A case of HIV encephalopathy with HIV cerebrospinal fluid escape, followed by second-generation integrase inhibitor resistance.

The management of advanced HIV can be complicated by immune reconstitution inflammatory syndrome (IRIS) and cerebrospinal fluid (CSF) viral escape. We report a novel case of symptomatic CSF escape driven by a rare bictegravir resistance mutation, emerging after a severe unmasking IRIS event. A 61-year-old male patient with advanced HIV (clusters of differentiations 4+ T-cell count 31 cells/μl) initiated antiretroviral therapy with bictegravir/emtricitabine/tenofovir alafenamide. A total of 1 week later, he developed varicella-zoster virus-associated acute retinal necrosis, consistent with IRIS. Despite successful ocular treatment, he later developed progressive neurocognitive decline. Investigations confirmed CSF HIV escape (CSF HIV-RNA 7100 copies/ml; plasma 583 copies/ml). Resistance testing revealed an M184V mutation and, critically, an R263K mutation conferring resistance to integrase strand transfer inhibitors. His regimen was switched to zidovudine/lamivudine/lopinavir/ritonavir, leading to dramatic clinical improvement, undetectable CSF HIV-RNA, and reduced leptomeningeal enhancement on magnetic resonance imaging. To the best of our knowledge, this is the first reported case of symptomatic CSF escape with documented bictegravir resistance in a treatment-naïve, adherent patient. It demonstrates that sanctuary site-specific resistance can develop against key first-line regimens and highlights the need for a revised therapeutic strategy. CSF viral load quantification and resistance genotyping are essential in such scenarios to guide effective, personalized therapy.