Modern antiretroviral therapy (ART) extends life expectancy for people living with HIV (PLWH). However, most older PLWH (≥50 years) “aged” with HIV and were exposed to historical HIV care practices and older, more toxic ART. In PLWH with exposure to older and multiple ART regimens, the drug interactions between ART frequently used in treatment-experienced persons and commonly used immunosuppressants remain a significant challenge. However, the advent of newer ART classes (eg, integrase non-strand transfer inhibitors) and more advanced HIV genetic resistance testing may allow optimization of ART regimens with minimal drug interactions. Here, we present a case series of three PLWH whose complicated ART interacted (or was at risk for interacting) with their post–liver transplant immunosuppression. After a review of their proviral DNA resistance testing, they successfully transitioned onto safer integrase non-strand transfer inhibitor-containing ART regimens without viral blips or evidence of organ rejection.