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Background It is well established that antiretroviral therapy (ART) with a lower pill burden are associated with better virologic suppression. However, many HIV providers are cautious when considering ART changes in heavily treatment-experienced patients for a variety of reasons: accumulation of complex resistance patterns, intolerance concerns with new agents, drug-interaction concerns, and a paucity of data on ART simplification in this population. The objective of our study was to evaluate the impact of pharmacist-led initiative to simplify ART among heavily treatment-experienced patients with high pill burdens on virologic control. Methods This was a prospective, observational cohort at a clinic in Paterson, NJ, USA. Patients were eligible if: heavily treatment experienced (≥10 years on ART with history of failure or resistance), ART with ≥ 4 pills daily, ≥ 48 weeks of data, and at clinic from September 2016 to present. The primary endpoint was to measure the effect of ART simplification (decrease of ≥ 2 pills daily) on virologic response (HIV RNA < 200 copies/mL) compared with continuation of regimens with a high pill burden. Secondary endpoints included difference in antiretroviral pill burden and monthly cost, based on average wholesale price (AWP). Results There were 94 patients eligible for the analysis. Most patients were male (65%), and either Black (53%) or Latinx (35%). The simplification and continuation groups had similar baseline characteristics: mean age (50 vs. 50 years old), daily pill burden (4.77 vs. 4.95), virologic response (82% vs. 87%), CD4 count (459 ± 265 vs. 528 ± 273), monthly ART cost ($4,585 vs. $4,159). M184V (50.0%) and K103N (23.4%) were the most commonly documented mutations. Thymidine-analog, atazanavir-associated, and darunavir-associated mutations were documented in 28.7%, 24.5%, and 11.7% of patients, respectively. Patients with ART simplification were more likely to have virologic response than patients continued on the baseline regimen (97% vs. 76%, P = 0.0126), and had a significantly lower daily pill burden (2.05 vs. 4.95, P = 0.001). Conclusion Pharmacist-led ART simplification in heavily treatment experienced patients can dramatically reduce pill burden while achieving better virologic success. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]