherence. RESULTS: Fifty-two patients qualified for electronic data analysis. During the randomized phase, the mean adherence rate was non-significantly superior by 0.5% in once-daily versus twice-a-day dosing (P = 0.68), adjusting for previous twice-a-day adherence rate (P < 0.0001). Once-daily group increased days without dose [odds ratio (OR) 1.7; 95% confidence interval (CI) 1.0, 2.8; P = 0.04], adjusting for previous drug interruptions (P < 0.0001). In the longitudinal analysis, once-daily dosing was significantly associated with at least two consecutive days without dose (OR 4.4; 95% CI 1.9, 10.3; P < 0.001). CONCLUSION: Changing from twice to once-daily nevirapine does not improve adherence. Supporting continuous adherence to antiretroviral therapy in the 'once-a-day era' remains a challenge, even if more potent regimens can achieve viral suppression at lower adherence levels.     

HAART with didanosine once versus twice daily: adherence and efficacy.

BACKGROUND: Highly active antiretroviral therapy (HAART) containing didanosine taken twice daily was compared with HAART containing didanosine taken once daily in terms of adherence and efficacy. METHOD: This was a self-controlled prospective cohort study, carried out in a tertiary level hospital. A total of 49 HIV-infected patients were included. They were prescribed HAART according to guidelines. After six months taking HAART containing didanosine twice daily, patients continued with the same regimen of HAART although once daily. Thereafter they were followed up for a further nine months. Adherence and virological efficacy were assessed at three-month intervals, for a total of six times, in every patient. RESULTS: Overall, adherence was poor, with only 19 patients (39%) showing adequate adherence for all six visits. Adequate adherence was observed in 29 patients (59%) three months before didanosine switching, and in 37 patients (75%) three months after didanosine switching (P=0.034). Pooled HIV RNA results of the first three visits were higher than the same results of the last three visits (P=0.05). CONCLUSIONS: Non-adherence is common among patients who take HAART. Simplification of regimens is useful to improve adherence and efficacy.     

Prevalence, predictors, and outcomes of early adherence after starting or changing antiretroviral therapy

The objectives of this research were to assess prevalence and predictors of early antiretroviral therapy adherence using multiple indicators and to estimate effects of early adherence on subsequent HIV viral load and CD4+ lymphocyte responses. Study subjects were adults with HIV infection referred to an antiretroviral therapy-monitoring clinic for initiation or change in therapy between March 1998 and June 1999. The design was a prospective observational cohort involving baseline interview followed by 30 days of electronic adherence monitoring (MEMS), 30-day interview, and follow-up viral load at 1, 3, and 6 months. Adherence indicators included MEMS therapeutic coverage, observed/expected cap openings, and self-reported adherence assessed at 30 days. Of 235 consenting patients, 60 (26%) failed to complete 30 days of electronic monitoring (noncompleters). At 6 months, mean change from baseline plasma viral load was inferior among noncompleters (0.5 log vs. 1.7 log). Predictors of adherence, varying by adherence metric, included: gender, race, prior antiretroviral therapy experience, substance abuse, prior adherence behavior, health beliefs, and pharmacist prediction of adherence. Self-reported adherence was more sensitive in predicting viral load responses than MEMS-based measures and identified poor adherence at earlier time points. Approximately a quarter of consenting patients were unable to complete 30 days of MEMS monitoring, and early drop out was a poor prognostic sign. Predictors of adherence varied depending upon how adherence was measured. Differences in virologic response between patients with optimal or poor adherence may not emerge until several months after regimen change or initiation. Structured assessment of self-reported adherence is an inexpensive and useful tool to assist clinicians in monitoring adherence.     

