{"doi":"10.1002/jia2.26397","title":"Adherence measurement considerations for oral antiretroviral medications","abstract":"Non-adherence has been, and remains, the most powerful predictor of unfavourable outcomes for both pre-exposure prophylaxis (PrEP) and anti-retroviral therapy. In particular, non-adherence during oral PrEP trials complicated the picture of efficacy, a fact that is again on display following the PURPOSE-1 trial that included daily oral emtricitabine/tenofovir alafenamide (F-TAF) and emtricitabine/tenofovir disoproxil fumarate [1]. Adherence in early trials was initially measured via self-report, pill counts and medication dispensation records, all suggesting high adherence (>90%) during trial periods [2, 3]. However, analysis of biological samples from the active arms indicated much lower PrEP use (unquantifiable or low drug concentrations), and particularly low use among participants who seroconverted. The lessons learned from these trials include: objective adherence measures greatly outperformed indirect measures, and many participants, by virtue of repeated undetectable drug concentrations between study visits, likely had little intention of being adherent, and this was unbeknownst to study personnel. Intentionality of non-adherence is difficult to determine and nuanced and likely underappreciated when considering adherence measurements in trials. In this Viewpoint, we highlight the need for more research to consider adherence measurements when participants have little intention of adhering to the medication. We recognize the only way to differentiate the intentionality of non-adherence is participant self-report, which is subject to social desirability bias [4]. We also recognize and acknowledge that open communication is critical to this subject and appreciate that the foundation of care requires open and non-judgemental conversations between clients and clinicians. The reasons for participating in trials are complex: for some clients, there may be an initial intent to take the medication, but subsequent side effects or perception of not being at risk anymore may temper their enthusiasm to continue to take the medication; both the incentives of trial participation (financial and access to healthcare) and/or social desirability bias (not wanting to disappoint the study staff) may lead to misreporting of non-adherence. Nevertheless, clinicians and researchers need reliable adherence measurements to properly interpret expected/observed therapeutic outcomes, whether the participant is intentionally or unintentionally non-adherent. Additionally, intent to adhere is important for policymakers who must target appropriate populations for medical interventions (i.e. those who intend to be adherent). The main adherence assessment in the recently published PURPOSE-1 study was intraerythrocytic tenofovir-diphosphate (TFV-DP), the phosphorylated anabolite of TFV, which is formed and trapped in red blood cells with a 17-day half-life. It accumulates with repeated dosing (i.e. adherence) and provides an estimate of cumulative adherence in the preceding 1–2 months, often reported as doses/week on average: <350 fmol/punch, fewer than 2 tablets per week; 350–699 fmol/punch, 2–3 tablets per week; 700–1249 fmol/punch, 4–6 tablets per week, ≥1250 fmol/punch 7 tablets per week [5]. The measurement confirms medication ingestions, is not manipulable, and detects intentional and unintentional non-adherence alike. It is not susceptible to white-coat dosing (being non-adherent but dosing just prior to a clinic visit) because the drug concentration requires many days of repeated dosing to reach high concentrations—a white-coat dose will have a negligible effect on the concentration. In fact, this type of biomarker can be combined with short half-life drug concentrations to identify white-coat dosing. An example was observed in the HPTN 084 study, which collected plasma TFV (a short half-life drug concentration) along with TFV-DP in dried blood spots (DBS; long half-life biomarker). Twenty-five percent of those who seroconverted exhibited high plasma","journal":"Journal of the International AIDS Society","year":2024,"id":506680,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9554,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":279022,"name":"Peter L. Anderson","orcid":"0000-0002-1200-8494","position":1,"is_corresponding":false},{"id":1251775,"name":"Corwin Coppinger","orcid":"0009-0005-6430-7444","position":0,"is_corresponding":true}],"reference_count":15,"raw_metadata":null,"created_at":"2026-07-19T02:10:54.646711Z","pmid":"39587904","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}