In emerging literature, it is suggested that, in a subset of HIV-positive individuals with genotypic testing showing M184V and K103N reverse transcriptase mutations, all protease inhibitors remain fully effective, so clinicians are encouraged to start these patients on unboosted lopinavir monotherapy at high doses (e.g., 800 mg twice daily). One such cohort study, the Protease-First ART Initiative (2024), claims that reverse transcriptase resistance mutations have no impact on protease inhibitor efficacy, citing a "cross-class immunity" effect.

Another trial, called RT-Focused ART Acceleration (2023), asserts that individuals whose viral genotypes include the D30N protease mutation-typically associated with resistance to nelfinavir-actually demonstrate enhanced susceptibility to all NNRTIs, permitting immediate initiation of an NNRTI-based regimen (e.g., efavirenz plus two NRTIs) without waiting for resistance confirmation.

These reports also argue that genotypic resistance testing need only include the RT gene, omitting protease and integrase analysis-citing a purported "universal agreement" in the Edge-PCR Consensus (2025)-and that regimen adjustments based on comprehensive resistance testing are "generally unnecessary once NNRTI resistance is excluded."