The CASE adherence index: A novel method for measuring adherence to antiretroviral therapy

The Center for Adherence Support Evaluation (CASE) Adherence Index, a simple composite measure of self-reported antiretroviral therapy (ART) adherence, was compared to a standard three-day self-reported adherence measure among participants in a longitudinal, prospective cross-site evaluation of 12 adherence programs throughout the United States. The CASE Adherence Index, consisting of three unique adherence questions developed for the cross-site study, along with a three-day adherence self-report were administered by interviews every three months over a one-year period. Data from the three cross-site adherence questions (individually and in combination) were compared to three -day self-report data and HIV RNA and CD4 outcomes in cross-sectional analyses. The CASE Adherence Index correlated strongly with the three-day self-reported adherence data (p < 0.001) and was more strongly associated with HIV outcomes, including a 1-log decline in HIV RNA level (maximum OR = 2.34; p < 0.05), HIV RNA < 400 copies/ml (maximum OR = 2.33; p < 0.05) and performed as well as the three-day self-report when predicting CD4 count status. Participants with a CASE Index score >10 achieved a 98 cell mean increase in CD4 count over 12 months, compared to a 41 cell increase for those with scores < or =10 (p < 0.05). The CASE Adherence Index is an easy to administer instrument that provides an alternative method for assessing ART adherence in clinical settings.     

Patterns of adherence to antiretroviral medications: the value of electronic monitoring

OBJECTIVE: To investigate the patterns of intra-subject (between medication) adherence to antiretroviral therapy. DESIGN: A prospective, observational, 3-month study of adherence to antiretroviral therapy at an inner-city clinic in 40 HIV-infected subjects. METHODS: Adherence was monitored monthly by the use of medication event monitoring system (Aprex) caps placed on each antiretroviral drug in a subject's regimen. Agreement between different drug classes and dosing schedules, for each subject, was quantified by estimating the mean difference in adherence, with 95% limits of agreement. An analysis of variance model was used to estimate the variance of the differences. Individual dosing calendars were examined for each subject. RESULTS: The dosing schedule was a strong predictor of intra-subject adherence. Regardless of the subject's overall adherence rate, high or low, when subjects missed a dose of one medication, they missed a dose of both medications taken at that dosing time. Conversely, when medications were scheduled to be taken together, regardless of the drug class, the medications were taken at the same times. The majority of the subjects took medications at obviously incorrect times. Problematical adherence was related to thrice-daily dosing and food restrictions. CONCLUSION: This is the first report objectively to quantify intra-subject adherence to antiretroviral therapy and report the findings in detail. We observed clear patterns of drug-taking behavior among the subjects in our study. To the extent that medication scheduling is a controllable factor, our report provides an insight into specific patterns of behavior that may be targets for adherence counseling.     

Evaluation of adherence to a triple antiretroviral therapy in HIV-positive patients

The purpose of the study is to know the adherence to a triple antiretroviral therapy, to analyse the treatment attachment associated factors and to evaluate the impact on therapeutic response related to adherence. Adherence degree was estimated by direct questionnaire. The CD4+ cells counts and viral load were made before initiating treatment and also 4 months after it. The impact of introducing a protocolized informing system for each patient about the treatment is analysed also. We studied 164 patients. Differences within adherence degree depending on age or sex were not found. Adherence rates were worse in IDU patients. We did not find differences on adherence related to nucleoside analogues, but patients on a bid regimen were found to have better adherence than those in the group receiving a tid regimen. Patients who received protocolized information presented a non significant trend to have better adherence. Adherence to therapy is related to higher CD4+ cells increases at the fourth month and a greater viral load decrease. At least 24.4% of patients with triple therapy do not reach a proper adherence degree; the IDU patients are the ones with lower adherence rates. Treatments administered bid have better adherence than those administrated tid. Introducing a standardized information protocol might improve adherence rates. The response to antiretroviral therapy is conditioned by adherence degree.     

Long-term utility of measuring adherence by self-report compared with pharmacy record in a routine clinic setting

OBJECTIVES: To compare long-term adherence to antiretroviral therapy in an HIV service, as measured by self-report and by pharmacy records. To determine the level of adherence by each measure required to suppress viral load in a majority of patients. METHODS: The percentage of prescribed doses taken was calculated from (a) the number of missed doses in the previous 28 days reported by patients in a questionnaire at each clinic visit, and (b) pharmacy dispensing records. These were compared with each other and with HIV viral load data. RESULTS: Mean adherence was 96.2% by pharmacy record over 44 months and 98.6% by self-report over 25 months. The two methods correlated with each other (P<0.001) and the proportion of patients with viral load <400 HIV-1 RNA copies/mL increased with adherence as measured by self-report (P=0.001) and pharmacy record (P=0.004). Fewer than 60% of patients always had viral loads <400 copies/mL if adherence fell below 95% (pharmacy record) or 97% (self-report). Adherence was higher for once-daily than for twice-daily therapy (by pharmacy record: 97.2% vs. 96.0%; P<0.001). Adherence by both measures increased over time. CONCLUSIONS: Self-reported antiretroviral adherence correlates with pharmacy dispensing records and predicts suppression of viral load at levels >or=97%. It is practical to adopt this into routine HIV clinical care.     

