HIV regimen adherence Lessons for Long Acting IM injectables from oral ART & PrEP
Measures to improve ART & PrEP adherence • Inherent drug improvement to increase tolerability • Single regimen ART • Fewer side effects Concern – if oral ART • Improved delivery method adherence is difficult monitor, what lessons can be learnt to • Long acting intramuscular injectables improve chance of success for • Oral ART pharmacy refills for longer periods adherence to infrequent LA • Monitored adherence support IMs injectables? • Objective technological measures (EAMs, RNA & drug levels) • Subjective personal measures (self-report, caregiver report, SMS) • Person-centred approaches using both/either of above
Review of published studies • Search of published studies using PubMed • Papers between 2009 – 2017 • Searched for ‘adherence’ and; • SMS, short message service • MEMS, MEMS-cap, EAM • Peer support, peer to peer, counselling, support • Economic incentive, cash incentive, voucher • HIV RNA test, plasma drug levels, hair • Filtered for HIV studies (PrEP & ART) • Reviewed 57 studies
Technological measures of adherence SMS & Instant EAMs Real-time Drug levels HIV RNA Digital medicine messaging (MEMS-cap) wireless EAMs (plasma or hair) testing systems Barriers to success, e.g. Failure of Self-report bias, Pocket dosing, Mobile network Dose masking Cost & equipment one/more tech no airtime curiosity openings loss, battery life (delayed testing) requirements components Combinations of measures to cross-validate adherence & develop intelligent testing procedures based on individual’s behaviour patterns
SMS – Surveys to understand adherence behaviour Haberer et al 2017 1 : • N = 373, Uganda • Daily SMS surveys - monitoring sexual behaviour & PrEP use in serodiscordant couples Mean reported PrEP adherence: 92% on surveys concurrently reporting sex, 84% on surveys reporting no sex Higher PrEP adherence associated with increased HIV risk FIGURE 1. Mean PrEP adherence as associated with risk for HIV transmission. Circles indicate risk behaviors for HIV acquisition: <6 months of ART use by the partner living with HIV, sex reported within the serodiscordant partnership, and reported condomless sex. Mean reported PrEP adherence concurrent with each overlap of behaviors is shown in the legend. Haberer et al 2017.
SMS – Reminders during adherence lapses Sabin et al 2015 2 : • N = 120, China • Individualised SMS reminders sent to patients if dose-taking was late by 30+ mins (recorded from MEMS data) • MEMS-generated data also used in counselling for ‘late’ patients Improve ART adherence (93.3%) vs control group (no SMS or FIGURE 2. Monthly mean adherence among intervention and control subjects, stratified by pre-intervention counselling) (84.7%) period optimal (≥95%) or suboptimal (<95%) adherence, using an on -time adherence measure Note: Pre-intervention period refers to Months 1 – 3; intervention period is the subsequent 6-month period (Months 4 – 9) during which subjects received triggered reminders and data-informed counselling. Sabin et al 2015.
Electronic Adherence Monitoring – Understanding the difference between self-report & MEMS adherence Musinguzi et al 2016 3 : • N = 1147, 6048 person-months, Uganda • Self-reported PrEP adherence was compared with MEMS data, unannounced pill counts & TDF plasma levels (N = 365, SSDD: 74%) SSDD vs <SSDD levels was poor for self-reported adherence (AROC 0.54 – 0.56) & UPC (AROC 0.58), but moderate for MEMS monitoring FIGURE 3. Receiver – operating curves for the sensitivity of self-reported adherence, unannounced pill counts, and electronic monitoring to detection of steady-state daily dosing plasma tenofovir levels. EM, electronic monitoring; SR, self-reported; SSDD, steady-state daily dosing; UPC, unannounced pill counts. Musinguzi et (AROC 0.70). al 2016.
Electronic Adherence Monitoring – Real-time wireless monitoring to understand risk of viral rebound Haberer et al 2015 4 : • N = 479, Uganda • Measured interruptions to adherence using real-time wireless EAMs; interruptions 48+ hours followed up with HIV RNA testing Odds of viral rebound increased by 25% with each day beyond 48 hours (OR: 1.25; P = 0.007) Viral rebound was also associated with 30-day adherence before the FIGURE 4. Association between duration of adherence interruption and viral rebound. A total of 587 interruptions were seen among 261 of the total 479 participants (54%). Viremia exceeded 5% of interruptions lasting longer than 7 interruption (OR: 0.73; P = 0.02). days. Twenty-one interruptions (3%) were longer than 14 days, none of which had detectable HIV RNA during the interruption or at the subsequent routine quarterly assessment. Haberer et al 2015.
