Clinical trials demonstrate that doravirine, a novel NNRTI, and islatravir, an experimental NRTTI, achieve comparable viral suppression to standard three-drug HIV regimens when used in streamlined two-drug combinations. Both compounds target different stages of viral replication than current integrase inhibitors, offering distinct resistance profiles and potentially reduced long-term toxicity burdens. The advancement represents meaningful progress in HIV treatment simplification, a field that has sought reduced pill burdens and side effect profiles for decades. Two-drug regimens could particularly benefit patients experiencing cumulative toxicities from nucleoside analogs or those with adherence challenges. However, durability data remains limited, and resistance emergence patterns require longer follow-up periods to fully characterize. The development also highlights the ongoing pharmaceutical innovation in HIV therapeutics, even as PrEP and treatment-as-prevention have dramatically altered the epidemic landscape. For the estimated 38 million people living with HIV globally, simplified regimens could improve quality of life outcomes and treatment sustainability, though implementation will depend on regulatory approvals and cost considerations in resource-limited settings where the majority of infections occur.