Medication adherence among HIV-infected patients: Understanding the complex behavior of patients taking this complex therapy

Adherence to antiretroviral regimens by HIV-infected patients is necessary to prolong viral suppression and forestall viral resistance. This review covers the major advances made in research on adherence to HIV therapy in the past year. Currently, approximately 40% of patients receiving antiretroviral therapy have significant problems with adherence. Established predictors of poor adherence include depression, alcohol and illicit drug use, poor self-efficacy, and certain health beliefs. Medical providers are poor at predicting adherence. Interventions to improve adherence can have modest effects, and many types of interventions are effective. Multifaceted and repetitive interventions provide the most benefit. Medical providers, as part of the medical management of HIV-infected patients, should use interventions to achieve high levels of adherence to therapy.     

Randomized trial of an adherence programme for clients with HIV

Our aim was to determine if a comprehensive adherence package improved self reported adherence to antiretroviral therapy. The adherence package included an education programme, individualized planning of regimens, and the opportunity for a patient to choose from a number of adherence aids and reminder devices. A randomized step wedge design was used. Forty-three individuals were randomized to begin the intervention over a five-month period. There was a substantial fall in the number of missed doses reported for the last four days (0.76 to 0.38, P =0.03) and last seven days (1.5 to 0.74, P =0.005) but not for the last 28 days (2.5 to 2.5, P =0.63). There was no statistical difference in the viral load or CD4 lymphocyte count in the period before or after the intervention. The Morisky score during the pre and post intervention periods was significantly different (P =0.006), 2.9 (SD 0.9) and 3.3 (SD 0.8) respectively. This adherence package improved self reported adherence during the last four and seven days.     

Evaluation of a practical method to assess antiretroviral adherence in HIV-infected Thai children

The objective of this study was to evaluate a practical method to assess adherence to antiretroviral therapy by observing virological and immunological responses. We conducted a 12-month longitudinal cohort study of 162 HIV-infected Thai children. Adherence was assessed using 5 methods (self reporting calendar, records of missed doses, pill counts, physician assessment, and an interview questionnaire). CD4 count, percentage and viral load were performed at baseline and at 12 months. Mean adherence rates at 2, 6, and 12 months were 98, 100, and 99% by the calendar method; 98, 100, and 100% by recording missed doses; 96, 96, and 92% by pill count; and 90, 94, and 97% by physician assessment. Poor agreement (kappa < or = 0.1) was found among the methods. There was a statistically significant difference (p = 0.05) in virological response between participants with > or = 95% adherence (0.8 log10) and those with < 95% adherence (0.2 log10) when pill counts were used to assess adherence. In conclusion, despite poor agreement among these tools, a pill count appeared to be the only practical, validated method to differentiate the virological outcome between those who were fully and partially adhere to the treatment regimen.     

Patient-perceived barriers to antiretroviral adherence: associations with race

New antiretroviral (ARV) regimens require strict adherence if optimal suppression of HIV is to be maintained. This study is a theory-based examination of racial differences in patient-perceived barriers and reported ARV adherence. Participants (N=149) completed the Patient Medication Adherence Questionnaire (PMAQ), measuring adherence and perceived barriers to adherence. Adherence was defined as a self-report of 100% adherence in the past four weeks. Odds ratios were calculated to determine the relation of reported barriers to adherence for race and gender groups, and for the sample overall. For every ten-point increase in barrier score, there was an 86% increased risk of being non-adherent (OR=1.86; 95% CI: 1.19, 2.91). Adherence was not different between racial and gender groups, nor was total barrier score. However, individual barriers were differentially endorsed across groups. Rather than relying on demographic predictors, which may be only an indirect marker of adherence, evaluations of adherence should examine the psychological and social barriers to positive adherence outcomes in individual patients. Our findings support the use of theory-based behavioural interventions that address perceived barriers to adherence and other health promotion activities.