Project Summary/Abstract Electronic adherence monitoring (EAM) technologies are widely used to support antiretroviral adherence. Unfortunately, EAMs such as Wisepill assume, but cannot verify, actual ingestion of oral medication. In contrast, My/Treatment/Pill (MyTPill), an innovative technology that directly measures ingestion, comprises a digital pill containing a medication and tiny radio emitter in a gelatin capsule. When the digital pill is ingested, gastric contents dissolve the capsule to activate the emitter. The digital pill “syncs” real-time ingestion data to a smartphone application to provide vivid, indisputable measures of medication ingestion. Head-to-head comparisons of EAMs, however, have yet to be performed. Identifying the superior EAM would improve virologic suppression by enabling real-time interventions to support ART adherence. In this randomized controlled trial, we will compare MyTPill to WisePill among N=80 HIV+ men/women taking prescription opioids and once-daily ART regimens containing tenofovir and emtricitabine with a viral load >200/mL. HIV+ patients on prescription opioids have difficulty adhering to ART regimens, although the reasons are not fully known. Given the high prevalence of prescription opioid misuse among HIV+ individuals—triple that of HIV-negative persons—and striking rates of suboptimal ART adherence (46% worse than those who do not misuse), strategies to improve ART adherence in this population are critically needed. Participants will be randomly assigned in a crossover trial to (1) MyTPill x 3 mos, then WisePill x 3 mos; or (2) Wisepill x 3 mos, then MyTPill x 3 mos. Adherence measured via MyTPill and WisePill will be compared to dried blood spot (DBS) concentrations of tenofovir diphosphate (for cumulative adherence) and emtricitabine triphosphate (for recent adherence). Participants will provide DBS samples on multiple random times according to a schedule that prevents anticipation of sampling but which assesses cumulative/recent ART adherence. We will also examine which aspects of prescription opioid use, pain, withdrawal, and demographic, social, structural, and other environmental contexts (measured by timeline follow back and quantitative interviews) are most closely linked to ART adherence. Furthermore, we will examine how these aspects affect MyTPill and WisePill measures of ART adherence. Primary Aim: Determine if MyTPill, as compared to Wisepill, exhibits: (1) better measures recent and cumulative ART adherence when using DBS as the “gold standard”; and (2) better participant experience as assessed by observed and self-reported measures (e.g., study retention, fidelity to study, protocol relative subjective index, qualitative interviews). Secondary Aim: Examine which aspect(s) of prescription opioid use (e.g., prescribed use/misuse of opioids as measured by MyTPill, technology subversion, pain, demographic, social, other structural factors) are most closely linked to ART nonadherence (per D...