HIV RNA testing – MEMS-based predictive testing Petersen et al 2015 5 : • N = 1478, 16 sites in USA • Applied machine learning algorithm to MEMS data, CD4+ T cell counts & ART regimen Improved classification of virological failure from MEMS, to predict selective RNA testing 25 – 31% of HIV RNA tests could be avoided Cost savings: $16-$29/person-mth FIGURE 5: Cross-validated ROC Curves for classification of virological failure using four Super Learner prediction models and three- month “average adherence” (percent prescribed doses recorded by MEMS). Failure defined as HIV RNA level>400 copies/ml. Sensitivity for failure detection ≥95%. Petersen et al 2015.
HIV RNA testing – new technologies for POC tests Gurrala et al 2016 6 : • Development of a novel chip based, point-of-care HIV-1 viral load assay; amplifies & detects HIV-1 RNA • N = 991 clinical samples Sensitivity: 95% (in vitro) & 88.8% (on- chip) at >1000 RNA copies/reaction Median time to detection: 20.8 mins Sensitivity, specificity & reproducibility FIGURE 6: (a) Image of prototype chip for amplification and detection of nucleic acids close to that required for a low-power compatible with a USB port. (b) Schematic of a chip. Each chamber functions independently, when the pH of the chamber changes the ISFET point-of-care device e.g. USB stick (ion sensitive field effect transistor) generates an electrical signal. Gurrala et al 2016.
Combining technological measures & meaningful support Technological measures of Economic Peer Culturally adherence incentives support sensitive support Person-centred support through understanding what matters to individuals in order to motivate adherence using most appropriate technological measures
Economic Incentives El Sadr 2017 7 & Greene 2017 8 : • N = 1061, 18 test sites, USA • Offered vouchers for linkage to care ($125), & quarterly vouchers conditional on viral suppression ($70) Incentives did not increase linkage to care (AOR: 1.10; 95%CI, 0.73-1.67; P = .65), but significantly increased viral suppression (4.9% higher than control) (95%CI, 1.4%-8.5%; P = .007) Qualitative follow up (Greene 2017) showed broader positive impact, including patients proactively attending the doctor El Sadr et al. 2017
Understanding personal barriers to adherence Blashill et al 2015 9 : Odds compared to zero syndemics • N = 331, USA 4.1 times 5.0 times greater • greater odds of Undertook diagnostics of odds of being non- 8.5 times being non- adherent greater (95% CI: adherent psychosocial syndemics & odds of 0.84, 20.4, (95% CI: being non- P = 0.08) 1.02, 24.4, adherent P = 0.047) monitored adherence to ART using (95% CI: 1.7, 42.9, P = 0.01) MEMS Co-occurring psychosocial problems have an additive effect on the risk for poor ART adherence FIGURE 8: Percent Adherence by Syndemic Group. Blashil et all 2015. Integrative cognitive-behavioural Psychosocial syndemics are psychosocial issues which occur together in one patient’s life, and can include childhood abuse, current violence, alcohol or substance abuse/dependence, post-traumatic stress disorder, anti-social personality disorder, anxiety spectrum disorders, mood disorders, and psychotic interventions to support adherence disorders should be given attention
Person-centred, nurse-led monitoring De Bruin et al 2017 10 : • N = 221, Netherlands • AIMS is a nurse-led 1-2-1 behavioural intervention, incorporating pre- & during- study MEMS data, for adherence goal setting At 5, 10 & 15 months log viral load was 1·26 times higher (95% CI 1·04 – 1·52) in the control group than in AIMS group AIMS was cost-effective: reduced lifetime societal costs by €592/patient & increased QALYs by 0·034/patient
Culturally sensitive peer support Bogart et al 2017 11 : • N = 215, USA • Peer-delivered MEMS-informed counselling, adapted for HIV+ African Americans; “Rise” • Addressed culturally congruent adherence barriers (e.g., medical mistrust, HIV stigma) & assisted with linkage to supportive services Adherence improved relative to Fig. 2 Adherence and nonadherence patterns from baseline to 6-month follow-up. Bogart et al 2017. control group, with large cumulative Adherence improved over time relative to control group, (OR = 1.30 per month (95% CI = 1.12 – 1.51, p < 0.001), representing large cumulative effect after 6 mths (OR = 4.76, Cohen’s d = 0.86). effect after 6 mths (OR: 4.76)
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